CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation

Author: David Kozma

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CRC Handbook of

OPTICAL RESOLUTIONS VIA

DIASTEREOMERIC SALT FORMATION

© 2002 by CRC Press LLC

CRC Handbook of

OPTICAL RESOLUTIONS VIA

DIASTEREOMERIC SALT FORMATION Edited by David Kozma

CRC Press Boca Raton London New York Washington, D.C.

© 2002 by CRC Press LLC

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Library of Congress Cataloging-in-Publication Data CRC handbook of optical resolutions via diastereomeric salt formation / edited by Dávid Kozma ; foreword by Kazuhiko Saigo. p. cm. Includes bibliographical references and index. ISBN 0-8493-0019-3 (alk. paper) 1. Resolution (Chemistry)--Handbooks, manuals, etc. 2. Diastereoisomers--Handbooks, manuals, etc. I. Kozma, Dávid. QD481 .C73 2001 541.2¢252—dc21

2001035243

This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from CRC Press LLC for such copying. Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe.

Visit the CRC Press Web site at www.crcpress.com © 2002 by CRC Press LLC No claim to original U.S. Government works International Standard Book Number 0-8493-0019-3 Library of Congress Card Number 2001035243 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper

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Foreword The authors have undertaken a comprehensive survey of studies on a fascinating method for obtaining enantiopure compounds: optical resolution of racemates by the diastereomeric salt formation. In the 21st century, enantiopure forms will increasingly become a very valuable series of organic compounds in the fields of pharmaceutical and agricultural chemicals, liquid crystal materials, nonlinear optics, etc. There are several known methods for obtaining enantiopure compounds, including optical resolution of racemates by preferential crystallization and by diastereomer formation, chemical asymmetric transformation of one of the enantiomers of racemates, biological asymmetric transformation of one of the enantiomers of racemates, chemical asymmetric synthesis, and biological asymmetric synthesis. Among them, optical resolution by diastereomeric salt formation, which is one of the diastereomer formations, has been successfully applied to and is widely used for obtaining enantiopure forms of valuable organic compounds, not only in the laboratory but also on an industrial scale. This handbook covers all aspects of the optical resolution of racemates by diastereomeric salt formation. There have been a variety of results on the optical resolution of racemates by diastereomeric salt formation since Louis Pasteur first discovered the methodology approximately 150 years ago. In 1981, Jacques, Collet, and Wilen published a book concerning the optical resolution of racemates through crystallization (Enantiomers, Racemates and Resolutions; Krieger Publishing); the book focuses on theoretical explanations rather than practical examples of the optical resolution of racemates by diastereomeric salt formation. On the other hand, in 1978–1981, Newman published a series of books concerning the procedures for the optical resolution of racemates by diastereomeric salt formation (Optical Resolution Procedures for Chemical Compounds; Optical Resolution Information Center); these books are simple collections of the experimental sections published in scientific papers and therefore contain no theoretical explanation of resolution phenomena. Therefore, a new book, containing both the theoretical aspects and practical examples of the optical resolution of racemates by diastereomeric salt formation was warranted. Under these circumstances, the authors have prepared a book responding to this need. This handbook has the following distinctions. • The importance of resolvability (Fogassy’s parameter), which permits the direct comparison of the efficiencies of independent resolution procedures, is emphasized, and its definition is thoroughly explained throughout the text. • There are clear explanations of the mechanism and kinetics, including the equilibria between a racemate and a resolving agent in a solution and between a solution and a crystal not only for resolutions using an equimolar amount of resolving agents, but also for resolutions employing half the amount of resolving agent and for resolutions under immiscible two-liquid-phase conditions with concrete examples. • There are very valuable lists of commonly used acidic and basic resolving agents (50 of each), along with their physical data, CA number, and catalog numbers. • Structural modification of a resolving agent and the correlation between the resolvability and the structures of a racemate and a resolving agent are exemplified. • The definite methods for the selection of a suitable resolving agent for a given racemate are presented. • There are explanations on the optimization of parameters (solvent, initial concentration, and temperature), initiation of crystallization, separation of crystals/liquid, improvement

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of the optical purity of the first-generation salt, recovery of components, and enantiomeric enhancement. • Several modified methods for optical resolution by diastereomeric salt formation are presented with definite examples. • There are short summaries of 4000 resolutions by diastereomeric salt formations; these are invaluable for researchers and others who want to resolve an unknown racemate. Thus, this handbook serves as a companion book for researchers, engineers, and graduates who are working on or who intend to work on the optical resolution of racemates by diastereomeric salt formation. In addition, this handbook will contribute significantly to further progress in the field of optical resolution of racemates by diastereomeric salt formation. Professor Kazuhiko Saigo Department of Integrated Biosciences Graduate School of Frontier Sciences The University of Tokyo

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Editor Dávid Kozma, Ph.D., is a research fellow at the Department of Organic Chemical Technology, Budapest University of Technology and Economics, Hungary. He received an M.Sc. degree in 1987 and a Ph.D. degree in 1993. He had worked as a scale-up engineer at the Chinoin Pharmaceutical Factory (Budapest, Hungary) between 1987 and 1990, at F. Hoffmann-LaRoche AG (Basel, Switzerland) between 1996 and 1998, and as visiting scientist at the University of Copenhagen (Denmark) between 1990 and 1991. His field of interest is the investigation of the physicochemical background of optical resolutions. He is the co-author of 45 scientific papers and a number of patents.

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Contributors Mária Ács, Ph.D. (deceased) Department of Organic Chemical Technology Budapest University of Technology and Economics Budapest, Hungary Elemér Fogassy, Ph.D., D.Sc. Professor Department of Organic Chemical Technology Budapest University of Technology and Economics Budapest, Hungary Csaba Kassai*, Ph.D.* Department of Organic Chemical Technology Budapest University of Technology and Economics Budapest, Hungary David Kozma, Ph.D. Department of Organic Chemical Technology Budapest University of Technology and Economics Budapest, Hungary

* Present address: Egis Pharmaceuticals Co., Budapest, Hungary.

© 2002 by CRC Press LLC

Mihály Nógrádi, Ph.D., D.Sc. Professor Department of Organic Chemistry Budapest University of Technology and Economics Budapest, Hungary With the Contribution of: Zoltán Juvancz, Ph.D. Vituki Plc. Budapest, Hungary Gábor Seres, Ph.D. Institute for Drug Research, Ltd. Budapest, Hungary

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Table of Contents Chapter 1 Introduction Chapter 2 Basic Concepts and Nomenclature of Stereochemistry 2.1 Chirality, Enantiomers, and Diastereomers 2.2 Stereochemical Nomenclature 2.3 Principles of Separation of Diastereomers and Enantiomers Chapter 3 Resolution by Formation and Fractional Crystallization of Diastereomeric Salts 3.1 The Concept of Resolvability 3.2 Stoichiometry of Resolution 3.2.1 Resolution with One Equivalent of Resolving Agent 3.2.2 Resolution with Half Equivalent of Resolving Agent in Combination with an Achiral Additive 3.2.3 Use of a Half Molar Equivalent of Resolving Agent without an Achiral Additive 3.3 Salt-Salt Resolution 3.4 Resolution with the Enantiomer of the Resolving Agent 3.5 Reciprocal Resolution 3.6 Mutual Resolution 3.7 Resolution with a Difunctional Resolving Agents 3.8 Resolution of Amphoteric Racemates 3.9 Resolution by Salt Formation of Compounds Lacking Acidic or Basic Groups 3.10 Asymmetric Transformations During Resolution by Salt Formation Chapter 4 Resolving Agents 4.1 Basic Resolving Agents 4.2 Acidic Resolving Agents (Including Amino Acids) 4.3 Research on Resolving Agents 4.3.1 Attempts to Devise a Generally Applicable Resolving Agent 4.3.2 Correlation of the Efficiency of Resolution with the Structure of Racemate and Resolving Agent 4.3.3 Systematic Modification of the Resolving Agent 4.3.4 Formation of a Quasi-Racemate as an Important Factor in Resolution 4.3.5 Resolutions with a Derivative of the Racemate 4.3.6 Resolution with a Mixture of Structurally Similar Resolving Agents

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Chapter 5 Selection of the Resolving Agent 5.1 Selection of the Resolving Agent by Experimentation 5.1.1 Selection of the Resolving Agent by Small-Scale Preliminary Preparative Experiments 5.1.2 Selection of the Resolving Agent by Combined Application of Several Resolving Agents 5.1.3 Selection of the Resolving Agent by Distillation Tests 5.1.4 Selection of the Resolving Agent Based on the Principle of Maximum Similarity 5.1.5 Selection of the Resolving Agent by Statistical Evaluation 5.2 Selection of a Resolving Agent Based on the Determination of Physicochemical Parameters 5.2.1 Solubility 5.2.2 Selection of a Resolving Agent Based on Melting Point Phase Diagrams of Diastereomeric Salt Pairs 5.2.3 Determination of the Optical Rotation of Diastereomeric Salts 5.3 Selection of the Resolving Agent Based on Theoretical Considerations Chapter 6 Resolution in Practice: Selection of the Optimal Parameters 6.1 Reacting the Components 6.1.1 Selection of the Solvent 6.1.2 Determination of the Initial Concentration 6.2 Initiation of Crystallization 6.2.1 Producing an Oversaturated Solution 6.2.2 Initiation of Crystallization 6.2.3 Significance of the Purity of Starting Materials 6.2.4 Separation of a Noncrystalline Phase 6.3 Role of Temperature in Resolution 6.3.1 Temperature Dependence of the Resolution of Pipecolic Acid Xylylides with Tartaric Acid and O,O ¢ -Dibenzoyltartaric Acid 6.3.2 Temperature Dependence of the Resolution of Phenylsuccinic Acid with Proline 6.4 Separation of Crystals and Mother Liquor 6.5 Further Purification of Diastereomeric Salts with the Aid of a Chiral Additive 6.6 Recovery of the Components from the Diastereomeric Salts 6.7 Upgrading of Optical Purity without a Chiral Additive (Enantiomeric Enrichment) Chapter 7 Alternative Methods of Resolution by Diastereomeric Salt Formation 7.1 Classification of Alternative Resolution Processes by Type of Phase Transition 7.2 Resolution by Distillation 7.3 Resolution by Extraction 7.3.1 Resolution by Extraction Using One Molar Equivalent of Resolving Agent 7.3.2 Resolution by Extraction Using a Half Equivalent of Resolving Agent 7.3.3 Resolution by Extraction Using a Half Equivalent of Resolving Agent Combined with an Achiral Additive 7.3.4 Resolution by Extraction of Diastereomeric Complexes

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7.4 7.5

7.6

Resolution by Supercritical Extraction Resolution by Sublimation 7.5.1 Resolution by Sublimation Using One Equivalent of Resolving Agent 7.5.2 Resolution by Sublimation Using a Half Equivalent of Resolving Agent Mechanical Separation of Diastereomeric Salt Mixtures

Chapter 8 Detailed Descriptions of Selected Resolutions Appendices A1 Resolutions Ordered According to the Resolving Agent (D. Kozma and C. Kassai) A2 Commercially Produced Resolving Agents and Optically Active Industrial Products That May Be Eligible as Resolving Agents (C. Kassai and D. Kozma) A3 Chiral Selective Chromatographic Analysis (Z. Juvancz and G. Seres) A3.1 General Aspects of Chiral Selective Chromatography A3.2 Chiral Selective Gas Chromatography A3.3 Chiral Selective Supercritical Fluid Chromatography A3.4 Chiral Separation by Liquid Chromatography A3.5 Chiral Separation by Capillary Electrophoresis

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1

Introduction

In the course of their development starting more than one billion years ago, living organisms opted at some point for one enantiomer of the chiral compounds they are built up. Thus, all protein-forming amino acids have an L configuration, nucleic acids exclusively contain D sugars, etc. Consequently, living systems respond stereoselectively to any chiral substance introduced; that is, different enantiomers of a compound (e.g., a drug) often have different biological effects. In addition to the main and intended effect of a drug, it has several side effects which are, to a first approximation, randomly distributed among the antipodes of the compound. Therefore, if it is found that the desired effect of a chiral drug is associated with one of its enantiomer, it is rational to apply only the active enantiomer, thereby reducing the side effects to about half per unit weight. Also, with chiral insecticides such as the pyrethroids, enantiomerically pure agents are generally much more effective and less burdensome to the environment. It is thus no wonder that today registration of a chiral drug in its racemic form is extremely difficult and pharmaceutical companies invest considerable effort to be able to market enantiomerically pure products. There are two main approaches available to produce a single enantiomer of a compound starting from achiral or racemic starting material: (1) enantioselective synthesis and (2) resolution of racemates. Enantioselective synthesis has undergone an amazing development in the last few decades and there are highly selective methods at our disposal leading to the desired enantiomer of a chiral compound. Unfortunately, very few such methods could be developed for economical industrial procedures, due to the price of the reagents to be used and the often extreme conditions (very low temperatures, strictly anhydrous conditions) required. Although seemingly an antediluvian method, resolution still dominates the pharmaceutical industry and much of the research initiatives. Resolution of racemates can be accomplished by two basically different methods: (1) formation of diastereomeric derivatives by reacting the racemate with a chiral compound (the resolving agent), followed by separation of the products; and (2) by chromatography on a chiral stationary phase. The latter is an elegant and efficient method useful for analytical purposes and to separate small quantities of a racemate, but its use is very restricted in large-scale production. A racemate can interact with the resolving agent in two ways: (1) bond formation (i.e., when a pair of diastereomeric compounds is formed); and through secondary forces, that is, (2) by formation of diastereomeric complexes or (3) by formation of diastereomeric salts. It is the latter method that is the subject of this handbook. Resolution by salt formation is a time-honored method discovered approximately 150 years ago by Louis Pasteur, and the number of resolutions accomplished since using this method now total about 10,000. The principle is very simple: the pair of enantiomers, being the mirror image of each other and therefore having (apart from optical rotation) exactly identical physicochemical properties, is transformed without establishing a chemical bond with one, preferably pure enantiomer of the resolving agent to a pair of non-mirror-image derivatives (salts or complexes) (i.e., diastereomers), which owing to their different scalar properties can be separated by conventional methods. Although the principle is simple, finer details and driving forces of the process have remained rather unexplored to date. The process involves the interaction of not only two isolated molecules but rather that of a larger array and at present there is no adequate methodology available to study such phenomena in detail.

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The obscurity of the underlying processes did not prevent tenacious chemists from developing several efficient resolution procedures, both on a laboratory and an industrial scale. Research in this field is primarily based on analogy, intuition, experience, and—last but not least—good luck. Resolution involves a significant amount of know-how, best transferred by personal contact; perhaps this is the reason why no handbook has thus far been written about resolution by diastereomeric salt formation. This handbook attempts to fill this gap and to transmit the authors’ practical experiences amassed over the decades in their laboratory. The authors’ intent is to present a handbook that enables those inexperienced in the field to plan, carry out, and optimize resolutions without consulting the literature. The authors not only present in a systematic order various methods of resolution (Chapters 3 and 7), but give guidance to the selection of the resolving agent (Chapter 5) and the way experiments must be performed (Chapter 6). To be able to be apply this information in practice, a large body of data is presented to the reader in an easily readable form. Thus, Chapter 4, dealing with resolving agents, provides all available data for the most frequently used acidic and basic resolving agents (50 each), and Chapter 8 presents detailed descriptions of procedures for 50 resolutions (some yet unpublished or in patents) elaborated for industrial application. These can be used as analogues for the planning of new resolutions. Appendix 1 is a collection of the most important data for approximately 4000 resolutions. This database allows one to compare the structures of racemates and resolving agents and may give ideas for the selection of the most appropriate agent. Appendix 2 is a collection of nearly 500 optically active compounds produced on a commercial scale, which may be candidates as resolving agents. Appendix 3 is a short, practical introduction to chromatographic methods amenable to the determination of optical purity. This topic has been exhaustively covered in several other handbooks; nevertheless, the authors deemed it necessary that the reader should be informed not only about preparing an optically active product, but also about methods to check its purity. Despite its dimensions, this compilation is not comprehensive and the authors apologize to colleagues whose work has been omitted. Because there is no precedent for such a handbook, it is not restricted to presenting only recent developments and does include several instructive examples from the older literature. Unfortunately, data in the older literature and foremost in patents are often incomplete; for example, data for optical purity and yields are missing and occasionally the absolute configuration of the enantiomers has not been assigned. Such sources are included only when they provide valuable methodological information and the description is sufficiently detailed to permit reproduction. It is necessary to point out here that, owing to the supramolecular character of resolution, it is highly unlikely that an enantiomerically pure product can be obtained in a single step. This can, however, be overcome by well-established purification processes in which the purity of the product can be enhanced as desired. Owing to the still rather obscure mechanism of resolution, separation of a new racemate remains a challenge. It is the authors’ hope that this handbook will help readers to be able to answer this challenge—ever more often successfully.

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2

Basic Concepts and Nomenclature of Stereochemistry

2.1 CHIRALITY, ENANTIOMERS, AND DIASTEREOMERS This handbook deals with the separation of enantiomers by formation and separation of diastereomeric salts. Enantiomers and diastereomers, commonly called as stereoisomers, fall under the broader concept of isomerism, which always involves the comparison of at least two species. Constitutional isomers, as distinguished from stereoisomers, are molecules with identical composition and molecular mass, but which differ in the connectedness of their atoms (e.g., n-butane and isobutane). Their differences can be characterized by listing the nature and number of atoms connected to each of their atoms but avoiding words indicating directions such as under and above, right and left, etc. Stereoisomers are molecules of identical constitution but nevertheless different. Differences between diastereomers can be expressed in scalar terms, that is, by differences in the distances of certain characteristic pairs of atoms. (E )-1,2-Dibromoethane and (Z )-1,2-dibromoethane are, for example, diastereomers and differ in the distance of the bromine atoms being longer in the E isomer than in the Z isomer (see Fig. 2.1). Differences between diastereomers of any complexity can be characterized by a set of statements concerning distances but avoiding terms referring to directions such as left and right, or clockwise and anticlockwise. Because diastereomers differ in certain interatomic distances, their scalar properties (e.g., melting point, boiling point, the absolute value of optical rotation (if present), spectra, etc.) are also different, although these differences may not be of measurable magnitude. That is, diastereomers behave in almost every respect as different compounds. An enantiomeric relationship can only exist between chiral molecules. Chirality is a general property of objects and means that an object is not superimposable (not identical) to its mirror image. A pair of chiral objects is the human hand. Asymmetric objects are all chiral, but symmetric objects lacking an alternating axis of symmetry (in the simplest case, a mirror plane) are also chiral. A chiral molecule and its mirror image are called a pair of enantiomers. Examples of an asymmetric (CHFClBr) and a symmetric pair of enantiomers (1,3-dideuterioallene) are shown in Fig. 2.1. All interatomic distances in a pair of enantiomers are identical and therefore enantiomers cannot be distinguished by scalar quantities, only by terms expressing direction (left and right, clockwise and anticlockwise). As a consequence, all scalar properties of enantiomers (melting point, IR, NMR, and mass spectra, etc., including any relationship to achiral objects or phenomena) are strictly identical and cannot serve to distinguish them. The relationship of enantiomers to chiral objects (molecules) and phenomena (e.g., circularly polarized light) is different and offers opportunities for their differentiation and/or separation. By definition, an enantiomeric relationship always involves two and only two species, while more than two diastereomers of compounds having the same constitution may exist. A typical example is tartaric acid. Diastereomers may be achiral [e.g., (E)- and (Z)-1,2-dibromoethane] or chiral, and a set of diastereomers may include both chiral and achiral species. For example, among the isomers of 1,2-dibromocyclopropane the R,R and S,S stereoisomers are chiral and enantiomers of each other, while the R,S stereoisomer is achiral and its relationship to the other two is diastereomeric (Fig. 2.1).

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FIGURE 2.1 Enantiomers and diastereomers.

2.2 STEREOCHEMICAL NOMENCLATURE 1

Conventions for the characterization of stereoisomers are laid down in the respective IUPAC rules. Somewhat different procedures are used in Chemical Abstracts and in Beilsteins Handbook of Organic Chemistry. Only the bare essentials of stereochemical nomenclature are presented here. © 2002 by CRC Press LLC

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Diastereomers are distinguished by prefixes indicating relative configuration. Relative configuration describes the spatial relationship within a molecule and is based on differences in interatomic distances of selected groups. Geometrical isomers are a subclass of diastereomers and are stereoisomers that differ in the arrangement of groups attached to the terminals of a double bond. They are distinguished by the prefixes E and Z*. The distance of a pair of selected groups in the E isomer is longer than in the Z isomer. The relative configuration of groups attached to a ring is described by the prefixes cis and trans, as exemplified again by 1,2-dibromocyclopropane. In open-chain molecules, the relative configuration of two groups is most conveniently characterized by the prefixes syn and anti. The relative configuration of two groups is syn when they are on the same side of the chain drawn in zigzag conformation, and anti when they are on opposite sides (see Fig. 2.1). The relative configuration of compounds containing chiral centers (at least two) can be distinguished by looking at the set of symbols assigned to the chiral centers. Different combinations of symbols indicate different relative configurations. For example, (R,R)- and (S,S)1,2-dibromocyclopropanes (identical symbols) are diastereomers of (R,S)-1,2-dibromocyclopropane (different symbols). Chiral compounds can be characterized and their enantiomers distinguished unequivocally by defining their absolute configuration. Absolute configuration describes the spatial arrangement of selected groups of a molecule by determining the sequence of these groups following rules put down following certain conventions. Currently, the system of conventions devised by Cahn, Ingold, and 2 Prelog (C.I.P. conventions) is used exclusively. To be able to apply these rules, four different types of chirality can be distinguished: central, axial, planar, and helical. From our point of view, only chiral centers and, among them, centers of asymmetry are of relevance. Centers of asymmetry are atoms to which four different substituents are attached. The configuration around this center is denoted by the symbols R or S. For details of the procedure by which these symbols are assigned, one can 1,2 refer to the literature. Symbols used in the earlier literature, such as D, L, d, l, should be strictly avoided except for amino acids and sugars, where D and L remain in use. Plus (+) and minus (−) signs indicating the sense of optical rotation are only to be used with compounds of unknown absolute configuration or with compounds having several chiral centers (e.g., alkaloids).

2.3 PRINCIPLES OF SEPARATION OF DIASTEREOMERS AND ENANTIOMERS Because diastereomers differ in many of their scalar properties, their separation is, in principle, feasible using any method (crystallization, distillation, chromatography, etc.) exploiting differences in such features. The separation of enantiomers, however, being identical in all of their scalar properties, can only be realized with a chiral aid. This can be appreciated by looking at a two-dimensional representation of this situation (Fig. 2.2). In two dimensions, achiral objects (symbolizing molecules) are represented by figures (e.g., a rectangle) that can be brought into superposition with their mirror image by translation and/or rotation within the plane of paper, while with figures representing chiral objects (e.g., a rectangular triangle with unequal perpendicular sides), this is impossible (Fig. 2.2a). Any conceivable association of mirror-image triangles (“enantiomers”) with the “achiral” rectangle in Fig. 2.2 leads to mirror-image figures (i.e., enantiomers), which again cannot be separated. Association, in turn, with a “chiral” figure (“resolving agent”) gives rise to non-mirror-image figures, related as diastereomers, which can be separated by conventional methods (Fig. 2.2b). After separation, the diastereomers are each decomposed to give the pure enantiomers and the resolving agent.

* Prefixes trans and cis should not be used for specific compounds, only for classes of compounds (e.g., cis- and transolefins). © 2002 by CRC Press LLC

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FIGURE 2.2 Interactions between a pair of enantiomers and an achiral and chiral partner represented in two dimensions. (R and S are enantiomeric molecules, A an achiral and Ch a chiral partner.)

The term “association” covers a broad range of interactions, including chemical bond formation, salt and complex formation, adsorption, etc. The present work focuses on methods based on the formation of solid salts and therefore some words must be added concerning solid phases. The statement that enantiomers can only be separated with a chiral aid strictly applies only to racemic mixtures. If the compound is a solid, a limited amount of the enantiomer in excess can be obtained by recrystallization provided that the solid phase is a © 2002 by CRC Press LLC

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conglomerate of (1) crystals of the pure enantiomers or (2) the pure enantiomers and a separate racemic phase. Note that mechanical separation of crystals of conglomerate-forming enantiomers also requires a virtual chiral aid, the concept of the human mind about left and right.

REFERENCES 1. Nomenclature of Organic Chemistry, Part e, Pure Appl. Chem., 45, 11 (1979). 2. R.S. Cahn, C.K. Ingold, and V. Prelog, Angew. Chem. Int. Ed. Engl., 5, 385 (1966).

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3

Resolution by Formation and Fractional Crystallization of Diastereomeric Salts

Reaction of a racemic (DL) acid or base with an optically active base or acid (R) gives a pair of diastereomeric salts. Members of this pair exhibit different physicochemical properties (e.g., solubility, melting point, boiling point, adsorption, phase distribution) and can be separated owing to these differences. The most important method for the separation enantiomers—that is, fractional crystallization of diastereomeric salts—is the subject of this chapter, while some other methods are presented in Chapter 7. In solution, both strong and weak interactions can develop between the resolving agent and 1 the enantiomers to be separated (Fig. 3.1). With resolution via diastereomeric salts, preferential precipitation of that particular salt can, in principle, be anticipated in which the total of secondary interactions is higher. In some cases, however, interactions between the enantiomers themselves are stronger than those present in the salts, whereupon it is the racemic phase that crystallizes. Formation of diastereomeric salts involves, as elementary steps, dissociation and protonation 2 processes as summarized in Fig. 3.2. As seen in Fig. 3.2, the outcome of resolution depends on the relative solubility and dissociation constants of the salts, the relative pKa and pKb values of the components, as well as the temperature dependence of these parameters. Dissociation of both the starting compounds and their salts is 3,4 significantly affected by pH. Resolution by means of diastereomeric salt formation was first accomplished by Louis Pasteur 5,6 in the middle of the 19th century. He used an equimolar amount of resolving agent and up to 7 this day this is the most frequently used approach, although, as it will be shown in Chapters 3.2.2 through 3.7, other molar ratios and techniques can also be successfully applied.

3.1 THE CONCEPT OF RESOLVABILITY For a numerical characterization of resolution processes, resolvability (S), also called Fogassy’s parameter, can be conveniently used. This parameter permits easy comparison of the efficiency of resolution procedures. Resolvability is the product of yield ( y) and enantiomeric purity (e.e.): S = y × e.e.

(3.1)

The value of y can be between 0 and 2. A value of 1 corresponds to the theoretical amount of one of the diastereomeric salts. PD + PL y = -----------------0.5c 0

(3.2)

where PD and PL are the quantities (mol/l) of diastereomeric salts precipitated and c0 is the initial concentration of the racemate. If instead of a racemate the starting material is an enantiomerically enriched mixture, 0.5c0 is replaced by the initial concentration of the enantiomer in excess.

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FIGURE 3.1 Graph of possible interactions in the reaction mixture of resolution (R resolving agent, D and L enantiomers, DL racemate, DR and LR diastereomeric salts).

FIGURE 3.2 Equilibrium model of resolution by diastereomeric salt formation exemplified by the resolution of a base. Ks: solubility constant, Kd: dissociation constant, Kb: base constant, Ka: acid constant, PD and PL the precipitated salts, subscripts D for the less soluble salt (DHR) and L for the more soluble salt.

The range of enantiomeric purity is 0 to 1; that is, 0 to 100%. In preparative resolutions, enantiomeric purity or enantiomeric excess (e.e.) can be well-approximated by optical purity (o.p.) PD – PL [ α ]λ - ≅ ----------------e.e. = -----------------P D + P L [ α ] λt max t

(3.3)

Accordingly, the value of S varies in the range of 0 to 1, where unity corresponds to complete separation. This value is, of course, always given for one of the diastereomeric salts, namely that which preferentially crystallizes. Very rarely, when resolution is accompanied by an asymmetric transformation, the value of S may exceed unity. Resolvability can also be expressed as follows: PD + PL PD – PL PD – PL - × ------------------- = ----------------S = -----------------0.5c 0 PD + PL 0.5c 0

(3.4)

3.2 STOICHIOMETRY OF RESOLUTION 3.2.1 RESOLUTION

WITH

ONE EQUIVALENT

OF

RESOLVING AGENT

Racemic acids and optically active bases, as well as racemic bases and optically active acids, can form pairs of diastereomeric salts; and the diastereomeric relationship of these salts forms the basis of the separation of the racemate into enantiomers. Out of the several physical parameters that are © 2002 by CRC Press LLC

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different for diastereomeric salts, the most commonly used for their separation is solubility, on which fractional crystallization is based. The simplest process consists of reacting the racemate in a suitable solvent with one molar equivalent of the resolving agent, whereupon the less soluble salt preferentially crystallizes, usually contaminated with some of the more soluble diastereomer. When both the racemate and the resolving agent contain a single basic or acidic functional group, then the stoichiometric ratio means the reaction of one molar equivalent of each partner. In the case of bi- or polyfunctional partners, the situation becomes more complex because, for example, with a monofunctional base, tartaric acid may form both a neutral and an acid salt. To form a neutral salt requires a half equivalent; while for an acid salt, one equivalent of tartaric acid is the stoichiometric amount. In general, the amount of resolving agent is considered to be stoichiometric when its molar ratio to the racemate is the same as that in the crystallizing salt. In the course of resolution, usually separate solutions containing stoichiometric amounts of racemate and resolving agent are prepared and then combined. With good luck, sooner or later crystallization starts and one of the diastereomeric salts precipitates preferentially. Sometimes, no separate solutions are prepared but the partners are weighed into the same vessel, solvent added, whereupon (occasionally promoted by heating) a clear solution is formed, followed by crystallization. It is a generally accepted rule of thumb that crystallization should start from clear solution. After crystallization is complete, the solid is separated from the mother liquor, which contains the salt of the opposite enantiomer in excess. By addition of a strong achiral acid or base to each of the two phases, the enantiomers are liberated. They can crystallize directly or can be separated by extraction from the salt of the resolving agent formed with the added achiral acid or base. From the mother liquors obtained in this way the resolving agent can be recovered. Most of the resolutions accomplished thus far were carried out with one equivalent of the resolving agent, although, as shown in Chapters 3.2.2 and 3.2.3, the use of less than one equivalent usually does not involve a loss in efficiency. The flow diagram of a typical resolution is shown in Fig. 3.3, while Chapter 8 provides detailed examples of 50 resolutions to be used as models for the design and realization of new resolutions.

3.2.1.1 The Equilibrium Model of Resolution Resolution of a basic racemate (DL) with an optically active acid (RH) is described by Eq. (3.5), where the solubility of the diastereomeric salt DHR is less than that of salt LHR. The equilibrium represented by Eq. (3.5) is a sum of partial equilibria shown in Fig. 3.3 and represented by Eqs. (3.6) through (3.13). In this equilibrium, two diastereomeric salts, PD and PL, are present in the solid phase and the precipitated salt is in equilibrium with the dissolved salts. DL + 2RH

DHR↓ + LHR

(3.5)

PD(solid)

DHR(solution)

KsD = [DHR]

(3.6)

PL(solid)

LHR(solution)

KsL = [LHR]

(3.7)

Provided that the initial concentrations of the D and L enantiomers are equal, Eq. (3.8) holds for the following process: D – P L = [ ΣL ] dissolved – [ ΣD ] dissolved © 2002 by CRC Press LLC

(3.8)

0019_frame_C03.fm Page 12 Monday, August 6, 2001 1:20 PM

FIGURE 3.3 Flow diagram of resolution by distereomeric salt formation (DL: racemate, R: resolving agent).

The total of enantiomers in solution is described by the following equation: +

[ ΣL ] dissolved = [ LHR ] + [ LH ] + [ L ]

(3.9)

+

[ ΣD ] dissolved = [ DHR ] + [ DH ] + [ D ]

(3.10)

and that of the resolving agent by: [RH]0 = PD + PL + [DHR] + [LHR] + [RH] + [R]

(3.11)

Dissociation of the dissolved salt must also be considered:

© 2002 by CRC Press LLC

+

−

+

−

DHR

DH + R

LHR

LH + R

+

−

[ DH ] [ R ] K dD = --------------------------[ DHR ] +

(3.12)

−

[ LH ] [ R ] K dL = -------------------------[ LHR ]

(3.13)

0019_frame_C03.fm Page 13 Monday, August 6, 2001 1:20 PM

Protonation of enantiomers and resolving agent can be described by the following equations: LH

DH

+

+

RH

L+H

D+H

−

R +H

+

+

+

+

[ L][ H ] K bL = ------------------+ [ LH ]

(3.14)

+

[ D][ H ] K bD = -------------------+ [ DH ] −

(3.15)

+

[ R ][ H ] K RH = ----------------------[ RH ]

(3.16)

KbL = KbD = Kb

(3.17)

Considering the above equations, the total of enantiomers can be expressed as follows: +

+ K b [ LH ]  [ LH ] [ LH ] - 1 + ------------- [ ΣL ] dissolved = K sL + [ L ]  1 + --------------- = K sL +  -------------------- [H+]     [L]  + + K b K sL K dL  [ H ] [ H ] b K sL K dL  K ----------------------= K sL +  ----------------------+ ---------= K + + ---------1 1 sL  [ H + ] [ R− ]    K RH [ RH ]  Kb  Kb 

K sL K dL = K sL +  --------------- [ RH ] 

+

K b [ H ]  --------- + ---------- K RH K RH 

(3.18)

Expressing [RH] from Eq. (3.18) and taking into account equilibrium (3.16), one arrives at Eq. (3.19): [ RH ] 0 – ( P D + P L ) – ( K sL + K sD ) [ RH ] = ------------------------------------------------------------------------------K RH 1 + ----------+

(3.19)

[H ]

Inserting [RH] into Eq. (3.19), one obtains: K RH  Kb [H+] [ ΣL ] dissolved = K sL  --------- + ----------- + 1 + ----------+  K RH K RH [ H ]

K sL K dL  ------------------------------------------------------------------------------  [ RH ] 0 – ( P D + P L ) – ( K sL + K sD )

+ Kb [H ] Kb  + ---------- + ---------= K sL +  1 + ---------+  [ H ] K RH K RH

K sL K dL  ---------------------------------------------------------------------  [ RH ] 0 – 0.5c 0 y – ( K sL + K sD )

+ Kb [H ] Kb  + ---------- + ---------[ ΣD ] dissolved = K sD +  1 + ---------+  [ H ] K RH K RH

K sD K dD  ---------------------------------------------------------------------  [ RH ] 0 – 0.5c 0 y – ( K sL + K sD )

(3.20)

(3.21)

Subtracting Eq. (3.20) from Eq. (3.21) obtains Eq. (3.22): [ ΣL ] dissolved – [ ΣD ] dissolved = P D – P L = 0.5c 0 S 1 +

Kb [H ] Kb  - + ----------- + --------= K sL – K sD +  1 + ---------+  [ H ] K RH K RH K sL K dL – K sD K dD  ×  --------------------------------------------------------------------- [ RH ] 0 – 0.5c 0 y – ( K sL + K sD ) © 2002 by CRC Press LLC

(3.22)

0019_frame_C03.fm Page 14 Monday, August 6, 2001 1:20 PM

In Eq. (3.22), two parameters (k and S1) are unknown and therefore it is not suitable for actual calculations, but may provide useful general information. If S1 only depends on the relative solubility of the pair of diastereomeric salts, one obtains: K sL – K sD S 1 = ---------------------0.5c 0

(3.23)

Apart from the equilibrium constants, efficiency of resolution also depends on pH and the amount of resolving agent. S1 as a function of pH is described by: +

S1 = f([H ]) +

and has a minimum at [H ] =

(3.24)

K b K RH .

3.2.1.2 Complete Resolution Using One Molar Equivalent of Resolving Agent An important requirement for efficient resolution is that the solubility of the diastereomeric salts be significantly different; otherwise, poor resolution can be anticipated. Even when the solubility difference of the salts is small, resolution may succeed if crystals of the pure salts are available because seeding with the pure diastereomer may induce crystallization of the same salt. After removal of the crystals, by seeding the mother liquor with crystals of the other pure diastereomer, crystallization of the latter can be induced. The mother liquor can then be saturated again with the mixture of diastereomers and the entire cycle repeated. It is evident that such a “quasi-continuous” process does not work when there is a large difference in the solubility of the diastereomeric salts. Alternating crystallizations can often be quite useful because they provide easy access to both enantiomers; nevertheless, only a few examples have been reported. The reason for this may be that, if for a given resolving agent, only a small difference was found in the solubilities of diastereomeric salts, further experiments with that particular agent have been abandoned. In the following, some examples for this technique are described that indicate that the rate of crystallization may often be more important for successful resolution than the solubility difference of the diastereomeric salts.

On attempted resolution of the dicarboxylic acid 3.1 with strichnine, it has been observed that no crystallization took place from 10 to 30 w/w% solutions of the salt even after standing at −15°C 8 for several days. However, on inoculation with any of the pure diastereomeric salts, crystals rich in the corresponding isomer started to precipitate. Alternating seeding with the two diastereomers and keeping the concentration of the mother liquors at 10 to 15 w/w%, both diastereomeric salts could be obtained from the same solution. After a single crystallization from 95% ethanol, optically pure enantiomers of 3.1 could be obtained from the salts. The same was observed with the resolution 9 of 2-aminobutane-1-ol with L-glutamic acid.

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0019_frame_C03.fm Page 15 Monday, August 6, 2001 1:20 PM

TABLE 3.1 Resolution of Racemic 2-Amino-butan-1-ol with Equimolar L-Glutamic Acid (2.0 moles each) No. of Fraction

Yield (g)

Yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14

150 3.6 6.1 55.0 25.0 20.0 17.2 75.0 3.3 2.3 4.6 8.9 16.5 16.0

64

11 9 32

4 7

[α]D

20

+3.2 −3.8 +2.5 −0.1 −9.2 −9.2 −4.4 −9.7 +2.8 +0.7 0.0 −9.6 −9.6 −8.7

Equimolar amounts of racemic 2-aminobutan-1-ol and L-glutamic acid were dissolved in a small amount of water at 70°C, followed by dilution of the resulting syrup with ethanol. On seeding the cooled solution with the diastereomeric salt formed from the (+)-amine, the same salt crystallized. After filtering the product and cooling the solution, a salt enriched in the (−)-amine could be obtained. Adding more ethanol yielded further fractions and this operation was repeated until 85% of the salt was recovered. The remaining 15% failed to crystallize. Details of this experiment are shown in Table 3.1. It can be seen that the composition of the individual fractions is significantly different. Note that only the original solution containing a 1:1 mixture of diastereomers was seeded; nevertheless, all subsequent fractions contained one of the diastereomeric salts in excess. It is remarkable that the crystallizing salt was not always the one that was in excess in the solution. Thus, in the case of fraction 2, it was the salt of the (−)-amine that was in excess in both phases. Because the mass of fraction 2 was small, the (−)-amine salt still remained in excess in the solution, but it was the (+)-amine salt that was in excess in fraction 3. Fraction 11 was racemic and fraction 4 nearly so, despite the fact that the salt of one of the enantiomers was still in excess in the solution. This indicated that from fraction 2 on, crystallization was spontaneous and the rate of crystal growth exceeded that of nucleus formation, explaining the occasional crystallization of the minor diastereomer. 10 Resolution of base 3.3 with tartaric acid was performed in ethanol. The optical purity of the diastereomeric salt hardly improved after seven recrystallizations because the solubility difference of the diastereomeric salts was small. On continuing the recrystallizations, however, fractions 8 and 9 behaved quite differently. Optical purity improved dramatically and the salt crystallized alternately as needles or plates. Decomposition of the needle-shaped crystals gave the (+)-3,3, while that of the plate-shaped crystals gave (−)-3,3. In another experiment, complete resolution could be achieved in a way that the solution was seeded at the very beginning with one form of the crystals, followed, after removal of the product, by seeding with the other form. Resolution of amine 3.4 with mandelic acid in ethanol failed due to co-crystallization of the 11 diastereomeric salts. The salts contained ethanol as solvate. Inoculation with one of the pure solvates induced preferential crystallization of the corresponding salt. By alternating seeding, both salts could be obtained in high optical purity. © 2002 by CRC Press LLC

0019_frame_C03.fm Page 16 Monday, August 6, 2001 1:20 PM

On resolution of racemic 3-bromocamphor-8-sulfonic acid (3.5) in water with 1-(4-tolyl)ethylamine, first the salt of the levorotatory acid precipitated; but further fractions contained alternatingly 12 the salts of dextro- and levorotatory acids.

3.2.2 RESOLUTION WITH HALF EQUIVALENT OF RESOLVING AGENT IN COMBINATION WITH AN ACHIRAL ADDITIVE In resolutions with one equivalent of resolving agent, it is the resolving agent proper that keeps the other enantiomer in solution. The former can be substituted by an achiral reagent of similar character; that is, it is possible to achieve resolution with but one half equivalent of the resolving agent. Although this technique has been known for nearly a century and is almost universally applicable, it has not become general practice. In this case, the equation of resolution must be modified as follows: DL + RH + AH

DHR ↓ LHA

(3.25)

where DHR is the less soluble diastereomeric salt and I the achiral additive. It follows from equilibrium (3.25) that the yield of the process depends primarily on the solubility of the less soluble diastereomeric salt and the optical purity of the precipitate depends on the ratio of the solubility of the two salts. In practice the achiral additive is a strong acid or base, most often hydrochloric acid or sodium hydroxide, respectively. Solubility of the salt of the enantiomer remaining in solution is usually better than that of the salt formed with the resolving agent, thus allowing one to work in higher concentrations and thereby giving, in general, more of the precipitating salt. Of course, even some of the more soluble diastereomeric salt is present; but due to the much higher solubility of its salt with the achiral acid, contamination of the crystallizing salt is much less. This is the reason why the optical purity of enantiomers obtained by this method is most often better than those obtained using one equivalent of the resolving agent—saying nothing of the economic advantage of this approach. With the half-equivalent method, operations and processes are the same as shown in Fig. 3.3; only the way in which crystallization of the diastereomeric salt is arranged is different. 3.2.2.1 Calculation of Parameters S, y, and e.e. in Equilibrium Systems by the Pope-Peachey Method Equation (3.22) is, in itself, unsuitable for calculations but can be used to evaluate actual cases. Calculations presented here are based on the general Pope-Peachey method adapted for resolutions carried out with less than one equivalent of resolving agent and an achiral additive considering the equilibria in Eqs. (3.6) through (3.13). In our calculations, the following assumptions were made: 1. The solvent is water (Kw). 2. Conservation of charge is observed, assuming that the achiral acid used is completely dissociated: −

[ AH ] 0 = [ A ] Kw + + + − − ---------- – [ H ] – [ HD ] – [ HL ] + [ R ] + [ A ] = 0 + [H ] © 2002 by CRC Press LLC

(3.26)

0019_frame_C03.fm Page 17 Monday, August 6, 2001 1:20 PM

3. For a monofunctional base and a monofunctional acid, the overall material balance can be expressed as: +

+

−

[D]0 + [L]0 − [RH]0 = [HD ] + [HL ] + [D] + [L] − [R ][RH]

(3.27)

Substituting Eqs. (3.6) through (3.17) into Eqs. (3.26) and (3.29) give: K dL K sL  [ D ] [ H + ] K sL K sD  K b K sD K dD  1 +  ----+ 1 + ----------------- + -----------------------[ D ] [ H ] – ------------------------ --------------------+  K b K b K sD K dD K dD K sD [ H + ] [ D][ H ]  +

K b K dD K sD [ H ] --------------------- – [ D ] 0 – [ L ] 0 + [ RH ] 0 = 0 – -----------------------K RH [ H + ] [ D ] K b K dD K sD  1 K dL K sL  Kw + + – ------ + -----------------------[ D ] [ H ] + [ AH ] 0 = 0 ---------- – [ H ] + -----------------------+ +   K K K K b b sD dD [H ] [ D][ H ]

(3.28)

(3.29)

In this way, one arrives at two equations containing two unknowns. Thus, with the knowledge of the thermodynamic parameters of the system, parameters S, y, and e.e. of the resolution can be calculated. As an example, calculations for the resolution of racemic 1-phenylethylamine with 2-phenylpro13 pionic acid are presented here. The dependence of parameters S, y, and e.e., as well as of pH on the quantity of resolving agent, is shown in Fig. 3.4. It can be seen that yield is at maximum when using one molar equivalent of resolving agent, but this is associated with a minimum of optical purity. Using more or less of the resolving agent equally results in improved optical purity. In addition, resolvability shows a minimum at an equivalent amount of resolving agent, which also supports the practicability of using less than one equivalent of the resolving agent. 14–16 The following examples present resolutions with molar equivalents other than 1:1 or 1:0.5.

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0019_frame_C03.fm Page 18 Monday, August 6, 2001 1:20 PM

+

FIGURE 3.4 Dependence of parameters S, y, e.e., and [H ] on the quantity of resolving agent.

SCHEME 3.1

3.2.2.2 Mechanism and Kinetics of a Resolution Carried Out Using the Pope-Peachey Method This chapter section discusses the mechanism of the resolution of N-methylamphetamine (MA) by tartaric acid (TA) using the Pope-Peachey method (see Scheme 3.1). Three parallel experiments were carried out in ethanol as solvent for each of five different reaction times. The mixtures were left standing without stirring and temperature control until work-up. Tartrate and hydrochloride contents of the precipitated salts were determined by titration and the optical purity established by measuring the rotations of the base liberated from the salts. Results are shown in Table 3.2. It could be established that the precipitate was practically the tartrate, while the hydrochloride always stayed in solution. Mass and tartrate content of the precipitated salt was almost the same in every experiment, indicating that all the tartrate precipitated at the beginning of the process. The optical purity of the precipitated salt was poor at shorter reaction times; but with the progression © 2002 by CRC Press LLC

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TABLE 3.2 Kinetics of the Resolution of Methamphetamine with Tartaric Acid (three parallel experiments each) Time of Crystallization

Mass of Precipitated Salt (g)

Tartrate Content of Precipitated Salt (m/m%)

Hydrochloride Content of Precipitated Salt (m/m%)

%

Average

0.986 0.966 0.983 1.005 0.895 0.972 0.882 0.965 0.990 0.970 0.997 0.973 0.863 0.953 0.961

45.34 45.09 45.27 46.08 45.83 46.26 45.77 46.88 46.83 46.14 46.92 46.36 45.98 46.25 45.98

1.46 1.34 1.43 1.21 0.96 1.33 0.97 0.92 0.96 0.99 0.91 1.04 0.94 0.99 1.14

25.13 25.66 26.07 26.56 28.04 27.19 26.56 36.29 29.93 34.13 31.96 32.12 41.27 29.73 42.11

27.41

15 min

90 min

5h

24 h

115 h

o.p.

26.98

26.93

30.26

55.34

FIGURE 3.5 Effect of stirring on the kinetics of the resolution of methamphetamine with tartaric acid.

of time, it gradually improved. This proved that there was an exchange of the base between the precipitated tartrate and the hydrochloride remaining in solution. With the progress of time, the R enantiomer became enriched in the solid phase while the S enantiomer in the solution. R, S-MA ⋅ TA (solid ) +R, S-MA ⋅ HCl (solution)

R-MA ⋅ TA (solid ) + S-MA ⋅ HCl (solution)

(3.30) When the same experiment was performed with intensive stirring, the optical purity of the precipitated salt reached 55% within 2 h. The same resolution was also studied in water with ice cooling (1) without stirring, (2) with stirring, as well as (3) with stirring and seeding (Fig. 3.5). In this case also, the mass of the precipitate was © 2002 by CRC Press LLC

0019_frame_C03.fm Page 20 Monday, August 6, 2001 1:20 PM

almost constant; only its optical purity changed with time. Note that without seeding, after an induction period, the optical purity increased rapidly at the beginning, and later on gradually slower. With stirring, maximum optical purity could be achieved after 6 h; with both stirring and seeding 2 h was sufficient. It can be concluded that seeding is advantageous; but if seed crystals are not available, stirring efficiently promotes the establishment of the equilibrium. 3.2.2.3 Examples for the Application of the Pope-Peachey Method

For the resolution of 2-(4-nitrophenyl)-propionic acid (3.9), 1-phenylethylamine (3.10) proved to 17 be the best. For economic reasons, less than one equivalent was used; but instead of the usual 0.5, 0.67 equivalents (3 mol 3.9 was reacted with 2 mol 3.10 and 1 mol NaOH in water).

Resolution of 2-(6-methoxy-2-naphthyl)-propionic acid (Naproxen) was accomplished by the 18 Pope-Peachey method in a water/toluene biphasic system. First, the aqueous solution of the racemate was adjusted to pH 9.5 with sodium hydroxide; toluene was then added, followed by gradual addition of 0.6 molar equivalents of dihydroabietylamine in water at 80°C. The final water:solvent ratio was 1:1. After 1 h stirring at 80°C, the mixture was allowed to cool to room temperature. Enantiomers of the substrate were recovered from both the precipitated diastereomeric salt and the aqueous mother liquor. Toluene probably served for the dissolution of the resolving agent poorly soluble in water.

The Pope-Peachey method is not necessarily restricted to the use of strong mineral acids or bases in an aqueous medium. For example, resolution of the base 3.12 was carried out in an ethanol: 19 methanol (49:1) mixture with a half equivalent of mandelic acid and a half equivalent of acetic acid. Resolution of the Tröger’s base type compound 3.13 (Pavin) with 3.5 (3-bromocamphor-8sulfonic acid) failed due to co-precipitation of the crystalline salt of the levorotatory base with the 20 resinous other salt. This was avoided by reacting the hydrochloride of the base with a half equivalent of the ammonium salt of the resolving agent. The precipitating salt was free of resin and gave a © 2002 by CRC Press LLC

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TABLE 3.3 Molar Ratios Applied in the Resolution of Amine 3.14 with 3-Bromocamphor-10-Sulfonic Acid (3.5) Using the Pope-Peachey Method Base (molar equivalents) 2 2 2

Achiral Acid (molar equivalents)

3.5 (molar equivalents)

Achiral Base (NH4OH) (molar equivalents)

HCl (2) H2SO4 (1) H2SO4 (1.5)

1 1 1

1 — 1

product of high optical purity, albeit in low yield. With inorganic acids, base 3.13 forms salts of relatively poor solubility in water. Therefore, much water is needed to keep them in solution, which also dissolves much of the diastereomeric salt, resulting in low yield. Therefore, an acid was looked for that would form with the base salts more readily soluble in water. Interestingly, a chiral acid (3.5) was found to be suitable. Note that this acid is not suitable for the resolution of 3.13 because both diastereomeric salts are highly soluble. The best procedure was to dissolve the base with one equivalent of 3-bromocamphor-10-sulfonic acid, followed by the addition of a half equivalent of 3.5 ammonium salt. The amount of water can be reduced to maximize the precipitation of the salt, while the 3-bromocamphor-10-sulfonic acid salt remains in solution throughout. 21 Resolution of base 3.14 was also realized with 3.5. Results obtained with three different molar ratios are shown in Table 3.3. Best results were obtained with a ratio of 2:1.5.

3.2.3 USE

OF A

HALF MOLAR EQUIVALENT ACHIRAL ADDITIVE

OF

RESOLVING AGENT

WITHOUT AN

The Pope-Peachey method is primarily carried out in water, but it can also be efficiently adapted to organic solvents. If the free chiral acid or base is significantly more soluble in an organic solvent than in water, it is reasonable to try a variant of the method in which the role of the achiral additive is taken over by the solvent. In this case, the reaction formula of resolution can be written as: DL + RH

DHR↓ + L

(3.31)

There are several examples for resolutions by this method. Thus, N-benzyloxycarbonylamino acids were resolved with the enantiomers of ephedrine in ethyl acetate by adding 0.55 molar equivalents of ephedrine to the protected racemic amino acids, whereupon the ephedrine salt of one of the enantiomers precipitated. After filtering off the salt, the other enantiomer could be recovered as the free base from the mother liquor.22 Japanese researchers studied the resolution of the threo-acid 3.15, an intermediate in the 23 manufacturing of Dilthiazem.

The molar ratio of racemate and resolving agent was varied in the range of 0.15 to 1.0 in aqueous methanol. They found that when more than a half equivalent of the resolving agent was © 2002 by CRC Press LLC

0019_frame_C03.fm Page 22 Monday, August 6, 2001 1:20 PM

FIGURE 3.6 Effect of molar ratio on the resolution of lysine 3.16 with 3.15.

added, the optical purity of the precipitated salt sharply declined. If for the characterization of the efficiency of resolution the product of resolvability and molar ratio of the resolving agent was used, it became apparent that a half equivalent of resolving agent was optimal (see Fig. 3.6).

Large-scale resolution of S-methyl-S-phenylsulfoximine (3.17) was studied by Brandt and 24 Gais. Although this compound can be satisfactorily resolved with one molar equivalent of 10-camphorsulfonic acid in acetone followed two recrystallizations from acetonitrile to afford the pure diastereomeric salt, the procedure could be dramatically improved by using a half equivalent of the resolving agent. In this way, under otherwise identical conditions, the optical purity of the salt obtained in 84% yield and containing the (+)-base increased to >99% already after the first recrystallization. For the recovery of the other enantiomer, a simple and ingenious method was found, which may probably be generalized. An additional 0.1 molar equivalent of resolving agent was added to the mother liquor, resulting in the precipitation of more of the diastereomer rich in the (+)-enantiomer. This was filtered off and from the mother liquor the (−)-base could be obtained in 97 to 99% o.p. and high yield. The process is illustrated in Fig. 3.7. It must be noted that the same authors found an interesting method to increase the optical purity of salts of 95 to 98%. The salt was suspended in acetone (i.e., the solvent used for resolution) and two molar equivalents of the racemate (calculated on the amount of the minor enantiomer) was dissolved in this mixture. After stirring the suspension for 12 h at room temperature, a diastereomeric salt of >99% o.p. could be recovered. According to the authors, the method was also successful with diastereomeric salts of less than 95% o.p. A negative example is the resolution of N-methyl-2-phenylpropylamine (3.18) with one molar equivalent of (S)-mandelic acid in ethanol to which, to induce crystallization, a large volume of diethyl ether was added. Twelve recrystallizations were required to obtain the pure diastereomeric 25 salt, from which the (−)-base could be recovered in 30% yield. Results did not improve on using a half equivalent of the resolving agent; again, 12 recrystallizations were necessary. One can draw the conclusion that even if yields and optical purity are the same, resolutions with a half equivalent of resolving agent offer significant advantages of economy. © 2002 by CRC Press LLC

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FIGURE 3.7 Resolution of S-methyl-S-phenylsulfoximine (3.17) with 10-camphorsulfonic acid (CSA).

3.2.3.1 Resolution in Two Immiscible Solvents Selection of the optimal solvent is crucial in resolutions (see Chapter 5.2.1). Polar solvents are usually the best. Because the most polar, cheapest, and in addition non toxic, nonflammable solvent is water, this should be one’s first choice. However, a common problem is that most organic compounds are sparingly soluble in water. This problem can often be resolved by using water and a solvent that is immiscible with water and a half equivalent of the resolving agent. The first example 26 of such an approach was disclosed in a patent.

The N-benzylamine 3.19 was resolved with 10-camphorsulfonic acid in a mixture of water and methyl-isobutylketone. The racemic amine was first dissolved in the organic solvent, then water, and a half equivalent of the resolving agent was added. The less soluble diastereomeric salt separated on the phase boundary. When precipitation was complete, the salt was filtered off and one enantiomer was recovered from the salt, while the other from the two-phase mixture that contained the substrate as the free base. Water often serves to dissolve not only one of the salts, but also one of the reagents, (e.g., tartaric acid). The organic phase immiscible with water may dissolve one or both components. As organic solvent, chlorinated hydrocarbons are useful. Toluene often fails and even if not, results are inferior to those obtained in chloroform. Racemic bases are usually freely soluble in organic solvents and sparingly in water, while acidic resolving agents are most often more soluble in water than in organic solvents. In resolutions conducted in a system of two immiscible liquid phases, apart from the usual solid-liquid partition, partition between the two liquid phases is also established; that is, that part of the enantiomeric mixture which remains in solution is also partitioned between the two liquid phases (this permits elimination of one purification step). Solid-liquid and liquid-liquid partitions are not independent and are established simultaneously as shown in Fig. 3.8. © 2002 by CRC Press LLC

0019_frame_C03.fm Page 24 Monday, August 6, 2001 1:20 PM

FIGURE 3.8 Equilibria in resolutions using two liquid phases.

Resolution in a system of two immiscible solvents carried out with one half equivalent of resolving agent can be described as follows: water

DL + RH

water-immiscible solvent

DHR↓ + L solvent

(3.32)

The simplest case is when only the racemate is soluble in the organic phase and both the resolving agent and diastereomeric salt are not. Enantiomers are distributed among the aqueous and organic phase. D water

D organic

[ D ] organic [ L ] organic K = ------------------- = -----------------[ D ] water [ L ] water

(3.33)

then: [ L ] organic – [ D ] organic [ L ] water – [ D ] water = --------------------------------------------K

(3.34)

Subtracting Eq. (3.10) from (3.9) and considering equilibria according to Eqs. (3.6), (3.7), (3.12), and (3.13), one arrives at Eq. (3.35). [H ] 0.5c 0 S = [ ΣL ] – [ ΣD ] = K sL – K sD +  1 + ----------- ( [ L ] water – [ D ] water )  Kb  +

(3.35)

Substituting Eq. (3.34) into (3.35) results in Eq. (3.36), which can be regarded as the basic equation of two-phase resolution: + [ H ] [ L ] organic – [ D ] organic 0.5c 0 S = K sL – K sD +  1 + ----------- -------------------------------------------- K Kb 

(3.36)

From Eq. (3.36) the difference in solubility KsL − KsD can readily be determined because the enantiomer content of the organic phase (L + D) and its enantiomeric purity (i.e., (L − D)/(L + D)) can be determined directly. An optimal pH is decisive for the success of resolution and is adjusted by adding an achiral acid or base, but caution is necessary because of eventual acid- or base-catalyzed decomposition or racemization. In a mixture of water and a solvent immiscible with water, the pK for organic bases insoluble in water is different from the value in water only. Owing to a partition between the two phases, the pK value of the organic base (or acid) increases in the aqueous phase, an advantage from the point of view of resolution. If the salt (e.g., hydrochloride) of a base sparingly soluble in water is partially decomposed in the presence of a solvent readily dissolving the free base with © 2002 by CRC Press LLC

0019_frame_C03.fm Page 25 Monday, August 6, 2001 1:20 PM

less than one equivalent (e.g., half equivalent) of alkali, the pH in the aqueous phase is a function of the dissociation constant of the base and the partition coefficient. If the latter is in favor of the organic phase, then it can be deduced and also verified by experiment that the actual pH value of 27 the aqueous phase is higher than it would have been without the presence of an organic phase. During the process of resolution, the solution is in a metastable state until crystallization is complete. Crystallization can be controlled by a suitable choice of temperature and concentration. Crystallization must be terminated at a section of the saturation curve where the concentration of the less soluble diastereomeric salt is at a minimum. This condition can be best approached using a mixture of two-solvents phase (immiscible phase) because when crystallization initiated from the aqueous phase is finished, due to the organic solvent, the concentration of material dissolved in the aqueous phase becomes severely diminished. The use of two immiscible solvents is also advantageous for suppressing the salt effect. As long as the diastereomeric salt that does not crystallize (or the corresponding enantiomer) stays in the aqueous phase, these can be regarded as external substances. In such cases, the salt effect can either promote or inhibit salt precipitation or even prevent crystallization altogether. Favorable conditions for crystal nucleus formation can significantly contribute to the success of a resolution. On the phase boundary of the immiscible solvents, the activation energy (∆Ghet) will be less than in the inside of any of the liquid phases (∆Ghom). Because both polar and apolar groups are present in the racemate and the resolving agent, along the phase boundary polar groups are mainly oriented toward the aqueous phase while the apolar parts of the molecules are oriented toward the organic phase. Consequently, the concentration of both partners is increasing at the phase boundary, enhancing the chance of their encounter and thereby the chance for the formation of crystal nuclei resulting in faster crystallization. 28 Marsó investigated the kinetics of the resolution of tetramisol in a two-phase system. In the first four hours, an intensive exchange of enantiomers was observed between the two phases before equilibrium was established (cf. Fig. 3.9). Table 3.4 compares resolutions performed by three different methods: (1) classical resolution with one equivalent of the resolving agent, (2) the Pope-Peachey method, and (3) resolution in a two-phase system with a half equivalent of the resolving agent.

FIGURE 3.9 Time dependence of optical purity of the precipitated salt and the substrate remaining in the two solvent phases in the resolution of tetramisol with O,O′-dibenzoyltartaric acid using water and dichloroethane. © 2002 by CRC Press LLC

1:1 Ratio Racemate

Resolving Agent OMe

CN OMe NH2

Ph

CN NH2 OH HN

Ph

N Ph

N

S

N N

COOH O

OH COOH O NH2

y

e.e.

Pope-Peachey S

Achiral Additive

y

e.e.

Two Phases S

Solvent

y

e.e.

S

0019_frame_C03.fm Page 26 Thursday, August 23, 2001 2:05 PM

© 2002 by CRC Press LLC

TABLE 3.4 Comparison of Resolutions Carried out with the Original Pope-Peachey Method and with its Two-Phase Modification

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It can be seen that in each case, the classical method was the least efficient, the Pope-Peachey method performed better, while the two-phase method proved best. Note, however, that while with the two-phase method, the optical purity was better than with the other two, yields were occasionally less than with the Pope-Peachey approach. For practical purposes, methods yielding higher optical purity are to be preferred because in this case it is simpler to arrive at an optically pure end product. Realization of the two-phase method on an industrial scale is minimally more complicated than single-solvent methods and the higher optical purity more than compensates for the inconvenience. When calculating the efficiency of resolution, the nonnegligible amount of diastereomeric salt remaining in the aqueous phase was not accounted for. This can be recycled further, thereby increasing the efficiency of the method. As shown in Table 3.5, the two-phase method was successful in some cases in which traditional methods failed. It appears that for the resolutions of bases in a two-phase system, O,O¢-dibenzoyltartaric acid is the optimal agent. 3.2.3.2 Two-Phase Resolutions with the Addition of an Intermediate Solvent A further development in two-phase resolutions is the addition of a third solvent that is miscible with both of the original solvents. When resolution of methamphetamine (3.20) by O,O¢-dibenzoyltartaric acid was carried out instead of methanol in a water–dichloroethane system, efficiency of the operation (S) increased twofold, but the optical purity of the product was poor and further purification was necessary. If, however, methanol was added to the system, resolvability did not diminish while optical purity improved at the expense of yield (see Table 3.6) and the product did not require further purification.

TABLE 3.5 Two-Phase Resolutions Carried out with O,O ¢-Dibenzoyltartaric Acid in a Water-Chloroform Two-Phase System O

O N O

N NH

N

N

Cl

N

N

N

O

CONH2 O

O

O

TABLE 3.6 The Role of the Intermediate Solvent in Two-Phase Resolution of 3.20 by O,O ¢-Dibenzoyltartaric Acid H 2O (ml) — 15 15 15 15

© 2002 by CRC Press LLC

Ph

ClCH2CH2Cl (ml)

MeOH (ml)

Yield (%)

o.p. (%)

S

— 60 60 60 60

40 — 3 6 18.8

71.7 94.8 93.0 90.5 79.6

54.4 82.5 85.2 87.8 97.9

0.39 0.78 0.79 0.79 0.78

0019_frame_C03.fm Page 28 Monday, August 6, 2001 1:20 PM

Note that the thermodynamic equilibrium has already been established in the two-phase system in 29 the absence of methanol; therefore, addition of the latter could not enhance S further.

3.3 SALT–SALT RESOLUTION Organic compounds, including acids and bases, are generally sparingly soluble in water and therefore only very dilute aqueous solutions can be prepared therefrom. In contrast, their salts are, most often, much more soluble. It is therefore reasonable in such cases not to directly react the racemate and the resolving agent, but rather their salts with some inorganic acid or base (e.g., hydrochloric or sulfuric acid or barium hydroxide), respectively. This method can be applied both when one or a half equivalent of the resolving agent is used. DL⋅Cl2 + 2R⋅Na DLCl2 + RNa

DR↓ + LR + 2NaCl DR↓ + LCl + NaCl

(3.37) (3.38)

The reagents can be brought together in one of the following ways: 1. The simplest method is to mix with the solvent half equivalents of both the resolving agent and the appropriate achiral additive. In practice, this means the adjustment of pH. Because it is better to work with solutions, should the components not dissolve, the mixture should be warmed. 2. Separate solutions of the racemate and of the resolving agent neutralized with the achiral additives are prepared and combined thereafter. However, this method cannot be applied, for example, when it is the acid salt of tartaric acid which precipitates from solution, because, while the neutral salt of the racemic base (if it is monobasic) with hydrochloric acid can be prepared in water, but the acidic (sodium or ammonium) salt of tartaric acid is poorly soluble and therefore the diastereomeric salt cannot be crystallized from solution. In this case, the problem can be solved by adding 0.25 equivalents of tartaric acid and a neutralized solution of 0.25 equivalents of tartaric acid to the neutralized solution of the racemate. This protocol was followed in the resolution of compound 3.21 with tartaric acid in water.

Another approach would be to add the solid salt of one of the components to a neutralized aqueous solution of the other component. An example is the resolution of acid 3.22, wherein its solid sodium salt was added to an aqueous solution of 1-phenylethylamine neutralized with hydrochloric acid. In an other example, the calcium salt of O,O′-dibenzoyltartaric acid mono-N, N-dimethylamide (3.23) was added as a solid to an aqueous solution of racemic 2-amino-1-phenyl-1,3-propanediol hydrochloride. Although no clear solution was formed, the salt that precipitated initially as an oil crystallized soon thereafter. © 2002 by CRC Press LLC

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TABLE 3.7 Typical Examples for Salt–Salt Resolution Salt Forming Acid

Racemate

Resolving Agent

Salt Forming Base

Solvent

Ref.

O

NH2 O Ph NH2

NH OH

NH2

Cl COOH Se

Se

COOH Cl Br

COOH

Cl I

SO3H

O HO

N OH

COOH

O COOH SO3H

OH

O

O OH

O

O

30

Racemic lysine was resolved in water with N-acetyl-3,5-dibromo-L-tyrosine. It was found better, however, when a half equivalent of the ammonium salt of the resolving agent was reacted with the hydrochloride of the racemate. In this way, liberation of the acid component could be omitted. The efficiencies of the two methods do not significantly differ; but with the second, some solvent could be saved. With hydroxy acids, salt formation inhibits lactonization, while with aminoketones that of Schiff bases. Most often, however, the salt-salt method helps to eliminate solubility problems. As solvent, besides water, methanol can also be often used. When a barium salt of the acid and a sulfuric acid salt of the base are reacted, contamination with inorganic salts can be completely eliminated, provided that crystallization of the diastereomeric salt is not instantaneous. Examples for salt-salt resolutions can be found in Table 3.7.

3.4 RESOLUTION WITH THE ENANTIOMER OF THE RESOLVING AGENT For a given racemate, it is difficult to predict, that with a given resolving agent, which of the diastereomeric salts will be less soluble. Marckwald’s rule states that resolution with the enantiomer of a resolving agent can be carried out under identical conditions and with the same yield because the two processes are of strictly mirror-image character. The precipitating salt will be the mirror image © 2002 by CRC Press LLC

0019_frame_C03.fm Page 30 Monday, August 6, 2001 1:20 PM

of that crystallizing from the original solution. Accordingly, the following equations can be written: DL + 2RH DL + 2R*H

DHR↓ + LHR

(3.39)

DHR* + LHR*↓

(3.40)

where RH and R*H denote enantiomeric entities. When DHR is less soluble than LHR, then LHR* will be also less soluble than DHR*, and vice versa. Exploiting Marckwald’s rule (i.e., using both enantiomers of the resolving agent), we can produce both pure enantiomers of the substrate more rapidly than by processing the mother liquor. Because the precipitating (i.e., less soluble) salt is always more pure and can be purified more conveniently than the one recovered from the mother liquor, it is a routine procedure to treat the impure other enantiomer recovered from the mother liquor with the enantiomer of the original resolving agent. This usually provides the other enantiomer in satisfactory optical purity. With resolving agents of natural origin (e.g., with most alkaloids), the antipodal agent is usually not available, but it has been observed that certain alkaloids behave as quasi-mirror images and can be used in a complementary way to obtain both enantiomers of a substrate in a pure form. This phenomenon has already been observed by Pasteur, who found that with cinchotoxine, one enantiomer of racemic tartaric acid formed the less soluble salt, while with chinotoxine formed the other enantiomer. Similar findings were reported for the pairs cinchonine and cinchonidine, quinine and quinidine, as well as for quinine and cinchonidine. In Table 3.8, 50 randomly selected resolutions are presented all of which were attempted with at least two alkaloids. Experiments shown in the same line were carried out in the same solvent. The data in Table 3.8 do not confirm quasi-enantiomeric behavior in resolutions for the pairs quinine–quinidine and cinchonine–cinchonidine because the number of salts formed from both antipodes of the substrates is the same. Salt-forming tendency with the agent of opposite configuration can be best observed with the quinine–cinchonidine pair, where in 11 cases out of 14, quasi-enantiomeric behavior was apparent. With 26 resolutions carried out with brucine, however, there was only one example found when with another alkaloid the salt of the other enantiomer could not be precipitated.

3.5 RECIPROCAL RESOLUTION The question concerning reciprocal resolution and its condition appears to be a theoretical one; nevertheless, it has practical implications. In reciprocal resolution, the roles of substrate and resolving agent are interchanged; that is, resolution of a racemic mixture of a compound used in the primary process as the resolving agent is attempted with one of the enantiomers of the compound that had been originally subjected to resolution. In this case, all four of the following equations should hold: DL + 2RH

DHR↓ + LHR

(3.41)

DHR* + LHR*↓

(3.42)

RHR*H + 2D

DHR↓ + DHR*

(3.43)

RHR*H + 2L

LHR + LHR*↓

(3.44)

DL + 2R*H

The question is: if resolution is possible according to Eqs. (3.41) and (3.42), then is the reciprocal process (i.e., resolution of the racemic form of the resolving agent by one of the enantiomers of which was former the racemate) also possible? If Eq. (3.41) holds, then Eq. (3.42) should also be valid because the two processes are in a mirror-image relationship. At the same time, the relationship between Eqs. (3.41) and (3.43) (or 3.44) or between Eqs. (3.42) and (3.43) (or 3.44) is diastereomeric, which means reciprocal 92 resolution is not necessarily feasible. © 2002 by CRC Press LLC

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TABLE 3.8 Summary of 50 Resolutions Carried out with at Least Two, Randomly Selected Alkaloids Strychnine

Brucine

Morphine

− − + − + − + −

−

− + − − +

Quinine + + + − + − − − − − + + + − + +

Quinidine

Cinchonine

− + + + + − − − −

− − +

− +

− − + +

+ + − − −

+ + +

− − + − − − + + −

+ + +

+ − + + +

+

+ −

− − + + −

+ − −

+ + − +

− −

+

− − −

+ − +

+ +

+

−

Cinchonidine

+ − − + −

−

+ + − +

− + −

− − − − − −

+

+ − +

+

−

+ −

+

Ref. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91

Note: Plus and minus signs indicate the sense of rotation of the enantiomer recovered from the less soluble diastereomeric salt.

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0019_frame_C03.fm Page 32 Monday, August 6, 2001 1:20 PM

FIGURE 3.10 Flow diagram of reciprocal resolution.

Based on Eq. (3.43), resolvability can be calculated as follows: + Kb  Kb [H ] - + --------0.5c 0 S = K sR* – K sR  1 + ----------- + ---------+  K RH [ H ] K RH

K sR* K dR* – K sR K dR*  ----------------------------------------------------------------------------  [ D ] 0 – ( P D + P L ) – ( K sR* + K sR )

(3.45)

where KsR and KsR* stand for solubilities in reactions (3.43) and (3.44), and KdR and KdR* for the dissociation constants of salts DR and DR*, respectively. Because KsR and KsD and KdR and KdD are identical, and because DR* and LR are enantiomers and therefore have the same physicochemical characteristics (KsR* = KsD and KdR* = KdD) considering Eqs. (3.6) and (3.12), then Eq. (3.46) can be rewritten as follows: + K sL K dL – K sD K dD Kb Kb   [H ] - - ------------------------------------------------------------------ + --------0.5c 0 S = K sL – K sD  1 + ----------- + --------- K RH [ H + ] K RH  [ D ] 0 – 0.5c 0 y – ( K sL + K sD )

(3.46)

Thermodynamic constants influencing resolution are the same in Eqs. (3.22) and (3.46); therefore, the efficiency of normal and reciprocal resolution should be equal, lest there does not emerge some special interaction between the salts in solution, such as formation of associates. The flow diagram of reciprocal resolution is shown in Fig. 3.10. From the solution formed on the left side, DR precipitates; while on the right side, the mirror image thereof (i.e., LR*). In both cases, LR remaining in solution influences the solubility of the precipitating salt. Note that the relationship of the media from which two diastereomeric salts (DR and LR*) separate is not enantiomeric. The media are identical and chiral (LR); therefore, the relationship of the two systems is diastereomeric: DR + LR vs. LR* + LR. From the scheme it is apparent that the cycle of compounds can be tapped at any point and, provided that loss of recovery in the course of the operations is negligible. Further, if racemization is feasible, an inexpensive resolving agent can be obtained. Nevertheless, applications of this method are rare. It may be economical in industrial resolutions in which the optically active form of the resolving agent is very expensive or not available at all. The following elaborates on the second item of Table 3.9 (for further details of the procedure, see Chapter 8). An intermediate of the chemical synthesis of L-tryptophane used by the Abbot Laboratories was Ν-acetyl-DL-tryptophane. This was selected for resolution because it was of acidic character and could be readily racemized. It was known from the literature that this compound 98 could be resolved with 1-phenylethylamine. Since the inexpensive racemic resolving agent was available, reciprocal resolution was attempted and gave excellent results. First N-acetyl-DLtryptophane was reacted in ethanol with half molar equivalent of (S)-base and half molar equivalent of potassium hydroxide, giving N-acetyl-L-tryptophane in 73% yield and 99% o.p. Then, with the © 2002 by CRC Press LLC

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TABLE 3.9 Some Examples for Reversed Resolutions Compound 1

Compound 2

Ref.

N-acetyl-L-tryptophane recovered from the diastereomeric salt, racemic 1-phenylethylamine was resolved applying the Pope-Peachey methodology, that is, using half a mole of the optically active acid and half a mole of hydrochloric acid in ethanol. A salt of 99% o.p. was obtained in good yield. Starting from 60 g (S)-base, 12.5 kg N-acetyl-L-tryptophane and 8.6 kg (S)-base could be produced in 17 operations. The N-acetyl-D-tryptophane remaining in the mother liquor after each operation was racemized with acetic anhydride and recycled. Reverse resolution failed with Reference 99. Resolution of racemic lysine can be performed in water with N-acetyl-3,5-dibromo-L-tyrosine, when it is the monohydrate of the L,L-salt which crystallized. However, when racemic N-acetyl-3,5-dibromotyrosine was reacted with L-lysine, the racemate phase containing two moles of water crystallized. The latter was rapidly lost on standing in air. The higher stability of the racemic phase as compared to the L,L-salt was also indicated by their melting point: 166 to 168°C for the L,L-salt and 265 to 270°C for the anhydrous racemate.

3.6 MUTUAL RESOLUTION Resolution of a racemate with another racemate is called mutual resolution. In a favorable case, the following separation is possible: DL + RHR*H

DHR

DHR↓ + LHR*

(3.47)

DHR + LHR*↓

(3.48)

LHR*

DL + RHR*H

where DL is a basic racemate and RHR*H is an acidic “resolving agent” in racemic form. © 2002 by CRC Press LLC

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TABLE 3.10 Some Examples for Reciprocal Resolution Base

Acid

Ref.

In the first case, the solution is seeded with the diastereomeric salt DHR, while in the second with LHR*. After crystallization of one of the diastereomeric salts is finished, the other mirror-image salt starts to separate from the mother liquor. The relationship of the two systems is enantiomeric and the mirror-image pairs form a conglomerate. The outcome of the process is analogous to that of the direct crystallization method. Their difference is practical rather than of theoretical character. In mutual resolution, of the four pairwise enantiomeric compounds, crystallization of one is initiated by seeding; while with direct crystallization, there is only one pair of enantiomers present, of which one has to be recovered. Because mutual resolution promises simultaneous resolution of two compounds, it should be of high practical value. Unfortunately, to date there have only been a few pairs of racemates to which the method could be successfully adapted. Table 3.10 presents such examples.

3.7 RESOLUTION WITH DIFUNCTIONAL RESOLVING AGENTS If the resolving agent or the compound to be resolved contains more than one acidic or basic function, resolution may follow more than one stoichiometry. The most frequently used dibasic resolving agents include tartaric acid and its O-acyl derivatives. Resolution can be performed by forming either the acid or the neutral salt. Table 3.11 shows the effect of molar ratio on the result of resolution, including resolutions with a half equivalent of resolving agent and taking into account whether the pair of salts is forming a eutectic mixture or a separate racemic phase. Resolution can only be expected with eutectic-forming diastereomeric salts, but in this case, at least in principle, by using any molar ratio. At a 1:1 ratio and neutral salt formation, however, efficient resolution cannot be anticipated because in this case one of the diastereomeric salts must be separated from the mixture of free acid and the other diastereomeric salt. On the other hand, in case of acid salt formation and an acid:base ratio of 1:4, no efficient resolution can be expected, because now one can either separate the optically pure diastereomeric salt in a maximum yield of 50% or recover the unreacted enantiomer in a maximum yield of 33%. Resolution should be efficient in the case of acid salts with a 1:1 or 1:2 acid:base ratio; in case of neutral salt formation with a © 2002 by CRC Press LLC

Molar Ratio ( acid:base) 1:1

1:2

1:4

Racemic Active Racemic Active Racemic Active Diastereoisomeric Enan- Enan- Diastereoisomeric Enan- Enan- Diastereoisomeric Enan- EnanSalt Salt tiomer tiomer tiomer tiomer tiomer tiomer Salt conglomerate —

—

—

—

—

—

—

—

—

—

—

—

—

2

2

2

Acidic salt formation 1:1 molecular compound —

—

3

conglomerate 1/2

Neutral salt formation

—

4

1/2 1:1 molecular compound

Note:

and

represent the enantiomers of the base, and

represents the optically active chiral dicarboxylic acid.

2

—

0019_frame_C03.fm Page 35 Monday, August 6, 2001 1:20 PM

© 2002 by CRC Press LLC

TABLE 3.11 Resolution Possibilities by Reacting a Chiral Dicarboxylic Acid with a Racemic Base

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TABLE 3.12 Effect of Molar Ratio on Resolution with O,O′-Dibenzoyltartaric Acid

Racemate

Acid: Base Molar Ratio

Type of Precipitated Salt

Configuration

o.p. (%)

Yield (%)

S

1:2 or 1:4 acid:base ratio, the second figures correspond to the half equivalent method. With a given dibasic resolving agent, some substrates form only one type of salt (acid or neutral) while others are capable of forming both types. With tartaric acid methamphetamine forms only an acid salt, while with O,O′-dibenzoyl- and di-p-toluoyl-tartaric acids only a neutral salt. Nevertheless, the efficiency of resolution with all three resolving agents is about the same. When with a given dibasic resolving agent a racemate is capable of forming both a neutral and acid salt, different enantiomers may be in excess in the precipitating salt when using different molar ratios. With this trick, resolution of both enantiomers can be accomplished without using another resolving agent to recover the enantiomer forming a more soluble salt. Table 3.12 presents two 104 examples of this kind based on the work of Leigh. Compound 3.24 was reacted with 0.25 equivalents O,O′-dibenzoyltartaric acid in aqueous acetone, whereupon the neutral salt of the S enantiomer separated. On addition of a half mole of the resolving agent, the acid salt of the R enantiomer precipitated.

With the resolution of racemic diacids, variation of the molar ratio can be applied in the same way. The salt precipitating first is filtered off and after partial concentration of the solution, or after adding 105 more of the resolving agent, separation of the other salt starts. Three examples for this method are presented in Table 3.13. In the course of the resolution of 2-hydroxy-2-phenylethylamine, it was observed that while the acid salt precipitated as a viscous syrup, the neutral salt was crystalline and permitted efficient 109 resolution. Neutral salts are, however, often unstable and transform spontaneously, partially or totally to the acid salts. To suppress such disproportionation, the neutral salt of 3.24 that separated 110 from ethanol was purified by recrystallization from a 0.5 M ethanolic solution of tartaric acid.

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TABLE 3.13 Some Examples for the Resolution of Racemic Dibasic Acids

COOH O

COOH

I

I

I

HOOC

I

COOH

TABLE 3.14 Physicochemical Data for the Salts of 3.27 with O,O¢-Dibenzoyltartaric Acid 1:1 Salt

m.p. (∞C ) 20

[ a ]D

(DMF) Solubility (g/l MeOH)

1:2 Salt

R , R -R

R,R-S

R,R-2 R

R,R-2 S

160–162 -191∞

Oil —

187–193 (dec.) -270∞

170–172 (dec.) +292∞

7

Complete miscibility

4

33

TABLE 3.15 Resolution of 3.27 with O,O¢-Dibenzoyltartaric Acid at Various Molar Ratios Acid : Base Molar Ratio

Precipitating Salt

Yield (%)

o.p. (%)

1:4 1:2 3:4 1:1

Neutral salt of R isomer Mixture of neutral salts containing the salt of the R base in excess Neutral salt of R isomer Acidic salt of R isomer

26 64 30 25

>99 27 >99 89

It is not unprecedented that the less soluble neutral and acid salts both contain the same enantiomer 111 in excess. Resolution of base 3.27 was accomplished with O,O¢-dibenzoyltartaric acid. To find the optimal molar ratio, neutral and acid salts were prepared from the pure enantiomers. Data for the salts are shown in Table 3.14. The data in Table 3.14 suggested that with both molar ratios it was the salt of the R base that was more stable. It was also observed that on recrystallization, the acid salt of the R base transformed to the neutral salt. In preparative scale experiments, the molar ratio was varied in the range of 0.25 to 1.0 (Table 3.15). In conformity with solubility data, resolution was optimal at 3:4 base:acid ratio, when the least soluble neutral salt crystallized and the most soluble acid salt of the S enantiomer remained in the mother liquor. Nevertheless, for large-scale operations, a base:acid ratio of 1:4 was selected because, while efficiency was only marginally less, two thirds of the resolving agent could be saved. © 2002 by CRC Press LLC

0019_frame_C03.fm Page 38 Thursday, August 23, 2001 2:07 PM

TABLE 3.16 Resolution of Alanine Derivatives by Diastereomeric Salt Formation

Derivative

Resolving Agent

H2N

Solvent

Enantiomer in Excess in the Precipitated Salt

Ref.

Ph O O

H2N

Ph O O

Ph N OH

Ph O O N H

Ph

OH O

O N H

Ph

OH O

O N H

OH O

O N H

OH O

O

N H

OH O

O Ph O

N H

OH O

O Ph O

N H

OH O

3.8 RESOLUTION OF AMPHOTERIC RACEMATES Amphoteric racemates are an important group of substrates, enough to mention amino acids. If acidic or basic character dominates (e.g., in aspartic acid, there are two carboxylate groups for one amino group), the compound can be resolved as a simple acid or base. With compounds having one carboxyl and amino group each, one of the functional groups must be masked. Preparation of such derivatives has been thoroughly elaborated in peptide chemistry. In Table 3.16, the resolution of six different derivatives of alanine with ten different resolving agents is shown to illustrate the plethora of possibilities for the resolution of amphoteric compounds by salt formation.

3.9 RESOLUTION BY SALT FORMATION OF COMPOUNDS LACKING ACIDIC OR BASIC GROUPS If resolution of a neutral compound by salt formation is intended, the compound must be transformed to a derivative containing an acidic or basic group. Resolution via derivatization is typical for alcohols, aldehydes, and ketones. Alcohols are almost exclusively transformed to their hemiphthalates and Table 3.17 provides some examples for this procedure. Resolution of hemiphthalates should be first attempted with brucine in acetone, and eventually in ethyl acetate. Other basic alkaloids and 1-phenylethylamine may also be the reagent of choice. © 2002 by CRC Press LLC

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TABLE 3.17 Resolution of Some Racemic Alcohols via Their Hydrogen Phthalate Esters

TABLE 3.18 Resolution of Some Racemic Alcohols via their Hydrogen 3-Nitrophthalate Esters

Occasionally, when the hemiphthalate is not crystalline, phthalic anhydride may be replaced by 3-nitrophthalic anhydride as shown in Table 3.18, but it must be emphasized that phthalic anhydride is satisfactory in most cases. In principle, any other dicarboxylic acid can also serve for derivatizing; but in practice, only succinic anhydride is used for this purpose. Some resolutions via hemisuccinates are shown in Table 3.19. Aldehydes and ketones can be simply derivatized with 4-hydrazinobenzoic acid. For example, the carbonyl compounds 3.28 and 3.29 were resolved with brucine in methanol as their hydrazones 139 with 4-hydrazinobenzoic acid.

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TABLE 3.19 Resolution of Some Racemic Alcohols via Their Hydrogen Succinate Esters

3.10 ASYMMETRIC TRANSFORMATIONS DURING RESOLUTION BY SALT FORMATION There are several types of compounds that undergo continuous racemization under the conditions of their resolution, thereby permitting to obtain in a single step, at least in principle, one of the enantiomers quantitatively (S = 2). This phenomenon, called asymmetric transformation, is associated with certain structural features of the racemate. With resolutions based on the formation of diastereomeric salts and performed by the addition of one molar equivalent of resolving agent, crystallization of the salt must be conducted in a way that the rate of precipitation of the salt should not exceed the rate of racemization. Although the rate of crystal formation is controlled by the rate of racemization, the final yield is determined by the solubility of the salt. Note that in contrast to resolutions without asymmetric transformation (i.e., when the mother liquor contains the enantiomer forming the more soluble salt in excess), now the mother liquor contains a racemate. The process can be described by the following equation: (D

L) + 2R

2DR↓

(3.49)

where DR represents the less soluble salt. Of course, transformation goes toward the enantiomer forming the less soluble salt; and with the proper choice of the resolving agent, the required enantiomer can be recovered in almost quantitative yield. It is often a derivative of the substrate that racemizes during resolution and therefore a systematic search for derivatives undergoing transformation is recommended. One of the oldest examples of resolution accompanied by asymmetric transformation is the resolution of 2-(4-carboxybenzyl)-hydrindan-1-one with brucine. Owing to a keto-enol tautomerism accom140 panying the precipitation of the less soluble salt, base-catalyzed racemization takes place (Scheme 3.2). One of the intermediates in the synthesis of emetine also undergoes asymmetric transformation effected by camphorsulfonic acid in ethyl acetate. It is a unique feature of this reaction that two centers of asymmetry undergo inversion simultaneously. On protonation, ring c is opened, eliminating the center of asymmetry at the anellation of rings b and c, followed by enolization of the © 2002 by CRC Press LLC

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SCHEME 3.2

SCHEME 3.3

carbonyl group destroying the adjacent center of asymmetry. The poorly soluble camphorsulfonate 141 of the S,S-enantiomer crystallizes and gives the desired enantiomer in 85% yield (Scheme 3.3). During resolution of 2-phenylglycine nitrile (3.30) with tartaric acid and O,O′-dibenzoyltartaric 142 acid in various solvents, asymmetric transformation was generally observed. Mixtures of an apolar and a polar solvent were used, with or without the addition of aqueous ammonia.

Results (shown in Tables 3.20 and 3.21) indicate that ammonia promotes asymmetric transformation. Resolution was also feasible with O,O′-dibenzoyltartaric acid but optical purity was poor (Table 3.21). As shown in Table 3.22, asymmetric transformation also takes place in various solvents with the 4-methoxy analog of 3.30. Note that resolution in ethanol gives less good results than those conducted in aqueous acetone, although racemization of the nitrile in the absence of tartaric acid is faster in ethanol. Best results can be achieved in a dichloroethane–dimethylformamide—ammonia system. When resolved with tartaric acid in ethanol, esters of phenylglycine undergo asymmetric transformation in the presence of carbonyl compounds. In Table 3.23, the effect of adding various oxo compounds on the efficiency of resolution in ethanol with tartaric acid at room temperature is shown. © 2002 by CRC Press LLC

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TABLE 3.20 Resolution of 2-Phenylglycine Nitrile (3.30) with Tartaric Acid Combined with Asymmetric Transformation in Various Solvent Mixtures Solvent 1 Toluene Toluene ClCH2CH2Cl ClCH2CH2Cl Toluene Toluene

Solvent 2

Solvent 3

DMF DMF DMF DMF MeOH H2O

— Ammonia — Ammonia Ammonia Me2CO

Solvent Ratio 5:1 200 : 40 : 1 180 : 30 200 : 40 : 1 200 : 48 : 1 200 : 40 : 60

y (%) 62 60 65 70 66 68

e.e. (%) 99 98 55 98 85 100

TABLE 3.21 Resolution of 2-Phenylglycine Nitrile (3.30) with O,O ′-Dibenzoyltartaric Acid Combined with Asymmetric Transformation in Various Solvent Mixtures Solvent 1 Toluene Toluene ClCH2CH2Cl ClCH2CH2Cl

Solvent 2

Solvent 3

Solvent Ratio

y (%)

e.e. (%)

MeOH MeOH MeOH DMF

Me2CO Ammonia Ammonia Me2CO

100 : 38 : 10 100 : 20 : 1 100 : 20 : 1 100 : 10 : 20

55 77 76 62

40 57 25 41

TABLE 3.22 Resolution of 2-(4-Methoxyphenyl)glycine Nitrile with Tartaric Acid Combined with Asymmetric Transformation in Various Solvent Mixtures Solvent 1 EtOH Me2CO Toluene Toluene Toluene ClCH2CH2Cl ClCH2CH2Cl

Solvent 2

Solvent 3

Solvent Ratio

y (%)

e.e. (%)

— H2O H2O DMF DMF DMF DMF

— — Me2CO — Ammonia Ammonia —

— 100 : 20 10 : 10 : 1 100 : 20 100 : 20 : 1 100 : 20 : 1 90 : 15

52 75 75 62 85 90 82

80 96 100 98 98 98 82

One molar equivalent of an aldehyde is sufficient, while two equivalents of ketones are necessary. Optical purity does not depend much on the structure of the ketone additive, while with 143 aldehydes the results are more structure dependent.

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TABLE 3.23 Effect of Adding an Oxo Compound to the Resolution of 2-Phenylglycine Esters Combined with Asymmetric Transformation Oxo Compound (molar equivalents) O

CHO

O2N

CHO

Ester

Time (h)

e.e. (%)

y (%)

CHO

CH3

CHO

CH2O O

O

O

O

O

O

O

O Ph

Resolution of amine 3.31 can be accomplished with 3-bromocamphor-8-sulfonic acid (3.5). Because there is a keto group adjacent to the center of chirality, racemization by enolization can be anticipated and therefore the possibility of resolution combined with asymmetric transformation was explored. In fact, the salt containing the S enantiomer crystallized from an acetic acid–isopropyl acetate mixture at 50∞C with 96% e.e., but the yield was a mere 25%. Working in isopropyl acetate containing 3% trifluoroacetic acid, a product of 98% e.e. could be recovered in 90% yield, but the process required 5 to 7 days. Finally, to promote the asymmetric transformation, an excess of 3.5 in isopropyl acetate was used. Optimization experiments are shown in Table 3.24. It can be seen from this table that already a small excess of the resolving agent is © 2002 by CRC Press LLC

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TABLE 3.24 Optimization of the Resolution of 3.31 Molar Equivalents of 3.5 1.05 1.20 1.05 (slow addition, seeding) 1.2 (slow addition, seeding)

Time (h)

y (%)

e.e. (%)

7–9 3 3 2

90 93 90 90

97.9 98.1 99.4 99.0

TABLE 3.25 Kinetics of the Resolution of 1,2,3,4Tetrahydroisoquinoline-3-Carboxylic Acid (3.32) Carboxylic Acid Butanoic acid

Hexanoic acid

Reaction Time (h)

Yield (%)

o.p. (%)

2 4 6 8 10 12 14 2 4 6 8 10 15 20 25

92.7 91.2 90.7 90.0 87.5 88.0 87.0 92.7 90.2 87.0 86.8 91.7 87.3 87.8 87.3

22.7 42.5 56.9 64.8 74.9 78.7 76.6 11.7 16.4 42.4 55.8 65.2 80.4 90.1 89.9

sufficient to trigger asymmetric transformation and that adding seed crystals improves the optical 144 purity of the product and can thus be recommended.

In the course of the resolution of 3.32 with 10-camphorsulfonic acid in higher aliphatic carboxylic acids as solvent, asymmetric transformation takes place. The kinetics of the process has been studied in butanoic and hexanoic acids and the results are shown in Table 3.25. Figure 3.11 demonstrates the time dependence of the process. With hexanoic acid, establishment of the equilibrium takes longer but resolvability is better. Table 3.26 provides some additional examples for resolution by salt formation associated with an asymmetric transformation. © 2002 by CRC Press LLC

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FIGURE 3.11 Time dependence of resolvability of 3.32 in butanoic and hexanoic acids.

TABLE 3.26 Examples for Asymmetric Transformations Occurring During Resolution by Diastereomeric Salt Formation Racemate

Resolving Agent

Solvent/Additive

Ref.

NH2 NH2 O NH2 NH2 O

O

Ph

N

NH2 O NH2 OMe O

F

NH2 O

OMe O NH2 OMe O

Cl

NH2 OMe O

S

NH2 S

COOMe

O

N

NH2 N Ph

(Continued) © 2002 by CRC Press LLC

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TABLE 3.26 Examples for Asymmetric Transformations Occurring During Resolution by Diastereomeric Salt Formation (continued) Racemate

Resolving Agent

Solvent/Additive

Ref.

O N Ph

O Ph

N N

N F O S HN N O

HOOC

COOH

S

S

HOC

COH

HOOC S HOOC

COOH S COOH

HO3S

O Br

REFERENCES 1. B. Zsadon, M. Ács, E. Fogassy, F. Faigl, C. Novák, G. Pokol, and A. Újházy, Reactive Polymers, 6, 197 (1987). 2. E. Fogassy, F. Faigl, M. Ács, and A. Grofcsik, J. Chem. Res. (S), 346 (1981); J. Chem. Res. (M), 3981 (1981). 3. E. Fogassy, F. Faigl, M. Ács, K. Simon, É. Kozsda, B. Podányi, M. Czugler, and G. Reck, J. Chem. Soc. Perkin Trans. 2., 1385 (1988). 4. K. Simon, É. Kozsda, Z. Böcskei, F. Faigl, E. Fogassy, and G. Reck, J. Chem. Soc. Perkin Trans. 2., 1395 (1990). 5. L. Pasteur, C.R. Acad. Sci., 37, 162 (1853). 6. L. Pasteur, Ann. Chim., 38, 437 (1853). 7. P. Newman, Optical Resolution Procedures for Chemical Compounds, Vol. 1–3. Optical Resolutions Information Center New York (1978–1983). 8. C.G. Overberger, K.-H. David, and J.A. Moore, Macromolecules, 5, 368 (1972). 9. F. Radke, Ph.D. thesis, Iowa State College (1952). 10. W.R. Brode, and I.J. Wernert, J. Am. Chem. Soc., 65, 1685 (1933). 11. K. Saigo, I. Sugiura, I. Shida, K. Tachibana, and M. Hasegawa, Bull. Chem. Soc. Jpn., 59, 2915 (1986). 12. A.W. Ingersoll and S.H. Babock, J. Am. Chem. Soc., 55, 341 (1933). 13. M. Leclerq and J. Jacques, Nouv. J. Chim., 3, 629 (1979). 14. R. Adams, D.C. Blomstrom, and K.V.T. Sundstrom, J. Am. Chem. Soc., 76, 5478 (1954). 15. J.A. Edwards, B. Berkoz, G.S. Lewis, O. Halpern, J.H. Fried, A.M. Strosberg, L.M. Miller, S. Urich, F. Liu, and A.P. Roszkowski, J. Med. Chem., 17, 200 (1974). 16. German Patent, 1, 274, 586 (1968). 17. A. Fredga, Arkiv Kemi, 7, 241 (1954). 18. British Patent 1,426,186 (1976). 19. U.S. Patent, 3, 417, 094 (1968). © 2002 by CRC Press LLC

0019_frame_C03.fm Page 47 Monday, August 6, 2001 1:20 PM

20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71.

W.J. Pope and C.S. Gibson, J. Chem. Soc., 97, 2207 (1910). C.S. Gibson and L.J. Simonsen, J. Chem. Soc., 107, 1148 (1915). K. Oki, K. Suzuki, S. Tuchida, T. Sato, and H. Kotake, Bull. Chem. Soc. Jpn., 43, 2554 (1970). M. Senuma, M. Shibazaki, S. Nishimoto, K. Shibata, K. Okamura, and T. Date, Chem. Pharm. Bull., 37, 3204 (1989). J. Brandt and H.-J. Gais, Tetrahedron: Asymmetry, 8, 909 (1997). M.S. Raaasch, Ph.D. thesis, The Ohio State University (1941). German Patent 1.235.946 (1972). J.J. Kaufmann, N.M. Semo, and W.S. Koski, J. Med. Chem., 18, 647 (1975). K. Marsó, Ph.D. thesis, Technical University of Budapest (1988). D. Kozma and E. Fogassy, Synth. Commun., 29, 4315 (1999). F.J. Kearley and A.W. Ingersoll, J. Am. Chem. Soc., 73, 5783 (1951). H. Takamatsuo, Yakugaku Zasshi, 76, 1219 (1956). A. McKenzie and N. Walker, J. Chem. Soc., 646 (1928). J. McL. Macdonald and E. Stedman, J. Chem. Soc., 2513 (1932). A. Fredga, Uppsala Universitets Arsskrift, 5 (1935). H.J. Backer and H.W. Mook, J. Chem. Soc., 2125 (1928). J. Read and A.M. McMath, J. Chem. Soc., 2723 (1932). R. Kuhn and T. Wieland, Chem. Ber., 73, 971 (1940). A. Fredga and K.I. Sandstrom, Arkiv Kemi, 23, 245 (1965). E.E. Pedersen and K.A. Jensen, Acta Chem. Scand., 2, 651 (1948). E.T. Stiller, S.A. Harris, J. Finkelstein, J.C. Keresztesy, and K. Folkers, J. Am. Chem. Soc., 62, 1785 (1940). A. Grussner, M. Gatzi-Fichter, and T. Reichstein, Helv. Chim. Acta, 23, 1276 (1941). F. Feist, Liebegs Ann. Chem., 436, 125 (1924). E. Buchner and R. von der Hide, Chem. Ber., 38, 3112 (1905). K. Mori, Tetrahedron, 31, 1381 (1975). A. Fredga, J. Prakt. Chem., 150, 124 (1938). A. Fredga, Arkiv Kemi Mineral Geol., 12A, No. 27 (1938). M.-O. Hedblom, Swed. J. Agric. Res., 1, 43 (1971). M.-O. Hedblom, Arkiv Kemi, 31, 489 (1969). H. Scheibler and A.S. Wheeler, Chem. Ber., 44, 2684 (1911). T. Miyazawa, K. Takashima, Y. Mitsuda, T. Yamada, S. Kuwata, and H. Watanabe, Bull. Chem. Soc. Japan, 52, 1539 (1979). T. Raznikiewicz, Acta Chem. Scand., 18, 467 (1961). T. Raznikiewicz, Arkiv Kemi, 18, 467 (1961). W. von E. Doering, M. Franck-Neumann, D. Hasselmann, and R.L. Kaye, J. Am. Chem. Soc., 94, 3833 (1972). A. Fredga and K. Styram, Arkiv Kemi, 14 (1959). J.E. Némortin, E. Jonsson, and A. Fredga, Arkiv Kemi, 30, 403 (1969). A. Fredga and M. Tenow, Arkiv Kemi, Mineral. Geol., 16B, No. 9 (1942). S. Stallberg-Stenhagen, Arkiv Kemi, Mineral. Geol., 25A, No. 10 (1947). A. Fredga and E. Andersson, Arkiv Kemi, Mineral. Geol., 14B, No. 18 (1940). K. Pettersson, Arkiv Kemi, 7, 39 (1954). K. Mori, Tetrahedron, 34, 915 (1978). R. Trave and L. Garanti, Gazz. Chim. Ital., 90, 612 (1960). A. Fredga and R. Sandberg, Suomen Kemi, B31, 42 (1958). K. Serck-Hanssen, Arkiv Kemi, 10, 135 (1957). C.E. Wood and M.A. Comley, J. Chem. Soc., 125, 2630 (1924). A. Fredga and U. Sahlberg, Arkiv Kemi, Mineral. Geol., 18A, No. 16 (1944). R. Ahlberg, Chem. Ber., 61B, 811 (1928). A. Fredga, E. Gamstedt, and L. Ekermo, Arkiv Kemi, 29, 515 (1968). M. Matell, Arkiv Kemi, 4, 473 (1952). A. Fredga, Arkiv Kemi, 25, 87 (1965). R. Roger and D.G. Neilson, J. Chem. Soc., 627 (1960). S. Gronowitz and S. Larsson, Arkiv Kemi, 8, 567 (1955).

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0019_frame_C03.fm Page 48 Monday, August 6, 2001 1:20 PM

72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125.

M-O. Hedblom and K. Olsson, Arkiv Kemi, 32, 309 (1970). A. Fredga and K.-I. Sandstorm, Arkiv Kemi, 23, 245 (1965). A. Fredga, A. Kijellqvist, and E. Tornqvist, Arkiv Kemi, 32, 301 (1970). A. Fredga, E. Thimson, and K. Rosberg, Arkiv Kemi, 32, 369 (1970). A. Fredga, I. Kiriks, and C. Lundstrom, Arkiv Kemi, 25, 249 (1966). A. Fredga and I. Avalaht, Arkiv Kemi, 24, 425 (1965). J. Sjöberg, Arkiv Kemi, 12, 565 (1958). J. Sjöberg, Arkiv Kemi, 11, 439 (1957). J. Sjöberg, Arkiv Kemi, 12, 251 (1957). A. Fredga and K. Olsson, Arkiv Kemi, 30, 409 (1969). A. Fredga and U. Löfroth, Arkiv Kemi, 23, 239 (1965). B. Sjöberg, Arkiv Kemi, 9, 295 (1956). A. Fredga, Arkiv Kemi, 8, 463 (1955). R. Hakansson and A. Svensson, Chem. Scripta, 7, 186 (1975). A. Almqvist and R. Hakansson, Chem. Scripta, 11, 180 (1977). A. Fredga and L.-B. Agensas, Arkiv Kemi, 15, 327 (1960). D.F. Detar and J.C. Howard, J. Am. Chem. Soc., 77, 4393 (1955). K. Pettersson, Arkiv Kemi, 7, 279 (1954). K. Mislow, Stereoisomerism, in Comprehensive Biochemistry, M. Florkin, and E.M. Stoll, Eds., Elsevier, Amsterdam (1962). French Patent 1.559.885 (1969). L.R. Overby, J. Org. Chem., 23, 1393 (1958). Swiss Patent 478.759 (1969). E. Fogassy and M. Ács, unpublished results. E. Fogassy, M. Ács, L. Töke, Optikai Izomerek Elöálítása, Akadémiai Kiadó, Budapest (1987). V. du Vigneaud and R.R. Sealock, J. Biol. Chem. 96, 511 (1932). F.J. Kearley and A.W. Ingersoll, J. Am. Chem. Soc., 73, 5783 (1951). T. Shiraiwa, M. Morita, M. Iwafuji, and H. Kurokawa, Nippon Kagaku Kaishi, 1743 (1983). C. Wong and K. Wang, Tetrahedron Lett., 40, 3813 (1978). A.W. Ingersoll, J. Am. Chem. Soc., 47, 1168 (1925). European Patent, 0.036.265 (1986). T. Leigh, Chem. Ind. (London), 36 (1977). German Patent (east) DD 301838 (1994). T. Shiraiwa, Y. Sado, S. Fujii, M. Nakamura, and H. Kurosawa, Bull. Chem. Soc. Jpn., 60, 824 (1987). T. Purdie, J. Chem. Soc., 67, 944 (1895). M. Rieger and F.H. Westheimer, J. Am. Chem. Soc., 72, 28 (1950). J. Read and I.G.M. Campbell, J. Chem. Soc., 2682 (1930). H. Musso and W. Steckelberg, Justus Liebigs Ann. Chem., 693, 187 (1966). H. Tomori, H. Yoshihara, and K. Ogura, Bull. Chem. Soc. Jpn., 69, 3581 (1996). W. Langenbeck and O. Herst, Chem. Ber., 86, 1524 (1953). U.S. Patent 2,991,307 (1961). M.S. Dunn, M.P. Stoddard, L.B. Rubin, and R.C. Bovie, J. Biol. Chem., 151, 241 (1943). U.S. Patent 3,028,395 (1962). T. Kato and Y. Tsuchiya, Agr. Biol. Chem., 26, 467 (1962). G. Gal, J.M. Chemerda, D.F. Reinhold, and R.M. Purick, J. Org. Chem., 42, 142 (1977). K. Vogler and P. Lanz, Helv. Chim. Acta, 49, 1348 (1966). L.R. Overby and A.W. Ingersoll, J. Am. Chem. Soc., 82, 2067 (1960). R.H. Pickard and J. Kenyon, J. Chem. Soc., 99, 45 (1911). C.S.L. Baker, P.D. Landor, S.R. Landor, and A.N. Patel, J. Chem. Soc., 4348 (1965). M.P. Balfe, M. Irwin, and J. Kenyon, J. Chem. Soc., 312 (1941). P.A. Lavene and H.L. Haller, J. Biol. Chem., 81, 425 (1929). H.W.J. Hills, J. Kenyon, and H. Phillips, J. Chem. Soc., 139, 576 (1936). M. Vogel and J.D. Roberts, J. Am. Chem. Soc., 88, 2262 (1966). K.A. Thaker and N.S. Dave, J. Sci. Ind. Res. (India), 20B, 329 (1961). M. Rösner, Ph.D. thesis, Technical University Hannover, West Germany (1975).

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0019_frame_C03.fm Page 49 Monday, August 6, 2001 1:20 PM

126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 149. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149.

J. Kenyon and D.R. Snellgrove, J. Chem. Soc., 127, 1169 (1925). J. Kenyon and R. Poplett, J. Chem. Soc., 273 (1945). W. Logemann, P. Giraldi, D. Artini, and J. Franceschini, Z. Physiol. Chem., 298, 87 (1954). A.F. LeC. Holding, and W.A. Ross., J. Chem. Soc., 145, (1954). J.B. Cohen, J. Marshall, and H.E. Woodman, J. Chem. Soc., 107, 887 (1915). P.A. Levene, R.E. Marker, and A. Rothen, J. Biol. Chem., 100, 589 (1933). W. Reeve, R. Bianchi, and J.R. McKee, J. Org. Chem., 40, 339 (1975). T. Ishizaki, H. Miura, and H. Nohira, Nippon Kagaku Kaishi, 1381 (1980). P.W. Feit, Chem. Ber., 93, 116 (1960). W. Hückel and F. Mossner, Liebigs Ann. Chem., 637, 57 (1960). German Patent 2263880 (1973). H. Kaehler, F. Nerdel, G. Engemann, and K. Schwerin, Liebigs Ann. Chem., 757, 15 (1972). H. Lauchs, Ber., 54, 830 (1921). H.T. Openshaw and N. Whitaker, J. Chem. Soc., 1461 (1963). F. Faigl, Ph.D. thesis, Technical University of Budapest (1981). R.J. Alabaster, A.W. Gibson, S.A. Johnson, J.S. Edwards, and I.F. Cottel, Tetrahedron: Asymmetry, 8, 447 (1997). T. Shiraiwa, T. Furukawa, T. Tschida, S. Sakata, M. Sunami, and H. Kurosawa, Bull. Chem. Soc. Jpn., 64, 3729 (1991). J.D. Mosely, B.J. Williams, S.N. Owen, and H.M. Verrier, Tetrahedron: Asymmetry, 7, 3351 (1996). U.S. Patent 3,976,680 (1976). P.J. Raider, P. Davis, D.L. Hughes, and E.J.J. Grabowski, J. Org. Chem., 52, 955 (1987). A. Pohland, L.R. Peters, and H.R. Sullivan, J. Org. Chem., 28, 2483 (1963). S.H. Wilen, J.Z. Qi, and P.G. Williard, J. Org. Chem., 56, 485 (1991). N. Cohen, B.L. Banner, J.F. Blount, G. Weber, M. Tsai, and G. Saucy, J. Org. Chem., 39, 1824 (1974). R. Hakansson and A. Svensson, Chem. Scripta, 7, 186 (1975).

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4

Resolving Agents

Sections 4.1 and 4.2 of this chapter compile a list of the most often used acidic and basic resolving agents (50-50) as well as their physical data. The authors also comment on their availability because this is of prime practical importance. For the compounds the following data are given (if available and in this order): Box 1: Abbreviation, molecular formula, molecular mass, structural formula, full name Box 2: Optical rotation, m.p., b.p., number of resolved compounds (NRC), solvent used for resolution Box 3: Chemical Abstracts (CA) and Beilstein (BN) registry numbers, reference for preparation, commercial sources It must be emphasized that any optically pure chiral organic acid or base may be a candidate as resolving agent; that is, it is worthwhile to try any substance available in reasonable quantities in the given institution prepared by asymmetric synthesis or otherwise. It is therefore advisable to keep a record of any optically active chiral intermediate arising during manufacturing and regard them as potential resolving agents. In this way, useful application may be found for the unwanted enantiomer which would otherwise be discarded of a product manufactured in optically active form.

4.1 BASIC RESOLVING AGENTS

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4.2

ACIDIC RESOLVING AGENTS (INCLUDING AMINO ACIDS)

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4.3

RESEARCH ON RESOLVING AGENTS

4.3.1 ATTEMPTS

TO

DEVISE

A

GENERALLY APPLICABLE RESOLVING AGENT

1

Hoeve and Wynberg undertook the elaboration of generally applicable acidic and basic synthetic resolving agents. First, they deﬁned the important characteristics of an ideal resolving agent: 1. It should be a strong acid or base to secure formation of stable salts with weakly basic or acidic racemates, respectively. 2. The center of chirality should be as close as possible to the functional group involved in salt formation to provide signiﬁcant differences in the stereostructure of the diastereomeric salts. 3. It should be conformationally as rigid as possible to limit the number of energetically possible conformations. 4. Both enantiomers should be available. 5. It should be chemically stable and should not racemize under the conditions of resolution. 6. It should be readily recoverable. 7. It should be nontoxic. 8. Starting materials for its preparation should be readily available and inexpensive. 4.3.1.1 Resolutions with Cyclic Phosphoric Diesters 1

For the resolution of bases, a series of phosphoric diesters were prepared. Those with an aryl substituent (4.2) formed much better crystallizing salts than the norbornene derivative 4.1.

© 2002 by CRC Press LLC

TABLE 4.1 Some Phosphoric Diester Type Resolving Agents X H 2-F 2-Cl 2-Br 2,6-Cl2 2,4-Cl2 2-OMe 2-NO2 2-Me 4-Cl 4-Me

Trivial Name Phencyphos 2-Fluorocyphos 2-Chlocyphos 2-Brocyphos 2,6-Dichlocyphos 2,4-Dichlocyphos 2-Anicyphos 2-Nitrocyphos 2-Tocyphos 4-Chlocyphos 4-Tocyphos

SCHEME 4.1

Because cyclic phosphoric diesters are rather strong acids, they can form stable salts not only with amines but also with amino acids. The geminal dimethyl group with an adjacent aryl group lends sufﬁcient rigidity to the molecule and X-ray studies have shown that the ring assumed a chair conformation. The racemic diesters can be prepared from substituted benzaldehydes according to Scheme 4.1. Diesters prepared according to this scheme are shown in Table 4.1. The racemic cyclic diesters can be readily resolved with ephedrine, 4-hydroxyphenylglycin, or 2-amino-1-phenyl-1,3-propanediol. Table 4.2 shows resolution of bases with optically active phosphoric diesters. Of the ten racemates shown in Table 4.2, nine could be resolved with at least one of the cyclic phosphoric diesters. Nevertheless, strictly speaking, none of these esters can be regarded as a generally applicable resolving agent. Note that substitution of the aryl group has a signiﬁcant role. Thus 2-chlocyphos proved to be the most efﬁcient agent, with which eight of the ten racemates could be resolved, four of them with high efﬁciency. It is interesting that its isomer 4-chlocyphos failed to form separable diastereomeric salts with any of the racemates. This may indicate that a chlorine atom in the ortho-position stabilizes, while one in a para-position destabilizes interactions between the partners. A too bulky ortho-substituent is also destabilizing, as shown by the fact that the 2-methoxy derivative is a better resolving agent than the 2-ethoxy analog. © 2002 by CRC Press LLC

TABLE 4.2 Resolution of Bases with Optically Active Cyclic Phosphoric Esters Shown in Table 4.1

H N O NH2 NH2

Cl

Cl NH2 Ph

O

HN COOH

S H2N NH2 COOH

NH2 COOH NH2 HO COOH NH2 Ph

COOH

NH2 Ph

S

COOH

COOH NH2

4.3.1.2 Basic Analogs of Cyclic Phosphoric Diesters 2

Because cyclic phosphoric diesters proved to be potent resolving agents, Wynberg and co-workers prepared some basic analogs (shown in Table 4.3). Among them, cyclic amidines have a rather rigid structure comparable to that of cyclic phosphoric diesters and were therefore expected to give readily crystallizing salts with various acids. The noncyclic aminoalcohols are more ﬂexible, but this disadvantage may be compensated for by additional interactions with the free hydroxyl group. As also shown in Table 4.3, both types of compounds can be well-resolved with cyclic phosphoric diesters. This is an interesting example for resolution with compounds with a signiﬁcant difference in chemical character but close analogy in their structure. An interesting feature of the above experiments is that for successful resolution, ortho-chloro substitution of the phenyl ring in one of the partners (acid or base) is an essential condition. Resolution fails, however, when both partners are ortho-chloro-substituted or not substitutited at all. Note that it is irrelevant which of the partners is substituted. Resolution of the piperidine derivatives shown in Table 4.3 with cyclic phosphoric diesters failed, although it was possible to resolve the unsubstituted compound (X = H) with tartaric acid and the 2-chloro compound with (1S)-10-camphorsulfonic acid, both with poor efﬁciency. Despite expectations, none of the three groups of bases in Table 4.3 proved to be efﬁcient resolving agents for racemic acids, except for the phosphoric diesters used for their resolution proper. With other acids, usually not even crystalline salts were formed. It is difﬁcult to explain this failure. While as compared to the cyclic phosphoric diesters, the salt-forming center in the bases is different but is closer to the center of chirality. With the aminoalcohols, the difference is even more conspicuous, but all these features are insufﬁcient to explain the ﬁndings. © 2002 by CRC Press LLC

TABLE 4.3 Resolutions with Optically Active Amidines, Aminoalcohols, and Piperidines Prepared in Analogy with Cyclic Phosphoric Diesters

Amidine

X

Y

[ α ] 578

Resolving Agent 4.2

X

H H Cl Cl Cl Cl

H H H H Cl Cl

+246 −249 No resolution −231 No resolution

(−)-Phencyphos (−)-2-Chlocyphos (−)-Phencyphos (−)-2-Chlocyphos (−)-Phencyphos (−)-2-Chlocyphos

H 2-Cl H 2-Cl H 2-Cl

H H Cl Cl

No resolution +6.7 −28.7 No resolution

(−)-Phencyphos (−)-2-Chlocyphos (−)-Phencyphos (−)-2-Chlocyphos

H 2-Cl H 2-Cl

H Cl

No resolution No resolution

(−)-Phencyphos (−)-Phencyphos

H H

21

Aminoalcohol

Piperidenes

4.3.2 CORRELATION OF RACEMATE

EFFICIENCY OF RESOLUTION RESOLVING AGENT

OF THE AND

WITH THE

STRUCTURE

4.3.2.1 Statistical Analysis in Search of a Correlation Selection of the suitable resolving agent for a given racemate is usually done by trial and error. It 3 was a challenging task to ﬁnd out whether it was possible to predict, at least for a certain group of compounds, which enantiomer of a racemate is forming the less soluble salt in a given solvent with a given resolving agent, as well as to estimate expected yields and optical purity. Using the methods of mathematical statistics, such an approach has been elaborated for the phenylglycine derivatives 4.3. Correlations could be established between racemate structure, solvent, optical purity, and yield (resolvability S).

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TABLE 4.4 Data on Resolutions of 2-Arylglycine Derivatives with Tartaric Acid Carried Out for Statistical Studies Racemate

No. R 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

1

H H H H H H H H H OH OH OCH3 OCH3 OCH3 OCH3 OCH3 Cl OCH3 OCH3 OCH3 H H H

Product R

2

COOCH3 COOCH3 COOEt COOEt CONH2 CONH2 CN CN CN COOCH3 CN CN CN CN CN CN COOCH3 CONH2 CONH2 CONH2 CONH2 CN CN

Solvent MeOH EtOH MeOH EtOH H 2O Me2CO H 2O Me2CO PhMe MeOH EtOAc H 2O MeOH EtOH Me2CO PhMe MeOH MeOH Me2CO H 2O MeOH MeOH EtOH

Conﬁg. D D D D L L D D D D D D D D D D D L L L L L L

y

e.e.

Sexp

Scalc.

0.26 1.20 0.50 0.72 0.86 0.95 0.95 1.20 1.50 0.76 0.81 0.80 0.88 0.83 0.90 1.60 0.28

0.62 0.27 0.97 0.97 0.85 0.80 0.15 0.78 0.48 0.24 0.90 0.60 0.71 0.73 0.88 0.60 0.85

0.16 0.32 0.45 0.70 −0.73 −0.76 0.14 0.94 0.72 0.18 0.73 0.48 0.62 0.61 0.79 0.96 0.24 −0.61 −0.50 −0.70 −0.59 0.54 0.58

0.12 0.17 0.62 0.68 0.86 −0.54 0.34 0.66 0.79 0.15 0.76 0.48 0.60 0.66 0.80 0.93 0.22 −0.60 −0.40 −0.72 −0.75 0.46 0.51

Experimental data used for the linear regression analysis as well as calculated S values are compiled in Table 4.4. Racemates 1–17 were resolved with one molar equivalent of tartaric acid. Using the correlation obtained from experimental data for 1–17 predicted values for racemates 18–23 were calculated and the predictions were also veriﬁed by experiment. Efﬁciency of resolution is characterised by a parameter (S) called resolvability: S = y × e.e.

(4.1)

where y is the yield of the crystalline diastereomeric salt, while e.e. is its enantiomeric purity, both divided by one hundred. Yields were based on one half of the quantity of racemate. The sign of S is positive if the enantiomer in excess in the precipitated salt is R and negative if it is S. The range of S is −1 to +1. Based on experimental values of S, the effect of the structure of racemate and resolving agent, as well as of experimental conditions (solvent, etc.) on the outcome of resolution has been investigated. When setting up a model for calculation, it has been assumed that formation of the diastereomeric salts is not only inﬂuenced by ion-ion interactions, but also by secondary interactions (dipole-dipole and van der Waals interactions, etc.). 1 2 The structure of the racemate was characterized by parameters for substituents R and R , that is, hydrophobic constants π, inductive and mesomeric parameters F and R according to Swain and Lupton for their electronic structure, and ﬁnally the steric parameters MR. The Taft parameter σ * © 2002 by CRC Press LLC

was calculated by the following equation: σ * = 1.38F + 0.14R. The effect of solvent polarity on salt formation was accounted for by the empirical polarity factor ET . Linear regression analysis of data for the resolution of phenylglycine derivatives based on the above parameters gave equations with very good statistical values. The equations allow several interpretations of the correlation between conditions and results of resolution, but do not, in essence, differ. Some of the possible equations are the following: Equation

n

r

F

s

Eq.

S = 0.517 π2 + 2.280 σ2* − 0.015 ET − 0.001 S = 0.524 π2 + 2.082 σ2* − 0.016 ET + 0.017 MR1 + 0.107 S = 4.374 σ2* + 0.107 MR2 − 0.014 ET − 2.529 S = 4.183 σ2* + 0.110 MR2 − 0.015 ET + 0.021 MR1 − 2.461

17 17 17 17

0.967 0.971 0.964 0.970

63 50 57 48

0.140 0.137 0.147 0.140

(4.2) (4.3) (4.4) (4.5)

where n is the number of resolutions, r the correlation coefﬁcient of the equation, F the value of the Fischer test, and s the standard deviation of the equation. According to the Fischer test, statistical signiﬁcance of the equations is better than 99.9%. According to the above equations, a change of π2, σ 2*, MR1, and MR2 in the positive direction corresponds to an increase of resolvability. That is, if R1 and R2 are very hydrophobic, electron attracting, and bulky groups, preferred crystallization of the salt containing the R enantiomer in excess can be predicted. The equations also adequately describe the situation when R2 is hydrophilic, only weakly electron attracting, and small (such as the amide group). In this case, crystallization of the salt containing the S enantiomer can be anticipated from a polar solvent. The predictive power of the equations was tested by calculating parameters for six known resolutions (see Table 4.4, items 18–23) not included in the calculations. The correlation between calculated and experimental data was very good, the conﬁguration of the crystallizing diastereomer was in every case correctly predicted, and yields agreed within an error margin of 15%. 4.3.2.2 Structural Correlations Between Racemate and Resolving Agent in the Resolution of Ephedrine Derivatives The correlation between the structures of racemate and resolving agent and the efﬁciency of resolution with cyclophos derivatives (4.2) in a series of chloroephedrines (4.4) was investigated 4,5 by Dutch researchers.

Y Y Y Y

= = = =

H Ephedrine 2-Cl 2-Chloroephedrine 2,6-Cl2 2,6-Dichloroephedrine 4-Cl 4-Chloroephedrine

Section 4.3.1.1 has already demonstrated that, in contrast to ephedrine, substitution on the phenyl ring in cyclic phosphoric diesters is important for their resolving power. With an unsubstituted phenyl ring, resolution of ephedrine failed but resolution was efﬁcient when there was a chlorine substituent on the phenyl ring. The effect of chloro-substitution on the phenyl ring of ephedrine was next studied. Considering the complementarity principle mentioned in Section 4.3.1.1 and valid with cyclic phosphoric diesters, it could be expected that phenylphos should be suitable for the resolution of chloroephedrines, while when both partners are chloro-substituted resolution would fail. © 2002 by CRC Press LLC

TABLE 4.5 Physicochemical Data of the Salts of Chloroephedrines with Phosphoric Esters 4.2

Racemate

Resolving Agent

2-Chloroephedrine

Phencyphos (n) (p) 2-Chlocyphos (n) (p) 2,6-Dichlocyphos (n) (p) 4-Chlocyphos (n) (p) 2-Chlocyphos (n) (p) 2,6-Dichlocyphos (n) (p) 2-Chlocyphos (n) (p) 2,6-Dichlocyphos (n) (p)

2,6-Dichloroephedrine

4-Chloroephedrine

Solubility (g/100 g iPrOH)

m.p. (°C)

1.41 1.28 0.21 2.54 0.99

233 226 261 205 234

a

a

a

0.98

246

40.8 ± 0.6

a

a

a

3.79 0.25

208 241

b

a

a

b

0.13 3.91 1.41

251 179 220

b

43.5 ± 2.0 45.5 ± 1.1

a

a

a

0.89

238

40.5 ± 2.0

Heat of Fusion (kJ/mol) 41.0 47.0 60.2 45.6 45.0

± ± ± ± ±

0.5 0.2 0.7 0.3 0.6

b

Note: n-salt: (−)-base.(+)-acid or (+)-base.(−)-acid, p-salt: (−)-base.(−)-acid or (+)-base.(+)-acid a b

Did not crystallize Inconsistant results.

TABLE 4.6 Maximum Resolvability Values (S) Calculated from Solubility Data. Positive Values Indicate Higher Solubility for the p-salts, Negative Values that of the n-salt Phosphoric Diesters Y Y Y Y

= = = =

H 2-Cl 2,6-Cl2 4-Cl

Ephedrines Y=H

Y = 2-Cl

Y = 2,6-Cl2

−0.05 0.76 0.81 0.88

−0.09 0.92

−0.93

b

a

b

Y = 4-Cl a

−0.64 b

b

a

Not determined. Preliminary experiments indicated poor resolvability. The salt having a higher solubility is an oil at room temperature. Preliminary preparative-scale experiments indicated high resolvability.

b

Preliminary experiments were carried out with 2- and 4-chloro- as well as with 2,6-dichloroephedrine, using 2-chloro- and 2,6-dichloro-substituted cyclic phosphodiesters. While phenylphos did not resolve any of the ephedrine derivatives, the two chloro-diesters were both suitable for the resolution of all three substituted ephedrines. In addition, the pure diastereomeric salts were prepared and their physicochemical data determined (see Table 4.5). Maximum resolvabilities calculated from solubility data using Eq. (5.10) deduced in Section 5.2.1.1 are shown in Table 4.6. © 2002 by CRC Press LLC

With a cyclic phosphoric diester unsubstituted at the phenyl ring, neither ephedrine nor its substituted derivatives could be resolved efﬁciently. One substituent at the phenyl ring of the phosphodiester gave satisfactory results with any of the ephedrines, while 2,6-dichloro-substitution provided even better results. Looking now at the ephedrine partner, an ortho-chloro-substituent enhanced resolvability, whereas a para-chloro-substituent exerted the opposite effect. These results clearly indicated that substitution at the phenyl ring of the phosphodiester plays a more important role than that at the ephedrine molecule.

4.3.3 SYSTEMATIC MODIFICATION

RESOLVING AGENT

OF THE

6

Dai and co-workers studied the resolution of the compounds 4.5.

1

2

(a) R = R = H; 1 2 (b) R = Me, R = H; 1 2 (c) R = H, R = Me Because compounds 4.5 are weak bases (pKa ≈ 2.2), resolution was attempted with (1S)-10camphorsulfonic acid, a strong acid. The diastereomeric salts separated as well-developed crystals from ethyl acetate, but their decomposition produced only the racemate. The crystal structure of the salt formed from 4.5 was determined by X-ray crystallography. The 1:1 salt forms monoclinic crystals of group P21 in a way that along the crystallographic 21 axis, a column ﬁxed by salt bonds is formed, in which alternately the two enantiomers of the base are built in. Weak interactions between the aromatic rings and the camphorsulfonic acid do not prevent the incorporation of both enantiomers. It appears that the carbonyl group that distinguishes the two sides of camphorsulfonic acid is not bulky enough to select between enantiomers of the base. Transformation of the ketone to its benzenesulfonylhydrazone gave, in 99% yield, a resolving agent 4.6 that proved to be efﬁcient with all three racemates (4.5).

4.3.4 FORMATION OF IN RESOLUTION

A

QUASI-RACEMATE

AS AN IMPORTANT

FACTOR

In crystalline racemates, heterochiral assemblies dominate over homochiral ones because, by complementing each other, a pair of mirror-image structures can form more compact (i.e., lower 7 energy) crystals than a single enantiomer alone. Thus, for example, racemic tartaric acid can be resolved by mixed-crystal formation with malic acid, a structurally closely related diacid. (S)-Malic acid preferentially crystallizes with (R,R)12 tartaric acid, forming a quasi-racemate. The same tendency to form the more stable salt with the quasi-enantiomeric form of the resolving agent can also be observed with resolution by salt © 2002 by CRC Press LLC

TABLE 4.7 Some Examples for Resolution Exploiting Quasi-racemate Formation Enantiomer in Excess in the Precipitated Salt

Resolving Agent

o.p. (%)

Yield (%)

S [Ref.]

formation. An important condition for the formation of quasi-racemic crystals is that the structure of the partners should be as similar as possible. From Table 4.7, which presents some examples for this phenomenon, it can be clearly seen that resolvability increases with structural similarity. Close similarity can be readily realized if, for example, a base is resolved with its optically active amide formed with a dibasic acid or when an amino acid is resolved with its amide. It can be concluded from the above observations that successful resolution can be hoped for if a resolving agent structurally similar to the racemate can be found. With resolutions on an industrial scale, it is worthwhile to transform the enantiomer otherwise to be discarded into a compound of opposite character and try it as a resolving agent (see Chapter 5).

4.3.5 RESOLUTIONS

WITH A

DERIVATIVE

OF THE

RACEMATE

A special case occurs when resolution is accomplished with a derivative of a pure enantiomer of the original racemate having opposite character. This method, of course, cannot be applied when resolution of a new racemate is attempted because at the beginning of experiments no pure enantiomer is available. However, this approach can be very useful for the optimization of resolutions on a large scale. For example, an amine can be transformed into an acid by amidation with a dicarboxylic acid and used for resolution of the original amine. In the case of amino acids, derivatization is even more simple because a large arsenal of protecting groups, as elaborated by peptide chemists, is available to protect either the amino or the carboxyl group. The resulting monofuctional compound can then be used as a resolving agent. Examples for such procedures are shown in Table 4.8 and indicate that resolution by this method is generally very efﬁcient and often superior to the use of conventional resolving agents. © 2002 by CRC Press LLC

TABLE 4.8 Resolutions Performed Using a Derivative of the Enantiomer of the Racemic Substrate Enantiomer in Excess in Precipitated Salt

e.e. (%)

Resolving Agent

COOH

Y (%)

S [Ref.]

COOH HN

NH2

Ph O

OH OH HN

O 2N

O COOH

NH2 O NH2

O

O HO

HO

N

N HN

H2N

O

O

O COOH NH2

O

COOH

Cl O

(Continued) © 2002 by CRC Press LLC

TABLE 4.8 Resolutions Performed Using a Derivative of the Enantiomer of the Racemic Substrate (continued) Enantiomer in Excess in Precipitated Salt

e.e. (%)

Resolving Agent

Y (%)

S [Ref.]

F

F

N

N H

O COOH

NH2

NH

COOH

O COOH Cl

COOH NH2

An important advantage of this approach is that by derivatization, the unwanted enantiomer can be recycled and the price of the resolving agent, often the most expensive item, therefore reduced. H N O O

OH

Derivatization, of course, has its limitations because not every derivative is suitable for resolution. For example, Felder and Pitre transformed 1-phenylethylamine with three dicarboxylic acids (succinic, maleic, and phthalic acids) to hemiamides. All three proved useful for the resolution of various racemates, except for 1-phenylethylamine, which could only be resolved with the hemisuccinate. Resolution of 2-terc-butylglycinol (4.7) was attempted with 14 different optically active acids, among them with its N-acetyl derivative. Results are compiled in Table 4.9 showing data for the 22 best experiments. A half equivalent of the resolving agent was used in all cases. It can be seen that the best resolving agents were the derivatives of the substrate. Of the seven derivatives, only one failed to give a crystalline salt, while ﬁve of the seven non-derivative agents gave noncrystalline salts. Finally, (S)-N-(2-naphthoyl)-2-terc-butylglycin (4.8) proved to be the © 2002 by CRC Press LLC

TABLE 4.9 Preliminary Experiments for the Resolution of 2-tert-Butylglycinol (4.7) Resolving Agent

Solvent

L-Aspartic

acid L-Glutamic acid L-Pyroglutamic acid (R)-Mandelic acid (1R)-Camphor-(10)-sulfonic acid

iPrOH iPrOH iPrOH iPrOH Toluene/ MTBE iPrOH iPrOH EtOH iPrOH iPrOH iPrOH iPrOH iPrOH

N-Formyl-L-2-terc-butylglycine after recrystallization N-Acetyl-L-2-terc-butylglycine N-Acetyl-L-proline N-Acetyl-(2S,4R)-hydroxyproline N-Benzoyl-L-2-terc-butylglycine N-(1-naphthoyl)-L-2-terc-butylglycine N-(2-Naphthoyl)-L-2-terc-butylglycine Second crop After recrystallization

iPrOH iPrOH

N-(2,6-Dichlorobenzoyl)-L-2-tercbutylglycine N-Pivaloyl-L-2-terc-butylglycine a

Yield (%)

R:S Ratio in Precipitated Salt

a

— —

60 67

83:17 52:48

45 33 54

54 33 72

94:6 99:1 37:63 — — 19:81 37:63 94:6

7 70 55

89:11 99:1 70:30

a

—

a a

iPrOH

The salt did not crystallize.

most efﬁcient agent, and it was the salt with the R enantiomer of the racemate that crystallized preferentially. The process was adapted to large scale.

4.3.6 RESOLUTION WITH A MIXTURE RESOLVING AGENTS 23,24

OF

STRUCTURALLY SIMILAR

It was observed by Dutch researchers that if a mixture of structurally related compounds is used as the resolving agent, results are much better than with the individual pure compounds. This study was prompted by the idea that ﬁnding the optimal resolving agent can be accelerated when for preliminary trials a mixture of resolving agents is used. By analysis of the precipitated diastereomeric salts they wanted to ﬁnd the particular component of the mixture that gave the least soluble salt with the racemate. Thus, to racemic 1-(2-chlorophenyl)ethylamine, an aqueous solution of three di-O-acyltartaric acids (dibenzoyl, di-p-toluoyl, and dianisoyl) was added, whereupon immediate precipitation was observed. The precipitate contained the base in high (95%) optical purity. Analysis of the acid component revealed that it was a 20:5:1 mixture of the dibenzoyl, di-p-toluoyl, and dianisoyl tartaric acids and this ratio did not change upon recrystallizations. They found that with each individual racemate the ratio of incorporated acids was different. Results were similar with mixtures of other structurally related resolving agents; but when the agents were of dissimilar structure, co-crystalliztion of resolving agents was not observed. Results of the resolutions are compiled in Tables 4.10 through 4.14.

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TABLE 4.10 Resolutions with M-mix (4.9 M1:M2:M3) Racemate

e.e. (%)

Solvent

Ratio of Resolving Agents in the Precipitated Salt

Br NH2 Cl NH2 OH NH2

TABLE 4.11 Resolution with M1/M2 Mix (4.9 M1:M2) Racemate

e.e. (%)

Solvent

Ratio of Resolving Agents in the Precipitated Salt

Br

NH2

NH2 O

NH2 Cl

NH2

Br

NH2

NH2 OH

O HO

© 2002 by CRC Press LLC

P

O O

X

P1: X = H P2: X = Cl P3: X = OMe

TABLE 4.12 Resolutions with P-mix (4.10 P1:P2:P3)

NH2 Cl

NH2

NH2 NH2 COOH

NH2 CONH2

HO

H N

Ph

N H

OH N

N

NH2

NH2 HO COOH NH2 F CN

NH2 F COOCH3

OH

HN

N H

Ph

N H Cl NH2 CN NH2 OH NH2 O OH Br NH2 OH

Ph NH2

NH2 COOH

© 2002 by CRC Press LLC

TABLE 4.13 Resolutions with T-mix (4.11 T1:T2:T3) Racemate

Solvent

e.e. (%)

Ratio of Resolving Agents in the Precipitated Salt

OH Ph

N H

O

Ph O

N Ph

Ph

N Ph

Ph

Ph

N H O N H

TABLE 4.14 Resolution with PE-II Mix ((4.12 PE1:PE2:PE3) Racemate

Solvent

OH COOH OH F COOH OH Br COOH OH Cl COOH

Br COOH COOH COOH

© 2002 by CRC Press LLC

e.e. (%)

Ratio of Resolving Agents in the Precipitated Salt

TABLE 4.15 Resolution of Mixtures of Different but Closely Related Racemates

Racemate

Resolving Agent(s)

Solvent

e.e. (%)

Ratio of Compounds in the Precipitated Salt

TABLE 4.16 Resolution by Complex Formation with a Mixture of Resolving Agents

Racemate

Resolving Agent X

Solvent

e.e. (%)

Ratio of Resolving Agents in the Precipitated Complex

X HO

OH

O

O X

X X= H, OMe

Resolution with a mixture of structurally related resolving agents can be extended to the resolution of mixtures of racemates composed of close analogs (Table 4.15) and may involve not only diastereomeric salt formation, but also complex formation (Table 4.16). It can be assumed that for each racemate there exists a best-ﬁtting component, that being the optimal resolving agent. This forms the diastereomeric salt of lowest energy, which should be of highest density owing to optimal space-ﬁlling. Due to the limited number of available resolving agents, in practice the chance of ﬁnding the theoretically best agent is poor and, even when found, it may be too expensive. Unfortunately, at the present level of computational possibilities, the 25 optimal resolving agent cannot yet be found by calculations either. In practice, the best-ﬁtting agents can be expected to be found among quasi-racemate forming compounds, that is, among compounds having a structure very similar to that of the racemate. The more stable diastereomeric salt contains quasi-antipodal forms of substrate and resolving agent, approximating in this way the more stable heterochiral crystal structure. Unfortunately, quasiracemate forming resolving agents are rare and, therefore, most often the conventional resolving agents must be applied. Fitting of the partners is usually improved when solvent molecules are incorporated into the lattice. It has been observed that solvated crystals are more stable than unsolvated ones. According to X-ray studies, solvent molecules stabilize the crystal structure by forming additional hydrogen bonds. © 2002 by CRC Press LLC

Analysis of the crystal structure of diastereomeric salts reveals that polar groups participating in the formation of salt bonds form a hydrophilic layer, while the other, less polar sections of the molecule are part of a hydrophobic domain. Solvents of low molecular weight are usually incorporated into the hydrophilic domain where they exert their stabilizing effect. When using a mixture of structurally closely related resolving agents, molecules of the resolving agents co-crystallizing with the enantiomers of the racemate are complementing each other in the crystal lattice and provide the best possible ﬁt not only in the hydrophilic, but also in the hydrophobic domain. Resolving agents of dissimilar structure, however, even if applied in combination, do not co-crystallize in the diastereomeric salt because they are not complementary to each other. Mixtures of structurally closely related resolving agents can be regarded as a supramolecular mixture, and the ratio of their incorporation into the diastereomeric salt is controlled by the nature of the racemate. Unfortunately, it cannot be unambigously deﬁned which resolving agents are complementary to each other. For example, mandelic acid and its 4-methyl and 4-bromo derivatives appear to be structurally closely related; but in fact, 4-bromomandelic acid is not incorporated into the crystal lattice of the other two. The three structurally very similar cyclic phosphoric diesters (P-Mix) in turn co-crystallized in 19 cases out of 20. Often for sufﬁcient ﬁt not all three esters are necessary; in several cases, only two or even one resolving agent is incorporated into the diastereomeric salt. It appears that the fastest procedure to resolve a new racemate is using a mixture of structurally related agents. A disadvantage is, however, that a stock of 15 to 20 resolving agents belonging to ﬁve or six structural types must be available because there is no generally applicable mixture, and there exists no generally useful individual resolving agent either. Another requirement is that one should be in possession of an analytical method suitable for the determination of the individual components in a mixture. Also, one or two components of the recommended mixtures are often not available commercially and must be synthesized. Co-crystallizing resolving agents can only be separated with difﬁculty, or not at all, because being structurally very similar, their physicochemical properties are also rather similar. Fortunately, the mixture recovered from the diastereomeric salt can be recycled and therefore separation of the components is usually avoidable.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

W. Hoeve and H. Wynberg, J. Org. Chem., 50, 4508 (1985). A.D. van der Haest, Ph.D. thesis, University of Groningen (1992). E. Fogassy, F. Faigl, F. Darvas, M. Acs, and L. Toke, Tetrahedron Lett., 21, 2841 (1980). A.D. van der Haest, H. Wynberg, F.J.J. Leusen, and A. Bruggink, Recl. Trav. Chim. Pays-Bas, 109, 523 (1990). A.D. van der Haest, H. Wynberg, F.J.J. Leusen, and A. Bruggink, Recl. Trav. Chim. Pays-Bas, 112, 230 (1993). X. Dai, A. Wong, and S.C. Virgil, J. Org. Chem., 63, 2597 (1998). E. Fogassy and D. Kozma, Tetrahedron Lett., 36, 5096 (1995). Hungarian Patent 193201 (1986). E. Fogassy et al., unpublished results. Hungarian Patent 193199 (1986). Hungarian Patent 195174 (1989). V.A. Arsenijevic, C.R. Acad. Sci., 245, 317 (1957). J. Bálint, M.Sc. thesis, Technical University of Budapest (1991). Hungarian Patent 193199 (1984). Hungarian Patent 195174 (1984). Hungarian Patent 193201 (1984). E. Fogassy et al., unpublished results. Hungarian Patent 202.825 (1991).

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5

Selection of the Resolving Agent

5.1 SELECTION OF THE RESOLVING AGENT BY EXPERIMENTATION 5.1.1 SELECTION OF THE RESOLVING AGENT PREPARATIVE EXPERIMENTS

BY

SMALL-SCALE PRELIMINARY

The suitable resolving agent is still selected almost exclusively by experimentation. The first choice is an optically active compound of a character opposite that of the racemate and available in the laboratory. When the elaboration of an industrial procedure is intended, expensive or not readily available compounds should be a priori avoided. The first experiments should preferably be carried out on a millimole scale. An advantage of natural optically active alkaloids is that due to their relatively high molar mass, they yield, even with a small amount of the racemate, measurable quantities of the products. Preliminary resolution of the racemic acid 5.1 (0.5 mmol) was attempted 1 in ethanol with six natural alkaloids (1.0 mmol each). Experiments were evaluated by determining the optical rotation of the acid liberated from the precipitated salt (see Table 5.1).

Partial resolution was observed with each of the resolving agents. For the preparation of the (−)-acid, quinidine was the best; while for that of the (+)-acid, cinchonine and cinchonidine were best. Finally, resolution was successfully carried out with cinchonine. It is useful to perform preliminary experiments in several solvents. In this way, eventual solvate formation can be exploited, which is known to improve resolvability. At the same time, information can be collected about the solubilities of diastereomeric salts. Methanol, ethanol, acetone, ethyl acetate, water, or mixtures thereof are most often used as solvents. Resolution of acid 5.2 was tried with ten different resolving agents in four different solvents 2 (see Table 5.2). In addition to natural alkaloids, some synthetic bases were also included.

The higher the number of resolving agents and solvents tested in the preliminary experiments, the higher the probability of finding the best agent and conditions. The conclusion drawn from the tests shown in Table 5.2 was that for obtaining (+)-5.2, morphine was optimal; while for its antipode, 1-(2-naphthyl)ethylamine was optimal. In fact, resolution on a preparative scale was successfully

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TABLE 5.1 Preliminary Experiments for the Resolution of Acid 5.1 with Various Alkaloids [ α ] D (EtOH) of Acid Liberated from the Precipitated Salt 20

Resolving Agent

−4.6 −55 −45 −79 +79 +80

Strychnine Brucine Quinine Quinidine Cinchonine Cinchonidine

TABLE 5.2 Preliminary Experiments for the Resolution of Acid 5.2 Using Various Bases and Solvents [ α ]D from MeOH

[ α ]D from EtOH

[ α ]D from Me2CO

[ α ]D from EtOAc

Oil −2 0 Oil −2 Oil +23 Oil −2 −21

Oil +13 0 Oil 0 Oil 0 Oil −3 −8

Oil +4 0 Oil −2 Oil +20 Oil 0 −5

+2 +4 0 Oil 0 Oil +26 Oil 0 −26

20

Resolving Agent Cinchonine Cinchonidine Quinine Quinidine Brucine Strychnine Morphine Ephedrine 1-Phenylethylamine 1-(2-Naphthyl)ethylamine

20

20

20

accomplished with above-mentioned bases. It is almost certain that with a narrower selection of bases, the best resolving agents could not have been found because morphine, as an opiate, is not a preferred compound; and among synthetic bases, 1-phenylethylamine would probably have been the first choice. The number of preliminary experiments is, however, often restricted by the limited availability of the racemate. The quantity required for testing can be drastically reduced when, for the determination of enantiomeric purity, chiral chromatography or NMR is used instead of optical rotation; and, instead of the liberated enantiomer, a sample of the precipitated salt is examined. In this way it is possible to work on a smaller scale, the salt is not lost, and it can be reused for recrystallization trials. 3 The above approach was used in preliminary experiments for the resolution of base 5.3. In the first series of experiments, five commercial acids were tried in methanol.

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TABLE 5.3 Preliminary Experiments for the Resolution of 5.3 Resolving Agent

Solvent

Solvent of Recrystallization

Yield (%)

o.p. (%)

Tartaric acid (S)-Malic acid (1R,3R )-Camphoric acid O, O ′-Dibenzoyltartaric acid (S)-Mandelic acid

MeOH MeOH MeOH MeOH MeOH AcOEt iPrOH iPrOH iPrOH

MeOH × 2 iPrOH × 1 — — MeOH × 1 — — MeOH × 2 EtOH × 3

17 75 20 31 43 100 62 29 56

0 5.2 8.2 51.6 76.8 0 97.4 100 100

TABLE 5.4 Preliminary Experiments for the Resolution of Various N-acyl Derivatives of 5.4

Me2CO

EtOH

Me2CO

EtOH

(1R,2S )Ephedrine EtOH

− ± − −

− − ± +

− − + −

Oil + Oil −

− − − −

Quinine Acyl Group Benzyloxycarbonyl Benzoyl Phthaloyl Tosyl

Brucine

Note: (−) and (+) sign of the optical rotation of N-acyl derivatives liberated from the precipitated salt; ( (±) racemic).

With four of the acids, partial resolution was observed, the most efficient being mandelic acid. Subsequently, the mandelic acid salt was recrystallized from various solvents. Note that from ethyl acetate it was the racemic salt that crystallized; that is, if the first series of testing was carried out in this solvent, mandelic acid could not have been found as the optimal resolving agent. Finally, base 5.3 was resolved with mandelic acid in isopropanol. Preliminary experiments with 5.3 are summarized in Table 5.3. With compounds of amphoteric character, a third variable—namely, the method of derivatization— should also be considered. This considerably increases the number of necessary experiments. With amino acid 5.4, all three parameters were concurrently involved (see Table 5.4). The results confirmed that this was not unnecessary because crystalline salts were obtained with two resolving 4 agents in two different solvents and with three derivatives. The best choice was resolution of the phthaloyl derivative with brucine in acetone.

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TABLE 5.5 Preliminary Experiments for the Resolution of 5.5 Resolving Agent

Solvent

Acid:Base 1:1 20 [ α ]D

Acid:Base 1:2 20 [ α ]D

(1R,2S )-Ephedrine Strychnine Brucine Quinine

Me2CO MeOH MeOH MeOH

−15.1 +26.5 +3.2 +27.1

−9.7 +14.8 +2.9 +1.6

With racemic diacids, resolution can proceed either via the neutral or acid salt; therefore, preliminary tests should be carried out using both stoichiometries. In experiments with acid 5.5, 5 the molar ratio of racemate and resolving agent was also varied (see Table 5.5). Preliminary experiments revealed that both enantiomers can be best obtained via their acid salts.

5.1.2 SELECTION OF THE RESOLVING AGENT OF SEVERAL RESOLVING AGENTS

BY

COMBINED APPLICATION

6

Dutch scientists have patented an interesting and efficient method that accelerates the selection of the best resolving agent. In the course of preliminary experiments, a mixture of three to six compounds was added to the racemate instead of the usual single agent. With any luck, one of the resolving agents forms a sparingly soluble salt with one of the enantiomers of the racemate. This is separated and analyzed to identify the resolving agent. The procedure is exemplified in the following experiments. To a solution of racemic 1-phenylethylamine (10 mmol) in toluene-isopropanol containing a trace of water, a mixture of six N-acetylamino acids (1.6 mmol each) was added. HPLC analysis of the precipitate revealed that the salt was exclusively formed with N-acetyl-L-4-hydroxyphenylglycine and contained the base in 62% e.e. Next, the experiment was repeated with an equivalent amount of N-acetyl-L-4-hydroxyphenylglycine, resulting in a diastereomeric salt containing 1-phenylethylamine of 94% e.e. The advantage of quickly finding the appropriate resolving agent is partially offset by the fact that, to obtain an analyzable amount of precipitate, more of the racemate is required than in tests with a single agent. Also, a reliable analytical method capable of quantitating the components of the mixture is indispensable. Unlike the example cited above, the precipitate is usually composed of the diastereomeric salts of more than one resolving agent (see Section 4.3.6). This often provides much more efficient separation than the use of a single resolving agent. Simultaneous application of several resolving agents can be justified even when a single agent gives satisfactory separation. The chance that the resolving agents co-crystallize can be diminished when the mixture is composed of compounds that are structurally as different as possible.

5.1.3 SELECTION

OF THE

RESOLVING AGENT

BY

DISTILLATION TESTS

Among alternative methods of resolution, the distillation technique described in detail in Section 7.2 may also be suitable to find a suitable resolving agent. The racemate is layered over a half equivalent of the resolving agent and, after a certain period of time, the unreacted racemate is distilled off. The resolving agent producing a distillate of highest optical purity is chosen for further experiments. If no stable salt is formed, the total of racemate distills off unchanged and can be used for the subsequent experiment. When resolution can be achieved by the distillation method, resolution by fractional crystallization from an appropriate solvent will probably also be successful. © 2002 by CRC Press LLC

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Because the residue obtained after resolution with distillation contains an excess of the more stable diastereomeric salt (i.e., the one that would precipitate during fractional crystallization), this product can be used as seed in fractional crystallization. An important limitation of the method is that it works only with volatile racemates, primarily with amines.

5.1.4 SELECTION OF THE RESOLVING AGENT BASED OF MAXIMUM SIMILARITY

ON THE

PRINCIPLE

Accepting the hypothesis that structurally analogous racemates can be resolved with the same resolving agent in the same solvent, the number of preliminary experiments can often be reduced. It is therefore useful to review—before experimenting—known procedures for the resolution of analogs, and first conditions used for the resolution of the closest racemate under optimum conditions should be tried. If a crystalline salt is obtained but is of poor enantiomeric purity, the resolving agent should be retained and experiments continued in another solvent. When no crystalline salt can be produced, resolution of the next analog in the similarity series should be taken as an example, etc. In this respect, it is important to define what can be regarded as a similar structure.

7

When resolution of 5.6 was undertaken, resolution of 5.7 was already known. The authors just 8 copied the conditions and resolved 5.6 successfully.

Acids 5.8 through 5.11 differ only in the position and nature of the halogen atom and could 9 all be resolved under identical conditions with quinine in ethanol. Acids 5.12 and 5.13 are constitutional isomers; nevertheless, both could be resolved with 10 amphetamine in aqueous ethanol.

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Of base 5.14 only 0.5 g was available; but of a rather similar compound, 5.15, there was much more at hand. The two compounds are very similar around the center of chirality and, from the point of view of resolution, this is the most important feature. First trials were carried out for the resolution of 5.15 with tartaric acid, dibenzoyl- and di-4-toluyltartaric acid, mandelic acid, malic acid, and camphor-10-sulfonic acid in water, methanol, ethanol, and ethylacetate. Di-p-toluyltartaric acid in methanol proved to be the best. When the method was adapted to 5.14, resolution was successful on the first attempt and with about the same efficiency. F N N OH

Cl

N OH

Compounds 5.16 differ only in one of the ortho-substituents and, in fact, all four could be resolved 11 with cinchonidine in ethyl acetate-methanol (9:1). Structurally similar compounds can often be resolved with the same agent, but the solubilities of the diastereomeric salts are not necessarily similar and a change of solvent may be required.

Thus, both 5.17 and 5.18 can be resolved with cinchonidine; while for the trans-acid (5.18), the best solvent is ethylacetate and for the cis-isomer (5.17), a 1:1 mixture of ethylacetate and 12 chloroform proved optimal.

Note, however, that not all cis-trans pairs can be resolved under similar conditions. Thus, the cis-amine 5.19 can be resolved with mandelic acid in methanol and the salt can be purified by

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TABLE 5.6 Resolution of Hydroxy and Dihydroxy Carboxylic 14,15 Acids of Related Structure in Ethanol Racemate

Resolving Agent

OH

COOH

F

OH

COOH F

OH

COOH

F OH

OH Cl

COOH

OH OH COOH Cl

OH OH COOH

Cl OH

OH COOH

Cl OH

OH COOH Cl OH OH Cl

COOH

recrystallization from benzene-isopropanol, whereas the trans-amine 5.20 requires tartaric acid in 13 methanol. For the purification of both salts, pure methanol is suitable. Table 5.6 shows the resolution of some structurally similar hydroxy and dihydroxy carboxylic acids. It is apparent that, despite the variety of racemates and resolving agents, ethanol is the solvent of choice throughout. The nine racemates can be divided into three groups (monohydroxy acids, syn- and anti-dihydroxy acids). Within the same group, ortho- and meta-halogenated compounds could be resolved with the same agent, while the para-substituted derivatives required another one. No common resolving agent was found for compounds in different groups. In Table 5.7, resolutions of 16 structurally similar 2-aryloxypropionic acids with different substitutions at the aromatic ring are compiled. While as solvent ethanol or aqueous ethanol was useful with all of them, resolutions required seven different agents. Comparing the monomethyl and monomethoxy compounds, it appears that the behavior in resolution of compounds substituted at the same position is more similar than of those having the same substituent but at a different position.

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TABLE 5.7 Resolution of Some 2-Aryloxypropionic Acids O

O

O COOH

COOH

COOH

O

O

COOH

O

O

COOH

O

COOH

O

O

O

COOH

COOH

O

O

COOH

COOH

O

O COOH

COOH

Cl

O COOH

O

Cl

O COOH

O

COOH

COOH

Cl

Cl

O H

O O

O COOH

The S enantiomer of acid 5.21 was tried for the resolution of 18 bases in methanol-isopropanol 29,30 Results are shown in Table 5.8 in the order of efficiency. mixtures. Note that in the successfully resolved compounds, a hydrogen atom, amino, alkyl, or aryl group is attached to the chiral center. Exceptions are compounds 16 and 17. Interestingly, the products have the same configuration (S) as the resolving agent. Despite the fact that the acids collected in Table 5.9 only differ in the position of the carboxyl group, they require different resolving agents. The reason for this may be that the carboxyl group 31 is directly attached to the center of chirality. © 2002 by CRC Press LLC

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TABLE 5.8 Resolution of Bases with Acid 5.21

TABLE 5.9 Effect of the Position of the Carboxyl Group on the Resolution of Isomeric Acids Racemate

© 2002 by CRC Press LLC

Resolving Agent

Solvent

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Sometimes, very close analogs cannot be resolved under similar conditions. For example, base 32 5.23 can be resolved while 5.22 cannot.

Verapamil (5.24) is a cardiac drug marketed in the racemic form. Its resolution by diastereomeric salt formation has not been reported, despite the fact that its close analog, Galopamil (5.24), differing only by an additional methoxy group, can be well resolved with dibenzoyltartaric acid in isopro33 panol. Several attempts by the authors of this book to resolve Verapamil in analogy to Galopamil also failed completely. As demonstrated by the above examples, the principle of similarity can be successfully applied to select both a suitable resolving agent and the proper solvent. Because it offers a logical, resultoriented order of the experiments to be carried out, elaboration of the best method can be promoted. Unfortunately, the concept of similarity of racemates is ill-defined and our present knowledge does not permit its quantification, leaving ample room for experience and intuition. Another problem is that an analogous, already resolved racemate is not always available or the reported resolving agent may not be at hand. A further factor of uncertainty is that literature data may not represent an optimum and there exists a more efficient procedure for that particular compound. Therefore, in case of failure, further optimization is recommended, eventually with another resolving agent.

5.1.5 SELECTION

OF THE

RESOLVING AGENT

BY

STATISTICAL EVALUATION

Despite the availability of several methods to assist in the selection of the resolving agent (see above), this is most often still a matter of trial and error. The usual routine is to try, one after the other, resolving agents available in the laboratory. When a considerable number of such agents are at one’s disposal, the question arises as to the sequence in which one should try them to find the best agent with minimal effort. Appendix 1, showing the frequency of successful resolutions with a given agent, enables one to set up such a list of priority. The listing in Appendix 1 is a statistical compilation of data available in the literature, but there is no guarantee that each method has been optimized. Nevertheless, the frequency at which a particular resolving agent has been used is a useful indicator of its availability and ease of handling (see Tables 5.10 and 5.11). © 2002 by CRC Press LLC

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TABLE 5.10 Relative Frequencies (%) of the Use of a Selection of Acidic Resolving Agents Resolving Agent Tartaric acid O,O′-Dibenzoyltartaric acid Camphor-10-sulfonic acid O,O′-Di-4-toluyltartaric acid; (S)- or (R)-Mandelic acid (1R)- or (1S)-3-Bromocamphor-8-sulfonic acid N-Acetylleucine (S)- or (R)-Malic acid (R)-(+)-6,6′-Dinitrobiphenyl-2,2′-dicarboxylic acid Camphoric acid

% 34.2 16.6 9.8 8.4 6.3 3.5 1.7 1.4 1.0 1.0

Note: Relative frequencies ≥1% were included based on Appendix 1.

TABLE 5.11 Relative Frequencies (%) of the Use of a Selection of Basic Resolving Agents Resolving Agent Brucine Quinine (S)- or (R)-1-Phenylethylamine Cinchonidine Strychnine Ephedrine Cinchonine (1S, 2S)- or (1R, 2R)-4-Nitrophenyl-2-aminopropane-1,3-diol Morphine Amphetamine Fenchylamine L-Leucinamide 1-(1-Naphthyl)-ethylamine (S)- or (R)-O-Benzyl-2-aminobutan-1-ol Tyrosine hydrazide

% 21.3 15.6 12.3 10.3 6.4 5.8 4.2 2.6 1.7 1.4 0.6 0.6 0.6 0.6 0.5

Note: Relative frequencies ≥0.5% were included based on Appendix 1.

5.2 SELECTION OF A RESOLVING AGENT BASED ON THE DETERMINATION OF PHYSICOCHEMICAL PARAMETERS 5.2.1 SOLUBILITY 5.2.1.1 Calculation of Resolvability from Solubility Data Resolvability can be expressed as a function of the solubility of the pure diastereomeric salts and from such data for a series of salts, the most efficient resolving agents can be selected. © 2002 by CRC Press LLC

0019_frame_C05.fm Page 100 Monday, August 6, 2001 1:23 PM

Calculation is based on the following considerations: ptotal = psolid + psolution

(5.1)

ntotal = nsolid + nsolution

(5.2)

k

p psolid ←→ psolution

k

n nsolution nsolid ←→

p solution yp = [psolution] = -------------V

(5.3)

n solution yn = [nsolution] = -------------V

(5.4)

where p and n are the quantities of the two pure diastereomeric salts. The initial concentration of the diastereomeric salts before fractional crystallization can be written as: p total + n total c0 = ------------------------V

or

Vc0 = ptotal + ntotal

(5.5)

Enantiomeric purity (e.e.) and yield ( y) can be expressed as: n solid + p solid y = --------------------------0.5c 0 V

(5.6)

n solid – p solid e.e. = --------------------------n solid + p solid

(5.7)

In the resolution of a racemic mixture with one equivalent of the resolving agent, the following equations hold: psolid + psolution = nsolid + nsolution

(5.8)

nsolid − psolid = nsolution − psolution

(5.9)

or

Based on Eqs. (5.1) through (5.9), resolvability S can be written as: y p – yn S = --------------0.5c 0

(5.10)

and the correlation between resolvability and initial concentration is depicted in Fig. 5.1. Table 5.12 compiles the calculated and experimental values for the resolvability of ephedrine 34 with various cyclic phosphoric diesters (see Section 4.3.1.1). The table demonstrates good correlation between calculated and experimental values. In both cases, the dichloro derivative proved to be the best resolving agent. Note, however, that calculated values are higher than experimental ones, indicating that, in practice, either optimum conditions could not be realized or certain factors were not accounted for in the calculations. Deviation between the two sets of data is, however, not excessive, indicating that the above calculations are suitable © 2002 by CRC Press LLC

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TABLE 5.12 Calculation of Resolvability of Racemic Ephedrine with Various Cyclic Phosphoric Esters in Isopropanol Cylic Phosphoric Ester Phenycyphos 2-Fluocyphos 2-Chlocyphos 2-Brocyphos 2,6-Dichlocyphos

Resolvability (calc.)

Resolvability (found)

−0.05 0.55 0.75 0.42 0.81

0.0 0.36 0.53 0.33 0.70

Note: For abbreviations, see Chapter 4, Section 4.3.1.1.

FIGURE 5.1 Correlation of resolvability and concentration of the initial mixture.

to predict the behavior of quasi-ideal mixtures. By preparing the pure diastereomeric salts with several resolving agents, the most efficient one can be selected. 5.2.1.2 Selection of the Resolving Agent by Determination of the Solubility Triangular Diagram: Correlation Between Eutectic Point and Resolvability A more detailed picture than the one obtained by comparison of the solubilities of salt pairs can be gleaned about the resolution process if solubilities for diastereomeric mixtures of different compositions are also determined and plotted on a triangular diagram. This may reveal eventual deviations from ideal behavior. A triangular diagram, plotting the solubilities for a conglomerate forming a pair of diastereomeric salts in an appropriate solvent at different temperatures, permits the determination of all the parameters of resolution (i.e., both the optimal initial concentration and also the attainable resolvability). If one only wants to predict resolvability, then it can be calculated as follows. In a thermodynamic equilibrium, the higher melting salt precipitates from a solution having a composition pertinent to the given isotherm, in 100% optical purity, while a salt mixture of eutectic composition stays in solution. If the initial mixture contains an equal amount of both salts (Z), the quantity remaining in solution of the higher melting salt is Y: Zx Y = ----------1–x © 2002 by CRC Press LLC

(5.11)

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FIGURE 5.2 Graphical representation of the correlation between resolvability and the position of the eutectic point.

where x is the molar fraction of the higher melting salt at the eutectic point. The amount of precipitate is: Zx Z ( 1 – 2x ) Z – Y = Z – ----------- = -----------------------1–x 1–x

(5.12)

The yield (y) is the quotient of the quantity of precipitate [Z − Y] and the initial quantity in the solution [Z ]: Z (1 – 2 x)

-----------------------1 – 2x 1–x y = ------------------- = --------------Z 1–x

(5.13)

Because the precipitate is optically pure, resolvability (S) and yield are equal: S=y1

(5.14) 35

Therefore, resolvability calculated from the phase diagram is: 1 – 2x S = --------------1–x

(5.15)

The correlation between resolvability and the position of the eutectic point is graphically depicted in Fig. 5.2. With the aid of Eq. (5.15), resolvability can be calculated; and when one determines the triangular diagram of solubility for the salts of a given racemate with different resolving agents, the most efficient resolving agent can be readily selected. An important limitation of the method is its high demand on time and labor.

5.2.2 SELECTION OF A RESOLVING AGENT BASED ON MELTING POINT PHASE DIAGRAMS OF DIASTEREOMERIC SALT PAIRS 5.2.2.1 Calculation of Resolvability from Binary Melting Point Phase Diagrams Determined Using the Pure Diastereomeric Salts 36

Jacques and co-workers observed that the eutectic point of solubility curves determined at different temperatures fall nearly on a straight line. The DR:LR ratio (see Fig. 6.1) corresponding to this straight line is approximately equal to the eutectic composition of the binary melting point phase diagram © 2002 by CRC Press LLC

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of the salt pair. Their finding was confirmed by the phase diagram of the diastereomeric salts 37 formed from 1-phenylethylamine and 2-phenylpropionic acid, and Ács’ group added to this 38,39 two further examples. This observation can simplify the selection of the best resolving agent because the construction of a binary phase diagram is much less demanding than that of a triangular diagram and can, in general, be plotted by determining thermal data for the diastereomeric salts or can be calculated therefrom. Melting point phase diagrams can be constructed either by determining the melting points of mixtures of different composition prepared from the diastereomeric salts or by calculation from the melting points and heats of fusion of the pure salts. In the case of conglomerates, the diagram 40,41 can be calculated using the simplified form of the Schröder-Van Laar equation: f

∆H 1 1 ln x = ----------a-  ------f – ------f  R Ta T  where x f Ta f ∆H a f T R

= = = = =

(5.16)

Molar fraction of the component in excess Melting point of the pure salt (K) Heat of fusion of the pure salt (KJ/mol) Final temperature of melting of a mixture of molar fraction x (K) Universal gas constant

The point of intersection of the melting point curve of the two pure diasteromeric salts defines the eutectic point. Melting point and heat of fusion data can be conveniently obtained by differential 42,43 scanning calorimetry (DSC). Fouquey et al. were the first to study the melting point phase diagrams of diastereomeric salts. They assumed that most diastereomeric salts are sufficiently stable not to decompose below their melting point and therefore construction of the phase diagram is feasible. Nevertheless, there have been very few phase diagrams for diastereomeric salts reported 44 in the literature. According to Eq. (5.15), resolvability only depends on the position of the eutonic point. Assuming that the eutonic point of solubility phase diagrams coincides with the eutectic point of the melting point phase diagram of the corresponding diastereomeric salt pair, with the aid of Eq. (5.15) the attainable resolvability can be calculated from the melting point phase diagram alone. Table 5.13 compares experimental resolvabilities and those calculated from the position of the eutectic point in order to check the postulated coincidence of eutonic and eutectic points and for the verification of the usefulness of Eq. (5.15). It can be seen that there is a satisfactory agreement between experimental and calculated values. Note that both experimentally observed resolvability and the construction of binary phase diagrams involve a margin of error. Resolvability can thus be calculated from thermal data of the pure diastereomeric salts determined by DSC. By performing this with several resolving agents, there is a fair chance to find the best one. 5.2.2.2 Calculation of Resolvability by DSC of a Mixture of Diastereomeric 45 Salts Formed from the Racemate When tackling a resolution problem, the pure enantiomers are usually not at one’s disposal and therefore the pure diastereomeric salts for thermal analysis cannot be prepared. The racemate, however, is available and, if transformed to a pair of diastereomeric salts, we arrive at a 1:1 mixture of the latter (p + n salt). The DSC curve of this mixture exhibits two peaks (see, for example, Fig. 5.3). © 2002 by CRC Press LLC

0019_frame_C05.fm Page 104 Monday, August 6, 2001 1:23 PM

TABLE 5.13 Comparison of Calculated and Observed Resolvability Racemate

Resolving Agent

Sexp

Calc. xeu

From Kozma, D., Ph.D. thesis, Technical University of Budapest, Hungary, 1993.

FIGURE 5.3 Representative DSC curve of a p + n salt. © 2002 by CRC Press LLC

Scalc.

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The first peak corresponds to the final temperature of the melting of the eutectic (T1), whereas the second one is the same for the 1:1 mixture (T2). The area under the first peak is proportional to the heat of fusion of the eutectic (∆H1); the area under the second peak is proportional to the heat of fusion of the higher melting salt (i.e., the minor component of the eutectic [∆H2]). To be able to calculate the heats of fusion of the pure components, one must know the mass ratio of the two phases. The latter quantity, depending on the composition of the eutectic, as well as the melting point of the higher melting salt are unknown. Supposing, however, that the Schröder-Van Laar equation is valid for both a 1:1 ratio and for the eutectic composition, two equations can be written. In this way, the number of equations and unknowns becomes equal and the problem can be solved. The heat of fusion of the higher melting salt is: 2 – 2x ∆H m = --------------- ∆H 2 1 – 2x

(5.17)

where x is the molar fraction of the higher melting salt in the eutectic. For a 1:1 composition, the Schröder-Van Laar equation is as follows: 2 – 2x

--------------- ∆H 2 1 1 1 – 2x ln 0.5 = -----------------------  ------ – -----  T m T 2 R

(5.18)

1/Tm can be obtained from Eq. (5.18) as: R ln 0.5 1 1 ------ = ----------------------- + ----2 – 2x Tm --------------- ∆H 2 T 2 1 – 2x

(5.19)

The Schröder-Van Laar equation in the eutectic point is: 2 – 2x --------------- ∆H 2 1 – 2x 

1 1 ln x = ----------------------- ------ – -----  T m T 1 R

(5.20)

Substitution of Eq. (5.19) into Eq. (5.20) gives: 2 – 2x --------------1 – 2x

R ------------ = ----------------------------- = B  1 1 ln 2x  ----- – ----- ∆H 2 T 2

(5.21)

T 1

Equation (5.21) can be solved by numerical methods. Table 5.14 provides parameter B as a function of x, the molar fraction of the eutectic. B can be calculated from experimental data. By substituting x into the Schröder-Van Laar equation, the heat of fusion and melting point of the higher melting salt can be calculated. The heat of fusion of the lower melting component (Ha) can be calculated by assuming that the heat of fusion of the eutectic is a weighted sum of the values for the pure components: ∆H eut = ( 1 – x )∆H a + ∆H m x

(5.22)

∆Heut can also be expressed in terms of the material balance: ∆H eut = 2 ( 1 – x )∆H 1

(5.23)

The heat of fusion of the lower melting component can be determined from Eqs. (5.22) and (5.23) as: x ∆H a = 2∆H 1 – -----------∆H m 1–x © 2002 by CRC Press LLC

(5.24)

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TABLE 5.14 Dependence of Parameter B on Molar Fraction (x) x 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10 0.11 0.12 0.13 0.14 0.15 0.16 0.17 0.18 0.19 0.20 0.21 0.22 0.23 0.24 0.25

−B

x

0.516 0.634 0.734 0.826 0.917 1.008 1.100 1.195 1.294 1.398 1.507 1.623 1.746 1.877 2.017 2.168 2.331 2.508 2.700 2.910 3.140 3.393 3.673 3.983 4.328

0.26 0.27 0.28 0.29 0.30 0.31 0.32 0.33 0.34 0.35 0.36 0.37 0.38 0.39 0.40 0.41 0.42 0.43 0.44 0.45 0.46 0.47 0.48 0.49

−B 4.715 5.151 5.644 6.207 6.852 7.597 8.465 9.485 10.70 12.15 13.92 16.09 18.83 22.32 26.88 33.03 41.58 53.99 73.00 104.4 161.9 285.5 636.9 2524

Note: To be used in Eq. (5.21).

The above method allows one to construct the approximate shape of the melting point phase diagram of conglomerate forming pairs of diastereomeric salts, but it cannot determine which salt is associated with which leg of the diagram. For the calculation of resolvability, even this approximate form of the phase diagram is useful. Examples of the application of this method based on DSC measurements of p + n salts are summarized in Table 5.15. It is seen that values obtained for the pure salts are mostly in good agreement with values calculated from DSC data for the p + n salt. In a similar way, the eutectic composition can be calculated from DSC data for diastereomeric 46 salt mixtures of compositions other than 1:1. 5.2.2.3 Use of Thermoanalytical Data for the Design of Resolution Processes: A Fast Method for the Selection of the Resolving Agent First, a series of 1:1 diastereomeric mixtures are prepared from the racemate and the available resolving agents (10-mg samples are sufficient) and their DSC curves recorded. A single peak on the DSC diagram indicates that a solid solution or a 1:1 molecular complex was formed, in which case efficient resolution is hopeless. A salt giving two peaks is most probably a conglomerate, or eventually a molecular complex of a composition other than 1:1. Resolution in this case should be feasible. If several resolving agents produce a DSC diagram with two peaks, the individual eutectic points should be determined by means of calculations described in Section 5.2.2.2. Unless economic or other © 2002 by CRC Press LLC

Racemate

Resolving Agent

∆H2

Ta T1

T2

∆H1

∆H2

y

Note: y: values for the pure salts; S: values for the p+n salts; temperature in K; ∆H1, etc. in kJ/mol.

S

T

∆Hm

Tm S

y

S

y

x S

y

S

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© 2002 by CRC Press LLC

TABLE 5.15 Calculation of Data for Melting Point Phase Diagrams Based on DSC of 50% Salt Mixtures

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TABLE 5.16 Limitations of Constructing Melting Point Phase Diagrams of Diastereomeric Salts Limitation

Elimination

Pure enantiomers are not available Salt decomposes prior to melting Amorphous or polymorphic salt Crystallizes with the solvent

Comment

Measuring the p+n salt Decomposition may be avoided when using a closed vessel DSC carried out by programmed heating in an open vessel to remove solvent

Less accurate

Phase diagram cannot be calculated Structure of solvent-free salt is less or more remote than its structure of the solvate

considerations do not preclude, that particular resolving agent should be opted for, the eutectic point of which is most remote from the 1:1 composition because it may be the most efficient. Preparative-scale experiments should be carried out thereafter until resolvability calculated from the position of the eutectic point has not been reached. When there is more than one hopeful candidate and the pure enantiomers are already available, preparation of the pure diastereomeric salts is recommended so that identification of the higher and lower melting salts is possible. Because with all diastereomeric salts it is the higher melting one that precipitates preferentially, that particular resolving agent should be selected which gives the highest melting salt with the enantiomer needed. There are, however, several limitations to the determination of melting point phase diagrams and these are summarized in Table 5.16.

5.2.3 DETERMINATION

OF THE

OPTICAL ROTATION

OF

DIASTEREOMERIC SALTS

Optical rotation is a characteristic of chiral compounds that can be determined very simply and therefore it lends itself as an easy way to predict the efficiency of a given resolution process. 47 According to Walden, optical rotation of a diastereomeric salt is the sum of the molar rotations [M] of its component ions: [M]p = [M]a + [M]c

and

[M]n = [M]a − [M]c

(5.25)

where the subscripts a, c, p, and n identify the anion, cation, p-salt, and n-salt, respectively. It follows that the molar rotation of ions is: [ M ] p – [ M ]n [ M ] a = -----------------------------2

and

[ M ] p + [ M ]n [ M ] c = -----------------------------2

(5.26)

With accurate measurements it can be demonstrated that most often there is some deviation from additivity. Table 5.17 tabulates the calculated and experimental optical rotations for some diastereomeric salt pairs. It can be seen that the two values differ, more or less, in every case. It is interesting to note that the deviation is always higher for the less soluble salt precipitating from solution. Deviations between calculated and experimental values can be ascribed to incomplete dissociation. Based on the above experience, it can be anticipated that the salt showing less deviation between calculated and experimental rotation will preferentially remain in solution, while the ion-pair with stronger cohesion will precipitate.

5.3 SELECTION OF THE RESOLVING AGENT BASED 54 ON THEORETICAL CONSIDERATIONS The interaction between the individual enantiomers of the racemate and the resolving agent can be explored by single-crystal X-ray crystallography of the pure salts. This is often prevented by lack of good-quality single crystals and the prediction of a crystal structure by computation is still not possible. © 2002 by CRC Press LLC

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TABLE 5.17 Prediction of Resolvability Based on the Optical Rotation of Diastereomeric Salts Base

a

Acid

Precipitated Salt

p-salt Found

Calc.

n-salt ∆%

a

Found

Calc.

∆%a

Ref.

∆% = (Calculated − Experimental)/Experimental × 100.

FIGURE 5.4 Primary and secondary interactions in diastereomeric salts.

The method described in the following is, to the authors’ knowledge, the only one capable of modeling resolution by diastereomeric salt formation. This model, based on the principle of three-point interaction, neglects the solid-phase environment of the given salt pair and considers the interactions of resolving agent and the pair of enantiomers. Interaction of two mirror-image molecules and the resolving agent are depicted in Fig. 5.4. It is assumed that the strongest first-order interaction between the partners in diastereomeric salts formed from amines and acids is that between the ammonium and carboxylate groups (D ↔ F), while the most probable conformation is the one in which the mutual orientation of groups A, B, and E—as well as of J, H, and G—is optimal for steric interactions and electronic effects. One can also postulate that secondary interactions exist between the other ligands, among which interaction A ↔ J is the strongest. This is present in both salts and therefore there is still no difference between the two salts. Due to the diastereomeric relationship of the salts, however, interactions of the remaining pairs must be different for the two diastereomers. The difference between the two diastereomers is controlled by these interactions, their presence, absence, and intensity. As secondary interactions, hydrogen bonds and interactions associated with charge migrations are most frequent and can be either attractive or repulsive. The simplest way to qualitatively evaluate possible interactions is by constructing Dreiding models. After recognizing possible secondary interactions, they can be ordered according to Taft’s electronic © 2002 by CRC Press LLC

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TABLE 5.18 Characterization of Resolution Based on Three-Point Interaction

Racemate

Resolving Agent

Enantiomer in Excess in Precipitated Salt

S

1 + l g S *

Differentiating Interaction

CN H2N

CH2-3,4-(MeO)2-C6H3 HO NH

HO 3,4,5-Me3-C6H2

OH

COOH HO

R,R p-O2N-C6H4

Ph

OH NH2

OH COOH

OH p-O2N-C6H4

OH NH2

COOH H2N

Ph CH2Ph

H 2N CH2OH Ph

N H

parameter s *. The sum of s * values of interacting groups should be calculated for both diastereomeric salts, and the difference of the sums characterizes the difference of the diastereomeric salt:

* * * |S ( s * E + s R ) – S ( s E + s R )| > 0

(5.27)

where E and E symbolize the enantiomers and R symbolizes the resolving agent. In practice, even this addition can be omitted because calculation can be restricted to the third interaction, which is the main origin of the difference and the pertinent Ds * is sufficient for the numerical characterization of the process. Application of the this modeling to some resolutions is exemplified in Table 5.18. A comparison of carefully constructed Dreiding models observing the principle of three-point interaction permits (with some practice) to find out with a high probability which of two diastereomeric salts is the more stable and consequently which would precipitate preferably during resolution. Using a broader database than the one in Table 5.18, it was established that there was a numerical correlation between experimentally found resolvability and DSs *. S = f (DSs *)

(5.28)

This correlation can be approximated by a linear equation: 1 + logS = a DSs * + b

(5.29)

Depending on the database used, this approximation shows a range of deviations. Available data support a correlation between Taft’s polar parameter (s *) and the experimentally realizable resolvability, but also indicate that, apart from the factors taken into account in the above model, other factors do exist that influence resolvability. For example, see Table 5.19. © 2002 by CRC Press LLC

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TABLE 5.19 Values for Parameters F, R, and * for Some Common Functional Groups Functional Group Br Cl F I NO2 OH NH2 NHOH SO2NH2 CF3 CN CHO COOH CH2Br CH2Cl CH2I CONH2 CH3 OCH3 NHCH3 CH2CN COCH3 OCOCH3 CO2CH3 NHCOCH3 CH2CH3 CH2OCH3 OCH2CH3 NHC2H5 N(CH3)2 CH(CH3)2 C3H7 C4H9 C6H5 OC6H5 Cyclohexyl COC6H5 CO2C6H5 OCOC6H5 CH2C6H5 CH2OC6H5

F

R

0.44 0.41 0.43 0.40 0.67 0.29 0.02 0.06 0.41 0.38 0.51 0.31 0.33 0.10 0.10 0.09 0.24 −0.04 0.26 −0.11 0.21 0.32 0.41 0.33 0.28 −0.05 0.01 0.22 −0.11 0.10 −0.05 −0.06 −0.07 0.08 0.34 −0.13 0.30 0.33 0.23 −0.08 0.02

−0.17 −0.15 −0.34 −0.19 0.16 −0.64 −0.68 −0.40 0.19 0.19 0.19 0.13 0.15 0.05 0.03 0.03 0.14 −0.13 −0.51 −0.74 −0.18 0.20 −0.07 0.15 −0.26 −0.10 0.02 −0.44 −0.51 −0.92 −0.10 −0.08 −0.13 −0.08 −0.35 −0.10 0.16 0.13 −0.08 −0.01 0.02

* 0.5834 0.5448 0.5458 0.5254 0.9470 0.3106 −0.676 0.0268 0.5924 0.5510 0.7304 0.4460 0.4764 0.1450 0.1422 0.1284 0.3508 −0.0734 0.2874 −0.2554 0.2646 0.4696 0.5560 0.4764 0.3500 −0.0830 0.0166 0.2420 −0.2232 0.0092 −0.0830 −0.0940 −0.1148 −0.0992 0.4202 −0.1934 0.4364 0.4736 0.3062 −0.1118 0.0304

Note: Taft’s parameter (σ *) can be calculated from the parameters for inductive (F) 55,56 and mesomeric effects (R): σ * = 1.38F + 0.14R.

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REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49.

R. Hakansson and A. Svensson, Chem. Scripta, 7, 186 (1975). J. Sjöberg, Arkiv Kemi, 12, 565 (1958). S. Higashijima, H. Itoh, Y. Senda, and S. Nakano, Tetrahedron: Asymmetry, 8, 3107 (1997). Y. Seto, K. Torii, K. Bori, K. Inabata, S. Kuwata, and H. Watanabe, Bull. Chem. Jpn., 47, 151 (1974). A. Fredga and A. Sikström, Arkiv Kemi, 8, 433 (1955). European Patent Application 0 838.448 (1998). M. Saucier, J.-P. Davis, Y. Lambert, and I. Monkovic, J. Med. Chem., 20, 676 (1977). B.F. Tullar, W. Wetterau, and S. Archer, J. Am. Chem. Soc., 70, 3959 (1948). H.R. Burjorjee, Kamakshi, B.K. Menon, and D.H. Peacock, Proc. Ind. Acad. Sci., Sect. 1A, 407 (1934). K. Pettersson, Arkiv Kemi, 7, 279 (1954). R. Adams and N.K. Sundholm, J. Am. Chem. Soc., 70, 2667 (1948). H.E. Zimmerman, S.S. Hixson, and E.F. McBridge, J. Am. Chem. Soc., 92, 2000 (1970). A.E. Weber, Ph.D thesis, University of Washington (1974). A. Collet and J. Jacques, Bull. Soc. Chim. France, 3857 (1972). A. Collet, Bull. Soc. Chim. France, 215 (1975). A. Fredga and M. Andersson, Arkiv Kemi, 25, 223 (1966). A. Fredga and M. Andersson, Arkiv Kemi, 21, 555 (1964). A. Fredga and R. Backstrom, Arkiv Kemi, 25, 455 (1966). A. Fredga, I. Kiriks, and C. Lundstrom, Arkiv Kemi, 25, 249 (1966). A. Fredga and I. Avalaht, Arkiv Kemi, 24, 425 (1965). M. Andersson, Arkiv Kemi, 26, 335 (1967). A. Fredga and K. Olsson, Arkiv Kemi, 30, 409 (1969). A. Fredga and K.I. Sandstrom, Arkiv Kemi, 23, 245 (1965). A. Fredga and F. Plénat, Arkiv Kemi, 24, 577 (1965). A. Fredga and K. Olsson, Arkiv Kemi, 30, 409 (1969). A. Fredga and K.-I. Sandstorm, Arkiv Kemi, 23, 245 (1965). A. Fredga, A. Kijellqvist, and E. Tornqvist, Arkiv Kemi, 32, 301 (1970). A. Fredga, E. Thimson, and K. Rosberg, Arkiv Kemi, 32, 369 (1970). M. Pallavicini, E. Valoti, L. Villa, and O. Piccolo, Tetrahedron: Asymmetry, 7, 1117 (1996). M. Pallavicini, E. Valoti, L. Villa, and O. Piccolo, Tetrahedron: Asymmetry, 8, 1069 (1997). F. Loiodice, A. Longo, P. Bianco, and V. Tortorella, Tetrahedron: Asymmetry, 6, 1001 (1995). J.D. Albright and H.R. Snyder, J. Am. Chem. Soc., 81, 2239 (1959). European Patent Application 0 029.175 (1981). A.D. van der Haest, Ph.D. thesis, University of Groningen (1992). D. Kozma, M. Ács, and G. Pokol, J. Chem. Soc. Perkin Trans 2, 435 (1992). S.H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 33, 2725 (1977). M. Leclercq and J. Jacques, Bull. Soc. Chim. Fr., 2052 (1975). M. Ács, F. Faigl, G. Réti, E. Fogassy, G. Pokol, M. Czugler, and K. Simon, in Proc. 41st Int. Meeting on Phys. Chemistry: Dinamics of Molecular Crystals, Elsevier, Amsterdam (1987). E. Fogassy, F. Faigl, M. Ács, K. Simon, É. Kozsda, B. Podányi, M. Czugler, and G. Reck, J. Chem. Soc. Perkin Trans. 2, 1385 (1988). I. Schröder, Z. Phys. Chem., 11 449 (1893). J.J. Van Laar, Arch. Neerl., 264 (1903). C. Fouquey and J. Jacques, Tetrahedron, 23, 4009 (1967). C. Fouquey and J. Jacques, Tetrahedron, 26, 5637 (1970). J. Jacques, A. Collet, and S.H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, New York (1981). D. Kozma, Ph.D. thesis, Technical University of Budapest (1993). E. Ebbers, G.J.A. Arians, B. Zwanenburg, and A. Bruggink, Tetrahedron: Asymmetry, 9, 2745 (1998). P. Walden, Z. Phys. Chem., 15, 196 (1894). W.J. Pope and J. Read, J. Chem. Soc., 101, 758 (1912). W.J. Pope and C.S. Gibbson, J. Chem. Soc., 101, 939 (1912).

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50. 51. 52. 53. 54. 55. 56.

E. Fogassy, M. Ács, J. Felméri, and Z. Aracs, Per. Pol., 20, 247 (1976). Hungarian Patent 178519 (1978). Hungarian Patent 169844 (1974). E. Fogassy, M. Ács, and I. Hermecz, Per. Pol., 20, 263 (1976). E. Fogassy, F. Faigl, and M. Ács, Tetrahedron, 41, 2837 (1985). C. Hansch, A. Leo, S.H. Unger, K.H. Kim, D. Nikaitani, and E.J.Lien, J. Med. Chem., 16, 1207 (1973). C.G. Swain and E.C. Lupton, J. Am. Chem. Soc., 90, 4328 (1968).

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6

Resolution in Practice: Selection of the Optimal Parameters

6.1 REACTING THE COMPONENTS 6.1.1 SELECTION

OF THE

SOLVENT

In resolution by diastereomeric salt formation, the selection of a suitable solvent is of prime importance. Is it possible to induce crystallization of the salt in the selected solvent? If yes, which enantiomer is predominant in the precipitate and what is its enantiomeric purity? A solvent is often not only a medium for crystallization, but may be incorporated as solvate into the crystal lattice. Solvate formation, in general, stabilizes the crystal lattice and therefore preferential crystallization of solvates can be expected. Note that sometimes it is the less stable diastereomeric salt that forms a solvate and thus it is the opposite enantiomer that is in excess in the precipitate. Unfortunately, diastereomeric salts were rarely the object of detailed physicochemical studies and therefore the phenomenon of solvation has not been frequently recorded. From achiral solvents, provided that no solvate formation takes place, preferential crystallization of the same diastereomeric salt can be expected and, for a given pair of diastereomeric salts, the maximum resolvability should be the same because interaction with the solvent does not involve any additional chiral interaction. This is, of course, only true for thermodynamically controlled crystallization and therefore it is not surprising that in practice experimental values for resolvability may differ in different solvents. The relative frequencies of the use of several solvents and solvent mixtures in resolutions shown in Appendix 1 are summarized in separate columns for bases and acids in Table 6.1. Studies by Faigl et al. discussed in Section 4.3.2.1 (Reference 3 in Chapter 4) on the resolution of a series of analogs with the same resolving agent but in different solvents indicated that resolvability depends not only on the properties of ligands attached to the center of chirality (bulk, polarity, and hydrophobicity), but also on the empirical polarity factor of the solvent (ET). Equations (4.2) through (4.5) can be reduced to the following form: S = dE T + C

(6.1)

where ET is the polarity factor of the solvent and C is a constant combining the other factors. From Eq. (6.1) it follows that, in resolution of a given racemate with a given resolving agent, the resolvability and solvent polarity are in linear correlation. Consequently, for resolution an as polar solvent as possible should be selected. The most polar, cheapest, and safest solvent is, of course, water. A further advantage of water is its powerful hydrogenbond forming ability, which facilitates its incorporation into the crystal lattice and, as we know, solvate formation is an advantage in resolution. Unfortunately, most organic compounds are sparingly soluble or practically insoluble in water. For industrial processes, the advantages of water are so overwhelming that water should be tested as a solvent in any case. Two-phase methods of resolution (Section 3.2.3.1) and salt-salt resolution (Section 3.3) have been elaborated just to overcome solubility problems. Because salts are generally more soluble in water than the racemic acids or bases, resolution is often

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TABLE 6.1 Relative Frequencies of the Use of Various Solvents in Resolutions Racemate Solvent

Base (%)

Acid (%)

EtOH 96% MeOH H 2O Acetone EtOH-H2O Abs. EtOH EtOAc iPrOH MeOH-Et2O MeOH-H2O EtOH-Et2O Et2O EtOH-EtOAc Acetone-EtOH MeOH-EtOAc CH2Cl2 CHCl3 Dioxane Nondefined Other

19.19 14.51 13.48 8.42 5.57 5.27 3.15 2.93 2.34 2.05 1.39 1.10 0.95 0.66 0.51 0.29 0.22 0.07 5.13 12.75

18.50 10.54 15.63 7.84 9.61 3.63 6.37 0.97 0.35 2.26 0.53 2.26 0.80 0.31 1.73 0.29 0.58 0.31 6.55 11.11

accomplished by suspending in water both partners, insoluble alone in water, followed by heating to promote the formation and dissolution of the diastereomeric salts.

Base 6.1 is practically insoluble in water; its resolution with tartaric acid was accomplished by 1 a remarkable technique. The racemic base was dissolved in benzene and tartaric acid in water. From the mixture of the two immiscible phases, benzene was distilled. The resulting solution was left standing overnight, diluted with additional water, whereupon a salt precipitated from which the optically active base was recovered. The same procedure was applied to the resolution of racemic tartaric acid with quinotoxine, with the difference that in this case it was the resolving agent that was dissolved in the organic phase and the racemate in water. Water may, however, hydrolyze certain compounds. Thus, when resolution of racemic 2,3dibromosuccinic acid (6.2) was attempted with morphine in water, the precipitated salt was primarily © 2002 by CRC Press LLC

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morphine hydrobromide. In methanol, however, hydrolysis could be suppressed and the compound 2 was successfully resolved. Although less polar than water, methanol and ethanol are more frequently used as solvents than water. Use of higher alcohols is rare; among them, only isopropanol has some significance. Acetone and ethyl acetate are also among the often-used solvents. An interesting solvent effect was observed with the resolution of acid 6.3. Its cichonidine salt 3 separated both from methanol and water as an oil, but from a 1:1 mixture of the two as crystals. Solvent mixtures are also used for the fractional crystallization. With solvent mixtures not only can solubility be controlled more precisely, but the chances of solvate formation are enhanced. The most common solvent mixture is 96% ethanol, but mixtures containing more water are also used. Acetone-water mixtures and ethyl acetate saturated with water may also be useful. Azeotropic mixtures are convenient in industrial processes because the solvent mixture can be recovered without a shift in its composition. Unfortunately, the exact composition of mixtures is often not disclosed in publications and thus reproduction of such experiments can be difficult. If owing to poor solubility of starting materials so much solvent must be used that the solution is not oversaturated with respect to the diastereomeric salt, addition of another solvent reducing solubility may be helpful. For example, when acid 6.4 was resolved with quinine, the components were first dissolved in hot ethanol, followed by dilution with water until the solution became cloudy. 4 Thereafter, some ethanol was added, just to get a clear solution. Note that the start of turbidity and the reverse process are temperature dependent; and because this was not exactly specified in the description reproduction of the procedure, it may be problematic.

Even less information is available on the resolution of N-methylephedrine (6.5) with tartaric acid, for where it was only mentioned that the diastereomeric salt was recrystallized from a small 5 amount of methanol containing some ether. Because the composition of a solvent mixture is crucial for efficient resolution, this should be always exactly specified.

6

Acid 6.6 was resolved with brucine in water. Unfortunately, due to the poor solubility of the components, very large volumes were necessary. However, resolution in 50% aqueous ethanol gave not only better yields, but resulted in substantial savings in volume, time, and labor. In successive stages of the purification of the precipitated diastereomeric salt different solvents are often applied. One reason for this is that with increasing enantiomeric purity, the solubility of the salt decreases. Some pertinent examples are compiled in Table 6.2. Unfortunately, publications rarely disclose the reason for applying an unusual solvent. The number of eligible solvents can be further extended—when the use of mixtures is also considered. Sometimes, a variation of the composition of such mixtures can further improve the efficiency of the process. Note that a change of solvent may involve the appearance of polymorphic forms. © 2002 by CRC Press LLC

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TABLE 6.2 Resolutions with the Successive Application of Different Solvents

HOOC

COOH

8

O

7 6

5

R R= a) 8-OMe; b) 7-OMe; c) 5-OMe; d) 6-Br MeOOC

COOH O

N

HO

O2N

N H

NH

H2N

OH N

Ph

HO OH

OMe

O

O

O

N H

COOH

The salt of base 6.7 with O,O¢-dibenzoyltartaric acid was fractionally crystallized from the 14 following solvents : (1) benzene-diethyl ether, (2) benzene, (3) ethanol-diethyl ether, (4) ethanol, and (5) methanol. Three polymorphic forms with different melting points (113, 142–143, and 162–165∞C) but of the same specific rotations could be observed after the last crystallization. The effect of a solvent change on the outcome of resolution was often reported. When base 6.8 was resolved with natural tartaric acid, it was observed that to arrrive at the pure diastereomeric salt 15 of the (+)-base, 10 recrystallizations were necessary from methanol and 14 from ethanol. Interestingly, when the resolution was carried out in water, it was the salt of the (-)-base that was obtained pure after 23 recrystallizations. In this way, simply by changing the solvent, both enantiomers could be obtained without taking recourse to the expensive unnatural (2S,3S)-tartaric acid. © 2002 by CRC Press LLC

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In the resolution of acid 6.9 with cinchonidine, it was the salt of the (+)-acid that separated 16 from ethanol. On recrystallization from 96% ethanol of the salt obtained by evaporation of the mother liquor, the product was enriched in the other enantiomer. Although the salts were not studied, it is assumed that from aqueous ethanol a hydrate of the salt separated.

In the course of the resolution of base 6.10, it was observed that if sufficient water was present, the (−)-base formed hydrated salts with tartaric acid, (S)-malic acid, and N-benzoyl-L-threonine 17 and these salts were the less soluble ones in water. On the other hand, the (+)-base did not form hydrates with the above-mentioned acids. On a preparative scale, resolution was carried out in methanol followed by water. In this way, almost complete separation of the enantiomers became possible: from methanol the unsolvated salt of the (+)-base crystallized, while recrystallization from water of the residue obtained after evaporation of the mother liquor provided the hydrated salt of the (−)-base. Experimentation with various solvents is frequently done in the initial phase of elaborating a process, but usually only the best solvent is published. Table 6.3 shows the resolution of N-acetylphenylalanine with (2S,3S)-2-amino-1-(4-nitrophenyl)18 1,3-propanediol in three different solvents. It can be seen that, within experimental error, resolvabilities are the same. Because resolution in water requires the smallest volume, even when disregarding expenses, water should be the solvent of choice. Resolution of base 6.11 was studied in various solvents with a half equivalent of di-O-p19 toluyltartaric acid. The components were dissolved hot in the chosen solvent and the solution rapidly cooled to room temperature, whereupon crystallization started (Table 6.4). It can be seen that the efficiency of resolution was significantly different for the individual solvents. Moreover, in methanol, the configuration of the predominant enantiomer was opposite. The mixture was not stirred during crystallization and the time until crystallization was terminated was very short; therefore, thermodynamic equilibrium might not have been established. Resolution in methanol and ethylacetate was repeated, also allowing more time for crystallization. Results are shown in Table 6.5 In methanol, thermodynamic equilibrium was established on the fourth day, efficiency of resolution significantly improved within this period, but longer reaction times did not further improve resolvability.

TABLE 6.3 Resolution of N-Acetylphenylalanine with (2S,3S)-2-Amino-1-(4-nitrophenyl)-1,3-propanediol in Various Solvents Solvent Water Ethanol n-Propanol

© 2002 by CRC Press LLC

Solvent:Racemate Ratio

S

5:1 20:1 40:1

0.81 0.80 0.78

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TABLE 6.4 Yields and e.e. of Diastereomeric Salts of 6.11 Separated after 10 min of Crystallization Solvent

y (%)

e.e. (%)

S

Config. of Enantiomer in Excess

Acetone Toluene Acetonitrile Chloroform Ethyacetate Methanol

63 104 99 104 91 93

20 26 35 37 48 11

13 27 35 38 44 10

R R R R R S

TABLE 6.5 Resolution of 6.11 in Methanol and Ethyacetate Solvent (ml) Methanol (10)

Ethyacetate (15)

Time

y (%)

e.e. (%)

S

Config. of Enantiomer in Excess

10 min 4 days 45 days 10 min 4 days 45 days 5 months

93 71 75 91 99 95 103

11 70 68 48 7 26 23

10 50 51 44 7 25 24

S S S R R S S

In ethyacetate, however, the optical purity of the precipitated salt—and thereby resolvability— much deteriorated on the fourth day. Working up the experiment after 45 days gave the surprising result that, while the weight of the precipitate did not change, it was the S enantiomer that became predominant in the salt. This result did not change on further staying. Changing the dominant configuration in the precipitated salt caused by solvation was observed several times; but in the present case, none of the diastereomeric salts were solvated with either of the two solvents. An explanation for the above findings may be that, in an aprotic solvent, crystallization is under kinetic control. On prolonged standing, the faster crystallizing but less stable salt gradually dissolved and gave way to the more stable diastereomer. In a protic solvent such as methanol, it was the thermodynamically more stable diastereomer that precipitated in excess directly and its optical purity improved on standing in contact with the solution. Resolution was repeated with the Pope-Peachey method in the presence of a half equivalent of hydrochloric acid and it was found that in this way that maximum resolvability could be reached faster than in the above-described, long-term methanol experiment ( y = 53.5%, o.p. = 95.5%, S = 51.2%). Resolution of mandelic acid (6.12) with cinchonine was also studied in several solvents (see Table 6.6). From water or ethanol containing a high percentage of water, the diastereomer containing the S enantiomer in excess separated as a hydrate and resolvability dropped with the percentage of water content. When the water:ethanol ratio reached 2:1, it was the R enantiomer that became 20 predominant in the salt, now not solvated with water. The diastereomeric salt separating from ethyacetate and ethyacetate saturated with water was of much higher optical purity and resolvability was best in these experiments. It is interesting that although © 2002 by CRC Press LLC

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TABLE 6.6 Resolution of Mandelic Acid (6.12) with Cinchonine in Various Solvents Salt Solvent Water (50 ml) Water:EtOH (4:1) (25 ml) Water:EtOH (2:1) (15 ml) Anhydr. EtOAc (110 ml) Ethyacetate satd. with water (30 ml)

Config.

y (%)

o.p. (%)

S

Solvate

S S R R R

100 55 88 82 73

28 13 9 36 61

0.28 0.07 0.08 0.30 0.45

H 2O H 2O — EtOAc EtOAc

TABLE 6.7 Resolution of Mandelic Acid (6.12) with Aminoalcohol 6.13 in Various Solvents Solvent

ml

y

o.p.

S

H2O EtOAc EtOAc satd. with H2O

5 25 20

0.48 1.33 0.85

0.36 0.16 0.68

0.17 0.21 0.58

incorporation of water into the crystal lattice is possible, it is not overly favored because even from solutions of rather high water content, no hydrate separated. Incorporation of ethyacetate is evidently much more favored because it is incorporated even from water containing ethyacetate. 21 Crystallographic studies by Larsen and co-workers demonstrated that secondary interactions in an unsolvated pair of diastereomeric salts are rather limited.

The resolution of mandelic acid (6.12) with (S)-6.13 was studied in water, ethyacetate, and 22 ethyacetate saturated with water. Resolution was successful in each solvent, but efficiency differed significantly. In ethyacetate saturated with water, resolvability was about three times higher than in pure solvents. An explanation for this may be either the lack of solvate formation or that the salts were very soluble in water and almost insoluble in ethyacetate. Therefore, ethyacetate saturated with water provided better conditions for efficient resolution (Table 6.7). Resolution of 1-phenylethylamine (PEA) is routinely done with natural tartaric acid [(+)-TA] in methanol; but to investigate the role of solvent, several other solvents (water, ethanol, acetonitrile, methanol:acetonitrile 1:1, methanol water 1:1) were also tested. Crystalline diastereomeric salts separated from each. In salts crystallizing from methanol containing solvents, the S enantiomer was in excess, while in the others the R enantiomer dominated (see Table 6.8). Both the crude and © 2002 by CRC Press LLC

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TABLE 6.8 Resolution of 1-Phenylethylamine with Tartaric Acid [(+)-TA] in Various Solvents Solvent (ml) Methanol (50) Water (30) Acetonitrile (250) Ethanol (50) Methanol:acetonitrile (1:1) (80) Methanol:water (1:1) (35) a

Salt Weight Loss %

a

<0.1 4.9 2.0 1.4 <0.1 1.4

y (%) 66.7 100.0 175.9 144.4 144.4 118.5

o.p. (%)

S

72.1 12.3 4.6 4.2 20.4 4.4

0.48 0.12 0.08 0.06 0.30 0.05

Weight loss on heating to 80°C.

SCHEME 6.1

the pure salts were examined by thermal analysis and X-ray powder diffraction. The salts separating from methanol or methanol-acetonitrile did not contain crystal solvate, while the other salts were hydrated to different extents but lost their water at relatively low temperature (i.e., in the range of 30 to 80°C). The hydrate water content of the crystals may have come from traces in water in the solvents used without drying or from the laboratory atmosphere. X-ray powder diffraction patterns indicated that the salt separating from methanol was not a simple mixture of diastereomeric salts, 23 but rather a new crystal modification. Salts crystallizing from water or ethanol are also not simple salt mixtures, but represent different crystal forms. Only the salt precipitating from acetonitrile proved to be, according to the powder pattern, a mixture of two diastereomeric salts, being in fact what we would normally expect in case of eutectic forming pairs of salts. Based on the above experimental data, the order of relative stability of diastereomeric salts is as follows: (S)-PEA ⋅ (+)-TA > (R)-PEA ⋅ (+)-TA · hydrate > (R)-PEA ⋅ (+)-TA 1-Phenylethanesulfonic acid (PES) is a highly acidic resolving agent and is thus suitable to resolve amino acids without derivatization. Leucine was resolved with PES in two different solvent 24 mixtures (Scheme 6.1). The salt separating from methanol-acetonitrile contained L-leucine in excess, while from the salt precipitating from aqueous acetonitrile D-leucine could be recovered. The reason for this inversion of configuration was studied by various physicochemical methods and single-crystal X-ray crystallography. It was found that on crystallizing from water containing solvents the D-Leu ⋅ (−)-PES salt formed a hydrate, while the L-Leu ⋅ (−)-PES salt failed to take up water even when kept in a chamber of 75% relative humidity. Physicochemical and crystal structure data for the two pure salts and of the hydrate are collected in Table 6.9. © 2002 by CRC Press LLC

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TABLE 6.9 Physical and Crystal Structure Data for Leu ⋅ (−)-PES Salts m.p. (°C)

Salt

∆H (kJ/mol)

Solubility (g/100 g solvent)

D-Leu ⋅ (−)-PES

171.5

29.6

4.2 (MeCN:MeOH, 9:1) 0.07 (MeCN)

L-Leu⋅ (−)-PES

221.2

33.4 (dec.)

1.2 (MeCN:MeOH, 9:1) 0.03 (MeCN) 4.2 (MeCN:H2O, 95:5)

D-Leu⋅ (−)-PES · H2O

77 (−H2O) 171.2

62.7 27.6

2.0 (MeCN:H2O, 95:5)

Single-crystal Parameters Monoclinic C2, Z = 4 a: 21.1, b:5.5, c:20.7, ß: 137.4° 3 Dx = 1.296 g/cm Monoclinic P21, Z = 2 a:14.8, b:5.8, c:9.8, ß: 107.4° 3 Dx = 1.313 g/cm Orthorhombic P212121, Z = 4, a:10.2, b:27.8, c:6.1, ß: 90° 3 Dx = 1.285 g/cm

A comparison of crystal structures revealed that the crystals of the more soluble D-Leu ⋅ (−)-PES salt were the least stable and transformed by incorporation of solvate water to the much more stable hydrate.

6.1.2 DETERMINATION

OF THE INITIAL

CONCENTRATION

After having selected the best solvent, the next task is to determine the optimum initial concentration of the partners. If solubility data for the diastereomeric salts are not available or there is insufficient time or material to determine them, then (provided that the components are thermally stable), as a rule of thumb, solutions saturated at their boiling points should be combined. If on cooling, more than the calculated amount of diastereomeric salt (i.e., half of the total mass of the components) separated, the initial concentration must be lowered until the mass of precipitate drops to about the calculated value. With thermally unstable racemates, working with solutions saturated at room temperature cannot be avoided, even if a low concentration of the resulting solution does not permit crystallization of the diastereomeric salt. In this case, oversaturation must be reached by partial evaporation. With poorly soluble components, both may be dissolved in the same portion of solvent because the solubility of the diastereomeric salts is often higher than that of the starting components. A method exploiting the higher solubility of salts is salt-salt resolution—when both the racemate and the resolving agent are dissolved and reacted in form of a salt with an achiral partner (cf. Section 3.3). When optimization of a resolution process is intended, finding the best initial concentrations is always advised and this can be achieved with the aid of the solubility triangular diagram of the diastereomeric salts (Fig. 6.1). The triangular diagram in Fig. 6.1 is divided by the solubility isotherm (A–E–A’) and the straight lines connecting its eutonic point (E) with the apexes representing the pure salts (E–LR and E–DR) into four fields. Within quadrangle F–A–E–A’, the solution is unsaturated; in this domain, no crystallization (i.e., resolution) can be expected. In the triangle E–DR–LR, the saturated solution is in equilibrium with both diastereomeric salts; therefore, in this domain, no optically pure product can be isolated. In triangles A’–E–LR and E–A–DR, the pure salts are in equilibrium with the saturated solution and therefore separation of optically pure product can be expected. Resolution of a racemate starts at some point lying on the straight line B–F. Along the section F–G there is no crystallization, and the salt separating along section B–O is optically impure. Section O–G belongs to successful resolution; in this concentration range, salt LR separates with © 2002 by CRC Press LLC

0019_frame_C06 Page 124 Monday, August 6, 2001 1:30 PM

FIGURE 6.1 General solubility triangular diagram of a conglomerate-forming pair of diastereomeric salts.

gradually decreasing yield as proceeding toward point G, according to the rule of material balance. The optimal concentration of resolution is thus represented by point O.

6.2 INITIATION OF CRYSTALLIZATION After having reacted the racemate and the resolving agent in the given solvent, to secure efficient separation by fractional crystallization, complete dissolution of the diastereomeric pair of salts is required and the less soluble salt should separate from this solution. To induce crystallization, an oversaturated solution must be produced and seed crystals may be necessary for triggering crystallization.

6.2.1 PRODUCING

AN

OVERSATURATED SOLUTION

6.2.1.1 Oversaturation by Cooling A controlled way to arrive at an oversaturated solution is to cool a saturated solution. It must be emphasized that it is the temperature difference—and not cooling to the lowest possible temperature— which is essential. In an appropriate system, it may be sufficient, to cool a hot or boiling solution to room temperature. One should keep in mind that it is at room temperature where the next operation (i.e., separation of the precipitate from the mother liquor) is most conveniently performed. On a small scale, keeping the solution while filtering off the product at a low temperature is cumbersome and working at a poorly defined temperature may result in a nonreproducible process. On an industrial scale, solid-liquid separation can be carried at a well-defined temperature, but lower than ambient temperature involves costly installations and higher operational expenses. When a racemate is sufficiently stable, it is practical to choose the boiling point of the solution as the initial temperature of crystallization because in this way difficulties connected with the control of temperature can be avoided. With thermally unstable racemates, room temperature can © 2002 by CRC Press LLC

0019_frame_C06 Page 125 Monday, August 6, 2001 1:30 PM

be selected as upper point. If room temperature is not low enough, +5°C and −20°C are convenient lower points, which can be realized in the refrigerator and its deep-freeze compartment, respectively. Note that slower diffusion at low temperature may impede crystallization. For example, when 1-phenylethylamine was resolved with [(1R)-(endo,anti)]-3-(+)-bromocamphor-8-sulfonic acid, crystallization failed to start even at −70°C and in the presence of seed crystals. At room temperature, 25 however, crystallization was instantaneous. 6.2.1.2 Oversaturation by Partial Evaporation of the Solvent In laboratory-scale resolutions, it is a time-honored method to allow the mixture to slowly evaporate in an open vessel in order to produce an oversaturated solution. Oversaturation by partial removal of the solvent is practical in the following cases: • The solubility difference of the diastereomeric salts is only slightly temperature dependent. • Both the racemate and the resolving agent are much less soluble than the salts. • In preliminary experiments when solubilities of the components is not exactly known. It goes without saying that to be able to elaborate a reproducible process, the amount of solvent removed must be determined. Removal of solvent by spontaneous evaporation from an open vessel is a typical laboratory procedure and on an industrial scale it has been replaced by distillation. Under such conditions, reproducibility poses no problems. In the laboratory, however, the amount of removed solvent must be determined by weighing the residue because incomplete condensation incurs considerable losses.

26

The diacid 6.14 was resolved with strychnine in a chloroform-ethanol mixture. Crystallization started on partial evaporation of the solvent. It is probable that by distillation, the authors’ intention was not to remove the more volatile chloroform, because the salt was then repeatedly recrystallized from a chloroform-ethanol mixture. In the case of mixed solvents, even giving the quantity of the distillate is not very informative because, on distillation, the composition of the solvent changes in an ill-defined manner. Therefore, reports of similar methods should be accepted with a grain of salt.

6.2.2 INITIATION

OF

CRYSTALLIZATION

6.2.2.1 Spontaneous Crystallization In favorable cases, crystallization starts spontaneously from a oversaturated solution of the salts. The probability of crystal seed formation is also dependent on the quantity of solute, and the probability that crystallization begins from 1 g substance is 100 times more likely than it is from 10 mg. Seed formation can be promoted by sonication or subjecting the solution to cycles of heating and cooling. © 2002 by CRC Press LLC

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When resolution of the diacid 6.15 was first attempted with quinine, an oily salt was obtained which only crystallized after several months. Searle and Adams repeated the experiment with the same result but observed that if a chloroform solution of the reaction mixture was evaporated several 27 times to dryness, the salt readily crystallized. It appears that evaporation with chloroform removed some minor volatile contaminant inhibiting crystallization or it was the mechanical effect of working over several times the product that increased the chance of crystallization. In general, formation of crystal seeds is a lengthy process. In the resolution of base 6.16 with tartaric acid, the components were dissolved in boiling methanol and because no crystallization started at room temperature, the solution was cooled to 28 −10°C. The first crystals appeared after 7 days and, at this point, complete crystallization was brought about by adding equal volumes of acetone over 4 days.

The brucine salt of acid 6.17 started to crystallize from water after standing for 6 weeks and 29 gave well-formed prisms. Base 6.18 was resolved with 4,6,4′,6′-tetranitrodiphenic acid in ethanol. 30 The sticky precipitate crystallized as transparent yellow needles after 1 month. Resolutions similar to the above examples (i.e., requiring very long times for proper crystallization) are rather common. With spontaneous crystallization, time is only one problem; another is poor reproducibility because spontaneous crystallization does not necessarily lead to the separation of the thermodynamically more stable salt. It is likely that non-genuine crystal seeds were often formed because the process was induced by foreign bodies such as dust particles coming from the air.

On resolution of diacid 6.19 with quinine in acetone, crystallization failed to start even after 1 day; but when the stopper of the flask was removed, next day crystals separated that gave, 31 after a single recrystallization from chloroform-acetone, the optically pure diastereomeric salt. It is not clear which among several factors—that is, evaporation of the solvent, prolonged standing, or foreign bodies—was responsible for crystallization. Crystallization induced by scratching the wall of the flask can be regarded either as spontaneous crystallization or crystallization with seeding. In the latter case, the seed crystals are produced © 2002 by CRC Press LLC

0019_frame_C06 Page 127 Monday, August 6, 2001 1:30 PM

in situ. Scratching with a metal spatula is not recommended; doing so with a glass rod is both more efficient and avoids metal contamination. Glass rods with a tip with a worn surface by previous scratching are best. One takes out a drop of solution with the rod and scratches the neck of the flask. If crystals are formed, these are washed with the mother liquor into the bulk of the solution and, if necessary, this operation is repeated. The method is more efficient with a hot solution because by rapid evaporation the sample becomes concentrated sooner. 6.2.2.2 Crystallization Using Seed Crystals 6.2.2.2.1 Crystallization with the Aid of Seed Crystals Prepared from the Pure Enantiomer and the Resolving Agent If possible, initiation of crystallization by seeding should be the method of choice. In this way, crystallization of the thermodynamically more stable salt can be promoted even if precipitation of the other salt is kinetically favored. Optimum optical purity can be achieved if, after addition of the seed crystals, crystallization is not too fast, because rapid crystallization always results in reduced optical purity.

It was recorded that in the resolution of base 6.20 with tartaric acid, the purest salt could be 32 obtained when a solution in 95% ethanol was seeded and left standing undisturbed for 2 days. On stirring, crystallization started even without seeding, but optical purity was lower and the product could be filtered off less readily. On resolution of base 6.21 with one molar equivalent of tartaric acid, it was observed that on combining aqueous solutions of the components, crystallization was instantaneous but optical purity 33 poor. Crystallization was attenuated by first adding half of the tartaric acid solution at 15°C, whereupon crystallization started. The solution was cooled and after 30 min the second half of the resolving agent was added. The mixture was stirred for 45 min before the product was filtered. Preparation of homogenous seed crystals is, in general, an arduous task because it requires at least one of the pure enantiomers. If no information is available about the two diastereomeric salts, both must be prepared pure, and then one must determine which one is more stable and use that one for seeding. Note that seed crystals must be crystallized from the same solvent as the one used for resolution, because of eventual solvate formation. Unfortunately, in the case of a new resolution, the pure enantiomers are rarely available. In the synthesis of natural products, one of the pure enantiomers is sometimes available. In this case, the pair of diastereomeric crystals is prepared using this single enantiomer and both enantiomers of the resolving agent. In this way, solubilities and melting points can be determined. For initial resolution experiments, that particular enantiomer of the resolving agent should be used the salt of which proved to be more stable. 6.2.2.2.2 Crystallization by Seeding with Crystals Prepared from the Racemate or by Recrystallization of a Sample Withdrawn from the Reaction Mixture When, and this is generally the case, the pure enantiomers are not available, one can try to take out a sample of the reaction mixture, let it evaporate, and if the residue is a solid, this can be used as seed. This procedure was successful with the resolution of compounds 6.22 and 6.23. © 2002 by CRC Press LLC

0019_frame_C06 Page 128 Monday, August 6, 2001 1:30 PM

When aminopropanol 6.22 was reacted with camphor-10-sulfonic acid in acetone, no crystal34 lization took place without seeding. A small portion of the solution was evaporated and the residue crystallized after standing in a dessicator. The solution was seeded with the solid and the separated salt was filtered off after 2 days. The product was then recrystallized twice, first with the addition of seed crystals. For the second recrystallization, seeding was unnecessary. The half ester 6.23 was reacted with strychnine in water, but the mixture failed to crystalline 35 on cooling or scratching, while applying the technique described with 6.22, the salt crystallized overnight in the refrigerator, giving after two recrystallizations one of the diastereomeric salts in 97% o.p. Because the evaporated small sample of the original solution proved to be a 1:1 mixture of the two diastereomeric salts, it would not have been unexpected if the salt separating on seeding were a similar mixture. This is probably the situation in many cases, which remained unreported due to their failure. The fact that resolution of 6.23 was nevertheless successful can probably be ascribed either to faster crystallization of the more stable salt or the long time of crystallization favoring the precipitation of the more stable salt. Because, in general, seeding with a 1:1 mixture of diastereomeric salts rarely gives rise to a product of high optical purity, this method should only be used as a last resort. Chances for successful resolution can be enhanced by repeated recrystallization of the sample to arrive at optically pure or at least highly enriched seed crystals. This, of course, requires that sufficient starting material be available. The better the purity of the seed, the higher the purity that can be expected of the precipitate separating from the bulk of the solution, thereby saving labor and material.

Resolution of base 6.24 well exemplifies the role of seed crystals. In the first experiment, the 36 racemate was resolved with tartaric acid in methanol. Crystallization was spontaneous, seven recrystallizations were needed to reach constant optical rotation, and two more did not improve further optical purity. In a second experiment using the remainder of the racemate, seed crystals from the first one were used, requiring five recrystallizations to obtain the optically pure salt (Table 6.10). TABLE 6.10 Resolution of 6.24 with Tartaric Acid Using Seed Crystals of the Pure Salt Salt Number of Crystallizations

Methanol (ml)

1 2 3 4 5

160 50 50 30 18

Base

g

m.p. (°C)

[ α ] 546

23.0 16.0 12.3 9.9 7.1

156.0–157.2 160.5–161.7 163.5–164.5 165.0–166.0 165.2–166.3

+115.8 +128.6

25

Note: 27.8 g of 6.24 was resolved with 29.55 g of (+)-tartaric acid. © 2002 by CRC Press LLC

0019_frame_C06 Page 129 Monday, August 6, 2001 1:30 PM

This example illustrates the clever tactics of the authors: they used approximately one third of the racemate to obtain pure seed crystals, followed by efficient resolution of the remaining two thirds using the latter. 6.2.2.2.3 Crystallization by Seeding with a Salt of an Analog In want of the pure enantiomers, crystals of a salt formed from an as close as possible analog may be helpful. Because the resolving agent is at our disposal, the problem reduces to finding the closest analog of the racemate to be resolved. Seeding with the Salt of an Isotope Isomer. The Preparation of compounds labeled with an isotope for metabolism studies is a common task. In this case, close similarity between labeled and unlabeled compound is obvious and therefore it is highly probable that the pure enantiomer of the unlabeled compound should provide suitable seed crystals.

6.2.2.2.3.1

As an example, resolution of tritiated 6.25 with O,O′-dibenzoyltartaric acid can be quoted. On resolution of the labeled compound, the same procedure as with the unlabeled one was followed, 37 and the salt solution was seeded with the salt of the unlabeled (+)-enantiomer. 6.2.2.2.3.2 Seeding with a Salt Formed from the Resolving Agent and Another Optically Active Compound. The salt of the racemic diamine 6.26 with tartaric acid failed to crystallize even after standing

for several days; only a viscous syrup was obtained. However, when the mixture was seeded with the tartaric acid salt of natural coniin (6.27), the hemitartrate of the diamine soon crystallized as 38 glistening needles. Although the structures of the two compounds differ considerably, it seems that due to a lucky coincidence they formed isomorphic crystals.

6.2.2.2.3.3 Seeding with a Salt Formed from the Resolving Agent and an Optically Inactive Compound. The liquid base 6.28 was added dropwise without dilution to solid tartaric acid. The resulting

syrup did not crystallize despite the fact that after a certain time small needles could be observed 39 under the microscope. When, however, crystals of the tartaric acid salt of achiral 2-picoline (6.29) were added, crystallization soon started. Although the two bases have a similar constitution, owing to the aromatic character of 2-picoline, they are nevertheless rather different.

Scholz and co-workers reported an interesting phenomenon in connection with the resolution 40 of base 6.30 with tartaric acid. Resolution with natural (R,R)-tartaric acid gave a viscous syrup, © 2002 by CRC Press LLC

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whereas the salt with unnatural (S,S)-tartaric acid crystallized; however, the base liberated from the product was racemic, indicating that a 1:1 molecular complex of the diastereomeric salts was formed. Because the probability of crystallization of the salts produced by mirror-image resolving agents should be identical, it appears that crystallization in the second experiment was induced by a contamination originating from the laboratory atmosphere that was isomorphic with the diastereomeric salts derived from (S,S)-tartaric acid.

The resolution of 1-(3,4-dimethoxyphenyl)-ethylamine (6.31) was accomplished with 6.32. The salts failed to crystallize from 96% ethanol, but slow evaporation of the solution gave a syrup that slowly deposited some crystals. These were separated and successfully used as seed crystals in a second experiment. In the following experiments, no seeding was needed because seeds were probably coming from the laboratory atmosphere. Note that crystallization induced by seed crystals present in the laboratory following a successful resolution is a rare event.

From an aqueous solution of the racemic acid 6.33 and 6.34, no crystals separated, while spontaneous evaporation of the solvent gave a solid mass. Using the latter as seed for a new batch, 41 the less soluble diastereomeric salt soon crystallized and efficient resolution could be achieved. Nevertheless, in each further experiment, even in the same laboratory, addition of seed crystals was necessary to initiate crystallization. Base 6.35 was resolved in water with (1R)-3-bromocamphor-8-sulfonic acid, and to attenuate 42 crystallization, ethanol was added. From the unpurified diastereomeric salt, the base was liberated, which gave after a single recrystallization from petroleum ether the dextrorotatory enantiomer in high optical purity. Unfortunately, this first successful experiment could not be repeated even after 12 trials; from the precipitated salt only the racemic base could be recovered. It can be assumed that during the first experiment there were no interfering crystal seeds present in the laboratory © 2002 by CRC Press LLC

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atmosphere; and in a kinetically controlled crystallization, it was the salt of the dextrorotatory base of which the first crystal nuclei appeared and this resulted in the the first successful resolution. Failure in subsequent experiments may be due to the presence of seeds of the thermodynamically more stable 1:1 molecular complex, which contaminated the laboratory and thwarted further attempts at resolution. Perhaps resolution would have been successful in another laboratory.

43

As a reproduction of an earlier work, Hoback resolved base 6.36 with (1R)-3-bromocamphor8-sulfonic acid. Previously, Clemo and co-workers claimed that the reported resolution could not be repeated. Despite the latter claim, Hoback succeeded in the resolution of 6.36 with the same resolving agent. In addition, instead of ten, four recrystallizations were sufficient and the salt obtained had a m.p. 20°C higher than originally reported. This discrepancy can again be explained by the presence (or absence) of isomorphic crystal nuclei in the laboratory atmosphere. 6.2.2.3 Initiation of Crystallization by Precipitation with a Second Solvent An efficient method for inducing crystallization can be precipitation by the addition of a second solvent, as exemplified in Table 6.11. The diastereomeric salt is dissolved in the first solvent and to this solution a second solvent, miscible with the first but in which the salt is less soluble, is added gradually until crystallization begins. This method is primarily applied when, on cooling to room temperature, crystallization fails to start. Therefore, precipitation is most often performed at room temperature, but the method can be combined with the recooling technique as well. In this case, the second solvent is added to the hot solution of the salt (Items 1 and 8 in Table 6.11). Most often, the first solvent is a polar one to which a less polar solvent is added. Use of highly apolar solvents is discouraged because this causes a sharp drop in the solubility of the salt, resulting in too fast precipitation and poor optical purity. Unfortunately, there are no ideal solvent pairs known for triggering crystallization. In some cases, the roles can be interchanged; for example, methanol/acetone vs. acetone/methanol, or water/ethanol vs. ethanol/water. From reports in the literature it is not always clear whether the second solvent served to initiate crystallization in an oversaturated solution, or it was oversaturation that was achieved by the addition of the second solvent. In the examples in Table 6.12, with two exemptions, the second solvent was added at room temperature, presumably only to initiate crystallization.

Base 6.37 was resolved in n-butanol with 4-nitrobenzoyl-L-glutamic acid. To the solution, petroleum ether was added dropwise over 5 min at room temperature or as long as necessary for the formation of seed crystals.53 Thereafter, the solution was cooled to 0°C and then a substantial volume of petroleum ether was added to the mixture over a period of 2 h. The mixture was kept at 0°C overnight. It is clear that in this procedure the second solvent played a dual role: it first initiated crystallization and later completed precipitation. Note that the second solvent was added gradually © 2002 by CRC Press LLC

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TABLE 6.11 Resolutions by Precipitation with a Second Solvent

MeO

OMe N

MeO

OMe

MeO NH

MeO

p-Cl-C6H4

MeO N

MeO

H HO

NH Ph

N H

MeO NH

MeO

p-Cl-C6H4

HOOC

SO2

SO2 S

Ph

NH2 OH NHCOCH3

COOH

a

DBTA = O,O¢-dibenzoyltartaric acid; TA = tartaric acid.

over a rather long period of time. Slow addition provided favorable conditions for the separation of the less soluble salt, giving enough time to the two phase system to reach equilibrium. The second solvent is often used only to securre complete precipitation. Thus, base 6.38 was 54 resolved with (1R)-3-bromocamphor-8-sulfonic acid in acetone. The first crop of crystals was filtered off and carbon tetrachloride added to the mother liquor, giving an additional crop of product as pure as the first generation. 55 A special use of a second solvent was described by Balieu and co-workers. Base 6.39 was resolved with tartaric acid in a very concentrated aqueous solution, 335 g tartaric acid was suspended in 200 ml water, to which 100 ml of the liquid racemate was slowly added with stirring. This extremely concentrated solution failed to crystallize until ethanol was layered over the viscous syrup. Crystallization started at the interface and propagated later to the entire solution mass. The salt was separated from the viscous mother liquor by centrifugation. © 2002 by CRC Press LLC

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6.2.3 SIGNIFICANCE

OF THE

PURITY

OF

STARTING MATERIALS

Chemical purity of the racemate may be of prime importance for the initiation of crystallization. In practice, however, the racemate may contain up to a few percent contamination. Impurities can both promote and inhibit crystallization.

It was reported that resolution of bases 6.40 with tartaric acid was influenced by a small amount 56 of contamination. If the contaminant forms a eutectic with the separating diastereomeric salt, it increases its solubility and can even prevent its crystallisation completely. On the other hand, it may stabilize the crystal lattice by hydrogen bonds and thereby promote the formation of the first crystal nuclei. It is the latter situation when reproduction of a process may be very difficult, because different batches may contain various amounts of contamination and may behave therefore quite differently. Fractional crystallization in the course of resolution is also a purification process in itself and therefore complete purification of the racemate before resolution can be omitted. One can conclude that complete purity of the starting racemate is mostly unnecessary, but information about the contamination profile of the components, including the resolving agent, is essential.

6.2.4 SEPARATION

OF A

NONCRYSTALLINE PHASE

The diastereomeric salt often precipitates as a liquid or an amorphous solid. Separation and work-up in this case is not recommended because the product is usually racemic or of low optical purity.

Reaction of base 6.41 with tartaric acid in acetone gave an oil. The reaction mixture was warmed and an acetone-chloroform mixture was added until complete dissolution of the oil. From this 57 solution the diastereomeric salt crystallized. Base 6.42 and tartaric acid were reacted in ethanol at room temperature, giving a sticky gum that was brought into solution by boiling. From the boiling solution, crystals of hydrogen tartrate 58 of the levorotatory enantiomer separated. © 2002 by CRC Press LLC

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TABLE 6.12 Effect of the Mode of Addition of the Resolving Agent on the Efficiency of Resolution l-Phenylethyl-Amine with (lg)-3-Bromocamphor-lo-Sulfonic Acid Base:Acid Molar Ratio

Solvent

1:0.5 1:0.5

Petroleum ether Ether

1:1

Ether

1:1

Ether

1:1

Ether

1:1

Ether:Me2CO: EtOH 140:2.5:2.5 Ether

1:0.5

1:1

1:0.5

1:0.5

Ether:Me2CO: EtOH 28:1:1 Ether:Me2CO: EtOH 28:1:1 Ether:Me2CO: EtOH 140:5:5

Comments

S

Resolving agent added as a solid; no resolution within 3 weeks Resolving agent added as a solid; crystals were covered by a viscous syrup, which on standing for 2 days disintegrated to a powder Resolving agent added in solution; the salt precipitated as a viscous oil, which was separated and processed Resolving agent added in solution; the salt precipitated as a viscous oil, which solidified on standing, work-up after 24 h Resolving agent added in solution; the salt precipitated as a viscous oil, which solidified on standing, work-up after 17 days Resolving agent added in solution; the salt precipitated as a viscous oil, which solidified on standing, work-up after 24 h

0 0.2 0 0 0 0.27

Resolving agent added in solution; the salt precipitated as a viscous oil, which started to crystallize within 1 h; the powdery crystals transformed to needles on standing for 2 weeks Resolving agent added in solution; the salt crystallized within 3 h, filtered off after 2 days

0.38

Resolving agent added in solution; the salt crystallized within 3 h, filtered off after 2 days

0.80

Resolving agent added in solution; on seeding with the more stable salt, it crystallized within 25 min; filtered off after 20 h

0.75

0.80

Base 6.43 was resolved with O,O′-dibenzoyltartaric acid in ether. The amorphous precipitate was brought into solution by heating and the addition of some acetone. Heating was continued 59 until formation of a crystalline precipitate started. Stewart and Allen studied the resolution of 1-phenylethylamine with (1S)-3-bromocamphor60 10-sulfonic acid. The resolving agent was added in three different ways. (1) as a solid to a solvent in which was insoluble, (2) as a solid to a solvent in which it was soluble, (3) in solution and the experiments were carried out both with 1.0 and with 0.5 equivalents of the resolving agent. Results are presented in Table 6.12. From their experiments, the authors drew the important conclusion that success of a resolution depends more on the rate of crystal formation than on the solubility difference of the diastereomeric salts. Precipitation of a liquid phase (oil) impedes resolution because it increases the time necessary for the formation of a solid phase. The viscous liquid behaves as a solvent and crystallization is more difficult

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than from a more dilute solution. Therefore, precipitation of an oily phase must be avoided at the beginning of the process; later, however, it is a useful indicator that crystallization must be terminated. 61 When base 6.44 was resolved with tartaric acid in ethanol, a crystalline precipitate formed. After filtering the crystals, additional fractions were obtained by adding some diethyl ether, which decreased the solubility of the salts. Collection of further crops was continued until the appearance of an oily phase did not indicate the end of crystallization. Oils obtained at the end of crystallization are preferably combined with the mother liquor.

6.3 ROLE OF TEMPERATURE IN RESOLUTION Most of the resolutions are carried out under non-isothermic conditions and therefore the role of temperature is not negligible. Difficulties in repeating reported procedures can often be traced back to disregarding temperature. Reaction temperatures are often not reported at all or not exactly enough, (e.g., “room temperature,” “with heating,” etc.). The key step in resolution is fractionated crystallization, the success of which depends on the solubility of diastereomeric salts which, of course, are highly dependent on temperature. Room temperature may vary even in the same laboratory by as much as ±10°C, depending on the season and the hour of the day. In an average European laboratory, room temperature is about 20 to 22°C; but, for example, in 62 a Chinese publication, room temperature was specified as 13°C. Exact control of temperature is not only important because of the temperature dependence of solubility, but also because at different temperatures different polymorphic forms may crystallize. For example, sodium ammonium tartrate, when crystallized below 26°C, forms a conglomerate of enantiomorphic crystals that were separated by Pasteur in his famous experiment by hand picking. At at higher tempreature, however, it forms a molecular complex crystallizing in another polymorphic form that cannot be mechanically separated. Therefore, it is essential for the sake of reproducibility that the temperature of the reaction mixture be carefully monitored and recorded. In resolution, temperature plays multiple roles. First, the temperature at which the components can be dissolved in the chosen solvent should be determined. Note that formation of a diastereomeric salt is usually a highly exothermic process and taking a small amount of solvent some low boiling component (such as 1-phenylethylamine) may be lost by evaporation due to the liberation of reaction heat on mixing the components. Solubility permitting, it is expedient to dissolve the components separately and mixing them thereafter. Often, to prevent the rapid separation of a sparingly soluble diastereomeric salt, hot solutions are combined. When elaborating an industrial procedure, the temperature of crystallization must be optimized and, in laboratory experiments, it is important to overcool the solution. Crystallization of more than the theoretical amount of one of the diastereomeric salts should be avoided; in this case, either the temperature of crystallization must be elevated or the amount of solvent increased. Because with very few exceptions solubility increases with temperature, by working at higher temperature, solvent can be saved. First of all, in industrial resolutions, apart from saving solvent, an extra advantage is that a smaller vessel is needed. 63 Ingersoll et al. observed when resolving racemic 3-bromocamphor-8-sulfonic acid with L-1-(4-tolyl)ethylamine that the solubility difference between diastereomeric salt was much higher in the range of 50 to 80°C than at room temperature and therefore they carried out crystallization by cooling from 80 only to 50°C.

6.3.1 TEMPERATURE DEPENDENCE OF THE RESOLUTION OF PIPECOLIC ACID XYLYLIDES WITH TARTARIC ACID AND O,O′-DIBENZOYLTARTARIC ACID In elaborating the title resolution, the temperature of the process was also optimised. To a boiling solution of the racemic base, a hot solution of the resolving agent was gradually added, the clear solution allowed to cool to a given temperature, and kept with intensive stirring at this temperature for 64 2 h. The precipitated crystals were filtered off at the same temperature. Results are shown in Table 6.13. © 2002 by CRC Press LLC

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TABLE 6.13 Resolution of Pipecolic Acid Xylylides with Tartaric (TA) and O,O'-Dibenzoyltartric acid (DBTA) at Various Temperatures (optimum temperatures in boldface) Racemate Solvent

Resolving Agent

Temperature (°C)

Yield (%)

o.p. (%)

Plotting yields and optical purity data as a function of temperature, the point of intersection of the two curves gives the optimum temperature (see Fig. 6.2). It is apparent that in four cases out of five, the optimum temperature of resolution was in the range of 45 to 50°C, indicating that in contrast to normal crystallization, for resolution it is not always true that crystallization should be completed at the lowest practical temperature. As a function of temperature, the two most important characteristics of the diastereomeric salt (i.e., yield and optical purity) are changing in opposite © 2002 by CRC Press LLC

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FIGURE 6.2 Determination of the optimum temperature in resolution of N-2,6-xylyl-2-methylcyclohexane1-carboxamide.

FIGURE 6.3 Resolution of phenylsuccinic acid with L-proline as a function of temperature.

directions and this is the reason why resolution should be carried out at a temperature corresponding 65 to the intersection of the two curves.

6.3.2 TEMPERATURE DEPENDENCE OF THE RESOLUTION OF PHENYLSUCCINIC ACID WITH PROLINE Phenylsuccinic acid (6.45) is a dibasic acid. When reacted with one equivalent of L-proline (6.46) salt of the (−)-acid crystallizes from ethanol, while with two equivalents of the resolving agent that 66 of the (+)-acid precipitates from isopropanol. Looking at the temperature dependence of the process, the authors found that the efficiency of the resolution via the neutral salt is less temperature sensitive than the one via the acid salt. The latter improved with increasing temperature and reached an optimum at 40°C (see Fig. 6.3).

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6.4 SEPARATION OF CRYSTALS AND MOTHER LIQUOR For separation of crystals from the mother liquor, the routine operation is filtration in the laboratory and centrifugation in industry. Centrifugation may become the method of choice, even in the laboratory, when working with very small quantities or when the precipitate is gel-like or otherwise 67 difficult to filter off. For example, 2-ethoxy-2-phenylethylamine forms a gel with tartaric acid, a g˙ el that can only be separated by centrifugation.

A resolution carried on the smallest scale ever by fractional crystallization was the one of base 6.47. Base (18.8 mg) was reacted with (1S)-10-camphorsulfonic acid (23 mg) in a mixture of 0.2 ml methanol and 2.0 ml acetone directly in a 5-ml centrifuge tube; 8 mg of a salt separated, from which the authors not only managed to determine its melting point, record its IR spectrum and optical 68 rotation, but also liberated the base and purified it by sublimation to obtain 2 mg of the active base. Of the racemic base 6.48, a very small amount (38 mg) was also available. It was resolved with O,O′-dibenzoyltartaric acid (39 mg) in 0.6 ml of methanol, giving 11 mg of the salt separated 69 by filtration. On an industrial scale, filtration is only used when the reaction mixture is of relatively small volume or if it must be kept at a certain temperature, which is difficult to maintain during centrifugation. With crystals that are difficult to filter off, centrifugation usually provides fast separation. Unexpected difficulties may nevertheless emerge. Thus, the salt of 1-phenylethylamine with (R)-mandelic acid forms, from water, oblong hexagonal plates that obstruct the pores of the tissue of the centrifuge and form, under the effect of centrifugal forces, a compact layer on the inner wall of the centrifuge drum, thus obstructing the passage of mother liquor. Japanese researchers have 70 eliminated this problem by changing the crystal form of the salt. They observed that when a small amount (even as little as 0.007 mol%) of (R,R)-bis-1-phenylethylamine was added, instead of oblong hexagonal plates, much shorter hexagons crystallized, which could then be centrifuged more readily. Interestingly, neither the R,S nor the S,S diastereomers failed to be incorporated into the chains formed by (R)-mandelic acid molecules. Mother liquor and crystals can also be separated by decantation or, in industry, by siphoning. This method is especially useful when the recovery of further crystal fractions from the mother liquor is intended because a few crystals are always carried over and serve as seeds in the next step.

Separation of the solid phase can be carried out in multiple steps. For example, on resolution of base 6.49 with tartaric acid, the components were dissolved in water and crystallization was 71 initiated by adding ethanol to oversaturate the solution. After standing for 2 days, crystallization © 2002 by CRC Press LLC

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of the oily precipitate was still incomplete. At this point, the crystals were separated from the oil and after standing for another 5 days under the mother liquor, the oil crystallized. Separation of the crystals obviously helped to establish an equilibrium and the completion of resolution.

6.5 FURTHER PURIFICATION OF DIASTEREOMERIC SALTS WITH THE AID OF A CHIRAL ADDITIVE The optical purity of the first generation of a diastereomeric salt is very rarely of adequate optical purity. There are two main methods or their combination available to improve optical purity of the salt: with or without a chiral additive (for the latter, see Chapter 6.7). Enrichment with a chiral additive usually means that the diastereomeric salt in not decomposed until its purity has not been enhanced to the highest possible level by fraction crystallizations. Alternatively, after each step, the salt can be decomposed and the partially resolved substrate is subjected to another resolution process with (1) the same resolving agent, (2) with the other enantiomer of the same resolving agent to separate the minor enantiomer, or (3) with another resolving agent. The routine procedure is repeated recrystallizations from the original solvent until an optically pure diastereomeric salt is obtained. The end point can be monitored by taking the melting point and/or by any method suitable for the determination of optical purity. Most often, several recrystallization are necessary. Some resolutions with tartaric acid are compiled in Table 6.14, in which a high number of recryztallizations was required.

75

Base 6.50 was resolved with tartaric acid in methanol. The precipitated salt contained the (+)enantiomer in excess. Because the salt had already decomposed at 40°C, it could not be purified by recrystallization; therefore, the base was recovered from the salt and subjected to repeated resolution with the same agent. The procedure was repeated four times until the product became optically pure. Faster upgrading of optical purity can occasionally be achieved by repeating the resolution with the antipode of the original resolving agent, whereupon crystallization of the salt of the minor component can be expected. TABLE 6.14 Resolutions Involving a High Number of Recrystallizations

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TABLE 6.15 Purification of Diastereomeric Salts by Trituration

O NH

O O 2N

COOH Br

Ph H

COOH S N

O

N

OH N

N Cl

CO2H

N

N O O2N

O-t-Bu NH2 OH OH

69

An example is the resolution of diamine 6.51 with tartaric acid in ethanol. The optically impure enantiomer was recovered from the salt and subjected to resolution with unnatural (2S,3S)tartaric acid. The pure (+)-enantiomer of the base could be recovered from the mother liquor. Recrystallization can sometimes be replaced by trituration with a cold solvent as shown in Table 6.15. As can be seen, trituration can be performed either in a single or in several steps, or even changing the solvent or using a solvent mixture. If batchwise trituration is not effective, continuous extraction may be the method of choice.

6.6 RECOVERY OF THE COMPONENTS FROM THE DIASTEREOMERIC SALTS Recovery of components from the diastereomeric salts is accomplished by treatment with an acid or a base. In small-scale laboratory experiments, often only the target compound is recovered by adding an agent of the same character as the compound (i.e., an acid or a base), but stronger than the compound to be recovered. This agent gives a salt with the resolving agent and the target compound liberated can be filtered off or extracted with a suitable solvent. © 2002 by CRC Press LLC

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Decomposition of the salts is generally performed in water by adding a 1.5 to 2.0 equivalents of a mineral acid or base. If recovery of both components is intended and one of them is insoluble in water, it is practical to separate the latter one first because it does not interfere later with the recovery of the other partner. If one of the components decomposes in water, liberation can be carried out in an anhydrous medium, for example, by introducing ammonia gas or hydrogen chloride gas 83 into the solution (see resolution of base 6.53).

Base 6.52 was resolved with tartaric acid in methanol. The salt was suspended in dry diethyl ether and, by introducing hydrochloric acid gas, the resolving agent was liberated first, followed by ammonia gas to recover the base. Decomposition of the salt in a solvent is also a practical proposition when the target compound is too soluble in water and therefore its recovery by multiple extraction is inefficient. Ion exchange resins can also act as a strong acid or base. Separation is carried out from an aqueous solution. Using an acidic resin, the effluent contains the pure organic acid, while the base is retained by the resin. The base can be eluted from the column by a strong mineral acid and recovered from the resulting salt solution by adding a strong mineral base followed by extraction of the organic base. This method is especially attractive when only the recovery of the target compound is intended or when conventional techniques of recovery fail (e.g., with acid 6.53). On resolution of 6.53 with quinine, the diastereomeric salt was decomposed with hydrochloric acid, followed by extraction, to give a polymeric product. Passing, in turn, the aqueous solution of the salt through a cation exchange resin, the basic component was retained on the column while the acidic component was recovered without polymerization by evaporation of the eluate 84 in vacuum. An interesting method for the decomposition of a diastereomeric salt was reported in connection with the resolution of racemic asparagine with O,O′-dibenzoyltartaric acid. This amphoteric compound was resolved without derivatization in aqueous methanol. The precipitate was refluxed with three times its weight of methanol, whereupon the resolving agent dissolved and optically active asparagine was left behind as a solid. As an explanation, it can be assumed that it was not a genuine diastereomeric salt that was formed, but rather a complex and the equilibrium of complex formation was shifted toward the decomposition of the complex during boiling with a solvent that dissolved 86 one component and not the other.

6.7 UPGRADING OF OPTICAL PURITY WITHOUT A CHIRAL 85 ADDITIVE (ENANTIOMERIC ENRICHMENT) Optically impure enantiomers liberated from the diastereomeric salts—but not racemates—can be purified, apart from repeated resolution, without any chiral aid (enantiomeric enrichment). For this purpose, conventional recrystallization, crystallization from melt, flotation (separation by density differences), selective precipitation, and distillation after partial salt formation can be applied. Enantiomeric enrichment is always based on the distribution of the initial enantiomeric mixture between two separable phases. The efficiency of the separation is determined by the difference between composition of the two phases. The degree of enrichment can be characterized by the ratio © 2002 by CRC Press LLC

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of the enantiomeric excess of the two phases or by the ratio of the enantiomeric excess of the starting mixture and the enriched phase. From a practical point of view, yield should also be considered; that is why we suggest the use of the term Efficiency of the Enantiomeric Enrichment (EEE) for the evaluation enantiomer enrichment experiments. EEE can be defined as the ratio of the enantiomer content (enantiomeric excess) in the enriched and the initial enantiomeric mixture: op e r EEE = --------op 0

(6.2)

where ope = Enantiomeric excess in the enriched phase (%) op0 = Enantiomeric excess in the initial mixture (%) r = Ratio of the amount of enriched and initial mixture (%) EEE values should only be calculated for the enriched phase (op0 < ope); thus, EEE ranges from >0 to 100. For example, EEE = 90 means that 90% of the enantiomer in excess of the initial enantiomeric mixture was transferred into the enriched phase. Several types of phase equilibria are conceivable and can result in enrichment. Methods of enantiomeric enrichment can be classified according to the type of phase transition. The enantiomers can be separated as such, or in form of a suitable achiral derivative (e.g., as a salt). Table 6.16 summarizes, without regard to their practical value, concievable methods that can be applied for the enantiomers proper or for their equimolar derivatives with an achiral agent. Equations (6.3) and (6.4) represent examples of enantiomeric enrichment of an enantiomeric mixture of 50% e.e. (i.e., containing 75% E and 25% ∃. EE∃ EE∃.3A

E + E∃

(6.3)

EA + E∃.2A

(6.4)

where E represents the enantiomer in excess, ∃ its antipode, and A is an achiral salt forming agent. As in other binary systems, enantiomeric mixtures can also crystallize in three main forms. In the case of a solid solution, separation is impossible because of the isomorphism of the enantiomers. Separation is, however, possible if a racemic molecular compound or a conglomerate is formed. During separation, the enantiomeric mixture behaves as a binary mixture of the eutectic and the

TABLE 6.16 Possible Phase Equilibria in Enantiomeric Enrichment Processes Phase 1 Solid Solid Solid Liquid Liquid Solid

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Phase 2

Method of Separation

Liquid (melt) Liquid (solution)

Crystallization from melt Crystallization from solvent Sublimation Distillation Extraction Flotation

Vapor Vapor Liquid Solid

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TABLE 6.17 Enantiomeric Enrichment by Crystallization from Melt Solid Phase

Liquid Phase

Temp. (ºC)

o.p.0 (%)

o.p. (%)

y (%)

o.p. (%)

y (%)

EEE

6.54

0–5

6.55 6.56

20 25

21.5 29.2 52.3 79.5 42.6 48.2

69.2 72.5 76.9 93.0 15.5 83.5

10.0 39.0 44.9 60.0 60.0 32.1

6.2 2.6 29.2 54.2 83.3 28.5

84.3 59.0 55.1 40.0 40.0 64.7

32.2 96.8 66.0 70.2 78.2 55.4

Compound

racemate, or the eutectic and the pure enantiomer. In the case of conglomerate formation, the excess of the major enantiomer can be precipitated practically pure, leaving the racemate in the mother liquor. When a racemic molecular compound is formed, the purity of the solid phase depends on the purity of the starting mixture. If x0 > xeu , the system behaves as the mixture of the enantiomer in excess and the eutectic, and the former can precipitate in a pure state, leaving the eutectic in the liquid phase. When x0 < xeu , the system behaves as the mixture of the racemate and the eutectic and it is the pure racemate that precipitates. Enantiomer separation cannot be achieved when the eutectic composition coincides with that of starting mixture x0 = xeu. The simplest way of enantiomer enrichment is to gradually cool the melted enantiomeric mixture, whereupon a portion of the mixture, the racemic or the optically active part, crystallizes. The solid can be separated by filtration. This is convenient when the crystallization temperature is close to room temperature. A special apparatus is required if the melting temperature is too low or too high. Three examples of such separations from our practice are summarised in Table 6.17.

In the case of compound 6.54, four experiments with different starting e.e. values were accomplished. The solid phase was always of higher e.e. than the starting mixture, which was in accordance 86 with the fact that compound 6.54 forms a conglomerate. By increasing x0, e.e. of the solid phase increased, but EEE was the highest when the initial enantiomeric purity was about 30%. In case of © 2002 by CRC Press LLC

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compound 6.55, the enantiomer is enriched in the mother liquor, which indicated that this substance forms a racemic phase and the eutectic molar fraction should be greater than 0.71. Optically active 6.56 concentrated in the solid phase, leaving open the question of whether 6.56 formed a conglomerate or a racemic compound with xeu < 0.74. We never obtained completely optically pure or racemic products, probably due to contamination from the viscous liquid phase, of which a substantial amount adhered to the solid. Recrystallization of non-racemic enantiomeric mixtures from a solvent is the most frequently used method of enantiomeric enrichment and is also based on solid-liquid phase transition. Some of our enantiomeric enrichment experiments by recrystallization (nine compounds) are presented in Table 6.18.

= = =

Preparative chemists usually consider a recrystallization successful when the enrichment occurs in the solid phase. It can be seen, however, from Table 6.18, that while efficient enantiomer separation could be achieved in each case, enrichment in the mother liquor was most often found. At least six of the nine substances form racemic compounds (o.p. < o.p.0), while our data do not permit a decision for compounds 6.57, 6.58, and 6.71. During recrystallization, 6.55 behaves as when crystallizing from melt, but the EEE value is lower. In the cases of compounds 6.57, 6.58, 6.60, 6.61, and 6.71, EEE values of about 90 indicate that efficient separation can be achieved. Enrichment of 6.60 to 88.8% e.e. is a good example of the fact that for efficient separation it is not enough when one phase contains the pure enantiomer only, but its quantity is less than it is theoretically possible. With 6.72 · HCl, it is certain that the salt forms a racemic compound (xeu being between 0.97 and 1) because the enantiomeric excess of the precipitated material is lower than that of the starting mixture. © 2002 by CRC Press LLC

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TABLE 6.18 Enantiomeric Enrichment by Recrystallization of Enantiomeric Mixtures Enantiomeric Mixture 6.55

Solvent

6.57 6.58 6.59

Acetonewater iPrOH EtOH Water

6.60

EtOAc

6.61 6.62 6.71 6.72 • HCl

EtOH EtOH Acetone MeOH

Solid Phase

Liquid Phase

o.p.0 (%)

o.p.0 (%)

y (%)

o.p. (%)

39.1

19.0

63.4

77.6 65.6 50.6 75.3 86.3 40.2 52.8 61.4 85.0 88.8 65.2 58.3 84.0 85.0 92.4 94.8

95.9 100 43.1 86.4 92.6 4.8 8.8 9.8 98.2 100 14.8 29.7 95.2 77.2 85.0 93.1

74.0 64.0 44.0 48.3 73.8 42.0 47.7 33.3 45.0 24.4 35.0 58.1 81.3 51.9 31.0 61.9

y (%)

EEE

60.1

36.6

56.3

25.5 0.0 56.9 66.8 72.8 69.0 95.1 92.2 78.6 64.4 100 97.5 38.3 92.2 94.8 97.5

26.0 36.0 55.0 50.3 24.7 56.5 51.0 63.7 51.8 73.5 60.0 40.0 16.9 47.1 67.0 37.8

91.5 97.6 61.9 55.4 79.2 97.0 91.9 95.7 52.0 27.5 92.0 66.9 92.1 51.0 68.7 38.7

The eutectic composition of 6.59 has not been determined, but the purity of the precipitate improved when x0 increased from 0.75 to 0.86, which indicated that its eutectic point is around 0.8 molar fraction. In the literature there are only two examples of enantiomeric enrichment by solid-vapor phase 87,88 equilibrium. Nevertheless, the method is quite promising, first of all for industrial applications because it can be accomplished without producing any waste. Unfortunately, the method is limited to the rare cases when the compound is volatile. The EEE value for the sublimation of 1-phenylpropyl phenyl sulfide is quite high (76.0), while for different mandelic acid fractions it is between 12 and 40. It is quite simple to distribute an enantiomeric mixture between liquid-vapor or liquid-liquid phases; but because the enantiomers in the liquid phase behave ideally regardless of the enantiomer 89 content, it is doubtful that measurable separation can be achieved. Another rare separation method exploits the density difference between racemic molecular compounds and the pure enantiomers.90 Crystals of the optically active and racemic species can be separated by suspending the crystals in an indifferent solvent adjusted to a density between that of the enantiomer and the racemate. Table 6.19 illustrates the application of this method. © 2002 by CRC Press LLC

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TABLE 6.19 Enantiomeric Enrichment Using Density Difference Sample 6.73 hydrogen fumarate 6.74

Upper Phase

Lower Phase

o.p.0 (%)

o.p.0 (%)

y (%)

o.p. (%)

y (%)

EEE

50

45

64

61

34

41.5

70 50

57 90

48 44

75 13

50 55

53.6 79.2

Enantiomeric enrichment can be accomplished by the use of a nonequivalent amount of an 91,92 achiral agent but only a few data are available on such separations. Separation is based on a multicomponent equilibrium system in which the achiral salt forming agent reacts preferentially with either the enantiomer or racemate: EE∃ + A EE∃ + 2A

EA + E∃

(6.5)

E + E∃.2A

(6.6)

The amount of achiral agent is selected to be equivalent to either the optically active [Eq. (6.5)] or the racemic part [Eq. (6.6)], depending on whether one wants to prepare the salt of the racemate or that of the enantiomer. Separation can be accomplished by phase equilibria similar to those listed in Table 6.16. No example for enantiomeric enrichment by the use of nonequivalent amounts of an achiral agent, an analog of crystallization from melt, has been reported. It should be advantageous for enantiomer enrichment of liquid enantiomeric mixtures that can easily be separated by filtration from a partially formed solid salt. A practical realization of the above principle is selective precipitation (Table 6.20): an achiral salt is formed and from its aqueous solution part of the material is precipitated by partial neutralization with a strong acid or base. The precipitate and the solute always have different enantiomeric purities. EEE values are in about the same range as in recrystallization. It can be seen from Table 6.21 that this rarely applied method sometimes gives very efficient enantiomer separation. For example, in case of 6.59, selective precipitation gives more efficient enrichment (o.p.0 = 85% → o.p.e = 98.6%) than the recrystallization (o.p.0 = 86.3% → o.p.e = 92.6%). In the case of 6.71, recrystallization gives better results; while for 6.62, efficiency of the the two methods is comparable. With 6.63 and 6.70, the nature of the precipitate (racemic or optically active) depended on the enantiomeric purity of the starting material, while for example in the case of 6.65, the enantiomer was enriched always in the solid phase. There is no published example of enantiomeric enrichment with a nonequivalent amount of an 93 achiral agent by sublimation and only one for distillation. (Table 6.21). Compound 6.73 of different enantiomeric purities was reacted with 0.375 mole of an achiral dicarboxylic acid and the remaining free base was separated by distillation. When oxalic acid or succinic acid was applied, the purity of the distillate depended on the enantiomeric purity of the starting mixture, while using fumaric acid it was always the enantiomerically enriched product that distilled. This method can be used efficiently as a last step in large-scale production of an optically active volatile compound because enantiomeric enrichment is combined with an efficient chemical purification, but the EEE values are rather low for practical separation. Among enantiomeric enrichments using nonequivalent amounts of an achiral agent, liquidliquid phase transition is represented by selective extraction. In selective extraction, the enantiomeric mixture is dissolved in water in the form of a salt and the partially liberated enantiomer is extracted by a water-immiscible solvent. Selective extraction of the same enantiomeric mixtures proved less efficient than selective precipitation. © 2002 by CRC Press LLC

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TABLE 6.20 Enantiomeric Enrichment by Selective Precipitation Solid Phase Enantiomeric Mixture

Precip. Agent

Solvent

6.59 ⋅ HCl

NH4OH

EtOH-water

6.63 ⋅ Na

HCl

Water

6.64 ⋅ NH 6.65 ⋅ Na

HCl HCl

Water Water

6.62 ⋅ Na

HCl

Water

6.69 ⋅ NH3

HCl

Water

6.66 ⋅ NH3

HCl

Water

6.67 ⋅ HCl 6.68 ⋅ HCl 6.70 ⋅ Na

NaOH NaOH NaOH

Water Water Water

6.71 ⋅ HCl

NaOH

Water

Liquid Phase

o.p.0 (%)

o.p. (%)

y (%)

o.p. (%)

y (%)

EEE

60.6 85.0 48.3 66.4 75.0 48.6 22.3 31.7 43.4 68.0 76.0 88.6 53.2 88.0 31.0 37.6 40.1 56.7 53.8 80.3 25.8 71.1 80.0

11.4 20.0 7.4 14.3 90.5 23.3 37.8 57.8 81.1 85.7 86.0 89.7 27.7 77.5 5.2 16.0 24.3 43.8 0.0 5.0 10.2 77.2 81.0

42.5 18.2 24.3 15.9 28.1 72.6 45.5 45.5 47.6 42.3 34.8 46.4 23.4 34.6 28.1 53.2 44.2 51.1 42.8 12.7 35.6 14.3 27.9

97.1 98.6 63.5 78.3 68.3 91.2 6.2 4.6 4.7 49.1 64.1 86.3 62.4 97.5 44.0 67.0 53.1 66.7 94.0 99.6 36.3 63.7 78.0

57.0 69.7 73.2 82.0 68.4 26.5 35.9 35.9 35.3 49.3 34.7 30.9 71 61.5 65.0 39.0 55.3 40.4 57.0 65.5 58.9 75.2 71.1

91.3 80.9 96.2 96.7 33.9 49.7 77.1 83.0 88.9 53.3 39.4 47.0 83.3 68.1 92.3 69.5 73.2 47.5 99.6 81.2 82.9 15.5 28.3

TABLE 6.21 Enantiomeric Enrichment of 6.73 by Distillation of the Free Base after Partial Salt Formation by Achiral Acids Achiral Acid

o.p.0 (%)

Distillate o.p. (%)

Residue o.p. (%)

EEE (%)

Oxalic acid

12.5 25.0 50.0 75.0 87.5

26.6 44.6 63.6 65.7 71.5

7.8 18.5 45.5 78.1 92.8

53.2 44.6 31.8 26.0 26.5

Succinic acid

12.5 25.0 50.0 75.0 87.5

27.3 61.7 75.2 74.2 83.6

7.6 12.8 41.6 75.3 88.8

54.6 61.7 37.6 25.1 25.4

Fumaric acid

12.5 25.0 50.0 75.0 87.5

41.8 68.5 95.5 96.3 97.6

2.7 10.5 34.9 67.9 84.1

83.6 68.5 47.8 32.1 27.9

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When enantiomeric mixtures are separated by any method, they behave as a mixture of the optically active (or racemic) compound and the eutectics, and separation can always be achieved to some extent; but for an efficient enantiomer separation, one of the phases should be solid. In several cases, the precipitate has a lower enantiomeric excess than the starting mixture; in this case, it is usually not necessary to look for another method because the work-up of the mother liquor can give the enriched enantiomer. This simple fact is often neglected. Enantiomeric enrichment experiments can inform whether the investigated compound forms a conglomerate or a racemic compound. Our and other authors’s observations indicate that racemic compounds are more frequent than conglomerates. Enantiomeric enrichment methods using nonequivalent amounts of achiral agent are sometimes very efficient, even when simple recrystallization is not satisfactory; therefore, this method deserves more attention.94–104

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33.

R.B. Woodward and W.E. Doering, J. Am. Chem. Soc., 67, 860 (1945). A. McKenzie, J. Chem. Soc., 101, 1196 (1912). G. Cleason, Arkiv Kemi, 30, 277 (1968). J.B. Conant and G.H. Carlson, J. Am. Chem. Soc., 54, 4056 (1932). W.N. Nagai and S. Kanao, Justus Liebigs Ann. Chem., 470, 157 (1929). H. Wren and G.L. Miller, J. Chem. Soc., 157 (1935). K. Takeda, S. Hagishita, M. Sugiura, K. Kitahonoki, I. Ban, S. Miyazaki, and K. Kuriyama, Tetrahedron, 26, 1435 (1970). J.H. Ager, A.E. Jacobson, and E.L. May, J. Med. Chem., 12, 288 (1969). C.A.R. Baxter and H.C. Richards, J. Med. Chem., 14, 1033 (1971). J.W.E. Glattfield and C.N. Cameron, J. Am. Chem. Soc., 49, 1043 (1927). K. Wetterlin, J. Med. Chem., 15, 1182 (1972). C. Comoy, Ch. Marot, T. Podana, M.-L. Baudin, L. Morin-Allory, G. Guillaumet, B. Pfeiffer, D.-H. Caignard, P. Renard, M.-C. Rettori, G. Adam, and B. Guardiola-Lemaitre, J. Med. Chem., 39, 4285 (1996). Y. Kato and T. Wakabayashi, Synth. Commun., 7, 125 (1977). D.H.R. Barton, D.S. Bhakuni, G.M. Chapman, G.W. Kirby, L.J. Haynes, and K.L. Stuart, J. Chem. Soc. C, 1295 (1967). F.G. Mann and J.W.G. Porter, J. Chem. Soc., 456 (1944). B. Sjöberg, Arkiv Kemi, 9, 295 (1956). British Patent, 656, 500 (1951). H. Geipel, J. Prakt. Chem., 9, 104 (1959). J. Bálint, Ph.D. thesis, Technical University of Budapest (1997). D. Kozma, Á. Nyéki , M. Ács, and E. Fogassy, Tetrahedron: Asymmetry, 5, 315 (1994). S. Larsen, H. Lopez de Diego, and D. Kozma, Acta Cryst., B49, 310 (1993). D. Kozma, J. Sztatisz, K. Tomor, G. Pokol, and E. Fogassy, J. Therm. Anal. Cal., 60, 409 (2000). D. Kozma, C. Novák, K. Tomor, G. Pokol, and E. Fogassy, J. Therm. Anal. Cal., 61, 45 (2000). R.Yoshioka, K. Okamura, S. Yamada, K. Aoe, and T. Da-te, Bull. Chem. Soc. Jpn., 71, 1109 (1998). T.D. Stewart and C. Allen, J. Am. Chem. Soc., 54, 4027 (1932). R.D. Haworth and F.H. Slinger, J. Chem. Soc., 1321 (1940). N.W. Searle and R. Adams, J. Am. Chem. Soc., 55, 1649 (1933). P. Newman, Optical Resolution Procedures for Chemical Compounds, Vol. 1, Amines and Related Compounds. 173, 1978. A. Wohl and R. Maag, Chem. Ber., 42, 627 (1909). B.R. Brown and D.L. Hammick, J. Chem. Soc., 99 (1948). G. Stork and F.H. Clarke, Jr., J. Am. Chem. Soc., 83, 3114 (1961). U.S. Patent 2.773.901, 1954. A. Hagerdon, F. Braun, and W. Güthlein, German Patent 1.274.586, 1967.

© 2002 by CRC Press LLC

0019_frame_C06 Page 149 Monday, August 6, 2001 1:30 PM

34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83.

A.F. Casy and J.L. Myers, J. Pharm. Pharmacol., 16, 455 (1964). E. Berner and R. Leonardsen, Tids. Kjem., 64 (1943). B. Langström, Chem. Scr., 5, 170 (1974). M.M. Abdel-Monem, D.L. Larson, H.J. Kupferberg, and P.S. Portoghese, J. Med. Chem., 15, 494 (1969). E. Bamberger, Chem. Ber., 23, 291 (1890). O. Engels, Chem. Ber., 33, 1087 (1900). M. Sholtz and H. Müller, Chem. Ber., 2842 (1901). E. Fogassy, unpublished results. C.S. Gibson, J. Chem. Soc., 342 (1927). K.F. Hoback, Ph.D. thesis, West Virginia University (1955). C.J. Dippel, Rec. Trav. Chim. Pays-Bas., 50, 525 (1931). A.C. Barker and A.A. Battersby, J. Chem. Soc. C, 1317 (1967). A. Brossi and F. Burkhart, Helv. Chim. Acta, 44, 1558 (1961). V. Prelog, A. Langeman, O. Rodig, and M. Ternbah, Helv. Chim. Acta, 42, 1301 (1959). W.F.M. Van Bever, C.J.E. Niemegeers, and P.A.J. Jansen, J. Med. Chem., 17, 1047 (1974). A. Brossi, H. Besendorf, B. Pellmont, M. Walters, and O. Schnider, Helv. Chim. Acta, 43, 1459 (1960). F.B. Kipping, J. Chem. Soc., 18 (1935). R. Vince and S. Daluge, J. Med. Chem., 17, 578 (1974). W. Tochtermann, H. Kuppers, and C. Franke, Chem. Ber., 101, 3808 (1968). U.S. Patent 2.644.010 (1953). W.I. Patterson and R. Adams, J. Am. Chem. Soc., 57, 762 (1935). E. Balieu, P.M. Boll, and E. Larsen, Acta Chem. Scand., 23, 2191 (1969). G.R. Clemo, C. Gardner, and R. Raper, J. Chem. Soc., 1958 (1939). T. Kametani and S. Shibuya, J. Chem. Soc., 5565 (1965). J.M. Gulland and R.D. Haworth, J. Chem. Soc., 131, 1834 (1928). P. Newman, Optical Resolution Procedures for Chemical Compounds, Vol. 1, Amines and Related Compounds, 1978, 404. T.D. Stewart and C. Allen, J. Am. Chem. Soc., 54, 4027 (1932). British Patent, 750.156 (1956). M.Wang, S.Z. Liu, J. Liu, and B.-F. Hu, J. Org. Chem., 60, 7364 (1995). A.W. Ingersoll and S.H. Babcock, J. Chem. Am. Soc., 55, 341 (1933). K. Nemák, D. Kozma, and E. Fogassy, Mol. Cryst. Liq. Cryst., 276, 31 (1996). T.D. Stewart and C. Allen, J. Am. Chem. Soc., 54, 4027 (1932). T. Shiraiwa, Y. Sado, S. Fujii, M. Nakamura, and H. Kurokawa, Bull. Chem. Soc. Jpn., 60, 824 (1987). W.R. Brode and I.J. Wernert, J. Am. Chem. Soc., 65, 1685 (1933). E.E. van Tamelen and J.S. Baran, J. Am. Chem. Soc., 80, 4659 (1958). C. Szántay and M. Bárczai-Beke, Chem. Ber., 102, 3963 (1969). K. Sakai, Y. Maekawa, K. Saigo, M. Sukegawa, H. Murakami, and H. Nohira, Bull. Chem. Soc. Jpn., 65, 1747 (1992). M. Gullotti, A. Pasini, P. Fantucci, R. Ugo, and R.D. Gillard, Gazz. Chim. Ital., 102, 855 (1972). G.H. Cocolas, E.C. Robinson, and T.C. Spaulding, J. Pharm. Sci., 60, 1749 (1971). W.R. Brode and I.J. Wernert, J. Am. Chem. Soc., 55, 1685 (1933). M.M.-L. Chan and J.B. Robinson, J. Med. Chem., 17, 1057 (1974). D. Terunuma, T. Okada, T. Araki, and H. Nohira, Chem. Lett., 675 (1975). M. Walter, H. Besendorf, and O. Schnider, Helv. Chim. Acta, 46, 1127 (1963). P.A. Levene and M. Kuna, J. Biol. Chem., 141, 391 (1941). P.H. Mazzocchi and R.S. Lustig, J. Am. Chem. Soc., 97, 3714 (1975). J.-P. Bourquin, G. Schwarb, G. Gamboni, R. Fischer, L. Ruesch, S. Guldimann, V. Theus, E. Schenker, and J. Renz, Helv. Chim. Acta, 42, 259 (1959). M. Tramontini, L. Angiolini, C. Fouquey, and J. Jacques, Tetrahedron, 29, 4183 (1973). M.S. Ashwood, A.W. Gibson, P.G. Houghton, G.R. Humphery, D.C. Roberts, and S.H.B. Wright, J. Chem. Soc. Perkin Trans. 1, 641 (1995). J. Kucera, Collect. Czech. Chem. Commun., 20, 968 (1955). S.V. Rogozhin, V.A. Davankov, and Y.P. Belov, Izv. Akad. Nauk SSSR, Ser. Khim., 955 (1973).

© 2002 by CRC Press LLC

0019_frame_C06 Page 150 Monday, August 6, 2001 1:30 PM

84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104.

F.W. Bachelor and G.A. Miana, Can. J. Chem., 47, 4089 (1969). D. Kozma and E. Fogassy, Enantiomer, 2, 51 (1997). M. Ács, G. Pokol, F. Faigl, and E. Fogassy, J. Therm. Anal., 33, 1241 (1988). H. Kowart and D.P. Hoster, J. Org. Chem., 32, 1867 (1967). D.L. Garin, D.J.C. Greco, and L. Kelly, J. Org. Chem., 42, 1249 (1977). A. Horeau and J.P. Guetté, Tetrahedron, 30, 1293 (1974). D. Kozma, C. Kassai, and E. Fogassy, Tetrahedron Lett., 36, 3245 (1995). E. Fogassy, F. Faigl, and M. Ács, Tetrahedron Lett., 22, 3093 (1981). E. Fogassy, F. Faigl, and M. Ács, Tetrahedron, 41, 2841 (1985). D. Kozma, Z. Madarász, M. Ács, and E. Fogassy, Chirality, 7, 381 (1995). J. Jacques, A. Collet, and S.H. Willen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, New York (1981). R.A. Sheldon, Chirotechnology, Marcel Dekker, New York (1993). M. Ács, E. Fogassy, F. Faigl, E. Faigl-Birkás, and Z. Török, presented at 14th Int. Conf. on the Synthesis of Natural Products, Nancy (1988). T. Gizur, K. Harsányi, and E. Fogassy, J. Pract. Chem., 336, 628 (1994). E. Fogassy, M. Ács, G. Tóth, K. Simon, T. Láng, L. Ladányi, and L. Párkányi, J. Mol. Struct., 147, 143 (1986). É. Kozsda, Ph.D. thesis, Technical University of Budapest (1991). J. Bálint, M.Sc. thesis, Technical University of Budapest (1992). E. Fogassy, M. Ács, and I. Hermecz, Per. Pol., Chem. Eng., 20, 263 (1976). Fogassy, M. Ács, I. Hermecz, and I. Máthé, Per. Pol., Chem. Eng., 21, 229 (1977). M. Ács, E. Fogassy, F. Faigl, K. Tomor, K. Simon, K. Marsó, M.J. Brienne, and J. Jacques, Mol. Cryst. Liq. Cryst. Inc. Nonlin. Opt., 156, 193 (1988). F. Faigl, K. Simon, A. Lopara, É. Kozsda, R. Hargitai, M. Czugler, M. Ács, and E. Fogassy, J. Chem. Soc. Perkin Trans. 2, 57 (1990).

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7

Alternative Methods of Resolution by Diastereomeric Salt Formation

7.1 CLASSIFICATION OF ALTERNATIVE RESOLUTION PROCESSES BY TYPE OF PHASE TRANSITION Although diastereomeric salts are almost exclusively separated by fractional crystallization, several other methods based on phase transition may be suitable for their separation. In Table 7.1, methods of preparative significance are classified according to the type of phase transition. Although few examples have been published about alternative methods, they become even more significant due to various advantages as compared to resolution by fractional crystallization.

7.2 RESOLUTION BY DISTILLATION Using a half equivalent of the resolving agent, the portion not involved in salt formation contains the other enantiomer in excess. With fractional crystallization, this remains in the mother liquor. If the substrate is volatile, it can, however, be separated from the salt by distillation. Organic acids often decompose during distillation, but many organic bases can be distilled under reduced or even atmospheric pressures and in this case it may not be necessary to work out the resolution of the racemate by fractional crystallization. There are several reasons why the distillation method should be attempted, including: 1. Resolution by fractional crystallization failed 2. Fractional crystallization would require unreasonably large volumes 3. Only a high number of crystallizations would give an optically pure product Note that distillation also involves chemical purification and may thus save one operation in the 1 technological process. Realization of the method is quite simple. A half equivalent of solid resolving agent and one equivalent of liquid racemate are mixed and, after standing for 0.5 to 1 h, the free enantiomer is distilled off, preferably under reduced pressure. The distillate is, in an ideal case, the pure enantiomer, while its antipode and the resolving agent can be recovered from the remaining salt. The following illustrates the method for the resolution of N-methylamphetamine (MA) by distillation (Scheme 7.1). MA is a readily distillable base, while its salts are solid. Tartaric acid (7.1) and its two O-acyl derivatives (i.e., O,O′-dibenzoyltartaric acid (7.2) and O,O′di-4-toluoyltartaric acid (7.3) are equally efficient in resolving MA by fractional crystallization. Being diacids, they can form acid and neutral salts with bases. Tartaric acid itself forms an acid salt, while its diacyl derivatives give the neutral salts. The applied base:acid ratio was varied from 1:1 to 4:1. If half of the base remains unreacted, a 2:1 ratio corresponds to an acid salt, while 4:1 corresponds to a neutral salt. In the case of tartaric acid, only with a molar ratio of 1:1 could a distillate be obtained, indicating that with this resolving agent even an acid salt was not formed. Lack of a distillate in the case of the O-acyl derivatives proved that, indeed, salt formation took place.

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TABLE 7.1 Methods for Resolution by Forming Diastereomeric Salts Phase 1

Phase 2

Method

Molar Equivalents of Resolving Agent

Liquid

Gas Liquid Solid

Distillation Extraction Fractional crystallization from solution

0.5 1.0 or 0.5 1.0 or 0.5

Solid

Gas Liquid Solid

Sublimation Supercritical extraction Flotation, manual separation of conglomerates

1.0 or 0.5 0.5 1.0 or 0.5

SCHEME 7.1

Tartaric acid and molar ratios of both 2:1 and 4:1 gave more than the expected amount of a racemic distillate, showing that under these conditions N-methylamphetamine failed to form a salt with tartaric acid and therefore resolution could not take place. In contrast to tartaric acid, the two O-acyl derivatives (7.2 and 7.3) are capable of resolving N-methylamphetamine and with a molar ratio of 2:1; nearly 70% optical purity and 50% yield could be realized (i.e., in the residue, the ratio of neutral and acid salt were approximately the same). By changing the molar ratio to 3:1, the composition of the residue did not change but the amount of distillate doubled, along with a slight increase in optical purity. Interestingly, a further increase in the molar ratio to 4:1 had no effect on the quantity of the distillate and optical purity was between that achieved with molar ratios 2:1 and 3:1. The amount of base in the residue was higher than calculated for a neutral salt, indicating that the salt retained some of the base. When the residue obtained after resolution with O,O′-dibenzoyltartaric acid and a molar ratio of 4:1 was treated with four times its weight of powdered potassium hydroxide, part of the base could be distilled off as a racemate. The base recovered from the salt after this operation was of higher optical purity than the original distillate. It seems, therefore, that on salt formation, the more stable diastereomeric salt remains in the residue. Chiral selectivity was better with the benzoyl derivative than with the 4-toluyl compound. While yields are the same, optical purity is better with the former. Is must be mentioned that in the above experiments, O,O′-dibenzoyltartaric acid monohydrate was used. With the anhydrous form, the optical purity of the distillate was higher. This can be explained by assuming that in case of the hydrate, there is competition between water and the base for the binding sites in the complex. A resolvability value of 0.74 compares well with industrial resolution technologies of N-methylamphetamine using fractional crystallization. The efficiency of resolution can be somewhat improved by mixing the components in the presence of a solvent, which is then evaporated before distilling the base. On reacting the base with the O-acyltartaric acids in methanol, no distillate could be obtained with a molar ratio of 2:1, indicating complete formation of a neutral salt. With a ratio of 4:1, in turn, the distillate was of high optical purity and an S value of 0.72 showed that this method was superior to simple mixing of acid and base without a solvent. Note that, as a practical advantage, much less solvent was used than is usual in fractional crystallization. Results are summarized in Table 7.2. © 2002 by CRC Press LLC

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TABLE 7.2 Resolution of N-Methylamphetamine by Distillation

Resolving Agent 7.1

7.2

a

7.2 b 7.2 7.3

7.3

b

L-7.4 L-7.5 L-7.6 (+)-7.7 (S)-7.8 (R,R)-7.9 (2R,3R)-7.10 (R)-7.11 (R)-7.12 (R)-7.13 (S)-7.14 7.15 (1S)-7.16 L-7.17 D-7.18 a

Anhydrous.

b

Base:Acid Molar Ratio

Yield of Distillate (%)

o.p. of Distillate

S

1:1 2:1 4:1 1:1 2:1 3:1 4:1 4:1 2:1 4:1 1:1 2:1 3:1 4:1 2:1 4:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1

80.5 127.5 142.0 — 40.3 87.3 80.5 94.0 — 94.0 — 47.0 87.3 80.5 — 94.0 181.2 60.0 174.4 87.3 47.0 67.1 73.8 73.8 73.8 53.7 73.8 80.5 60.4 60.4 94.0

0.0 0.0 0.0 — 71.9 58.9 67.6 78.2 — 76.1 — 67.8 49.9 58.8 — 56.2 0.0 0.0 0.0 7.9 0.0 0.0 0.0 0.0 0.0 0.0 15.1 0.0 0.0 0.0 10.6

0.0 0.0 0.0 — 0.29 0.51 0.54 0.74 — 0.72 — 0.32 0.44 0.47 — 0.53 0.0 0.0 0.0 0.07 0.0 0.0 0.0 0.0 0.0 0.0 0.11 0.0 0.0 0.0 0.10

Crystallized from solution.

Fifteen other acids, two of them diacids, invariably used in a 2:1 molar ratio, were also tested for the resolution of N-methylamphetamine by the distillation method. Aspartic acid (7.4) and glutamic acid (7.6) failed to form a salt with the substrate that distilled off unchanged as a racemate. N-formylaspartic acid (7.5) is capable of salt formation and the residue is a mixture of acid and neutral salt, but the distillate was again racemic. © 2002 by CRC Press LLC

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In resolutions with 12 monocarboxylic acids, the amount of distillate was always less than half of the base introduced, indicating that not only salt formation but also partial complex formation with the salt took place. Resolution was successful with only three monocarboxylic acids (7.7, 7.14, and 7.18), but both optical purities and yields were very poor. It is interesting that while with trans-permethric acid partial resolution was successful, it failed with the cis-stereoisomer. The N,N-dimethylamide (7.9) of the efficient O,O′-dibenzoyltartaric acid was completely inefficient (see Table 7.3). In Tables 7.3 to 7.7, the resolution of further amines by distillation is summarized.

TABLE 7.3 Resolution of 7.19 by Distillation

Resolving Agent Tartaric acid Tartaric acid © 2002 by CRC Press LLC

Base:Acid Molar Ratio

o.p. of Distillate (%)

4:1 2:1

7.9 12.4

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TABLE 7.4 Resolution of 7.20 by Distillation

TABLE 7.5 Resolution of 7.21 by Distillation Resolving Agent Tartaric acid DBTA ⋅ monohydrate DBTA (S)-Mandelic acid

Base:Acid Molar Ratio

o.p. of Distillate (%)

2:1 2:1 2:1 2:1

0.0 30.9 43.1 0.0

TABLE 7.6 Resolution of 7.22 by Distillation Resolving Agent

Base:Acid Molar Ratio

Tartaric acid DBTA DpTTA (S)-Mandelic acid

2:1 2:1 2:1 2:1

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o.p. of Distillate (%) 0.0 0.0 0.0 0.0

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TABLE 7.7 Resolution of 7.23 by Distillation

Resolving Agent Tartaric acid DBTA DpTTA

Base:Acid Molar Ratio

o.p. of Distillate (%)

2:1 2:1 2:1

0.0 5.0 17.1

SCHEME 7.2

Tartaric acid, which did not even react with N-methylamphetamine under the experimental conditions, successfully resolved 2-amino-1-butanol. As with N-methylamphetamine, anhydrous O,O′-dibenzoyltartaric acid resolved N-(2,3-epoxypropyl)piperidine better than its monohydrate. The allyl derivative of N-methylamphetamine, in turn, could not be resolved with any of the agents studied. In the examples discussed above, it was always the free base that was distilled off and the other enantiomer was recovered from the remaining salt by conventional methods. In one example, 2 however, both enantiomers could be obtained by distillation. Amphetamine was resolved, as shown in Scheme 7.2, using a half equivalent of its hemiamide with phthalic acid. On distillation at low temperature, a distillate enriched in one of the enantiomers was collected. On further heating, the salt decomposed and the other enantiomer distilled off, accompanied by transformation of the hemiphthalate to the phthalate. By careful hydrolysis of the latter, the resolving agent could be recovered. © 2002 by CRC Press LLC

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7.3 RESOLUTION BY EXTRACTION 7.3.1 RESOLUTION BY EXTRACTION USING ONE MOLAR EQUIVALENT OF RESOLVING AGENT Resolution by extraction was first accomplished by Shapiro and Newman. Substituted phenylacetic acids were reacted with one equivalent of brucine and, because the salts failed to crystallize, they 3 distributed them between water and chloroform. Marginal resolution could be achieved, which could be improved by repeated distribution. According to their calculations in the studied system, 60 to 300 steps or a liquid-liquid extraction column of corresponding plate number would have been necessary to obtain a product of 90% o.p. (see Table 7.8).

7.3.2 RESOLUTION BY EXTRACTION USING OF RESOLVING AGENT

A

HALF EQUIVALENT

By reacting 1 mol racemic base with 0.5 mol sodium hydrogen tartrate in a water-benzene system, 4 resolution can be achieved. In the organic phase, 0.5 mol of the enantiomerically enriched free base accumulates; whereas in the aqueous phase, one finds the mixed salt of sodium and of the base enriched in the other enantiomer. The equilibrium is illustrated by: benzene-water

2 ( R,S )-Base + Na-hydrogen- ( R,R )-tartrate

( R )-Base ⋅ Na- ( R,R )-tartrate(aq) + ( S )-Base ( benzene )

(7.1)

Application of the method is illustrated by the resolution of amphetamine and some of its derivatives (Table 7.9). Experimental data revealed that enantiomer separation was possible in each case, but efficiency of resolution was not superior to other methods. Two-phase resolution sems to be justified only when all the traditional methods failed.

7.3.3 RESOLUTION BY EXTRACTION USING A HALF EQUIVALENT AGENT COMBINED WITH AN ACHIRAL ADDITIVE

OF

RESOLVING

Resolution by extraction of the racemic carboxylic acids 7.25 through 7.29 with a half equivalent 5 of resolving agent and a half equivalent of an achiral additive has been elaborated by Rábai. These acids did not provide crystalline diastereomeric salts with conventional alkaloids. The problem could be solved by reacting one equivalent of the racemic acid with 0.5 equivalent of the alkaloid and 0.5

TABLE 7.8 Resolution of 7.24 by Extraction Y

X

OH OH OAc OAc HN-COH

H NO2 H NO2 H

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Aqueous Phase [α]D −16.0 +1.4 −16.4 −2.3 −2.3

Organic Phase [α]D −2.1 +8.1 +1.6 +1.6

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TABLE 7.9 Resolution of Amphetamine Derivatives Without Crystallization in a Water-Benzene Mixture

NH2

NH

NH

O2N

NH

H2N

NH

Br

N

a

35 ml in each experiment.

equivalent of sodium hydroxide. In this way, two diastereomeric salts of the enantiomers and sodium salts of the enantiomers were formed. The mixture was then distributed between water and chloroform. Results with a series of alkaloids are shown in Table 7.10.

It can be seen that high optical purity cannot be realized in a single step, but, for example, in the case of 7.25, repetition of the procedure three times gave a product of 95% o.p. © 2002 by CRC Press LLC

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TABLE 7.10 Resolution of Some Aromatic Acids by Partition Between Water and Chloroform

Racemate 7.25

7.26 7.27

7.28 7.29

o.p. of Enantiomer in Excess in the Organic Phase (%)

Resolving Agent Quinine Quinidine Cinchonine Dihydroabietylamine Cinchonidine Brucine Quinine Brucine Cinchonine Quinine Quinine Quinine

43 35 11 3 24 5 18 1.8 2.4 7.6 11.9 1.3

The composition of the organic phase (y) and the aqueous phase (z) at equilibrium can be described by: 1 ⁄2

[a – { ( x + a ) – bx } ] y = -------------------------------------------------------x 2

(7.2) 1 ⁄2

[l – d + a – { ( x + a ) – bx } ] z = ------------------------------------------------------------------------1–x 2

(7.3)

βd + l 4βd - ; β is the separation constant for the (+)-enantiomer; d and l the molar where a = -------------; b = β----------β–1 –1 fractions of the (+) and (−) enantiomers before extraction, and x the molar fraction of the chiral base. Equations (7.2) and (7.3) permit the calculation of y and z for any value of d, l, and x for a given value of β. For example, if the concentration of the racemate in solution is infinite or only a catalytic amount of resolving agent is used (d/x → ∞), enantiomeric excess in the organic phase can be described as y = β − 1/β + 1. The efficiency of the resolution (S) and the optimum quantity of the chiral base (xopt) can be given by S = yx/d and xopt = (βd − l)/(β − 1) if the condition that 1/(β + 1) < d < β/(β + 1) is valid. In case of a racemate, when d = l = 0.5xopt, the use of a half equivalent of the resolving agent is optimal. p Whether maximum separation is feasible in a single step depends on the selectivity value β of p n the more soluble salt or enantiomer, which is defined by the formation constants k and k , molar n p HO * volume (V), the polarity of both the diastereomeric salts (δ and δ ) and the solvents (δ 2 and δ ), respectively, and finally by the temperature. The polarity of solvents can be characterized by 6 Hildebrand’s polarity constant :

H O

∗

p 2V ( δ – δ ) ( δ 2 – δ ) k p ln β = ln  ----n- + ---------------------------------------------------------k  RT n

p

(7.4)

Because molar volumes of the salts are very close, they can be taken as equal (V) in the calculations. © 2002 by CRC Press LLC

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TABLE 7.11 Partition Coefficients and Maximum Resolvability of Some Organic Acids 7.25 Base (−)-Brucine (−)-Quinine (+)-Quinidine (+)-Cinchonidine (−)-Cinchonidine (−)-3-Pinanmethyl amine

β 1.20 7.38 −4.55 −2.04 2.63 1.0

7.26 S

β

S

0.05 0.46 0.36 0.18 0.24 0.0

1.0 3.57 −2.44 −1.52 1.73 1.0

0.0 0.31 0.22 0.10 0.14 0.0

FIGURE 7.1 Solvent dependence of partition coefficient of 7.25 ⋅ (quinine)2 salt.

By judicious selection of the resolving agent, the difference between the diastereomeric salts can be maximized. Table 7.11 provides partition coefficients for two selected racemates with six optically active bases and resolvability values. The solvent effect in the resolution of acid 7.25 with quinine is as expected according to Eq. (7.4). Figure 7.1 shows the solvent dependence of the partition coefficient for the (+)-7.25 ⋅ (quinine)2 salt. Within experimental error, the correlation is linear.

7.3.4 RESOLUTION

BY

EXTRACTION

OF

DIASTEREOMERIC COMPLEXES

Resolution by extraction can be performed not only with diastereomeric salts, but also using 7 diastereomeric complexes. Prelog and co-workers studied the partition of salts of chiral bases between water and solvents containing a lipophilic tartaric acid ester.

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TABLE 7.12 Resolutions with the Lanthanide Complexes 7.31–7.34 e.e. in the Organic Phase (%) Amino Acid

7.31

(±)-Phenylglycine (±)-Phenylalanine (±)-Tryptophan

11 2 3

7.32

7.33

7.34

13 7 4

19 15 23

49 24 30

Note: 0.0015 mmol of amino acid was dissolved in 3 ml water and 0.030 mmol complex in 3 ml chloroform.

With the aid of compound 7.30, it is possible to transfer from an aqueous solution to chloroform the sodium salts of N-acetyl- and N-tert-butoxycarbonyltryptophan enantioselectively, while not8 derivatized amino acids cannot be transferred in this way.

The camphor-derived β-diketone lanthanide complexes 7.31 through 7.34 prepared by Japanese 9 authors are, in turn, capable of transferring zwitterionic, underivatized amino acids into the organic phase. The results are shown in Table 7.12.

7.4 RESOLUTION BY SUPERCRITICAL EXTRACTION Extraction with supercritical fluids, first of all CO2, is gaining increasing importance as a gentle method of extraction. It is employed on an industrial scale for preparing extracts of medicinal plants or for the decaffeination of coffee and tea. Its application for resolution is possible using a half equivalent of the resolving agent: the salt remains undissolved and the free substrate appears in the extract. Because handling of supercritical fluids is not simple and requires expensive apparatus, its 10,11 application is only justified with heat-sensitive compounds. For resolution with supercritical CO2, the apparatus shown in Figure 7.2 was used. Solution of the racemate and a half equivalent of resolving agent in methanol was evaporated onto Perfilt. The resulting solid was placed into the extractor and extracted with supercritical CO2. The extract was left to expand in the separator, from which the extracted material could be recovered. The method was tested by resolving five racemic carboxylic acids with five optically active bases; the results are shown in Table 7.13. More or less resolution was observed with all combinations and, in some cases, efficient separation could be recorded. Resolution of cis-chrysanthemic acid (7.36) with N-2-benzylaminobutanol (i.e., the experiment giving the best result) was studied in more detail (Fig. 7.3 a–c). First of all, solubility of the components in CO2 at 39°C and 100 bar was determined and it was found that the solubility of cis-chrysanthemic acid (0.36 mass%) was almost twice that of 2-benzylaminobutanol (0.17 mass%). Perfilt, used as support, was insoluble in supercritical CO2. Fractions collected at certain intervals of time were collected and analyzed. The extract contains (+)-chrysanthemic acid in excess, along with a small amount of the salt carried over, while the residue was the diastereomeric salt. © 2002 by CRC Press LLC

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TABLE 7.13 Prevailing Configuration and Enantiomeric Purity (%) of the Products in Extract and Remaining Salt in Resolutions by Supercritical Extraction

COOH

COOH

Cl

COOH

Cl COOH Cl Cl

FIGURE 7.2 Flow diagram of a supercritical extraction apparatus.

The dissociation of the salt and the dissolving power of CO2 can be influenced by the pressure and temperature of the extraction. Variation of pressure (in the range of 90 to 150 bar) has a direct effect on both yield and optical purity (Fig. 7.4); both parameters increase with pressure. Working at 33∞C, e.e. increased from 44 to 62% with an elevation of pressure from 90 to 150 bar. Investigation of the effect of temperature was limited by the relatively narrow temperature range (32 to 50∞C) of the supercritical state (Fig. 7.5b). All experiments were carried out at 100 bar. E.e. was © 2002 by CRC Press LLC

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FIGURE 7.3 Supercritical extraction of the N-2-benzylaminobutanol salt of cis-chrysanthemic acid of various initial enantiomerical purity (a: e.e. = 0%, b: e.e. = 58%, c: e.e. = 79%).

significantly dependent on temperature and increased from 25 to 65% on lowering the temperature from 50 to 32°C. Resolution with supercritical CO2 is a complex function of pressure and temperature. For the sake of a better understanding, values of optical purity can also be plotted as a function of the density 3 of the fluid (Fig. 7.6). For 0.6 g/cm , the optical purity is a linear function of density; while beyond this point, it does not change with the density of the medium. The advantages of resolution by supercritical extraction can be summarized as follows: 1. Solubility, and therefore material transport, can be simply influenced by the pressure and temperature of the system. 2. Differences of solubility, dissociation constant, and stability may be more pronounced than in ordinary solvents. 3. CO2 is an ideal solvent, being nontoxic, inflammable, readily accessible, and less expensive than organic solvents. 4. It can be removed easily. 5. It does not involve environmental problems. © 2002 by CRC Press LLC

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FIGURE 7.4 Effect of pressure and mass of CO2 passed on (a) yield and (b) enantiomeric excess of extract. Pressure (bar): 150; 120; 100; 90.

6. Critical temperature of CO2 (31°C), and thus separation at low temperature, is possible, an advantage with heat-sensitive substances. 7. Upscaling of the process is easy. Although high pressure involves some safety problems, hazards can be minimized by using up-to-date equipment.

7.5 RESOLUTION BY SUBLIMATION Resolution by sublimation also avoids recrystallization. It can be accomplished with both one half and one equivalent of the resolving agent.

7.5.1 RESOLUTION BY SUBLIMATION USING ONE EQUIVALENT OF RESOLVING AGENT A typical example for working with one equivalent of the resolving agent is the resolution of 4,4,4-trifluoro-3-hydroxybutanoic acid (7.40) with 1-phenylethylamine.

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FIGURE 7.5 Effect of temperature and mass of CO2 passed on (a) the extraction curve and (b) enantiomeric excess. Temperature (°C): 32; 35; 37; 47–50.

FIGURE 7.6 Effect of CO2 density on the enantiomeric excess of the total extract obtained by a single extraction.

DSC measurements of the diastereomeric salts in an open crucible directed attention to the method. The DSC curves significantly deviated from those expected and sublimation of the sample was 12 −3 observed. On repetition of the experiment in a laboratory-scale apparatus at 95°C and 10 Torr pressure, it was found that the sublimate was enriched in the salt of the (R)-acid, while the residue in the (S)-acid (see Table 7.14 for details). © 2002 by CRC Press LLC

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TABLE 7.14 Resolution of the Salt of 3-Hydroxy-4,4,4-trifluorobutanoic Acid with (R)-1-phenylethylamine by Sublimation

o.p. (%) of Acid Racemic

Sublimate from experiment no. 1 Residue from experiment no. 1

Yield of Sublimate (%)

T (°C)

P (Torr)

100 110 140 90

0.005 0.003 760 0.002

31 50

90

0.002

42

41

[α]D, (o.p. %)

Yield of Residue (%)

+1.7 (11) 69 +1.3 (9) 50 Slow decomposition +3.1 (21) 59 +2.1 (14)

58

[α]D, (o.p. %) −0.8 (5) −1.3 (9) +0.9 (6) −2.4 (16)

It can be seen that, due to decomposition of the salt at higher temperature, it is expedient to work under the best vacuum possible. Poor optical purity of the diastereomeric salts can be improved by repeated sublimation. The authors mentioned that the method was also applicable to 3-hydroxybutanoic acid, but no experimental details were disclosed.

7.5.2 RESOLUTION BY SUBLIMATION USING OF RESOLVING AGENT

A

HALF EQUIVALENT

On studying the resolution of N-methylamphetamine with tartaric acid, O,O′-dibenozyl- and O,O′di-p-toluoyltartaric acids by sublimation, it was found that the hydrochloride was much more volatile than the diastereomeric salts and therefore turned their attention to the Pope-Peachey method. A half equivalent of resolving agent and one equivalent of the racemic base was dissolved in methanol containing a half equivalent of HCl and the solution was evaporated to dryness. The residue was subjected to sublimation in a laboratory apparatus at 0.1 Torr pressure in a bath kept at 120°C. With tartaric acid and O,O′-dibenzoyltartaric acid, practically all of the hydrochloride evaporated and the optical purity of the sublimate containing the R enantiomer in excess was 34.9%. This is in accordance with fractional crystallization using a similar molar ratio, where it is also the R enantiomer that remains in the mother liquor. Experiments with O,O′-di-p-toluoyltartaric acid were unsuccessful since not only the hydrochloride, but also the organic salt sublimed.

7.6 MECHANICAL SEPARATION OF DIASTEREOMERIC SALT MIXTURES Pasteur accomplished probably the first resolution by separating, under the microscope, enantiomorphic crystals of ammonium tartrate. This method of separation is, in principle, also applicable to diastereomeric salts, but examples are extremely rare because other physicochemical characteristics, such as crystal chirality, are also different.

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The brucine salts of diacid 7.41 can be partially separated mechanically; nevertheless, its preparative resolution was carried out by fractional crystallization of the dehydroabietylamine salt from 13 ethanol. In the resolution of base 7.42, mechanical separation is an integral part of the laboratory-scale 14 resolution. When the racemic base was reacted with O,O′-dibenzoyltartaric acid in aqueous acetone, the diastereomeric salts separated overnight in two macroscopically distinguishable crystal forms. These were separated by hand picking and recrystallized to yield the pure salts. Combination of fractional crystallization and mechanical separation may enable the acceleration of the resolution process. Easily recognizable differences in the crystal forms of the diastereomeric salt are rare; but if present, first of all in laboratory experiments involving a small amount of material, it should be attempted. Mechanical separation is only possible, of course, with well-developed crystals; and with the aid of a microscope, the chances for successful separation can be readily predicted. Mechanical separation can be useful for producing the first seed crystals.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

M. Ács, T. Szili, and E. Fogassy, Tetrahedron Lett., 49, 7325 (1991). M. Ács, A. Mravik, E. Fogassy, and Z. Böcskei, Chirality, 6, 314 (1994). E. Shapiro and R.F. Newton, J. Am. Chem. Soc., 65, 777 (1943). M. Ács, D. Kozma, and E. Fogassy, ACH—Models in Chemistry, 132, 475 (1995). J. Rábai, Angew. Chem. Int. Ed. Engl., 31, 1631 (1992). J.H. Hildebrand and R.L. Scott, Regular Solutions, Prentice-Hall, Englewood Cliffs, NJ (1962). V. Prelog, S. Mutak, and K. Kovacevic, Helv. Chim. Acta, 66, 2279 (1983). A. Echavarren, A. Galán, J.-M. Lehn, and J. de Mendoza, J. Am. Chem. Soc., 111, 4994 (1989). H. Tsukube, J. Uenishi, T. Kanatani, H. Itoh, and O. Yonemitsu, Chem. Commun., 26, 477 (1996). E. Fogassy, M. Ács, T. Szili, B. Simándi, and J. Sawinsky, Tetrahedron Lett., 35, 257 (1994). B. Simándi, S. Keszei, E. Fogassy, and J. Sawinsky, J. Org. Chem., 62, 4390 (1997). M. Ács, C. von dem Bussche, and D. Seebach, Chimia, 44, 90 (1990). A. Almqvist and R. Hakansson, Chem. Scripta, 11, 186 (1977). G. Gottarelli and B. Samori, J. Chem. Soc., Perkin Trans. 2, 1971 (1972).

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8

Detailed Descriptions of Selected Resolutions

The experimental details of resolutions are presented in this chapter. These were selected to represent as many types of resolutions as possible. It must be kept in mind that methods published in patents are often described with less precision than those appearing in journals of respectable reputation. Note: In this chapter, boldface numbers stand for compound names and not for formulae. 1. Resolution of 2-Phenylglycine Amide (8.1) with (2R,3R)-3-(2-Aminophenylthio)1 2-hydroxy-3-(4-methoxyphenyl)propionic Acid (8.2) Salt-salt resolution with less than one equivalent of an amphoteric resolving agent (reverse of Example 7). a. To a solution of (±)-8.1 (3.7 g, 19.8 mmol) in water (40 ml) heated to 70°C, add a solution of 8.2 (3.6 g, 11.3 mmol) in 0.25 N NaOH (44 ml) heated to 70°C and clarified with charcoal. If necessary, the pH of both solutions should be adjusted separately to 6.5 to 7.5 by addition of NaOH solution. The combined solution is allowed to cool to RT (room temperature) and then kept in an ice bath for 30 min. During crystallization, pH should be maintained in the range 6.5 to 7.6. The crystals are filtered to give the salt 20 containing (S)-8.1 in excess: yield 5.0 g, [ α ] D = −215 (c = 0.3; H2O). The filtrate contains 20 (R)-8.1: 1.37 g, [ α ] D = +92 (c = 1; 1 N HCl), o.p. 100%. b. The above salt (5.0 g) is dissolved in water (100 ml), heated to 70°C, and the solution adjusted to pH 3 with 1 N HCl. It is kept in an ice bath for 30 min and the precipitate filtered to give 8.2 (3.4 g): ([α] = –335 (c = 0.3; EtOH). The filtrate contains (S)-8.1⋅⋅ HCl 20 (1.48 g): [ α ] D = −82 (c = 1; H2O), o.p. 89%. 2. Resolution of (±)-cis-3-Acetoxy-5-(2-dimethylaminoethyl)-2-(4-methoxyphenyl)2,3-dihydro-1,5-benzothiazepin HCl [(±)-diltiazem ⋅ HCl)] (8.3 ⋅ HCl) 2 with (S)-2-(6-Methoxy-2-naphthyl)propionic acid (8.4) Resolution of a base as its hydrochloride with 0.5 equivalent of resolving agent. a. To a solution of 8.3 ⋅ HCl (9.0 g, 20 mmol) in water (100 ml), add a solution of 8.4 (2.4 g, 10.4 mmol) in MeOH (10 ml). The slowly crystallizing mixture is stirred for 6 h at RT and then 30 min in ice. The precipitate is filtered and then washed with water (5 ml), 20 giving the salt (6.8 g, 98%): m.p. 121°C, [ α ] D = −67.8 (c = 3; MeOH). b. The above salt is stirred until dissolution with CHCl3 (30 ml) and 1 N NaOH (20 ml). After separation, the aqueous phase is extracted twice with CHCl3, and the combined extracts dried over Na2SO4 and acidified with 8 ml EtOH-HCl (17.5 g, HCl/100 ml).

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20 Evaporation gives (2R,2R)-8.3 ⋅ HCl (4.0 g, 89%) : [α ] D = −94.7 (c = 3; MeOH), o.p. 94%. c. The mother liquor obtained in the first step is evaporated and the residue (5.0 g) treated 20 as described in (b), giving crude (2S,2S)-8.3⋅⋅ HCl (5.0 g): [ α ] D = +65.6 (c = 3; MeOH). 20 Recrystallization from EtOH (15 ml) gives the pure salt: 3.4 g, [ α ] D = +100.9 (c = 3; MeOH), o.p. 100%), m.p. 207–209°C. Evaporation of the mother liquor affords (±)-8.3⋅⋅HCl (1.5 g); the total yield of (2S,2S)8.3⋅⋅ HCl is 89%. d. Recovery of the resolving agent: aqueous solutions remaining after extraction with CHCl3 are combined, and 8.4 is precipitated by adding cc HCl (10 ml). Filtration and washing 20 with water (2 × 5 ml) yields 8.4 (2.2 g, 92%) : [ α ] D = +66.8 (c = 1; CHCl3), m.p. 133–135°C.

3. Resolution of 1-(4-Fluorophenyl)-2-Methylamino)propane (8.5) 3 with Tartaric Acid (TA) Resolution of a base as its hydrochloride with 0.5 molar equivalents of resolving agent and 0.5 equivalents of inorganic acid (Pope-Peachey method). To 8.5 (83.5 g, 0.5 mol), add a solution of TA (37.5 g, 0.25 mol) in water (77 ml) with cooling, followed by cc HCl (25.0 g, 0.25 mol). The mixture is cooled to 0 to 5°C and stirred at this temperature for 5 h. Filtration and washing with ice-water gives the hemi-tartrate-dihydrate of (R)8.5 (69.5 g, m.p. 85–88°C). The salt is suspended in water (200 ml), CH2Cl2 (50 ml) is added, and the mixture adjusted to pH 13 with 20% aq. NaOH. After separation, the aqueous phase is extracted with CH2Cl2 (2 × 50 ml), the combined extracts dried over Na2SO4 evaporated, and the residue distilled in vacuo (b.p. 20 20 72°C/133 pA, [ α ] D = +3.38 (c = 2; EtOH), n D 1.4910). The acidic aqueous mother liquor of salt formation is adjusted to pH 13 with 20% NaOH, the oily product extracted with CH2Cl2 (3 × 70 ml), and the extract dried over Na2SO4 and distilled in vacuo. The distillate is diluted with acetone (40 ml) and acidified with ethanolic HCl to pH 2. After cooling, the crystals are filtered, washed with some acetone, and dried, giving (S)-8.5⋅⋅ HCl (42.5 g): 20 20 m.p. 152–154°C, [ α ] D = −4.9 (c = 2; EtOH). [ α ] D = +3.38 (c = 2; EtOH) of (R)-8.5 liberated from the salt (o.p. 45.3%). 4. Resolution of (±)-2-(4-Chlorophenyl)-3-Methylbutanoic acid (8.7) 4 with 2-(3,4-Dimethoxyphenyl)-3-methylbutylamine (8.6) Resolution with 0.5 equivalents of the quasi-enantiomer of a structurally similar compound. To a solution of (±)-2-(4-chlorophenyl)-3-methylbutanoic acid (8.7) (2.1 g, 10 mmol) in 4.6 N NaOH (2.4 ml, 10 mmol), add at 50°C a solution of (+)-8.6 (1.0 g, 5 mmol) in 0.8 N HCl (6.15 ml, 5 mmol). The solution is cooled in ice and seeded with the salt of (S)-8.7 and (+)-8.6. After standing at 0°C for 5 h, the salt is filtered, suspended in water (10 ml) and decomposed with cc HCl. The product is filtered and washed with water (2 × 0.5 ml) to give (S)-8.7 (0.9 g, 86%): 20 [ α ] D = +21.4 (c = 1; CHCl3), o.p. 45%. 20 Acidification of the mother liquor gives (R)-8.7 (0.9 g, 87%): [ α ] D = −22.1 (c = 1, CHCl3), o.p. 46%.

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5. Resolution of (±) trans-2,2-Dimethyl-3-(1-isobutenyl)-cyclopropane-1-carboxylic acid [(±)-trans-Chrysanthemic acid] (8.8) with (R)-2-Phenylpropionic 5 amide (8.9) and (R)-2-Phenylglycinenitrile (8.10) Salts with a resolving agent and its derivative of the same configuration contain opposite enantiomers in excess. Repeated resolution of an enantiomerically enriched mixture.

a. To a solution of (±)-8.8 (3.4 g, 20 mmol) in MeOH (20 ml), add 5 N NaOH (5.0 ml), followed by 8.9 (1.52 g, 20 mmol) as a solid and H2O (8 ml). The mixture is stirred at 55°C until a clear solution is obtained, cooled to 0°C, and the crystals filtered and washed with H2O. The product is suspended in a mixture of H2O (10 ml) and CHCl3 (10 ml) and acidified with 5 N HCl to pH 1. The organic phase is separated and the aqueous phase extracted with CHCl3 (2 × 10 ml). After drying over Na2SO4, the organic phase 20 is evaporated to give (1R)-8.8 (0.8 g): [ α ] D = +25.6 (c = 1; CHCl3), o.p. 99%. Evaporation of the original mother liquor and work-up of the residue as described above gives (1S)20 8.8 (2.5 g) : [ α ] D = −7.8 (c = 2; CHCl3), o.p. 30%. b. To a solution of (±)-8.8 (10.2 g, 61 mmol) in H2O (40 ml), add 5 N NaOH (12.4 ml) and a solution of 8.10 (5.1 g, 38.6 mmol) in H2O (30 ml) at 25°C. The mixture is cooled to 10°C, and the crystals are filtered, washed with H2O (2 × 10 ml), and worked up as 20 described in (a) to give (1S)-8.8 (5.0 g) : [ α ] D = −13 (c = 1; CHCl3), o.p. 50%. Processing 20 of the original mother liquor as described in (a) gives (1R)-8.8 (5.1 g): [ α ] D = +12 (c = 1; CHCl3). c. Repeated resolution of (1S)-8.8 of 50% o.p. (5.0 g) with 8.10 under the same conditions 20 as described in (b) yields (1S)-8.8 (3.3 g) : [ α ] D = −25.3 (c = 1; CHCl3), o.p. 97%. Repeated resolution of optically impure (1R)-8.8 (5.1 g) from (b) with 8.9 produces 20 (1R)-8.8 (3.2 g) : [ α ] D = +25.6 (c = 1; CHCl3), o.p. 98%. Processing of the combined mother liquors yields almost-racemic 8.8. d. (±)-8.8 (10.2 g, 61 mmol) was first resolved as described in (b) with 8.10 (5.1 g, 38.6 mmol). After separating the crystals, the mother liquor rich in the (R)-8.8 is treated at 50°C with 8.9 ⋅ HCl (2.8 g, 15 mmol), cooled to 5°C, and the crystals filtered and washed with H2O (2 × 5 ml). The moist salt is suspended in H2O (15 ml), acidified with 5 N HCl to pH 1, and the oily precipitate extracted with CHCl3 (3 × 10 ml). 20 Drying over Na2SO4 and evaporation yields (1R)-8.8 (2.3 g) : [ α ] D = +25.2 (c = 1; CHCl3).

6. Resolution of (±)-3-(2-Aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionic 6 acid (8.2) with (R)-2-Phenylpropionic amide (8.9) Resolution of an amphoteric compound by use of a half equivalent of resolving agent (inverse process of Example 1).

a. To a solution of (±)-8.2 (6.4 g, 20 mmol) in H2O (17 ml) and 0.5 N NaOH (43 ml), add a solution of (R)-8.9 (2.0 g, 11 mmol) in MeOH (80 ml) and 1 N HCl (20 ml) at 80°C. The solution is neutralized with 1 N NaOH and allowed to cool with stirring. When crystallization starts, leave the solution standing for another hour and then in ice for 30 min; finally, the salt (3.5 g) rich in (2S,3S)-8.2 is filtered. © 2002 by CRC Press LLC

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The above salt is dissolved in H2O (70 ml) by heating to boiling and adjust to pH 3 with 1 N HCl. The solution is cooled in ice for 30 min and the crystals filtered to give 20 (2S,3S)-8.2 (2.1 g, 65%) : m.p. 138–139°C, [ α ] D = +346° (c = 0.3; EtOH), o.p. 97%. b. (±)-8.2 (3.2 g, 10 mmol) is dissolved in H2O (30 ml) and 0.5 N NaOH (21.5 ml) at 80°C. To this the two mother liquors obtained in (a) and adjusted to pH 7 are added. The solution is allowed to cool with stirring; and when crystals start to separate, it is kept in ice for 30 min. The salt is filtered and decomposed as described in (a) to yield (2S,3S)20 8.2 (1.3 g, 81%) : m.p. 134–136°C, [ α ] D = +327° (c = 0.3; EtOH), o.p. 91%. 7. Resolution of (±)-3-(2-Aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl) 7 propionic Acid (8.2) by L-Lysine (8.27) Resolution of an amphoteric racemate with 0.5 equivalent amphoteric resolving agent. A solution of L-8.27 (14.6 g, 0.1 mol) in H2O (14.6 ml) is added to a stirred solution of (±)-8.2 (69.8 g, 0.2 mol) in MeOH (700 ml). The mixture is stirred at room temperature for 1 h and filtered to 25 give 45.5 g of a yellow solid that has [ α ] D = −98 (c = 1; 0.1 N NaOH). The crude salt is refluxed with MeOH (645 ml) for 30 min. The mixture is cooled to room temperature, filtered, and washed with 25 MeOH to give 43.2 g (44%) of the optically pure L-lysine salt of (2S,3S)-8.2: [ α ] D = −103° (c = 1; 0.1 N NaOH). This salt is dissolved in hot H2O (1200 ml) and the mixture made acidic (pH 2.1) with aqueous HCl. The separated solid is collected, washed with H2O, and dried in vacuo at 60°C to give 25 29 g (41.8% from (±)-8.2) of (2S,3S)-8.2: m.p. 111°C, [ α ] D = +121° (c = 1; CHCl3). The optical purity of this material was determined to be 99.7% by HPLC [conditions: column, CHIRALPAK WM (Daicel CO., Ltd.) 4.6 × 250 mm; column temperature 50°C; mobile phase, a mixture of 0.5 M copper(II) sulfate solution and acetonitrile (8:2); the flowrate was adjusted so that retention time of the (2S,3S)-8.2 peak was about 19 min]. 8. Enantiomeric Enrichment of (2R,3R)-3-(2-Aminophenylthio)-2-hydroxy-38 (4-methoxyphenyl)propionic Acid (8.2) Enantiomeric enrichment by partial precipitation. a. To a solution of 8.2 (7.8 g, 24 mmol) rich in (2R,2R)-8.2, [ α ] D = +314° (c = 0.3; EtOH) in H2O (70 ml) and 1 N NaOH (24 ml) heated to 80°C, add 1 N HCl (5.6 ml) heated to 80°C. After stirring for 1 h, the solution is cooled in ice and, after stirring for 30 min, the crystals 20 are filtered to give a product (2.7 g, 34%) of [ α ] D = +259° (c = 0.3; EtOH). The mother liquor is heated again to 80°C and adjusted with 1 N HCl (about 17 ml) to pH 3. After stirring for 1 h in ice, the precipitate is separated to give a product (4.8 g, 62%) of 20 [ α ] D = +347° (c = 0.3; EtOH), o.p. 97%. 20 b. To a solution of 8.2 (6.4 g, 20 mmol) [ α ] D = +226° (c = 0.3; EtOH) (i.e., containing less than the eutectic concentration of (2R,2R)-8.2) in H2O (58 ml) and 1 N NaOH (42 ml) heated to 80°C, add 1 N HCl (7.0 ml) heated to 80°C. After stirring for 1 h, the solution is cooled in ice and after stirring for 30 min the crystals are filtered and 20 washed with H2O (2 × 5 ml) to give a product (1.5 g, 23%) of [ α ] D = +81° (c = 0.3; EtOH). The mother liquor is heated again to 80°C and adjusted to pH 3 with 1 N HCl (5 ml). After stirring for 1 h at RT and then in ice for 30 min, the precipitate is separated 20 to give a product (3.0 g, 47%) of [ α ] D = +151° (c = 0.3; EtOH). The mother liquor is adjusted at 80°C with 1 N HCl (about 5 ml) to pH 3, stirred 1 h, cooled in an ice bath, and the crystals filtered to give optically pure product (2R,2R)-8.2 20 (1.6 g, 25%): [ α ] D = +357° (c = 0.3; EtOH). 20

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9. Resolution of (±)-2-Amino-3-hydroxy-1-(4-nitrophenyl)-1-propanone (8.11) 9 with (+)-2-Phthaloylamino-1-(4-nitrophenyl)propane-1,3-diol (8.12) Resolution with a derivative of the racemate. Second-order asymmetric transformation during resolution. To a solution of (±)-8.11⋅⋅ HCl (4.6 g, 18.7 mmol) in H2O (20 ml) and MeOH (6 ml), add a solution of 8.12 (7.2 g, 20 mmol) and NaHCO3 (1.7 g) in H2O (25 ml) and MeOH (10 ml) at 35–37°C. The solution is adjusted by the addition of aqueous NaHCO3 solution to pH 7.0–7.2 and stirred for 24 h. The crystals are filtered, washed with H2O (3 × 5 ml) to give the salt (9.0 g, m.p. 144°C). The filtrate is acidified with cc HCl to pH 1 and precipitated 8.12 is filtered and washed with H2O. The mother liquor is evaporated to dryness, giving (±)-8.11⋅⋅ HCl (0.9 g). The salt (9.0 g) is suspended in 20% HCl (50 ml), stirred for 30 min, the resolving agent filtered off, washed with H2O (2 × 5 ml), and dried (5.4 g). The filtrate is evaporated to dryness 20 to give (+)-(2S,3S)-8.11⋅⋅ HCl (3.6 g): [ α ] D = +54 (c = 2; 2 N HCl). 10. Resolution of (±)-2,6-Dimethyl-3-ethyl-6,7,8,9-tetrahydro-4Hpyrido[1,2-a]pyrimidin-4-one (8.13) with O,O’-Dibenzoyltartaric 10 Acid (DBTA) One enantiomer forms a neutral, the other one an acid salt with the same resolving agent (a–f). Enantiomeric enrichment by crystallization from melt (g). [Example 9]. a. To a solution of (±)-8.13 (20.6 g, 100 mmol) in MeOH (50 ml), add a solution of DBTA (9.5 g, 25 mmol) in MeOH (30 ml). After seeding with the pure acid salt, the solution is left standing overnight. The precipitate is filtered off and washed with 20 MeOH (2 × 3 ml), giving the salt (12.7 g, 45%), m.p. 122–128°C, [ α ] D = –109 (c = 1; MeOH). b. To the mother liquor, add another portion of DBTA (9.5 g, 25 mmol), seed again, and leave standing overnight to yield more of the salt (10.5 g, 37.2%), m.p. 124–130°C, 20 [ α ] D = −107 (c = 1; MeOH). c. To a solution of (±)-8.13 (10.3 g, 50 mmol) in CHCl3 (40 ml), add a solution of DBTA (4.7 g, 12.5 mmol) in CHCl3 (40 ml) and water (10 ml). After seeding with the pure neutral salt, the solution is stirred in an ice bath for 30 min, the precipitate is filtered and washed with CHCl3 (2 × 5 ml) to give the neutral salt (5.4 g, 57%), m.p. 128–130°C. d. The second mother liquor obtained in experiment (a) is evaporated. To the residue, add H2O (10 ml) followed by DBTA (11.4 g, 24.5 mmol) dissolved in CHCl3 (30 ml). A precipitate is formed, which is filtered off with difficulty [15.1 g, 53%, m.p. 138–140°C, 20 [ α ] D = −39 (c = 1; MeOH)]. The latter is suspended in H2O (26 ml) and after the addition of cc NH4OH (18 ml), the mixture is extracted with CHCl3 (3 × 30 ml). After 20 drying over Na2SO4, the extracts are evaporated to give (6S)-8.13 (6.25 g, 61%): [ α ] D = +93.3 (c = 6.25; CHCl3), o.p. 97%. e. To the salts obtained in experiment (a) (12.7 + 10.5 g, yield 82%) suspended in water (3.8 ml), add cc NH4OH (50 ml) and extract the solution with CHCl3 (3 × 110 ml). The extracts are dried over Na2SO4 and evaporated to yield (6R)-8.13 (10.2 g, 99%): 20 [ α ] D = +95 (c = 1.33; CHCl3), o.p. 100%. f. Decomposition of the salt obtained in experiment (b) (5.4 g) as described in (d) gives 20 (6S)-8.13 (3.4 g, 66%): [ α ] D = +54.9 (c = 1; CHCl3), o.p. 58%. © 2002 by CRC Press LLC

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g. Impure (6S)-8.13 (3.4 g) obtained in experiment (f) is heated to 54°C and then left standing at 25°C. The crystals are filtered and pressed thoroughly to yield (6S)-8.13 20 (1.9 g, 66%): [ α ] D = +95 (c = 3.3; CHCl3), o.p. 58%. The filtrate (2.2 g) is of 34% o.p. 11. Resolution of (±)-2-Phenylglycine (8.14) with (1S)-(±)-Camphor-1011 sulfonic Acid (8.15) Resolution of an amphoteric compound with a large excess of strongly acidic resolving agent by fractional precipitation (a, b). Recovery of the resolving agent (c). a. 8.15 (70 g, 0.30 mol) and (±)-8.14 (30.2 g, 0.20 mol) are dissolved in boiling water (200 ml). If cloudy, charcoal is added, the solution filtered, allowed to cool to RT and stand for 2 h, followed by cooling to 2°C and maintaining this temperature for 2 h. 20 The crystals are filtered and washed with H2O to yield the salt (34.5 g), [ α ] D = −50 (c = 2; 1 N HCl). The mother liquor and washings are combined and stirred, after the addition of 10% NaOH (28 ml), for 1 h. The precipitate is filtered to give (±)-8.14 (2.9 g, 9.7%), while the mother liquor is adjusted to pH 7–7.2 with more of 10% NaOH. After stirring for 1 h, the precipitate is separated and washed with water and MeOH to give L-8.14 (13.6 g, 20 90%): [ α ] D = +160 (c = 1; 1 N HCl), o.p. 100%. b. The salt obtained in experiment (a) (33.5 g) is dissolved in hot water (100 ml), cooled to 25°C, and adjusted to pH 7–7.2 with 10% NaOH. After stirring for 1 h, the precipitate 20 is filtered and washed with H2O and MeOH to give D-8.14 (12.8 g, 87%): [ α ] D = −158 (c = 1; 1 N HCl). c. To the combined mother liquors from experiments (a) and (b), add cc HCl (30 ml), evaporate the solution to dryness, and recrystallize the residue from EtOAc to afford 20 8.15 (63 g, 90%): m.p. 188–190°C, [ α ] D = +27 (c = 10; H2O). Increasing the excess to 2 molar equivalents resulted in somewhat lower yields and o.p.

12. Resolution of (±)-cis-2-Hydroxycylopent-4-en-1-ylacetic Acid (8.17) 12 and its Lactone (8.16) with (R)-1-Phenylethylamine ((R)-PEA) Resolution with 0.5 equivalent of resolving agent in a two-phase system without an achiral additive. To a solution of (±)-8.18 (32.8 g, 20 mol) in water (35 ml), add (R)-PEA (14.0 g, 0.116 mol) and dichloroethane (54 ml). The mixture is cooled to 5°C and, over a period of 3 h, cc HCl (14 ml, 0.168 mol) is added with stirring at this temperature. Stirring is continued for 1 h, and the product filtered off and washed with dichloroethane (2 × 5 ml) to give the salt (19.7 g, 75%): 20 [ α ] D = −22 (c = 2; MeOH). The above salt is dissolved in warm H2O (40 ml), the solution left standing at RT for 3 h, and 20 then cooled to 5°C. Finally, the product filtered to give the pure salt (17.1 g, 87%): [ α ] D = −26° (c = 2, MeOH). From the mother liquor, almost racemic 8.18 (1.6 g, 5%) can be recovered as the sodium salt. Decomposition of the pure salt (26.3 g) with 1 N HCl gives, after the usual work-up (1S,5R)20 2-oxabicylo[3.3.0]oct-6-en-3-one (8.16) (11.9 g): [ α ] D = −106 (c = 1; CHCl3), o.p. 81%. © 2002 by CRC Press LLC

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13. Separation of the Enantiomer in Excess from 2-Oxabicylo[3.3.0]oct-6-en-3-one 13 (8.16) of 20–80% o.p. Enantiomeric enrichment by crystallization from melt. a. Lactone 8.16 (245 g, o.p. 52.3%) is cooled to 0 to 5°C, seeded with crystals of pure (1R,5S)-8.16, and kept at this temperature for 30 min. The crystals are filtered and 20 pressed thoroughly at 0–5°C to give (1R,5S)-8.16 (110 g, 45%): [ α ] D = +100 (c = 1; CHCl3), o.p. 77%. The o.p. of (1R,5S)-8.16 in the filtrate (135 g, 55%) was 29%. The crystals are suspended at 0°C in Et2O (100 ml) and the undissolved crystals filtered to give (1R,5S)-8.16 (75 g, 75%), o.p. 88%. Evaporation of the mother liquor gave (1R,5S)-8.16 (25 g, 25%), o.p. 42%. b. Seeding of the noncrystalline fraction from experiment (a) (105 g, o.p. 29%) at 10°C with pure (1R,5S)-8.16 and keeping the mixture at this temperature for 1 day and then at −5°C for 3 h yields (1R,5S)-8.16 (41 g, 39%) of 72.5% o.p. The filtrate contains almost racemic 8.16 (62 g, 59%), o.p. 2.6%. c. A similar procedure starting from (1S,5R)-8.16 (120 g) of 79.5% o.p. affords in the first step a crystalline product (72 g) of 93% o.p. and, after the second, (1S,5R)-8.16 (61.2 g) of 100% o.p. 14. Resolution of (±)-1-(3,4-Dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4methyl-5H-2,3-benzodiazepine (8.18) with O,O’-Dibenzoyltartaric 14 Acid (DBTA) Resolution with 0.5 equivalent of resolving agent without an achiral additive in a twophase system (a, b). Enantiomeric enrichment by crystallization (c). a. To a solution of (±)-8.18 (38.2 g, 100 mmol) in CHCl3 (100 ml), add H2O (100 ml), followed by a solution of DBTA (18.8 g, 50 mmol) in warm CHCl3 (50 ml). On scratching, crystals separate. After keeping the mixture below 5°C for 30 min, the salt crystallising with 3 moles H2O is filtered and washed with CHCl3 (3 × 30 ml) to give 20 the salt (34.3 g, 87%): [ α ] D = +100–130 (c = 2; CHCl3). To a suspension of the above salt (27.7 g, 35 mmol) in H2O (50 ml), add cc NH4OH (20 ml) with stirring. The precipitating oil is extracted with CHCl3 (3 × 30 ml), dried over Na2SO4, and the extract evaporated to give (R)-8.18 (13.0 g, 97.5%) as a syrup that 20 slowly crystallises: m.p. 145°C, [ α ] D = +350 (c = 3; CHCl3), o.p. 61%. b. To the combined mother liquors and filtrates from experiment (a), add cc NH4OH (20 ml), separate the organic phase, extract the aqueous phase with CHCl3 (3 × 30 ml), dry the extracts over Na2SO4, and evaporate to give (S)-8.18 (19.1 g) as a syrup that slowly crys20 tallises: m.p. 142°C, [ α ] D = −320 (c = 3; CHCl3), o.p. 56%. c. The product of experiment (b) is dissolved at 50°C in MeOH (740 ml). On cooling and scratching, the racemic phase crystallises. After keeping the mixture at 5°C overnight, the crystals are filtered, suspended in water (40 ml) at 80°C and, after stirring for 10 min and cooling, the product is filtered to give almost racemic 8.18 (3.1 g, 16%): 20 m.p. 145–150°C, [ α ] D = −15 (c = 3; CHCl3). After treatment with charcoal, H2O (50 ml) is added to the methanolic mother liquor and it is 20 heated to 80°C, stirred for 10 min and cooled to RT to give (S)-8.18 (15.0 g, 78%): [ α ] D = −360 (c = 3; CHCl3), o.p. 63%. © 2002 by CRC Press LLC

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15. Resolution of 3-Methoxy-10-(2-methyl-3-dimethylaminopropyl)-phenthiazine 15 (8.19) with O,O’-Dibenzoyltartaric Acid (DBTA) Resolution by 0.8 molar equivalent resolving agent. Enantiomeric enrichment by crystallization of the pure base or its salt with an achiral acid. (±)-8.19 (100 g, 0.33 mol), DBTA⋅⋅ H2O (101.4 g, 0.27 mol), isopropanol (1500 ml), and isopropanol/ HCl (containing 1.11 g HCl) are mixed and heated to 60°C. The solution is stirred a few hours at this temperature, followed by seeding with the pure salt. The crystals are separated to give the salt m.p. (95.7 g, 159°C). The salt is treated with a mixture of water (80 ml) and cc NH4OH (30 ml), whereupon impure (R)-8.19 precipitates. This is filtered and recrystallized from 5 times its weight of EtOH to give 20 optically pure (R)-8.19 (41.5 g, 83%): [ α ] D = +16 (c = 5; CHCl3). The isopropanol mother liquor is evaporated and the residue treated with H2O (100 ml) and cc NH4OH (35 ml), the precipitate filtered and recrystallized from 5 times its weight of EtOH to give 20 optically pure (S)-8.19 (40.0 g, 83%): [ α ] D = −16 (c = 5; CHCl3). From the combined ethanolic mother liquors, some racemic base (12 g) and almost all of the resolving agent can be recovered. The optically impure base can also be purified by transforming it to the maleinate, followed by recrystallization from H2O.

16. Resolution of (±)-syn-2-Amino-1-(4-nitrophenyl)-1,3-propane-1,3-diol (8.20) 16 with O,O’-Dibenzoyltartaric Acid N,N’-dimethylamide (8.21) Resolution with 0.5 equivalent of the calcium salt of the resolving agent (a); continuous resolution of an enantiomerically enriched mixture in a foam column (b). a. To a solution of (±)-8.20⋅⋅ HCl⋅⋅ H2O (53.3 g, 0.20 mol) in H2O (200 ml) heated to 70°C, add the calcium salt of 8.21 (47.6 g, 0.10 mol). After transient dissolution of the components, the salt of (2R,3R)-(−)-8.20 precipitates, while (2S,3S)-(+)-8.20 stays in solution. After stirring for 5 min, the mixture is cooled to 5°C, the product filtered off, washed with H2O (3 × 50 ml), and decomposed without drying with a mixture of H2O (100 ml) and cc HCl (15 ml) at 60°C. After cooling to RT, the precipitated resolving agent is filtered and washed with H2O (3 × 30 ml). The filtrate is adjusted to pH 9.2 at 60°C with cc NH4OH (20 to 25 ml) and cooled to RT. The precipitate is filtered and washed with H2O (3 × 30 ml) to give (2R,3R)20 8.20 (18.1 g, 96%): m.p. 164–166°C, [ α ] D = −29.3 (c = 1; MeOH), o.p. 97%. b. The apparatus is a five-cell foam column of 3-liter capacity divided by vertical walls into five compartments and provided with an inlet of filtered, compressed air for stirring and as a foam-forming agent. By means of a dosage pump, a neutral mother liquor arising from the resolution yielding (2R,3R)-8.20 (see above) is fed into the column at a rate of 4.0 l/h. At the same time, with the aid of a vibrational powder dosage device, (±)-8.20⋅⋅ HCl⋅⋅ H2O is fed into the upper part of the first cell at a rate of 580 g/h and, with another dosage device, the calcium salt of 8.21 is fed at a rate of 493 g/h. The individual cells are kept 65, 64, 62, 38 and 25°C. The average residence time in the column is 45 min. The suspension continuously leaving the column is led to a filter and the solid worked up © 2002 by CRC Press LLC

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as described under in the previous example (15). In this way, 221 g/h of (2R,3R)-8.20, 20 m.p. 164–166°C, [ α ] D = −29.3° (c = 1, MeOH), o.p. 97% can be produced. 17. Resolution of (±)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3carboxylic acid (±)-(8.22) with (2S,3S)-2-Amino-1-(4-nitrophenyl)17 1,3-propanediol [(2S,3S)-8.20] Salt-salt resolution. On fractional decomposition of the salt, the racemic phase precipitates and enantiomer stays in solution. Repeated resolution of an optically impure enantiomer. a. (±)-(8.22) (123 g, 0.60 mol) is suspended in H2O (250 ml) and the pH adjusted with cc NH4OH to 7. To this solution, add 8.20⋅⋅ HCl (88 g, 0.35 mol). On seeding with crystals of the pure salt and keeping the solution overnight at RT, the product is filtered to give a salt rich in (R)-8.22. The mother liquor is acidified with cc HCl to pH 4 and left standing for 1 h at 0 to 5°C. The precipitated crystals are filtered and washed with 20 H2O to give 8.22 containing 25 to 35% of the R enantiomer, (61 g, m.p. 134°C), [ α ] D = +27–32 (c = 2; MeOH), to be recycled into the process. The filtrate is adjusted to pH 2 with cc HCl and extracted with CHCl3 (3 × 150 ml). The extracts are dried over Na2SO4 20 and evaporated to give (S)-8.22 (23 g): m.p. 117°C, [ α ] D = +106–110 (c = 2; MeOH), o.p. 96–100%. b. The moist salt obtained in experiment (a) (137.8 g) is dissolved in H2O (900 ml) with heating and adjusted at 30°C to pH 2 with cc HCl. The solution is extracted with CHCl3 (2 × 150 ml), and the extracts dried over Na2SO4 and evaporated to give (R)-8.22 20 (38.3 g): m.p. 116°C, [ α ] D = −90 (c = 2; MeOH). This is dissolved in H2O (80 ml) by adjusting the pH to 7 by the addition of cc NH4OH and the solution processed as 20 described above to give (R)-8.22 (30.2 g): m.p. 119°C, [ α ] D = −110 (c = 2; MeOH), o.p. 100%.

18. Resolution of 2-(4-Hydroxyphenoxy)propionic acid [(±)-8.23] with 18 (R)-1-Phenylethylamine [(R)-PEA] and L-Phenylalanine (8.24) Different resolving agents give different enantiomers. a. (±)-8.23 (3.6 g, 20 mmol) and (R)-PEA (10 mmol) are dissolved in EtOAc (25 ml), the precipitated salt (2.7 g) is filtered and decomposed at 60°C with a mixture of H2O (5 ml) 20 and cc HCl (3 ml) to give (S)-8.23⋅⋅ HCl (1.1 g, 61%): [ α ] D = −58.1 (c = 1; acetone), o.p. 96.5%. The mother liquor is extracted with EtOAc (4 × 5 ml). Evaporation of the extracts 20 yields more (S)-8.23⋅⋅ HCl (0.5 g): [ α ] D = −33.2, o.p. 55%. Evaporation of the mother liquor of salt formation and decomposition, as described 20 above, gives (R)-8.23⋅⋅ HCl (1.9 g): [ α ] D = +45.4, o.p. 84%. b. (±)-8.23 (7.3 g, 40 mmol) and 8.24 (6.6 g, 50 mmol) are dissolved at 60°C in H2O (60 ml). After standing at RT for 48 h, the salt is filtered off, washed with H2O (6 ml), and decomposed with 5% HCl/EtOAc (30 ml). After standing overnight, 8.24 ⋅ HCl (4.5 g) is filtered and washed with EtOAc (10 ml). After washing with H2O (10 ml), the combined EtOAc 20 solutions are evaporated to give (R)-8.23⋅⋅ HCl (3.3 g, 90%): [ α ] D = +29.2, o.p. 48%. © 2002 by CRC Press LLC

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19. Resolution of (±)-2-Acetamido-3-phenylpropionic Acid (N-Acetylphenylalanine) 19 [(±)-8.25] with D-Phenylglycinamide (8.26) Salt-salt resolution (a). Enantiomeric enrichment by selective precipitation (c). a. A suspension of (±)-8.25 (15.7 g, 76 mmol) in H2O (35 ml) is adjusted with stirring and heating to pH 7 with cc NH4OH, followed by the addition of 8.26 HCl (7.8 g, 42 mmol) as a solid. When crystallization starts, the solution is cooled with stirring to RT and then kept in ice for 12 h. The salt is filtered and washed with water (2 × 3 ml); yield 11.7 g (86%). The salt (10.0 g, 28 mmol) is decomposed with a mixture of H2O (20 ml) and 5 N NaOH (2 ml). After stirring for 30 min, 8.26 is filtered and washed with water (2 × 3 ml); yield 3.6 g (86%). The mother liquor is acidified with 5 N HCl (10 ml), and L-8.25 is filtered and washed 20 with H2O; yield 5.4 g (93%), [ α ] D = +43.2 (c = 1; EtOH), o.p. 96%. b. The original salt (10.0 g, 28 mmol) is stirred with 20% HCl for 30 min. The product is filtered, suspended in H2O (20 ml), and the undissolved material filtered to give L20 8.25 (5.0 g, 86%): [ α ] D = +45 (c = 1; EtOH), o.p. 100%. c. The mother liquor from experiment (a) is acidified with cc HCl (5 ml), whereupon impure D-8.25 (8.1 g) precipitates. This is suspended in H2O (20 ml) and adjusted with heating and cc NH4OH to pH 7. The solution is cooled to RT and 5 N HCl (2.3 ml) is added dropwise with stirring. (±)-8.25 precipitates, which is filtered and washed with H2O (yield 2.3 g). On adding more cc HCl (3 ml) to the mother liquor, D-8.25 (5.2 g) 20 is obtained: [ α ] D = −45 (c = 1; EtOH), o.p. 100%. 20. Resolution of Racemic Phenylsuccinic Acid (8.28) Using L-Proline (8.29) 20 as a Resolving Agent Resolution with one molar equivalent of resolving agent. Resolving agent added as solid. Enantiomeric enrichment by fractional crystallization. No special drying of solvents is necessary. Dissolve 1.94 g (0.01 mol) racemic-8.28 in 50 ml 2propanol in a dry 250-ml round-bottom flask. Add 1.15 g (0.01 mol) of finely ground L-8.29. Mix the contents of the flask for 2 to 3 min with a stirring rod and then reflux for 30 min. During reflux, as all of the proline dissolves, the (+)-bis-proline salt usually begins to precipitate out of solution. Air cool the flask for 15 to 20 min to approximately 30°C. If the (+)-salt has not crystallized at this point, seeding the solution with the salt from another batch and vigorous stirring will initiate crystallization. Filter and wash the solid twice with 15 ml acetone (m.p. 160–161°C, [ α ] D = +13.5) (c = 1.00; MeOH) to give the salt. Add (+)-salt to 10 ml of 6 M HCl cooled in ice water. Stir this mixture for 5 min. Filter and 20 wash the solid twice with cold H2O (15 ml). After drying 0.39 g (40%), [ α ] D = +151 (c = 4.0; acetone). Recrystallization from H2O will yield optically pure (+)-8.28 with a melting point of 25 185–186°C and [ α ] D = +171 (c = 4.0; acetone). To isolate (−)-phenylsuccinic acid, evaporate the filtrates and stir the residue with 10 ml of 6 M HCl for 10 min. Filtration gives (−)-8.28 (0.61 g): m.p. 169–171°C, [ α ] D = −67 (c = 4.0; acetone). Alternatively, if optically pure (−)-phenylsuccinic acid is desired, the residue is dissolved in 40 ml absolute EtOH. Add 0.39 g (−)-8.29 and stir at RT for 30 min. Evaporate the EtOH to isolate the (−)-monoproline salt. Add 20 ml acetone to the (−)-salt and stir for 2 to 3 min. Filter and then dry the salt; 1.14 g, m.p. 142–144°C, [ α ] D = −96 (c = 1.00; MeOH)). Add all the (−)-salt to 10 ml of 6 M HCl and stir at 0°C for 5 min. Filter and © 2002 by CRC Press LLC

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wash the solid twice with H2O (15 ml) to obtain (−)-8.29 0.57 g, m.p. 176–179°C, [ α ] D = −160 (c = 4.0; acetone). Recrystallization from H2O yields optically pure (−)-phenylsuccinic acid (0.38 g, 39%): m.p. 185–186°C, [ α ] D = −170 (c = 4.0; acetone). 21

21. Resolution of Racemic t-Butylsulfinylacetate (8.30) by (1R,2S)-Ephedrine (8.31)

Resolution of a racemate with sulfur as the chiral center. Enhancement of enantiomeric purity by recrystallization of the distereomeric salts. The racemic acid 8.30 (1.64 g, 10 mmol) and 8.31 (1.65 g, 10 mmol) are dissolved in acetone (12.5 ml) and the solution kept at 3 to 5°C in a refrigerator for 2 h. The white crystals of the salt 8.30 ⋅ 8.31 formed are isolated by removal of the solvent by decantation (1.9 g, [ α ] D = −52.95 (c = 1.7; CHCl3)). Next, the crystals are dissolved at ca. 30°C in a mixture of acetone (50 ml) and CHCl3 (15 ml) and kept in the refrigerator for 12 h. The white crystals formed are filtered and dried in vacuo (0.81 g, [ α ] D = −96.9 (c = 0.65; CHCl3)). The crystalline salt 8.30 ⋅ 8.31 is again dissolved at ca. 30°C in a mixture of acetone (40 ml) and CHCl3 (15 ml) and left to crystallize at RT for 48 h. Filtration gives the diastereomerically pure salt: 0.3 g, [ α ] D = −110.3 (c = 0.35; CHCl3), m.p. 170–173°C. 22. Resolution of Racemic Mercaptosuccinic Acid (8.32) by (1S,2S)22 2-Amino-1-phenyl-1,3-propanediol (8.33) Resolution of a chiral dicarboxylic acid by two different resolving agents with different molar ratios. Liberation of the racemate from the diastereomeric salt by ion exchange resin. a. (±)-8.32 (13.5 g, 90.0 mmol) and (S)-8.33 (30.1 g, 180 mmol) are dissolved in MeOH (125 ml). After stirring the solution for 2.5 h, the precipitated (R)-8.32⋅(S)-8.33 salt (21.4 g) is collected. The filtrate is evaporated in vacuo at 30°C to give the (S)-8.32⋅(S)-8.33 salt as a syrup. The (S)-8.32⋅(S)-8.33 salt is crystallized from 90 ml MeOH to give the purified salt. To solutions of (R)-8.32⋅(S)-8.33 and (S)-8.32⋅(S)-8.33 + salts in water (45 ml), add Amberlite IR-120B ion exchange resin in the H form (2.5 g per 1 g salt), and allow the mixtures to stand for 1 day at RT with occasional stirring. After removing the ion exchange resin by filtration, the filtrates are evaporated in vacuo and the (R)- and (S)-8.32 thus obtained are recrystallized from H2O (15 ml). 20 (R)-8.32⋅(S)-8.33 salt: yield 20.7 g, m.p. 129–131°C, [ α ] D = +34.7 (c = 1.00; H2O)⋅⋅ (R)-8.32: yield 5.47 g (81.0% based on half the starting amount of (RS)-8.32), m.p. 149– 20 150°C, [ α ] D = +64.8 (c = 1.00; EtOH). 20 (S)-8.32: yield 5.22 g (77.3%), m.p. 149–150°C, [ α ] D = −64.8 (c = 1.00; EtOH).

b. (RS)-8.32 (15.0 g, 100 mmol) and (S)-PEA (12.1 g, 100 mmol) are dissolved in npropanol (80 ml). After standing overnight at –10°C, the preciptated (R)-8.32⋅(S)-PEA salt (14.5 g) is collected by filtration, washed with a small amount of cold n-propanol, and dried. This salt is then recrystallized three times from n-propanol (40 ml) to obtain the purified (R)-8.32⋅(S)-PEA salt. After removal of the (R)-8.32 ⋅(S)-PEA salt, the filtrates are combined and evaporated in vacuo at 30°C to give the (S)-8.32⋅(S)-PEA salt as a syrup. Solutions of the purified (R)-8.32 ⋅(S)-PEA salt and crude (S)-8.32 ⋅(S)PEA salt in H2O (100 ml) are treated with Amberlite IR-120B ion exchange resin in + the H form in a manner similar to that described for the 8.32⋅(S)-8.33 salt to give © 2002 by CRC Press LLC

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(R)- and (S)-8.32. (S)-8.32 (9.36 g, 62.3 mmol) and (R)-PEA (7.55 g, 62.3 mmol) are dissolved in 40 ml n-propanol and the resulting solution allowed to stand overnight at –10°C. The precipitates (12.2 g) are recrystallized from 40 ml n-propanol to give purified (S)-8.32 ⋅ (R)-PEA salt (10.9 g). Treatment of this salt with Amberlite IR-120B yields (S)-8.32. (R)-8.32⋅(S)-PEA salt: yield 9.25 g, [ α ] D = +21.6 (c = 1.00; H2O). 20 (R)-8.32: yield 4.98 g (66.4% based on half the starting amount of (RS)-8.32, [ α ] D = +64.8 (c = 1.00; EtOH). 20 (S)-8.32: yield 5.65 g (75.3%) : [ α ] D = −64.8 (c = 1.00; EtOH). 20

23. Resolution of (R,S)-tert-Leucinol (8.36) by N-(2-Naphthoyl)23 (S)-tert-leucine (8.37) Resolution with 0.5 equivalent derivative (quasi-racemate formation). Recovery of the other enantiomer using a different resolving agent. a. Salt (R)-8.36⋅(S)-8.37: (RS)-8.36 (175.8 g, 1.5 mol) and (S)-8.37 (214.0 g, 0.75 mol) are dissolved in iPrOH (4.5l) at 53°C. While slowly stirring, the mixture is cooled to 39°C over 6 h, then to 24°C overnight and to 15°C in an ice-water bath. The colorless crystals formed are filtered off, washed with 4 × 150 ml iPrOH and dried; yield 218.3 g (72%). Concentration of the filtrate to 2 l affords an additional 21.9 g (7%) product. The total quantity is recrystallized from iPrOH (4 l), filtered off at 15°C, washed portionwise with iPrOH 20 (300 ml), and dried:yield 210.6 g (70%), m.p. 184–189°C, [ α ] D = +41.6 (c = 1.0; MeOH); e.e. = 97.4% (GC, Lipodex E). b. Salt (S)-8.36⋅(S)-Mandelic acid: The mother liquor of the fractional crystallization is evaporated, the resulting oil dissolved in H2O (500 ml), and the mixture concentrated to 500 g. At 55°C, 6 N HCl is used to adjust the pH to 5.5, the solution is seeded with a few crystals of (S)-8.37, and 6 N HCl is added until a pH of 1.8 is achieved. The suspension is cooled to 18°C while being stirred, and the crystals filtered at pH 1.35, washed portionwise with H2O (250 ml), and dried in vacuo at 75°C : yield 34.0 g (S)-8.37. The filtrate is adjusted to pH 7.0 with aqueous NaOH and concentrated to 220 g. 50% aqueous NaOH (45 ml) is added to adjust the pH to 13. After addition of toluene (300 ml), the mixture is warmed to 50 to 55°C, the water layer separated, and at 55°C extracted again with toluene (300 ml). The organic extracts are pooled and evaporated. The resulting yellowish oil (98.2 g, 0.82 mol 8.36) is dissolved in iPrOH (3 l), and the solution is filtered and warmed to 60°C. (S)-Mandelic acid (114.0 g, 0.75 mol) is added and dissolved. After production of the first crystals by scratching, the suspension is slowly cooled with stirring, kept at 15°C for 4 h, and filtered. The resulting colorless crystals are recrystallized from iPrOH (1560 ml and a second time from 1500 ml), filtered, washed, and dried: yield 127.3 g (63% with respect to the starting 20 amount of (R,S)-8.36), m.p. 152–157°C, [ α ] D = +72.6 (c = 1.0; MeOH), e.e. = 98% (GC, Lipodex E). c. (R)-tert-Leucinol [(R)-8.36]: Concentrated HCl (50 ml) is added dropwise to a stirred suspension of salt (R)-8.36 ⋅ (S) -8.37 (210.3 g, 0.5 mol) in H2O (1300 ml). After warming to 50°C, the mixture is stirred for 15 min. On cooling to 5°C, the pH drops to 1.005. After 30 min, the colorless crystals are filtered, washed with ice-cold water (1 l), and dried in vacuo at 80°C to afford © 2002 by CRC Press LLC

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141.5 g (99%) of recovered (S)-8.37, which is analytically pure. The filtrate is adjusted to pH 7.5 with 10 M aqueous NaOH, concentrated to 146 g, and divided exactly into two parts. One half is used to prepare (R)-tert-butyl-oxazolidine-2-one (from (R)-8.36 by acylation with ethyl chloroformate and cyclization with NaOH in toluene); the other half for the isolation of (R)-8.36, as follows. Half of the above filtrate (73 g, containing 0.25 mol (R)-8.36) is concentrated to 60 g and, after addition of toluene (100 ml), adjusted to pH 13.0 with 10 M aqueous NaOH. After being heated to 50°C, the water layer is separated and extracted again with 75 ml toluene at 50°C. The pooled organic extracts are treated with Na2SO4, filtered, and evaporated to give 24.2 g of almost colorless oil. Distillation affords a colorless, hygroscopic oil that crystallizes at room 20 temperature: yield 22.9 g (78%), b.p. 89–91°C/13 mbar; [ α ] D = −38.1 (c = 2.0; EtOH); e.e. = 97.4 (GC, Lipodex E). 24. Resolution of N-Benzyl-3-(RS)-(4-fluorophenyl)-1,4-oxazin-2-one (8.38) by [(1S)-(endo,anti )]-(—)-3-Bromocamphor-8-sulfonic acid (BCS) via 24 a Crystallization-Induced Asymmetric Transformation Asymmetric transformation during resolution. To a solution of racemic-8.38 (5.0 g, 17.5 mmol) in isopropyl acetate (47.0 ml), add (S)-(±)-8.38⋅⋅ (−)BCS salt as seed (0.5 g, 99% e.e.) and heat the thin slurry to reflux temperature (89°C). A 0.91 M solution of (−)-BCS in isopropyl acetate (23 ml = 6.5 g, 21.0 mmol) is then added via a syringe pump over a period of 3 h, and the resultant slurry stirred at 89°C for 48 h. The slurry is cooled to 0 to 5°C and aged for 1 h. Filtration and washing with isopropyl acetate (10.0 ml) affords the (S)-8.38⋅⋅ (−)-BCS salt (9.4 g excluding seed) in 90% yield and 99% e.e. in a single crop. The free (S)-8.38 base is recovered in quantitative yield by partitioning the (S)-8.38⋅⋅ (−)-BCS salt between ammonium hydroxide solution and a suitable organic solvent (e.g., EtOAc or toluene). The procedure described has been demonstrated on a multi-kilo scale. 25. Optical Resolution of DL-tert-leucine (8.39) with (1S)-(+)-Camphor-1025 sulfonic Acid (8.15) Resolution of an amphoteric racemate by a strong acid. Liberation of the enantiomers from the salt by ion exchange resin.

DL-8.39 (20 g, 0.153 mmol) and (+)-8.15 (35.44 g, 0.153 mmol) are dissolved in hot 95% EtOH (55.4 g) and the solution is stirred in a thermostatted water bath (20°C) overnight (minimum crystallization duration, 10 h). The solid is collected, washed with a small amount of absolute EtOH, and dried in air. Yield 23.5 g (43%) of salt A, m.p. ca. 188–195°C (by DSC). To determine the e.e. of 8.39 in this salt, ca. 150 mg are cleaved by percolation through a Dowex 1X2 column (OH form) using 1 20 N AcOH as the eluent; the recovered 8.39 shows [ α ] D = +14.5° (c = 1; AcOH), e.e. ~47%. The mother liquors evaporated to dryness and cleaved back by the same procedure yielded 10.8 g (54%) 8.39 25 with [ α ] D = −13.2 (c = 1; AcOH), e.e. ~43%. Recrystallization of A in 95% EtOH (34.8 g) at 20°C (overnight stirring) produces salt A1 (14.2 g, 61%), m.p. 189–198°C, e.e. of 8.39 85%. Recrystallization of A1 (13.9 g) in 32.4 g EtOH yields A2 (9.5 g, 68%), m.p. 204–207°C, e.e. = 95%. Finally, recrystallization of A2 (9.4 g) from 36.4 g EtOH affords A3 (4.5 g), m.p. 209–211°C, which on cleavage (Dowex 1X2 (OH), 1 N 25 25 AcOH) yields 1.5 g (95%) L-8.39, [ α ] 546 = +30.0, [ α ] 365 = +110.1 (c = 1; AcOH), e.e. ≥98%.

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In contrast, the sample of 8.39 recovered from the original mother liquors (10.2 g) is combined with (−)-8.15 (18.1 g) in 34.6 g of 95% EtOH to give 17.6 g of salt C1, e.e. ca. 80%. Two recrystallizations of this salt as described above for A1 eventually afford salt C3 (6.6 g), m.p. 208–210°C, from 25 25 25 which D-8.39 is recovered in 98% yield (2.3 g); [ α ] D = −31.4, [ α ] 546 = −37.4, [ α ] 365 = −11.6 (c = 1; AcOH), e.e. ≥98%. The overall yield of pure L- and D-8.39 from DL-8.39 is ca. 23%, without taking into account the partially resolved 8.39 that can be recovered in ca. 90% yield from the mother liquors using the ion exchange procedure. (+)- and (−)-8.15 can easily be recovered from the resin by elution with dilute ammonia. This method is especially suitable for obtaining gram quantities (1 to 10 g) of resolved 8.39 in a short time (ca. 3 days overall). 26. Resolution of (+)-trans-4-Aminoflavan (8.40) by (1S)-(+)-Camphor-1026 sulfonic Acid (8.15) Resolution with 1.1 molar equivalent of resolving agent. 1.33g (5.3 mmol) of (1S)-8.15 is gradually added to (±)-8.40 (1.09 g, 4.8 mmol) dissolved in dry pyridine (13 ml), and the reaction mixture is kept at 60°C for 1 h. After 24 h at room temperature, the crude product is collected and repeated crystallization from pyridine gives 0.45 g (45%) of the 20 (1S)-8.15 salt of (+)-ent-8.40: m.p. 243°C, [ α ] D = +52 (c = 0.5; EtOH). Concentration of the mother liquors yields 0.32 g (32%) of the respective salt with (−)-8.40, 20 m.p. 236°C, [ α ] D = +28 (c = 0.5; EtOH). a. (2S,4R)-(+)-4-Aminoflavan Hydrochloride [(+)-8.40⋅⋅ HCl]: (1S)-8.15 salt of (+)-ent-8.40 (0.45 g, 1.0 mmol) is boiled for 1 h with 2% HCl (50 ml), and the hot solution is filtered. Crystallization of the filtrate commences immediately. The crude product is crystallized from 2% HCl and yields 0.17 g (75%) of (+)-ent-8.40 20 hydrochloride, m.p. 260°C, [ α ] D = +24 (c = 0.5; EtOH). b. (2S,4R)-(+)-4-Aminoflavan [(+)-ent-8.40]: (+)-ent-8.40 hydrochloride (0.26 g, 1.0 mmol) is dissolved in hot H2O (20 ml) and the cooled solution is made alkaline by the addition of 1.5% NaOH. The slightly yellow precipitate is collected and washed with ice-cold water. Yield 0.16 g (71%), m.p. 116°C 20 (dec.), [ α ] D = +14 (c = 0.5; EtOH). c. (2R,4S)-(−)-4-Aminoflavan Hydrochloride [(−)-8.40 ⋅ HCl]: (1S)-8.15 salt of (−)-8.40 (0.45 g, 1.0 mmol) is treated as shown for the preparation of 20 (+)-ent-8.40: yield 0.09 g (42%), m.p. 263–264°C, [ α ] D = −22 (c = 0.5; EtOH). d. (2R,4S)-(−)-4-Aminoflavan [(−)-8.40]: (−)-8.40⋅⋅ HCl (0.26 g, 1.00 mmol) is treated as shown for the preparation of (+)-ent20 8.40: yield 0.14 g (63%), m.p. 116°C (dec.): [ α ] D = −14 (c = 0.5; EtOH). 27. Optical Resolution of (RS)-3-Amino-1-(tert-butylcarbonylmethyl)-2,3dihydro-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (8.41) 27 by (S)-Mandelic Acid (MA) Resolution with 0.4 molar equivalents of resolving agent, using both enantiomers of the resolving agent. (S)-MA (19.4 kg, 127.5 mol) is added to a solution of (RS)-8.41 (112 kg, 319.5 mol) in CH3CN (2240 l). The mixture is cooled to −5°C, seeded, and stirred for 3 h. The resultant precipitate © 2002 by CRC Press LLC

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is collected by filtration, washed with cold CH3CN (20 l), and dried to give the (S)-8.41 ⋅ (S)MA salt (25.7 kg, 16%). The filtrate is quickly evaporated below 15°C and the residue partitioned between CH2Cl2 (500 l) and 1 M NaOH (70 l). The organic base is washed with H2O and evaporated. The residue is taken up in acetonitrile (2350 l) and (R)-MA (21.9 kg, 143.9 mol) added. The mixture is cooled to 5°C, seeded, and stirred for 3 h. The resultant precipitate is collected by filtration, washed with cold CH3CN (20 l), and dried to give the (R)-8.41 ⋅ (R)-MA salt (36.9 kg, 23%). The same cycle is repeated to provide second crops of the (S)-mandelate (20.9 kg, 13%) and the (R)-mandelate (16.1 kg, 10%). 28

28. Resolution of trans-1,2-Cyclobutanedicarboxylic Acid (8.42) Resolution using two alkaloids as resolving agents.

a. (1S,2S)-(+)-trans-1,2-Cyclobutanedicarboxylic Acid: (+)-Enriched-8.42 (20.4 g) and cichonidine (40.6 g) are dissolved in boiling water (700 ml). The resulting salt crystallizes instantly. The reaction mixture is left overnight and then filtered. The mother liquor is separated and the solid dissolved in boiling water (900 ml), which is filtered hot and then left for crystallization. The resulting solid is filtered, dissolved in boiling water (750 ml) (with difficulty), and again left for cystallization. After separation, a suspension of the solid in H2O (900 ml) is warmed to 80°C, treated with ammonia to reach pH 10, and boiled. After the solution is cooled to RT, the liberated cinchonidine is filtered and the filtrate extracted with CHCl3 to remove the remaining cinchonidine. The aqueous phase is acidified with HCl to ca. pH 1 and evap29 orated to dryness. Extraction with benzene gives (+)-8.42: m.p. 118–119°C; [ α ] D = +156.4 (c = 1; H2O). (+)-Enriched-8.42 (6.19 g, [α]D = +54.3 (c = 1; H2O ) is isolated from the combined mother liquors by the same procedure. The recovery is 88%. b. (1R,2R)-(−)-trans-1,2-Cyclobutanedicarboxylic Acid: (−)-Enriched-8.42 (10.7 g) is dissolved in H2O (715 ml) and a solution of quinine (25 g) in EtOH (90 ml) is added. The mixture is boiled for over 45 min to evaporate EtOH and the volume is adjusted to 2 l with boiling water. After cooling to 35°C, a white solid is isolated from the mother liquor. The white crystalline product is dissolved again in boiling H2O (700 ml) and left for crystallization. The resulting crystalline precipitate is separated from the mother liquor and redissolved in H2O (1000 ml), and then made alkaline with ammonia (ca. pH 10) and cooled to 0°C. Liberated quinine is filtered and the filtrate is acidified with 12 N HCl (ca. pH 1). It is then extracted with Et2O (8 × 150 ml). Et2O is evaporated and the crude diacid (3 g) is examined for specific rotation, which is very high (ca. −168°). The crude 27 product is recrystallized twice from benzene, giving the (−)-8.42: m.p. 115°C, [ α ] D = −167.2 (c = 1; H2O). From the combined mother liquors, (−)-enriched-8.42 (5.47 g, [ α ] D = −40) is isolated according to the same procedure. The recovery is 71%. 29. Resolution of (±)-Bicyclo[3,3,0]octane-3-spiro-5′-hydantoin-1-carboxylic 29 Acid (8.43) with Brucine Resolution with one molar equivalent of brucine. Determination of the enantiomeric purity by HPLC after derivatization. © 2002 by CRC Press LLC

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A stirred mixture of 8.43 (1.308 g, 5.49 mmol) and (−)-(S)-brucine dihydrate (2.363 g, 5.49 mmol) in MeOH (300 ml) is refluxed overnight. The hot reaction mixture is filtered and 0.504 g (2.11 mmol) unreacted acid is recovered (39%). After 24 h, the precipitated salts are collected by filtration (1.724 g, 2.41 mmol, 44%). Three recrystallizations yield (+)-(1S∗,3S∗,5R∗)-8.43⋅(−)-brucine salt (71.5%, calculated from the total diastereomeric salts); m.p. = 191°C. To a stirred suspension of this material (600 mg, 0.84 mmol) in H2O (5 ml) in an ice bath, add NH4OH (25%) (0.12 ml, 0.84 mmol) and allow to stand for 1 h. After extraction with CH2Cl2 (2 × 25 ml) to remove the free brucine, the aqueous layers are acidified with 3% HCl to give 180 mg (0.75 mmol) (90%) of (+)-8.43 as a white precipitate; [ α ] D = +28.9 (c = 1; 1 N NaOH). The combined methanol solutions are evaporated to dryness in vacuo, and the more soluble salt is isolated by recrystallization from acetone-water (yield 0.471 g, 0.65 mmol, 12%). Three more recrystallizations in the same solvent mixture give * * * (−)-(1R ,3R ,5S )-8.43⋅(−)-brucine salt (19.5%, calculated for the total diastereomeric salts); m.p. = 156°C. The salt is destroyed as above and the free acid is found to have a specific rotation of [ α ] D = −29.8 (c = 1; 1 N NaOH). −)-8.43: Derivatization Enantiomeric Purity Determination of (+)-8.43 and (− −)-(1R*,3R*,5S*)to Methyl 3′′-methyl-(+)-(1S*,3S*,5R*)- and (− −)-8.44] bicyclo[3,3,0]octane-3-spiro-5’-hydantoin-1-carboxylate [(+)- and (− A suspension of (+)-8.43 in dry acetone (20 ml) is stirred with anhydrous K2CO3 (0.112 g, 0.81 mmol) under an argon atmosphere for 1 h prior to the addition of methyl iodide (1.135 g, 7.99 mmol). After being stirred for 24 h, another portion of methyl iodide is added and the solution is stirred overnight. The reaction mixture is filtered and the filtered cake is washed with acetone. The combined acetone solutions are evaporated in vacuo. The resulting white solid is dissolved in CH2Cl2 and any undissolved material removed by filtration. Evaporation of the filtrate to dryness yields a white solid that can be purified by rapid passage through a short silica gel column using EtOAc as eluent, to give (+)-8.44 81 mg (79%). Similarly, (−)-8.43 gave (−)-8.44 in 76% yield; m.p. = 133°C. Chiral-HPLC analysis is performed on a Waters LC apparatus equipped with a MAXIMA 820 software, using a chiral-AGP column (10 cm, 1 ml/min) and 2-propanol (0.5%) in 0.01 M sodium phosphate buffer (pH 5.5) as the mobile phase. A Waters 490 UV detector (236 nm) was used. The retention time was 7 min for (+)-8.44 and 9 min for (−)-8.44. E.e. was ≥99%. 30. Resolution of cis-2-Amino-3,3-dimethyl-1-indanol (8.45) 30 with Mandelic Acid (MA) Resolution by both enantiomers of mandelic acid. Enantiomeric purity determination by HPLC. a. (1R,2S)-2-Amino-3, 3-dimethyl-1-indanol (S)-mandelic acid salt [(+)-(1R,2S)-8.45-(S)MA]: To a solution of rac-8.45 (5.28 g, 29.8 mmol) in EtOH (10 ml), add (S)-MA (4.53 g, 29.8 mmol). To the resulting suspension of the diastereomeric salt mixture add EtOH (60 ml) and reflux the suspension to completely dissolve the diastereomeric salt. The clear solution is allowed to stand at RT for 1 h (from the point when the precipitation started), and then for 1 h at 0°C. The precipitate is collected and washed with cold EtOH (10 ml). Recrystallization of the precipitate from EtOH (70 ml) under similar conditions gives diastereomerically pure (+)-8.45-(S)-MA (3.40 g, 10.3 mmol, 35% based on rac-8.45 20.4 used) as colorless needles: [ α ] D = +38.3 (c = 1.98; MeOH); m.p. 202.0–202.5°C. © 2002 by CRC Press LLC

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To the diastereomeric salt (+)-8.45-(S)-MA (20.0 mg, 0.0607 mmol) dissolved in pyridine (2 ml), add acetic anhydride (1 ml) and allow the reaction mixture to stand for 12 h at RT. Then evaporate the excess pyridine and acetic anhydride and purify the residue by PTLC (EtOAc) to give (1R,2S)-2-acetamido-3,3-1-indanol acetate (8.46) (15.8 mg, 100%). Chiral HPLC analysis (Daicel Chiralcel OD, hexane:2-propanol (9:1), α 1.38), the shorter retention time for the 1R,2S isomer) of 8.46 indicated that (+)-8.45 was diastereomerically pure. An analytical sample of (1R,2S)-8.46 can be recrystallized from hexane:benzene 20.8 (9:1) to give colorless needles: [ α ] D = −170 (c = 1.00; CHCl3); m.p. = 123.0–123.5°C. b. (1R,2S)-2-Amino-3,3-dimethyl-1-indanol [(1R,2S)-8.45]: To a stirred suspension of (+)-8.45-(S)-MA (3.40 g, 10.3 mmol) in CH2Cl2 (100 ml), add 2 M aqueous KOH (200 ml). The phases are separated and the aqueous layer extracted with CH2Cl2 (3 × 10 ml). Usual work-up of the combined organic layer and extracts 18 gives (1R,2S)-8.45 (1.79 g, 10.1 mmol, 98%) as a colorless powder: [ α ] D = −16.8 (c = 1.00; MeOH); m.p. = 100.5–101.0°C. To aminoalcohol (1R,2S)-8.45 (15.6 mg, 0.0880 mmol) dissolved in pyridine (2 ml), add acetic anhydride (1 ml) and allow the reaction mixture to stand for 12 h at RT. Then evaporate pyridine and excess acetic anhydride and purify the residue by PTLC (EtOAc) to give (1R,2S)-8.46 (22.9 mg, 100%). Chiral HPLC analysis of (1R,2S)-8.46 indicated that (1R,2S)-8.45 was enantiomerically pure. c. (1S,2R)-2-Amino-3,3-dimethyl-1-indanol⋅(R)-mandelic acid salt [(−)-(1S,2R)-8.45⋅ (R)-MA)]: The combined filtrates of the crystallization and recrystallization performed to obtain (1R,2S)-8.45 are concentrated under reduced pressure to give a solid mass, which is subsequently treated with 2 M aqueous KOH (300 ml) and extracted with CH2Cl2 (3 × 100 ml). Usual work-up of the extracts yields (1S,2R)-enriched 8.45 (3.39 g, 19.1 mmol), which is then treated with (R)-MA (2.91 g, 19.1 mmol) to give the diasteromeric salt mixture. Crystallization of this salt mixture from EtOH (70 ml) according to the procedure given for the preparation of (+)-8.45 gave diastereomerically pure (−)-8.45 20.8 (3.63 g, 11.0 mmol, 37%) as colorless needles: [ α ] D = −38.9 (c = 2.08; MeOH). The other physical data were identical with those of (1S,2R)-8.45. Chiral HPLC analysis of 20.8 (1S,2R)-8.46 gave [ α ] D = +170 (c = 1.00; CHCl3); the other physical data were identical with those of (1R,2S)-8.46), derived from (−)-8.45 ⋅(R)-MA in a procedure similar to the preparation of (1R,2S)-8.46; the results indicated that (−)-8.45 ⋅ (R)-MA was diastereomerically pure. 31. Resolution of DL-4-Hydroxyphenylglycine (8.47) by [(1S)-(endo,anti)]−)-3-Bromocamphor-8-sulfonic acid (− −)-(BCS)31 (− Complete resolution, including racemization of the unwanted enantiomer and the recovery of the resolving agent.

a. Resolution of DL-4-hydroxyphenylglycine (8.47) with d-3-bromocamphor-8-sulfonic acid (BCS): A mixture of DL-4-8.47 (30 g) and D-BCS monohydrate (59.1 g) is dissolved in H2O (290 ml) at 95°C and stirred at 25°C for 2 h. The precipitated crystals are filtered, washed with a small amount of cold water, and dried to give crude D-4-8.47-D-BCS 25 (40.2 g), [ α ] D = +4.9 (c = 1; 1 N HCl). The crude salt (40.0 g) is recrystallized from 25 0.5% D-BCS aqueous solution (300 ml) to give D-4-8.47-D-BCS (35.5 g), [ α ] D = +2.9 © 2002 by CRC Press LLC

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(c = 1; 1 N HCl), m.p. = 243–245°C (dec.). Authentic D-4-8.47-d-BCS: [ α ] D = +2.9 (c = 1; 1 N HCl). Preparation of D-4-hydroxyphenylglycine: The pure D-p-8.47-(−)-BCS (30.0 g) obtained above is dissolved in H2O (250 ml) at 95°C. The solution is adjusted to pH 6 with 2 N NaOH (ca. 31 ml), concentrated to about 70 g, and stirred at 5°C for 2 h. The precipitated crystals are filtered, washed 25 with H2O, and dried to give D-4-8.47 (9.6 g):[ α ] D = −158.3 (c = 1; 1 N HCl). Recovery of optically impure L-4-hydroxyphenylglycine: After separation of the less soluble D-4-8.47-(−)-BCS in the above resolution process, the mother liquor is adjusted to pH 6 with 2 N NaOH, concentrated to about 130 g, and stirred at 5°C for 2 h. The precipitated crystals are filtered, washed with H2O, and 25 dried to give optically impure L-4-8.47 (12.6 g), [ α ] D = +129.3 (c = 1; 1 N HCl). Racemization of optically impure L-4-hydroxyphenylglycine: Optically impure L-4-8.47 (10.0 g) obtained from the above procedure is dissolved in 2 N HCl (30 ml). The mixture is heated in an autoclave at 140°C for 12 h. After reaction, the mixture is adjusted to pH 6 with 2 N NaOH and stirred at 5°C for 2 h. The precipitated crystals are filtered, washed with H2O, and dried to give DL-4-8.47 (9.2 g), 25 [ α ] D = 0 (c = 1; 1 N HCl). Racemized 8.47 can be reused for resolution. Reuse of (−)-3-bromocamphor-8-sulfonic acid: The sodium salt of (−)-BCS remaining in the mother liquors after the separation of Dand L-4-8.47 can be reused as a resolving agent by the addition of an equivalent amount of hydrochloric acid. To the mother liquor after the separation of D-4-8.47 (9.6 g) in the preceding procedure, add DL-4-8.47 (9.1 g) and 2 N HCl (31 ml). Heat the mixture at 95°C for 2 h. The precipitated crystals are filtered, washed with a small amount of 25 cold water, and dried to give crude D-4-8.47-(−)-BCS (14.7 g): [ α ] D = +3.9 (c = 1; 1 N HCl). 25

b.

c.

d.

e.

32. Resolution of 2-Chloroethyl-(2-chloro-2-phenylethyl)-amine (8.48) 32 by O,O′-Dibenzoyltartaric Acid (DBTA) Resolution of two structurally similar racemates with the same resolving agent. Enantiomeric enrihment by fractional crystallization. Racemic 8.48⋅⋅ HCl (10 g) is dissolved in H2O (100 ml) and DBTA⋅⋅ H2O (7.4 g) in a mixture of CH2Cl2 (40 ml) and MeOH (2 ml). The two solutions are mixed, stirred vigorously for 1 h, and then filtered. The filtrate is suspended in H2O (100 ml), CH2Cl2 (20 ml) added, and the mixture cooled in ice. A solution of NaOH (2 g) in H2O (10 ml) is added with stirring and cooling. After complete dissolution, the phases are separated and the aqueous phase is extracted with CH2Cl2 (2 × 20 ml). The organic phases are combined, dried over Na2SO4, and acidified with HCl dissolved in isopro20 panol. The solvent is evaporated in vacuo to yield 3.98 g, [ α ] D = −52.2 (c = 1; MeOH), m.p. 20 172–174°C. From the mother liquor, 5.47 g of [ α ] D = +38.5 (c = 1; MeOH), m.p. 173–175°C, was obtained. a. Enantiomeric enrichment: 20 8.48⋅⋅ HCl (3.40 g, [ α ] D = −52.2 (c = 1; MeOH)) is dissolved in hot MeOH (10.5 ml). The mixture is cooled with ice and left at 0°C for 20 min. The crystals are filtered and the mother liquor evaporated. 20 Crystals: 1.23 g, [ α ] D = −72.5 (c = 1; MeOH), m.p. 175–176°C. 20 Product from the mother liquor: 2.11 g, [ α ] D = −40.5 (c = 1; MeOH), m.p. 173–175°C. © 2002 by CRC Press LLC

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From 8.48⋅⋅ HCl, [ α ] D = +38.5 (c = 1; MeOH); [ α ] D = +55.0° (c = 1; MeOH), m.p. 175–176°C; 20 and [ α ] D = +27.2° (c = 1; MeOH), m.p. 172–174°C products were obtained. 20 After repeated recrystallizations of another batch, a product of [ α ] D = +78.6 (c = 1; MeOH), m.p. 176–177°C was obtained, the optical rotation of which did not change after further recrystallization. 20

20

Resolution of 2-Chloroethyl-(2-hydroxy-2-phenylethyl)-amine (8.49) with O,O’-Dibenzoyltartaric Acid (DBTA) Racemic 8.49⋅⋅ HCl (15.0 g), DBTA⋅H2O (12.0 g), and NaOH (1.3 g) are dissolved in a hot mixture of EtOH (40 ml) and H2O (40 ml). With cooling and scratching, crystallization commences. The mixture is left to crystallize overnight and then filtered and washed with EtOH:H2O 1:1 (2 × 5 ml). The salt is suspended in H2O (50 ml) and a solution of NaOH (3 g) in H2O (10 ml) added. The mixture is extracted with CH2Cl2 (3 × 20 ml). The organic phases are combined, dried over Na2SO4, and acidified with HCl dissolved in isopropanol. The solvent is evaporated in vacuo to yield 5.52 g; 20 [ α ] D = +34.8 (c = 1; H2O), +43.7 (c = 1; MeOH), m.p. 138–141°C. From the mother liquor 8.75 g; 20 [ α ] D = −21.2 (c = 1; H2O), −26.6 (c = 1; MeOH), m.p. 145–147°C, is obtained. Enantiomeric enrichment: 8.49⋅⋅ HCl from the preceding experiment (5.00 g) is dissolved in hot MeOH (5.0 ml). The mixture is left to crystallize at RT for 10 min and then filtered. The mother liquor is evaporated. Crystals: 20 1.25 g, [ α ] D = +17.1 (c = 1; MeOH), m.p. 152–154°C. Product from the mother liquor: 3.69 g, 20 [ α ] D = +52.7 (c = 1; MeOH), m.p. 138–141°C. 20 From 8.49⋅⋅ HCl (8.30 g): [ α ] D = −26.6 (c = 1; MeOH); 4.25 g, −5.8° (c = 1; MeOH), m.p. 156–158°C; 20 and 3.98 g, [ α ] D = −48.8 (c = 1; MeOH), m.p. 148–151°C products were obtained. 33. Resolution of 6-Fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (8.50) 33 with its N-Phthaloyl Derivative Resolution of a base with its acidic derivative. Enantiomeric enrichment by crystallization from melt and by fractional crystallization of an achiral salt. a. Preparation of the resolving agent (R)-N-phthaloyl-8.50: 20 (R)-8.50 (10.0 g, 60.5 mmol, [ α ] D = +70.2 (c = 1; EtOH)), phthalic anhydride (9.0 g, 60.8 mmol), and N,N-dimethylaminopyridine (catalytic amount) are dissolved in CH2Cl2 (50 ml) and the mixture kept under reflux for 1.5 h. Then the solvent is evaporated. Ethyl acetate (10 ml) is added and the solution is seeded. The mixture is left to crystallize overnight and then cooled to −10°C. The crystals are filtered, washed 20 with ethyl acetate (2 × 4 ml), and dried: 14.4 g (76%), m.p. 143–145°C, [ α ] D = −236 (c = 1; MeOH). b. Optical resolution of racemic 8.50 by N-phthaloyl-(R)-8.50: Racemic 8.50 (3.70 g, 22.4 mmol) is dissolved in hexane (35 ml) and (R)-N-phthaloyl8.50 (7.0 g, 22.3 mmol) is added. After seeding, it is left at RT for 24 h with occasional stirring. The product is filtered, washed with hexane (4 × 3.5 ml), and dried; yield 20 8.71 g, m.p. 117–119°C, [ α ] D = −199.2 (c = 1; MeOH). Water (35 ml), 37% HCl (3.5 ml), and CH2Cl2 are added and the mixture stirred for 10 min. The phases are separated, and the aqueous phase is washed with CH2Cl2 (2 × 5 ml). NaOH (2.5 g) is dissolved in the aqueous phase and extracted with CH2Cl2 (3 × 20 ml). The combined organic phase is dried over Na2SO4 and the solvent evaporated; 20 yield 1.58 g of semi-solid oil, [ α ] D = −52.5 (c = 1; EtOH). The mother liquor of the resolution is then evaporated. Further work-up is the same 20 as above; yield: 1.66 g of semi-solid oil, [ α ] D = +51.6 (c = 1; EtOH). © 2002 by CRC Press LLC

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c. Enantiomeric enrichment by crystallization from melt: 20 8.50 base (22.0 g, 133.2 mmol, [ α ] D = +48.8 (c = 1; EtOH), e.e. 69.2%) is cooled to 0 to 5°C and seeded by the (+)-enantiomer. The crystalline mass is homogenized and filtered on a glass filter cooled to 0°C. During continuous filtration, the mass is left to warm up to RT (22°C). The white crystalline 8.50 base is remaining on 20 the filter: 6.5 g (29.5%), [ α ] D = +65.8 (c = 1; EtOH), e.e. 93.3%; the filtrate: 15.1 g 20 (68.6%), [ α ] D = +40.3 (c = 1; EtOH), e.e. 57.2% of oily 8.50 base. d. Enantiomeric enrichment by recrystallization of the 8.50⋅HCl salt: 20 8.50 (66.0 g, 399.5 mmol, [ α ] D = +7.2 (c = 1; EtOH), e.e. 10.2%) and 37% HCl (35 ml, 419.0 mmol, d = 1.18) are dissolved in hot water (200 ml). After cooling and scratching, white crystals precipitate. The obtained thick suspension is filtered at 20°C and washed with 0°C water (3 × 15 ml). The wet 8.50⋅⋅ HCl is suspended in H2O (150 ml), NaOH (13.0 g, 325 mmol) dissolved, and the solution is extracted with CH2Cl2 (3 × 50 ml). The combined organic phase is dried over Na2SO4 and the solvent evaporated in vacuo. Yield: 48.0 g (72.7%) 20 [ α ] D = +1.0 (c = 1; EtOH), e.e. 1.4%) of 8.50 base. In the mother liquor NaOH (7.0 g, 175.0 mmol) is dissolved and the solution extracted with CH2Cl2 (3 × 50 ml). The combined organic phases are dried over Na2SO4 and the 20 solvent evaporated in vacuo. Yield: 13.9 g (21.1%, [ α ] D = +25.8 (c = 1; EtOH), e.e. 36.6%) of 8.50 base. 34. Resolution of 6-Fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (8.50) with 34 [(1R)-(endo,anti )]-(+)-3-Bromocamphor-8-sulfonic acid (+)-(BCS) Resolution by both enantiomers of the racemate. Racemic 8.50 (2.0 g, 12.1 mmol) and (t)-BCS ammonium salt (4.0 g, 12.2 mmol) are dissolved in hot HCl (1.5 ml conc. HCl and 20 ml H2O). The mixture is cooled to room temperature. Crystallization is initiated by scratching. After standing at room temperature with occasional stirring for 1 h, the product is filtered. The diastereomeric salt is recrystallized twice from 5% HCl solution (5 ml) to give (+)-8.50, 1.71 g, [ α ] D = +86.3 (c = 1; MeOH, m.p. 169–172°C). Ethyl acetate (20 ml) is added to the salt and the mixture washed with 1 M Na2CO3 (3 × 10 ml). The organic phase is dried over Na2SO4 and the solvent is evaporated in vacuo. Yield: white crystals (0.52 g, [ α ] D = +70.0 (c = 1; EtOH), m.p. 40–42°C). To the mother liquor ethyl acetate (20 ml) is added and the mixture is washed with 1 M Na2CO3 (3 × 30 ml). The organic phase is dried over Na2SO4 and the solvent evaporated in vacuo. Yield: oily crystalline material (1.10 g, [ α ] D = −33.4 (c = 1; EtOH)). (−)-8.50 is obtained in a similar way using the other enantiomer of the resolving agent. 35. Resolution of S-Methyl-S-phenylsulfoximine (8.51) with (1S)35 (+)-Camphor-10-sulfonic Acid (8.15) Resolution with 0.5 molar equivalent resolving agent (a). Purification of the diastereomeric salt in the mother liquor by the addition of further amounts of resolving agent (b). Purification of the precipitated diasteromeric salt by addition of the racemate (c). Regeneration of the resolving agent (d). a. A solution of (+)-8.15 (87.3 g, 376 mmol) in dry acetone (550 ml) is gradually added at RT under stirring to a solution of racemic 8.51 (116.6 g, 751 mmol) in dry acetone (430 ml). © 2002 by CRC Press LLC

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After the addition of about one third of the (+)-8.15 solution, fine white crystals of the salt (+)-8.51⋅⋅ (+)-8.15 begin to precipitate. The resulting suspension is stirred at RT for 12 h. The crystals are filtered with the aid of a glass filter, washed thoroughly with dry acetone (4 × 100 ml), and dried in vacuo to give the salt (+)-8.51⋅(+)-8.15 (123.0 g, 84%) of ≥99% d.e. as colorless crystals: m.p. 178°C; [α]D = +43.9 (c = 1.20; acetone). Base treatment of the salt (+)-8.51⋅⋅ (+)-8.15 and distillation (89°C, 0.1 torr) gives the sulfoximine 47.3 g, 96%, of ≥99% e.e. as a colorless oil, which solidifies in the freezer: [ α ] D = +36.2 (c = 1.10; acetone). b. The filtrate remaining from the above isolation of (+)-8.51⋅⋅ (+)-8.15, which contains (−)8.51 (79% e.e.), is treated with solid (+)-8.15 (17.5 g, 75.4 mmol). After concentration of the solution in vacuo, the resulting oil is treated, while stirring, with dry acetone (2 ml) and dry toluene (800 ml), whereupon a fine suspension forms. The suspension is stirred at RT for 1 day and kept at 2°C for 1 day. Filtration and drying of the solid material in vacuo gives the salt (−)-8.51⋅(+)-8.15 (5.6 g) of 45% d.e. Concentration of the filtrate and distillation gives (−)-8.51, 43 g, 74% of 97–99% e.e. c. The salt (+)-8.51⋅⋅ (+)-8.15 (30 g, 77.4 mmol) of 97% d.e. is suspended in dry acetone (100 ml) and (±)-8.51 (0.50 g, 3.22 mmol) is added to the suspension. After stirring the suspension at RT for 18 h, it is filtered. The solid is thoroughly washed with dry acetone (3 × 75 ml) and dried in vacuo to give the salt (+)-8.51⋅⋅ (+)-8.15 (29.1 g, 97%) of ≥99% d.e. as a colorless powder: [ α ] D = +43.9 (c = 1.20; acetone). Base treatment of the salt (+)-8.51⋅⋅ (+)-8.15 and distillation yields the sulfoximine (+)-8.51 (11.2 g, 96%) of ≥99% e.e.: [ α ] D = +36.2 (c = 1.10; acetone). d. Recovery of (+)-10-camphorsulfonic acid: The basic aqueous solution that remains from the treatment of the salt (+)-8.51⋅ (+)8.15 and extraction of the sulfoximine (+)-8.51 is passed through a column containing an acidic cation exchanger (Lewatit S100). Concentration of the eluate in vacuo and recrystallization of the residue from ethyl acetate yields (+)-8.15 in 97% yield: m.p. 193°C; [ α ] D = +19.8 (c = 2.0; H2O). 36. Resolution of 2-(3-Chlorophenyl)-3,4a,5,6,7,7a-hexahydrocyclopentapyrimidin-4-one (8.52) with O,O´-Dibenzoyl36 tartrate (DBTA) Resolution in two-phase solvent system (a−c). Enantiomeric enrichment by fractional crystallization (d, e). a. 6.0 g (0.024 mol) racemic 8.52 is dissolved in a mixture of CHCl3 (100 ml) and H2O (50 ml). A solution of DBTA (4.7 g, 0.0125 mol) in CHCl3 (30 ml) is added to the two-phase solution of the racemic base in 15 min at RT. From the stirred solution, crystallization can be induced by scratching the wall of the vessel with a glass rod. The resulting suspension is stirred at 5°C overnight and then filtered. The precipitate is washed on the filter three times with 5 ml of 5°C CHCl3 and dried under an infrared lamp. 20 The precipitate is (+)-8.52⋅DBTA. Yield:7.3 g (96.9%), [ α ] D = −54.6 (c = 1; dimethylformamide). b. 7.0 g (+)-8.52⋅⋅ DBTA is suspended in H2O (20 ml) and treated with cc NH4OH (3 ml). An oily precipitate solidifies after stirring the reaction mixture for 1 h at RT. The precipitated (+)-8.52 is filtered and washed three times with 2 ml of 0°C water and 20 dried under an infrared lamp. Yield: 2.65 g (95.6%), [ α ] D = +35 (c = 1; 1 N HCl). © 2002 by CRC Press LLC

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c. The two-phase mother liquor from the resolution is treated with cc NH4OH (3 ml) and stirred for 2 h at RT; then the phases are separated. The evaporation of the organic 20 phase in a rotary evaporator results in the raw (−)-8.52. Yield:2.9 g (96.7%), [ α ] D = −34.8 (c = 1; 1 N HCl). 20 d. 2.0 g raw (+)-8.52 ( [ α ] D = +35) is dissolved in 10 ml boiling ethanol; on cooling back to RT, and after inoculation with small amount of racemic-8.52, a white crystalline material precipitates. The reaction mixture is stirred at 5°C overnight and then filtered. The precipitate is washed on the filter twice with 5°C ethanol (0.5 ml), and dried under 20 an infrared lamp. Yield:0.7 g (35%) [ α ] D = +8 (c = 1; 1 N HCl). The mother liquor is evaporated to dryness in vacuo, yielding the optically pure (+)20 8.52. Yield: 1.2 g (60%), [ α ] D = +54 (c = 1; 1 N HCl), m.p. 117–118°C. 20 e. 2.9 g raw (−)-8.52 ( [ α ] D = −34.8) is dissolved in 14.5 ml boiling ethanol; on cooling back to RT, and after inoculation with a small amount of racemic-8.52, a white crystalline material precipitates. The reaction mixture is stirred overnight at 5°C and then filtered. The precipitate is washed twice on the filter with 5°C ethanol 20 (0.7 ml) and dried under an infrared lamp. Yield: 1.0 g (35%), [ α ] D = −8 (c = 1; 1 N HCl). The mother liquor is evaporated to dryness in vacuum, yielding the optically pure 20 (−)-8.52. Yield: 1.7 g (58.5%), [ α ] D = −54 (c = 1; 1 N HCl), m.p. 117–118°C. 37. Optical Resolution of RS-6-Phenyl-2,3,5,6-tetrahydro-imidazo[2,1b] 37 thiazole (8.53) with O,O´-Dibenzoyl-tartrate (DBTA) Resolution in two-phase solvent system. Enantiomeric enrichment by partial precipitation (e). a. A suspension of 40.8 g (0.2 mol) RS-8.53, dichloroethane (100 ml), water (80 ml) is warmed until a clear solution forms. To the hot solution, slowly add 25 g (0.066 mol) DBTA ⋅ H2O in hot 1,2-dichloroethane (100 ml). The system is stirred continuously. A white crystalline powder begins to precipitate. The system is allowed to cool at RT. Finally, the crystallization is perfected with stirring at 10°C for 30 min. The (−)-8.5320 (−)-DBTA (26.9 g, [ α ] D = −130.1 (c = 5; MeOH)) should be collected on a filter and washed with cold water (20 ml). The combined mother liquor and the washings are used for the recovery of the racemate and the preparation of (+)-8.53. b. The crude (−)-8.53-(−)-DBTA is pulverized and suspended in 95 ml H2O. This suspension is treated with conc. NH4OH until the pH reaches 9.5. The resulting mixture is shaken with three 70-ml portions of toluene. The combined toluene extracts are then washed with two 50-ml portions of H2O and dried over magnesium sulfate. To this solution, 0.1 mol HCl dissolved in isopropanol (20 ml) is added drop by drop with continuous stirring. Crytallization occurs slowly, and the solution is allowed to stand at 0°C for 2h. The product should be filtered and washed with a small volume of toluene containing 15% isopropanol. (−)-8.53⋅HCl is collected as white prism 16 g (67% for 20 the S-isomer of the starting racemate), m.p. 213–215°C, [ α ] D = – 125.5 (c = 1; H2O), o.p. 93%. c. The aqueous and the organic phases of the combined mother liquor and the washings are separated. Both the organic layer and the aqueous phases are washed with either water or 1,2-dichloroethane (30-ml each). The combined organic phase and the washings are used for the preparation of (±)-8.53. The combined aqueous phase is treated with aqueous 40% NaOH (10 ml), cooled to 10°C, and maintained at this temperature for 30 min with stirring. A white precipitate © 2002 by CRC Press LLC

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starts forming immediately. The product is filtered and washed with H2O (15 ml). The racemic acid is collected, 9.4 g (23%). d. The organic phase of the above procedure is dried over MgSO4 and concentrated in vacuo to dryness. The oily residue crystallizes quickly. (+)-8.53 is collected, 13.7 g 20 (67%), m.p. 50–52°C, [ α ] D + 72.1 (c = 5; MeOH). e. Partially resolved 8.53 is treated with 40 ml of an aqueous solution containing a sufficient amount (half equivalent to the enantiomeric excess of hydrogen chloride) to convert excess (+)-8.53 into its hydrochloride salt, which is highly soluble in water. The system is stirred for 15 min. The precipitate is filtered and washed with H2O. The 20 nearly racemic fraction is collected, 4.1 g, m.p. 88–89°C, [ α ] D = 0 (c = 5; MeOH). The mother liquor is slowly adjusted to pH 9.5 with conc. NH4OH while stirring. After 30 min of stirring at 5°C, the precipitate is filtered and washed with H2O. (+)-8.53 20 is collected, 9.4 g, m.p. 57–59°C, [ α ] D = +100.2 (c = 5; MeOH).

38. Resolution of Racemic-2,2-Diphenyl-3-methyl-4-dimethylaminobutanenitrile 38 (8.54) by Tartaric Acid (TA) Effect of seeding during crystallization of the diasteromeric salt. Racemic 8.54 (2 kg) and TA (1120 g) are dissolved in 95% EtOH (15 l). The solution is cooled to 5°C, seeded with a trace of D-nitrile D-bitartarate if available, and allowed to stand at 5°C for 2 days. Rapid crystallization without seeding can be obtained by stirring, but a precipitate is produced that filters very slowly and resolution will not be effective. The solid is collected, washed with cold 95% EtOH is added (2 l), and dried as thoroughly as possible by suction filtration. A sample converted to the free D-8.54 has m.p. 82–92°C. The crude salt is then dissolved in 95% EtOH (4 l) at 50°C, cooled rapidly to 5°C, and maintained at this temperature for 24 h. The resulting precipitate is collected, washed with cold 95% EtOH, and dried in vacuo, giving 25 about 1220 g (+)-8.54⋅bitartrate; m.p. 75–95°C, [ α ] D = +63.8 (C = 1.6, H2O). The recrystallized (+)-8.54⋅bitartrate is converted to (+)-8.54 by dissolving the salt in H2O (15 l) and treating with NH4OH. The solution is seeded with a sample of the (+)-8.54 at the point of incipient turbidity, and NH4OH is added slowly with good stirring to effect optimal crystallization. The base is separated, washed well with water, dried, and recrystallized from 95% EtOH (2 l), yielding approx25 imately 610 g pure (+)-8.54 m.p. 101.5−102.2°C, [ α ] D = +70.1.

39. Resolution of 3-Dimethylamino-2-methyl-1,1-diphenylpropan-1-ol (8.55) +)-Camphor-10-sulfonic Acid (8.15)39 with (1S)-(+ Initiation of the crystallization of the diastereomeric salt with seed crystals prepared from the racemate. A solution of racemic 8.55 (26.9 g) and (+)-8.15 (23.2 g) in acetone (100 ml) is seeded (seed material obtained by leaving the oil left after evaporating some of the above solution to stand in a desiccator until it solidifies) and stored at room temperature for 48 h. The mother liquors are decanted and the crystals dissolved in hot acetone (150 ml) and reseeded; the crystals that separate have 17 [ α ] D = – 27.9 (c = 1.0; H2O). One recrystallization from acetone (150 ml) (no seed added) gives 16 material with [ α ] D = – 29.1 (c = 1.0; in H2O). © 2002 by CRC Press LLC

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±)-6-Dimethylamino-4,4-diphenyl-3-heptanone (8.56) 40. Resolution of (± 40 with 4-Nitrobenzoyl-L-glutamic Acid (8.57) Crystallization of the diastereomeric salt with the help of a second solvent. (±)-8.56 (2.6 g) and 8.57 (2.6 g) are dissolved in boiling butanol (13 ml) and the solution is cooled to approximately 20°C. Petroleum ether (1–3ml; b.p. 30–60°C) is added to this solution over a period of 5 min (or longer if necessary to ensure formation of seed crystals). The resulting mixture is then cooled to 0°C, and additional petroleum ether (12 ml) is added over 2 h. The crystalline slurry thus formed is allowed to stand overnight at 0°C, after which the crystalline salt is removed by filtration, washed with two 25-ml portions of 1:1 petroleum ether: butanol mixture, and dried at 50°C to produce 2.9 g (+)-8.56⋅8.57 salt. 41. Resolution of 1,2-bis-(4-Pyridyl)-oxirane (8.58) with 41 O,O′-Dibenzoyl-tartrate (DBTA) Mechanical separation of diastereomeric salts. Racemic 8.58 (2.1 g) is dissolved in a minimum volume of warm acetone added to a solution of DBTA (3.97 g) in warm acetone, and set aside overnight. The resulting precipitate is composed of two macroscopically different types of crystals that are mechanically separated. One fraction gives, after recrystallization from acetone, shiny leaflets (2.05 g), m.p. 139–141°C. The other fraction, after recrystallization from acetone, gives needles (1.9 g), m.p. 145–146°C. After basification with 20% aqueous NaOH, extraction with CHCl3, and crystallization from cyclohexane, the first fraction yields 8.58 (0.9 g), m.p. 98–100°C [α]D = −226.2 (c = 0.5; H2O). The fraction with m.p. 145–146°C gives, by the same procedure, epoxide (0.9 g), m.p. 99–100°C, [α]D = +228 (c = 0.5; H2O).

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Hungarian Patent 204774 (1991). Hungarian Patent 208684 (1993). Hungarian Patent 200990 (1990). Hungarian Patent 202825 (1990). Hungarian Patent 205594 (1990). Hungarian Patent 202896 (1991). M. Senuma, M. Shibazaki, S. Nishimoto, K. Shibata, K. Okamura, and T. Date, Chem. Pharm. Bull., 37, 3204 (1989). Hungarian Patent 204782 (1991). Hungarian Patent 195174 (1989). Hungarian Patent 195174 (1989). Hungarian Patent 182475 (1983). Hungarian Patent 177583 (1983). Hungarian Patent 181416 (1985). Hungarian Patent 178516 (1981). Hungarian Patent 152208 (1966). Hungarian Patent 163526 (1973). Hungarian Patent 171090 (1978). Hungarian Patent 208662 (1992). Hungarian Patent 193202 (1986). R. Stephani and V. Cesare, J. Chem. Ed., 74, 1226 (1997).

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21. J. Drabowitz, B. Dudzi´nski, M. Mikol ajczyk, M.W. Wieczorek, and W.R. Majzner, Tetrahedron: Asymmetry, 9, 1171 (1998). 22. T. Shiraiwa, M. Ohkubo, M. Kubo, H. Miyazaki, M. Takehata, H. Izawa, K. Nakagawa, and H. Kurokawa, Chem. Pharm. Bull., 46, 1364 (1998). 23. K. Drauz, W. Jahn, and M. Schwarm, Chem. Eur. J., 1, 538 (1995). 24. R.J. Alabaster, A.W. Gibson, S.A. Johnson, J.S. Edwards, and I.F. Cottrell, Tetrahedron: Asymmetry, 8, 447 (1997). 25. J. Viret, H. Patzelt, and A. Collet, Tetrahedron Lett., 27, 5865 (1986). 26. A.L. Tökés, Liebigs. Ann. Chem., 89 (1989). 27. G. Semple, H. Ryder, M. Ohta, and M. Satoh, Synth. Commun., 26, 721 (1996). 28. J.-J. Brunnet, A. Herbowski, and D. Neibecker, Synth. Commun., 26, 483 (1996). 29. C. Avedaño, E. de la Cuesta, R. González, L. Prieto, C. Pedregal, and M. Espada, Tetrahedron, 51, 3271 (1995). 30. A. Sudo and K. Saigo, Tetrahedron: Asymmetry, 7, 2939 (1996). 31. S. Yamada, C. Hongo, R. Yoshioka, and I. Chibata, Agric. Biol. Chem., 43, 395 (1979). 32. J. Bálint, K. Marthi, M. Ács, G. Egri, and E. Fogassy, Enantiomer, 2, 27 (1997). 33. J. Bálint, G. Egri, G. Vass, J. Schindler, A. Gajáry, A. Friesz, and E. Fogassy, Tetrahedron: Asymmetry, 11, 809 (2000). 34. J. Bálint, G. Egri, E. Fogassy, Z. Böcskei, K. Simon, A. Gajáry, and A. Friesz, Tetrahedron: Asymmetry, 10, 1079 (1999). 35. J. Brandt and H.J. Gais, Tetrahedron: Asymmetry, 8, 909 (1997). 36. D. Kozma, G. Egri, and E. Fogassy, Synth. Commun., 29, 2265 (1999). 37. M. Ács, E. Fogassy, and F. Faigl, Tetrahedron, 41, 2465 (1985). 38. A.A. Larsen and B.F. Tullar, U.S. Patent 2773901 (1956). 39. A.F. Casy and J.L. Myers, J. Pharm. Pharmacol., 16, 455 (1964). 40. E.E. Howe and M. Tischler, U.S. Patent 2644010 (1953). 41. G. Gottarelli and B. Samori, J. Chem. Soc., Perkin Trans. 2, 1971 (1972).

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Appendix 1 Resolutions Ordered According to the Resolving Agent D. KOZMA AND C. KASSAI In this data base a large number of resolutions have been collected in order to facilitate the selection of the best resolving agent according to the "similarity principle" (cf. Chapter 5.1.4). Data are divided into two main groups: (i) acidic and amphoteric racemates (acids and amino acids) and (ii) racemates without an acidic group (bases). The main groups were subdivided according to the resolving agents and also the solvent used were reported. Presentation of data is illustrated by the following sample box:

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RESOLUTION OF ACIDS Phenyletylamine C 3 H 5 IO 3

I

H2O

COOH

E. Hannerz, Chem. Ber., 598, 1367 (1926)

Pheta. 1

C3H8O2N2

COOH

H2N

EtOAc

NH2

E. Felder, D. Pitre and S. Boveri, Hoppe-

Pheta. 2

Seyler's Z. Physiol Chem. 351, 943 (1970) C17H16O4N2

H benzoyl N CH2 C COOH H N benzoyl H

EtOAc

COOH

HOOC

H2O

Cl

E. Felder, D. Pitre and S. Boveri, Hoppe-

Pheta. 3

C 4 H 4 Cl 2 O 4

Cl

B. Holmberg, Svensk Kem. Tidsk, 24, 105

Pheta. 4

Seyler's Z. Physiol Chem. 351, 943

(1912)

(1970) C 4 H 5 Cl 3 O 3

OH

COOH

Cl3C

OH

EtOH

D. Borrmann and R. Wegler, Chem. Ber.,

Pheta. 5

COOH NH2

H2O

F. W. Bachelor and G. A. Miana, Can. J.

Pheta. 6

100, 1575 (1967) HOOC

C4 H6 O5

COOH

HOOC

Chem.,45, 79 (1967) C 4 H 7 NO 4

C 4 H 7 NO 4

O

H 2 O, MeOH, Acetone

MeOH, benzene COOH

10:60:40 v/v % K. Harada, Bull Chem. Soc. Japan, 37,

Pheta. 7

N. K. Kochetkov, A. M. Likhosheratov and

Pheta. 8

1383 (1964)

V. N. Kulakov, Tetrahedron, 25, 2313 (1969)

COOH

O

Pheta. 9

C5H6O4 MeOH, Et 2 O

O

33:66 v/v % J-F. Tocanne and C. Asselineau, Bull. Soc. Chim. Fr., 3346 (1965)

C 5 H 8 NO 3

COOH

Acetone

N O Pheta. 10

B. Chion, J. Lajzerowicz, D. Bordeaux, A. Collet and J. Jacques, J. Phys. Chem., 82, 2682 (1978)

COOH

C5H6O4 Acetone

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OAc

COOH

C5H8O4 CH 2 Cl 2 , Petrolether 33:67 v/v %

Pheta. 11

G. T. Pearce, W. E. Gore and R. M.

Pheta. 12

Silverstein, J. Org. Chem., 41, 2797

G. Losse and H. Raue, Chem. Ber., 101, 1532 (1968)

(1976)

H C COOH Br

C 5 H 9 BrO 2

COOH

Et2O

C 5 H 1 0 NO 2 petroleum, Et2O 50:50 v/v %

Pheta. 13

Y. A. Ovchinnikov, V. T. Ivanov and A.

Pheta. 14

G. Odham, Arkiv Kemi, 20, 507 (1962)

A. Kirgushkin, Izv. Akad. Nauk SSSR, 2046 (1962) C 5 H 1 1 NO 2

NH2

COOH

C 5 H 1 1 NO 2

COOH

Acetone, MeOH 96:4 v/v %

Pheta. 15

P. Alaupovic, Croat. Chem. Acta, 29, 131

Pheta. 16

(1957)

L. R. Overby and A. W. Ingersoll, J. Am. Chem. Soc., 73, 3363 (1951)

C 7 H 1 3 NO 3

COOH

H2O

C 5 H 1 1 NO 3 COOH

HO

NHAc

Pheta. 17

MeOH, Acetone

NH2

L. R. Overby and A. W. Ingersoll, J. Am.

Pheta. 18

Chem. Soc., 73, 3363 (1951)

MeOH, Acetone

J. Oh-hashi and K. Harada, Bull. Chem. Soc. Japan, 30, 2287 (1966)

C 1 2 H 1 5 NO 4 COOH

HO

H2O

NH2

OH C COOH H

S

C6H6O3S EtOAc

N benzoyl H

Pheta. 19

J. Oh-hashi and K. Harada, Bull. Chem.

Pheta. 20

S. Gronowitz, Arkiv Kemi, 13, 87 (1958)

Soc. Japan, 30, 2287 (1966) OH C COOH H

EtOAc, MeOH

S. Gronowitz, Arkiv Kemi, 13, 231 (1958)

C 6 H 8 Br 2 O 4

Br

COOH

HOOC

Pheta. 22

B. Holmberg and E. Müller, Chem. Ber. 58, 1601 (1925)

C6H8O4

O

O

COOH

iPrOH, iPr 2 O 50:50 v/v %

© 2002 by CRC Press LLC

H2O

Br

70:30 v/v %

S

Pheta. 21

C6H6O3S

C6H10O2

COOH

Et2O

Y. Kato and T. Wakabayashi, Synth.

Pheta. 23

Pheta. 24

G. Stallberg, Acta Chem. Scand., 11, 1430

Comm., 7, 125 (1977)

COOH

(1957) C6H10O2

C6H10O3

Et2O

O

COOH

EtOH, Acetone 20:80 v/v %

E. J. Corey and T. Hase, Tetrahedron

Pheta. 25

H. Wollweber, H. Horstmann and K. Meng,

Pheta. 26

Lett., 335 (1979) C6H10O3S2

S

COOH

O

S

Eur. J. Med. Chem., 11, 159 (1976) C6H10O3S2 S

H2O

S

COOH

H2O

O

A. Fredga, Svensk. Kem. Tids., 54, 26

Pheta. 27

B. Holmberg, Chem. Ber., 59, 1558 (1926)

Pheta. 28

(1942) COOH

C 6 H 1 1 NO 3 EtOH

NHAc

D. Pitre and S. Boveri, Farmaco, Ed. Sci.,

Pheta. 29

COOH

O

N

EtOAc, MeOH

S

Pheta. 30

26, 733 (1971)

M. Matell, Acta Chem. Scand., 14, 677 (1960)

C 6 H 1 1 NO 3 S O

N

C6H12O3

COOH

COOH

S

Pheta. 31

OH

B. Holmberg, Chem. Ber., 59, 1558

Pheta. 32

(1926) COOH

Pheta. 33

C 6 H 1 3 NO 2

W. A. H. Huffman and A. W. Ingersoll, J.

H2N

Pheta. 35

COOH

NHAc

Pheta. 34

H2O

III, U. S. Patent 3,651,138 (1972)

C 8 H 1 5 NO 3 H2O

W. A. H. Huffman and A. W. Ingersoll, J. Am. Chem. Soc., 73, 3366 (1951) NHAc

C6H14N2O2

T. T. Yee, J. A. Cahill and J. A. Meyers

© 2002 by CRC Press LLC

J. P. Vigneron, M. Dhaenens and A.

COOH

Am. Chem. Soc., 73, 3366 (1951) NH2

EtO2

Horeau, Tetrahedron, 33. 507 (1977)

H2O

NH2

C 6 H 1 1 NO 3 S

AcNH

Pheta. 36

COOH

C10H18N2O4 H2O

T. T. Yee, J. A. Cahill and J. A. Meyers III, U. S. Patent 3,651,138 (1972)

C 7 H 9 NO 4

O

EtOAc

N HOOCH2C

PO3H2

MeOH

O

I. Fleming, J. Chem. Soc. C, 2765 (1968)

Pheta. 37

C 7 H 1 0 NO 3 P

NH2

M. Hoffmann, Folich J. Chem., 52, 851

Pheta. 38

(1978) HN CBZ

C 1 5 H 1 8 NO 3 P

COOH

o r C 1 6 H 2 0 NO 3 P

P (OR)(OH) O

C7H10O2 Acetone

MeOH

R=Me, Et M. Hoffmann, Folich J. Chem., 52, 851

Pheta. 39

Ph.D. Thesis of P.W. Marr, University of

Pheta. 40

(1978) HO

Toronto, Toronto, Canada (1972) C7H10O5

COOH

H N

S

abs. EtOH

COOH

S

COOH

HO

C 7 H 1 1 NO 4 S 2 MeOH

OH

E. E. Smissman, J. T. Suh, M. Oxman and

Pheta. 41

Pheta. 42

R. Daniels, J. Am. Chem. Soc., 84, 1040

A. Fredga, Svensk. kem. Tids., 53, 221 (1941)

(1962)

O

COOH

MeOH

N CONHCH3 OCH3

R. G. Kostyanovsky, V. f. Rudchenko, O.

Pheta. 43

C7 H1 2 O2

C7H12N2O5

O Pheta. 44

A. D'yachenko, I. I. Chervin, A. B.

O

H2O

J. Kenyon and M. C. R. Symons, J. Chem. Soc., 3580 (1953)

Zolotoi and L. O. Atovmyan, Tetrahedron, 35, 213 (1979) C7H12O3

O

COOH

C7H12O4 COOH

MeOH

MeCl

OAc

F. I. Carroll, G. N. Mitchell, J. T.

Pheta. 45

Pheta. 46

Blackwell, a. Sobti and R. Meck, J. Org.

G. Losse and H. Raue, Chem. Ber., 101, 1532 (1968)

Chem., 39, 3890 (1974) C7H14O4

COOH

HO

OH

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C7H14O4

OH COOH

abs. EtOH HO

abs. EtOH

N. K. Kochetkov, A. M. Likhosherstov

Pheta. 47

Pheta. 48

N. K. Kochetkov, A. M. Likhosherstov and

and V. N. Kulakov, Tetrahedron, 25, 2313

V. N. Kulakov, Tetrahedron, 25, 2313

(1969)

(1969)

OH

C 8 H 6 Cl 2 O 3

Cl

C 8 H 6 Cl 2 O 3

OH

COOH

Cl

COOH

Cl

Cl J. R. W. Hoover, G. L. Dunn, D. R. Jakas,

Pheta. 49

Pheta. 50

J. R. W. Hoover, G. L. Dunn, D. R. Jakas,

L. L. Lam, J. J. Taggart, J. R. Guarini, and

L. L. Lam, J. J. Taggart, J. R. Guarini, and

L. Phillips, J. Med. Chem., 17, 34 (1974)

L. Phillips, J. Med. Chem., 17, 34 (1974)

OH

OH

C 8 H 7 ClO 3

C 8 H 7 NO 5

COOH

COOH O2N

Cl

J. R. W. Hoover, G. L. Dunn, D. R. Jakas,

Pheta. 51

Pheta. 52

J. R. W. Hoover, G. L. Dunn, D. R. Jakas,

L. L. Lam, J. J. Taggart, J. R. Guarini, and

L. L. Lam, J. J. Taggart, J. R. Guarini, and

L. Phillips, J. Med. Chem., 17, 34 (1974)

L. Phillips, J. Med. Chem., 17, 34 (1974)

C8H7N3O2

N3 COOH

C8H8O4S

Acetone

S

COOH

EtOAc

COOH Pheta. 53

G. Bison, H. Schübel and P. Janssen,

Pheta. 54

K. Pettersson, Arkiv Kemi, 7, 39 (1954)

German Patent (Offen.) 2,127,991 (1972) NH2 COOH

NHAc

C 9 H 9 NO 3 H2O

T. Shirai, Y. Tashiro and S. Aoki, German

Pheta. 56

Offen. 2,449,492 (1975)

SO3H

T. Shirai, Y. Tashiro and S. Aoki, German Offen. 2,449,492 (1975)

C 8 H 1 1 NO 3 S

NH2

Pheta. 57

H2O

AcO

HO

Pheta. 55

C 1 3 H 1 3 NO 5

COOH

NHCHO SO3H

H2O

V. M. Potapov, A. P. Terent'ev and V. M.

Pheta. 58

C 9 H 1 1 NO 4 S H2O

V. M. Potapov, A. P. Terent'ev and V. M.

Dem1yanovich, Zhur. Osch. Khim., 29,

Dem1yanovich, Zhur. Osch. Khim., 29, 953

953 (1959)

(1959)

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CH2COOH

C8H12O2

NHCOCH2Cl

C 8 H 1 4 ClNO 3

H2O

COOH

H2O

Ph. D. Thesis of P. W. Marr, University of

Pheta. 59

E. Adberhalden and A. Schmitz, Biochem.

Pheta. 60

Toronto, Canada (1972) COOH

Z., 214, 158 (1929)

C 9 H 7 Cl 3 O 3 H 2 O, EtOH

O Cl

C9H7F3O2

CF3

H 2 O, EtOH

COOH

80:20 v/v%

33:67 v/v%

Cl Cl

Ph. D. Thesis of Magnus Matell, Uppsala,

Pheta. 61

C. Aaron, D. Dull, J. L. Schmiegel, D.

Pheta. 62

Sweden (1953)

Jaeger, Y. Ohashi, and H. S. Mosher, J. Org.

OH F3C

Cl

C9H7F3O3

COOH

H N

Chem., 32, 2797 (1967) COOH

C 9 H 8 Cl 3 NO 2 Acetone, H2O

Cl

50:50 v/v%

Cl

J. R. E. Hoover, G. L. Dunn, D. R. Jakas,

Pheta. 63

A. Fredga, Arkiv Kemi, 11, 23 (1957)

Pheta. 64

L. L. Lam, J. J. Taggart, J. R. Guarini and L. Phillips, J. Med. Chem., 17, 34 (1974) OH COOH

EtOH

OH

Cl

C 9 H 9 ClO 4

A. Collet, Bull. Soc. Chim. Fr., 215

Pheta. 65

C 9 H 9 NO 4 O2N

COOH

Benzene

F. Nerdel and H. Harter, Liebigs Ann.

Pheta. 66

(1975)

Chem., 621, 22 (1959) C 9 H 9 NO 4

COOH O2 N

EtOH, H2O 17:83 v/v%

A. Fredga, Arkiv Kemi, 7, 241 (1954)

Pheta. 67

C 9 H 9 NO 4 COOH

EtOH

O2 N

F. Nerdel and H. Würgan, Liebigs Ann.

Pheta. 68

Chem., 621, 34 (1959) O2N

COOH NH2

HO

C9H9N3O7 abs. EtOH

O2 N HO

NO2

Pheta. 69

COOH NHAc

C11H11N3O8 abs. EtOH

NO2

D. Pitré and E. B. Grabitz, Hoppe-Seyler's Z. Physiol. Chem., 333, 105 (1963)

© 2002 by CRC Press LLC

Pheta. 70

D. Pitré and E. B. Grabitz, Hoppe-Seyler's Z. Physiol. Chem., 333, 105 (1963)

OH

C9H10O2 COOH

C9H10O3

COOH

EtOH, Benzene 20:80 v/v%

K. Pettersson, Arkiv Kemi, 10, 283

Pheta. 71

Pheta. 72

(1956)

J. R. E. Hoover, G. L. Dunn, D. R. Jakas, L. L. Lam, J. J. Taggart, J. R. Guarini and L. Phillips, J. Med. Chem., 17, 34 (1974)

OH

C9H10O3

COOH

J. R. E. Hoover, G. L. Dunn, D. R. Jakas,

Pheta. 73

C9H10O3

OH

COOH

Pheta. 74

H2O

L. Smith, J. Prakt, Chem., 84, 731 (1911)

L. L. Lam, J. J. Taggart, J. R. Guarini and L. Phillips, J. Med. Chem., 17, 34 (1974) OH H3CO

OH

C9H10O4

COOH

C9H10O4

COOH H3CO

J. R. E. Hoover, G. L. Dunn, D. R. Jakas,

Pheta. 75

Pheta. 76

J. R. E. Hoover, G. L. Dunn, D. R. Jakas, L.

L. L. Lam, J. J. Taggart, J. R. Guarini and

L. Lam, J. J. Taggart, J. R. Guarini and L.

L. Phillips, J. Med. Chem., 17, 34 (1974)

Phillips, J. Med. Chem., 17, 34 (1974)

OH

C9H10O4 COOH

EtOH

COOH S

EtOAc COOH

OH

Pheta. 77

A. Collet, Bull. Soc. Chim. Fr., 215

Pheta. 78

(1975) COOH NH2

Pheta. 79

COOH

C 9 H 1 1 NO 2 HN

Benzene Pheta. 80

Chem. Soc., 82, 2067 (1960)

NH2

Pheta. 81

Benzene

L. R. Overby and A. W. Ingersoll, J. Am.

COOH NHCHO

H2O

J. Am. Chem. Soc., 76, 2801 (1954)

CBZ

C 1 7 H 1 7 NO 5

Chem. Soc., 82, 2067 (1960)

C 9 H 1 1 NO 2

F. H. Radke, R. B. Fearing and S. W. Fox,

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A. Fredga and O. Palm, Arkiv Kemi, Mineral. Geol., 26A, No. 26 (1949)

L. R. Overby and A. W. Ingersoll, J. Am.

COOH

C9H10O4S

Pheta. 82

C 1 0 H 1 1 NO 3 H2O

F. H. Radke, R. B. Fearing and S. W. Fox, J. Am. Chem. Soc., 76, 2801 (1954)

H N

COOH

C 9 H 1 1 NO 2

C 9 H 1 1 NO 4

OH COOH

Acetone, MeOH

H2O

NH2

70:30 v/v% OH

P. S. Portoghese, J. Med. Chem., 8, 147

Pheta. 83

A. Neuberger, Biochem. J., 43, 599 (1948)

Pheta. 84

(1965) COOH

D

C 9 H 1 3 DO 2

COOH

MeOAc

C 9 H 1 6 NO 3 Acetone

N O

H. Gerlach, Helv. Chim. Acta, 49, 1291

Pheta. 85

Pheta. 86

(1966)

Am. Chem. Soc., 97, 1209 (1975) C9H16O2

COOH

COOH

EtOAc

W. V. E. Doering and K. B. Wiberg, J.

Pheta. 87

C9H16O2 EtOAc

Pheta. 88

Am. Chem. Soc., 72, 2608 (1950) OCH3 COOH CF3

K. Flohr, R. M. Paton and E. T. Kaiser, J.

A. Maccioni, Boll. Chim. Farm., 23, 41 (1965)

C10H9F3O3

COOH

EtOH

C 1 0 H 1 0 Cl 2 O 4 EtOH

O Cl CH3O

Cl J. A. Dale, D. L. Dull and H. S. Mosher, J.

Pheta. 89

Pheta. 90

E. Gamstedt, Arkiv Kemi, 32, 151 (1970)

Org. Chem., 34, 2543 (1969) COOH

C 1 0 H 1 0 Cl 2 O 4

COOH

Acetone

EtOAc

O

C10H10O2

OCH3 Cl

Cl Pheta. 91

A. Fredga and E. Gamstedt, Arkiv Kemi, 28, 109 (1967)

Pheta. 92

M. Sc. Thesis of H. M. Schwartz, University of Toronto, Toronto, Canada (1975)

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C10H10O4S

COOH S

C 1 0 H 1 1 ClO 3 O

COOH

EtOH, H2O

COOH

17:83 v/v%

Cl

Ph.D Thesis of P. Fitger, University of

Pheta. 93

M. Matell, Arkiv Kemi, 6, 365 (1953)

Pheta. 94

Lund, Sweden (1924) C10H12O2

COOH

Benzene, EtOH

EtOH, H2O

80:20 v/v%

50:50 v/v%

K. Pettersson, Arkiv Kemi, 10, 283

Pheta. 95

C10H12O2

COOH

A. Weidler and G. Bergson, Acta Chem.

Pheta. 96

Scand., 18, 1484 (1964)

(1956) C10H12O2

COOH

C10H12O2

COOH

EtOH, H2O

EtOAc

50:50 v/v% H. E. Smith, B. G. Padilla, J. r. Neergard

Pheta. 97

A. M. Schrecker, J. Org. Chem., 22, 33

Pheta. 98

and F.-M. Chen, J. Am. Chem. Soc., 100,

(1957)

6035 (1978) C10H12O2S S

COOH

H2O

B. Holmberg, Arkiv Kemi Mineral. Geol.,

Pheta. 99

abs. EtOH

M. Guetté, J. Capillon and J.-P. Guetté,

Pheta. 100

13A, No. 8 (1939) O

COOH

NH2

Tetrahedron, 29, 3659 (1973) C 1 0 H 1 3 NO 3

HN

Pheta. 102

Farmaco, Ed. Sci., 23, 244 (1968) OH

C 1 0 H 1 3 NO 3

HO

Pheta. 103

HO

N

G. Büyük and E. Hardegger, Helv. Chim. Acta, 58, 682 (1975)

C 1 1 H 1 3 NO 4 iPrOH

CHO

D. Pitre, S. Boveri and N. Buser, Farmaco, Ed. Sci., 23, 244 (1968)

EtOH HOOC

COOH

O

iPrOH

D. Pitre, S. Boveri and N. Buser,

Pheta. 101

C10H12O3

COOH

HO

Pheta. 104

COOH

NH2

C 1 0 H 1 3 NO 4 EtOH

E. W. Tristram, J. Ten Broeke, D. F. Reinhold, M. Sletzinger, and D. E. Williams, J. Org. Chem., 29, 2053 (1964)

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COOH

HO

C 1 0 H 1 3 NO 7 CH2COOH

EtOH

NHAc

HO

O

C 1 2 H 1 5 NO 5 H3COOC

E. W. Tristram, J. Ten Broeke, D. F.

Pheta. 105

Pheta. 106

Reinhold, M. Sletzinger, and D. E.

NO2

F. Kienzle, G. W. Holland, J. L. Jernow, S. Kwoh and P. Rosen, J. Org. Chem., 3440

Williams, J. Org. Chem., 29, 2053 (1964) H

C

C10H14O4

HOOC

Pheta. 107

Y. Inouye and M. Ohno, Agr. Biol.

C10H14O4

H

MeOH

COOH

H

(1973)

COOH COOH

Pheta. 108

Chem., 21, 265 (1957)

J. M. Gardlik, L. K. Johnson, L. A. Paquette, B. A. Solheim, J. P. Springer and J. O. Clardy, J. Am. Chem. Soc., 101, 1615 (1979) C10H16O4

C10H16O2 H HOOC

H

EtOH, H2O

COOH COOH

50:50 v/v% Pheta. 109

I. G. M. Campbell and S. H. Harper, J.

Pheta. 110

Sci. Food Agric., 3, 189 (1952) NO2

Chem., 36, 1243 (1962)

C 1 0 H 1 7 NO 6 S COOCH3

C11H10O2

EtOAc, Et2O

MeOH, H2O HOOC

COOH

Pheta. 111

M. Janczewski and T. Bartnik, Polish J.

J. Vasilevksis, J. A. Gualtieri, S. D.

Pheta. 112

80:20 v/v% L. A. Paquette, W. B. Farnham and S. V. Ley, J. Am. Chem. Soc., 97, 7273 (1975)

Hutchings, R. C. West, J. W. Scott, D. R. Parrish, F. T. Bizzaro, G. F. Field, J. Am. Chem. Soc., 100, 7423 (1978) I

C11H10O2

Ph

C C CHCOOH H3C

COOH

EtOAc

C 1 1 H 1 2 I 3 NO EtOH

I

I

N

Pheta. 113

L. Crombie, P. A. Jenkins and J. Roblin, J. Chem. Soc., Perkin 1, 1090 (1975) COOH

C11H12O2 H2O

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Pheta. 114

D. Pitré and s. Voberi, J. Med. Chem., 11, 406 (1968) COOH

C11H12O2 H2O

H. Veldstra and C. van de Westeringh,

Pheta. 115

A. Fredga and L. Westman, Arkiv Kemi, 7,

Pheta. 116

Rec. Trav. Chim., 70, 1113 (1951)

193 (1954)

C11H12O2

COOH

COOH

COOH

M. Sc. Thesis of H. M. Schwartz,

Pheta. 117

C11H12O4 H2O

A. Fredga, Arkiv Kemi Mineral. Geol.,

Pheta. 118

26B, No. 11 (1948)

University of Toronto, Toronto, Canada (1975) COOH

C11H14O2

C11H14O2 COOH

EtOH

EtOH, H2O 63:37 v/v%

K. Pettersson and G. Willdeck, Arkiv

Pheta. 119

C. Aaron, D. Dull, J. L. Schmiegel, D.

Pheta. 120

Kemi, 9, 333 (1956)

Jaeger, Y. Ohashi, And H. S. Mosher, J. Org. Chem., 32, 2797 (1967)

COOH

C11H14O2

C11H14O3

HO COOH

EtOH, H2O

EtOH

63:37 v/v%

G. Sörlin and G. Bergson, Arkiv Kemi,

Pheta. 121

M. Guetté, J. Capillon and J.P. Guetté,

Pheta. 122

29, 593 (1968) C11H14O3

OH COOH

Pheta. 123

Tetrahedron, 29, 3659 (1973)

O

H2O

M. Matell, Arkiv Kemi, 1, 455 (1949)

C11H14O4S

O S COOH

Pheta. 124

abs. Et 2 O

J. E. Taylor and F. H. Verhoek, J. Am. Chem. Soc., 81, 4537 (1959)

NH2 H3CO

COOH

Et 2 O

H3CO

Pheta. 125

C 1 1 H 1 5 NO 4

K. Eischenberger and C. Egli, U. S. Patent 3,862,329 (1975)

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H3CO

NHAc COOH

Et 2 O

H3CO

Pheta. 126

C 1 3 H 1 7 NO 5

K. Eischenberger and C. Egli, U. S. Patent 3,862,329 (1975)

COOH OH

C11H20O3

COOH

C12H10O2

Et 2 O, Petroleum

EOH

25:75 v/v% B. Ekisson, G. Odham and B. Pettersson,

Pheta. 127

Ph. D. Thesis of H. U. Kuffner, University

Pheta. 128

Acta Chem. Scand., 25, 2217 (1971) H

of Vienna, Austria (1972)

C12H10O2

COOH

OH

MeOH, H2O

COOH

60:40 v/v% Pheta. 129

A. Fredga, Arkiv Kemi, 12, 547 (1958)

C 1 2 H 1 3 NO 3 CH2Cl2

N

Pheta. 130

M. R. Harnden and N. D. Wright, J. Chem. Soc., Perk. 1, 1012 (1977)

NHAc

C12H14N2O5

COOH

C12H14O2

EtOH

COO O2 N

Pheta. 131

H. E. Smith and J. M. Luck, J. Org.

Pheta. 132

Chem., 23, 837 (1958)

M. Sc. Thesis of H. M. Schwartz, University of Toronto, Toronto, Can. (1975)

COOH NHAc HO

Pheta. 133

COOH

C 1 2 H 1 5 NO 4 Acetone

H. R. Almond, Jr., D. T. Manning and C.

C12H16O2 EtOH

Pheta. 134

Niemann, Biochemistry, 1, 243 (1962)

K. Pettersson and G. Willdeck, Arkiv Kemi, 9, 333 (1956)

C12H16O2

C 1 1 H 1 3 BrO 2 COOH

COOH

EtOH, H 2 O 60:40 v/v%

Br Pheta. 135

C. Fuganti and P. Grasselli, J. Chem. Soc. Chem. Comm., 995 (1979)

Pheta. 136

M. Miyakado, N. Ohno, Y. Okuno, M. Hirano, K. Fujimoto and H. Yoshioka, Agr. Biol. Chem., 39, 267 (1975)

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C11H14O2

COOH

C12H16O3 COOH

EtOH, H 2 O 60:40 v/v%

EtOH, H 2 O 60:40 v/v%

OCH3

M. Miyakado, N. Ohno, Y. Okuno, M.

Pheta. 137

Pheta. 138

M. Miyakado, N. Ohno, Y. Okuno, M.

Hirano, K. Fujimoto and H. Yoshioka,

Hirano, K. Fujimoto and H. Yoshioka, Agr.

Agr. Biol. Chem., 39, 267 (1975)

Biol. Chem., 39, 267 (1975)

C12H16O2 COOH

EtOH, H 2 O

COOH

H3CO

NH2

H3CO

C 1 2 H 1 7 NO 4 MeOH

70:30 v/v%

C. Aaron, D. Dull, J. L. Schmiegel, D.

Pheta. 139

Pheta. 140

British Patent 936,074 (1963)

Jaeger, Y. Ohashi and H. S. Mosher, J. Org. Chem., 32, 2797 (1967) COOH

H3CO

NHAc

H3CO

C 1 4 H 1 9 NO 5 MeOH

British Patent 936,074 (1963)

Pheta. 141

C12H18O2S2

S COOH

S

Pheta. 142

French Patent 1,389,391 (1965)

C13H12O2S

Ph COOH S

C13H12O2S

S

EtOH, H 2 O

COOH

73:27 v/v% K. Pettersson, Arkiv Kemi, 7, 279 (1954)

Pheta. 143

C13H14O4 HOOC

H

MeOH

H

EtOAc

EtOH, H 2 O 50:50 v/v%

Pheta. 144 Ph

M. Matell, Arkiv Kemi, 5, 187 (1953)

H

C C H Et

C COOH

C13H16O2 EtOAc

O O

Pheta. 145

S. Yake, Y. Inouye, M. Ohno and S. Takei, Agr. Biol. Chem., 26, 362 (1962)

© 2002 by CRC Press LLC

Pheta. 146

Ph. D. Thesis of J. Robbins, University of California, Berkely, California

C13H16O2

COOH

C13H16O4

COOH

HOOC

iPrOH

Pheta. 147

M. Sc. Thesis of H. M. Schwartz,

H. Keberle, W. Riess and K. Hoffmann,

Pheta. 148

Arch. Int. Pharmacodyn., 164, 117 (1962)

University of Toronto, Toronto, Canada (1975) C13H16O5

AcO

iPr 2 O, abs. EtOH

AcO

COOH O

COOEt

Et 2 O

75:25 v/v% Pheta. 149

R. Barner and M. Schmid, Helv. Chim.

C13H16O8

COOH

OAc

Pheta. 150

Acta, 62, 2384 (1979)

R. Grewe and S. Kersten, Chem. Ber., 100, 2546 (1967)

C13H18O2

C13H18O3

COOH

EtOH

Hexane, CHCl 3

COOH

OCH3 Pheta. 151

K. Pettersson and G. Willdeck, Arkiv

Pheta. 152

Kemi, 9, 333 (1956) COOH OH

H. E. Zimmerman, T. P. Gannett and G. E. Keck, J. Org. Chem., 44, 1982 (1979)

C13H26O3

C 1 4 H 1 4 FeO 2

Et 2 O

H

Et 2 O

Fe H

Pheta. 153

M. M. Shemyakin, Y. Y. Orchinnikov, V.

Pheta. 154

COOH

H. Mechtler and K. Schlögl, Monatsh. Chem., 97, 754 (1966)

T. Ivanov and P. Y. Kostetskii, Zh. Obsch. Khim., 37, 2617 (1967)

COOH

C14H16O2 MeOH, Et 2 O

C 1 5 H 1 3 ClO 2 Cl

COOH

EtOAc

33:67 v/v%

Pheta. 155

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

© 2002 by CRC Press LLC

Pheta. 156

R. Adams and L. O. Binder, J. Am. Chem. Soc., 63, 2773 (1941)

I

C 1 5 H 1 3 ClO 3

O

EtOAc

COOH

Cl

HO

C 1 5 H 1 3 I 2 NO 4

O COOH

T. Tamegai, T. Tanaka, T. Kaneko, S.

Pheta. 157

H2O

H2N

I

C. R. Harington, Biochem. J., 22, 1429

Pheta. 158

Ozaki, M. Ohmae and K. Kawabe, J.

(1928)

Liquid Chromatog., 2, 551 (1979) HO

O

C 1 6 H 1 3 I 2 NO 5

I O

C 1 5 H 1 4 ClNO 3

H2O

EtOH

N

I

C. R. Harington, Biochem. J., 22, 1429

Pheta. 159

COOH

Cl

NH CHO

HOOC

J. R. Carson U. S. Patent 3,752,826 (1973)

Pheta. 160

(1928) C15H14O2

COOH

COOH S

EtOH, H 2 O

EtOH, H 2 O

80:20 v/v% M. B. Watson and G. W. Youngson, J.

Pheta. 161

33:67 v/v% Pheta. 162

Chem. Soc. C, 258 (1968) COOH

C15H14O2S

S

EtOH

W. A. Bonner, J. Am. Chem. Soc., 74, 1034 (1952)

W. A. Bonner, J. Org. Chem., 32, 2497

EtOAc

Pheta. 164

(1967) HOOC

H

H

OCH3

C15H18O7

COOCH3

AcNH

L. F. Tietze, Angew. Chem. Internat.

Pheta. 165

Ph

W. S. Marshall, U. S. Patent 3,600,437 (1971)

O

AcO

C15H14O3

COOH

O Pheta. 163

C15H14O2S

Pheta. 166

Edit., 12, 757 (1973)

O

C 1 5 H 1 9 NO 5

O

Methyl-ethyl-ketone COOH

M. Rosenberger, A. J. Duggan, R. Borer, R. Müller and G. Saucy, Helv. Chim. Acta, 55, 2663 (1972)

C15H20O4

HO CH2COOH O

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Tetrahydrofuran

OH H

Cl Cl

H

COOH

C 1 6 H 1 2 Cl 2 O 3 Acetone

Pheta. 167

J. W. Scott, F. T. Bizzaro, D. R. Parish

J. Nickl, W. Engel, A. Eckenfels, E. Seeger

Pheta. 168

and G. Saucy, Helv Chim.Acta, 59, 290

and G. Engelhardt, U. S. Patent 3,655,743

(1976)

(1972)

OH H

OH

C 1 6 H 1 3 ClO 3

H

Acetone

Cl

H

Pheta. 169

Acetone

COOH

F

J. Nickl, W. Engel, A. Eckenfels, E.

H

COOH

J. Nickl, W. Engel, A. Eckenfels, E. Seeger

Pheta. 170

Seeger and G. Engelhardt, U. S. Patent

and G. Engelhardt, U. S. Patent 3,655,743

3,655,743 (1972)

(1972) C 1 6 H 1 3 NO 3

COOH N

Et2O, CH2Cl2

T. Y. Shen, C. P. Dorn, Jr., and J. P. Li,

C 1 6 H 1 5 ClO 6 H2O

O O

OCH3 Cl

Pheta. 172

U. S. Patent 3,899,506 (1975) COOH S

OCH3

O O

50:50 v/v%

O

Pheta. 171

C 1 6 H 1 3 FO 3

A. Brossi, M. Baumann and F. Burkhardt, Helv. Chim. Acta, 45, 1292 (1962)

C16H16O2S

COOH

EtOH

OH

C16H16O3 EtOH

Ph

Pheta. 173

W. A. Bonner and R. A. Grimm, J. Org.

Pheta. 174

Chem., 32, 3022 (1967)

A. Guarnieri, S. Burnelli, A. Andreani, I. Busacci, A. M. Barbaro and M. Gaiardi, Farmado,Ed. Sci., 33, 761 (1978)

COOH

C 1 6 H 1 7 NO 3

tBu

C16H26O4 Cyclohexan

NHAc

COOEt COOH Pheta. 175

H. R. Almond, Jr., D. T. Manning and C. Niemann, Biochemistry 1, 243 (1962)

Pheta. 176

Ph. D. Thesis of R. Becker, Technical University of Hannover, West Germany (1975)

© 2002 by CRC Press LLC

C17H8O8

COOH

MeOH

C 1 7 H 1 2 Cl 2 O 2

HOOC Cl

EtOAc, EtOH 50:50 v/v%

O O C O O

Cl COOH

Pheta. 177

W. H. Mills and C. R. Nodder, J. Chem.

S. Hagishita and K. Kuriyama, Tetrahedron,

Pheta. 178

Soc., 1407 (1920) O

28, 1435 (1972) C17H14O3S

COOH

C17H16O2

COOH

CH3CN

MeOH

S

Pheta. 179

J. Ackrell, Y. Antonio, F. Franco, R.

B. Kainradl, E. Langer, H. Lehner and K.

Pheta. 180

Landeros, A. Leron, J. M. Muchowski, M.

Schlögl, Liebigs Ann. Chem., 766, 16

L. Maddox, P. H. Nelson, W. H. Rooks,

(1972)

A. P. Roszkowski and M. B. Wallach, J. Med. Chem., 21, 1035 (1978) COOH

H

C17H16O2

COOH

C17H16O2

CHCl 3 , EtOH

Pheta. 181

H. Falk, P. Reich-Rohrwig and K.

Pheta. 182

Schlögl, Tetrahedron, 26, 511 (1970)

Chem. Soc., 92, 7623 (1970)

C 1 7 H 1 7 NO 2

C17H24O2

EtOH

Et 2 O

N

CH2Ph COOH

Pheta. 183

M. H. Delton and D. J. Cram, J. Am.

COOH

British Patent 1,209,669

Pheta. 184

H. Eberhardt and K. Schlögl, Liebigs Ann. Chem., 760, 157 (1972)

COOH

COOH

C17H26O4 Et 2 O

H3CO

Pheta. 185

OCH3

H. S. Aaron and C. P. Ferguson, J. Org. Chem., 33, 684 (1968)

© 2002 by CRC Press LLC

C17H26O4 Et 2 O, EtOAc

H3CO

Pheta. 186

OCH3

H. S. Aaron and C. P. Ferguson, J. Org. Chem., 33, 684 (1968)

COOH

C 1 8 H 1 7 NO 2

CN

COOH

OH

EtOH

C18H36O3 Et 2 O, light petroleum 33:67 v/v%

W. Klötzer, Monatsh. Chem., 87, 346

Pheta. 187

K. A. Karlsson and I. Pascher, Chem. Phys.

Pheta. 188

(1956)

Lipids, 12, 65 (1974) C 1 9 H 1 8 FeO 2

Ph COOH

C19H26O6

(CH2)10

Et 2 O

CHCl 3

HOOC

Fe

O

O H3COOC

Pheta. 189

H. Falk, C. Krasna and K. Schlögl,

Pheta. 190

Monatsh. Chem., 100, 254 (1969) NO2

NO2

G. Helmechen and V. Prelog, Helv. Chim. Acta, 55, 2612 (1972) NH2

C20H12N2O10S2

NH2

C20H16N2O6S2

H2O HO2S

SO2H

Pheta. 191

H2O HO2S

S. Murahasi, Sci. Papers Inst. Phys.

Pheta. 192

Chem. Research (Tokyo), 17, 297 (1932) COOH

SO2H

S. Murahasi, Sci. Papers Inst. Phys. Chem. Research (Tokyo), 17, 297 (1932)

C20H18O3 Acetone

C 2 0 H 2 0 ClNO 3 H3CO

COOH

iPrOH

N CH2

Cl

Ac

Pheta. 193

H. Neudeck and K. Schlögl, Chem. Ber.,

Pheta. 194

British Patent 957,900 (1964)

110, 2624 (1977) C 2 1 H 2 3 NO 3 S

H3CO

COOH

EtOH

Pheta. 195

C 2 1 H 2 3 NO 4 H3CO

COOH

iPrOH

N CH2

N

SCH3

OCH3

British Patent 957,900 (1964)

© 2002 by CRC Press LLC

Pheta. 196

British Patent 957,900 (1964)

Ph C COOH

C23H26O2 EtOH, H 2 O

C 4 H 9 NO 3

OH

COOH

H2N

EtOH

66:34 v/v% Pheta. 197

D. F. Dickel, G. DeStevens, U. S. Patent

Pheta. 198

3,786,085 (1974)

B. Ringdahl and J. C. Craig, Acta Chem. Scand., B34, 731 (1980)

C7H10O3

OH COOH

EtOAc, MeOH

Acetone

H O

Pheta. 199

E. J. Corey and J. Mann, J. Am. Chem.

Pheta. 200

Soc., 95, 6832 (1973)

Acetone, Hexane

O Pheta. 201

O

K. Mori and H. Ueda, Tetrahedron Lett., 22, 461 (1981)

C8H8O3

HOOC

C7H12O2

H

H Cl2C

C 8 H 1 0 Cl 2 O 2

H COOH

Benzene

50:50 v/v%

P. A. Grieco, W. Owens, C. L. J. Wang,

Pheta. 202

P. E. Burt, M. Elliot, A. W. Farnham, N. F.

E. Williams, W. Schillinger, K. Hirotsu

Janes, P. H. Needham and A. Pulman,

and J. Clardy, J. Med. Chem., 23, 1072

Pestic. Sci., 5, 791 (1974)

(1980) Cl F3C C

H

Pheta. 203

H

C14H14O3

C 9 H 1 0 ClF 3 O 2

COOH

H2O

T. Leigh, European Patent 10874 (1979)

CH3O

Pheta. 204

COOH

EtOH

J. Goto, M. Hasegawa, S. Nakamura, K. Shimada and T. Nambara, Chem. Pharm. Bull., 25, 847 (1977)

O

C16H14O3

C16H16O2

Et 2 O, Petroleum ether

Benzene COOH

COOH

Pheta. 205

N. Blazevic, M. Zinic, T. Kovac, V. Sunjic and F. Kajfez, Acta Pharm. Jugoslav., 25, 155 (1975)

© 2002 by CRC Press LLC

Pheta. 206

G. Comisso, M. Mihalic, F. Kajfez and V. Sunjic, Gazz. Chim. Ital., 110, 123 (1980)

COOH O

N N

C20H22N2O5 EtOAc

C4H6O4S

SH HOOC

COOH

PrOH

COOH

T. T. Chu and C. S. Marvel, J. Am.

Pheta. 207

T. Shiraiwa, M. Ohkubo, M. Kubo, H.

Pheta. 208

Chem. Soc., 55, 2841 (1933)

Miyazaki, M. Takehata, H. Izawa, K. Nakagawa and H. Kurokawa, Chem. Pharm. Bull., 46, 1364 (1998)

C10H10N2O2

Ph O

N

NaOH, H 2 O

Ph O

N

Et

C11H12N2O2

N

NaOH, H 2 O

N O

O

G. Coquerel, M-N Petit, R Bouaziz and D.

Pheta. 209

G. Coquerel, M-N Petit, R Bouaziz and D.

Pheta. 210

Depernet, Chirality, 4, 400, (1992)

Depernet, Chirality, 4, 400, (1992)

C11H12N2O2 NaOH, H 2 O

Ph O

Pr

C12H14N2O2

N

NaOH, H 2 O

N O

O

N N O

G. Coquerel, M-N Petit, R Bouaziz and D.

Pheta. 211

Pheta. 212

Depernet, Chirality, 4, 400, (1992) Ph O

iPr

C12H14N2O2

N

NaOH, H 2 O

G. Coquerel, M-N Petit, R Bouaziz and D. Depernet, Chirality, 4, 400, (1992) C12H14N2O2

PhCH2CH2 O

N

N

O Pheta. 213

NaOH, H 2 O

N O

G. Coquerel, M-N Petit, R Bouaziz and D.

Pheta. 214

Depernet, Chirality, 4, 400, (1992)

G. Coquerel, M-N Petit, R Bouaziz and D. Depernet, Chirality, 4, 400, (1992)

C16H14N2O2 Ph O

C8H14N2O2

NaOH, H 2 O, EtOH O

N

N N O

N O

Pheta. 215

G. Coquerel, M-N Petit, R Bouaziz and D. Depernet, Chirality, 4, 400, (1992)

© 2002 by CRC Press LLC

Pheta. 216

G. Coquerel, M-N Petit, R Bouaziz and D. Depernet, Chirality, 4, 400, (1992)

C 1 0 H 9 ClO 3

O

EtOH

Cl

C13H16O3

CH2COOH

1.) CHCl 3 , EtOH 2.) CHCl 3 ,Hexane

COOH

OCH3 F. Loiodice, A. Longo, P. Bianco and V.

Pheta. 217

F. Berardi, S. Santoro, R. Perrone, V.

Pheta. 218

Tortorella, Tetrahedron Asymmetry, 6,

Tortorella, S.Govoni and L. Lucchi, J. Med.

1001 (1995)

Chem., 41, 3940 (1998)

O

C 1 1 H 1 3 ClO 2

COOH

CHCl 3 , H 2 O

C8H10O7

O

O HOOC

EtOH

COOCH3

Cl E. Fogassy, L. Tőke, F. Faigl and L.

Pheta. 219

R. A. Ancliff, A. T. Rusell and A. J.

Pheta. 220

Szabó, Hungarian Patent, 196051 (1988)

Sanderson, Tetrahedron Asymmetry, 8, 3379 (1997)

C8H10O7

O O

O

EtOH

C13H14O5S O

EtOAc, MeOH

H3CO COOH

HOOC

COOCH3

S O

R. A. Ancliff, A. T. Rusell and A. J.

Pheta. 221

99:1 v/v%

D. H. Boschelli, J. B. Kramer, S. S.

Pheta. 222

Sanderson, Tetrahedron Asymmetry, 8,

Khatana, R. J. Sorenson, D. T. Connor, M.

3379 (1997)

A. Ferin, C. D. Wright, M. E. Lesch, K. Imre, G. C. Okonwo, D. J. Schrier, M. C. Conroy, E. Ferguson, J. Woelle and U. Saxena, J. Med. Chem., 38, 4597 (1995)

S

C17H14O3S

COOH

Acetone, Hexane

MeOH O

50:50 v/v%

COOH

M. Yamamoto, M. Masaki and H. Nohira,

Pheta. 223

C. Fehr, J. Galindo, Helv. Chim. Acta, 78,

Pheta. 224

Chirality, 2, 280 (1990)

N

539 (1995)

C9H9O3S

S COOH O

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C10H15O2

C11H13O3S

S

EtOH

N Et

COOH O

EtOH

V. Leskovšek Cizej, U. Urleb, J.

Pheta. 225

Pheta. 226

Heterocyclic Chem., 33, 97 (1996) COOH

C 1 1 H 1 1 BrO 3

O

EtOH

V. Leskovšek Cizej, U. Urleb, J. Heterocyclic Chem., 33, 97 (1996)

PO2H2

CBZ-HN

C15H16O5P EtOH

Ph

Br Y. Nomoto, H. Takai, T. Ohno, K.

Pheta. 227

Pheta. 228

A. Mucha and R. Tyka, Phosphorus, Sulfur, and Silicon, 92, 129 (1994)

Nagashima, K. Yao, K. Yamada, K. Kubo, M. Ichimura, A. Mihara and H. Kase, J. Med. Chem., 39, 297 (1996) Ph

C16H14O4 O

EtOH, H2O

O

COOH

N

Et2O

N N N

95:5 v/v%

W. Quaglia, M. Pigini, S. K. Tayebati, A.

Pheta. 229

C18H18N5O

H N

Pheta. 230

Ph

O

R. M. Moriarty and S. G. Levy, J. Heterocyclic Chem., 32, 155 (1995)

Piergentili, M. Giannella, A. Leonardi, C. Taddei and C. Melchiorre, J. Med. Chem., 39, 2253 (1996) Ph

Ph

N N N

O

Et2O

Ph

N

Pheta. 232

Heterocyclic Chem., 32, 155 (1995) Ph

H N

N N N N

N N N

Pheta. 234

Heterocyclic Chem., 32, 155 (1995)

O

Pheta. 235

R. M. Moriarty and S. G. Levy, J.

O O O H

W. G. Dauben, J. Y. L. Lam and Z. R. Guo, J. Org. Chem., 61, 4816 (1996)

© 2002 by CRC Press LLC

CH2Ph

Et2O

O

R. M. Moriarty and S. G. Levy, J. Heterocyclic Chem., 32, 155 (1995)

C9H10O4 THF

H N

N

Et2O

R. M. Moriarty and S. G. Levy, J.

Et2O

Heterocyclic Chem., 32, 155 (1995)

O

Pheta. 233

O Ph

O

(9-fluorenyl)

(9-fluorenyl)

C17H14N5O2

H N

N N N

R. M. Moriarty and S. G. Levy, J.

Pheta. 231

Ph

C23H20N5O

H N

N

S Ph

Pheta. 236

COOH CH2Ph

C18H20O2S MeOH

W. L. Mock and J. Z. Zhang, J. Org. Chem., 55, 5791 (1990)

O

C7H8O4

HOOC

C16H22O4 O

EtOAc

EtOAc

COOH

O O R. B. Cain, A. A. Freer, G. W. Kirby and

Pheta. 237

Pheta. 238

A. Reyes and E. Juaristi, Synth. Comm., 25,

1053 (1995)

G. V. Rao, J. Chem. Soc., Perkin Trans. 1, 202 (1989)

C16H14O4

O Ph

O

COOH CONH2

EtOAc

C 1 1 H 1 2 ClNO 3 H2O

COOH

Cl

Pheta. 239

A. Reyes and E. Juaristi, Synth. Comm.,

Pheta. 240

M. R. Caira, R. Clauss, L. R. Nassimbeni, Janet L. Scott and A. F. Wildervanck, J.

25, 1053 (1995)

Chem. Soc., Perkin Trans.2, 763 (1997) C17H16O2

CHO

C24H13O6P

O

H2O

O O P O OH

OH

H2O

O

Pheta. 241

E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 242

9, 715(1998)

E. Juaristi et al., Tetrahedron Asymmetry, 9, 715(1998)

C 1 3 H 2 3 NO 4

C7H12O H2O, SO2

COOH N COOtBu

Pheta. 243

O

E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 244

9, 715(1998)

COOH

Pheta. 245

9, 715 (1998) C9H10O2

E. Juaristi et al., Tetrahedron Asymmetry, 9, 715(1998)

© 2002 by CRC Press LLC

E. Juaristi et al., Tetrahedron Asymmetry,

COOH

Pheta. 246

C10H12O2

E. Juaristi et al., Tetrahedron Asymmetry, 9, 715(1998)

Pr

C11H14O2

C12H16O2

COOH

Ph CH COOH

E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 247

E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 248

9, 715 (1998)

CF3

9, 715 (1998) C9H7F3O2

COOH

C10H12O3

COOH

OCH3 E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 249

E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 250

9, 715(1998)

9, 715 (1998)

COOH

C11H14O3

COOH

OCH3

OCH3

E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 251

C12H16O3

E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 252

9, 715 (1998)

9, 715 (1998) C13H18O3

COOH

CF3

C10H9F3O3

COOH

OCH3 OCH3 Pheta. 253

E. Juaristi et al., Tetrahedron Asymmetry,

E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 254

9, 715 (1998)

C4H5F3O3

OH

CF3

Pheta. 255

9, 715 (1998)

COOH

E. Juaristi et al., Tetrahedron Asymmetry, 9, 715 (1998)

© 2002 by CRC Press LLC

Ph

H

Pheta. 256

O

H

C9H8O3

COOH

E. Juaristi et al., Tetrahedron Asymmetry, 9, 715 (1998)

C10H10O4

O COOH

H

O

COOH

N H

C 1 1 H 1 7 NO 5

COOCH3

OCH3 Pheta. 257

E. Juaristi et al., Tetrahedron Asymmetry,

E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 258

9, 715 (1998)

9, 715 (1998) C 8 H 8 SO 4

C 1 8 H 2 0 NO 3

COOH

S COOH HOOC

N N

Pheta. 259

E. Juaristi et al., Tetrahedron Asymmetry,

E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 260

9, 715 (1998)

Ph

Et

COOH

9, 715 (1998) C 1 1 H 1 5 NO 2

O

HOOC E. Juaristi et al., Tetrahedron Asymmetry,

COOCH3 E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 262

9, 715 (1998)

9, 715 (1998) C9H18O

OH

O O

Pheta. 263

E. Juaristi et al., Tetrahedron Asymmetry,

Pheta. 264

9, 715 (1998) OH

C17H28O

E. Juaristi et al., Tetrahedron Asymmetry, 9, 715 (1998)

OH H

E. Juaristi et al., Tetrahedron Asymmetry,

C 3 1 H 3 1 NO 4

CH2Ph O

Pheta. 266

1.) MeOH N

CH2Ph COOH

2.) Et2O

P. Dostert, M. Varasi, A. D. Torre, C. Monti and V. Rizzo, J. Med. Chem., 27, 57, (1992)

© 2002 by CRC Press LLC

C6H12O3

9, 715 (1998)

O CH2Ph

Pheta. 265

C7H8O7

O O

N

Pheta. 261

O

C 1 1 H 9 ClO 3

O

COOH

EtOH

C18H16O2 CH3CN

Cl COOH

Pheta. 267

F. Loiodice, A. Longo, P. Bianco and V.

C. K. F. Chiu, PCT Int. Appl. WO 93, 22,

Pheta. 268

Tortorella, Tetrahedron Asymmetry, 6,

269 (1993)

1001 (1995) OCH3

Bu

EtOH, Et2O

N

O

C16H26O6

50:50 v/v%

N COOH BOC

Pheta. 269

T. N. Johansen, B. Ebert, H. Bräuner-

C7H10O7

O O

O HOOC

EtOH

COOCH3 R. A. Ancliff, A. T. Russell and A. J.

Pheta. 270

Osborne, M. Didriksen, I. T. Christensen,

Sanderson, Tetrahedron, Asymmetry, 8,

K. K. Soby, U. Madsen, P. Krogsgaard-

3379 (1997)

Larsen and L. Brehm, J. Med. Chem., 41, 930 (1998)

COOH

NC

C13H14N2O4

C13H14N2O4 COOH

1.) CH3CN

Toluene

2.) H2O

NO2 Pheta. 271

Cl

O. Achmatowicz, I. Malinowska and B.

Pheta. 272

Szcechner, Tetrahedron, 53, 7917 (1997) COOH

C8H16O2 Hexane

Pheta. 273

Benzene or

Nissan Chem Ind. KK., 91-159959, C91069225, NISC 07.09.89

Sumitomo Chem. Ind. KK., 91-019166/03, C91-008214, SUMO 00.00.89

HOOC OH

H2N Ph

Pheta. 274

C12H12N2O4 EtOH, H2O

O

N

90:10 v/v%

B. Ebert, S. Lenz, L. Brehm, P. Bregnedal, J. J. Hansen, K. Frederiksen, K. P. Bogeso and P. Krogsgaard-Larsen, J. Med. Chem., 37, 878 (1994)

© 2002 by CRC Press LLC

C14H16O6

COOH Ph

COOH

H

COOH

M. Pallavicini, E. Valoti, L. Villa and O.

Pheta. 275

MeOH

Ph

O

O O O

C16H14O4

M. Kawashima, Jpn. Kokai Tokkyo Koho

Pheta. 276

JP 05 78, 276 (1993)

Piccolo, Tetrahedron Asymmetry, 7, 4, 1117 (1996)

COOH

C10H11O3

COOH

H2O

NHCHO

C12H17O2 iPr2O

N Et

Toray Ind. Inc., 91-040115/06, C91-

Pheta. 277

H. Moser, G. Rihs and H. Sauter, Z.

Pheta. 278

017252, TORA 22.05.89

Naturforsch, 37b, 451(1982)

threo-1-p-Nitro-phenyl-2-amino-propane-1,3-diol C 3 H 7 NO 2

NH2

COOH

C 1 7 H 1 9 NO 2

NBz2

EtOH, H 2 O

COOH

EtOH, H 2 O

46/54 % Prdiol. 1

G. Amiard, R. Heymes and L. Velluz, U.

46/54 % G. Amiard, R. Heymes and L. Velluz, U. S.

Prdiol. 2

S. Patent 2,991,307 (1961)

HO

COOH NH2

C3 H7 NO3

Patent 2,991,307 (1961) COOH

HO

MeOH, H 2 O

C1 7 H1 9 NO3 MeOH, H 2 O

NBz2

25/75 % Prdiol. 3

G. Amiard, R. Heymes and L. Velluz, U.

25/75 % G. Amiard, R. Heymes and L. Velluz, U. S.

Prdiol. 4

S. Patent 2,991,307 (1961)

HO

COOH NH2

C3 H7 NO3

Patent 2,991,307 (1961) COOH

HO HN

MeOH

O2N

Prdiol. 5

G. Amiard, R. Heymes and L. Velluz, U. S. Patent 2,921,959 (1960)

© 2002 by CRC Press LLC

Prdiol. 6

O

C9 H9 N3 O8 MeOH

NO2

G. Amiard, R. Heymes and L. Velluz, U. S. Patent 2,921,959 (1960)

C3 H7 NO3

COOH

HO

H2O

NH2

R. Perlotto and M. Vignolo, Rarmaco, Ed.

Prdiol. 7

HN

Sci., 21, 30 (1966) C 4 H 9 NO 2

C 1 8 H 2 1 NO 2

COOH

EtOH, H 2 O

NH2

H2O

tosylate

R. Perlotto and M. Vignolo, Rarmaco, Ed.

Prdiol. 8

Sci., 21, 30 (1966) COOH

C1 0 H1 3 NO6 S

COOH

HO

EtOH, H 2 O

NBz2

60:40 v/v % G. Amiard, R. Heymes and L. Velluz,

Prdiol. 9

60:40 v/v % G. Amiard, R. Heymes and L. Velluz, U. S.

Prdiol. 10

U. S. Patent 2,991,307 (1961)

Patent 2,991,307 (1961)

C 4 H 9 NO 3

OH

COOH

Patent 2,991,307 (1961)

C 5 H 9 NO 2 N H

H2O

50:50 v/v %

G. Amiard, R. heymes and L. Velluz, U. S.

Prdiol. 12

S. Patent 2,991,307 (1961)

COOH

MeOH, H 2 O

NBz2

50:50 v/v % G. Amiard, R. Heymes and L. Velluz, U.

Prdiol. 11

COOH

MeOH, H 2 O

NH2

C 1 8 H 2 1 NO 3

OH

COOH

N O2N

C12H12N3O7 H2O

O

NO2

G. Amiard, R. Heymes and L. Velluz, U.

Prdiol. 13

G. Amiard, R. Heymes and L. Velluz, U. S.

Prdiol. 14

S. Patent 2,794,025 (1957)

Patent 2,794,025 (1957) HO

C 5 H 9 NO 3

HO COOH

N H

Dioxane, H 2 O 95:5 v/v %

C 1 2 H 1 1 NO 8 COOH

N O2N

O

Dioxane, H 2 O 95:5 v/v %

NO2

British Patent 785,012 (1957)

Prdiol. 15

Prdiol. 16

C5H10O3 COOH

NH2

H 2 O, Acetone

COOH

OH

Prdiol. 17

British Patent 785,012 (1957) C 5 H 1 1 NO 2 H 2 O, EtOH 50:50 v/v %

L. A. Shchukins, R. G. Vdovina, Y. B. Shvetsov and A. V. Karpova, Izv. Akad Nauk SSSR, 310 (1962)

© 2002 by CRC Press LLC

Prdiol. 18

G. Amiard, R. Heymes and L. Velluz, U. S. Patent 2,991,307 (1961)

C 1 9 H 2 3 NO 2

NBz2

COOH

C 5 H 1 1 NO 2

COOH

H 2 O, EtOH

NH2

50:50 v/v % G. Amiard, R. Heymes and L. Velluz, U.

Prdiol. 19

Prdiol. 20

S. Patent 2,991,307 (1961)

Patent 2,991,307 (1961) C6H10O3

OH

H 2 O, MeOH

NBz2

H2O O

O

50:50 v/v %

G. Amiard, R. Heymes and L. Velluz, U.

Prdiol. 21

50:50 v/v %

G. Amiard, R. Heymes and L. Velluz, U. S.

C 1 9 H 2 3 NO 2 COOH

H 2 O, MeOH

Prdiol. 22

S. Patent 2,991,307 (1961)

E. S. Zhdanovich, G. S. Kozlova, T. D. Marieva, T. V. Mel'nikova and N. A. Preobrazhenskii, Zhur. Org. Khim., 4, 1359 (1968)

C6H10O4

COOH

HOOC

C 6 H 1 1 NO 4

NH2

H2O

G. Bettoni, C. Cellucci and F. Berardi, J.

Prdiol. 23

COOH

HOOC

Prdiol. 24

Heterocyclic Chem., 17, 603 (1980)

EtOH

M. Claesen, A. Vlietinck and H. Vanderhaeghe, Bull. Soc. Chim. Belges, 77, 587 (1968)

C6H12O4

OH

COOH

NH2

EtOH

COOH

OH

MeOH, H 2 O 60:40 v/v %

L. S. Bergelson, E. V. Dyatlovitskaya, M.

Prdiol. 25

C 6 H 1 3 NO 2

Prdiol. 26

Tichy and V. V. Voronkova, Izv. Akad.

G. Amiard, R. Heymes and L. Velluz, U.S. Patent 2, 991,307 (1961)

Nauk SSSR., 1612 (1962)

HN

benzyl

C 2 0 H 2 5 NO 2

COOH

MeOH, H 2 O

COOH

EtOH

COOH

60:40 v/v %

G. Amiard, R. Heymes and L. Velluz,

Prdiol. 27

Prdiol. 28

U.S. Patent 2, 991,307 (1961)

COOH

MeOH

C7H12O4 EtOH

CN

Prdiol. 29

A. Collet, M.-J. Brienne and J. Jacques, Bull. Soc. Chim. Fr., 336 (1972)

C 7 H 1 1 NO 2 COOH

C7H10O4

COOH J. Knabe and W. Koch, Arch. Pharm. (Weinheim), 305, 757 (1972)

© 2002 by CRC Press LLC

Prdiol. 30

G. Bettoni, c. Cellucci and F. Berardi, J. Heterocyclic Chem., 17, 603 (1980)

C8H7N3O2

N3

COOH

Acetone

A. L. Palomo, German Patent (Offen.)

Prdiol. 31

COOH C2D5

Prdiol. 32

1,966,221 (1971)

CN COOH C2 D 5

O

C 8 H 1 3 NO 2

MeOH, Et 2 O

COOH CN

Prdiol. 34

Cl

EtOH

J. Knabe and N. Franz, Arch. Pharm.

C 9 H 9 ClO 4

OH OH

Cl

COOH

EtOH

COOH

A. Collet, Bull. Soc. Chim. Fr., 215

Prdiol. 35

H2O

(Weinheim), 308, 313 (1975)

C 9 H 9 ClO 4 OH

J. Knabe andk W. Fürst, Arch. Pharm.

C 8 H 8 D 5 NO 3

(Weinheim), 312, 86 (1979) OH

EtOH

(Weinheim), 312, 86 (1979)

J. Knabe andk W. Fürst, Arch. Pharm.

Prdiol. 33

C 8 H 8 D 5 NO 2

CN

Prdiol. 36

A. Collet, Bull. Soc. Chim. Fr., 215 (1975)

(1975)

CH2OH COOH

C9H10O3

COOH

H2O

C 9 H 1 1 NO 2 a.) H 2 O

NH2

b.) n-PrOH c.) EtOH G. Fodor, J. Rakoczi and Gy. Csepreghy,

Prdiol. 37

Prdiol. 38

H. Geipel, J. Prakt. Chem., 9, 104 (1959)

Acta Chim. Hung., 28, 409 (1961)

COOH

NHAc

C 1 1 H 1 3 NO 3

C9H12O2

a.) H 2 O

Et 2 O

H

b.) n-PrOH

COOH

c.) EtOH H. Geipel, J. Prakt. Chem., 9, 104 (1959)

Prdiol. 39

Prdiol. 40

O. Cervinka and O. Kriz, Coll. Czech. Chem. Comm., 33, 2342 (1968)

H N

O

C10H13N5O4

O

EtOH, H 2 O

O N N

NH2

92:8 v/v%

C10H14O4

H

O COOH

O

COOH

Prdiol. 41

R. G. Vdovina, A. V. Karpova and W. S. Chaman, Zh. Obsch. Khim., 37, 1007 (1967)

© 2002 by CRC Press LLC

Prdiol. 42

R. A. Cutler, R. J. Stenger and C. M. Suter, J. Am. Chem. Soc., 74, 5475 (1952)

COOH NH2

C11H12N2O2

COOH

H2O

C13H14N2O3 H2O

NHAc

N H

N H

G. Amiard, R. Heymes and L. Velluz, U.

Prdiol. 43

G. Amiard, R. Heymes and L. Velluz, U. S.

Prdiol. 44

S. Patent 2,797,226 (1957) COOH NH2

Patent 2,797,226 (1957)

C11H12N2O2

COOH

C13H14N2O3

NHAc

H2O

H2O

N H

N H

L. Velluz, G. Amiard and R. Heymes,

Prdiol. 45

L. Velluz, G. Amiard and R. Heymes, Bull.

Prdiol. 46

Bull. Soc. Chim. Fr., 38 (1954) O

COOH

H2N

Soc. Chim. Fr., 38 (1954)

C 1 1 H 1 3 NO 3

C 9 H 1 1 NO 3

OH COOH

EtOH

H2O

NH2 F. Morlacchi, V. Losacco and V.

Prdiol. 47

C. Alberti, B. Camerino and A. Vercellone,

Prdiol. 48

Tortorella, Gazz. Chim. Ital., 105, 349

Gazz. Chim. Ital., 83, 930 (1953)

(1975) C 1 1 H 1 3 NO 4

OH COOH

H2O

O

N

C11H15N5O4

O

abs. EtOH

N N

NHAc

N

COOH NH2

C. Alberti, B. Camerino and A.

Prdiol. 49

N

O

Prdiol. 50

R. G. Vdovina, A. V. Karpova and E. S.

Vercellone, Gazz. Chim. Ital., 83, 930

Chaman, Zh. Obsch. Khim., 37, 1007

(1953)

(1967) C19H21N5O7

O

C 1 2 H 1 3 NO 2

abs. EtOH

N

Acetone COOH CN

N N

COOH N CBZ H

Prdiol. 51

R. G. Vdovina, A. V. Karpova and E. S. Chaman, Zh. Obsch. Khim., 37, 1007 (1967)

© 2002 by CRC Press LLC

Prdiol. 52

J. Knabe and H. Junginger, Pharmazie, 7, 443 (1972)

HOOC

NHCO2CH2Ph COOH

OH

C 1 4 H 1 7 NO 6 abs. EtOH

MeOH, iPr 2 O COOH H3CO

M. Claesen, A. Vlietinck and H.

Prdiol. 53

C16H14O4

Prdiol. 54

Vanderhaeghe, Bull. Soc. Chim. Belges,

22:78 v/v%

G. Nomine and J. Cerede, French Patent 1,205,651 (1960)

77, 587 (1968) COOH NH

PhOOC

C21H24N2O6 Ph

COOH

H2O

Ph

25:75 v/v%

S. D. Mikhno, N. S. Kulachkina and V.

Prdiol. 55

MeOH, Et 2 O

CN

COOH

C 6 H 9 NO 2

Prdiol. 56

M. Berezovski, Zhur. Org. Khim., 6, 81

J. Knabe and N. Franz, Arch. Pharm., 309, 173 (1976)

(1970) COOH

C 6 H 9 NO 2

C8H7N3O2

CF3

Acetone

O

CN

COOH

Prdiol. 57

J. Knabe and J. Plisch, Tetrahedron Lett.,

Prdiol. 58

A. L. Paloma, Afinidad, 28, 141 (1971)

745 (1973)

COOH

H Cl2C

H

OH

C 6 H 1 0 Cl 2 O 2 Benzene

P. E. Burt, M. Elliot, A. W. Farnham, N.

Prdiol. 60

F. Janes, P. H. Needham and d. A.

EtOH

NH2

HO

Prdiol. 59

C 9 H 1 1 NO 5 COOH

HO

B. Hegedus and A. Krasso, U. S Patent 3920728 (1975)

Pulman, Pestic. Sci., 5, 791 (1974) CN COOH

Br

Prdiol. 61

C 9 H 1 2 BrNO 2

C 9 H 1 5 NO 2

1.) H2O

COOH CN

2.) Acetone, Et2O

J. Knabe and N. Franz, Arch. Pharm. 309,

Prdiol. 62

173 (1976) OH COOH

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H2O

J. Knabe and N. Franz, Arch. Pharm. 309, 173 (1976)

C10H8O3

C 1 0 H 9 ClO 3

O Cl

COOH

EtOH

I. Iwai and Y. Kura, Yakugaku Zasshi, 80,

Prdiol. 63

Prdiol. 64

1193 (1960)

F. Loiodice, A. Longo, P. Bianco and V. Tortorella, Tetrahedron Asymmetry, 6, 1001 (1995)

HO

C 1 7 H 2 3 Cl 2 O 5

COOH

EtOH, H 2 O

O

O

COOH

HO

C4H3F3O3 EtOAc

CF3

96:4 v/v%

Cl

Cl

A. D. Gribble, R. J. Ife, A. Shaw, D.

Prdiol. 65

Prdiol. 66

McNair, C. E. Novelli, S. Bakewell, V. P.

S. P. Götzö, D. Seebach, Chimia, 50, 20 (1996)

Shah, R. E. Dolle, P. H. Groot, N. Pearce, J. Yates, D. Tew, H. Boyd, S. Ashman, D. S. Eggleston, R. C. Haltiwanger and G. Okafo, J. Med. Chem., 41, 3582 (1998) C3H2F3O3

OH F3C

EtOAc

COOH

Cl

C. von dem Bussche-Hünnefeld, C.

Prdiol. 67

C 1 1 H 9 ClO 3

O COOH

Prdiol. 68

EtOH

F. Loiodice, A. Longo, P. Bianco and V.

Cescato and D. Seebach, Chem. Ber., 125,

Tortorella, Tetrahedron Asymmetry, 6,

2795 (1992)

1001 (1995)

Strychnine SO3H

C 2 H 3 BrO 5 S H2O

COOH

Br

H. J. Backer and H. W. Mook, Rec. Trav.

Stryc. 1

SO3H

Cl

Stryc. 2

Chim., 47, 464 (1928)

COOH

Stryc. 3

H2O

H. J. Backer and W. G. Burgers, J. Chem. Soc., 127, 233 (1925)

C3H6O3

OH

COOH

C 2 H 3 ClO 5 S

SO3H

H2O

T. Purdie, J. Chem. Soc., 61, 754 (1892)

COOH

Stryc. 4

C3H6O5S H2O

A. P. N. Franchimont and H. J. Backer, Rec. Trav. Chim., 39, 751 (1920)

HO3S

COOH SO3H

Stryc. 5

C3H6O8S2 H2O

H. J. Backer and R. D. Mulder, Rec. Trav. Stryc. 6 Chim., 62, 53 (1943)

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NH2

COOH

C 3 H 7 NO 2 H2O

M. S. Dunn, M. P. Stoddard, L. B. Rubin and R. C. Bovie, J. Biol. Chem., 151, 241 (1943)

HN

C 1 0 H 1 1 NO 3

benzoyl

H2O

COOH

M. S. Dunn, M. P. Stoddard, L. B. Rubin

Stryc. 7

H HO

COOH Cl H COOH

C 4 H 5 ClO 5 EtOH

R. Kuhn and R. Zell, Chem. Ber., 59, 2514

Stryc. 8

and R. C. Bovie, J. Biol. Chem., 151, 241

(1926)

(1943) C4H6O7S

COOH

HOOC

H2O

SO3H

C4H6O10S2

SO3H COOH

HOOC

SO3H

H. J. Backer and J. M. van der Zanden,

Stryc. 9

Trav. Chim., 50, 645 (1931)

C 4 H 7 BrO 2 EtOH

Br

89:11 v/v %

H. J. Backer and J. M. van der Zanden, Rec.

Stryc. 10

Rec. Trav. Chim., 46, 473 (1927) COOH

EtOH, H 2 O

C 4 H 7 NO 5

OH

COOH

HOOC

NH2

R. Ahlberg, J. Prakt. Chem., 135, 335

Stryc. 11

Stryc. 12

(1932)

Y. Liwschitz, A. Singerman and Í. Wiesel, Isr. J. Chem., 6, 647 (1968) SO3H

C4H8O5S

COOH

C4H8O8S2 COOH

H2O

SO3H

H. J. Backer and J. H. De Boer, Rec.

Stryc. 13

Stryc. 14

Trav. Chim., 43, 297 (1924) SO3H

H2O

SO3H

Stryc. 15

H. J. Backer and N. Benninga, Rec. Trav. Chim., 55, 605 (1936) SO3H

C4H8O8S2 COOH

H. J. Backer and R. D. Mulder, Rec. Trav.

HO3S

Stryc. 16

Chim., 62, 53 (1943)

SO3H

COOH

C4H8O8S2 H2O

H. J. Backer and N. Benninga, Rec. Trav. Chim., 55, 605 (1936) NH2

C4H8O8S2

COOH

HO3S

H2O

SO3H

H2O

COOH

HO

C 4 H 9 NO 3 MeOH, H 2 O 50:50 v/v %

Stryc. 17

H. J. Backer and N. Benninga, Rec. Trav.

Stryc. 18

Chim., 55, 605 (1936) Ph

O

COOH

NHCHO

C 1 1 H 1 3 NO 4 MeOH, H 2 O 50:50 v/v %

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M. D. Armstrong, J. Am. Chem. Soc., 70, 1756 (1948) COOH

H2N OH

C 4 H 9 NO 3 H2O

M. D. Armstrong, J. Am. Chem. Soc., 70,

Stryc. 19

S. Lindstedt and G. Lindstedt, Arkiv Kemi,

Stryc. 20

1756 (1948) BzNH CH2 CH CH2 COOH

22, 93 (1962) C 1 1 H 1 5 NO 3

OH

H2O

S. Lindstedt and G. Lindstedt, Arkiv

Stryc. 21

COOH

HOOC

M-O. Hedblom, Arkiv Kemi, 31, 489

Stryc. 22

(1969)

C5H8O2S2 COOH

HOOC

EtOH

S S

G. Cleason, Arkiv Kemi, 30, 511 (1969)

C5H8O5

COOH

H2O

OH

H. A. Barker, Biochem. Prep., 9, 25 (1962)

Stryc. 24

C5H8O5

OCH3

COOH

HOOC

MeOH

S

S

Kemi, 22, 93 (1962)

Stryc. 23

C5H6O4S2

H2O

C5H8O5 COOH

HOOC

H2O

SO3H

T. Purdie, J. Chem. Soc., 67, 944 (1895)

Stryc. 25

H. J. Backer and J. Buining, Rec. Trav.

Stryc. 26

Chim., 47, 1000 (1928) NH2

C 5 H 9 NO 4

COOH

HOOC

H2O

E. Fischer, Chem. Ber., 32, 2451 (1899)

Stryc. 27

NH2

HN HOOC

H3C C CH2 COOH

H2O

C 1 2 H 1 3 NO 5

COOH

H2O

E. Fischer, Chem. Ber., 32, 2451 (1899)

Stryc. 28

OH

NH2

C 5 H 9 NO 4

benzoyl

HOOC CH CH2CH COOH

COOH

Y. K. Lee and T. Kaneko, Bull. Chem. Soc.

Stryc. 30

Chem., 146, 105 (1936) benzoyl

NH

HOOC

EtOH, H 2 O 95:5 v/v %

P. Pfeiffer and E. Heinrich, J. Prakt.

Stryc. 29

C 5 H 9 NO 5

OH

COOH

Japan, 46, 3494 (1973)

C 1 2 H 1 3 NO 6

SO3H

EtOH, H 2 O

COOH

C5H10O5S H2O

95:5 v/v % Y. K. Lee and T. Kaneko, Bull. Chem.

Stryc. 31

H. J. Backer and M. Toxopeus, Rec. Trav.

Stryc. 32

Soc. Japan, 46, 3494 (1973) COOH H

H HOOC

S

Chim., 45, 89 (1926)

C6H8O4S EtOH

S

COOH

EtOH, H 2 O

S COOH

© 2002 by CRC Press LLC

C6H8O4S2

95:5 v/v %

E. Jonsson, Acta Chem. Scand., 19, 2247

Stryc. 33

M-O. Hedblom. Swed. J. Agric. Res., 1, 43

Stryc. 34

(1965)

(1971) C 6 H 9 NO 2

COOH

Acetone CN J. Kenyon and W. A. Ross, J. Chem. Soc.,

Stryc. 35

C6H10O4

E. Berner and R. Leonardsen, Liebigs Ann.

Stryc. 36

3407 (1951)

Chem., 538, 1 (1939) C6H10O4S2

S S

H 2 O, MeOH

COOH

HOOC

A. Fredga, Arkiv Kemi Mineral Geol.,

COOH

HOOC

T. Posternak and J. -Ph. Susz, Helv. Chim.

Stryc. 38

Acta, 39, 2032 (1956) C 6 H 1 1 BrO 2 Acetone

Br

P. A. Levene, T. Mori, and L. A.

Stryc. 39

C 6 H 1 1 NO 2 S 2 S

N

Stryc. 40

Mikeska, J. Biol. Chem., 75, 337 (1927)

COOH

COOH

S

EtOAc, MeOH

M. Matell, Acta Chem. Scand., 14, 677 (1960)

C 6 H 1 1 NO 3 S O

N

H2O

OH

12A, No. 13 (1937) COOH

C6H10O6

OH

50:50 v/v % Stryc. 37

H2O

COOH

HOOC

C6H12O4

OH

EtOAc, MeOH

EtOAc

COOH

O

OH

M. Matell, Acta Chem. Scand., 14, 677

Stryc. 41

Stryc. 42

(1960)

L. S. Bergel'son, E. V. Dyatlovitskaya, M. Tichy and V. V. Voronkova, Izv. Akad. Nauk SSSR., 1612 (1962)

OCH3 COOH

C7H8O3S

T. Raznikiewicz, Arkiv Kemi, 18, 467

Stryc. 43

COOH

HOOC H Stryc. 44

Stryc. 45

C7H10O4S

C7H10O4

O M. E. Msurit, R. PO. Shternberg, A. M. Pakhomov, G. I. Basilevskaya, G. V. Smirnova, and N. A. Preobrazhenskii, Z. Obsh. Khim., 30, 2256 (1960)

© 2002 by CRC Press LLC

C. G. Overberger and Y. Shimokawa, Macromolecules, 4, 718 (1971)

H2O

O

C7H8O4 EtOH

(1961)

H5C2

H

Acetone, H 2 O 50:50 v/v%

S

HOOC

HOOC

Stryc. 46

S

COOH

EtOH

J. E. Némortin, E. Jonsson and A. Fredga, Arkiv Kemi, 30, 403 (1969)

COOH

EtOH, H2O

S

O

C7H12O3

H2O

COOH

HOOC

15:85 v/v%

S

A. Fredga nd M. Tenow, Arkiv Kemi,

Stryc. 47

C7H12O4

E. Berner and R. Leonardsen, Liebigs Ann.

Stryc. 48

Mineral. Geol., 16B, No. 9 (1942) COOH COOH

Chem., 538, 1 (1939)

C7H12O4

C7H12O4 COOH

H2O

H2O

COOH

P. W. Clutterback, H. Raistrick and F.

Stryc. 49

J. V. Braun and W. Reinhardt, Chem. Ber.,

Stryc. 50

Reuter, Biochem. J., 31, 987 (1937)

62, 2585 (1929)

C7H12O4 COOCH3

HOOC

H2O

E. Berner and R. Leonardsen, Tids.

Stryc. 51

COOCH3

HOOC

COOCH3

H2O

E. Berner and R. Leonardsen, Liebigs Ann.

Stryc. 52

Kjem., 64 (1943)

HOOC

C7H12O4

Chem., 538, 1 (1939) S

C7H12O4 H2O

COOH

C7H12O4S

COOH

EtOH, H 2 O 53:47 v/v%

E. Berner and R. Leonardsen, Liebigs

Stryc. 53

Stryc. 54

M. Matell, Arkiv Kemi, 3, 129 (1951)

Ann. Chem., 538, 1 (1939) COOH

HOOC OCH3

C7H12O5

COOH

H2O Cl

A. Lardon and T. Reichstein, Helv. Chim.

Stryc. 55

Cl

Stryc. 56

Acta, 32, 1613 (1949)

COOH

40:60 v/v%

M. H. Maguire and G. Shaw, J. Chem. Soc.,

C8H8O4S

H

C C C H

COOH K. Pettersson, Arkiv Kemi, 7, 39 (1954)

Stryc. 57

Acetone, H 2 O

2713 (1957)

EtOH

S

C 8 H 5 Cl 2 FO 3

F

O

Stryc. 58

C8H8O4S CHCl 3

J. H. Wotiz and R. J. Palchak, J. Am. Chem. Soc., 73, 1971 (1951)

COOH

C8H12O4 H2O

O

O

© 2002 by CRC Press LLC

HOOC

COOH

C8H12O4 EtOH

M. E. Maurit, R. P. Shternberg, A. M.

Stryc. 59

J. Böeseken and A. E. J. Peek, Rec. Trav.

Stryc. 60

Chim., 44m 841 (1925)

Pakhomov, G. I. Basilevskaya, G-V. Smirnova and N. A. Preobrazhenskii, Zh. Obsh. Khim., 30, 2256 (1960) HOOC

COOCH3

C8H12O6

COOH COOH

CHCl 3 , Et2O

OAc

C8H14O4 H2O

50:50 v/v% K. Serck-Hanssen, Arkiv Kemi, 10, 135

Stryc. 61

D. Pini, D. Lupinacci, and L. porri, Gazz.

Stryc. 62

(1957) COOH

Chim. Ital, 104, 1295 (1974) COOH

C8H14O4 H2O

H2O

COOH

COOH

E. Berner and R. Leonardsen, Liebigs

Stryc. 63

C8H14O4

K. Nagarajan, Ch. Weissmann, H. Schmid

Stryc. 64

Ann. Chem., 538, 1 (1934)

and P. Karrer, Helv. Chim. Acta, 46, 1212 (1963)

COOH

C8H14O4

COOH

H 2 O, EtOH

COOH

C 9 H 7 Cl 3 O 3 H 2 O, EtOH

O Cl

50:50 v/v%

80:20 v/v%

Cl Cl A. Fredga and U. Sahlberg, Arkiv Kemi

Stryc. 65

M. S. Smith, R. L. Wain and F. Wightman,

Stryc. 66

Mineral. Geol., 18A, No. 16 (1944) COOH

Ann. Appl. Biology, 39, 295 (1952)

C 9 H 7 Cl 3 O 3

COOH

EtOH

O

H 2 O, EtOH

O NO2

Cl

Cl

Cl

25:75 v/v%

Cl

M. Matell, Arkiv Kemi, 9, 157 (1955)

Stryc. 67

C 9 H 8 ClNO 5

Stryc. 68

A. Fredga, E. Gamstedt and L. Ekermo, Arkiv Kemi, 29, 515 (1968)

COOH O

C 9 H 8 Cl 2 O 3 EtOAc

Cl Cl

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COOH Cl

O Cl

C 9 H 8 Cl 2 O 3 EtOAc

A. Fredga, Croat. Chem. Acta, 29, 313

Stryc. 69

A. Fredga, Croat. Chem. Acta, 29, 313

Stryc. 70

(1957) COOH Cl

O

(1957) C 9 H 8 Cl 2 O 3

COOH

abs. EtOH

C 9 H 9 BrO 3 EtOH, H 2 O

O Br

50:50 v/v%

Cl

A. Fredga, Croat. Chem. Acta, 29, 313

Stryc. 71

A. Fredga and M. Andersson, Arkiv Kemi,

Stryc. 72

25, 223 (1966)

(1957) C 9 H 9 BrO 3

COOH

COOH

H 2 O, EtOH

O

53:47 v/v%

C 9 H 9 ClO 3 H 2 O, EtOH

O Cl

62:38 v/v%

Br

A. Fredga and M. Andersson, Arkiv

Stryc. 73

A. Fredga, A-M. Weidler and C. Grönwall,

Stryc. 74

Kemi, 21, 555 (1964) COOH

Arkiv Kemi, 17, 265 (1961) C 9 H 9 ClO 3

COOH

H 2 O, EtOH

O

H 2 O, EtOH

O I

50:50 v/v%

C 9 H 9 IO 3

50:50 v/v%

Cl

A. Fredga, A-M. Weidler and C.

Stryc. 75

A. Fredga, Arkiv Kemi, 25, 87 (1965)

Stryc. 76

Grönwall, Arkiv Kemi, 17, 265 (1961) COOH

C 9 H 9 NO 5

H2 N

EtOH

O

COOH

C 9 H 9 NO 6 EtOH

O O HOOC

NO2 Stryc. 77

E. Fourneau and G. Sandulesco, Bull. Soc. Chim. Fr., 33, 459 (1923)

Stryc. 78

S. Senoh, Y. Maeno and S. Imamoto, A. Komamine, S. Hattori, K. Yamashita and M. Matsui, Bull. Chem. Soc. Japan., 40, 379 (1967)

© 2002 by CRC Press LLC

COOH AcNH

C 1 1 H 1 1 NO 7

O

EtOH

C9H10O2 EtOH, H2O

COOH

75:25 v/v%

O HOOC

S. Senoh, Y. Maeno and S. Imamoto, A.

Stryc. 79

C. L. Arcus and J. Kenyon, J. Chem. Soc.,

Stryc. 80

Komamine, S. Hattori, K. Yamashita and

916 (1939)

M. Matsui, Bull. Chem. Soc. Japan., 40, 379 (1967) C9H10O2

C9H10O2

EtOH, H2O

COOH

EtOH, H2O

COOH

75:25 v/v% A. Fredga, Arkiv Kemi, 7, 241 (1954)

Stryc. 81

75:25 v/v% S. I. Goldberg and F-L. Lam, J. Org.

Stryc. 82

Chem., 31, 2336 (1966) OH

C9H10O4 OH

C9H10O4S

COOH

abs. EtOH

EtOH, H2O

COOH

COOH

33:67 v/v%

S

A. Collet, Bull. Soc. Chim. Fr., 215

Stryc. 83

S. Gronowitz and S. Larsson, Arkiv Kemi,

Stryc. 84

(1975) H N

8, 567 (1955) C 9 H 1 1 NO 2

COOH

EtOH

O

H N

C 9 H 1 1 NO 4 S

SO3H

EtOH, H2O 50:50 v/v%

M. Matell, Acta Chem. Scand., 7, 228

Stryc. 85

Stryc. 86

(1953) COOH S

Stryc. 87

Chim., 53, 1120 (1934) C9H12O2S4

S S

H. J. Backer and H. Mulder, Rec. Trav.

C9H14O2

H

EtOH

S

C C C

CHCl 3

HOOC M-O. Hedblom and K. Olsson, Arkiv Kemi, 32, 309 (1970)

© 2002 by CRC Press LLC

Stryc. 88

J. H. Wotiz and R. J. Palchak, J. Am. Chem. Soc., 73, 1971 (1951)

C 9 H 1 5 NO 4 HOCH2 C

S

CHCl 3

O

O

C9H16O2S H2O HOOC

N

O

F. Bergel, N. C. Hindley, A. L. Morrison

Stryc. 89

J. V. Braun and G. Werner, Chem. Ber., 62,

Stryc. 90

and A. R. Moss, Chem. Ber., 85, 711

1050 (1929)

(1952) C9H16O4 COOH

HOOC

COOH

EtOH COOH

C9H16O4 EtOH, H 2 O 50:50 v/v%

A. Fredga and H. Ostman, Acta Chem.

Stryc. 91

A. Fredga, Arkiv Kemi, 6, 277 (1953)

Stryc. 92

Scand., 10, 703 (1956) COOH

HOOC

Cl

C 1 0 H 9 ClO 4 EtOH, H 2 O

COOH

O

EtOH, H 2 O

Cl

Cl

56:44 v/v% M. Naps and I. B. Johns, J. Am. Chem.

Stryc. 93

C 1 0 H 1 0 Cl 2 O 3

43:57 v/v% M. Matell, Arkiv Kemi, 6, 365 (1953)

Stryc. 94

Soc., 62, 2450 (1940) COOH

C 1 0 H 1 0 Cl 2 O 4

O

EtOH, H 2 O

O Cl

COOH

H2O

75:25 v/v%

Cl

NO2

OCH3

E. Gamstedt, Arkiv Kemi, 32, 151 (1970)

Stryc. 95

C10H10N2O5 C N H

Stryc. 96

W. M. Colles and C. S. Gibson, J. Chem. Soc., 99 (1928)

COOH

C 1 0 H 1 1 ClO 3

COOH

MeOH, H2O

O Cl

O

55:45 v/v%

C 1 0 H 1 1 ClO 3 Acetone, H 2 O 67:33 v/v%

Cl

Stryc. 97

A. Fredga, A. Kijellqvist and E. Tornqvist, Arkiv Kemi, 32, 301 (1970)

© 2002 by CRC Press LLC

Stryc. 98

A. Fredga, A. Kijellqvist and E. Tornqvist, Arkiv Kemi, 32, 301 (1970)

C10H12O3

COOH

H2O, EtOH

O

C10H12O3

COOH O

H2O, EtOH

50:50 v/v%

A. Fredga and M. Andersson, Arkiv

Stryc. 99

75:25 v/v%

M. Matell, Arkiv Kemi, 6, 251 (1953)

Stryc. 100

Kemi, 25, 223 (1966) C10H12O3

COOH

EtOH, H 2 O

O OCH3

50:50 v/v%

A. Fredga, I. Kiriks and C. Lundstrom,

Stryc. 101

C 1 0 H 1 3 NO 2 H

C

HOOC

H

COOH

C 1 0 H 1 3 NO 2 S

NH2

M. Matsui, Y. Yamada and M. Nonoyama,

Stryc. 102

Agr. Biol. Chem., 26, 351 (1962) COOH

S

Chem., 17, 618 (1952)

C 1 0 H 1 3 NO 4 S H2O

SO3H

HN

H2O

M. D. Armstrong and J. D. Lewis, J. Org.

Stryc. 104

Chem., 17, 618 (1952) O

C 1 2 H 1 5 NO 3 S

NHAc

H2O

M. D. Armstrong and J. D. Lewis, J. Org.

Stryc. 103

MeOH

CN

Arkiv Kemi, 25, 249 (1966) S

C

C 1 0 H 1 3 NO 4 S

O HN SO3H

H. J. Backer and A. Bloemen, Rec. Trav.

Stryc. 105

H. J. Backer and J. H. De Boer, Rec. Trav.

Stryc. 106

Chim., 45, 110 (1926)

Chim., 43, 420 (1924)

C10H14O5 COOH

HOOC

COOH

C10H16O4

H2O

COOH

O

E. Berner, Acta Chem. Scand., 10, 268

Stryc. 107

SO3H

C14H17N2O4S H2O

N O

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A. Fredga and M. Matell, Bull. Soc. Chim. Belges., 62, 47 (1953)

(1956)

N

Stryc. 108

COOH

O

C11H14O3 H 2 O, EtOH 60:40 v/v%

H. J. Backer and M. Toxopeus, Rec. Trav.

Stryc. 109

A. Fredga and K. Olsson, Arkiv Kemi, 30,

Stryc. 110

Chim., 45, 890 (1926) COOH O

409 (1969)

C11H14O3

COOH

C12H12O4

EtOH, H 2 O

COOH

CHCl 3 , EtOH

25:75 v/v%

Stryc. 111

A. Fredga and E. Gamstedt, Arkiv Kemi,

22:78 v/v%

R. D. Haworth and F. H. Slinger, J. Chem.

Stryc. 112

28, 211 (1967) COOH

HOOC

Soc., 1321 (1940) C12H14O4 EtOH, H 2 O

HOOC

NO2 O2N NO2

O2 N

L. Westman, Arkiv Kemi, 12, 167 (1958)

MeOH

NO2

84:16 v/v% Stryc. 113

C13H5N5O12

H. A. Stearns and R. Adams, J. Am. Chem.

Stryc. 114

Soc., 52, 2070 (1930) C 1 3 H 1 3 NO 4 S

SO2 NH COOH

Stryc. 115

H2O

W. M. Colles and C. S. Gibson, J. Chem.

A. Fredga, T. Unge and R. Hakansson,

Stryc. 116

Chemica Scripta, 4, 123 (1973)

C13H18O3

C13H24O4

COOH COOH

EtOH, H 2 O

O

Acetone, H 2 O

O

Soc., 124, 2505 (1924) COOH

C13H18O3

COOH

EtOH

57:43 v/v%

Stryc. 117

M. Andersson, Arkiv Kemi, 26, 335

Stryc. 118

HOOC

NO2 O2N

COOH NO2

O2 N

C14H4N6O16

L. H. Boch, W. W. Moyer and R. Adams, J. Am. Chem. Soc., 52, 2054 (1930)

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C14H10O3

MeOH

NO2O2N

Stryc. 119

K. Kögl and H. Erxleben, Z. Physiol. Chem., 235, 181 (1935)

(1967)

COOH OH

Stryc. 120

EtOH, CHCl 3 50:50 v/v%

F. E. Ray and E. Kreiser, J. Am. Chem. Soc., 69, 3068 (1947)

SO3H

C14H14O3S

C14H14O4S2

H2O

E. E. Pedersen and K. A. Jensen, Acta

Stryc. 121

EtOH, H 2 O S

S

HOOC

COOH

Stryc. 122

Chem.Scand., 2, 651 (1948)

N COOH COPh

C 1 4 H 1 7 NO 3

C15H14O2

EtOH, H 2 O

EtOH, H 2 O

80:20 v/v%

R. K. Hill, T. H. Chan and J. A. Joule,

Stryc. 123

COOH

Stryc. 124

Tetrahedron, 21, 147 (1965) COOH

R. Hakansson, Chemica Scripta, 3, 177 (1973)

C15H14O3

50:50 v/v%

H. Rupe and W. Kerkovins, Chem. Ber., 45, 1398 (1912)

COOH COOH

Dioxane

C16H12N2O7 CHCl 3 , MeOH 12:88 v/v%

NHAc NO2

OH

R. P. Zelinski, B. W. Turnquest and E. C.

Stryc. 125

Stryc. 126

Martin, J. Am. Chem. Soc., 73, 5521

S. Sako, Bull. Chem. Soc. Japan., 9, 393 (1934)

(1951) C16H14O2 CHCl 3 , Et 2 O COOH

H

C 1 6 H 1 4 O 4 Se 2

COOH Se Se

EtOH, H 2 O COOH

50:50 v/v%

C C Ph

H

Stryc. 127

G. M. Kelkar, N. L. Pholnikar and B.V.,

Stryc. 128

Bhide, J. Ind. Chem. Soc., 24, 297 (1947)

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

C16H18O6S2 H2O

O HOOC

W. L. F. Armarego and E. E. Turner, J. Chem. Soc., 3668 (1956)

© 2002 by CRC Press LLC

EtOH O

SO3H SO3H

Stryc. 129

C16H22O4

Stryc. 130

A. Lüttringhaus and G.Eyring, Liebigs Ann. Chem., 604, 111 (1957)

C17H18O3

C 1 7 H 1 7 NO 4 NO2

COOH

EtOH

EtOH

COOH

M. S. Leslie and U. J. H. Mayer, J.

Stryc. 131

Stryc. 132

Chem. Soc., 1401 (1962) C18H12O4

COOH

EtOH, H 2 O

Soc., 611 (1961)

HOOC Ph

COOH H. Tatemitsu, F. Ogura and M. Nakagawa, Bull. Chem. Soc. Japan., 46, 915 (1973)

H3CO

COOH

C20H22O8

HO

COOH

CHCl 3

C18H16O4

HH

MeOH

Ph H H COOH

99:1 v/v%

Stryc. 133

M. S. Leslie and U. J. H. Mayer, J. Chem.

Stryc. 134

R. Stoermer, Chem.Ber., 56, 1683 (1923)

C20H26O6S2

SO3H

HO3S

H2O

OCH3

OH

R. D. Haworth and F. H. Slinger, J.

Stryc. 135

Stryc. 136

Chem. Soc., 1098 (1940)

A. E. Knauf and R. Adams, J. Am. Chem. Soc., 55, 4704 (1933)

C21H20O2 COOH

COOH

O

O

EtOH

C

O

O

EtOH COOH

M. S. Leslie and U. J. H. Mayer, J. Chem. Soc., 1401 (1962)

Stryc. 137

C21H26O2

Stryc. 138

C25H30O8 CH 2 Cl 2 , Acetone

M. S. Leslie and U. J. H. Mayer, J. Chem. Soc., 611 (1961) C 6 H 9 NO 6

H2N

HOOC HOOC

COOH

abs. EtOAc, MeOH 63:37 v/v%

O O

Stryc. 139

J. Schmidlin, G. Anner, J. R. Billeter, K. Heusler, H. Ueberwasser, P. Wieland and A. Wettstein, Helv. Chim. Acta, 40, 2291 (1957)

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Stryc. 140

W. Marki, M. Oppliger, P. Thanei and R. Schwyzer helv. Chim. Acta, 60, 798 (1977)

O

C12H12N2O7 NH

C13H16O2

COOH

H2O

CHCl 3

COOH

O2N HOOC

H. C. Winter, J. Am. Chem. Soc., 62,

Stryc. 141

Stryc. 142

3266 (1940)

N. Bodor, R. Woods, C. Raper, P. Kaerney and J. J. Kaminski, J. Med. Chem., 23474 (1980)

NO2

F

COOH

COOH

C16H10F2N2O8 MeOH

HOOC

C20H22N2O4

N N

abs. EtOAc, MeOH 63:37 v/v%

F

NO2 COOH

Stryc. 143

E. C. Kleiderer and R. Adams, J. Am.

Stryc. 144

Chem. Soc., 55, 716 (1933) BrClFCOOH

T. T. Chu and C. S. Marvel, J. Am. Chem. Soc., 55, 2841 (1933)

C 2 HBrClFO 2 Ethylene glycol

BrClFCH Stryc. 145

T. R. Doyle and O. Vogl, J. Am. Chem. Soc., 111, 8510 (1989)

(+)-2-amino-1-phenyl-1,3-propanediol C11H15O4P

C 1 1 H 1 4 ClO 4 P

Cl

EtOH, H 2 O O

O

EtOH, H 2 O

96:4 v/v%

15:85 v/v%

P

O

O OH

13Prdol. 1

O

P O OH

W. ten Hoeve, H. Wynberg, J. Org.

13Prdol. 2

Chem., 50, 4508 (1985)

W. ten Hoeve, H. Wynberg, J. Org. Chem., 50, 4508 (1985)

O-(2,4-dichloro-benzyl)-2-amino-butan-1-ol COOH

C5H8O5

AcNH

COOH

C10H11O3

COOH

O24clab. 1

J.Touet, L. Faveriel and Eric Brown, Tetrahedron, 51, 1709 (1995)

© 2002 by CRC Press LLC

O24clab. 2

J.Touet, L. Faveriel and Eric Brown, Tetrahedron, 51, 1709 (1995)

AcNH

H N

C10H11O4

COOH

Cl

COOH

C 1 0 H 1 0 ClO 4

O

OH

OH O24clab. 3

J.Touet, L. Faveriel and Eric Brown,

O24clab. 4

Tetrahedron, 51, 1709 (1995)

J.Touet, L. Faveriel and Eric Brown, Tetrahedron, 51, 1709 (1995)

3-methyl-2-phenylbutylamine C16H14O3

COOH

benzoyl 32Bua. 1

H. Nohira, S. Saio, M. Moriwaki, S. Kamiyama, K. Toyoda, J. Matsumoto, K. Maruo and T. Fujimoto, Eur. Pat. Appl. EP 703, 212 (1996)

O-(4-Bromo-benzyl)-2-amino-butan-1-ol COOH

C5H8O5

J.Touet, L. Faveriel and Eric Brown,

O4Brab. 2

Tetrahedron, 51, 1709 (1995)

OH

COOH

C 1 0 H 1 1 NO 3

O

COOH

O4Brab. 1

H N

C 1 0 H 1 1 NO 4

J.Touet, L. Faveriel and Eric Brown, Tetrahedron, 51, 1709 (1995)

H N

ClCH2

COOH

C 1 0 H 1 0 ClNO 4

O

O

N H

O4Brab. 3

OH

COOH

J.Touet, L. Faveriel and Eric Brown, Tetrahedron, 51, 1709 (1995)

© 2002 by CRC Press LLC

O4Brab. 4

J.Touet, L. Faveriel and Eric Brown, Tetrahedron, 51, 1709 (1995)

O-(4-chloro-benzyl)-2-amino-butan-1-ol C5H8O5

COOH

H N

J.Touet, L. Faveriel and Eric Brown,

J.Touet, L. Faveriel and Eric Brown,

O4clab. 2

Tetrahedron, 51, 1709 (1995) H N

C 1 0 H 1 1 NO 3

O

COOH

O4clab. 1

COOH

Tetrahedron, 51, 1709 (1995)

C 1 0 H 1 1 NO 4

COOH

H N

ClCH2

COOH

C 1 0 H 1 0 ClNO 4

O

O

OH

OH

J.Touet, L. Faveriel and Eric Brown,

O4clab. 3

O4clab. 4

Tetrahedron, 51, 1709 (1995)

J.Touet, L. Faveriel and Eric Brown, Tetrahedron, 51, 1709 (1995)

erythro-2-amino-1,2-diphenylethanol AcO

OAc

C22H16O8 1,4-dioxane

O

O O

12Phet. 1

O

Y. Adegawa, Y. Hashimoto, L. Fang, M. Nakamura, K. Kinbara, M. Hasegawa and K. Saigo, Bull. Chem. Soc. Jpn, 66, 900 (1993)

1-Hydroxy-2-aminobutane COOH

HOOC

Abut. 1

COOH

C 5 H 9 NO 4

NH2

NH2

H 2 O, EtOH

F. H. Radke, R. B. Fearing and S. W. Fox,

Abut. 2

J. Am. Chem. Soc., 76, 2801 (1954) COOH

HN

Abut. 3

CHO

J. Am. Chem. Soc., 76, 2801 (1954) C20H13O4P

n-BuOH

J. Am. Chem. Soc., 76, 2801 (1954)

O O P O OH

Abut. 4

THF

Y. Tamai, P. Heung-Cho, K. Iizuka, A. Okamura, S. Miyano, Synthesis, 222-223, (1990)

© 2002 by CRC Press LLC

n-BuOH

F. H. Radke, R. B. Fearing and S. W. Fox,

C 1 0 H 1 1 NO 3

F. H. Radke, R. B. Fearing and S. W. Fox,

C 9 H 1 1 NO 2

C6H10O3S

O S

Abut. 5

COOH

A. Stampa Diez Del Corral, M. Del Carme Onrubia Miguel and J. Irrure Perez, U. S. Patent 5, 367, 091 (1994)

Acetyl-3,5-dibromo-tyrosyne NH2

C6H14N2O2 H2O

COOH

H2N

F. J. Kearley and A. W. Ingersoll, J. Am.

Actyr. 1

Chem. Soc., 73, 5783 (1951)

3-Aminomethylpinane OH

C6H10O3 H2O

O

O J. Paust, S. Pfohl, W. Reif and W. Schmidt,

Amepi. 1

Liebigs Ann. Chem., 1024 (1978)

2-(1-aminoethyl)-naphtalene COOH H

C9H12O2 Acetone

Aenap. 1

M. Nakazaki, K. Naemura and N. Arashiba, J. Org. Chem., 43, 888 (1978)

Amine D (Hercules Powder Co) COOH

C19H30O2 EtOH

AmiD. 1

M. Farina and G. Audisio, Tetrahedron, 26, 1839 (1970)

© 2002 by CRC Press LLC

Amphetamine C 3 H 7 NO 2

NH2 COOH

C 5 H 9 NO 3

O

EtOH

EtOH

HN COOH

J. M. Gillingham, U. S. Patent 3,028,395

Amph. 1

Amph. 2

(1962)

COOH

HO

(1962) C 3 H 7 NO 3

J. M. Gillingham, U. S. Patent 3,028,395

Amph. 4

(1962) NH2 HOOC

COOH

EtOH

HN HO

Amph. 3

C 5 H 9 NO 4

O

EtOH

NH2

J. M. Gillingham, U. S. Patent 3,028,395

COOH

J. M. Gillingham, U. S. Patent 3,028,395 (1962)

C 5 H 9 NO 4

C 5 H 1 1 NO 2

COOH

H2O

H2O

NH2

J. M. Gillingham, U. S. Patent 3,028,395

Amph. 5

Amph. 6

(1962)

(1962) C 7 H 1 3 NO 3

COOH

J. M. Gillingham, U. S. Patent 3,028,395

COOH

S

H2O

NH2

HN

C 5 H 1 1 NO 2 S EtOH, H 2 O 95:5 v/v %

O

Amph. 7

J. M. Gillingham, U. S. Patent 3,028,395

Amph. 8

(1962) COOH

S

O

Amph. 9

(1962) C 7 H 1 3 NO 3 S

C9H8O3

COOH

EtOH, H 2 O

HN

J. M. Gillingham, U. S. Patnet 3,028,395

O

H2O

95:5 v/v %

J. M. Gillingham, U. S. Patnet 3,028,395

Amph. 10

(1962)

D. M. Bowen, J. I. DeGraw, Jr., V. R. Shah and W. A. Bonner, J. Med. Chem., 6, 315 (1963)

COOH

NH2

COOH

C 9 H 1 1 NO 2 HN

EtOH

C 1 1 H 1 3 NO 3 EtOH

O

Amph. 11

J. M. Gillingham, U. S. Patent 3,028,395 (1962)

© 2002 by CRC Press LLC

Amph. 12

J. M. Gillingham, U. S. Patent 3,028,395 (1962)

COOH NH2

HO

COOH

C 9 H 1 1 NO 3 abs. EtOH

HN

HO

C 1 1 H 1 3 NO 4 abs. EtOH

O

J. M. Gillingham, U. S. Patent 3,028,395

Amph. 13

J. M. Gillingham, U. S. Patent 3,028,395

Amph. 14

(1962) NH2

(1962) C11H12N2O2 EtOH

COOH

O

H N

C13H14N2O3 EtOH

COOH

N H

N H

J. M. Gillingham, U. S. Patent 3,028,395

Amph. 15

Amph. 16

(1962)

(1962) C11H12O3

OH COOH

Amph. 17

J. M. Gillingham, U. S. Patent 3,028,395

COOH H

EtOH

A. Schoofs, J-P. Guetté and A. Horeau,

Amph. 18

Compt. Rendus, 274, 1527 (1972)

C11H14O3 EtOH

E. R. Atkinson, D. D. McRitchie,L. F. Shoer, L. S. Harris, S. Archer, M. D. Aceto, J. Pearl and F. P. Luduena, J. Med. Chem., 20, 1612 (1977)

C11H14O3

HO C COOH

OH COOH

Amph. 19

C11H14O3S

S

E. R. Atkinson, D. D. McRitchie, L. F.

Amph. 20

E. R. Atkinson, D. D. McRitchie, L. F.

Shoer, L. S. Harris, S. Archer, M. D.

Shoer, L. S. Harris, S. Archer, M. D. Aceto,

Aceto, J. Pearl and F. P. Luduena, J. Med.

J. Pearl and F. P. Luduena, J. Med. Chem.,

Chem., 20, 1612 (1977)

20, 1612 (1977)

OH C COOH

C12H10O3S

OH C COOH

C12H14O3

S

Amph. 21

E. R. Atkinson, D. D. McRitchie, L. F.

Amph. 22

E. R. Atkinson, D. D. McRitchie, L. F.

Shoer, L. S. Harris, S. Archer, M. D.

Shoer, L. S. Harris, S. Archer, M. D. Aceto,

Aceto, J. Pearl and F. P. Luduena, J. Med.

J. Pearl and F. P. Luduena, J. Med. Chem.

Chem., 20, 1612 (1977

20, 1612 (1977)

© 2002 by CRC Press LLC

OH C COOH

C12H16O3S

C14H18O3

OH C COOH

EtOAc

S

E. R. Atkinson, D. D. McRitchie, L. F.

Amph. 23

E. R. Atkinson, D. D. McRitchie, L. F.

Amph. 24

Shoer, L. S. Harris, S. Archer, M. D.

Shoer, L. S. Harris, S. Archer, M. D. Aceto,

Aceto, J. Pearl and F. P. Luduena, J. Med.

J. Pearl and F. P. Luduena, J. Med. Chem.,

Chem., 20, 1612 (1977)

20, 1612 (1977)

C14H18O4

COOH

O

HOOC

E. J. Corey, S. M. Albonico, U. Koelliker,

Amph. 25

EtOAc

H

H

OH

C17H26O4

OH H

H

H

O

L. J. Chinn and H. L. Dryden, Jr., J. Org.

Amph. 26

T. M. Schaaf and R. K. Varma, J. Am.

Chem., 26, 3904 (1961)

Chem. Soc., 93, 1491 (1971) O

C18H14O3 COOH

COOH

IPrOH

O

J. P. Dunn, D. M. Green, P. H. Nelson, W. Amph. 28 H. Rooks, II, A. Tomolonis, and K. G. Untch, J. Med. Chem., 20, 1557 (1977)

Amph. 27

H3CO

COOH

MeOH, H2O

O

O

O O

O

Amph. 31

EtOH, H 2 O

F. Loiodice, A. Longo, P. Bianco and V. Tortorella, Tetrahedron Asymmetry, 6, 1001 (1995)

© 2002 by CRC Press LLC

CCl3

Isoamil-acetate, EtOAc 67:33 v/v%

E. J. Corey and J. Moinet, J. Am. Chem. Soc., 95, 6831 (1973) O

C 1 0 H 9 ClO 3 COOH

C 2 3 H 2 2 Cl 3 NO 5

Ph

C N O

P. Newman, Optical Resolution Amph. 30 Procedures for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

Amph. 29

Et2O

C. F. Huebner, U. S. Patent 3759927 (1973)

C12H14O3

33:67 v/v%

Cl

C10H10O4

H3CO

Cl

Amph. 32

C 1 1 H 9 ClO 3 COOH

EtOH, H2O

F. Loiodice, A. Longo, P. Bianco and V. Tortorella, Tetrahedron Asymmetry, 6, 1001 (1995)

COOH S

C8H8O4S

C13H12O2S

EtOAc

EtOH, H 2 O

COOH

COOH

50:50 v/v%

S

Amph. 33

K. Pettersson, Arkiv Kemi, 7, 39 (1954)

Amph. 34

K. Pettersson, Arkiv Kemi, 7, 279 (1954)

Anhydropylosine C13H16O5 O

abs. EtOH

COOH COOEt

A. Hofmann and P. Stadler, Swiss Patent

Anhp. 33

454,826 (1968)

Arginine NH2 HOOC

NH2

C 9 H 9 NO 4

COOH

HOOC

COOH

H 2 O, EtOH

C 9 H 9 NO 5 H 2 O, EtOH

HO

83:17 v/v%

57:43 v/v%

P. Friis and A. Kjaer, Acta Chem. Scand.,

Arg. 31

Arg. 2

17, 2391 (1963) O N

Scand., 17, 2397 (1963) C10H16N2O3S

N

H

H 2 O, iPrOH

H S

Arg. 3

A. Kjaer and P. O. Larsen, Acta Chem.

H

COOH

D. E. Wolf, R. Mozingo, S. A. Harris, R. C. Anderson and K. Folkers, J. Am. Chem. Soc., 67, 2100 (1945)

Aspartic acid HS

COOH NH2

Aspar. 1

H2O

P. Rambacher and S. Mäke, German Patent 2, 045, 998 (1974)

© 2002 by CRC Press LLC

C 3 H 7 NO 2 S

Binaphthyl-phosphoric acid COOH

C6H14N2O2

COOH

EtOH

NH2

BinP. 1

C 1 0 H 1 1 NO 3

O

MeOH

NH2

P. Bey, C. Danzin, v. Van Dorsselaer, P.

E. H. W. Bohme, R. E. Bambury, R. J.

BinP. 2

Mamont, M. Jung and C. Tardif, J. Med.

Baumann, R. C. Erickson, B. L. Harrison,

Chem., 21, 50 (1978)

P. F. Hoffman, F. J. McCarty, R. A. Schnettler, M. J. Vaal, and D. L. Wenstrup, J. Med. Chem., 23, 405 (1980)

N

OCH3

C10H15N3O MeOH

CN N BinP. 3

S. M. Bromidge, F. Brown, F. Cassidy, M. S. G. Clark, S. Dabbs, M. S. Hadley, J. Hawkins, J. M. Loudon, C. B. Naylor, B. S. Orlek and G. J. Riley, J. Med. Chem., 40, 4265 (1997)

Bornylamine C 9 H 9 NO 4 COOH

Et 2 O

O2 N

Born. 1

E. Miller and R. Illgen, Liebigs Ann.

COOH C OH

O2N

671 (1956)

C10H10O3

COOH

MeOH, Et 2 O

F. Nerdel and H. Rachel, Chem. Ber., 89,

C10H14O4 Et 2 O

COOCH3 H

50:50 v/v% Born. 3

MeOH, Et 2 O

F. Nerdel and H. Racher, Chem. Ber., 89,

Born. 2

Chem., 521, 72 (1936) COOH C OH

C 1 0 H 9 NO 5

P. Newman, Optical Resolution Procedures

Born. 4

671 (1956)

for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

d-3-bromochamphor-8-sulfonic acid S

COOH NH2

© 2002 by CRC Press LLC

C 5 H 1 1 NO 2 S H2O

S

COOH NH2 HCl

C 5 H 1 2 NO 2 SCl H2O

G. P. Wheeler and A. W. Ingersoll, J. Am.

Br38su. 1

G. P. Wheeler and A. W. Ingersoll, J. Am.

Br38su. 2

Chem. Soc., 73, 4604 (1951)

Chem. Soc., 73, 4604 (1951) NH2

C 6 H 7 NO 2 S

NH2

EtOAc

COOH

C 9 H 9 NO 3

COOH

H2O

HO

S

S. Gronowitz, I. Sjögren, L. Wernstedt

Br38su. 3

S. Yamada, C. Hongo, R. Yoshioka and I.

Br38su. 4

and b. Sjöberg, Arkiv Kemi, 23, 129

Chibata, Agric. Biol.Chem., 43, 395 (1979)

(1964)

2-p-bromophenylethylamine C6H12O4

OH

Acetone, Et 2 O

COOH OH

Brpha. 1

20:80 v/v % F. B. Armstrong, U. S. Muller, J. B. Reary, D. Whitehouse and D. H. G. Crout, Biochim. Biophys. Acta, 498 282 (1977)

N-benzyl-2-aminobutan-1-ol COOH

HOOC

C5H8O4

C 1 0 H 1 1 NO 3 O

COOH

N H

J. Touet, L. Faveriel and E. Brown,

BzaBu. 1

J. Touet, L. Faveriel and E. Brown,

BzaBu. 2

Tetrahedron, 51, 1709(1995)

Tetrahedron, 51, 1709 (1995)

C 1 0 H 1 1 NO 4

OH

O

O N H

BzaBu. 3

C 1 0 H 1 0 ClNO 4

OH

ClH2C

COOH

J. Touet, L. Faveriel and E. Brown,

BzaBu. 4

Tetrahedron, 51, 1709(1995) H3CO

COOH

H3CO

COOH

C13H16O6

N H

J. Touet, L. Faveriel and E. Brown, Tetrahedron, 51, 1709(1995)

H3CO

COOH COOH

H3CO OCH3

© 2002 by CRC Press LLC

COOH

C14H18O7

J. Touet, T. Ruault and E. Brown, Synth.

BzaBu. 5

J. Touet, T. Ruault and E. Brown, Synth.

BzaBu. 6

Comm., 24, 293 (1994)

Comm., 24, 293 (1994)

C5H8O4

COOH

Br

COOH

EtOAc

EtOAc

COOH

COOH

J. Touet, T. Ruault and E. Brown, Synth.

BzaBu. 7

C 4 H 5 BrO 4

J. Touet, T. Ruault and E. Brown, Synth.

BzaBu. 8

Comm., 24, 293 (1994) H3CO

COOCH3

H3CO

COOH

Comm., 24, 293 (1994)

C13H18O6

H3CO

EtOAc

H3CO

COOCH3 COOH

C14H20O7 EtOAc

OCH3

J. Touet, T. Ruault and E. Brown, Synth.

BzaBu. 9

BzaBu. 10

Comm., 24, 293 (1994)

J. Touet, T. Ruault and E. Brown, Synth. Comm., 24, 293 (1994)

C10H11O3

OH

C10H11O4

O O

COOH

N H

N H

J. Touet, T. Ruault and E. Brown, Synth.

BzaBu. 11

Comm., 24, 293 (1994) OH

BzaBu. 12

COOH

J. Touet, T. Ruault and E. Brown, Synth. Comm., 24, 293 (1994)

C 1 0 H 1 0 ClO 4

O

ClH2C

BzaBu. 13

N H

COOH

J. Touet, T. Ruault and E. Brown, Synth. Comm., 24, 293 (1994)

(1S,2R)-(-)-cis-2-Benzylaminocyclohexanemethanol C11H11F3O3

OCH3

EtOH, H2O 95:5 v/v% F3C

Bzcym. 1

COOH

Y. Aoki and H. Nohira, Chem.Lett., 113 (1993)

© 2002 by CRC Press LLC

2-benzylaminopropanol C10H16O2 H HOOC

EtOH, H2O

H

40:60 v/v% F. Horiuchi and M. Matsui, Agr. Biol. Chem.,

BzaPr. 1

37, 1713 (1973)

N-Benzyl-2-(hydroxymethyl)-cyclohexyl-amine COOH

HOOC

OH

C4H6O5

C 1 3 H1 6 O 2

Acetone, EtOH

iPrOH

66:34 v/v % COOH

J. Nishikawa, T. Ishizaki, F. nakayama, H. Bzcya. 1 Kawa, K. Saigo and H. Nohira, Nippon Kagaku Kaishi, 754 (1979)

Bzcya. 1

J. Nishikawa, T. Ishizaki, F. Nakayawa, H. Kawa, K. Saigo and M. Nohira, Nippon Kagaku Kaishi, 754 (1979)

Benzylisopropylamine O HOOC

BziPa. 1

O

N H

C 1 6 H 1 5 NO 5 O

Et 2 O

K. Undheim, P. Hamberg and B. Sjöberg, Acta Chem.Scand., 19, 317 (1965)

Camphoric acid NH2

COOH

H2N

C6H14N2O2

COOH

N

MeOH, H 2 O

OH

C 7 H 1 5 NO 3 MeOH

50:50 v/v % C. P. Berg, J. Biol. Chem., 115, 9 (1936)

Camp. 1

Camp. 2

D. M. Müller and E. Strack, Hoppe-Seyler's Z. Physiol. Chem., 353, 618 (1972)

C9H18N2

N N

Camp. 3

S. N. Calderon, R. B. Rothman, F. Porreca, J. L. Flippen-Anderson, R. W. McNutt, H. Xu, L. E. Smith, E. J. Nilsky, P. Davis and K. C. Rice, J. Med. Chem., 37, 2125 (1994)

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Camphorsulphonic acid COOH

C 4 H 9 NO 2

E. Fischer and H. Scheibler, Liebigs Ann.

Camps. 2

Chem., 383, 337 (1911)

Chem., 383, 337 (1911) NH2

C 8 H 9 NO 2

NH2 COOH

COOH

H2O

G. L. Clark and G. R. Yohe, J. Am.

Camps. 4

C11H12N2O2 H 2 O, MeOH 33:67 v/v%

N H

Camps. 3

MeOH

NH2

E. Fischer and H. Scheibler, Liebigs Ann.

Camps. 1

O

MeOH

NH2

C 5 H 1 1 NO 2

O

British Patent 842,839 (1960)

Chem. Soc., 51, 2796 (1929)

Carvomenthoxy-acetyl-chloride C 3 H 7 NO 2

NH2

COOH

H2O

K. Witkiewicz, F. Rulko and Z.

Carvo. 1

C 5 H 1 1 NO 2

NH2

COOH

Carvo. 2

Chabudzinski, Rocz. chem., 48, 651

K. Witkiewicz, F. Rulko and Z. Chabudzinsk, Rocz. Chem., 48, 651 (1974)

(1974) O

HN

C 6 H 1 1 NO 3

COOH NH2

COOH

Carvo. 3

K. Witkiewicz, F. Rulko and Z.

Carvo. 4

Chabudzinsk, Rocz. Chem., 48, 651

C 6 H 1 3 NO 2 H2O

K. Witckewicz, F. Rulko and Z. Chabudzinski, Rocz. Chem., 48, 651 (1974)

(1974)

Carbobenzoxy-phenylalanine COOH

NH2

Cbzala. 1

COOH

C 9 H 1 1 NO 2 HN

Et 2 O

T. Sokolowska, Pol. J. Chem., 40, 1895 (1966)

Cbzala. 2

CBZ

C 1 7 H 1 7 NO 5 Et 2 O

T. Sokolowska, Pol. J. Chem., 40, 1895 (1966)

Cholesteron-sulphonic acid NH2

COOH

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C 6 H 1 3 NO 2 EtOH

NH2

COOH

C 6 H 1 3 NO 2 EtOH

G. Triem, Chem. Ber., 71, 1522 (1938)

Chols. 1

COOH

C 9 H 1 1 NO 3 abs. EtOH

NH2

HO

G. Triem, Chem. Ber., 71, 1522 (1938)

Chols. 2

G. Triem, Chem. Ber., 71, 1522 (1938)

Chols. 3

Cinchoninium methohydroxide OCH3 O O

C9H16O2 COOH

Acetone

C 1 6 H 1 3 ClO 6 O

MeOH

O

H3CO Cl

T. L. Jacobs, R. Reed and E. Pacovska, J.

Cimeh. 1

Cimeh. 2

Am. Chem. Soc., 73, 4505 (1951)

D. Taub, D. H. Kuo, H. L. S.ates and N. L. Wendler, Tetrahedron, 19, 1. (1963)

Cinchotoxine C9H10O3

OH

abs. EtOH, Et 2 O

COOH

Citox. 1

H. King and A. D. Palmer, J. Chem. Soc., 121, 2577 (1922)

cis-dinitrobis-(ethylenediamine)-cobalt-(III)-acetate C 5 H 9 NO 4

NH2

H2O

COOH

EtaCo. 1

F. P. Dwyer, B. Halpern and K. R. Turnbull, Aust. J. Chem., 16, 727 (1963)

Codeine C 1 0 H 1 3 NO 2

CN COOH

C 1 1 H 1 1 NO 2

CN COOH

MeOH, H 2 O

MeOH, H 2 O 54:46 v/v%

Cod. 1

J. Knabe and H. Junginger, Pharmazie, 7, 443 (1972)

© 2002 by CRC Press LLC

Cod. 2

J. Knabe and D. Strauss, Arch. Pharm. (Weinheim), 305, 54 (1972)

C 1 1 H 1 5 NO 2

CN COOH

COOH

MeOH, H 2 O

Ph. D. Thesis of D. Strauss, Universitat

EtOH

S

48:52 v/v%

Cod. 3

C12H10O3S

OH

Ph. D. Thesis of B. W. J. Ellenbroek,

Cod. 4

des Saarlandes, West Germany (1969)

Catholic University of Nijmegen, Rotterdam, The Netherlands (1964)

trans-1,2-cyclohexane-dicarboxylic acid C 4 H 9 NO 2

COOH

dioxane

NH2

Cydca. 1

C 8 H 9 NO 2

NH2 COOH

K. Murakami, N. Katsuta, K. Takano, Y.

dioxane

K. Murakami, LN. Katsuta, K. Takano, Y.

Cydca. 2

Yamamoto, T. Kakegawa, K. Saigo and

Yamamoto, T. Kakegawa, K. Saigo and H.

H. Nohira, Nippon Kagaku Kaishi, 765

Nohira, Nippon Kagaku Kaishi, 765 (1979)

(1979)

N-benzyl-2-(hydroxymethyl)-cyclohexylamine C7H8N2O3S

COOH S

Acetone, EtOH

O

HN

5:95 v/v% NH2

Cyha. 1

J. Nishikawa, T. Ishizaki, F. Nakayama, H. Kawa, K. Saigo and H. Nohira, Nippon Kagaku Kaishi, 754 (1979)

Desoxyephedrine C 9 H 9 ClO 4

OH

OH Cl

COOH

C 1 5 H 1 5 NO 2 EtOAc

EtOH

COOH

NH2 Deph. 1

A. Collet, Bull. Soc. Chim. Fr., 215 (1975)

Deph. 1

T. R. Lewis, M. G. Pratt, E. S. Homiller, B. F. Tullar and S. Archer, J. Am. Chem. Soc., 71, 3749 (1949)

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dextro-erythro-1,2-diphenyl-2-methyl-aminoethanol C16H18N2O5S

O H C N O

S

H2O

N O

COOH

J. C. Sheehan and K. R. Henery-Logan, J.

DEame. 1

Am. Chem. Soc., 81, 3089 (1959)

α-Methyl-β β-phenylethylamine sulfate (Dexedrine sulfate) C14H28O3

COOH OH

Et 2 O, EtOH

M. Ikawa, J. B. Koepfli, S. G. Mudd and C.

Dexe. 1

Niemann, J. Am. Chem. Soc., 75, 1035 (1952)

Diphenylpropylamin C18H20O3 Et 2 O, MeOH

HO

L. A. Petrova, N. J. Beltsova, G. A.

Et 2 O

HO

80:20 v/v%

COOH

DPram. 1

C18H20O3

COOH

L. A. Petrova, N. J. Bel'tsova, G. A.

DPram. 2

Tsvetkova and A. I. Klimov, Zh. Obshch.

Tsvetkova and A. I. Klimov, Zh. Obshch.

Khim., 41, 2276 (1971)

Khim., 41, 2276 (1971)

Ethylhydrocupreidine OH

C9H10O3 EtOH

COOH

Ethcu. 1

H. King and A. D. Palmer, J. Chem. Soc., 121, 2577 (1922)

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Fenchylamine C 7 H 1 3 NO 3

C 5 H 1 1 NO 2 COOH

COOH

H2O

NH2

H2O

HN O

Fenca. 1

L. R. Overby and A. W. Ingersoll, J. Am.

Fenca. 2

Chem. Soc., 73, 3363 (1951)

COOH

S

NH2

L. R. Overby and A. W. Ingersoll, J. Am. Chem. Soc., 73, 3363 (1951) COOH

C 5 H 1 1 NO 2 S HN

H2O

C 7 H 1 3 NO 3 S H2O

O

Fenca. 3

G. P. Wheeler and A. W. Ingersoll, J. Am.

Fenca. 4

Chem. Soc., 73, 4604 (1951) COOH NH2

G. P. Wheeler and A. W. Ingersoll, J. Am. Chem. Soc., 73, 4604 (1951)

C 6 H 1 3 NO 2

COOH

H2O

C 8 H 1 5 NO 3 H2O

HN O

Fenca. 5

W. A. H. Huffman and A. W. Ingersoll, J.

Fenca. 6

Am. Chem. Soc., 73, 3366 (1951) (CH3)2 CH2CH2CH COOH

NH2

Fenca. 7

C 6 H 1 3 NO 2

Am. Chem. Soc., 73, 3366 (1951)

(CH3)2 CH2CH2CH COOH

NHAc

H2O

W. A. H. Huffman and A. W. Ingersoll, J.

Fenca. 8

Am. Chem. Soc., 73, 3366 (1951) NH2

COOH

W. A. H. Huffman and A. W. Ingersoll, J.

C 8 H 1 5 NO 2 H2O

W. A. H. Huffman and A. W. Ingersoll, J. Am. Chem. Soc., 73, 3366 (1951)

C 6 H 1 3 NO 2

C 8 H 1 5 NO 2

O

H2O

H2O

HN

COOH

Fenca. 9

W. A. H. Huffman and A. W. Ingersoll, J.

Fenca. 10

Am. Chem. Soc., 73, 3366 (1951) COOH

NH

Fenca. 11

Am. Chem. Soc., 73, 3366 (1951)

C 9 H 1 1 NO 2 HN

H2O

L. R. Overby and A. W. Ingersoll, J. Am. Chem. Soc., 73, 3363 (1951)

© 2002 by CRC Press LLC

W. A. H. Huffman and A. W. Ingersoll, J.

Fenca. 12

COOH

C 1 0 H 1 1 NO 3

O

H2O

L. R. Overby and A. W. Ingersoll, J. Am. Chem. Soc., 73, 3363 (1951)

COOH

COOH

C 9 H 1 1 NO 2

NH2

C 1 1 H 1 3 NO 3

HN

H2O

H2O O

L. R. Overby and A. W. Ingersoll, J. Am.

Fenca. 13

L. R. Overby and A. W. Ingersoll, J. Am.

Fenca. A

Chem. Soc., 73, 3363 (1951)

Chem. Soc., 73, 3363 (1951)

Galactamine C6H10O3

OH

EtOH O

O

F. Kagan, R. V. Geinzelman, D. I. Weisblat

Gala. 15

and W. Greiner, J. Am. Chem. Soc., 79, 3545 (1957)

2-(D-gluco-D-gulo-hepto-hexahydroxy-hexyl)-benzimidazole HO H

Glbzi. 1

C4H6O5

COOH H OH COOH

H2O

W. T. Haskins and C. S. Hudson, J. Am. Chem. Soc., 61, 1266 (1939)

Glutamic acid C6H14N2O2

NH2

Gluac. 1

H2O

COOH

H2N

R. D. Emmick, U. S. Patent 2,556,907 (1951)

1-Hydroxyhydrindamine (cis-2-amino-1-hydroxyhydrindene) C 2 H 2 ClIO 2

Cl

I

Hdra. 1

COOH

MeOH, EtOAc

A. M. McMath and J. Read, J. Chem. Soc., 537 (1927)

HO H

COOH H OH COOH

© 2002 by CRC Press LLC

SO3H

Br

Hdra. 1

COOH

H2O

H2O

J. Read and A. M. McMath, J. Chem. Soc., 2192 (1926)

C4H6O5

C 2 H 3 BrO 5 S

J. Read, W.G. Reid, J. Soc. Chem. Ind.,

Hdra. 1

8T, (1928)

Histidine C 4 H 7 NO 5

OH HOOC

COOH

EtOH, H 2 O

NH2

30:70 v/v %

Y. Liwschitz, A. Singerman and I. Wiesel,

His. 1

Isr. J. Chem., 6, 647 (1968)

Leucin-amide C 3 H 7 NO 2

NH2

EtOH

COOH

C 5 H 9 NO 3

O

EtOH

HN COOH

T. Kato and Y. Tsuchiya, Agr. Biol.

Leuam. 1

T. Kato and Y. Tsuchiya, Agr. Biol. Chem.,

Leuam. 1

Chem., 26, 467 (1962)

26, 467 (1962)

C 5 H 7 NO 3 O

Leuam. 1

COOH

N H

EtOH

NH2 HOOC

COOH

C 5 H 9 NO 4 H 2 O, MeOH 20:80 v/v %

T. Kato and Y. Tsuchiya, Agr. Biol.

T. Kato and Y. Tsuchiya, Agr. Biol. Chem.,

Leuam. 2

Chem., 26, 467 (1962)

26, 473 (1962) C 7 H 1 3 NO 3

C 5 H 1 1 NO 2

COOH

COOH

EtOH

EtOH

HN

NH2

O

Leuam. 3

T. Kato and Y. Tsuchiya, Agr. Biol.

Leuam. 4

Chem., 26, 467 (1962) H3C S CH2CH2 CH COOH

Leuam. 5

26, 467 (1962)

C 5 H 1 1 NO 2 S

H2N

Chem., 26, 467 (1962)

NH2

H3C S CH2CH2 CH COOH NHAc

EtOH

T. Kato and Y. Tsuchiya, Agr. Biol.

COOH

T. Kato and Y. Tsuchiya, Agr. Biol. Chem.,

Leuam. 6

EtOH

T. Kato and Y. Tsuchiya, Agr. Biol. Chem., 26, 467 (1962) COOH

C 9 H 1 1 NO 2 EtOH

HN

C 1 1 H 1 3 NO 3 EtOH

O

© 2002 by CRC Press LLC

C 7 H 1 3 NO 3 S

T. Kato and Y. Tsuchiya, Agr. Biol.

Leuam. 7

T. Kato and Y. Tsuchiya, Agr. Biol. Chem.,

Leuam. 8

Chem., 26, 467 (1962

26, 467 (1962 O

C11H12N2O2

NH2

EtOH

COOH

C13H14N2O3

NH

EtOH

COOH

N H

N H

T. Kato and Y. Tsuchiya, Agr. Biol.

Leuam. 9

Leuam. 10

Chem., 26, 467 (1962)

Leuam. 11

26, 467 (1962)

C 1 1 H 1 3 NO 4

COOH

EtOH

COOH

N H

T. Kato and Y. Tsuchiya, Agr. Biol. Chem.,

Y. Liwschitz, A. I. Vincze and E. Nemes, Bull. Res. Council Isr., 9A, 49 (1960)

Leucine C 8 H 8 Cl 2 O 3 S

Cl SO3H

H2O

Cl

R. Ryuzo and S. Yamada, Jpn. Kokai Tokkyo

Leu. 12

Koho JP 08 12, 645 (1996)

Lysine H H2N

COOH OH H COOH

C 4 H 7 NO 5 MeOH, H 2 O

C 9 H 9 NO 6

H2 N

O

O

COOH

EtOH, H 2 O 50:50 v/v %

45:55 v/v %

H. Okai, N. Imamura and N. Izumiya,

Lys. 13

HOOC

S. Senoh, Y. Maeno and S. Imamoto, A.

Lys. 14

Bull. Chem. Soc. Japan, 40, 2154 (1967)

Komamine, S. Hattori, K. Yamashita and M. Matsui, Bull. Chem. Soc. Japan., 40, 379 (1967)

C10H16O2 H

H

MeOH

HOOC

Lys. 15

C10H16O2

H

M. Matsui and F. Horiuchi, Agr. Biol. Chem., 35, 1984 (1971)

© 2002 by CRC Press LLC

HOOC

Lys. 16

H

MeOH

M. Matsui and F. Horiuchi, Agr. Biol. Chem., 35, 1984 (1971)

COOH

O

C11H12N2O2

NH2

MeOH

C13H14N2O3

NH

N H

MeOH

COOH N

Lys. 17

J. N. Coker, W. L. Kohlhase, M. Fields,

J. N. Coker, W. L. Kohlhase, M. Fields, A.

Lys. 18

A. O. Rogers and M. A. Stevens, J. Org.

O. Rogers and M. A. Stevens, J. Org.

Chem., 27, 850 (1962)

Chem., 27, 850 (1962)

2-N,N-dimethylamino-propane-1,3-diol C12H14O4

O

EtOAc, EtOH 93:7 v/v%

O CH2COOH MPrd. 1

French Patent 1,481,978 (1967)

2-(2,5-dimethylbenzylamino)-1-butanol COOH NH2

COOH

C 9 H 1 1 NO 2 HN

H2O

C 1 1 H 1 3 NO 3 H2O

O

Bzbu. 1

I. A. Halmos, U. S. Patent 4,151,198

I. A. Halmos, U. S. Patent 4,151,198 (1979)

Bzbu. 2

(1979)

1-menthoxy-acetyl chloride C 8 H 9 NO 2

NH2 COOH

Mentac. 1

D. F. Holmes and R. Adams, J. Am. Chem. Soc., 56, 2093 (1934)

l-Menthylamine H3C

COOH

COOH

C8H12O2 H2O

Mentam. 1

W. H. Perkin, J. Chem. Soc., 2129 (1910)

C11H12O2 Acetone

Mentam. 2

H. Veldstra and C. van de Westeringh, Rec. Trav. Chim., 70, 1113 (1951)

© 2002 by CRC Press LLC

C11H12O2 Et 2 O

COOH

Mentam. 3

COOH

C11H12O2 H2O

A. Neville, J. Chem. Soc., 89, 383 (1906)

Mentam. 4

H. Veldstra and C. van de Westeringh, Rec. Trav. Chim., 70, 1113 (1951)

C11H20O2

COOH

O

O S

H2O

M. S. Silver and R. Sone, J. Am. Chem.

Mentam. 6

F. B. Kipping, J. Chem. Soc., 1506 (1933)

Soc., 90, 6193 (1968)

Mono-1-Menthyl-phosphate NH2

COOH

H2N

C6H14N2O2 H 2 O, EtOH 40:60 v/v %

S. Watansbe and K. Suga, Isr. J. Chem., 7,

MenP. 1

483 (1969)

N-Methyl-α α-phenylethylamine C3H16O2 H H

Acetone

COOH

Ph. D. Thesis of J. Robbins, University of

Mepeta. 1

California, Berkely, California

α-Methyl-p-nitrobenzylamine HOOC

H Mebza. 1

O

CH2COOH

C6H6O7

COOH

EtOAc

C. W. Pery and S. Teitel, U. S. Patent 3,965,129 (1976)

© 2002 by CRC Press LLC

EtOH, H 2 O 50:50 v/v%

HOOC

Mentam. 5

C16H16O4S2

(-)-(2S)-2-[2-(α αS)-(4-chlorophenyl-α α-methyl-α α-phenylbenzyloxy)ethyl]-1-methylpyrrolidine COOH H C OH HO C H COOH

Mepyr. 1

C10H11N2O4

M. Uminski, L. Synoradzki, B. Filipiak, Z. Czarnocki, M. Panasiewicz, Pol. Patent 166, 042 (1995)

N-Methyl-quinine-hydroxide C 1 1 H 1 5 BrN 2 O 3

O

MeOH

NH Br

O

N

NH

O

O

J. Knabe and K. Philipson, Arch. Pharm.,

MeQui. 1

N H

C11H18N2O3

O

Et 2 O

NH O

S

J. Knabe and W. Geismar, Arch. Pharm.

MeQui. 3

O

299, 231 (1966) C11H18N2O2S

NH O

N H

MeOH

J. Knabe and K. Philipson, Arch. Pharm.,

MeQui. 2

299, 231 (1966) O

C11H16N2O3

O

MeQui. 4

(Weinheim), 301, 682 (1968)

N H

MeOH, EtOAc

O

F. I. Carroll and R. Meck, J. Org. Chem., 34, 2676 (1969)

C12H16N2O3 H2O

O N

NH O

MeQui. 5

J. Knabe and R. Krauter, Arch. Pharm., 298, 1 (1965)

Monomethyl-tartaric acid COOH NH2

Mmeta. 1

O

IPrOH

G. Losse, R. Wagner, P. Neuland and J. Rateitschak, Chem. Ber., 91, 2410 (1958)

© 2002 by CRC Press LLC

O

C 6 H 1 3 NO 2

NH2

Mmeta. 2

benzyl

C 1 3 H 1 9 NO 2 iPrOH

G. Losse, R. Wagner, P. Neuland and J. Rateitschak, Chem. Ber., 91, 2410 (1958)

N-Methylvaline C 6 H 1 3 NO 2 COOH HN

C13H15N3O7 COOH

EtOH, EtOAc 10:90 v/v %

EtOH, EtOAc N

10:90 v/v %

O NO2 O2 N

Y. A. Ovchinnikov, V. I. Ivanov and A.

Meva. 1

Y. A. Ovchinnikov, V. I. Ivanov and A. A.

Meva. 2

A. Kiryuskin, Izv. Akad. Nauk SSSR.,

Kiryuskin, Izv. Akad. Nauk SSSR., 2046

2046 (1962)

(1962) C 6 H 1 3 NO 2

COOH

C 1 4 H 1 9 NO 5 COOH

EtOH

HN

N

Y. A. Ovchinnikov, V. I. Ivanov and A.

Meva. 3

CBZ

Y. A. Ovchinnikov, V. I. Ivanov and A. A.

Meva. 4

A. Kiryuskin, Izv. Akad. Nauk SSSR.,

Kiryuskin, Izv. Akad. Nauk SSSR., 2046

2046 (1962)

(1962) C 6 H 1 3 NO 2

COOH

C14H18N2O7 COOH

EtOH N

HN

Y. A. Ovchinnikov, V. I. Ivanov and A.

Meva. 5

EtOH

EtOH

p-nitro-CBZ

Y. A. Ovchinnikov, V. I. Ivanov and A. A.

Meva. 6

A. Kiryuskin, Izv. Akad. Nauk SSSR.,

Kiryuskin, Izv. Akad. Nauk SSSR., 2046

2046 (1962)

(1962)

1-(2-naphtyl)-ethylamine C7 H1 2 O2 O

O

H2O

H2O

O R. Sandberg, Acta Chem. Scand., 16,

2Napet. 1

2Napet. 2

1124 (1962)

HOOC

2Napet. 3

H

COOCH3

A. Fredga and R. Sandberg, Suomen Kemi,

COOH

EtOAc

M. Matsui and Y. Yamada, Agr. Biol. Chem., 27, 373 (1963)

© 2002 by CRC Press LLC

O

B31, 42 (1958) C11H16O4

H

C8 H1 2 O4

COOH

C13H10O2 MeOH

2Napet. 4

A. Fredga and T. Svensson, Arkiv Kemi, 25, 81 (1965)

C15H20O2

HOOC

EtOH

M. Nakazaki, K. Yamamoto, M. Ito and

2Napet. 5

S. Tanaka, J. Org. Chem., 42, 3468 (1977)

1-α α-Naphtylethylamine H

O

EtOH

E. J. Corey, E. J. Trybulski, L. S. Melvin,

Napeta. 1

C5H8O2S

C4 H6 O3

COOH H

S

Napeta. 2

Jr., K. C. Nicolsou, J. A. Secrist, R. Lett,

COOH

EtOH

G. Cleason and H-G. Jonsson, Arkiv Kemi, 26, 247 (1966)

P. W. Sheldrake, J. R. Felck, D. J. Brunelle, M. F. Haslanger, S. Kim, and S. Yoo, J. Am. Chem. Soc., 100, 4618 (1978)

O O

C8 H1 0 O2

C8 H1 2 O2

EtOAc

Acetone

COOH E. J. Corey and B. B. Snider, J. Org.

Napeta. 3

Napeta. 4

R. Sandberg, Arkiv Kemi, 17, 327 (1961)

Chem., 39, 256 (1974) CF3 COOH OH

C8 H7 F3 O3 Benzene, EtOH 86:14 v/v%

J. A. Dale, D. L. Dull and H. S. Mosher, J.

Napeta. 5

C10H16O2 H HOOC

Napeta. 6

abs. EtOH H

German Patent 2,300,325 (1975)

Org. Chem., 34, 2543 (1969)

N H

Napeta. 7

COOH

C 1 3 H 1 2 ClNO 2

Cl COOH

Acetone

L. Berger and A. J. Corraz, U. S. Patent 3,868,387 (1975)

© 2002 by CRC Press LLC

C16H20O2 CH3CN

Napeta. 8

P. F. Juby, W. R. Goodwin, T. W. Hudyma and R. A. Partyka, J. Med. Chem., 15, 1297 (1972)

C21H29O4

C13H12O3

Hexane

MeOH

OCH3 H

H H3CO

COOH OCH3

T. Y. Jen, G. A. Hughes and H. Smith, J.

Napeta. 9

COOH

X. Borde, C. Nugier-Chauvin, N. Noiret

Napeta. 10

Am. Chem. Soc., 89, 4551 (1967)

and H. Patin, Tetrahedron Asymmetry, 9, 1087 (1998)

Ph

C 1 1 H 1 1 ClO 2

COOH

OH

EtOH

COOH

Cl

N Y. Nishii, K. Wakimura, T. Tsuchiya, S.

Napeta. 11

Napeta. 12

T. Takeuchi, T. Aoyanagi, Y. Muraoka and

Nakamura and Y. Tanabe, J. Chem. Soc.,

M. Tsuda, Jpn. Kokai Tokkyo Koho JP 04

Perkin Trans. 1, 1243 (1996)

01, 162 (1992)

C 1 4 H 1 9 NO 6

OH COOH NH p-methoxy-CBZ

Napeta. 13

C 5 H 1 1 NO 3

T. Takeuchi, T. Aoyanagi, Y. Muraoka and M. Tsuda, Jpn. Kokai Tokkyo Koho JP 04 01, 162 (1992)

NBPA C11H12O3S

O COOH

S

iPrOH

J. P. M. Houbiers, European Patent Appl.

NBPA. 1

81200234.3(1981)

N-benzyl-α α-phenylethylamine O

Cl

COOH

HN

N

Nbzpea. 1

NH2

EtOH

O

E. Juaristi et al., Tetrahedron Asymmetry, 9, 715 (1998)

© 2002 by CRC Press LLC

C10H11N2O4

α-Methyl-p-nitrobenzylamine HOOC

O

HOOC

COOH

C6H6O7

HO

H 2 O, MeOH

H

2:98 v/v %

C. W. Perry, A. Brossi, K. H. Deitcher,

Nbza. 1

C6H6O7

O

HOOC

EtOH

O

HOOC C. W. Perry, A. Brossi, K. H. Deitcher, W.

Nbza. 1

W. Tautz and S. Teitel, Synthesis, 492

Tautz and S. Teitel, Synthesis, 492 (1977)

(1977) NH2 COOH Cl

C 1 1 H 1 1 ClN 2 O 2 Ethyl methyl ketone

N H

C. W. Perry, A. Brossi, K. H. Delitcher,

Nbza. 3

W. Tautz and S. Teitel, Synthesis, 492 (1977)

N-Methyl-D-glucamine [=1-deoxy-1-(methylamino)-D-glucitol] C14H14O3 COOH

HO

NH2 Cl

MeOH

C 1 0 H 1 3 Cl 2 NO abs. EtOH

H3CO

Cl

E. Felder, D. Pitré and H. Zutter, U. K.

Ngluc. 1

M. Descamps, J. Radisson and G. Anne-

Ngluc. 2

Pat. Appl. GB 2025968A (1980)

Archard, U. S. Patent 5, 512, 680 (1996)

Nopinylamine, (6,6-Dimethylbicyclo[3.1.1]-hept-2-ylamine C6H10O3

OH

H2O O Nopa. 1

O J. Paust, S. Pfohl, W. Reif and W. Schmidt, Liebigs Ann. Chem., 1024 (1978)

1-Norephedrine NH2

COOH

C 5 H 1 2 NO 2 S

HN

EtOAc

COOH

SH

Neph. 1

O

C 6 H 1 2 NO 3 S EtOAc

SH

French Patent 2,148,050 (1973)

© 2002 by CRC Press LLC

Neph. 2

French Patent 2,148,050 (1973)

O

C 9 H 1 1 NO 4 S

O S

N H

COOH

H2O

COOH

Acetone HOOC

C. S. Gibson and B. Levin, J. Chem. Soc.,

Neph. 3

Neph. 4

2754 (1929) C14H20O3 COOH

Neph. 5

J. Owen and J. L. Simonsen, J. Chem. Soc., 1223 (1933)

OH

CH3CN

K. S. Fors, J. R. Gage, R. F. Heier, R. C. Kelly, W. R. Perrault and N. Wicnienski, J. Org. Chem., 63, 7348 (1998)

(+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline C10H11N2O4

OCH3

abs. EtOH H H C S

OH COOH NH2

Hoffman-La Roche AG, 91-08075/11, (C91-

8HiQui. 1

034411)

Ornithine C 4 H 7 NO 5

OH HOOC

COOH

H 2 O, MeOH

NH2

H. Okai, N. Imamura and N. Izumiya, Bull.

Ornit. 1

Chem. Soc. Japan, 40, 2154 (1967)

Pavine C 1 0 H 1 4 BrO 4 S

HO3S O

H2O

Br

Pav. 1

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C9H14O4

W. J. Pope and J. Read, J. Chem. Soc., 97, 2199 (1910)

Phenylalaninamide C 5 H 9 NO 4

NH2

H2O

COOH

HOOC

T. Kato and Y. Tsuchiya, Agr. Biol. Chem.,

Phalm. 1

26, 473 (1962)

(R)-2-Phenylglycinol C7H6N2O4

H HOOC

O

EtOH, H 2 O

O H

H

N

83:17 v/v%

N O

Phglyol. 1

J. A. Monn, M. J. Valli, S. M. Massey, M. M. Hansen, T. J. Kress, J. P. Wepsiec, A. R. Harkness, J. L. Grutsch, Jr., R. A. Wright, B. G. Johnson, S. L. Andis, A. Kingston, R. Tomlinson, R. Lewis, L. R. Griffey, J. P. Tizzano and D. D. Schoepp, J. Med. Chem., 42, 1027 (1999)

β-Phenylisopropylamine C 6 H 1 1 NO 3 S COOH

O

N

EtOAc, MeOH

COOH

Cl

S

C 9 H 9 ClO 3

O

EtOH, H 2 O 50:50 v/v%

M. Matell, Acta Chem. Scand., 14, 677

PhiPra. 1

M. Matell, Arkiv Kemi, 7, 437 (1954)

PhiPra. 2

(1960) C 9 H 9 NO 5

O COOH

EtOH

NO2 PhiPra. 3

C10H12O4 COOH

44:56 v/v%

OCH3 A. Fredga, Acta Chem. Scand., 23, 2216

A. Fredga, I. Kiriks and C. Lundstrom,

PhiPra. 4

(1969)

Arkiv Kemi, 25, 249 (1966) C11H14O3

O COOH

© 2002 by CRC Press LLC

EtOH, H 2 O

O

COOH

C13H18O3

EtOH, H2O

EtOH, H2O

50:50 v/v%

20:80 v/v%

A. Fredga and F. Plénat, Arkiv Kemi, 24,

PhiPra. 5

M. Matell, Arkiv Kemi, 8, 79 (1955)

PhiPra. 6

577 (1965)

C12H10O2

H COOH

COOH

O

MeOH

C12H16O3 EtOH, H2O 30:70 v/v%

PhiPra. 7

A. Fredga, Arkiv Kemi, 12, 547 (1958) COOH

O

PhiPra. 8

M. Matell, Arkiv Kemi, 6, 375 (1953)

C16H18O3 EtOH, H2O 70:30 v/v%

PhiPra. 9

M. Matell, Arkiv Kemi, 6, 375 (1953)

(-)-1-phenyl-propylamine C16H14O3 EtOAc

COOH

benzoyl Nissan Chem IND KK, 91-018170/03, NISC

PhPra. 1

17,10,89, C91-007644

(-)-(p-hydroxyphenyl)glycine C13H19O5P

O

C 1 1 H 1 4 ClO 4 P

Cl

EtOH, H2O

O

O

O

50:50 v/v%

Phgly. 1

OH

O

W. ten Hoeve, H. Wynberg, J. Org. Chem., 50, 4508 (1985) C 1 1 H 1 4 NO 6 P NO2

O

EtOH, H2O O

96:4 v/v%

P O

Phgly. 3

O

54:46 v/v%

P

P O

EtOH, H2O

OH

W. ten Hoeve, H. Wynberg, J. Org. Chem., 50, 4508 (1985)

© 2002 by CRC Press LLC

Phgly. 2

OH

W. ten Hoeve, H. Wynberg, J. Org. Chem., 50, 4508 (1985)

α-(p-nitrophenyl)ethylamine C11H16O2 Et2O COOH V. Rozenberg, N. Dubrovina, E. Sergeeva, D.

pnietam. 1

Antonov and Y. Belokon, Tetrahedron Asymmetry, 9, 653 (1998)

Prolin COOH

C10H10O4

C10H10O4

COOH

HOOC

iPrOH

iPrOH

COOH

Prol. 1

T. Shiraiwa, Y. Sado, S. Fuji, M.

Prol. 2

Nakamura and H. Kurokawa, Bull. Chem.

R. Stephani and V. Cesare, Journal of Chemical Education, 74, 1226, (1997)

Soc. Jpn., 60, 824 (1987) COOH

HOOC

C10H10O4 iPrOH or EtOH

Prol. 3

T. Shiraiwa, Y. Sado, S. Fuji, M. Nakamura and H. Kurokawa, Bull. Chem. Soc. Jpn., 60, 824 (1987)

threo-2-amino-1-(p-methylmercaptophenyl)-1,3-propanediol HO

COOH NH2

PrSHd. 1

C3 H7 NO3 MeOH

B. F. Tullar, U. S. Patent 3,056,799

COOH

HO HN

PrSHd. 2

C1 0 H1 1 NO4 MeOH

benzoyl

B. F. Tullar, U. S. Patent 3,056,799 (1962)

(1962)

HO

COOH NH2

PrSHd. 3

C 4 H 9 NO 3 MeOH

B. F. Tullar, U. S. Patent 3,056,799 (1962)

© 2002 by CRC Press LLC

COOH

HO HN

PrSHd. 4

C 1 1 H 1 3 NO 4 MeOH

benzoyl

B. F. Tullar, U. S. Patent 3,056,799 (1962)

C 5 H 1 1 NO 2

COOH NH2

EtOH, H2O

EtOH

COOH

95:5 v/v %

B. F. Tullar, U. S. Patent 3,056,799

PrSHd. 5

C 6 H 1 3 NO 2

NH2

B. F. Tullar, U. S. Patent 3, 056, 799 (1962)

PrSHd. 6

(1962) NH2

C 8 H 1 5 NO 2

O

EtOH

HN

COOH

G. Amiard, R. Heymes and L. Velluz, U. S.

PrSHd. 8

(1962) H N

H2O

N H

B. F. Tullar, U. S. Patent 3, 056, 799

PrSHd. 7

C11H12N2O2

COOH

Patent 2,797,226 (1957) C12H12N2O3

O

COOH

H2O

N H

G. Amiard, R. Heymes and L. Velluz, U.

PrSHd. 9

S. Patent 2,797,226 (1957)

threo-2-amino-1-(p-methylsulphonylphenyl)-1,3-propanediol COOH

HOOC

NH2

C 4 H 7 NO 4

C 4 H 9 NO 3

OH

COOH

H2O

MeOH

NH2

B. F. Tullar, U. S. Patent 3,056,799

Prsud. 1

Prsud. 2

B. F. Tullar, U. S. Patent 3,056,799 (1962)

(1962) C 1 1 H 1 3 NO 4

OH

COOH HN

MeOH

COOH

C 4 H 9 NO 3 EtOH

NH2

benzoyl

B. F. Tullar, U. S. Patent 3,056,799

Prsud. 3

HO

Prsud. 4

B. F. Tullar, U. S. Patent 3,056,799 (1962)

(1962) COOH

HO HN

Prsud. 5

C 1 1 H 1 3 NO 4

S

COOH NH2

EtOH

C 5 H 1 1 NO 2 S MeOH

benzoyl

B. F. Tullar, U. S. Patent 3,056,799 (1962)

© 2002 by CRC Press LLC

Prsud. 6

B. F. Tullar, U. S. Patent 3,056,799 (1962)

COOH

S HN

C 7 H 1 3 NO 3 S MeOH

O

B. F. Tullar, U. S. Patent 3,056,799

Prsud. 7

(1962)

Pseudoephedrine COOH

C 1 0 H 1 1 ClO 3

C15H20O5

EtOH, H 2 O

O

O

40:60 v/v%

COOEt COOH

Et 2 O

Cl

A. Fredga, A. Kijellqvist and E.

Pseph. 1

Pseph. 2

Tornqvist, Arkiv Kemi, 32, 301 (1970)

P. A. Stadler, St. Guttmann. H. Hauth, R. L. Hugguenin, E. Sandrin, G. Wersin, H. Willems and A. Hofmann, Helv. Chim. Acta, 52, 1549 (1969)

O

C17H12O3 EtOAc

HOOC

S. Haginshita and K. Kuriyama, J. Chem.

Pseph. 3

Soc. Perkin Trans. 2, 59 (1978)

α-phenyl-β β-(p-tolyl)-ethylamine C6H10O3

C10H16O2

H

H2O

O

OH

H

Acetone

HOOC

O

K. Mori, T. Takigawa and T. Matsuo,

Pteta. 1

Pteta. 2

Tetrahedron, 35, 933 (1979)

K. Okada, K. Fujimoto, Y. Okuno and M. Matsui, Agr. Biol. Chem., 37, 2235 (1973)

C 1 1 H 1 3 BrO 2 COOH

C11H14O2

COOH

EtOH, H 2 O 60:40 v/v%

EtOH, H 2 O 60:40 v/v%

Br Pteta. 3

M. Miyakado, N. Ohno, Y. Okuno, M. Hirano, K. Fujimoto and H. Yoshioka, Agr. Biol. Chem., 39, 267 (1975)

© 2002 by CRC Press LLC

Pteta. 4

M. Miyakado, N. Ohno, Y. Okuno, M. Hirano, K. Fujimoto and H. Yoshioka, Agr. Biol. Chem., 39, 267 (1975)

C12H16O3 COOH

EtOH, H 2 O 60:40 v/v%

OCH3

Pteta. 5

M. Miyakado, N. Ohno, Y. Okuno, M. Hirano, K. Fujimoto and H. Yoshioka, Agr. Biol. Chem., 39, 267 (1975)

2-Pyrrolidone-5-carboxylic acid S

C 5 H 1 1 NO 2 S

COOH NH2

Pyca. 1

NH2

COOH

H2N

Japanese Patent 45-32250 (1970)

NH2

H2N

MeOH

O

Pyca. 3

U. S. Patent 3,773,786 (1973)

Quinine methochloride NC

C 7 H 1 1 NO 2

COOH

CH3CN J. E. Baldwin, D. H. R. Barton and J.

QiCl. 1

Sutherland, J. Chem. Soc., 1787 (1965)

Quinotoxine HO H

Qitox. 1

COOH H OH COOH

C4H6O5 Benzene, H 2 O

R. B. Woodward and W. E. Doering, J. Am. Chem. Soc., 67, 860 (1945)

© 2002 by CRC Press LLC

MeOH

U. S. Patent 3,773,786 (1973)

Pyca. 2

C6H16N3O

NH2

C6H14N2O2

N-Salicyliden-D-p-Hydroxy-phenylglycin COOH

C 9 H 1 1 NO 2

COOH

H2O

NH2

H2O

HN

German Patent 2749203 (1977)

SPhgly. 1

C 1 0 H 1 3 NO 2

German Patent 2749203 (1977)

SPhgly. 2

Tartaric acid COOH

HS

C 3 H 7 NO 2 S EtOH

NH2

G. Losse and G. Moschall, J. Prakt.

Tarta. 1

C 1 2 H 1 7 NO 2 S

NH2

S

COOEt

G. Losse and G. Moschall, J. Prakt. Chem.,

Tarta. 2

Chem., 7, 38 (1958)

7, 38 (1958) C 5 H 7 NO 2

N H

COOH

C 5 H 9 NO 2

H2O

U. O. Hengartner, U. S. Patent 4,111,951

Tarta. 3

COOH

N H

S. Yamada, C. Hogo and I. Chibata, Agric.

Tarta. 4

Biol. Chem., 41, 2413 (1977) C 5 H 1 1 NO 2

COOH

COOBz

COOH

C 5 H 1 1 NO 2 S

G. Losse, R. Wagner, P. Neuland and J.

Tarta. 7

Rateitschak, Chem. Ber., 91, 2410 (1958) COOCH3

S

MeOH

NH2

COOH

C 6 H 1 3 NO 2 S MeOH

NH2

G. Losse, R. Wagner, P. Neuland and J.

Tarta. 8

Rateitschak, Chem. Ber., 91, 2410 (1958) S

MeOH, EtOH

G. Losse, R. Wagner, P. Neuland and J.

Tarta. 6

Rateitschak, Chem. Ber., 91, 2410 (1958) S

C 1 2 H 1 7 NO 2

NH2

MeOH, EtOH

G. Losse, R. Wagner, P. Neuland and J.

Tarta. 5

EtOH, H 2 O 78:22 v/v %

(1978) NH2

EtOH

Rateitschak, Chem. Ber., 91, 2410 (1958) O

C 5 H 1 1 NO 2 S

S

NH2

C 5 H 1 2 N 2 OS NH2

NH2

S. Tattsuoka, M. Honjo, Yakugaku

Tarta. 9

S. Tattsuoka, M. Honjo, Yakugaku Zasshi,

Tarta. 10

Zasshi, 73, 357 (1953) N

H2N

73, 357 (1953)

C6H9N3O2 COOH

N H

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H2O

COOH

H

N H

H

C 6 H 1 1 NO 2 MeOH

Tarta. 11

F. L. Pyman, J. Chem. Soc., 99, 1386

C. G. Overberger, K.-H. David and J. A.

Tarta. 12

Moore, Macromolecules, 5, 368 (1972)

(1911); R. M. Conrad, C. P. Berg, J., Biol., Chem., 117, 351 (1937) COOCH3 H

N H

Tarta. 13

C 7 H 1 3 NO 2

H

COOH

MeOH

H

C. G. Overberger, K.-H. David and J. A.

H3CO

Tarta. 15

COOH NH2 OCH3

C 1 3 H 1 9 NO 5 abs. EtOH

85:15 v/v % C. G. Overberger, K.-H. David and J. A.

Tarta. 14

Moore, Macromolecules, 5, 368 (1972) H3CO

Acetone, MeOH

H

N H

C 6 H 1 1 NO 2

Moore, Macromolecules, 5, 368 (1972) H3CO

COOH NH2 OCH3

H3CO

D. G. Musson, D. Karashima, H. Rubiero, Tarta. 16 L. L. Melmon, A. Cheng and N. Castagnoli, Jr., J. Med. Chem., 23, 1318 (1980)

C 1 3 H 1 9 NO 5 abs. EtOH

D. G. Musson, D. Karashima, H. Rubiero, L. L. Melmon, A. Cheng and N. Castagnoli, Jr., J. Med. Chem., 23, 1318 (1980)

α-Phenylethyl-thiuronium-acetat COOH

C 9 H 1 1 NO 2

NH2

COOH

C 1 0 H 1 1 NO 3

O

MeOH, H 2 O

HN

MeOH

13:87 v/v% Phthi. 1

W. Klötzer, Mönatsh. Chem., 87, 346

W. Klötzer, Mönatsh. Chem., 87, 346

Phthi. 2

(1956)

(1956)

Thiuronium chloride C8 H1 2 O2 MeOH

COOH R. Sandberg, Arkiv Kemi, 17, 327 (1961)

ThiCl. 1

Tyrosinamide NH2 HOOC

C 5 H 9 NO 4

COOH

C 5 H 1 1 NO 2 COOH

H2O

MeOH

NH2

Tyram. 1

T. Kato and Y. Tsuchiya, Agr. Biol. Chem., 26, 473 (1962)

© 2002 by CRC Press LLC

Tyram. 2

T. Kato and Y. Tsuchiya, Agr. Biol. Chem., 26, 467 (1962)

C 7 H 1 3 NO 3 COOH

MeOH

HN O

T. Kato and Y. Tsuchiya, Agr. Biol.

Tyram. 3

Chem., 26, 467 (1962)

Tyrosinhydrazid C 3 H 7 NO 2

NH2

EtOH

COOH

K. Vogler and P. Lanz, Helv. Chim. Acta,

Tyroh. 1

Tyroh. 2

Tyroh. 3

MeOH

Z. Grzonka and B. Liberek, Tetrahedron, 27, 1783 (1971) NH2

C 4 H 7 NO 2 MeOH

NH

N N N

H2N

49, 1348 (1966) COOH

C3H7N5

N

C 4 H 7 NO 2

COOH

HO

MeOH

OH

R. M. Rodebaugh and N. H. Cromwell, J.

Tyroh. 4

Heterocycl. Chem., 6, 993 (1969)

K. Okawa, K. Hori, K. Hirose and Y. Nakagawa, Bull. Chem. Soc. Japan, 42, 2720 (1969)

C 5 H 9 NO 2 N H

Tyroh. 5

COOH

MeOH

K. Vogler and P. Lanz, Helv. Chim. Acta.

C 5 H 9 NO 4

NH2 HOOC

Tyroh. 6

COOH

H2O

I. Sollin, U. S. Patent 2,945,879 (1960)

49. 1348 (1966) C 6 H 1 3 NO 2

NH2

COOH

Tyroh. 7

NH2

MeOH

K. Vogler and P. Lans, Helv. Chim. Acta,

Tyroh. 8

49, 1348 (1966) COOH

HOOC

HN

Tyroh. 9

CBZ

C 6 H 1 5 NO 4 MeOH

S. Hase, R. Kiyoi and S. Sakakibara, Bull. Chem. Soc. Japan., 41, 1266 (1968)

C 1 4 H 2 1 NO 7 MeOH

S. Hase, R. Kiyoi and S. Sakakibara, Bull. Chem. Soc. Japan., 41, 1266 (1968)

© 2002 by CRC Press LLC

COOH

HOOC

tBuOOC

tBuOOC

Tyroh. 10

HN

COOBz COOH

C 2 2 H 3 1 NO 8 abs. MeOH

N. T. Boggs, B. Godlsmith, R. W. Gawley, K. A. Koehler and R. G. Hiskey, J. Org. Chem., 44, 2262 (1979)

Yohimbine COOH

C 9 H 7 Cl 3 O 3

COOH

O

H 2 O, EtOH

O Cl

C9H10O3 CCl4, Cyclohexane

75:25 v/v%

Cl Cl M. S. Smith, R. L. Wain and F.

Yohi. 1

A. Fredga and M. Matell, Arkiv Kemi, 4,

Yohi. 2

Wightman, Ann. Appl. Biology, 39, 295

325 (1952)

(1952)

Brucine CH 2 ClIO 3 S

Cl

H2O

SO3H

I

J. Read and A. M. McMath, J. Chem.

Bruc. 1

Br

Bruc. 2

Soc., 2723 (1932) C 2 H 2 ClIO 2

W. J. Pope and J. Read, J. Chem. Soc., 105,

A. M. McMath and J. Read, J. Chem.

COOH

Cl

MeOH

COOH

Bruc. 3

H2O

COOH

811 (1914)

Cl

I

C 2 H 2 BrClO 2

Cl

H2O

OH

Bruc. 4

C 3 H 5 ClO 3

S. Tsunoo, Chem. Ber., 68, 1341 (1935)

Soc., 537 (1927) C3H6O4

COOH

HO

EtOH

OH

C. Neuberg and M. Silbermann, Chem.

Bruc. 5

C 3 H 7 NO 2

NH2

H2O

COOH

Bruc. 6

Ber., 37, 339 (1904)

M. S. Dunn, M. P. Stoddard, L. B. Rubin and R. C. Bovie, J. Biol. Chem., 151, 241 (1943)

HN

C 1 0 H 1 1 NO 3

benzoyl

H2O

COOH

M. S. Dunn, M. P. Stoddard, L. B. Rubin

Bruc. 7

HS

COOH NH2

Bruc. 8

and R. C. Bovie, J. Biol. Chem., 151, 241

C 3 H 7 NO 2 S MeOH

L. H. Werner, A. Wettstein and K. Miescher, Helv. Chim. Acta, 30, 432 (1947)

(1943) C 1 3 H 1 7 NO 3 S bz

S HN

COOH O

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MeOH

HO

COOH NH2

C3 H7 NO3 EtOH

L. H. Werner, A. Wettstein and K.

Bruc. 9

E. Wunsch and G. Fürst, Z. Physiol. Chem.,

Bruc. 10

Miescher, Helv. Chim. Acta, 30, 432

329, 109 (1962)

(1947); V. du Vigneaud, W.I. Patterson, J. Biol. Chem., 109, 97 (1935) HO HN

COOBz

C1 1 H1 3 NO3

O

EtOH

E. Wunsch and G. Fürst, Z. Physiol.

Bruc. 11

COOH HN

A. Stoll and Th. Petrzilka, Helv. Chim.

Bruc. 12

Acta, 35, 589 (1952)

C1 0 H1 3 NO6 MeOH

tosylate

A. Stoll and Th. Petrzilka, Helv. Chim.

Bruc. 13

MeOH

NH2

Chem., 329, 109 (1962) HO

C3 H7 NO3

COOH

HO

C3 H8 NO6 P

NH2 O

HOOC

Bruc. 14

Acta, 35, 589 (1952);

OH P O OH

MeOH

P. A. Levene and a. Schormüller, J. Biol. Chem., 106, 595 (1934)

E. Fischer and W.A. Jacobs, Chem. Ber., 39, 2942 (1906)

Cl HO

COOH H H COOH

C4 H5 ClO5 EtOH, H 2 O

HO

Bruc. 16

Ber., 61B, 481 (1928) O

H

Bruc. 17

COOH H

C4 H6 O3 MeOH

K. Harads and J. Oh-hashi, Bull. Chem.

Bruc. 19

COOH SH H COOH

R. A. Darrall, F. Smith, M. Stacey and J. C.

H HS

Bruc. 18

COOH SH H COOH

MeOH

(1969) COOH

MeOH

Brossi, Helv. Chim. Acta, 44, 955 (1961)

C4 H6 O4 S2

M-O. Hedblom, Arkiv Kemi, 31, 489

C4 H6 O4 S2

M. Gerecke, E. A. H. Friedheim and A.

© 2002 by CRC Press LLC

MeOH

Tatlow, J. Chem. Soc., 2329 (1951)

Soc. Japan, 39, 2311 (1966)

H HS

COOH

23:77 v/v %

R. Kuhn and T. Wagner - Jauregg, Chem.

Bruc. 15

C4 H5 F3 O3

CF3

Br

C 4 H 7 BrO 2 Acetone, CHCl 3 83:17 v/v %

Bruc. 20

P. A. Levene and M. Kuna, J. Biol. Chem., 141, 391 (1941)

COOH

HOOC

C 4 H 7 NO 4

NH2

H2O

E. Fischer, Chem. Ber., 32, 2451 (1899)

Bruc. 21

COOH NH2 H COOH

H H2N

C4H8N2O4 Acetone, H 2 O 90:10 v/v %

J. F. Biernat and S. Ludwicka, Pol. J.

Bruc. 22

Chem., 46, 1151 (1972) C4H8O3

COOH

H2O

OH

A. Kjaer, B. W. Christensen and S. E.

Bruc. 23

OH

COOH

HO

C4H8O4 H 2 O, EtOH

J. W. E. Glattfield and F. V. Sander, J. Am.

Bruc. 24

Hansen, Acta Chem. Scand., 13, 144

Chem. Soc., 43, 2675 (1921)

(1959) OH

C4H8O4

COOH

HO

OH

H 2 O, EtOH

J. W. E. Glattfield and F. V. Sander, J.

Bruc. 25

COOH

HO

C4H8O5S

COOH

Chem. Soc., 42, 2314 (1920) COOH

H2N

K. Balenovic and N. Bregant, Tetrahedron,

Bruc. 28

Chim., 45, 110 (1926) O

5, 44 (1959) NH2

C 1 2 H 1 1 NO 4 EtOH

N

C 4 H 9 NO 2 EtOH

H2O

H. J. Backer and A. Bloemen, Rec. Trav.

Bruc. 27

H2O

J. W. E. Glattfield and G. E. Miller, J. Am.

Bruc. 26

Am. Chem. Soc., 43, 2675 (1921) SO3H

C4H8O4

COOH

HS

C 4 H 9 NO 2 S Acetone, H 2 O

COOH

40:60 v/v %

O

K. Balenovic and N. Bregant,

Bruc. 29

D. Keglevic and B. Ladesic, Croat. Chem.

Bruc. 30

Tetrahedron, 5, 44 (1959) bz

C 1 2 H 1 5 NO 3 S

COOH

S HN

Acta, 31, 57 (1959)

COOH

Acetone, H 2 O

O

NH2

40:60 v/v % D. Keglevic and B. Ladesic, Croat. Chem.

Bruc. 31

HN

phtaloyl

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monomethylether

42, 209 (1959) C 1 2 H 1 3 NO 7

COOH

Etyleneglycol-

K. Vogler and P. Lanz, Helv. Chim. Acta,

Bruc. 32

Acta, 31, 57 (1959) OH

C 4 H 9 NO 3

OH

Etyleneglycolmonomethylether

C 4 H 9 NO 3

OH

COOH NH2

MeOH

K. Vogler and P. Lanz, Helv. Chim. Acta,

Bruc. 33

A. J. Zambito, W. L. Peretz and E. E.

Bruc. 34

42, 209 (1959) OH COOH

Howe, J. Am. Chem. Soc., 71, 2541 (1949) C11H12N2O6

COOH

MeOH

NH

C 4 H 9 NO 3

OH

MeOH

NH2

O O2N

A. J. Zambito, W. L. Peretz and E. E.

Bruc. 35

M. Brenner, K. Rüfenacht and E. Sailer,

Bruc. 36

Howe, J. Am. Chem. Soc., 71, 2541

Helv. Chim. Acta, 34, 2102 (1951)

(1949) C 1 1 H 1 5 NO 6 S

OH

COOH HN

COOH

MeOH

NH2

tosylate

M. Brenner, K. Rüfenacht and E. Sailer,

Bruc. 37

C 4 H 9 NO 3

OH

Bruc. 38

Etyleneglycolmonomethylether

H. Arold, J. Prakt. Chem., 24, 23 (1964)

Helv. Chim. Acta, 34, 2102 (1951)

COOH HN

phtaloyl

Etyleneglycol-

C 4 H 9 NO 3

COOH

HO

MeOH

monomethylether

H. Arold, J. Prakt. Chem., 24, 23 (1964)

Bruc. 39

NH2

C 1 2 H 1 3 NO 7

OH

Bruc. 40

S. Weiss and J. A. Stekol, J. Am. Chem. Soc., 73, 2497 (1951)

COOH

HO

C11H12N2O6

NH

MeOH

O2N

C 4 H 9 NO 3

COOH

H2N

EtOH

OH

O

S. Weiss and J. A. Stekol, J. Am. Chem.

Bruc. 41

Bruc. 42

Soc., 73, 2497 (1951)

O HN O

N H

H N

O

M. Tomita and Y. Sendju, Z. Physiol. Chem., 169, 263 (1927)

C11H12N2O6 H2O

H HOOC

NH

COOH H

C5H6O4 H2O, EtOH 70:30 v/v %

O

EtOH, EtOAc 33:67 v/v %

Bruc. 43

W. J. Pope and J. B. Whitworth, Chem. Ind. (London), 49, 748 (1930)

© 2002 by CRC Press LLC

Bruc. 44

W. von E. Doering and K. Sachdev, J. Am. Chem. Soc., 96, 1168 (1974)

S S

C5H6O4S2

HOOC

COOH

H2O, MeOH

HO

L. Schotte, Arkiv Kemi 9, 429 (1957)

O

O

62:38 v/v % Bruc. 45

C5H6O5

COOH

H2O, MeOH 70:30 v/v %

S-H. K. Suh and G. Hie, J. Pharm. Sci. 60,

Bruc. 46

930 (1971) COOH

HOOC

S

S

C5H6O4S2

C5H8N2O3

HOCH2 O

HN

MeOH

O

M-O. Hedblom, Arkiv Kemi, 31, 489

Bruc. 47

Bruc. 48

EtOH

N H

N. Takamura, S. Terashima, K. Achiwa and S. Yamada, Chem. Pharm. Bull., 15, 1776

(1969)

(1967) OH

C5H8O2S COOH

S

EtOH

G. Cleason and H-G. Jonsson, Arkiv

Bruc. 49

Bruc. 50

Kemi, 26, 247 (1966) OH

S. Tatsumi, M. Imaida and Y. Izumi, Bull.

Bruc. 52

H2O H. A. Barker, Biochem. Prep., 9, 25

Bruc. 53

C5H8O5 COOH

H2O E. B. Abbot, E. A. Kidney and A. McKenzie, Chem.Ber., 71, 1210 (1938) OH

C5H8O5 COOH

HOOC

S. Tatsumi, M. Imaida and Y. Izumi, Bull.

HOOC

Chem. Soc. Japan, 39, 1818 (1966) OH

H2O

OH

C5H8O5 H2O

Bruc. 51

C5H8O5

Chem. Soc. Japan, 39, 1818 (1966)

COOH

HOOC

COOH

HOOC

HOOC

Bruc. 54

C5H8O6

COOH OH

H2O

S. Tasumi, Y. Izumi, M. Imaida, Y. Fukuda and S. Akabori, Bull. Chem. Soc. Japan, 39,

(1962)

602 (1966) OH HOOC

C5H8O6

COOH OH

C 5 H 9 BrO 2 COOH

H2O

Acetone

Br

Bruc. 55

S. Tasumi, Y. Izumi, M. Imaida, Y. Fukuda and S. Akabori, Bull. Chem. Soc. Japan, 39, 602 (1966)

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Bruc. 56

P. A. Levene, T. Mori, and L. A. Mikeska, J. Biol. Chem., 75, 337 (1927)

C 5 H 9 NO 2 COOH

N H

Acetone

C12H11N3O7 COOH

N

Acetone

O2N

O

NO2

O. Kovacs, M. Halmos and G. Bernath,

Bruc. 57

O. Kovacs, M. Halmos and G. Bernath,

Bruc. 58

Acta Phys. Chem., 3, 118 (1957) O

C 5 H 9 NO 2 NH2

HOOC

Acta Phys. Chem., 3, 118 (1957) C 5 H 9 NO 3

HO

MeOH

COOH

N H R. Adams and D. Fles, J. Am. Chem.

Bruc. 59

Dioxane, H 2 O 95:5 v/v %

O. Kovacs, M. Halmos and G. Bernath,

Bruc. 60

Soc., 81, 4946 (1959)

Acta Univ. Szeg., Acta Phys. Chem. 3, 118 (1957)

HO

C 1 2 H 1 1 NO 8 COOH

N O 2N

O

COOH

HO

Dioxane, H 2 O

O

NH2

95:5 v/v %

C 5 H 9 NO 4 EtOH, Et2O 10:90 v/v %

NO2

O. Kovacs, M. Halmos and G. Bernath,

Bruc. 61

A. Miyako, Chem. Pharm. Bull., 8, 1074

Bruc. 62

Acta Univ. Szeg., Acta Phys. Chem. 3,

(1960)

118 (1957) COOH

HO O

HN

C 7 H 1 1 NO 4 EtOH, Et2O

O

Bruc. 64

COOH

C 6 H 9 NO 5

O

MeOH

N

P. A. Stadler and A. Hofmann, helv. Chim. Acta, 45, 2005 (1962)

(1960) HOOC

C 5 H 9 NO 4 MeOH

HN

10:90 v/v %

A. Miyako, Chem. Pharm. Bull., 8, 1074

Bruc. 63

COOH

HOOC

NH2 OH HOOC

COOH

C 5 H 9 NO 5 EtOH, H 2 O 95:5 v/v %

P. A. Stadler and A. Hofmann, Helv.

Bruc. 65

Chim. Acta, 45, 2005 (1962) CBZ HOOC

NH

OH

COOH

C 1 3 H 1 5 NO 8 EtOH, H 2 O 95:5 v/v %

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Bruc. 66

Y. K. Lee and T. Kaneko, Bull. Chem. Soc. Japan, 46, 3494 (1973)

COOH

C 5 H 1 0 NO 2 H2O

Y. K. Lee and T. Kaneko, Bull. Chem.

Bruc. 67

O. Schutz and W. Marckwald, Chem. Ber.,

Bruc. 68

Soc. Japan, 46, 3494 (1973)

29, 52 (1896)

C5H10O2

COOH

COOH OH

H2O K. Freudenberg and W. Lwowski, Liebigs

Bruc. 69

D. H. G. Crout and D. Whitehouse, J.

Bruc. 70

Ann. Chem.,592, 76 (1955)

Chem. Soc., Perkin 1, 544 (1977)

C5H10O4

OH

SO3H COOH

EtOH, CHCl 3

COOH

C5H10O3

C5H10O5

OH

F. Kogl, H. Duisberg and H. Erxleben.

Bruc. 71

H. J. Backer and D. van der Veen, Rec.

Bruc. 72

Liebigs Ann. Chem., 489, 156 (1931)

Trav. Chim., 55, 887 (1936)

C 5 H 1 1 NO 2

COOH

COOH

EtOH

E. Fischer and R. von Gravenitz, Liebigs

Bruc. 73

EtOH O

NH2

N H

E. Fischer and R. von Gravenitz, Liebigs

Bruc. 74

Ann. Chem., 406, 1 (1914)

Ann. Chem., 406, 1 (1914)

C 5 H 1 1 NO 2 COOH

C 6 H 1 1 NO 3 COOH

MeOH

NH2

HN

E. Fischer, Chem. Ber., 39, 2320 (1906)

Bruc. 75

COOH

S

NH2

C 5 H 1 1 NO 2 S

S

COOH NH2

COOH

C 6 H 1 1 NO 3 S

O

EtOH

HN

W. Windus and C. S. Marvel, J. Am. Chem.

Bruc. 78

Chem. Soc., 53, 3490 (1931) S

Soc., 53, 3490 (1931)

C 5 H 1 1 NO 2 S EtOH

MeOH

O

E. Fischer, Chem. Ber., 39, 2320 (1906)

Bruc. 76

EtOH

W. Windus and C. S. Marvel, J. Am.

Bruc. 77

C 6 H 1 1 NO 3

C 5 H 1 1 NO 3 COOH

HO

EtOH

NH2

H. Baganz, H. Baganz and E. Vorwerk,

Bruc. 79

A. Stoll and Th. Petrzilka, Helv. Chim.

Bruc. 80

Chem. Ber., 86, 1242 (1953) C 6 H 1 1 NO 4 COOH

HO HN

O

© 2002 by CRC Press LLC

Acta, 35, 589 (1952) NH2

COOH

EtOH SH

C 5 H 1 2 NO 2 S H2O

A. Stoll and Th. Petrzilka, Helv. Chim.

Bruc. 81

British Patent 585,413 (1947)

Bruc. 82

Acta, 35, 589 (1952) O

HN

NH2

C 6 H 1 2 NO 3 S H2O

COOH

O

H2N

COOH

C5H12N2O3 MeOH

SH

British Patent 585,413 (1947)

Bruc. 83

G. I. Tesser, R. J. F. Nivard and M. Gruber,

Bruc. 84

Rec. Trav. Chim., 81, 713 (1962) phtaloil HN

C6H6O4

C21H20N2O11 COOH

O HN

Methyl cellosolve

H

C6H6O6

COOH

75:25 v/v %

(1971) C6H8N2O2

H3C

O

N

H2O

COOH

EtOH, H 2 O

J. J. Gajewski, J. Am. Chem. Soc., 93, 4450

Bruc. 86

Gruber, Rec. Trav. Chim., 81, 713 (1962) HOOC

COOH

H

phtaloil

G. I. Tesser, R. J. F. Nivard and M.

Bruc. 85

HOOC

EtOH

N O

E. Buchner and R. von der Hide, Chem.

Bruc. 87

Bruc. 88

Ber., 38, 3112 (1905)

N. Takamura, S. Teyashima, K. Achiwa and S. Yamada, Chem. Pharm. Bull., 15, 1776 (1967)

N COOH S NH2

C6H8N2O2S

C6H8O3

CHCl 3 , Acetone

MeOH, H 2 O

50:50 v/v %

90:10 v/v %

Y. Seto, K. Torii, K. Bori, K. Inabata, S.

Bruc. 89

COOH

O

Bruc. 90

Kuwata and H. Watanabe, Bull. Chem.

M. Kinoshita and S. Umezawa, Bull. Chem. Soc. Japan., 32, 223 (1959)

Soc. Japan., 47, 151 (1974)

COOH

O Bruc. 91

C6H8O4 H2O

COOH

H HOOC

S

H

C6H8O4S H2O

O M. E. Maurit, R. P. Shternberg, A. M. Pakhomov, G. I. Basilevskaya, G. V. Smirnova and N. A. Preobrazhenskii, Zh. Obsh. Kim., 30, 2256 (1968)

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Bruc. 92

A. Fredga, J. Prakt. Chem., 150, 124 (1938)

S

COOH

S

COOH

C6H8O4S2 H2O M-O. Hedblom, Arkiv Kemi, 31,

Bruc. 93

COOH

H HOOC

H

Se

C 6 H 8 O 4 Se EtOH

A. Fredga, J. Prakt. Chem., 130, 180 (1931)

Bruc. 94

489 (1969) COOH

C 6 H 9 NO 2

D

COOH NH

CN

C 6 H 1 0 DNO 3

O

J. Kenyon and W. A. Ross, J. Chem. Soc.,

Bruc. 95

H. Lackner, Chem. Ber., 104, 3653 (1971)

Bruc. 96

3407 (1951) C6H10O4 H2O

COOH

HOOC

A. Fredga, Arkiv Kemi Mineral Geol.,

Bruc. 97

C6H10O4 COOH

HOOC

G. E. McCasland and S. Proskow, J. Am.

Bruc. 98

24A, No. 32 (1947) COOH

S O

MeOH

Chem. Soc., 78, 5646 (1956) C6H10O4S

COOH

H2O

O

C6H10O4S2 H 2 O, MeOH

S S

50:50 v/v % COOH

D. J. Cram and T. A. Whitney, J. Am.

Bruc. 99

Bruc. 100

Chem. Soc., 89, 4651 (1967) COOH

No. 13 (1937) OH

C 6 H 1 0 O 4 Se 2 MeOH

Se Se

A. Fredga, Arkiv Kemi Mineral Geol., 12A,

C6H10O6 COOH

HOOC

EtOAc

OH

COOH

Bruc. 101

A. Fredga, Uppsala Universitets Arsskrift

Bruc. 102

1935:5

S. Tatsumi, Y. Izmui, M. Imaida, Y. Fukuda and S. Akabori, Bull. Chem. Soc. Japan.,39, 602 (1966)

HOOC

HOHO

O

OH OH

C6H10O7

C 6 H 1 1 BrO 2

Br

COOH

EtOH, H 2 O

H2O

90:10 v/v % Bruc. 103

C. Niemann and K. P. Link. J. Biol. Chem., 106, 773 (1934)

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Bruc. 104

E. Fischer and H. Cari, Chem. Ber., 39, 3996 (1906)

C 6 H 1 1 NO 2

NH2 S

BuOH

COOH

A. Stoll and E. Seebeck, Helv. Chim.

Bruc. 105

HN S

O

A. Stoll and E. Seebeck, Helv. Chim. Acta,

Bruc. 106

34, 481 (1951)

C 6 H 1 1 NO 2 S 2 S

COOH

S

BuOH

COOH

Acta, 34, 481 (1951)

N

C 6 H 1 2 NO 3

C 6 H 1 1 NO 3 S O

N

EtOAc, MeOH

COOH

EtOAc, MeOH

S

M. Matell, Acta Chem. Scand., 14, 677

Bruc. 107

M. Matell, Acta Chem. Scand., 14, 677

Bruc. 108

(1960)

(1960)

COOH

HOOC

NH2

C 6 H 1 1 NO 4

HOOC

COOH

C 1 3 H 1 5 NO 5

benzoyl

Acetone, H 2 O

HN

Acetone, H 2 O 90:10 v/v %

M. S. Rabinovich, M. F. Shostakovskii

Bruc. 109

HOOC

S

Bruc. 110

and E. V. Preobrazhenskava, Zhur.

E. V. Preobrazhenskava, Zhur. Obsch.

Obsch. Khim., 30, 71 (1960)

Khim., 30, 71 (1960)

NH2

S

90:10 v/v % M. S. Rabinovich, M. F. Shostakovskii and

O

C 6 H 1 1 NO 4

COOH

H2O

NH2

C 1 0 H 1 5 NO 6

HN

H2O

COOH

HOOC HN

O

L. Hollander and V. du Vigneaud, J. Biol.

Bruc. 111

Bruc. 112

Chem., 94, 243 (1931-32)

COOH

EtOH, H 2 O

70:30 v/v %

50:50 v/v % Bruc. 114

Chem., 235, 181 (1935)

C. Neuberg and B. Rewald, Z. Physiol. Chem., 9, 403 (1908)

C6H12O3 COOH OH

Bruc. 115

C6H12O3 OH COOH

H2O

H. Scheibler and A. S. Wheeler, Chem.

Bruc. 116

Ber., 44, 2684 (1911)

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EtOAc

F. M. Dean, J. C. Roberts and A. Robertson, J. Chem. Soc., 1432, (1954)

C6H12O3 COOH

C6H12O2

EtOH, H 2 O

P. Kögl and H. Erxleben, Z. Physiol.

Bruc. 113

Chem., 94, 243 (1931-32)

C6H12O2

COOH

L. Hollander and V. du Vigneaud, J. Biol.

H2O

C6H12O3

HO

COOH

H2O

Bruc. 117

T. Tanabe, S. Yajima and M. Imaida,

J. S. Brooks and G. A. Morrison, J. Chem.

Bruc. 118

Bull. Chem. Soc. Japan., 41, 2178 (1968) COOH

C 6 H 1 3 NO 2 EtOH

NH2

Bruc. 119

E. Adberhalden, C. Froehlich and D.

COOH

C 7 H 1 3 NO 3

O

EtOH

HN

E. Adberhalden, C. Froehlich and D. Fuchs,

Bruc. 120

Fuchs, Hoppe Seyler's Z. Physiol. Chem.,

Hoppe Seyler's Z. Physiol. Chem., 86, 454

86, 454 (1913)

(1913)

NH2

C 6 H 1 3 NO 2

COOH

Bruc. 121

Soc. Perkin 1,2114 (1974)

HN

EtOH

E. Fischer and O. Warburg, Chem. Ber.,

O

C 7 H 1 3 NO 3

COOH

EtOH

E. Fischer and O. Warburg, Chem. Ber., 38,

Bruc. 122

38, 3997 (1905)

3997 (1905) C 6 H 1 3 NO 2

COOH

C 7 H 1 3 NO 3 COOH

EtOH HN

NH2

Bruc. 123

E. Adberhalden, W. Faust and E. Haase,

E. Adberhalden, W. Faust and E. Haase,

Bruc. 124

Hoppe Seyler's Z. Physiol. Chem., 228,

Hoppe Seyler's Z. Physiol. Chem., 228, 187

187 (1934)

(1934) C 6 H 1 3 NO 2

COOH

C 1 3 H 1 9 NO 5 S COOH

Acetone HN

NH2

Bruc. 125

EtOH

O

D. A. Jaeger, M. D. Broadhurst and D. J.

Bruc. 126

Cram, J. Am. Chem. Soc., 101, 717

Acetone

tosylate

D. A. Jaeger, M. D. Broadhurst and D. J. Cram, J. Am. Chem. Soc., 101, 717 (1979)

(1979) O

O

COOH COOH

C7H6O7

COOH

H2O

O

C7H10O2 Acetone, H2O 96:4 v/v%

Bruc. 127

C. Martius and G. Schorre, Liebigs Ann.

Bruc. 128

Chem., 570, 140 (1950) COOH

Chem. Soc., 77, 3807 (1955)

C7H10O2

COOH

Acetone

C7H10O3 Acetone

O

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K. Mislow and I. V. Steinberg, J. Am.

W. von E. Doering, M. Franck-Neumann,

Bruc. 129

R. K. Hill and A. G. Edwards, Tetrahedron,

Bruc. 130

D. Hasselmann and R. L. Kaye, J. Am.

21, 1501 (1965)

Chem. Soc., 94, 3833 (1972)

COOH OH

C7H10O3 Acetone or EtOAc

K. Chilina, U. Thomas, A. F. Tucci, K. D.

Bruc. 131

C7H10O3

COOH OH

Acetone or EtOAc

K. Chilina, U. Thomas, A. F. Tucci, K. D.

Bruc. 132

McMichael and C. M. Stevens,

McMichael and C. M. Stevens,

Biochemistry, 8, 2846 (1969)

Biochemistry, 8, 2846 (1969)

COOH

C7H10O4

COOH

H2O L. J. Goldsworthy and W. H. Perkin, J.

Bruc. 133

H2O

O

COOH

C7H10O4

O M. E. Msurit, R. PO. Shternberg, A. M.

Bruc. 134

Chem. Soc., 105, 2639 (1914)

Pakhomov, G. I. Basilevskaya, G. V. Smirnova, and N. A. Preobrazhenskii, Z. Obsh. Khim., 30, 2256 (1960)

HOOC

C7H10O4S2

S S

Acetone

O

C 7 H 1 1 NO 2

H N

abs. EtOH

O

HOOC Bruc. 135

L. Schotte, Arkiv Kemi, 9, 413 (1957)

T. C. Butler, J. Pharm. Exp. Ther., 113, 178

Bruc. 136

(1955) C 7 H 1 1 NO 3 O

H N

Acetone

O

C 7 H 1 1 NO 3 Isoamyl-acetate

COOH

COOH

Bruc. 137

E. Hardegger and H. Ott, Helv. Chim.

Bruc. 138

C.G. Overberger, J. H. Kozlowski and W.

Acta, 38, 312 (1955); W.H. Mills, A.M.

Radlmann, J. Poly. Sci. A1, 10, 2265

Bain, J. Chem. Soc., 97, 1866 (1910)

(1972)

OH

C7H12O3

OH

Acetone

Acetone

COOH

Bruc. 139

J. B. Kay and J. B. Robinson, J. Chem. Soc.C, 248 (1969)

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C7H12O3

COOH

Bruc. 140

J. Sanchez Real and J. Pascual, Anales Real Soc. Espan. Fiss. y. Qum. (Madrid)., 49B, 445 (1953)

C7H12O4 COOCH3

HOOC

MeOH

C7H12O6

OH

COOH

HOOC

H2O

OH

Bruc. 141

E. Berner and R. Leonardsen, Liebigs

Bruc. 142

Ann. Chem., 538, 1 (1939)

OH

HO

Bruc. 143

Liebigs Ann. Chem., 510, 206 (1934)

C7H12O6

C7H14O2

MeOH

OH HOOC

COOH

R. Grewe, W. Lorenzen and L. Vining,

NH2

COOH

Bruc. 144

C 7 H 1 5 NO 2

COOH

COOH

Bruc. 146

C 8 H 1 5 NO 3 EtOH

A. K. Mills and A. E. Wilder Smith, Helv. Chim. Acta, 43, 1915 (1960)

C 8 H 6 Br 2 O 5

C 8 H 6 Cl 2 O 3

Br

MeOH Br

O

HN

EtOH

A. K. Mills and A. E. Wilder Smith, Helv.

O

S. Pucci, P. Pino and W. Strino, Gazz. Chim. Ital., 98, 421 (1968)

Chim. Acta, 43, 1915 (1960) Br

Acetone

OH

Chem. Ber., 87, 793 (1954)

Bruc. 145

K. Freudenberg, W. F. Bruce and W. Gauf,

COOH

MeOH

COOH

Bruc. 147

N.S. Zefirov, A. F. Davydova and Y. K.

Bruc. 148

Yur'ev, Zh. Obsch. Khim., 35, 817 (1965)

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

NO2 OH COOH

OH

C 8 H 7 NO 5

COOH

H2O HO

A. McKenzie and P. A. Stewart, J. Chem.

Bruc. 150

Soc., 104 (1935) O

Cl

COOH COOH

H 2 O, EtOH 20:80 v/v%

NO2

Bruc. 149

C 8 H 7 NO 6

A. La Manna, M. Grassi and L. Arpesella, Farmaco, Ed. Sci., 10, 571 (1955)

C 8 H 8 Cl 2 O 5 MeOH

COOH

S

COOH

C8H8O4S EtOH

Cl

Bruc. 151

N. S. Zefirov, A. F. Davydova and Y. K. Yur'ev, Zhur. Obsch. Khim., 35, 1373 (1965)

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Bruc. 152

K. Pettersson, Arkiv Kemi, 7, 39 (1954)

SO3H COOH

C8H8O5S H2O

C8H9N2O3

O N F

O

EtOH

N O J. Brust, Rec. Trav. Chim., 47, 153

Bruc. 153

M. Yasumoto, A. Moriyama, N. Unemi, S.

Bruc. 154

(1928)

Hashimoto, and T. Suzue, J. Med. Chem., 20, 1592 (1977)

COOH

C8H10O3

H

COOH

EtOH, H2O H

O

H2O

99:1 v/v% HOOC

K. Mori, Tetrahedron, 34, 915 (1978)

Bruc. 155

C8H10O4

Bruc. 156

H

W. H. Mills and G. H. Keats, J. Chem. Soc., 1373 (1935)

C8 H1 2 O2

COOCH3

H

MeOH

COOH

C8 H1 2 O4 Acetone

COOH R. Sandberg, Arkiv Kemi, 17, 327 (1961)

Bruc. 157

Bruc. 158

T. Matsumoto, T. Okabe and K. Fukui, Chem. Lett., 773 (1973

HOOC

COOH

C8 H1 2 O4 H2O

H

S. K. Ranganathan, J. Indian Chem. Soc.,

Bruc. 159

HOOC

COOH

H2O

H

Bruc. 160

C8 H1 2 O4

H. N. Rydon, J. Chem. Soc., 829 (1936)

13, 419 (1936) H

COOH

HOOC

C8 H1 2 O4

COOH

H2O

C8H12O4 H2O

COOH

Bruc. 161

H. N. Rydon, J. Chem. Soc., 829 (1936) COOH

Bruc. 162

C8H12O4

H. N. Rydon, J. Chem. Soc., 1340 (1973) COOH

EtOAc

EtOH

HOOC

Bruc. 163

C8H12O4

COOH

R. Trave and L. Garanti, Gazz. Chim. Ital., 90, 612 (1960)

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Bruc. 164

J. J. Gajewski, J. Am. Chem. Soc., 97, 3457 (1975)

COOH COOH

C8H12O4

C8H12O4

OH

Acetone

H2O

COOH

O Bruc. 165

E. Berner and O. Steffensen, Acta Chem.

R. M. Lukes, G. I. Poos and L. H. Sarett, J.

Bruc. 166

Scand., 8, 64 (1954)

OH COOH COOH

Am. Chem. Soc., 74, 1401 (1953)

C8H12O6

C 8 H 1 3 NO 2

H2O

COOH

OH Bruc. 167

S. Tatsumi, M. Imaida and Y. Izumi,

H. S. Tager and H. N. Christensen, J. Am.

Bruc. 168

Bull. Chem. Soc. Japan., 39, 2543 (1966)

Chem. Soc., 94, 968 (1972)

C 9 H 1 3 NO 3 NHCHO

C 8 H 1 3 NO 2

H2O

NH2

H. S. Tager and H. N. Christensen, J.

H. S. Tager and H. N. Christensen, J. Am.

Bruc. 170

Am. Chem. Soc., 94, 968 (1972)

Chem. Soc., 94, 968 (1972)

C 9 H 1 3 NO 3 COOH

N O

H. S. Tager and H. N. Christensen, J.

Bruc. 172

Am. Chem. Soc., 94, 968 (1972)

C 9 H 1 3 NO 3 S

H

S

H2O

NHCHO

Bruc. 171

H2O

COOH

COOH

Bruc. 169

H2O

NH2

COOH H

H2O

J. Hoogmartens, P. J. Claes and H. Vanderhaeghe, J. Org. Chem., 39, 425 (1974)

CH2COOH COOH

C 8 H 1 3 NO 4 H2O

N H Bruc. 173

CH2COOH COOH

C 8 H 1 3 NO 4 H2O

N H A. Wohl and R. Maag, Chem. Ber., 42, 627 (1909)

Bruc. 174

A. Wohl and R. Maag, Chem. Ber., 42, 627 (1909)

C 8 H 1 3 NO 5

H

HO H N COOH COOEt

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C8H14O4 COOH

BuOH COOH

H2O

T. Wieland and H. Wehrt, Chem. Ber., 92,

Bruc. 175

Bruc. 176

2106 (1959)

A. Fredga, Arkiv Kemi Mineral. Geol., 23B, No. 2 (1946)

C8H14O4 COOH

HOOC

COOH

H2O

C 8 H 1 4 O 4 Se H2O

Se

COOH

W. A. Noyes and L. P. Kyriakides, J.

Bruc. 177

Bruc. 178

Am. Chem. Soc., 32, 1057 (1910)

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY (1981)

C8H14O6S HOOC

O

S

O

COOH

HCl, H2O

COOH

abs. EtOH

1/2 n

R. Ahlberg, Chem. Ber., 61B, 811 (1928)

Bruc. 179

C8H16O2

Bruc. 180

F. S. Prout, B. Burachinsky, W. T. Brannen, Jr. and H. L. Young, J. Org. Chem., 25, 835 (1960)

COOH

C 9 H 7 Cl 3 O 3 H 2 O, EtOH

O Cl

COOH O

NH

O

80:20 v/v%

C9H7O5 H 2 O, MeOH 30:70 v/v%

O

Cl Cl

Bruc. 181

Ph. D. Thesis of Magnus Matell, Uppsala,

Bruc. 182

Sweden (1953)

S. Senoh, Y. Maeno, S. Imamoto, A. Komamine, S. Hattori, K. Yamashita and M. Matsui, Bull. Chem. Soc. Japan., 40, 379 (1967)

COOH Cl

Cl

C 9 H 8 Cl 2 O 2

COOH O

abs. EtOH

Cl Bruc. 183

C. Fedtke and R. R. Schmidt, Z.

Bruc. 184

Naturforsch., 31, 252 (1976) COOH Cl

O

Bruc. 185

Acetone

Cl S. T. Collins and F. E. Smith, J. Sci. Food. Agric., 3, 248 (1952)

C 9 H 8 Cl 2 O 3

C9H8O2S COOH

H 2 O, EtOH Cl

S

77:23 v/v% M. Matell, Arkiv Kemi, 4, 473 (1952)

H 2 O, MeOH 50:50 v/v%

Bruc. 186

A. Fredga, Acta Chem. Scand., 9, 719 (1955)

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C 9 H 8 Cl 2 O 3

COOH

C9H8O3 COOH O

A. Fredga and C. V. C. Sarmiento, Arkiv

Bruc. 187

Br

H2O

3996 (1906) OH

C 9 H 9 BrO 3

OH COOH

EtOH

E. Fischer and H. Carl, Chem. Ber., 39,

Bruc. 188

Kemi, 7, 387 (1954) Br

C 9 H 9 BrO 2

C 9 H 9 BrO 3 COOH

EtOH

EtOH

Br

A. Collet and J. Jacques, Bull. Soc. Chim.

Bruc. 189

A. Collet and J. Jacques, Bull. Soc. Chim.

Bruc. 190

Fr., 3857 (1972)

Fr., 3857 (1972)

C 9 H 9 BrO 3

C 9 H 9 BrO 3

OH COOH

COOH

EtOH

O

MeOH, H 2 O 47:53 v/v%

Br

Br A. Collet and J. Jacques, Bull. Soc. Chim.

Bruc. 191

A. Fredga, Arkiv Kemi, 18, 501 (1962)

Bruc. 192

Fr., 3857 (1972) OH

C 9 H 9 ClO 3 COOH

EtOH

C 9 H 9 ClO 3

OH

COOH

Cl

EtOH

Cl

A. Collet and J. Jacques, Bull. Soc. Chim.

Bruc. 193

A. Collet and J. Jacques, Bull. Soc. Chim.

Bruc. 194

Fr., 3857 (1972)

Fr., 3857 (1972) C 9 H 9 ClO 3

OH COOH

C 9 H 9 ClO 3 COOH

EtOH

O

EtOH, H 2 O 40:60 v/v%

Cl

Cl

A. Collet and J. Jacques, Bull. Soc. Chim.

Bruc. 195

M. Matell, Arkiv Kemi, 7, 437 (1954)

Bruc. 196

Fr., 3857 (1972)

C 9 H 9 ClO 3 COOH

O

Cl

© 2002 by CRC Press LLC

COOH

EtOH, H 2 O 20:80 v/v%

C 9 H 9 FO 3

OH

F

EtOH

D. T. Witiak, T. C-L. Ho, R. E. Hackney

Bruc. 197

A. Collet and J. Jacques, Bull. Soc. Chim.

Bruc. 198

and W. E. Connor, J. Med. Chem., 11, 1086

(1968) C 9 H 9 IO 3

C 9 H 9 FO 3

OH COOH

F

Fr., 3857 (1972)

COOH

EtOH

O

H 2 O, Acetone 10:90 v/v%

I A. Collet and J. Jacques, Bull. Soc. Chim.

Bruc. 199

A. Fredga, Arkiv Kemi, 25, 87 (1965)

Bruc. 200

Fr., 3857 (1972) COOH

H2 N

C 9 H 9 NO 6

CBZ

H N

C 1 7 H 1 5 NO 9

COOH

EtOH, H2O O

Bruc. 201

COOH

O

90:10 v/v%

S. Senoh, Y. Maeno and S. Imamoto, A.

O

Bruc. 202

COOH

90:10 v/v%

S. Senoh, Y. Maeno and S. Imamoto, A. Komamine, S. Hattori, K. Yamashita and

M. Matsui, Bull. Chem. Soc. Japan., 40,

M. Matsui, Bull. Chem. Soc. Japan., 40,

379 (1967)

379 (1967)

Br COOH

HOOC

C 9 H 1 0 Br 2 O 4 EtOH

H. J. Backer and H. G. Kemper, Rec.

COOH

COOH

NH2

O2N

Bruc. 204

Trav. Chim., 57, 761 (1938)

O2 N

O

Komamine, S. Hattori, K. Yamashita and

Br

Bruc. 203

EtOH, H2O

C9H10N2O4 EtOH

F. Bergel and J. A. Stock, U. S. Patent 3,032,585 (1962) OH

C11H12N2O5

C9H10O3 COOH

HN

EtOH

EtOAc

O

Bruc. 205

F. Bergel and J. A. Stock, U. S. Patent

Bruc. 206

C9H10O4

COOH COOH

S. G. Cohen and S. Y. Weinstein, J. Am. Chem. Soc., 80, 725 (1964)

3,032,585 (1962)

SO3H

Acetone, H 2 O

COOH

C9H10O5S H2O

80:20 v/v% Bruc. 207

R. E. Pincock, M-M. Tong and K. R. Wilson, J. Am. Chem. Soc., 93, 1669 (1971)

© 2002 by CRC Press LLC

Bruc. 208

C. H. K. Mulder, Rec. Trav. Chim., 50, 719 (1931)

COOH

MeOH

NH2 Bruc. 209

C 9 H 1 1 NO 2

E. Fischer and W. Schoeller, Liebigs Ann.

COOH

Bruc. 210

Bruc. 211

C 9 H 1 1 NO 3

R. R. Sealock, M. E. and R. S. Schweet,

COOH

C 9 H 1 1 NO 3

O

H2O

HN

Bruc. 213

E. Fischer, Chem. Ber., 32, 3638 (1900) COOH

NH2

HO

MeOH

E. Fischer and W. Schoeller, Liebigs Ann.

HO

Bruc. 212

C 1 0 H 1 1 NO 4

O

EtOH

R. R. Sealock, M. E. and R. S. Schweet, J. Am. Chem. Soc., 73, 5386 (1951)

HN

HO

Bruc. 214

COOH

C 1 6 H 1 5 NO 4

benzoyl

H2O

E. Fischer, Chem. Ber., 32, 3638 (1900)

C 9 H 1 1 NO 3 abs. EtOH

COOH

HN

J. Am. Chem. Soc., 73, 5386 (1951)

HO

O

Chem., 357, 1 (1907)

EtOH

NH2

C 1 0 H 1 1 NO 3

HN

Chem., 357, 1 (1907) HO

COOH

COOH

abs. EtOH

HN

HO

C 1 1 H 1 3 NO 4

O

Bruc. 215

R. R. Sealock, J. Biol. Chem., 166, 1

Bruc. 216

(1946)

COOH

R. R. Sealock, J. Biol. Chem., 166, 1 (1946)

C9H12O4

C9H12O4

EtOH

H2O

COOH

COOH COOH

Bruc. 217

B. Kermark, Arkiv Kemi, 27, 11 (1967)

Bruc. 218

B. Akermark, Acta Chem. Scand., 21, 589 (1967)

H

H

COOH

HOOC

Bruc. 219

C9H12O4 H2O

H. J. Backer and H. B. J. Schurink, Rec.

H HOOC

Bruc. 220

Trav. Chim., 50, 921 (1931)

COOH CN Bruc. 221

© 2002 by CRC Press LLC

COOH

C9H12O4 H2O

H. Wynberg and J. P. M. Houbiers, J. Org. Chem., 36, 835 (1971)

C 9 H 1 3 NO 2

H COOH

H2O

E. Fischer and W. Brieger, Chem. Ber., 48, 1517 (1915)

H

C9H14O4 H2O

H COOH

Bruc. 222

J. W. Barrett and R. P. Linstead, J. Chem. Soc., 1069 (1935)

C9H14O4

H COOH

C9H14O4

COOH

H2O

COOH

H. Conroy and E. Cohen, J. Org. Chem.,

Bruc. 223

HOOC

S. K. Ranganathan, Current Sci., 6, 277

Bruc. 224

23, 616 (1958)

(1937) C9H14O4

COOH

C 9 H 1 5 NO 2

COOH

EtOAc D. C. Ayres and R. A. Raphael, J. Chem.

Bruc. 225

E. Fischer and E. Flatau, Chem. Ber., 42,

Bruc. 226

Soc., 1779 (1958) O

2981 (1909) C9H12O2

H N

C 9 H 1 6 NO 3

COOH

Acetone

S

Acetone N O

HOOC

Bruc. 227

H2O

CN

COOH

W. M. McLamore, W. D. Celmer, V. V.

Bruc. 228

Bogert, F. C. Pennington, V. A. Sobin and

K. Flohr, R. M. Paton and E. T. Kaiser, J. Am. Chem. Soc., 97, 1209 (1975)

I. A. Solomons, J. Am. Chem. Soc., 75, 105 (1943) C9H16O4 HOOC

C9H18O2

H2O

COOH

EtOH, H 2 O COOH

Bruc. 229

E. Berner and L. H. Landmark, Acta

Bruc. 230

Chem. Scand., 7, 1347 (1953)

E. Fischer, J. Holzapfel and H. V. Gwinner, Chem. Ber., 45, 247 (1912)

C9H18O2

COOH

C9H18O2

EtOAc Bruc. 231

20:80 v/v%

F. S. Prout, B. Burachinsky, W. T.

EtOAc

COOH

Bruc. 232

W. V. W. Doering and K. B. Wiberg, J. Am. Chem. Soc., 72, 2608 (1950)

Brannen, Jr. and H. L. Young, J. Org. Chem., 25, 835 (1960) Br

HOOC

Br COOH

C 1 0 H 2 Br 4 O 4 S 2

S

S Br

COOH COOH

EtOH

Br

EtOH

S

S Br

Bruc. 233

R. Hakansson and E. Wiklund, Arkiv Kemi, 31, 101 (1969)

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C 1 0 H 4 Br 2 O 4 S 2

Bruc. 234

Br E. Wiklund and R. Hakansson, Chemica Scripta, 6, 137 (1974)

COOH NO2

C10H4N2O8S2

S

COOH COOH

EtOH

S

EtOH Se

Se COOH

NO2

NO2

S. Gronowitz and P. Gustafson, Arkiv

Bruc. 235

C 1 0 H 4 N 2 O 8 Se 2

Bruc. 236

Kemi, 20, 289 (1962)

NO2 C. Dell'Erba, D. Spinelli, G. Garbarino and G. Leandry, J. Heterocyclic Chem., 5, 45 (1968)

COOH CH2OH

C 1 0 H 6 Br 2 O 3 S 2

Br

C 1 0 H 6 Br 2 O 3 S 2

Br

EtOH

S

S

EtOH

S

S

COOH CH2OH

Br

Br

E. Wiklund and R. Hakansson, Chemica

Bruc. 237

Bruc. 240

Scripta, 6, 137 (1974)

Scripta, 6, 76 (1974) C10H8O3

O

E. Wiklund and R. Hakansson, Chemica

C 1 0 H 9 NO 2

CN

abs. EtOH

COOH

MeOH

COOH

P. Ahlberg, Chemica Scripta, 3, 183

Bruc. 241

Bruc. 242

(1973)

(Weinheim), 305, 54 (1972) C10H10N2O3

COOH

EtOAc

N COOH NO

C10H10O2 Acetone, H 2 O 43:57 v/v%

E. J. Corey, R. J. McCaully and H. S.

Bruc. 243

J. Knabe and D. Strauss, Arch. Pharm.

Bruc. 244

A. Fredga, Chem. Ber., 89, 322 (1956)

Sachdev, J. Am. Chem. Soc., 92, 2476 (1970) O

COOH

H

C10H10O3

COOH

Benzene, abs. EtOH

EtOH COOH

50:50 v/v% J. M. Domagala and R. D. Bach, J. Org.

Bruc. 245

Bruc. 246

Chem., 44, 3168 (1979) COOH

O

© 2002 by CRC Press LLC

50:50 v/v%

H. Wren and H. Williams, J. Chem. Soc., 109, 572 (1916)

C10H10O4S Acetone, H 2 O

S O

C10H10O4

O HOOC

COOH

C10H10O6 H2O

O

D. J. Cram and T. A. Whitney, J. Am.

Bruc. 247

P. C. Guha and S. K. Ranganathan, Chem.

Bruc. 248

Chem. Soc., 89, 4651 (1967)

Ber., 72, 1379 (1939)

C 1 0 H 1 1 ClO 3

COOH O

EtOH, H 2 O

C10H12N2O6

COOH

O

60:40 v/v%

N H COOH

N H

H2O

O

Cl A. Fredga, E. Thimson and K. Rosberg,

Bruc. 249

P. Newman, Optical Resolution Procedures

Bruc. 250

Arkiv Kemi, 32, 369 (1970)

for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

COOH

O

C10H12O3 EtOH

A. Fredga and R. Backstrom, Arkiv Kemi,

Bruc. 251

C10H12O3

OH COOH

D. Biquard, Ann. Chim. Phys., 20, 97

Bruc. 252

25, 455 (1966)

(1933) C10H12O3

OCH3 COOH

EtOH

C10H12O4 COOH

Acetone

O

EtOH, H 2 O 15:85 v/v%

H3OC

L. Angiolini, P. Costa Bizzarri and M.

Bruc. 253

A. Fredga and I. Avalaht, Arkiv Kemi, 24,

Bruc. 254

Tramontini, Tetrahedron, 25, 4211 (1969)

O

C10H12O4

O

COOH

Bruc. 255

425 (1965)

COOH

H2O

M. G. Peter, G. Snatzke, F. Snatzke, K. N.

C 1 0 H 1 3 NO 2

NH2

H2O

V. du Vigneaud and O. J. Irish, J. Biol.

Bruc. 256

Nagarajan and H. Schmid, Helv. Chim.

Chem., 122, 349 (1937-38)

Acta, 57, 32 (1974) HN

O

C 1 1 H 1 3 NO 3

COOH

H2O

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C 1 0 H 1 3 NO 4 S

H N O

SO3H

H2O

V. du Vigneaud and O. J. Irish, J. Biol.

Bruc. 257

H. J. Backer and A. Bloemen, Rec. Trav.

Bruc. 258

Chem., 122, 349 (1937-38) O

N H

H2O

COOH

C. S. Gibson and J. L. Simonsen, J.

Bruc. 259

OH

C 1 0 H 1 3 NO 4 S

O S

Chim., 45, 110 (1926) C10H14N3O3S

NH2 COOH

S

K. Undheim and G. A. Ulssker, Acta Chem.

Bruc. 260

Chem. Soc., 798 (1915)

Scand., 27, 1059 (1973)

C10H14O2 EtOH COOH

C10H14O4 H

EtOAc O

COOH

Bruc. 261

MeOH

M. Tichy and J. Sicher, Coll. Czech.

Bruc. 262

Chem. Comm., 37, 3106 (1972) C10H16O4

O

COOH

J. D. Edwards, Jr. and T. Matsumoto, J. Org. Chem., 32, 1837 (1967)

HOOC

COOH

C10H16O4

COOH COOH Bruc. 263

M. Janczewski and T. Bartnik, Polish J.

Bruc. 264

Chem., 36, 1243 (1962) COOH COOH

Bruc. 265

A. Fredga and M. Matell, Bull. Soc. Chim. Belges., 62, 47 (1953)

C10H18O4 EtOH

J. Timmermans and J. van der Haegen,

C10H18O4 HOOC

Bruc. 266

Bull. Soc. Chim. Belges., 42, 448 (1933)

COOH

H2O

M. Tichy, P. Malon, I. Fric and K. Blaha, Coll. Czech. Chem. Comm., 42, 3591 (1977)

C10H18O4 EtOH HOOC

Bruc. 267

COOH

A. R. Battersby, S. W. Breuer and S. Garratt, J. Chem. Soc. C, 2467 (1968) COOH

C10H20O2 EtOH, H 2 O 10:90 v/v%

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C10H18O4 HOOC

Bruc. 268

COOH

H2O

L. Eberson, Acta Chem. Scand., 13, 40 (1959) COOH

C10H20O2 EtOAc

E. Fischer, J. Holzapfel and H. V.

Bruc. 269

F. S. Prout, B. Burachinsky, W. T. Brannen,

Bruc. 270

Gwinner, Chem. Ber., 45, 247 (1912)

Jr. and H. L. Young, J. Org. Chem., 25, 835 (1960)

COOH

S

C11H8O2S

Ph

Acetone

H

W. Tochtermann, C. Franke and D.

Bruc. 271

C 1 1 H 9 NO 2

CN COOH

MeOH

E. W. Yankee, B. Spencer, N. E. Howe and

Bruc. 272

Schafer, Chem. Ber., 101, 3122 (1968)

D. J. Cram, J. Am. Chem. Soc., 95, 4220 (1973)

C11H10O4

COOH

COOH CN

Acetone

Ph COOH

J. Kenyon and W. A. Ross, J. Chem. Soc.,

Bruc. 274

5153 (1959)

3407 (1951) C 1 1 H 1 1 NO 2

COOH

C11H12N2O2

O H N

EtOH, H 2 O 70:30 v/v%

N H

J. Sjöberg, Arkiv Kemi, 12, 251 (1957)

Bruc. 275

Acetone, H 2 O 75:25 v/v%

W. M. Jones, J. Am. Chem. Soc., 81,

Bruc. 273

C 1 1 H 1 1 NO 2

Et

abs. EtOH

N H

O

H. Sobotka, M. F. Holzman and J. Kahn, J.

Bruc. 276

Am. Chem. Soc., 54, 4697 (1932) C11H12N2O2

NH2

H N

abs. EtOH

COOH

O

C13H14N2O3 abs. EtOH

COOH

N H

N H

A. C. Shabica and M. Tishler, J. Am.

Bruc. 277

A. C. Shabica and M. Tishler, J. Am.

Bruc. 278

Chem. Soc., 71, 3251 (1949) NH2

C11H12N2O3

COOH N H

Chem. Soc., 71, 3251 (1949) H N

EtOH

C13H14N2O4 EtOH

COOH

OH

N H

Bruc. 279

O

M. Kotake, T. Sakan and T. Miwa, Chem. Ber., 85, 690 (1952)

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Bruc. 280

OH

M. Kotake, T. Sakan and T. Miwa, Chem. Ber., 85, 690 (1952)

COOH

C11H12N2O5

C11H12O2

EtOH

EtOH, H 2 O

NHAc

O2 N

H F. Bergel, M. C. E. Burnopn and J. A.

Bruc. 281

COOH

50:50 v/v%

C. H. DePuy, F. W. Breitbeil and K. R.

Bruc. 282

Stock, J. Chem. Soc., 1223 (1955)

DeBruin, J. Am. Chem. Soc., 88, 3347 (1966)

C11H12O2 MeOH HOOC

COOH

HOOC

C11H12O4 CHCl 3

COOH

L. Westman, Arkiv Kemi, 11, 431 (1957)

Bruc. 283

H. Des Abbayes and R. Dabard,

Bruc. 284

Tetrahedron, 31, 2111 (1975) C11H12O4

H

Acetone, MeOH

O

C11H12O5

COOH

EtOH, H 2 O

33:67 v/v%

H OH COOH

L. Novak, J. O. Jilek, B. Kakac, I. Ernest

Bruc. 285

HO

COOH

50:50 v/v% E. Sélégny and M. Vert, Bull. Soc. Chim.

Bruc. 286

and M. Protiva, Coll. Czech.

Fr., 2549 (1968)

Chem.Comm., 25, 2196 (1960) HOOC

C11H12O5

COOH

C 1 1 H 1 3 NO 4

COOH O

EtOH

Acetone

N

O

OCH3

M. Naps and I. B. Johns, J. Am. Chem.

Bruc. 287

J. Kenyon and K. Thaker, J. Chem. Soc.,

Bruc. 288

Soc., 62, 2450 (1940) COOBu O

N

2531 (1957)

C 1 5 H 2 1 NO 4

C 1 1 H 1 3 NO 4

O

Acetone

O

N J. Kenyon and K. Thaker, J. Chem. Soc.,

Bruc. 289

2531 (1957)

Bruc. 290

Acetone

O COOH J. Kenyon and K. Thaker, J. Chem. Soc., 2531 (1957)

C 1 5 H 2 1 NO 4 O

N

O COOBu

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Acetone

C11H14O2S Acetone

S COOH

J. Kenyon and K. Thaker, J. Chem. Soc.,

Bruc. 291

C. E. Hagberg and S. Allenmark, Chemica

Bruc. 292

2531 (1957) C11H14O3

OH COOH

Bruc. 293

Scripta, 5, 13 (1974)

COOH

H2O

J. A. Reid and E. E. Turner, J. Chem.

C11H14O3

OH

Acetone

D. S. Noyce, L. Gortler, M. J. Jorgenson, F.

Bruc. 294

Soc., 3219 (1951)

B. Kirby and E. C. McGoran, J. Am. Chem. Soc., 87, 4329 (1965) C11H14O4

OH COOH

C11H18O2

H

EtOAc

EtOH

O

COOH

Bruc. 295

D. S. Noyce, L. Gortler, M. J. Jorgenson,

C. C. J. Culvenor and T. A. Geissman, J.

Bruc. 296

F. B. Kirby and E. C. McGoran, J. Am.

Am. Chem. Soc., 83, 1647 (1961)

Chem. Soc., 87, 4329 (1965) C11H18O5 COOH

O

Bruc. 297

CHCl 3 , Acetone

COOH

H

C12H6O8S2

COOH

HOOC

EtOH S

S

HOOC

COOH

50:50 v/v%

H. H. Inhoffen, S. Schütz, P. Rossberg, O.

R. Hakansson and A. Svensson, Chemica

Bruc. 298

Berges, K-H. Nordsiek, H. Penio and E.

Scripta, 7, 186 (1975)

Höroldt, Chem. Ber., 91, 2626 (1958) C 1 2 H 9 NO 4 S

HOOC

COOH

abs. EtOH, H 2 O

S

C12H10N2O3S2 MeOH

33:67 v/v%

S

O2N

N

N

S O Bruc. 299

L. J. Owen and F. F. Nord, J. Org. Chem.,

Bruc. 300

16, 1864 (1951) HOOC

CH2OH

S

S

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G. Ege and W. Planer, Angew. Chem. Int. Ed., 758 (1969)

C12H10O4S2

HOOC

COOH

S

S

EtOH, H 2 O 50:50 v/v%

C12H12O3S2 EtOH

E. Wiklund and R. Hakansson, Chemica

Bruc. 301

E. Wiklund and R. Hakansson, Chemica

Bruc. 302

Scripta, 6, 174 (1974)

Scripta, 6, 174 (1974) CN

C12H12O4

COOH

C 1 2 H 1 3 NO 2 COOH

H2O

Acetone, H 2 O 83:17 v/v%

COOH T. M. Lyssy, J. Org. Chem., 27, 5 (1962)

Bruc. 303

G. Otani and S. Yamada, Chem. Pharm.

Bruc. 304

Bull., 21, 2119 (1973) HOOC

COOH

C12H14O4

COOH

EtOH, H 2 O L. Westman, Arkiv Kemi, 12, 167 (1958)

Bruc. 305

COOH

C12H14O4 H2O

J. Porath, Arkiv Kemi Mineral. Geol., 26B,

Bruc. 306

No. 16 (1948) C12H16O2

C12H16O2

COOH COOH

H. Kuritani, S. Imajo, K. Shingu and M.

Bruc. 307

J. H. Dopper, B. Greijdanus, D. Oudman

Bruc. 308

Nakagawa, Tetrahedron Lett., 1697

and H. Wynberg, Tetrahedron Lett., 4297

(1979)

(1975) C12H16O3 Et2O, Tetrahydrofuran

O

COOH

70:30 v/v% O

M. Ohno, M. Okamoto and N. Kawabe,

Bruc. 310

U. S. Patent 3,793,347 (1974)

COOH

Miescher, Helv. Chim. Acta, 30, 432 (1947) C12H22O4

abs. MeOH HOOC

HN

Bruc. 311

L. H. Werner, A. Wettstein and K.

C 1 3 H 1 7 NO 3 S

S

abs. MeOH

NH2

O

Bruc. 309

C 1 2 H 1 7 NO 2 S

S

COOH

H2O

O

L. H. Werner, A. Wettstein and K. Miescher, Helv. Chim. Acta, 30, 432 (1947)

© 2002 by CRC Press LLC

Bruc. 312

L. Eberson, Acta Chem. Scand., 13, 40 (1959)

C12H24O2

C13H12O2

Acetone, H2O

COOH

MeOH

COOH

75:25 v/v% W. Bleazard and W. Rothstein, J. Chem.

Bruc. 313

A. Fredga, Arkiv Kemi, 8, 463 (1955)

Bruc. 314

Soc., 3789 (1958) C 1 3 H 1 3 NO 4 S COOH HN O S O

H2O

C13H14O5

O HOOC

Acetone, MeOH

O

25:75 v/v%

O

W. M. Colles and C. S. Gibson, J. Chem.

Bruc. 315

D. H. Johnson, A. Robertson and W. B.

Bruc. 316

Soc., 124, 2505 (1924) OH OH COOCH3 COOH

O O

Whalley, J. Chem. Soc., 2971 (1950)

C13H16O8 MeOH

MeOH COOH

T. Matsumoto, K. Hidaka, T. Nakayama

Bruc. 317

C13H18O2

J. Almy and D. J. Cram, J. Am. Chem.

Bruc. 318

and K. Fukui, Bull. Chem. Soc. Japan.,

Soc., 91, 4459 (1969)

45, 1501 (1972) C13H18O3

COOH

EtOH, H 2 O

O

HOOC

M. Andersson, Arkiv Kemi, 26, 335

Cl

Bruc. 321

EtOAc

Cl

Soc., 54, 2104 (1932)

HOOC HOOC

C 1 4 H 6 Br 4 O 4 Br

Br

C 1 4 H 4 Cl 6 O 4

J. White and R. Adams, J. Am. Chem.

Bruc. 320

(1967)

Br

COOH Cl

Cl

78:22 v/v%

Bruc. 319

Cl Cl

EtOAc

Chem. Soc., 62, 1704 (1940)

© 2002 by CRC Press LLC

Cl

Cl

Br

E. A. Atkinson and H. J. Lawler, J. Am.

C 1 4 H 6 Cl 4 O 4

HOOC HOOC

Cl

Bruc. 322

CH 3 CN

Cl

E. R. Atkinson, Organic Preparations and Procedures, 3, 71 (1971)

I

I

I

I

HOOC HOOC

C14H6I4O4 abs. EtOH

NO2

O 2N

Bruc. 323

M. Rieger and F.H. Westheimer, J. Am.

R. Kuhn and O. Albrecht, Liebigs Ann.

Bruc. 324

Chem. Soc., 72, 28 (1950)

Chem., 458, 221 (1927)

C 1 4 H 8 Cl 2 O 2

Cl Cl

H2O

NO2 O2N

COOH

HOOC

C14H6N4O12

C14H8I2O4

I

I

EtOH

Bruc. 325

COOH

HOOC

COOH

HOOC

G. H. Christie, C. W. James and J.

M. Rieger and F. H. Westheimer, J. Am.

Bruc. 326

Kenner, J. Chem. Soc., 123, 1948 (1923)

Chem. Soc., 72, 28 (1950)

C 1 4 H 1 0 FNO 5

HOOC H3CO

EtOH NO2 F

Bruc. 327

C14H10N2O6

O2 N NO2

Acetone

HOOC

A. M. van Arendonk, B. C. Becker and R.

Bruc. 328

Adams, J. Am. Chem. Soc., 55, 4230

M. S. Leslie and E. E. Turner, J. Chem. Soc., 1758 (1930)

(1933)

HOOC

C14H10O4

COOH

C14H10O4

HOOC

EtOH

EtOH

COOH

Bruc. 329

J. Canceill and J. Jacques, Bull. Soc.

Bruc. 330

Chim. Fr., 2727 (1973) O 2N

J. Canceill and J. Jacques, Bull. Soc. Chim. Fr., 2727 (1973)

C 1 4 H 1 1 NO 4

COOH

MeOH

Acetone

COOH

Bruc. 331

R. Adams and J. B. Hale, J. Am. Chem. Soc., 61, 2825 (1939)

© 2002 by CRC Press LLC

C 1 4 H 1 1 NO 4

NO2

Bruc. 332

D. F. Detar and J. C. Howard, J. Am. Chem. Soc., 77, 4393 (1955)

COOH

C 1 4 H 1 1 NO 4

C 1 4 H 1 3 NO 4

H2O

COOH

abs. EtOAc

N

NO2

COOH

R. W. Stoughton and R. Adams, J. Am.

Bruc. 333

L. H. Bock and R. Adams, J. Am. Chem.

Bruc. 334

Chem. Soc., 52, 5263 (1930)

Soc., 53, 374 (1931)

C 1 4 H 1 3 NO 4 O

C 1 4 H 1 3 NO 4 S

COOH

O

abs. EtOH

NH

EtOH, H2O

HOOC NO2

50:50 v/v%

S

Bruc. 335

B. R. Baker, F. J. McEvoy, R. E. Schaub,

Bruc. 336

G. N. Jeand, J. Org. Chem., 21, 419 (1956)

J. P. Joseph, J. H. Williams, J. Org. Chem., 18, 178 (1952) C14H14O3

COOH

C14H14O4S2

HOOC S

Acetone S

COOH

EtOH, H2O 95:5 v/v%

OCH3 Bruc. 337

M. Janczewski and T. Bartnik, Polish J.

Bruc. 338

Chem., 42, 1253 (1968) COOH

HOOC

Bruc. 339

21, 349 (1963)

C14H14O4S2

Bruc. 340

Scripta, 3, 220 (1973)

C. Chang and R. Adams. J. Am. Chem. Soc., 53, 2353 (1931)

C 1 4 H 1 8 BrNO 3 COOH

abs. MeOH

N N COOH

E. Wiklund and R. Hakansson, Chemica

N

C14H16N2O4

HOOC

EtOH

S

S

S. Gronowitz and R. Beselin, Arkiv Kemi,

CHCl 3

O

O

OH OH COOCH3 COOH

C14H18O8 MeOH

Br

Bruc. 341

R. Adams and L. J. Dankert, J. Am. Chem. Soc., 62, 2191 (1940)

© 2002 by CRC Press LLC

Bruc. 342

T. Matsumoto, K. Hidaka, T. Nakayama and K. Fukui, Chem. Lett, 1 (1972)

NH2 COOH

C 1 4 H 1 9 NO 2 H2O

J. H. Poupaert, R. Cavalier, M. H. Cleasen

Bruc. 343

Bruc. 344

J. H. Poupaert, R. Cavalier, M. H. Cleasen and P. A. Dumont, J. Med. Chem., 18, 1268

1268 (1975)

(1975) C 1 4 H 1 9 NO 3

C 1 5 H 1 1 ClN 2 O 2

CN

Cl

Acetone

Acetone

N H

COOH

COOH

Bruc. 345

H. Pracejus and S. Winter, Chem. Ber.,

Bruc. 346

97, 3173 (1964) HO

HN

H. Parekh, A. R. Parikh and K. A. Thaker, J. Indian Chem. Soc., 50, 802 (1973)

C 1 5 H 1 1 FN 2 O 3

C15H12N2O2

COOH NH

MeOH

O F

H2O

and P. A. Dumont, J. Med. Chem., 18,

H N

O

C 1 5 H 1 9 NO 3

NHCHO COOH

CN

Acetone

NH O

Bruc. 347

J. H. Poupaert, J. Adline, M. H. Claesen,

Bruc. 348

P. De Laey and P. A. Dumont, J. Med.

H. Parekh, A. R. Parikh and K. A. Thaker, J. Indian Chem. Soc., 50, 802 (1973)

Chem., 22, 1140 (1979) HOOC

H N

CN

C15H12N2O2

HO

H N

CN

EtOAc

C15H12N2O3 Acetone

HOOC

Bruc. 349

H. Parekh, A. R. Parikh and K. A. Thaker,

Bruc. 350

J. Inst, Chemists (India), 45, 115 (1973)

J. Inst, Chemists (India), 45, 115 (1973)

C15H12N2O3 O HO

HN

abs. EtOH

H. Parekh, A. R. Parikh and K. A. Thaker,

NO2

OCH3

C 1 5 H 1 3 NO 5 EtOH

HOOC

NH O

Bruc. 351

J. H. Poupaert, R. Cavalier, M. H. Cleasen and P. A. Dumont, J. Med. Chem., 18, 1268 (1975)

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Bruc. 352

R. Adams and H. M. Teeter, J. Am. Chem. Soc., 62, 2188 (1940)

O

OH O

O

C15H13O6

C15H16O3

MeOH

COOH

EtOH, H 2 O

O

30:70 v/v%

COOH

M. Nakajima, J. Oda and H. Fukami, Agr.

Bruc. 353

Bruc. 354

M. Matell, Arkiv Kemi, 8, 79 (1955)

Biol. Chem., 27, 695 (1963) C15H22O3 O

COOH

EtOH

Y. Abe, T. Harukawa, H. Ishikawa, T.

Bruc. 355

C15H22O3

O COOH

Bruc. 356

Miki, M. Sumi and T. Toga, U. S. Patent

MeOH, H 2 O

M. Nakazaki and K. Naemura, Bull. Chem. Soc. Japan., 42, 3366 (1969)

2,862,953 (1958) C15H22O3 MeOH

COOH

O

C15H22O4 Acetone

OH

COOH

O

Y. Abe, T. Harukawa, H. Ishikawa, T.

Bruc. 357

Bruc. 358

J. C. Bonnafous, J. C. Mani, J. L. Olivé and

Miki, M. Sumi and T. Toga, J. Am.

M. Mousseron-Canet, Tetrahedron Lett.,

Chem. Soc., 78, 1416 (1956)

1119 (1973)

C16H11N3O3

C 1 6 H 1 2 ClNO 3

Cl

iPrOH

HOOC N

MeOH

NH O

NH

N H

O

J. W. Cornforth, J. Chem. Soc., Perkin 1,

Bruc. 359

COOH

Bruc. 360

2004 (1976)

M. K. Eberle, L. Brzechffa, G. G. Kahle, S. Talati and H. P. Weber, J. Org. Chem., 45, 3143 (1980)

C16H12N2O8 HOOC

COOH NO2

Bruc. 361

Acetone

C16H12N2O8 HOOC

NO2

D. W. Slocum and K. Mislow, J. Org. Chem., 30, 2152 (1965)

© 2002 by CRC Press LLC

COOH NO2

Bruc. 362

EtOH

NO2

H. Mix, Liebigs Ann. Chem., 592, 146 (1955)

C16H12O4

COOH

COOH

C 1 6 H 1 3 BrO 2

Br Ph

Ph COOH

Bruc. 363

K. Janczewski and K. Kurys, Rocz.

H. M. Walborsky, L. Barash, A. E. Young

Bruc. 364

Chem., 47, 661 (1973)

and F. J. Impastato, J. Am. Chem. Soc., 83, 2517 (1961)

Ph

F

Ph

C 1 6 H 1 3 FO 2

Ph

Acetone

Ph

COOH

Bruc. 365

H. M. Walborsky, L. E. Allen, H.-J.

COOH

C16H14O2 Acetone

H. M. Walborsky and F. M. Hornyak, J.

Bruc. 366

Traenckner and E. J. Powers, J. Org.

Am. Chem. Soc., 77, 6026 (1955)

Chem., 36, 2937 (1971)

C16H14O2 COOH

COOH

Acetone, CHCl 3

EtOH, H 2 O

80:20 v/v% Bruc. 367

M. Janczewski and T. Matyniea, Rocz.

COOH

157 (1935) O

C16H14O6

C 1 6 H 1 5 NO 3 NH

abs. EtOAc, MeOH 55:45 v/v%

W. Stanley, E. McMahon and R. Adams,

33:67 v/v%

Bruc. 370

J. Am. Chem. Soc., 55, 706 (1933) HOOC

MeOH, Et 2 O

HOOC

COOHCOOH Bruc. 369

50:50 v/v%

H. Wren and G. L. Miller, J. Chem. Soc.,

Bruc. 368

Chem., 40, 2029 (1966) OCH3 OCH3

C16H14O4

W. Stühmer and H. H. Frey, Arch. Pharm. (Weinheim), 286, 26 (1953)

C16H16O3

C16H16O3

EtOH

EtOH COOH

OH

Bruc. 371

OH

A. Corbellini and M. Angeletti, Atti. Acad. Lindei., 15, 968 (1932)

HOOC

OCH3 OCH3

Bruc. 372

K. Sisido, K. Kumazawa and H. Nozaki, J. Am. Chem. Soc., 82, 125 (1960)

C16H16O5

C16H18O2

Acetone OCH3

© 2002 by CRC Press LLC

COOH

M. Okigawa, Y. Kawahara, Y. Fujita, N.

Bruc. 373

H. Kuritani, S. Imajo, K. Shingu and M.

Bruc. 374

Hasaka and N. Kawano, Tetrahedron

Nakagawa, Tetrahedron Lett., 1697 (1979)

Lett., 47 (1979) COOH

HOOC

C16H20N2O4

H COOH

MeOH

C 1 6 H 2 1 NO 4 Acetone, MeOH

N

N

N

O

J. L. A. Webb, J. Org. Chem., 18, 1413

Bruc. 375

Bruc. 376

(1953) O

OH

Acetone, H 2 O COOH

Bruc. 378

D. F. Ewing and C. Y. Hopkins, Can. J. Chem., 45, 1259 (1967)

C17H10N2O6

C17H10N2O6

MeOH, Acetone

EtOH, MeOH

COOH

HOOC

NO2

NO2

NO2

E. S. Wallis and W. W. Moyer, J. Am.

Bruc. 379

33:67 v/v%

O

Chem. Soc., 73, 3448 (1951)

O2N

C16H32O4

H2O

H. E. Stavely and M. Berstecki, J. Am.

Bruc. 377

K. Wiesner, L. Poon, I. Jirkovsky and M.

HO

COOH O

O

Fishman, Can. J. Chem., 47, 433 (1969) C 1 6 H 2 3 NO 5

NH

O

H

Bruc. 380

Chem. Soc., 55, 2598 (1933) O COOH

Soc., 1188 (1931)

C17H12N2O6

CN

EtOH

N

Ph

O

M. S. Lesslie and E. E. Turner, J. Chem.

COOH Ph

C 1 7 H 1 3 NO 2 MeOH

O2N

Bruc. 381

H. F. Gram, B. J. Berridge, Jr., E. M.

Bruc. 382

E. W. Yankee, F. D. Badea, N. E. Howe

Acton and L. Goodman, J. med. Chem., 6,

and D. J. Cram. J. Am. Chem. Soc., 95,

85 (1963)

4210 (1973) C17H14O2

HOOC

© 2002 by CRC Press LLC

HOOC

C17H14O2

EtOH, H 2 O

EtOH, H 2 O

67:33 v/v%

67:33 v/v%

J. Paul and K. Schlögl, Monatsh. Chem.,

Bruc. 383

J. Paul and K. Schlögl, Monatsh. Chem.,

Bruc. 384

104, 274 (1973)

104, 274 (1973) C17H14O3

HOOC

C17H14O3

O COOH

Acetone, H 2 O

MeOH

Ph

O

M. J. Luche-Ronteix, S. Bory, M.

Bruc. 385

R. K. Hill and D. A. Cullison, J. Am.

Bruc. 386

Dvolaitzky, R. Lett and A. Marquet, Bull.

Chem. Soc., 95, 1229 (1973)

Soc. Chim. Fr., 2564 (1970) C17H16O2

COOH

C17H16O2

COOH

Acetone Ph

Bruc. 387

Ph

H. M. Walborsky, L. Barash, A. E. Young

D. T. Hefelfinger and D. J. Cram, J. Am.

Bruc. 388

Chem. Soc., 93, 4767 (1971)

and F. J. Impastato, J. Am. Chem. Soc., 83, 2517 (1961) C17H16O2

C17H16O2

EtOH

COOH

COOH

1.) MeOH, Acetone 2.) Acetone, CHCl 3 80:20 v/v%

Bruc. 389

M. Janczewski and E. Pawlowska, Rocz.

M. Janczewski and T. Matynia, Rocz.

Bruc. 390

Chem., 47, 665 (1973) Ph Ph

OCH3

Chem., 40, 2029 (1966)

C17H16O3 Acetone

COOH

HO

C17H16O5

COOH O

Acetone, MeOH 12:88 v/v%

OCH3

Bruc. 391

H. M. Walborsky, L. E. Allen, H. J.

Bruc. 392

Traenckner and E. J. Powers, J. Org.

A. Robertson, W. B. Whalley and J. Yates, J. Chem. Soc., 3117 (1950)

Chem., 36, 2937 (1971) COOH

C17H18O3 EtOH

C 1 7 H 2 3 BrO 4

O HOOC

EtOH Br O

Bruc. 393

M. S. Leslie and U. J. H. Mayer, J. Chem. Soc., 611 (1961)

© 2002 by CRC Press LLC

Bruc. 394

A. Lüttringhaus and H. Gralheer, Liebigs Ann. Chem., 550, 67 (1942)

COOH

C17H24N2O5

H H O

N H

COOH COOH

N H

H

C 1 8 H 1 1 BrO 4

MeOH Br COOH

H. Plieninger and J. Ruppert, Liebigs

Bruc. 395

K. Mislow and H. D. Perlmutter, J. Am.

Bruc. 396

Ann. Chem., 736, 43 (1970) HOOC COOH Cl

Chem. Soc., 84, 3591 (1962)

C 1 8 H 1 2 Cl 2 O 4

C18H14O4

HOOC COOH

EtOH

EtOH, H 2 O 40:60 v/v%

Cl

Bruc. 397

M. J. Brienne and J. Jacques, Bull. Soc.

M-J. Brienne and J. Jacques, Bull. Soc.

Bruc. 398

Chim. Fr., 190 (1973)

Chim. Fr., 190 (1973) C18H14O4

COOH

MeOH

HOOC

C18H16N2O5

N

COOH

EtOH

O N HOOC

Bruc. 399

S. Hagishita and K. Kuriyama,

Gj. Stefanovic, Lj. Lorenc, R. I. Mammuzic

Bruc. 400

Tetrahedron, 28, 1435 (1972)

and M. Lj. Mihailovic, Tetrahedron 6, 304 (1959)

C18H16O3

HOOC

HOOC

COOH

Acetone, H 2 O

C18H16O4 Acetone

O

Bruc. 401

M. J. Luche-Ronteix, S. Bory, M.

L. V. Dvorken, R. B. Smyth and K.

Bruc. 402

Dvolaitzky, R. Lett and A. Marquet, Bull.

Mislow, J. Am. Chem. Soc., 80, 486

Soc. Chim. Fr., 2564 (1970)

(1958)

COOH

COCH3

C18H16O6 HO

O

O

EtOH

O

C18H16O7 Acetone

COOH

O

OH COOH

Bruc. 403

R. K. Summerkbell, B. S. Sokolski, J. P.

Bruc. 404

F. M. Dean. P. Halewood, S. Mongkolsuk,

Bays, D. J. Godfrey and A. S. Hussey, J.

A. Robertson and W. B. Whalley, J. Chem.

Org. Chem., 32, 946 (1967)

Soc., 1250 (1953)

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COCH3 HO

C18H16O7

O

O

O

C18H18O2

Acetone, MeOH

COOH

O

OH

1.) MeOH, Acetone 2.) Acetone, CHCl 3 80:20 v/v%

F. M. Dean. P. Halewood, S.

Bruc. 405

Bruc. 406

M. Janczewski and T. Matynie, Rocz. Chem., 40, 2029 (1966)

Mongkolsuk, A. Robertson and W. B. Whalley, J. Chem. Soc., 1250 (1953) C18H18O3S O

C18H18O4

Acetone

S

COOH

HOOC

COOH

Bruc. 407

R. Andrisano, A. S. Angeloni, P. De

Bruc. 408

Maria and M. Tramontini, J. Chem. Soc.

M. P. Oommen and I. Vogel, J. Chem. Soc., 2148 (1930)

C, 2307 (1967) HOOC

OCH3 OCH3

COOH

C18H18O8

C18H26O2

EtOH OCH3 OCH3

Bruc. 409

HOOC

M. Okigawa, Y. Kawahara, Y. Fujita, N.

Bruc. 410

Hasaka and N. Kawano, Tetrahedron

M. Nakazaki, K. Yamamoto and M. Ito, Chem. Comm., 433 (1972)

Lett., 47 (1979) C18H26O2

C19H12N2O4

MeOH

COOH

EtOAc

N

HOOC O 2N

Bruc. 411

M. Nakazaki, K. Yamamoto, M. Ito and S. Tanaka, J. Org. Chem., 42, 3468 (1977) OH

Bruc. 412

W. I. Patterson and R. Adams, J. Am. Chem. Soc., 55. 1069 (1933)

C19H16O3

C19H18O2

EtOAc, EtOH

abs. EtOAc COOH

© 2002 by CRC Press LLC

Bruc. 413

K. Sisido, K. Kumazawa and H. Nozaki,

Bruc. 414

J. Am. Chem. Soc., 82, 125 (1960)

M. S. Newman and A. S. Hussey, J. Am. Chem. Soc., 69, 3023 (1947)

C 1 9 H 1 9 BrO 3 Br COOH

MeOH

C 1 9 H 1 9 ClO 3 Cl

O

Bruc. 415

MeOH COOH O

E. J. Cragoe, Jr., and A. M.

Bruc. 416

E. J. Cragoe, Jr., and A. M.

Pietruszkiewicz, J. Org. Chem., 22, 1338

Pietruszkiewicz, J. Org. Chem., 22, 1338

(1957)

(1957) C 1 9 H 1 9 FO 3

F COOH

C19H20O2

MeOH

COOH

EtOH

O

Bruc. 417

E. J. Cragoe, Jr., and A. M.

Bruc. 418

Pietruszkiewicz, J. Org. Chem., 22, 1338

M. Janczewski and E. Pawlowska, Rocz. Chem., 47, 665 (1973)

(1957) COOH

C20H13O3

HOOC

COOH

Acetone

C20H18O4 EtOH, H 2 O 70:30 v/v%

H Bruc. 419

OH W. Tochtermann and K. Stecher,

Bruc. 420

Tetrahedron Lett., 3847 (1967) HOOC

COOH

H3CO

M. J. Brienne and J. Jacques, Bull. Soc. Chim. Fr., 190 (1973)

C20H18O4

C20H22O2

EtOAc

Acetone

OCH3

HOOC

Bruc. 421

S. Hagishita and K. Kuriyama,

Bruc. 422

Tetrahedron, 28, 1435 (1972)

D. J. Cram, W. J. Wechter and R. W. Kierstead, J. Am. Chem. Soc., 80, 3126 (1958)

OCH3

HOOC

C20H22O6 H2O

H3CO

COOH

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Cl

COOH

C 2 1 H 1 3 ClO 2 EtOH

Bruc. 423

A. L. Wilds and R. E. Sutton, J. Org.

Y. Sakata, F. Ogura and M. Nakagawa,

Bruc. 424

Chem., 16, 1371 (1951) COOH

Bull. Chem. Soc. Japan., 46, 611 (1973)

C 2 1 H 1 3 ClO 2

C21H14O2

EtOH, H 2 O Cl

Bruc. 425

COOH

99:1 v/v%

Y. Sakata, F. Ogura and M. Nakagawa,

J. Meisenheimer and O., Beisswenger,

Bruc. 426

Bull. Chem. Soc. Japan., 46, 611 (1973) HOOC

C21H14O2

H

Acetone

Bruc. 427

EtOAc, MeOH

W. Tochtermann, H. Kuppers and C.

Chem. Ber., 65, 32 (1932) O2 N

Bruc. 428

Franke, Chem. Ber., 101, 3808 (1968)

COOH

C 2 1 H 2 3 NO 5 EtOAc

K. V. Narayanan, R. Selvarajan and S. Swaminathan, J. Chem. Soc. C, 540 (1968)

C22H14O4 COOH

O C

COOH

MeOH

C22H14O4 EtOH

HOOC

COOH Bruc. 429

A. Corbellini, Atti. Acad. Lincei, 13, 702

Bruc. 430

(1931)

COOH

F. Bell and W. H. D. Morgan, J. Chem. Soc., 1716 (1954)

C22H14O6

C22H16O2

EtOH

EtOH

COOH

HO

HO

COOH Bruc. 431

K. Well and W. Kuhn, Helv. Chim. Acta, 27, 1648 (1944)

© 2002 by CRC Press LLC

Bruc. 432

M. H. Harris, R. Z. Mazengo and A. S. Cooke, J. Chem. Soc. C, 2575 (1967)

COOH

OCH3

COOH

C22H16O3 Acetone

EtOH, H 2 O 99:1 v/v%

OCH3

Y. Sakata, F. Ogura and M. Nakagawa,

Bruc. 433

Y. Sakata, F. Ogura and M. Nakagawa,

Bruc. 434

Bull. Chem. Soc. Japan., 46, 611 (1973) O

C22H16O4 COOH

EtOH

C22H16O3

Bull. Chem. Soc. Japan., 46, 611 (1973) C22H18O8

H3COOC HOOC

COOCH3

MeOH

OH

HOOC H. Goudet, Helv. Chim. Acta, 14, 379

Bruc. 435

S. Hagishita and K. Kuriyama, Tetrahedron,

Bruc. 436

(1931)

28, 1435 (1972)

H3COOC

O

C22H18O8

COOCH3

O S

C22H20O6S3

S

MeOH

COOH

EtOH HOOC

HOOC

S. Hagishita and K. Kuriyama,

Bruc. 437

Bruc. 438

F. B. Kipping, J. Chem. Soc., 18 (1935)

Tetrahedron, 28, 1435 (1972) HOOC

C22H24N2O4

COOHCOOH

MeOH

N

abs. EtOH O

N

C22H24O6

O

HOOC

Bruc. 439

C. Chang and R. Adams, J. Am. Chem.

Bruc. 440

Soc., 56, 2089 (1934)

R. Adams and N. Kornblum, J. Am. Chem. Soc., 63, 188 (1941)

C22H26O4

C24H18O4

EtOH HOOC

Bruc. 441

COOH

M. S. Leslie and U. J. H. Mayer, J. Chem. Soc., 611 (1961)

© 2002 by CRC Press LLC

COOEt

EtOAc

HOOC

Bruc. 442

J. Meisenheimer and O. Beissenwenger, Chem. Ber., 65, 32 (1932)

C24H28O6

COOHCOOH

C25H16O2

MeOH O

EtOH

COOH

O

R. Adams and N. Kornblum, J. Am.

Bruc. 443

D. Gust, G. H. Senkler, Jr., and K.Mislow,

Bruc. 444

Chem. Soc., 63, 188 (1941) O

H

C25H16O2

COOH

O

C25H24O8

H

O

EtOH

H

O

Chem. Comm., 1345 (1972)

EtOH O

O

COOH

HOOC

H

O

A. Sonoda, F. Ogura and M. Nakagawa,

Bruc. 445

H. J. Backer and H. G. Kemper, Rec. Trav.

Bruc. 446

Bull. Chem. Soc. Japan., 35, 853 (1961)

N

C26H16N2O8

COOHCOOH N

Ph

Chim., 57, 1249 (1938)

Ph

EtOAc

EtOH

COOH COOH

HO Ph

E. H. Woodruff and R. Adams, J. Am.

Bruc. 447

COOH

C28H18N2O4

Ph

A. Corbellini and C. Pizzi, Atti Acad.

Bruc. 448

Chem. Soc., 54, 1977 (1932) HOOC

C26H20O3

HOOC

Lincei, 15, 287 (1932) HOOC

COOH

EtOH

EtOH

N

N

N

N

Ph

Ph

Ph

Ph

F. Bell, J. Chem. Soc., 1527 (1952)

Bruc. 449

C28H18N2O4

Bruc. 450

D. M. Hall and J. M. Insole, J. Chem. Soc., 2326 (1964)

COOH O O

C28H20O4

C30H18O4

MeOH

EtOH

Ph C Ph

© 2002 by CRC Press LLC

HOOC

COOH

E. P. Kohler, J. R. Walker, M. Tishler, J.

Bruc. 451

S. Goldschmidt, R. Riedle and A.

Bruc. 452

Am. Chem. Soc., 57, 1743 (1935)

Reichardt, Liebigs Ann. Chem., 604, 121 (1957)

C4H8O4

OH

COOH

H2O

COOH

J. W. E. Glattfield and J. W. Chittu, J.

J. W. E. Glattfield and L. R. Forbich, J.

Bruc. 454

Am. Chem. Soc., 55, 3663 (1933) C 4 H 9 NO 3

OH

COOH

Am. Chem. Soc., 56, 1209 (1934) C 4 H 9 NO 3

OH

COOH

MeOH

MeOH

NH2

NH2

T. Inui and T. Kaneko, Nippon Kagaku

Bruc. 455

H 2 O, EtOH

OH

OH

Bruc. 453

C4H8O5

OH

T. Inui and T. Kaneko, Nippon Kagaku

Bruc. 456

Zasshi, 82, 1078 (1961)

Zasshi, 82, 1078 (1961)

C7H10O3

COOH

H N

COOH

C 9 H 1 1 NO 2 EtOAc

O

A. Numata, T. Suzuki, K. Ohno and S.

Bruc. 457

T. Araga, T. Saito and H. Kotake, Nippon

Bruc. 458

Uyeo, Yakugaku Zasshi, 88, 1298 (1968) HOOC

O

Kagaku Zasshi, 86, 111 (1965)

C 9 H 1 5 NO 3 S

N

O

H2O

C 1 0 H 1 3 NO 4 S

O

S

N H

COOH

S

W. M. Duffin and S. Wilkinson, British

Bruc. 459

E. Takagi, Yakugaku Zasshi, 71, 658

Bruc. 460

Patent 585,413 (1947)

(1951)

C12H10N2O5

O

C 1 2 H 1 1 NO 4

O

COOH COOH

CONH2

O

O

Bruc. 461

EtOH

N

N

T. Tohyama and M. Onda, Yakugaku Zasshi, 84, 372 (1964)

© 2002 by CRC Press LLC

Bruc. 462

A. H. Beckett, G. Kirk and R. Thomas, J. Chem. Soc., 1386 (1962)

C 1 2 H 1 3 NO 3

O

H2O

O

C 1 2 H 1 3 NO 5 S N S

O

HN

EtOH

COOH

O

COOH

P. Karrer and H. Schneider, Helv. Chim.

Bruc. 463

Bruc. 464

Acta, 13, 1281 (1930) COOHCOOH O2 N

Chem. Comm., 19, 386 (1954) COOHCOOH

C14H7N3O10 H2O

NO2

O 2N

C14H7N3O10 NO2

NO2

Acetone

NO2

G. H. Christie and J. Kenner, J. Chem.

Bruc. 465

J. Ridinger and H. Czurbova, Coll. Czecz.

Bruc. 466

Soc., 123, 779 (1923) COOH

R. Kuhn and O. Albrecht, Liebigs Ann., 458, 221 (1927) NH2

C14H8I2O4 abs. MeOH

I

COOH

C 1 5 H 1 3 I 3 NO 3 iPrOH

I

I

O

I

HOOC I

N. W. Searle and R. Adams, J. Am.

Bruc. 467

Bruc. 468

Chem. Soc., 55, 1649 (1933) HOOC

F

F

COOH

C16H12F2O6

H. Nahm and W. Siedel, Chem. Ber., 96, 1 (1963)

OCH3 OCH3

COOH

EtOH, Acetone

C16H16O5 Acetone

80:20 v/v% OCH3 OCH3

N. Kawano, M. Okigawa, N. Hasaka, I. Kouno, Y. Kawahara and Y. Fujita, J. Org. Chem., 46, 389 (1981)

Bruc. 469

OH COOH H

Bruc. 471

C17H16O3

H

E. Wyrzykiewicz, M. Kielczewski and J. Bartz, Zeszyty Nauk Uniw. Poznaniu Mat., Fiz., Chem. 29 (1965); Chem. Ab. 65, 3781C (1966)

© 2002 by CRC Press LLC

Bruc. 470

HOOC

N. Kawano, M. Okigawa, N. Hasaka, I. Kouno, Y. Kawahara and Y. Fujita,k J. Org. Chem., 46, 389 (1981)

OCH3 OCH3

Dioxane, H 2 O 50:50 v/v%

C C Ph

OCH3

COOH

C18H18O8 EtOH

OCH3 OCH3

Bruc. 472

N. Kawano, M. Okigawa, N. Hasaka, I. Kouno, Y. Kawahara and Y. Fujita,k J. Org. Chem., 46, 389 (1981)

HO

COOH

C18H34O6

HO

COOH

abs. EtOH

COOH H N

O

NH

C11H14N2O4 MeOH

O

Bruc. 473

W. J. Gensler and H. N. Schlein, J. Am.

Bruc. 474

Chem. Soc., 78, 169 (1956)

J. Ezquerra, B.Yruretagoyena, C. Avendaňo, E. de la Cuesta, R. González, L. Prieto, C. Pedregal, M. Espada and W. Prowse, Tetrahedron, 51, 3271 (1995)

HOOC

O

N

C 1 1 H 1 1 NO 3

C32H22O2

Acetone

EtOH, CH 2 Cl 2

OH OH

Ph Ph

Bruc. 475

I. Zadrozna, J. Kurkowska and I. Makuch,

Bruc. 476

Synth. Comm, 27, 4181 (1997)

J. Bao, W. D. Wulff, J. B. Dominy, M. J. Fumo, E. B. Grant, A. C. Rob, M. C. Whitcomb, S.-M. Yeung, R. L. Ostrander and A. L. Rheingold, J. Am. Chem. Soc., 118, 3392 (1996)

C12H14O4

O

COOH COOH

Bruc. 477

C12H14O4

C. Rosini, R. Tanturli, P. Pertici and P.

Bruc. 478

COOH

EtOAc

R. Alajarin, J. J. Vaquero, J. Alvarez-

Salvadori, Tetrahedron Asymmetry, 7,

Builla, M. Pastor, C. Sunkel, M. F. de Casa-

2971-2982, (1996)

Juana, J. Priego, P. R. Statkow, J. SanzAparicio and I. Fonseca, J. Med. Chem., 38, 2830 (1995) C12H8N2O6

O N

COOH

O N

COOH

© 2002 by CRC Press LLC

H2O

OH O P OH O

C9H13O4P EtOH, Et2O 25:75 v/v%

M. Tichý, J. Závada, J. Podlaha and P.

Bruc. 479

Bruc. 480

F. Hammerschmidt and A. Hanninger, Chem. Ber., 128, 823 (1995)

Vojtíšek, Tetrahedron Asymmetry, 6, 1279 (1995) COOH H N

O

C 2 1 H 2 4 NO 3

HOOC

NH2 COOH

H

EtOH

C 7 H 1 1 NO 4

CH2Ph

A. A. Asselin and J. Schmid, U. S. Patent,

Bruc. 481

Bruc. 482

4, 925, 955, (1990)

J. Ezquerra, B. Yruretagoyena, C. Avendaňo, E. de la Cuesta, R. González, L. Prieto, C. Pedregal, M. Espada and W. Prowse, Tetrahedron, 51, 11, 3271(1995)

C 1 0 H 1 5 NO 4

COOH

NH2 COOH

J. Ezquerra, B. Yruretagoyena, C.

Bruc. 483

C 1 0 H 1 5 NO 4

COOH

NH2 COOH

Avendaňo, E. de la Cuesta, R. González,

Bruc. 484

J. Ezquerra, B. Yruretagoyena, C. Avendaňo, E. de la Cuesta, R. González, L.

L. Prieto, C. Pedregal, M. Espada and W.

Prieto, C. Pedregal, M. Espada and W.

Prowse, Tetrahedron, 51, 11, 3271(1995)

Prowse, Tetrahedron, 51, 11, 3271(1995)

Cinchonin C 3 H 5 BrO 2

Br

COOH

Cincho. 1

H2O

E. Fischer and O. Warburg, Liebigs Ann.,

C4H6O5

OH HOOC

Cincho. 2

COOH

MeOH

H. D. Dakin, J. Biol. Chem., 59, 7 (1924)

340, 123 (1905)

HO H

Cincho. 3

COOH H OH COOH

C4H6O5

H2O

O

COOH

H2N

J. Read, W.G. Reid, J. Soc. Chem. Ind.,

Cincho. 4

Cincho. 5

H 2 O, EtOH

G. Adembri and M. Ghelardoni, Gazz. Chim. Ital., 89, 1763 (1959)

C 5 H 9 NO 2 COOH

C4H8N2O3

75:25 v/v %

8T, (1928)

N H

NH2

EtOH

O

H2N

NH2

COOH

C5H10N2O3

EtOH, H 2 O 38:62 v/v %

E. Fischer and G. Zemplen, Chem. Ber., 42, 2989 (1909)

© 2002 by CRC Press LLC

Cincho. 6

G. Adembri and M. Ghelardoni, Gazz. Chim. Ital., 89, 1763 (1959)

O

CBZ

HN

COOH

H2N

C13H16N2O6

EtOH, H 2 O

COOH

38:62 v/v % G. Adembri and M. Ghelardoni, Gazz.

Cincho. 7

C6H5N3O2S

N3

S

S. Gronowitz, I. Sjögren, L. Wernstedt and

Cincho. 8

Chim. Ital., 89, 1763 (1959)

B. Sjöberg, Arkiv Kemi, 23, 129 (1964)

C6H6O5

HOOC

COOH

O

H2O

EtOAc

C6H8O4

O

O

COOH

EtOH, H 2 O 95:5 v/v %

H. B. Hill and F. W. Russe, Chem. Ber.,

Cincho. 9

Cincho. 10

K. Mori, Tetrahedron, 31, 1381 (1975)

37, 2538 (1904) C6H10O4 COOH

HOOC

H2O

E. Berner and R. Leonardsen, Liebigs

Cincho. 11

C6H10O6S HOOC

O

Cincho. 12

Ann. Chem., 538, 1 (1939)

S

O

Chim., 46, 212 (1927) COOH

EtOAc, MeOH

M. Matell, Acta Chem. Scand., 14, 677

Cincho. 14

C 1 3 H 1 7 NO 3

E. Fischer and R. Hagenbach, Chem. Ber.,

Cincho. 15

C7H10O4

HOOC

H2O

NH

benzoyl

E. Fischer and R. Hagenbach, Chem. Ber., 34, 3764 (1901)

(1960)

COOH

C 6 H 1 3 NO 2

H2O

NH2

S

Cincho. 13

H2O

H. J. Backer and W. Heijer, Rec. Trav.

C 6 H 1 1 NO 3 S COOH

O

N

COOH

O

O

Cincho. 16

34, 3764 (1901)

EtOH

M. Matsui, T. Ohno, s. Kitamura and M. Toyao, Bull. Chem. Soc. Japan., 25, 210 (1952)

C7H10O4S3

S HOOC

S

S

COOH

EtOH, H 2 O

OH

O2 N

COOH

C 8 H 7 NO 5

H2O

50:50 v/v% Cincho. 17

A. Fredga and A. Björn, Arkiv Kemi, 23,

COOH

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A. Fredga and E. Andersson, Arkiv Kemi, Mineral. Geol., 14B, No. 18 (1940)

91 (1964) OH

Cincho. 18

C8H8O3

Acetone, CHCl 3

NH2 COOH

C 8 H 9 NO 2

H2O

J. L. Norula and J. Kenyon, Current Sci.

Cincho. 19

Cincho. 20

(India), 32, 260 (1963)

E. Fischer and Weichhold, Chem. Ber., 41, 1286 (1908); M. Betti and M. Mayer, Chem. Ber., 41, 2071 (1908)

O

HN

COOH

C 9 H 9 NO 3

H2O

E. Fischer and Weichhold, Chem. Ber.,

Cincho. 21

C 8 H 9 NO 3

OH COOH

Cincho. 22

41, 1286 (1908); M. Betti and M. Mayer,

H2O

C.W. Porter and H. K. Ihrig, J. Am. Chem. Soc., 45, 1990 (1923)

Chem. Ber., 41, 2071 (1908) C8H10O3

COOH

EtOH, H2O H

HOOC

95:5 v/v%

O

K. Mori, Tetrahedron, 34, 915 (1978)

Cincho. 23

C8H14O6S

COOH

Cincho. 24

C 9 H 7 Cl 3 O 3

Cl

S

O

COOH

H2O, EtOH 35:65 v/v%

R. Ahlberg, Chem. Ber., 61B, 811 (1928) COOH

H 2 O, EtOH

O

O

C 9 H 8 ClNO 5

H 2 O, EtOH

O Cl

80:20 v/v%

40:60 v/v%

Cl NO2

Cl Cincho. 25

Ph. D. Thesis of Magnus Matell, Uppsala,

Cincho. 26

C 9 H 9 NO 6

OH O 2N

COOH

H3CO

Cincho. 27

A. Fredga, E. Gamstedt and L. Ekermo, Arkiv Kemi, 29, 515 (1968)

Sweden (1953)

OH COOH

H 2 O, EtOH 20:80 v/v%

P. Pratesi, A. La Manna, A. Campiglio

C9H10O4

H2O

H3CO

Cincho. 28

and V. Ghislandi, J. Chem. Soc., 2069

A. McKenzie and D. J. D. Pirie, Chem. Ber., 69, 861 (1936)

(1958) OH H3CO

COOH

C9H10O5

Acetonitrile

COOH NH2

C 9 H 1 1 NO 2

H2O

HO

Cincho. 29

M. D. Armstrong, A. McMillan and K. N. Cincho. 30 F. Shaw, Biochem. Biophys, Acta, 25, 422 (1957)

© 2002 by CRC Press LLC

E. Fischer and A. Mouneyrat, Chem. Ber., 42, 2383 (1909)

COOH HN

C 1 6 H 1 5 NO 3

H2O

benzoyl

E. Fischer and A. Mouneyrat, Chem. Ber.,

Cincho. 31

C 9 H 1 1 NO 2

COOH NH2 D. J. Cram. L. K. Gaston and H. Jager, J.

Cincho. 32

42, 2383 (1909) COOH

Am. Chem. Soc., 83, 2183 (1961) C 9 H 1 1 NO 4

MeOH

NH2

HO

COOH

HN

HO

benzoyl

MeOH

OH

OH

German Patent 1,963,992 (1973)

Cincho. 33

S

German Patent 1,963,992 (1973)

Cincho. 34

C9H12O2S4

COOH

COOH

EtOH

S

63:37 v/v%

M-O. Hedblom and K. Olsson, Arkiv

Cincho. 35

C10H12O3

EtOH, H 2 O

O

S CS

Cincho. 36

Kemi, 32, 309 (1970) HO

C 1 6 H 1 5 NO 5

A. Fredga and M. Andersson, Arkiv Kemi, 21, 555 (1964)

COOH

C10H12O4

O

H2O

COOH

HO

C10H12O5

EtOH

OCH3

OCH3 A. Weissberger and E. Dym, Liebigs Ann.

Cincho. 37

Cincho. 38

Chem., 502, 74 (1933)

N O

Cincho. 39

(1960)

C 1 1 H 1 1 NO 5 S

O

S O COOH

A. La Manna, Rarmaco, Ed. Sci., 15, 9

COOH

C11H12O2

Acetone, H 2 O

EtOH, H 2 O

83:17 v/v%

60:40 v/v%

C. M. Svahn and N. A. Jonsson, Acta

Cincho. 40

L. Westman, Arkiv Kemi, 12, 161 (1957)

Chem. Scand., B32, 137 (1978) O

COOH

C11H12O5

OCH3

Cincho. 41

G.R. Clemo, W. A. Cummings and R. Raper, J. Chem. Soc., 1923 (1949)

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COOH

H2O

H3CO

C 9 H 1 1 NO 3

OH

H2O

NH2 Cincho. 42

C. Alberti, B. Camerino and A. Vercellone, Gazz. Chim. Ital., 83, 930 (1953)

C 1 1 H 1 3 NO 4

OH COOH

COOH

H2O

C11H14O3

EtOH, H 2 O

O

HN

50:50 v/v% O

C. Alberti, B. Camerino and A.

Cincho. 43

Cincho. 44

Vercellone, Gazz. Chim. Ital., 83, 930

A. Fredga and U. Löfroth, Arkiv Kemi, 23, 239 (1965)

(1953) C11H14O3

OH COOH

C11H16O5

EtOH

EtOH O O

Cincho. 45 Br

M. Fileti, J. Prakt. Chem., 46, 560 (1892) COOH S

S HOOC

Cincho. 47

Cincho. 46

O

French Patent 1,496,817 (1967)

C 1 2 H 8 Br 2 O 4 S 2

OH

EtOH, H 2 O

COOH

EtOH

50:50 v/v% Br

S. Gronowitz and H. Frostling, Acta

Cincho. 48

Chem. Scand., 16, 1127 (1962)

A. McKenzie and W. S. Dennler, Chem. Ber., 60, 220 (1927)

C12H10O3S

OH COOH

COOH

EtOAc

75:25 v/v%

N Ph. D. Thesis of B. W. J. Ellenbroek,

C 1 2 H 1 3 NO 2

EtOH, H 2 O

S

Cincho. 49

C12H10O3

Cincho. 50

Catholic University of Nijmegen,

A. Fredga and L-B. Agensas, Arkiv Kemi, 15, 327 (1960)

Rotterdam, The Netherlands (1964) O

O

O

C 1 2 H 1 3 NO 5

COOH

abs. EtOH

HN

C13H10O2

MeOH

COOH

Cincho. 51

S. Yamada, T. Fujii and T. Shioiri, Chem. Pharm. Bull., 10, 680 (1962)

© 2002 by CRC Press LLC

Cincho. 52

A. Fredga and T. Svensson, Arkiv Kemi, 25, 81 (1965)

COOH

O

C 1 3 H 1 1 ClO 3

MeOH, H 2 O

Cl

P. M. Pope and D. Woodcock, J. Chem.

Cincho. 53

C13H12O2

EtOH

COOH

B. Sjöberg, Arkiv Kemi, 9, 295 (1956)

Cincho. 54

Soc., 577 (1955) C13H12O3

COOH

EtOH

O

Cincho. 55

E. Fourneau and Balaceano, Bull. Soc.

C 8 H 9 NO 3

M. S. Smith and R. L. Wain, Proc. Roy.

Cincho. 56

Soc., 139B, 118 (1951) COOH HO O

HO Cincho. 57

C. W. Ryan, U. S. Patent 3,705,900

C 1 3 H 1 7 NO 5

NH

EtOAc

NH2

EtOH

COOH

Chim. Fr., 37, 1602 (1925)

COOH

C13H12O3

O

EtOAc

O

C. W. Ryan, U. S. Patent 3,705,900 (1972)

Cincho. 58

(1972) HO

HO

OH

OH

HO

OH HOOC

Cincho. 59

C14H10O10

H N

COOH

C 1 4 H 1 3 NO 2

EtOH

EtOH

COOH

O. T. Schmidt and K. Demmler, Liebigs

Cincho. 60

Ann. Chem., 586, 179 (1954)

A. McKenzie and S. C. Bate, J. Chem. Soc., 107, 1681 (1915)

C 1 4 H 1 3 NO 4

OH N

C14H14O3

MeOH

COOH

O

OH

EtOH, H 2 O 46:54 v/v%

COOH

Cincho. 61

J. Meisenheimer, W. Theilacker and

Cincho. 62

M. Matell, Arkiv Kemi, 6, 251 (1953)

O. Beisswenger, Liebigs Ann. Chem., 495, 249 (1932) C14H14O4S2

Cl

COOH

Acetone, H 2 O

S

S

HOOC

COOH

© 2002 by CRC Press LLC

50:50 v/v%

C 1 4 H 1 6 Cl 2 O 8

H2O HOOC HOOC

COOH Cl

R. Hakansson, Chemica Scripta, 3, 177

Cincho. 63

Cincho. 64

(1973)

H. Stetter and O. E. Bander, Chem. Ber., 88, 1535 (1955)

C 1 4 H 1 7 NO 3

COOH

C15H14O3

OH Ph

MeOH

COOH

EtOH

CONHPh

R. Stoermer and H. J. Steinbeck, Chem.

Cincho. 65

Cincho. 66

Ber., 65, 413 (1932)

Soc., 74, 1060 (1952) C15H14O4

OH Ph

COOH

K. Mislow and M. Siegel, J. Am. Chem.

Acetone

Cl

C 1 5 H 1 6 Cl 2 O 3

O

Cl

CH 3 CN

O COOH

OCH3 A. G. Davies, F. M. Ebeid and J. Kenyon,

Cincho. 67

Cincho. 68

J. Chem. Soc., 3154 (1957)

E. J. Cragoe, Jr., E. M. Schultz, J. D. Schneeberg, G. E. Stokker, O.W. Woltersdorf, Jr., G. M. Fanelli, Jr., L. S. Watson, J. Med. Chem., 18, 225 (1975)

HOOC

COOH

C16H12O6S

Cl

C 1 6 H 1 6 Cl 2 O 4

O

Cl

EtOH, H 2 O S O

65:35 v/v%

O

EtOH O COOH

W. E. Truce and D. D. Emrick, J. Am.

Cincho. 69

Cincho. 70

Chem. Soc., 78, 6130 (1956)

E. J. Cragoe, Jr., E. M. Schultz, J. D. Schneeberg, C. E. Stokker, O. W. Woltersdorf, Jr., G. M. Panelli, Jr., L. S. Watson, J. Med. Chem., 18, 225 (1975)

HOOC

N

SO2Ph NO2

C16H16N2O6S

OH

EtOAc, EtOH

Ph

30:70 v/v%

Cincho. 71

R. Adams and J. R. Gordon, J. Am. Chem. Soc., 72, 2458 (1950)

© 2002 by CRC Press LLC

COOH

C16H16O4

EtOH

H3CO

Cincho. 72

K. Sisido, K. Kumazawa and H. Nozaki, J. Am. Chem. Soc., 82, 125 (1960)

Cl

C 1 7 H 1 3 ClO 3

C18H16O3

Acetone

CH 3 CN

O

COOH

COOH

T. Aono, S. Kishimoto, Y. Araki and S.

Cincho. 73

HOOC Ph H

H

Noguchi, Chem. Pharm. Bull, 26, 1776

Noguchi, Chem. Pharm. Bull, 26, 1776

(1978)

(1978)

COOH H

C18H16O4

abs. EtOH

Ph

HOOC Ph H

H R. Stoermer, Chem.Ber., 56, 1683 (1923)

Cincho. 75

T. Aono, S. Kishimoto, Y. Araki and S.

Cincho. 74

C18H16O4

HH

EtOH, H 2 O

COOH Ph

H

68:32 v/v%

R. Stoermer and F. Bacher, Chem. Ber., 55,

Cincho. 76

1874 (1922) H Ph HOOC

H

H COOH

C18H16O4

EtOH

H Ph

HOOC

R. Stoermer and F. Bacher, Chem. Ber.,

Cincho. 77

H Ph H

Cincho. 78

55, 1860 (1922)

C18H16O4

COOH Ph

EtOH, H 2 O 75:25 v/v%

R. Stoermer and F. Scholtz, Chem. Ber., 54, 85 (1921)

C 1 8 H 1 7 ClO 3

C18H18O4

COOHCOOH

EtOH

COOH

O

HH

EtOH

Cl

E. J. Cragoe, Jr., A. M. Pietruszkiewicz

Cincho. 79

Cincho. 80

and C. M. Robb, J. Org. Chem., 23, 971

S. Gronowitz and J. E. Skramstead, Arkiv Kemi, 28, 115 (1967)

(1958) PhSO2

N

COOH

C 1 8 H 2 1 NO 4 S

PhSO2

N

EtOAc

COOH

C 1 9 H 1 6 BrNO 4 S

EtOAc, MeOH 90:10 v/v% Br

Cincho. 81

R. Adams and J. S. Dix, J. Am. Chem. Soc., 80, 4579 (1958)

© 2002 by CRC Press LLC

Cincho. 82

R. Adams and R. H. Mattson, J. Am. Chem. Soc., 76, 4925 (1954)

PhSO2

COOH

N

C 1 9 H 1 6 ClNO 4 S

PhSO2

COOH

N

EtOAc, MeOH

C19H16N2O6S

EtOAc

90:10 v/v% Cl

NO2

R. Adams and R. H. Mattson, J. Am.

Cincho. 83

R. Adams and K. V. Y. Sundstrom, J. Am.

Cincho. 84

Chem. Soc., 76, 4925 (1954)

Chem. Soc., 76, 5474 (1954)

C20H18O8

EtOH HOOC

OH

H

OCH3

C22H26O8

OCH3

MeOH, CHCl 3 60:40 v/v%

O

O O

O O

O

COOH

H

HO

OCH3 OCH3

J. H. Hunt, J. Chem. Soc., 1926 (1957)

Cincho. 85

L. R. Row, P. Satyanarayana and G. S. R.

Cincho. 86

Subba Rao, Tetrahedron, 23, 1915 (1967) O

C30H14O8

COOH

O

abs. EtOH

C11H16O5

O

EtOH

O

COOH

O

O

HOOC

Cincho. 87

O

F. Bell and W. H. D. Morgan, J. Chem.

Cincho. 88

Soc., 1963 (1950) COOH O

French Patent 1496817 (1967) C 1 5 H 1 2 Cl 2 O 4

C 2 2 H 1 4 ClO 4

Cl

H 2 O, CH 3 CN

MeOH

50:50 v/v% Cl

R. Boccurt, M. Vignau and J. Raynal,

H O

O

O

HOOC Cl

Cincho. 89

H. Nahm and W. Siedel, Chem. Ber., 96, 1 (1963)

Cincho. 90

S. Stanchev, R. Rakovska, N. Berova and G. Snatzke, Tetrahedron Asymmetry, 6, 183 (1995)

© 2002 by CRC Press LLC

Cl

C 2 2 H 1 1 ClF 3 O 4

Cl

MeOH

N

C23H23N3O3 iPr

H O

O

N NH

O

HOOC

HOOC F3C

S. Stanchev, R. Rakovska, N. Berova and

Cincho. 91

Cincho. 92

G. Snatzke, Tetrahedron Asymmetry, 6,

M. T. David-Comte, G. Roussel, U. S. Patent 5, 498, 716 (1996)

183 (1995) Cl

C 1 8 H 1 2 ClN 3 O 3

N

O

NO2

NO2

C15H19N3O4

O

N N

COOH

O COOH

N H G. Goto and N. Fukuda, Eur. Pat. Appl.

Cincho. 93

Cincho. 94

EP 602, 814 (1994)

T. Ogawa, K. Matsumoto, C. Yokoo, K. Hatayama and K. Kitamura, J. Chem. Soc. Perkin Trans. 1, 525 (1993)

C 2 3 H 2 3 ClN 3 O 3

Cl N N NH

O

HOOC

Cincho. 95

M. T. D. Comte, Eur. Pat. Appl. EP 522, 971 (1993)

Cinchonidine C4H6O2S2 S

S

COOH

COOH

EtOH, H 2 O

Cl

G. Cleason, Arkiv Kemi, 30, 277 (1968)

Acetone, MeOH 80:20 v/v %

50:50 v/v % Cidin. 1

C 4 H 7 ClO 2

Cidin. 2

A. T. Bottini, V. Dev and M. Stewart, J. Org. Chem., 28, 156 (1963)

© 2002 by CRC Press LLC

C 4 H 9 NO 2

COOH

H2N

C 6 H 1 1 NO 3

O

iPrOH Y. Kakimoto and M. D. Armstrong, J.

Cidin. 3

Chem., 236, 3283 (1961)

C 4 H 9 NO 2

H

COOH

HOOC

H

COOH

COOH S

Cidin. 6

Bull. Chem. Soc. Japan, 42, 1393 (1969)

C5H6O4S2

C5H8O2

MeOH

S

M-O. Hedblom, Arkiv Kemi, 31, 489

Cidin. 7

O

O

Acetone, MeOH

H. Minato, Chem. Pharm. Bull., 9, 625

Cidin. 8

(1969)

(1961) C5H8O2S

COOH

S

H 2 O, EtOH

S. Inamasu, M. Horiike and Y. Inouye,

Patent 3,636,093 (1972) HOOC

C5H6O4

80:20 v/v %

A. M. Hoinowski and D. F. Hinkley, U. S.

Cidin. 5

iPrOH

Y. Kakimoto and M. D. Armstrong, J. Biol.

Cidin. 4

Biol. Chem., 236, 3283 (1961)

H2O

COOH

N H

C 5 H 9 BrO 2

COOH

EtOH

Acetone

Br

G. Cleason and H-G. Jonsson, Arkiv

Cidin. 9

Cidin. 10

Kemi, 26, 247 (1966)

J. Biol. Chem., 75, 337 (1927)

C 5 H 9 BrO 2

COOH

P. A. Levene, T. Mori, and L. A. Mikeska,

COOH

Acetone

MeOH, H 2 O

Br

40:60 v/v % H. Auterhoff and W. Lang, Arch. Pharm.

Cidin. 11

Cidin. 12

(Weinheim), 303, 49 (1970) C5H10O2S

COOH

COOH

S

Acetone

P. A. Levene, T. Mori, and L. A.

NH2 Cidin. 14

Mikeska, J. Biol. Chem.,75, 337 (1927)

EtOH

T. Tanabe, S. Yajima and M. Imaida, Bull. Chem. Soc. Japan., 41, 2178 (1968)

© 2002 by CRC Press LLC

EtOH

H. Baganz, H. Baganz and E. Vorwerk,

OH COOH Cidin. 16

C6H6O3S

H 2 O, EtOH

S

NH2

Cidin. 15

C 5 H 1 1 NO 2 S

Chem. Ber., 86, 1242 (1953)

C 6 H 1 3 NO 2 COOH

K. Freudenberg and W. Lwowski, Liebigs Ann. Chem.,592, 76 (1955)

SH

Cidin. 13

C 5 H 1 0 NO 2

80:20 v/v %

S. Gronowitz, Arkiv Kemi, 13, 87 (1958)

HOOC

O

C6H6O7

COOH

HOOC

MeOH, EtOAc

H

R. W. Guthrie, J. G. Hamilton, R. W.

Cidin. 17

COOH C

C6H8O2

Acetone

H

W. Runge, G. Kresze and E. Ruch, Liebigs

Cidin. 18

Kierstead, O. N. Miller and A. C.

Ann. Chem., 1361 (1975)

Sullivan, U. S. Patent 3,810,931 (1974)

S

COOH

S

COOH

C6H8O4S2

H2O

M-O. Hedblom, Arkiv Kemi, 31, 489

Cidin. 19

COOH

H2O

O

R. B. Bradbury and S. Masamune, J. Am.

Cidin. 20

Chem. Soc., 81, 5201 (1959)

(1969) C6H8O3S2

S O

S

EtOH, H 2 O

COOH

COOH

HOOC

S

83:17 v/v %

(1969)

C6H10O6

OH

COOH

HOOC

C 6 H 1 1 ClO 2

COOH

H2O

OH

Cl

K. Freudenberg, W. F. Bruce and E. Gauf,

Cidin. 23

W. G. Galetto and W. Gaffield, J. Chem.

Cidin. 24

Liebigs Ann. Chem., 510, 206 (1934)

O

COOH

Soc., 2437 (1969)

C 6 H 1 1 NO 3 S

COOH

EtOAc, MeOH

OH

S

M. Matell, Acta Chem. Scand., 14, 677

Cidin. 25

Acetone, H 2 O

M-O. Hedblom. Arkiv Kemi, 31, 489

Cidin. 22

Mineral Geol., 17B, No. 3 (1943)

N

C6H9O4S2

S

40:60 v/v %

A Fredga and M. Tenow, Arkiv Kemi,

Cidin. 21

C6H10O3

C6H12O3

CHCl3

P. A. Levene, T. Mori, and L. A. Mikeska,

Cidin. 26

J. Biol. Chem., 75, 337 (1927)

(1960) C6H12O3

COOH

O

H2O

COOH

C6H12O3

H2O

OH Cidin. 27

H. Scheibler and A. S. Wheeler, Chem.

R. Brettle and N. Polgar, J. Chem. Soc.,

Cidin. 28

Ber., 44, 2684 (1911) Br HOOC

1620, (1956)

C 7 H 1 0 Br 2 O 4

Br

COOH

Acetone, H2O 50:50 v/v%

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COOH

C H

C7H10O2

Acetone

L. Schotte, Arkiv Kemi, 9, 407 (1956)

Cidin. 29

W. Runge, G. Kresze and E. Ruch, Liebigs

Cidin. 30

Ann. Chem., 1361 (1975)

COOH C

Acetone

H Cidin. 31

C7H10O2

W. Runge, G. Kresze and E. Ruch,

H C HOOC

Acta, 62, 1025 (1979)

C7H12O3 COOH

COOH

EtOH

O

33:67 v/v%

O

Cidin. 33

M. Nakazaki, K. Naemura and S.

A. Fredga nd M. Tenow, Arkiv Kemi,

Cidin. 34

Nakahara, J. Org. Chem., 44, 2438 (1979) COOH

H3COOC

Mineral. Geol., 16B, No. 9 (1942)

C7H12O4

S

H2O, Acetone

COOH

C7H12O4S

COOH

EtOH, H 2 O

90:10 v/v% Cidin. 35

S. Stallberg-Stenhagen, Arkiv Kemi

C7H12O3

EtOH, H2O

S

H

H

Acetone

R. W. Lang and H-J. Hansen, Helv. Chim.

Cidin. 32

Liebigs Ann. Chem., 1361 (1975)

HO

C7H10O2

53:47 v/v% Cidin. 36

M. Matell, Arkiv Kemi, 3, 129 (1951)

Mineral. Geol. 25A, No. 10 (1947) C7H12O5

O

H2O

COOH

HOOC

COOH

C7H14O2

H2O, Acetone 34:66 v/v%

Cidin. 37

D. S. Noyce and J. H. Canfield, J. Am.

Cidin. 38

Chem. Soc., 76, 3630 (1954)

P. A. Levene and R. E. Marker, J. Biol. Chem., 98, 1 (1932)

C7H14O2

COOH Cidin. 39

C7H14O2

COOH

Acetone

P. A. Levene and R. W. Marker, J. Biol.

Cidin. 40

Chem., 111, 299 (1935) SH COOH

F. I. Carrroll and R. Meck. J. Org. Chem., 34, 2676 (1969)

C8H8O2S

Acetone

COOH

W. A. Bonner, J. Org. Chem., 33, 1831 (1968)

© 2002 by CRC Press LLC

Cidin. 42

C8H8O4S

EtOH, H 2 O

S COOH

Cidin. 41

EtOH

50:50 v/v%

K. Pettersson, Arkiv Kemi, 7, 39 (1954)

COOH COOH

C8H8O4S

C8H10O2

H 2 O, EtOH

H

50:50 v/v%

COOH

Acetone

S S. Gronowitz, Arkiv Kemi 11, 361 (1957)

Cidin. 43

K. Naemura and M. Nakazaki, Bull. Chem.

Cidin. 44

Soc. Japan., 46, 888 (1973 C8H10O2 COOH

H

HOOC

C8H10O2

Acetone

abs. EtOH

H

J. A. Berson, J. S. Walia, A. Remanick, S.

Cidin. 45

J. A. Berson and R. G. Bergman, J. Am.

Cidin. 46

Chem. Soc., 89, 2569 (1967)

Suzuki, P. Reynolds Warnhoff and D. Willner, J. Am. Chem. Soc., 83, 3986 (1961) COOH

C

C8H12O2

Acetone

H

W. Runge, G. Kresze and E. Ruch,

Cidin. 47

C8H12O2

H COOH

J. A. Berson and D. A. Ben-Efraim, J. Am.

Cidin. 48

Chem. Soc., 81, 4083 (1959)

Liebigs Ann. Chem., 1361 (1975) COOH

C8H12O4

COOH

H2O H. N. Rydon, J. Chem. Soc., 1340 (1973)

C8H12O4

EtOH

COOH

COOH

Cidin. 49

abs. EtOH

W. L. F. Armarego and T. Kobayashi, J.

Cidin. 50

Chem. Soc. C, 1635 (1969)

COOH COOH

C8H12O4

HOOC

O

EtOH, H2O

COOCH3 O

10:90 v/v% J. W. Barrett and R. P. Linstead, J. Chem.

Cidin. 51

Cidin. 52

COOH

EtOAc

COOH

C8H14O4

H 2 O, EtOH 50:50 v/v%

HOOC

Cidin. 53

K. Serck-Hanssen, Arkiv Kemi, 10, 135 (1957)

C8H14O2S2 S

EtOAc, Et2O 50:50 v/v%

Soc., 1069 (1935) S

C8H12O6

D. S. Acker and W. J. Wayne, J. Am. Chem. Soc., 79, 6483 (1957)

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Cidin. 54

A. Fredga and U. Sahlberg, Arkiv Kemi Mineral. Geol., 18A, No. 16 (1944)

C8H14O6

OH

COOH

HOOC

C8H16O2

H2O

COOH

Acetone

OH

K. Freudenberg, W. F. Bruce and E. Gauf,

Cidin. 55

P. A. Levene and M. Kuna, J. Biol. Chem.,

Cidin. 56

Liebigs Ann. Chem., 510, 206 (1934)

COOH

140, 255 (1941)

C 9 H 6 Cl 4 O 3

COOH

Benzene

O

H 2 O, EtOH

O Cl

Cl

Cl

80:20 v/v%

Cl

Cl

Cl

Cl A. Fredga and T. Raznikiewicz, Arkiv

Cidin. 57

C 9 H 7 Cl 3 O 3

Ph. D. Thesis of Magnus Matell, Uppsala,

Cidin. 58

Kemi, 14, 11 (1959) COOH

Sweden (1953) C 9 H 7 Cl 3 O 3

Cl

C 9 H 9 ClO 4

OH COOH

EtOH, H2O

O

75:25 v/v% Cl

EtOH

OH

Cl

Cl

A. Fredga and G. Ekstedt, Arkiv Kemi,

Cidin. 59

A. Collet, Bull. Soc. Chim. Fr., 215 (1975)

Cidin. 60

23, 123 (1964) C 9 H 9 ClO 4

OH COOH

Cl

COOH

EtOH

C9H9IO3

H 2 O, MeOH

O

OH

20:80 v/v%

I A. Collet, Bull. Soc. Chim. Fr., 215

Cidin. 61

A. Fredga, Arkiv Kemi, 25, 87 (1965)

Cidin. 62

(1975) O

NH2

C 9 H 9 NO 3

COOH

Acetone

C 9 H 9 NO 5

EtOH

O

COOH

NO2

Cidin. 63

M. K. Hargreaves and M. A. Khan, J. Chem. Soc. Perkin 2, 1204 (1973)

© 2002 by CRC Press LLC

Cidin. 64

E. Fourneau and G. Sandulesco, Bull. Soc. Chim. Fr., 33, 459 (1923)

C9H9N3O2

N N N

COOH

MeOH, H 2 O

COOH

88:12 v/v% H. Gustafsson, Acta Chem. Scand., B29,

Cidin. 65

NH2

C 9 H 1 1 NO 3

CHCl 3

H3CO

British Patent 1,450,596 (1976)

Cidin. 66

177 (1975) C9H12O3

COOH O

Acetone

M. Nakazaki, K. Naemura and H.

Cidin. 67

COOEt NHAc

HOOC

C 9 H 1 5 NO 5

EtOAc

S. G. Cohen and E. Khedouri, J. Am.

Cidin. 68

Kadowaki, J. Org. Chem., 41, 3728

Chem. Soc., 83, 1093 (1961)

(1976) C9H16O2S S

COOCH3

HOOC

C9H16O4

Acetone, H 2 O

EtOAc

HOOC

60:40 v/v% G. Blaeson and H-G. Jonsson, Arkiv

Cidin. 69

S. Stallberg-Stenhagen, Arkiv Kemi, 3, 249

Cidin. 70

Kemi, 31, 83 (1969) C 9 H 1 7 NO 5

O

HO

(1951)

NH

C9H18O2

Acetone, MeOH

COOH

Acetone

OH

COOH

E. T. Stiller and P. F. Wiley, J. Am.

Cidin. 71

F. Kögl and A. G. Boer, Rec. Trav. Chim.,

Cidin. 72

Chem. Soc., 63, 1237 (1941)

54, 779 (1935)

C9H18O2 COOH

C10H8O2

Acetone

C C CHCOOH H

R. Ikan, A. Markus and E. D. Bergman, J.

Cidin. 73

K. Shinga, S. Hagishita and M. Nakagawa,

Cidin. 74

Org. Chem., 36, 3944 (1971)

Tetrahedron Lett., 4371 (1967)

C10H10N2O2

N N

Cidin. 75

COOH

EtOAc, EtOH

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Cl

Cidin. 76

C 1 0 H 1 1 ClO 3

1.) H 2 O, EtOH

O

75:25 v/v%

H. Gustafsson, Arkiv Kemi, 31, 415 (1969)

COOH

27:73 v/v%

A. Fredga and K-I. Sandstorm, Arkiv Kemi, 23, 245 (1965)

COOH

C 1 0 H 1 1 ClO 3

COOH

EtOAc

O

H2O, EtOH

Cl

50:50 v/v%

A. Fredga, A. Kijellqvist and E.

Cidin. 77

Cidin. 78

Tornqvist, Arkiv Kemi, 32, 301 (1970)

COOH

C10H12O2

Ph. Gold-Aubert, Helv. Chim. Acta, 41, 1512 (1958

C10H12O2

COOH

EtOH

C 1 0 H 1 3 NO 2

abs. EtOH

NH2 R. Weidmann and A. Horeau, Bull. Soc.

Cidin. 79

Cidin. 80

U. S. Patent 3,758,559 (1973)

Chim. Fr., 117 (1967) COOH

C 1 2 H 1 7 NO 3

C10H12O3

OH COOH

abs. EtOH

EtOAc

NHAc U. S. Patent 3,758,559 (1973)

Cidin. 81

Cidin. 82

T. Matsumoto, I. Tanaka and K. Fukui, Bull. Chem. Soc. Japan., 44, 3378 (1971)

COOH

C10H12O4

NH2

EtOH, H 2 O

O

COOH

C 1 0 H 1 3 NO 2

abs. EtOH

63:37 v/v%

OCH3

Cidin. 83

A. Fredga and I. Avalaht, Arkiv Kemi, 24,

Cidin. 84

M. Sobocinska, G. Kupryszewski and M. M. Zobaczewa, Rocz. Chem., 48, 461

425 (1965)

(1974) H N

Cidin. 85

C 1 8 H 1 9 NO 5 CBZ COOH

abs. EtOH

M. Sobocinska, G. Kupryszewski and M. M. Zobaczewa, Rocz. Chem., 48, 461 (1974)

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COOH

C 1 0 H 1 3 NO 2

abs. EtOH NH2

Cidin. 86

F. W. Bollinger, J. Med. Chem., 14, 373 (1971)

COOH

C 1 2 H 1 5 NO 3

NH2 COOH

abs. EtOH

C 1 0 H 1 3 NO 2

H2O

NHAc F. W. Bollinger, J. Med. Chem., 14, 373

Cidin. 87

J. A. Garbarino, J. Sierra and R. Tapia, J.

Cidin. 88

(1971) O COOH

HN

Chem. Soc., Perkin 1, 1866 (1973) C 1 1 H 1 3 NO 3

C10H14N2O2 N

H2O

N

COOH

Acetone, EtOAc 67:33 v/v%

J. A. Garbarino, J. Sierra and R. Tapia, J.

Cidin. 89

H. Guastafsson, Arkiv Kemi, 29, 587

Cidin. 90

Chem. Soc., Perkin 1, 1866 (1973)

(1968)

C10H14O3

C10H14O5

HOOC OH H

H

O

COOH

HOOC

Cidin. 91

K. Adachi, K. Naemura and M. Nakazaki,

J. D. Ewards, Jr., T. Hase and N. Ichikawa,

Cidin. 92

J. Heterocyclic Chem., 4, 487 (1967)

Tetrahedron Lett., 5467 (1968) HOOC OH

C10H14O5

MeOH, EtOAc H

Cidin. 93

MeOH, EtOAc, Et2O

O

COOH

J. D. Ewards, Jr., T. Hase and N.

C10H14O6

H

HOOC Et O

COOH

S. Kiyooka, T. Hase and J. D. Ewards, Jr.,

Cidin. 94

Ichikawa, J. Heterocyclic Chem., 4, 487

Chem. Lett., 963 (1973)

(1967) C10H16O4

COOH COOH Cidin. 95

Acetone

OH

Cidin. 96

C10H16O5

COOH

Cidin. 97

J. D. Edwards, Jr., T. Hase, C. Hignite and T. Matsumoto, J. Org Chem., 31, 2282 (1966)

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H2O, EtOH

W. Hückel, M. Sachs, J. Yantschulewitsch and F. Nerdel, Liebigs Ann. Chem., 518 155 (1915)

OH

H

MeOH, EtOAc

H

C10H16O4

80:20 v/v%

M. Janczewski and T. Bartnik, Polish J. Chem., 36, 1243 (1962) HOOC

COOH COOH

C10H16O5

MeOH

O Cidin. 98

O

COOH J. D. Edwards, Jr. and T. Matsumoto, J. Org. Chem., 32, 2561 (1967)

C10H18O2

H COOH

COOH

H3OOC

MeOH

C10H18O4

Acetone, H2O 45:55 v/v%

F. C. Copp and J. L. Simonsen, J. Chem.

Cidin. 99

L. Ahlquist, J. Asselineau, C. Asselineau,

Cidin. 100

Soc., 415 (1940)

K. Serck-Hanssen, S. Stallberg-Stenhagen and E. Stenhagen, Arkiv Kemi, 14, 171 (1958) C10H20O3

OH

COOH

C11H10O2

Acetone

Acetone

COOH

C H

C. Asselineau and J. Asselineau, Bull.

Cidin. 101

W. Runge, G. Kresze and E. Ruch, Liebigs

Cidin. 102

Soc. Chim. Fr., 1992 (1967)

Ann. Chem., 1361 (1975)

C11H10O2S

COOH

COOH

EtOH, H 2 O

EtOAc, MeOH

43:57 v/v% J. Sjöberg, Arkiv Kemi, 11, 439 (1957)

J. Sjöberg, Arkiv Kemi, 12, 251 (1957)

Cidin. 104

C11H14O2

EtOH, H 2 O COOH

COOH

64:36 v/v%

A. Fredga and K. Olsson, Arkiv Kemi, 30,

Cidin. 106

Passoth, J. Biol. Chem., 88, 27 (1930) COOH

Cidin. 107

409 (1969)

C11H14O3

A. Fredga and U. Löfroth, Arkiv Kemi, 23, 239 (1965)

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C11H14O3

O

EtOH

O

C11H14O3

EtOH, H 2 O

O

3:97 v/v%

P. A. Levene, L. A. Mikeska and K.

Cidin. 105

94:6 v/v%

N

S Cidin. 103

C 1 1 H 1 1 NO 2

COOH

Cidin. 108

Acetone

T. J. Leitereg and D. J. Cram, J. Am. Chem. Soc., 90, 4019 (1968)

COOH

C11H14O3

C12H6O6S2

COOH

HOOC

EtOH, H 2 O

EtOH

S

S

80:20 v/v%

CHO

OCH3 C. Aaron, D. Dull, J. L. Schmiegel, D.

Cidin. 109

CHO

R. Hakansson and A. Svensson, Chemica

Cidin. 110

Scripta, 7, 186 (1975)

Jaeger, Y. Ohashi, and H. S. Mosher, J. Org. Chem., 32, 2797 (1967) C12H12O2

C12H12O2

Acetone

COOH C C CHCOOH

C C C

Et

Et

H

K. Shinga, S. Hagishita and M.

Cidin. 111

W. Runge, G. Kresze and E. Ruch, Liebigs

Cidin. 112

Nakagawa, Tetrahedron Lett., 4371

Ann. Chem., 1361 (1975)

(1967) C12H12O2

C12H12O2

EtOAc, Petrolether

COOH

54:46 v/v%

C C C

C C C Et

COOH

G. Kresze, W. Runge and E. Ruch,

Cidin. 113

H

W. Runge, G. Kresze and E. Ruch, Liebigs

Cidin. 114

Liebigs Ann. Chem., 756, 112 (1972)

Ann. Chem., 1361 (1975)

C12H12O6

O O

C 1 2 H 1 3 Br 2 NO 3

O COOH

N

EtOH Br

COOH

HOOC

Acetone

EtOAc, MeOH 90:10 v/v%

Br

M. Nakazaki, K. Naemura, Y. Sugano and Cidin. 116 Y. Kataoka, J. Org. Chem., 45, 3232 (1980)

Cidin. 115

C 1 2 H 1 3 Cl 2 NO 3

O N

R. Adams and N. K. Sundholm, J. Am. Chem. Soc., 70, 2667 (1948)

COOH

Cl

COOH

EtOAc, MeOH

C 1 2 H 1 3 NO 2

EtOH, H 2 O

90:10 v/v%

N

75:25 v/v%

Cl

Cidin. 117

R. Adams and J. R. Gordon, J. Am. Chem. Soc., 72, 2454 (1950)

© 2002 by CRC Press LLC

Cidin. 118

A. Fredga and L-B. Agensas, Arkiv Kemi, 15, 327 (1960)

C 1 2 H 1 5 NO 4

NO2 COOH

N

COOH

EtOH

C 1 2 H 1 6 BrNO 2

Acetone Br

P. M. G. Bavin, J. Med. Chem., 9, 52

Cidin. 119

R. Adams, D. C. Blomstrom and K. V. T.

Cidin. 120

Sundstrom, J. Am. Chem. Soc., 76, 5478

(1966)

(1954)

O

COOH

C12H16O3

O

O

O

EtOH

C13H8O8

H 2 O, EtOH COOH

HO

97:3 v/v%

OH OH

Cidin. 121

R. L. Coffin, W. W. Cox, R. G. Carlson

Cidin. 122

O. T. Schmidt, R. Eckert, E. Günther and

and R. S. Givens, J. Am. Chem. Soc.,

H. Fiesser, Liebigs Ann. Chem., 706, 204

101, 3261, (1979)

(1967)

COOH

C 1 3 H 1 1 BrO 2

Cl O

Acetone

COOH

C 1 3 H 1 1 ClO 2

EtOH, H 2 O 45:55 v/v%

Br

Cidin. 123

M. Janczewski and K. Kut, Rocz. Chem.,

Cidin. 124

42, 1159 (1968)

M. Matell and S. Larsson, Arkiv Kemi, 5, 379 (1953)

C13H12O2 COOH

COOH

Acetone, H2O

C13H12O2

MeOH

57:43 v/v% Cidin. 125

A. Fredga, Arkiv Kemi, 8, 463 (1955)

COOH

Cidin. 126

C13H12O2

COOH

55:45 v/v%

Cidin. 127

K. Pettersson, Arkiv Kemi, 7, 279 (1954)

© 2002 by CRC Press LLC

C 1 3 H 1 2 O 3 Se

Se

EtOH, H2O

S

B. Sjöberg, Arkiv Kemi, 9, 295 (1956)

EtOH, H2O 60:40 v/v%

Cidin. 128

B. Sjöberg, Arkiv Kemi, 15, 397 (1960)

C13H14O2

C13H14O2

Acetone

Et

C C CHCOOH

C COOH

K. Shingu, S. Hagishita and M.

Cidin. 129

G. Kresze, W. Runge and E. Ruch, Liebigs

Cidin. 130

Nakagawa, Tetrahedron Lett., 4371

Ann. Chem., 756, 112 (1972)

(1967) C13H14O2

C 1 3 H 1 6 BrNO 3

O COOH

N

EtOAc Br

C Et

EtOAc, MeOH 90:10 v/v%

COOH

G. Kresze, W. Runge and E. Ruch,

Cidin. 131

R. Adams and N. K. Sundholm, J. Am.

Cidin. 132

Liebigs Ann. Chem., 756, 112 (1972)

Chem. Soc., 70, 2667 (1948)

C 1 3 H 1 6 ClNO 3

O COOH

N

EtOAc, MeOH 90:10 v/v%

Cl

R. Adams and J. R. Gordon, J. Am.

Cidin. 133

C 1 3 H 1 6 INO 3

COOH

N

R. Adams and N. K. Sundholm, J. Am.

Cidin. 134

Chem. Soc., 72, 2454 (1950) O COOH

N O2N

Chem. Soc., 70, 2667 (1948)

C13H16N2O5

C13H16O2

EtOAc, MeOH

EtOH, H 2 O

90:10 v/v%

COOH

H

R. Adams and N. K. Sundholm, J. Am.

Cidin. 135

EtOAc, MeOH 90:10 v/v%

I

70:30 v/v%

J. Brugidou, H. Christol, J. M. Fabre, L.

Cidin. 136

Chem. Soc., 70, 2667 (1948)

Giral and R. Sales, Bull. Soc. Chim. Fr., 2906 (1974)

C13H16O5 O

COOH COOEt

abs. EtOH

COOH O

C 1 3 H 1 7 ClO 3

Acetone, H2O 45:55 v/v%

Cl

© 2002 by CRC Press LLC

A. Hofmann and P. Stadler, U. S. Patent

Cidin. 137

Cidin. 138

M. Matell, Arkiv Kemi. , 9, 157, (1955)

3,294,835 (1966) C13H18O3

COOH

C13H18O3 COOH

Benzene, Ligroine

O

OH

Cidin. 139

A. Fredga, T. Unge and R. Hakansson,

Cidin. 140

Chemica Scripta, 4, 123 (1973)

Jr., Chem. Lett., 283 (1973)

C13H26O2

O

COOH

Acetone

COOH

Cidin. 141

T. Matsumoto, K. Fukui and J. D. Edwards,

P. A. Levene and R. E. Marker, J. Biol.

C14H10O3

MeOH

Cidin. 142

T. Svensson, Arkiv Kemi, 26, 27 (1966)

Chem., 98, 1 (1932) C 1 4 H 1 1 BrO 5

HOOC Br

COOH O

COOH

C 1 4 H 1 1 ClO 5

EtOH

EtOH, EtOAc

Cl Cidin. 143

K. Takeda, S. Hagishita, M. Sugiura, K.

Cidin. 144

Kitahonoki, I. Ban, S. Miyazaki and K.

W. Bleazard and E. Rothstein, J. Chem. Soc., 3789 (1958)

Kuriyama, Tetrahedron, 26, 1435 (1970)

HOOC

COOH

C14H12O5

C14H14O2

EtOH, H2O

O Cidin. 145

COOH

30:70 v/v%

M-J. Brienne and J. Jacques, Bull. Soc.

EtOH, H2O 50:50 v/v%

Cidin. 146

M. Matell, Arkiv Kemi, 5, 187 (1953)

Chim. Fr., 2647 (1974) COOH

C14H14O2

C14H14O3 COOH

Acetone, H2O 90:10 v/v%

Cidin. 147

B. Sjöberg, Arkiv Kemi, 12, 573 (1958)

MeOH

H3CO

Cidin. 148

P. Wirth, G. E. M. Dannenberg, V. Schmied-Kowarzik, P.Weinhold and D. Gudel, German Patent (Offen.) 2,319,245 (1973)

© 2002 by CRC Press LLC

C14H14O3S

O

COOH

Acetone C C CHCOOH

S

A. P. Stoll and R. Süess, Helv. Chim.

Cidin. 149

C14H16O2

K. Shingu, S. Hagishita and M. Nakagawa,

Cidin. 150

Acta, 57, 2487 (1974)

Tetrahedron Lett., 4371 (1967)

C14H16O2

abs. EtOH Cl

H. E. Smith and T. C. Willis, Tetrahedron,

J. Diamond and N. J. Santora, U. S. Patent

Cidin. 152

26, 107 (1970)

H N

abs. EtOH

COOH

Ph COOH Cidin. 151

C 1 4 H 1 7 ClO 3

OH

3,821,267 (1974) C 1 4 H 1 7 NO 3

C14H18O5

EtOH

EtOAc

O COOH

O

COOEt

COOH W. L. F. Armarego and T. Kobayashi, J.

Cidin. 153

Cidin. 154

Chem. Soc. C, 1597 (1970)

W. Schlientz, R. Brunner, P. A. Stadler, A. J. Frey, H. Ott and A. Hofmann, Helv. Chim. Acta, 47, 1921 (1964)

C 1 4 H 1 9 NO 4

O COOH

N

C14H24O4S2

EtOAc

S

HOOC

R. Adams and H. W. Stewart, J. Am.

Cidin. 155

Cidin. 156

Chem. Soc., 63, 2859 (1941)

EtOAc, MeOH 50:50 v/v%

COOH

W. T. Hoeve and H. Wynberg, J. Org. Chem., 45, 2754 (1980)

C 1 5 H 1 0 ClF 3 O 3

C15H12O3S

S

iPrOH

O

S

COOH

EtOAc

O

COOH

CF3

Cidin. 157

F. E. Roberts, Jr., French Patent 1,538,286 (1968)

© 2002 by CRC Press LLC

Cidin. 158

M. Janczewski and R. Kutyla, Pol. J. Chem., 1463 (1979)

COOH

C15H14O2

COOH

EtOH

A. McKenzie and S. T. Widdows, J.

Cidin. 159

C15H14O2

Acetone

M. Janczewski and W. Podkoscielny,

Cidin. 160

Chem. Soc., 702 (1915)

Polish J. Chem., 39, 201 (1965)

C15H14O2

COOH

CH3OOC

Acetone

C15H14O5

MeOH

O COOH

M. Janczewski and W. Podkoscielny,

Cidin. 161

K. Takeda, S. Hagishita, M. Sugiura, K.

Cidin. 162

Polish J. Chem., 34, 1505 (1960)

Kitahonoki, I. Ban, S. Miyazaki and K. Kuriyama, Tetrahedron, 26, 1435 (1970)

HOOC 7 8 6

COOH

C15H14O6

COOH

EtOH, EtOAc

5

C15H18O2

EtOH

O R

a: 8-OMe b: 7-OMe c: 5-OMe K. Takeda, S. Hagishita, M. Sugiura, K.

Cidin. 163

P. F. Juby, T. W. Hudyma, U. S. Patent

Cidin. 164

Kitahonoki, I. Ban, S. Miyazaki and K.

3,696,111 (1972)

Kuriyama, Tetrahedron, 26, 1435 (1970) COOH

C15H18O2

EtOH

C 1 5 H 2 0 BrNO 3

O COOH

N

EtOAc, EtOH 95:5 v/v%

Br

British Patent 1,283,367 (1969)

Cidin. 165

Cidin. 166

R. Adams and H. W. Stewart, J. Am. Chem. Soc., 63, 2859 (1941)

C15H20O4

O

EtOH COOH O

© 2002 by CRC Press LLC

C16H14O2 COOH

Acetone, CHCl 3 80:20 v/v%

A. Lüttringhaus and H. Gralheer, Liebigs

Cidin. 167

M. Janczewski and T. Matyniea, Rocz.

Cidin. 168

Ann. Chem., 557, 108 (1947) C16H14O2

OH Ph

H COOH

MeOH, Et 2 O

O

80:20 v/v%

J. Nickl, W. Engel, A. Eckenfels, E.

Cidin. 169

C 1 6 H 1 5 NO 3

CHCl 3 , MeOH

C C H

Chem., 40, 2029 (1966)

COOH

N H

30:70 v/v%

W. Stühmer and H. H. Frey, Arch. Pharm.

Cidin. 170

Seeger and G. Engelhardt, U. S. Patent

(Weinheim), 286, 26 (1953)

3,655,743 (1972) C 1 6 H 1 6 BrNO 4 S

COOH

EtOAc, MeOH O S N O Br

EtOH

90:10 v/v%

COOH

R. Adams and J. R. Gordon, J. Am.

Cidin. 171

C16H20O2

Y. G. Perron, J. L. Douglass, U. S. Patent

Cidin. 172

Chem. Soc., 72, 2458 (1950) COOH Cl

3,696,145 (1972)

C 1 7 H 1 2 Cl 2 O 2

C17H12N2O6

MeOH

MeOH

O

Cl

O

N

COOH O2N S. Hagishita and K. Kuriyama,

Cidin. 173

F. Bergel, J. C. E. Burnop and J. A. Stock,

Cidin. 174

Tetrahedron, 28, 1435 (1972)

NC

H

Ph H

H

J. Chem. Soc., 1223 (1955)

C 1 7 H 1 3 NO 2

H H

EtOAc

Ph H COOH

COOH

C 1 7 H 1 3 NO 2

EtOAc, CHCl 3 50:50 v/v%

NC

Cidin. 175

H. E. Zimmerman, S. S. Hixson and E. F.

Cidin. 176

H. E. Zimmerman, S. S. Hixson and E. F.

McBrideg, J. Am. Chem. Soc., 92, 2000

McBrideg, J. Am. Chem. Soc., 92, 2000

(1970)

(1970)

© 2002 by CRC Press LLC

NC

Ph

C 1 7 H 1 3 NO 2

H

C17H14O3

EtOAc

H

C

Acetone

O

COOH

H

COOH

H. E. Zimmerman, S. S. Hixson and E. F.

Cidin. 177

Cidin. 178

T. Aono, S. Kishimoto, Y. Araki and S.

McBrideg, J. Am. Chem. Soc., 92, 2000

Noguchi, Chem. Pharm. Bull, 26, 1776

(1970)

(1978) C 1 7 H 1 5 NO 3

COOH

C17H16O2

EtOH

EtOH

COOH

N O

T. Kametani, K. Kigasawa, M. Huragi, H.

Cidin. 179

Cidin. 180

Ishimaru, S. Haga and K. Shirayama, J.

M. Janczewski and E. Pawlowska, Rocz. Chem., 47, 665 (1973)

Heterocyclic Chem., 15, 369 (1978) C 1 7 H 1 7 NO 4 S

O NH

O S

COOH

iPrOH, H 2 O

HOOC

O O S Ph N

C 1 7 H 1 8 BrNO 4 S

EtOAc

50:50 v/v%

Br

Cidin. 181

T. Petrzilka and Ch. Fehr, Helv. Chim.

Cidin. 182

Acta, 56, 1218 (1973) O O S Ph N

Soc., 72, 2458 (1950)

C 1 7 H 1 8 ClNO 4 S COOH

EtOAc, MeOH 90:10 v/v%

R. Adams and J. R. Gordon, J. Am. Chem.

Cl Cl

O

C 1 7 H 1 8 Cl 2 O 4

EtOH, H 2 O

O

Cl

COOH

Cidin. 183

R. Adams and M. J. Gortatowski, J. Am. Chem. Soc., 79, 5525 (1957)

Cidin. 184

E. J. Cragoe, Jr., E. M. Schultz, J. D. Schneeberg, G.E. Stokker, O. W. Woltersdorf, Jr., G. M. Fanelli, Jr., L. S. Watson, J. Med. Chem., 18, 225 (1975)

© 2002 by CRC Press LLC

O

C 1 7 H 1 8 INO 4 S

O S

Ph

COOH

N

EtOAc, MeOH

O Ph

C17H18N2O6S

O S

COOH

N

EtOAc

88:12 v/v%

I

NO2

R. Adams and M. J. Gortatowski, J. Am.

Cidin. 185

Cidin. 186

Chem. Soc., 79, 5525 (1957) HN

COOtBu

Chem. Soc., 79, 5525 (1957)

C 1 7 H 2 3 NO 6

C17H24O2

CH 3 CN

Acetone

COOH

O

R. Adams and M. J. Gortatowski, J. Am.

COOH

O

Cidin. 187

T. Kamiya, M. Hashimoto, O. Nakaguchi

Cidin. 188

and T. Oku, Tetrahedron, 35, 323 (1979)

A. T. Blomquist, R. E. Stahl, Y. C. Meinwald and B. H. Smith, J. Org. Chem., 26, 1687 (1961)

HOOC

COOH

C 1 8 H 1 2 Cl 2 O 4

C18H14O4

HOOC COOH

EtOH

Cl

MeOH, Acetone 40:60 v/v%

Cl

Cidin. 189

M. J. Brienne and J. Jacques, Bull. Soc.

Cidin. 190

Chim. Fr., 190 (1973)

S Et

Cidin. 191

28, 1435 (1972)

C18H22O4S2

COOH Et

Et

EtOH, H 2 O

PhCH2 N

Et COOH

50:50 v/v%

HO

S. Gronowitz and J. E. Skramstad, Arkiv Kemi, 28, 115 (1967)

CHCl 3

© 2002 by CRC Press LLC

Cidin. 192

N CH2Ph

H2O

O

O

M. Shibasaki, M. Matsubara, J. Ohnogi and K. Shibata, U. S. Patent 3,775,413 (1973)

C19H20O2

COOH

C19H17N2O3

O

S

H

S. Hagishita and K. Kuriyama, Tetrahedron,

C19H20O2

Et COOH H

EtOAc

H. E. Zimmerman, J. D. Robbins, R. D.

Cidin. 193

Cidin. 194

McKelvey, C. J. Samuel and L. R. Sousa,

J. Am. Chem. Soc., 96, 4630 (1974)

J. Am. Chem. Soc., 96, 4630 (1974)

C 1 9 H 2 3 NO 4 S

O O S Ph N

H. E. Zimmerman, J. D. Robbins, R. D.

McKelvey, C. J. Samuel and L. R. Sousa,

COOH

C20H16O3

COOH

O

EtOAc

MeOH

Ph

Et R. Adams and A. Ferretti, J. Am. Chem.

Cidin. 195

Cidin. 196

Soc., 83, 2559 (1961) O COOH

M. Janczewski and L. Bilczuk, Rocz. Chem., 39, 1927 (1965)

C20H18O3

C20H20O3

O

Aceton, H 2 O

CHCl 3 , MeOH, Et 2 O

67:33 v/v%

J. Paul and K. Schlögl, Monatsh. Chem.,

Cidin. 197

Cidin. 198

104, 274 (1973) H3CO H3CO H3CO H3CO

Cidin. 199

OCH3 OCH3

COOH COOH

Tetrahedron, 26, 511 (1970) C20H22O10

EtOH, H 2 O

O O S Ph N

C 2 0 H 2 5 NO 4 S COOH

EtOH

50:50 v/v% Pr

O. T. Schmidt and K. Demmler, Liebigs

Cidin. 200

Ann. Chem., 576, 85 (1952) O O S Ph N

H. Falk, P. Reich-Rohrwig and K. Schlögl,

C 2 0 H 2 5 NO 4 S COOH

EtOH

R. Adams and A. Ferretti, J. Am. Chem. Soc., 83, 2559 (1961)

O O S Ph N

C 2 1 H 2 7 NO 4 S COOH

EtOAc

tBu

Cidin. 201

R. Adams and A. Ferretti, J. Am. Chem. Soc., 83, 2559 (1961)

COOH

COOH

© 2002 by CRC Press LLC

Cidin. 202

R. Adams and J. S. Dix, J. Am. Chem. Soc., 80, 4579 (1958)

C22H14O4

C22H18O2

EtOH

Acetone

M. Kuritani, Y. Sakata, F. Ogura and M.

Cidin. 203

Cidin. 204

Nakagawa, Bull. Chem. Soc. Japan., 46,

M. S. Newman and R. M. Wise, J. Am. Chem. Soc., 78, 450 (1956)

605 (1975) COOH

COOH O

C22H26O5

MeOH

O O S Ph N

C 2 4 H 2 4 BrNO 4 S COOH

MeOH

Br

M. Nakatani, T. Kamikawa, T. Hase and

Cidin. 205

Cidin. 206

T. Kubota, Bull. Chem. Soc. Japan., 50,

R. Adams and K. B. Brower, J. Am. Chem. Soc., 78, 663 (1956)

945 (1977) C 2 4 H 2 5 NO 4 S

O O S Ph N

COOH

O O S Ph N

COOH

MeOH

C25H24N2O4S

MeOH

CH2Ph CN

R. Adams and K. B. Brower, J. Am.

Cidin. 207

Cidin. 208

Chem. Soc., 78, 663 (1956) C 2 5 H 2 7 NO 4 S

O O S Ph N

COOH

MeOH

R. Adams and K. Brower, J. Am. Chem. Soc., 78, 663 (1956)

O O S Ph N

C 2 5 H 2 7 NO 5 S COOH

MeOH

OCH3

R. Adams and K. R. Brower, J. Am.

Cidin. 209

Cidin. 210

Chem. Soc., 78, 663 (1956) O

COOH

Soc., 78, 663 (1956)

C30H14O8

COOH C

abs. EtOH O O

HOOC

O

© 2002 by CRC Press LLC

R. Adams and K. R. Brower, J. Am. Chem.

H

C6H8O2

Acetone

F. Bell and W. H. D. Morgan, J. Chem.

Cidin. 211

R. W. Lang and H. J. Hansen, Helv. Chim.

Cidin. 212

Soc., 1963 (1950)

Acta, 62, 1025 (1979) C10H12O2

COOH

C10H16O2

COOH

EtOH

D. Seyferth and Y. M. Cheng, J. Am.

Cidin. 213

D. J. Bennett, G. R. Ramage and J. C.

Cidin. 214

Chem. Soc., 95, 6763 (1973)

Simonsen, J. Chem. Soc., 418 (1940)

C11H12O3S

O S

C13H14O3 CH2COOH

Acetone

J. P. M. Houbiers, European Patent Appl. 8833 (1979)

COOH

HOOC

O

C19H16O2 HOOC

Acetone

COOH

C 1 0 H 9 ClO 3

Cidin. 218

EtOOC

EtOAc

Cl O F. Loiodice, A. Longo, P. Bianco and V. Tortorella, Tetrahedron Asymmetry, 6, 1001 (1995)

Cidin. 219

M. Nakazaki and k. Naemura, J. Org. Chem., 46, 106 (1981)

S

W. T. Hoeve and H.Wynberg, J. Org. Chem., 45, 2754 (1980)

Cidin. 217

Cidin. 216

C14H24O4S2

EtOAc

S

EtOH

O

COOH

Cidin. 215

H2O

O O

Cidin. 220

V. Boekelheide and E. Sturm, J. Am. Chem. Soc., 91, 902 (1969) N CBZ O

C15H16O7

EtOH

N H T. Negoro, M. Murata, S. Ueda, B. Fujitani, Y. Ono, A. Kuromiya, M. Komiya, K. Suzuki and J. Matsumoto, J. Med. Chem., 41, 4118 (1998)

C13H16O4

C 4 0 H 2 5 PO 4

Acetone

EtOH Ph Ph

O O P O OH

COOH

Cidin. 221

H. Meguro, H. Orui and Y. Nishida, Jpn. Cidin. 222 Kokai Tokkyo Koho JP 03 27, 376 (1991)

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J. Bao, W. D. Wulff, J. B. Dominy, M. J. Fumo, E. B. Grant, A. C. Rob, M. C. Whitcomb, S.-M. Yeung, R. L. Ostrander and A. L. Rheingold, J. Am. Chem. Soc., 118, 3392 (1996)

C15H16N2O6

O NH COOEt O

O

C 2 2 H 1 1 Cl F 3 O 4

Cl

EtOH

MeOH H O

O

N H

O

HOOC F3C

T. Negoro, M. Murata, S. Ueda, B.

Cidin. 223

Cidin. 224

S. Stanchev, R. Rakovska, N. Berova and

Fujitani and J. Ono, Jpn. Kokai Tokkyo

G. Snatzke, Tetrahedron Asymmetry, 6,1,

Koho JP 06, 192, 222 (1994)

183- (1995)

benzoyl

HN

C 1 6 H 1 5 NO 3

C17H14O3

O

CH3CN

EtOAc, EtOH

COOH OH

90:10 v/v%

Ph A. Olma, Polish J. Chem., 70, 1442

Cidin. 225

Cidin. 226

(1996)

COOH

P. Herold, J. W. Herzig, P. Wenk, T. Leutert, P. Zbinden, W. Fuhrer, S. Stutz, K. Schenker, M. Meier and G. Rihs, J. Med. Chem., 38, 2946 (1995)

O

COOH

C 1 1 H 9 ClO 3 EtOAc

Cl

HOOC

H N BOC OH

O Cidin. 227

F. Loiodice, A. Longo, P. Bianco and V.

Cidin. 228

C11H16N2O6 EtOAc

N

U. Madsen, K. Frydervang, B. Ebert, T. N.

Tortorella, Tetrahedron Asymmetry, 6,

Johansen, L. Brehm and P. Krogsgaard-

1001(1995)

Larsen, J. Med. Chem., 39, 183 (1996) C16H14O3

COOH

NO2

NO2

1.) EtOH, Et2O

O

2.) EtOAc

COOH

O

benzoyl

C15H19N3O4

N

Cidin. 229

T. Manimaran and A. A. Potter, PCT Int. Appl. WO 94 06, 747 (1994)

Cidin. 230

T. Ogawa, K. Matsumoto, C. Yokoo, K. Hatayama and K. Kitamura, J. Chem. Soc. Perkin Trans. 1, 525 (1993)

© 2002 by CRC Press LLC

C 2 3 H 2 3 ClN 3 O 3

Cl

C 2 0 H 1 9 ClN 3 O 4

N

Cl COOH

CH3OOC

N N

O

N H

HOOC

M. T. David Comte, Eur. Pat. Appl. EP

Cidin. 231

Cidin. 232

522, 971 (1993)

COOH

N2

O

Pfizer Ltd., 91-024596/04, C91-010544, PFIZ 22.07.89

C6H8O4

H2O COOH J.-J. Brunet, A. Herbowski, D. Neibecker,

Cidin. 233

Synth. Comm., 26, 483 (1996)

Dibenzoyl-d-tartaric acid C 3 H 7 NO 2

NH2

COOH

DBTA. 1

EtOH

G. Losse , H. Jeschkeit, Chem. Ber., 90,

COOBz

DBTA. 2

1275 (1957)

HO

COOH

EtOH

W. Langenbeck and O. Herst, Chem. Ber., 86, 1524 (1953)

C3 H7 NO3 MeOH

NH2

C 1 0 H 1 3 NO 2

NH2

C3 H8 N2 O2

O

NH2

HO

MeOH

NH2

DBTA. 3

G. Losse, H-J. Hebel and C. Kastner, J.

DBTA. 4

Prakt. Chem., 8, 339 (1959)

HO

COOH

Prakt. Chem., 8, 339 (1959)

HO

MeOH

NH2

DBTA. 5

C3 H7 NO3

G. Losse and M. Augustin, Chem. Ber.,

COOH NH2

DBTA. 7

DBTA. 6

© 2002 by CRC Press LLC

C1 0 H1 3 NO3 MeOH

G. Losse and M. Augustin, Chem. Ber., 91, 157 (1958)

C 4 H 7 NO 4 MeOH

G. Losse and G. Moschall, J. Prakt. Chem., 7, 38 (1958)

COOBz NH2

91, 157 (1958)

HOOC

G. Losse, H-J. Hebel and C. Kastner, J.

O

H2N DBTA. 8

NH2

COOH

C4H8N2O3 H2O

E. Fogassy, M. Acs and J. Gressay, Periodica Polytechnica, 20, 179 (1976)

C 5 H 1 1 NO 2 COOH

C 7 H 1 5 NO 2

COOEt

EtOH

NH2

W. Langenbeck and O. Herbst, Chem.

DBTA. 9

W. Langenbeck and O. Herbst, Chem. Ber.,

DBTA. 10

Ber., 86, 1524 (1953)

86, 1524 (1953) C 5 H 1 1 NO 2

COOH

C5H12N2O2 COOH

MeOH

NH2

G. Losse, H-J. Hebel and C. Kastner, J.

DBTA. 12

Prakt. Chem., 8, 339 (1959)

Prakt. Chem., 8, 339 (1959)

C 5 H 1 1 NO 2

COOH

MeOH

G. Losse and G. Müller, J. Prakt. Chem., 9,

DBTA. 14

9, 145 (1959)

COOH

H2N

NH2

145 (1959) C5H12N2O2 iPrOH

G. Losse and M. Augustin, Chem. Ber.,

COOH

H2N HCl

COOH

NH2

EtOH

G. Losse, G. Seltmann and H. Tischer, Z.

DBTA. 18

Physiol. Chem., 314, 224 (1959)

NH2

COOH DBTA. 19

C8H16N2O3

H N

COOEt

EtOH

O

O DBTA. 17

iPrOH

2418 (1958) C6H12N2O3

H N

NH2

C 5 H 1 3 N 2 O 2 Cl

G. Losse and M. Augustin, Chem. Ber., 91,

DBTA. 16

91, 2418 (1958)

NH2

MeOH

S

H2 N

G. Losse and G. Müller, J. Prakt. Chem.,

DBTA. 15

C 1 1 H 1 5 NOS

O

NH2

DBTA. 13

MeOH

NHNH2

G. Losse, H-J. Hebel and C. Kastner, J.

DBTA. 11

EtOH

NH2

90, 1275 (1957)

© 2002 by CRC Press LLC

Physiol. Chem., 314, 224 (1959)

C 6 H 1 3 NO 2

NH2

EtOH

G. Losse and H. Jeschkeit, Chem. Ber.,

G. Losse, G. Seltmann and H. Tischer, Z.

COOEt DBTA. 20

C 8 H 1 7 NO 2 EtOH

G. Losse and H. Jeschkeit, Chem. Ber., 90, 1275 (1957)

C 6 H 1 3 NO 2

NH2

MeOH

O

G. Losse, H-J. Hebel and C. Kastner, J.

DBTA. 21

NH2

MeOH

COOH

C6H14N2O

NH2

G. Losse, H-J. Hebel and C. Kastner, J.

DBTA. 22

Prakt. Chem., 8, 339 (1959)

Prakt. Chem., 8, 339 (1959)

C 6 H 1 3 NO 2

NH2

C 8 H 1 7 NO 2

COOEt

EtOH

COOH

EtOH

NH2 H. Pracejus and S. Winter, Chem. Ber.,

DBTA. 23

H. Pracejus and S. Winter, Chem. Ber., 97,

DBTA. 24

97, 3173 (1964) C6H14N2O2

NH2

COOH

H2N

3173 (1964)

H 2 O, iPrOH

NH2

40:60 v/v % F. J. Kearley and A. W. Ingersoll, J. Am.

DBTA. 25

C7H14N2O3

O N H

G. Losse, G. Seltmann land H. Tischer, Z.

DBTA. 26

Chem. Soc., 73, 5783 (1951)

NH2

Physiol. Chem., 314, 224 (1959)

C10H20N2O3

O N H

MeOH

COOPr

G. Losse, G. Seltmann land H. Tischer, Z.

DBTA. 27

NH2

NH2

HOOC

HN

NH

CBZ

MeOH

J. van Heijenoort and E. Bricas, Bull. Soc.

DBTA. 28

Chim. Fr., 2828 (1968)

C23H26N2O10

C 8 H 1 3 NO 2

MeOH

COOH

HOOC

C7H14N2O4

COOH

Physiol. Chem., 314, 224 (1959) CBZ

MeOH

COOH

N

COOH

EtOH

H

J. van Heijenoort and E. Bricas, Bull. Soc.

DBTA. 29

DBTA. 30

Chim. Fr., 2828 (1968)

Chem., 722, 1 (1969)

C 1 0 H 1 7 NO 2 N

COOEt

H. Pracejus and G. Kohl, Liebigs Ann.

COOH

abs. EtOH

Br

NH2

C 9 H 1 0 BrNO 2 abs. EtOH

H

DBTA. 31

H. Pracejus and G. Kohl, Liebigs Ann. Chem., 722, 1 (1969)

© 2002 by CRC Press LLC

DBTA. 32

R. Schwyzer and E. Surbeck-Wegmann, Helv. Chim. Acta, 43, 1073 (1960)

COOEt

C 1 1 H 1 4 BrNO 2 abs. EtOH

NH2

Br

DBTA. 33

COOH

R. Schwyzer and E. Surbeck-Wegmann,

COOEt

DBTA. 34

DBTA. 35

COOH

abs. EtOH

W. Langenbeck and O. Herbst, Chlem.

DBTA. 36

NHNH2 DBTA. 37

C9H12N2O2

COOH

abs. EtOH

DBTA. 38

C 9 H 1 1 NO 2 abs. EtOH

NH2

Prackt, Chem., 8, 339 (1959)

G. Losse, G. Müller, J. Prakt, Chem., 9, 145 (1959)

C15H14N2O3

COOH

abs. EtOH

S

G. Losse, H-J. Hebel and C. Kastner, J. Prackt, Chem., 8, 339 (1959)

G. Losse, H-J. Hebel and C. Kastner, J.

O

C 9 H 1 1 NO 2 abs. EtOH

NH2

Ber., 86, 1524 (1953)

COOH

W. Langenbeck and O. Herbst, Chlem. Ber., 86, 1524 (1953)

C 1 1 H 1 5 NO 2

NH2

abs. EtOH

NH2

Helv. Chim. Acta, 43, 1073 (1960)

C 9 H 1 1 NO 2

NH2

HO

C 9 H 1 1 NO 3 PrOH

H2N

NO2 DBTA. 39

G. Losse, G. Müller, J. Prakt, Chem., 9,

DBTA. 40

145 (1959)

Prakt. Chem., 8, 339 (1959) C9H12N2O2

O NH2

DBTA. 41

COOH

PrOH

NH2

HO

NH2

HO

DBTA. 42

Prakt. Chem., 8, 339 (1959)

NH2

HO

C 9 H 1 1 NO 4 Et 2 O

OH

G. Losse, H-J. Hebel and C. Kastner, J.

COOEt

G. Losse, H-J. Hebel and C. Kastner, J.

G. Losse, A Barth and W. Langenbeck, Chem. Ber., 94, 2271 (1961)

C 1 1 H 1 5 NO 4 Et 2 O

C 1 0 H 1 3 NO 2 abs. EtOH N

COOH

OH

DBTA. 43

G. Losse, A Barth and W. Langenbeck, Chem. Ber., 94, 2271 (1961)

© 2002 by CRC Press LLC

DBTA. 44

W. V. E. Doering and V. Z. Pasternak, J. Am. Chem. Soc., 72, 143 (1950)

NH2 COOH

C11H12N2O2

NH2

abs. EtOH

C12H14N2O2 abs. EtOH

COOCH3

N

N

G. Losse, J. Prakt. Chem., 7, 141 (1959)

DBTA. 45

G. Losse, J. Prakt. Chem., 7, 141 (1959)

DBTA. 46

C 1 1 H 1 5 NO 2 PrOH

O O NH2

G. Losse, Chem. Ber., 87, 1279 (1954)

DBTA. 47

Dehydroabietylamine C 2 H 2 ClFO 2

Cl

EtOAc

COOH

F

G. Bellucci, G. Berti, A. Borraccini and F.

Dha. 1

G. Belucci, F. Marioni and A. Marsili,

Dha. 2

Tetrahedron, 25, 4167 (1969)

C2H8O3 Et2O M. Okada, H. Sumiomo and I. Tajima, J.

Dha. 3

Acetone

Br

Macchia, Tetrahedron, 25, 2979 (1969)

O

C 4 H 7 BrO 2

COOH

C6H9N3O4

N3 HOOC

EtOH

COOH

M. Cleasen, G. Laridon and H.

Dha. 4

Am. Chem. Soc., 101, 4013 (1979)

Vanderhaeghe, Bull. Soc. Chim. Belges, 77, 579 (1968)

C6H9O4S2

S

COOH

HOOC

S

Dha. 5

COOH

O

EtOH, H 2 O

M-O. Hedblom. Arkiv Kemi, 31, 489

Dha. 6

(1969)

COOH

Et2O

M. Farina, E. M: Peronaci, Chim. Ind. (Milan), 48, 602 (1966)

© 2002 by CRC Press LLC

50:50 v/v %

M. S. Newman and H. Junjappa, J. Org. Chem., 36, 2606 (1971)

C7H14O2

Dha. 7

Et2O, benzene

N HOOC

70:30 v/v %

C 7 H 1 1 NO 5

NH2 Cl

Dha. 8

COOH

C 8 H 8 ClNO 2 MeOH

C. T. Holderge, U. S. Patent 3,479,339 (1969)

NHCHO Cl

C 9 H 8 ClNO 3 MeOH

COOH

C. T. Holderge, U. S. Patent 3,479,339

Dha. 9

MeOH

COOH

D. R. Palmer, British Patent 1,314,739

Dha. 10

(1969)

(1973) C 9 H 9 NO 3

NH2 COOH

C 8 H 9 NO 2

NH2

H2O, 2-Propanol

Cl

HN

H2O, 2-Propanol

COOH

40:60 v/v%

HO

C 1 1 H 1 0 NClO 4

O

40:60 v/v%

HO

British Patent 1,395,826 (1975)

Dha. 11

British Patent 1,395,826 (1975)

Dha. 12

C8H12O2

COOH

MeOH

J. P. Grosclaude, H. U. Gonzenbach. J. C.

MeOH

COOH H

N CHO

Dha. 13

C 8 H 1 3 NO 3 S

H

S

J. Hoogmartens, P. J. Claes and H.

Dha. 14

Perlberger and K. Schaffner, Helv. Chim.

Vanderhaeghe, J. Org. Chem., 39, 425

Acta, 59, 2919 (1961)

(1974) C8H14O4

C8H14O2 COOH

EtOH

A. Heymes, M. Dvolaitzky and J. Jacques, Bull. Soc. Chim. Fr., 2898 (1968)

Dha. 15

COOH

M. R. Cox, G. A. Ellestad, A. J. Hannaford, I. R. Wallwork, W. B. Whalley and B. Sjöbereg, J. Chem. Soc., 7257 (1965)

Dha. 16

C 9 H 7 Cl 3 O 3

C9H10O3

COOH

EtOH, H2O

O

MeOH

COOH

H3COOC

MeOH

O

80:20 v/v% Cl

Cl

Cl

A. Fredga and G. Ekstedt, Arkiv Kemi,

Dha. 17

Dha. 18

23, 123 (1964) COOH

NH2

HO

OH

© 2002 by CRC Press LLC

W. J. Gottstein and L. C. Cheney, J. Org. Chem., 30, 2072 (1965)

C 9 H 1 1 NO 4

COOH

MeOH

HN

HO

OCH3

C 1 7 H 1 7 NO 5 MeOH

benzoyl

A. Kaiser, M. Scheer, W. Hausermann

Dha. 19

A. Kaiser, M. Scheer, W. Hausermann and

Dha. 20

and L. Marti, U. S. Patent 3,969,397

L. Marti, U. S. Patent 3,969,397 (1976)

(1976) C9H16O4

C 1 0 H 4 Cl 2 O 4 S 2

Cl

Et 2 O

COOH

H3COOC

Cl

EtOH

S

S

COOH COOH M. R. Cox, H. P. Koch, and W. B.

Dha. 21

A. Almqvist and R. Hakansson, Chemica

Dha. 22

Scripta, 11, 186 (1977)

Whalley, J. Chem. Soc., Perkin 1, 174 (1973) COOH

C 1 0 H 1 1 ClO 3

C10H14O2

COOH

H 2 O, EtOH

O Cl

40:60 v/v%

A. Fredga and K-I. Sandstorm, Arkiv

Dha. 23

EtOH

H. Numan, C. B. Troostwijk, J. H. Wieringa

Dha. 24

Kemi, 23, 245 (1965)

and H. Wynberg, Tetrahedron Lett., 1761 (1977)

H COOH

C10H14O4

C10H18O2

COOH

MeOH, H 2 O

EtOAc COOCH3 H

Dha. 25

80:20 v/v%

H. L. Slates, Z. S. Zelawski, D. Taub and

R. D. Westland, M. L. Mouk, J. L. Holmes,

Dha. 26

N. L. K. Wendler, Tetrahedron, 30, 819

R. A. Cooley, Jr., J. S. Hong and M. M. Grenan, J. Med. Chem., 15, 968

(1974) (1972) C11H14O2

COOH

abs. EtOH

H 2 O, EtOH

O

COOH

C11H14O3

40:60 v/v%

Dha. 27

R. K. Hill and G. R. Newkome, Tetrahedron, 25, 1249 (1969)

© 2002 by CRC Press LLC

Dha. 28

A. Fredga and K. I. Sandstrom, Arkiv Kemi, 23, 245 (1965)

C11H14O3

COOH

EtOH

O

C 1 1 H 1 5 NO 5

NH2 H3CO

EtOAc

COOH

H3CO OCH3

A. Fredga and U. Löfroth, Arkiv Kemi,

Dha. 29

G. Schmidt and H. Rosenkranz, Liebigs

Dha. 30

23, 239 (1965) HN CBZ

H3CO

Ann. Chem., 124 (1975)

C 1 9 H 2 1 NO 8

C12H10O4S2

EtOAc

EtOH

COOH

H3CO

OCH3

G. Schmidt and H. Rosenkranz, Liebigs

Dha. 31

S

S

HOOC

COOH E. Wiklund and R. Hakansson, Chemica

Dha. 32

Ann. Chem., 124 (1975)

Scripta, 6, 174 (1974)

C12H12O3S2

COOH H

HOOC

EtOH, H 2 O

S

S

HOOC

CH2OH

O Dha. 34

Scripta, 6, 174 (1974)

W. S. Briggs, M. Suchy and C. Djerassi, Tetrahedron Lett., 1097 (1968)

C 1 2 H 1 7 BrO 2

C13H16O4

MeOH H

COOH

COOH

H. Hamill and M. A. McKervey, Chem.

Dha. 36

Comm., 864 (1969)

Cl Cl

Dha. 37

B. Sjöberg and S. Sjöberg, Arkiv Kemi, 22, 447 (1964)

C 1 4 H 6 Cl 4 O 4

HOOC HOOC Cl

Et 2 O

HOOC

Br

Dha. 35

MeOH, Acetone

H

50:50 v/v%

E. Wiklund and R. Hakansson, Chemica

Dha. 33

C12H14O5

O

EtOH

COOH

C14H10O3 MeOH

Cl

E. R. Atkinson, Organic Preparations and Procedures, 3, 71 (1971)

© 2002 by CRC Press LLC

Dha. 38

T. Svensson, Arkiv Kemi, 26, 27 (1966)

C14H12O4

HOOC COOH

C14H14O3 COOH

EtOH H3CO

M-J. Brienne and J. Jacques, Bull. Soc.

Dha. 39

Toluene, H 2 O 70:30 v/v%

Dha. 40

Britsh Patent 1,426,186 (1976)

Chim. Fr., 2647 (1974) C15H12O2

COOH

C15H18O4

COOH

MeOH

CH2OCH2Ph

EtOH, Et 2 O

OH

D. J. Cram, W. T. Ford and L. Gosser, J.

Dha. 41

Dha. 42

Am. Chem. Soc., 90, 2598 (1968)

H. Vorbruggen, U. Mende, H. Dahl, German Offen. 2,215,197 (1973)

COOH

C 1 6 H 1 5 NO 4

C 1 6 H 1 9 ClO 2

NH

MeOH, H 2 O

EtOH

O

87:13 v/v%

O

Cl COOH

W. J. Gottstein and L. C. Cheney, J. Org.

Dha. 43

Dha. 44

Chem., 30, 2072 (1965)

P. F. Juby, W. R. Goodwin, T. W. Hudyma and R. A. Partyka, J. Med. Chem., 15, 1297 (1972)

C16H24O3

CHCOOH

MeOH

H3CO

COOH HN

HO

HO

Ph

C 1 7 H 1 6 NO 5 MeOH

O

R. L. Clarke and S. J. Daum, J. Med.

Dha. 45

Dha. 46

U. S. Patent 3,714,242 (1973)

Chem., 13, 320 (1970) H3CO

COOH HN

HO

C 1 7 H 1 7 NO 5

Ph

C17H18O2

Ph

MeOH

abs. EtOH

O

T. J. Schwan and H. A. Burch, J. Pharm.

Dha. 47

Sci., 61, 1506 (1972)

Dha. 48

J. H. Dopper, B. Greijdanas and H. Wynberg, J. Am. Chem. Soc., 97, 216 (1975)

H

COOH

C18H18O2

H

EtOH Ph

© 2002 by CRC Press LLC

COOH

C18H18O2 EtOH

Ph

D. R. Galpin, E. M. Kandeel and A. R.

Dha. 49

D. R. Galpin, E. M. Kandeel and A. R.

Dha. 50

Martin, J. Pharm. Sci., 67, 1367 (1978) OCH3

C20H24O5 OCH3

H3CO

Martin, J. Pharm. Sci., 67, 1367 (1978)

Et 2 O, Petrolether

C23H14O2S HOOC

Et 2 O

S

COOH

E. Schleusener and C. H. Eugster, Helv.

Dha. 51

J. DeWit and H. Wynberg, Tetrahedron, 28,

Dha. 52

Chim. Acta, 55, 986 (1972) C23H22O2

Ph

Ph

Ph

4617 (1972)

COOH

COOH

EOH

C33H28O4 Dioxan

HOOC

Dha. 53

M. J. Brienne, C. Ouannes and J. Jacques,

G. Hass and V. Prelog, Helv. Chim. Acta,

Dha. 54

Bull. Soc. Chim. Fr., 613 (1967) COOH

52, 1202 (1969)

C37H36O4 Benzene, Et 2 O

H HOOC

Br

C 4 H 4 Br 2 O 2

Br

MeOH

40:60 v/v%

HOOC

Dha. 55

G. Hass and V. Prelog, Helv. Chim. Acta,

P. Newman, Optical Resolution Procedures

Dha. 56

52, 1202 (1969)

for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

HOOC Dha. 57

Br

C 5 H 6 Br 2 O 2

Br

MeOH

CF3

P. Newman, Optical Resolution

Dha. 58

Cl

C 4 H 2 ClF 5 O 3

H F O

F

COOH

C. G. Huang, L. A. Rozov, D. F. Halpern,

Procedures for Chemical Compounds,

G. G. Venice, J. Org. Chem., 58 (26), 7382-

Volume 2. Opt.Res. Inf. Center, NY 1981

7387, (1993)

© 2002 by CRC Press LLC

O

C 1 6 H 1 9 NO 5 OH OH

N

H3COOC

C 1 2 H 2 4 O 5 Si

COOH

CH3CN

O

MeOH

Si

O O

C. K. Chiu, M. Meltz, U. S. Patent 5, 280,

Dha. 59

K. Hirai, T. Okada, Jpn. Kokai Tokkyo

Dha. 60

122, (1994) C 3 HBrF 4 O 2

Br

F3 C

F

Koho JP 05 32, 680 (1993)

COOH

EtOAc

P. L. Coe, M. Löhr and C. Rochin, J.

Dha. 61

Chem. Soc. Perkin Trans. 1, 2803 (1998)

Ephedrine C 3 H 7 NO 2

NH2

COOH

H2O

L. R. Overby and A. W. Ingersoll, J. Am.

Eph. 1

HN

EtOAc COOH

L. R. Overby and A. W. Ingersoll, J. Am.

Eph. 2

Chem. Soc., 82, 2067 (1960)

COOH

HO

NH2

C 3 H 7 NO 3

Chem. Soc., 82, 2067 (1960)

HN

2:3 v/v Eph. 3

EtOAc, Petroleum ether CBZ

Eph. 4

H. Kotake, Bull. Chem. Soc. Japan, 43,

43, 2554 (1970)

N

2554 (1970) C 5 H 9 NO 4

OH OH

C 5 H 9 NO 4

O

EtOAc, Petroleum ether 2:3 v/v

OH OH

N

O

Eph. 5

2:3 v/v

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

and H. Kotake, Bull. Chem. Soc. Japan,

O

C 3 H 7 NO 3

COOH

HO

EtOAc, Petroleum ether

K. Oki, K. Suzuki, S. Tuchida, T. Saito

C 1 1 H 1 3 NO 5

CBZ

EtOAc, Petroleum ether 2:3 v/v

O

K. Oki, K. Suzuki, S. Tuchida, T. Saito

Eph. 6

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

and H. Kotake, Bull. Chem. Soc. Japan,

H. Kotake, Bull. Chem. Soc. Japan, 43,

43, 2554 (1970)

2554 (1970)

NH2 COOH

C 6 H 1 3 NO 2 EtOAc, Petroleum ether 2:3 v/v

© 2002 by CRC Press LLC

HN CBZ COOH

C 1 4 H 1 9 NO 5 EtOAc, Petroleum ether 2:3 v/v

Eph. 7

K. Oki, K. Suzuki, S. Tuchida, T. Saito

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

Eph. 8

and H. Kotake, Bull. Chem. Soc. Japan,

H. Kotake, Bull. Chem. Soc. Japan, 43,

43, 2554 (1970)

2554 (1970)

COOH

S

C 5 H 1 1 NO 2

COOH

S

EtOAc, Petroleum ether

NH2 Eph. 9

N CBZ H

2:3 v/v

K. Oki, K. Suzuki, S. Tuchida, T. Saito

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

Eph. 10

43, 2554 (1970)

2554 (1970)

C 5 H 1 1 NO 2

CBZ

EtOAc, Petroleum ether

O

COOH NH2

2:3 v/v K. Oki, K. Suzuki, S. Tuchida, T. Saito

EtOAc, Petroleum ether 2:3 v/v

Eph. 12

K. Oki, K. Suzuki, S. Tuchida, T. Saito and H. Kotake, Bull. Chem. Soc. Japan, 43,

43, 2554 (1970)

2554 (1970)

COOH

C 5 H 1 1 NO 2

HN CBZ

EtOAc, Petroleum ether

COOH

2:3 v/v K. Oki, K. Suzuki, S. Tuchida, T. Saito

C 1 4 H 1 9 NO 5 EtOAc, Petroleum ether 2:3 v/v

Eph. 14

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

and H. Kotake, Bull. Chem. Soc. Japan,

H. Kotake, Bull. Chem. Soc. Japan, 43,

43, 2554 (1970)

2554 (1970)

NH2 COOH

C 7 H 1 5 NO 2 , e r y t h r o

HN CBZ

EtOAc, Petroleum ether

COOH

2:3 v/v K. Oki, K. Suzuki, S. Tuchida, T. Saito

C 1 3 H 2 1 NO 5 EtOAc, Petroleum ether 2:3 v/v

Eph. 16

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

and H. Kotake, Bull. Chem. Soc. Japan,

H. Kotake, Bull. Chem. Soc. Japan, 43,

43, 2554 (1970)

2554 (1970)

NH2 COOH

C 8 H 1 7 NO 2 , t h r e o

HN CBZ

EtOAc, Petroleum ether

COOH

2:3 v/v Eph. 17

C 1 1 H 1 3 NO 5

and H. Kotake, Bull. Chem. Soc. Japan,

NH2

Eph. 15

2:3 v/v

H. Kotake, Bull. Chem. Soc. Japan, 43,

HO CH2 CH COOH

Eph. 13

EtOAc, Petroleum ether

and H. Kotake, Bull. Chem. Soc. Japan,

NH2

Eph. 11

C 1 3 H 1 7 NO 5 S

K. Oki, K. Suzuki, S. Tuchida, T. Saito

C 1 6 H 2 3 NO 5 , e r y t h r o EtOAc, Petroleum ether 2:3 v/v

Eph. 18

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

and H. Kotake, Bull. Chem. Soc. Japan,

H. Kotake, Bull. Chem. Soc. Japan, 43,

43, 2554 (1970)

2554 (1970)

© 2002 by CRC Press LLC

C 5 H 1 1 NO 2 COOH NH2

EtOAc, Petroleum ether

Eph. 20

2554 (1970) C 9 H 1 1 NO 2

Ph

EtOAc, Petroleum ether

K. Oki, K. Suzuki, S. Tuchida, T. Saito

COOH N CBZ H

Eph. 22

EtOAc, Petroleum ether 2:3 v/v

K. Oki, K. Suzuki, S. Tuchida, T. Saito and H. Kotake, Bull. Chem. Soc. Japan, 43,

43, 2554 (1970)

2554 (1970)

COOH H

C4H4O5 MeOH, Acetone 10:90 v/v %

J. Oh-hashi and K. Harada, Bull. Chem.

H H2N

Eph. 24

Soc. Japan, 40, 2977 (1967)

COOH OH H COOH

COOH

S

EtOH

C 4 H 7 NO 5 EtOH, H 2 O 80:20 v/v %

Y. Liwschitz, Y. E. Pfefferman and A. Singerman, J. Chem. Soc. C, 2104 (1967)

C4H4O5

HOOC

C 1 7 H 1 7 NO 5

and H. Kotake, Bull. Chem. Soc. Japan,

O

Eph. 23

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

43, 2554 (1970)

2:3 v/v

H HOOC

2:3 v/v

H. Kotake, Bull. Chem. Soc. Japan, 43,

NH2

Eph. 21

EtOAc, Petroleum ether

and H. Kotake, Bull. Chem. Soc. Japan,

COOH

Ph

N CBZ H

2:3 v/v

K. Oki, K. Suzuki, S. Tuchida, T. Saito

Eph. 19

C 1 3 H 1 7 NO 5 COOH

C 5 H 9 NO 4

COOH

HOOC

NH2 Eph. 25

M. S. Rabinovich and G. N. Kulikova,

Eph. 26

Zhur. Obsch. Khim., 35, 237 (1965)

K. Oki, K. Suzuki, S. Tuchida, T. Saito and H. Kotake, Bull. Chem. Soc. Japan, 43, 2554 (1970)

C 1 3 H 1 5 NO 7 COOH

HOOC HN

Eph. 27

C 5 H 9 NO 4 COOH

HOOC

NH2

CBZ

K. Oki, K. Suzuki, S. Tuchida, T. Saito

Eph. 28

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

and H. Kotake, Bull. Chem. Soc. Japan,

H. Kotake, Bull. Chem. Soc. Japan, 43,

43, 2554 (1970)

2554 (1970)

C 5 H 1 1 NO 2

C 1 3 H 1 5 NO 7 COOH

HOOC HN

CBZ

© 2002 by CRC Press LLC

COOH NH2

K. Oki, K. Suzuki, S. Tuchida, T. Saito

Eph. 29

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

Eph. 30

and H. Kotake, Bull. Chem. Soc. Japan,

H. Kotake, Bull. Chem. Soc. Japan, 43,

43, 2554 (1970)

2554 (1970) C 1 3 H 1 7 NO 5

C 5 H 1 1 NO 2 COOH

COOH HN

CBZ

K. Oki, K. Suzuki, S. Tuchida, T. Saito

Eph. 31

H2O

NH2

L. R. Overby and A. W. Ingersoll, J. Am.

Eph. 32

Chem. Soc., 73, 3363 (1951)

and H. Kotake, Bull. Chem. Soc. Japan, 43, 2554 (1970)

C 7 H 1 3 NO 3 COOH

COOH

S

H2O

NH2

NHAc L. R. Overby and A. W. Ingersoll, J. Am.

Eph. 33

C 5 H 1 1 NO 2 S

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

Eph. 34

Chem. Soc., 73, 3363 (1951)

H. Kotake, Bull. Chem. Soc. Japan, 43, 2554 (1970)

COOH

S HN

C 1 3 H 1 7 NO 5 S

W. Marki, M. Oppliger, P. Thanei and R.

Eph. 36

Schwyzer, Helv. Chim. Acta, 60, 798 (1977)

boc

C 2 0 H 3 3 NO 9 EtOAc

COOH

W. Marki, M. Oppliger, P. Thanei and R.

C6H9N3O4

N3 COOH

HOOC

M. Cleasen, G. Laridon and H.

Eph. 38

Vanderhaeghe, Bull. Soc. Chim. Belges,

(1977)

77, 579 (1968) C6H10O6

COOH

C6H10O6

EtOAc

N

O

COOH

M. Muroi, Y. Inouye and M. Ohno, Bull. Chem. Soc. Japan., 42, 2948 (1969)

© 2002 by CRC Press LLC

EtOH, EtOAc 6:94 v/v %

OH Eph. 39

Acetone

Schwyzer, Helv. Chim. Acta, 60, 798

OH HOOC

EtOAc

43, 2554 (1970)

tBuOOC

Eph. 37

C 6 H 9 NO 6

and H. Kotake, Bull. Chem. Soc. Japan,

HN

tBuOOC

COOH

HOOC

CBZ

K. Oki, K. Suzuki, S. Tuchida, T. Saito

Eph. 35

NH2

HOOC

Eph. 40

P. Block, Jr., J. Org. Chem., 30, 1307 (1965)

C 6 H 1 3 NO 2

NH2

HN

COOH Eph. 42

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

and H. Kotake, Bull. Chem. Soc. Japan.,

H. Kotake, Bull. Chem. Soc. Japan., 43,

43, 2554 (1970)

2554 (1970) C 6 H 1 3 NO 2

NH2

HN

COOH

CBZ

C 1 4 H 1 9 NO 5

COOH

K. Oki, K. Suzuki, S. Tuchida, T. Saito

Eph. 43

C 1 4 H 1 9 NO 5

COOH

K. Oki, K. Suzuki, S. Tuchida, T. Saito

Eph. 41

CBZ

Eph. 44

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

and H. Kotake, Bull. Chem. Soc. Japan.,

H. Kotake, Bull. Chem. Soc. Japan., 43,

43, 2554 (1970)

2554 (1970) C7H6O4

O

COOH

Et2O

O

C7H10O4 Acetone, H2O

COOH

HO

98:2 v/v%

O J. C. Sheehan and Y. S. Lo, J. Med.

Eph. 45

Eph. 46

Chem., 17, 371 (1974)

HOOC

COOH COOH

C6H10O6

NH2

MeOH

K. Reudenberg and W. Hohmann, Liebigs

Eph. 47

COOH

Eph. 48

Ann. Chem., 584, 54 (1953) HN

CBZ

COOH

CBZ

Et2O

C 1 5 H 2 1 NO 5

COOH

Eph. 50

Br

EtOAc

H. Kotake, T. Saito and K. Okubo, Bull. Chem. Soc. Japan., 42, 1367 (1969)

© 2002 by CRC Press LLC

C 7 H 1 5 NO 2 EtOAc

H. Kotake, T. Saito and K. Okubo, Bull. Chem. Soc. Japan., 42, 1367 (1969)

OH COOH

COOH

Eph. 51

Et2O

H. Kotake, T. Saito and K. Okubo, Bull.

NH2

Chem. Soc. Japan., 42, 1367 (1969)

HN

C 7 H 1 5 NO 2

Chem. Soc. Japan., 42, 1367 (1969)

C 1 5 H 2 1 NO 5

H. Kotake, T. Saito and K. Okubo, Bull.

Eph. 49

A. Fredga and A. Sikström, Arkiv Kemi, 8, 433 (1955)

Eph. 52

C 8 H 7 BrO 3 Benzene

A. Collet and J. Jacques, Bull. Soc. Chim. Fr., 3330 (1973)

C 8 H 7 BrO 3

OH

Br

OH

EtOH

COOH

COOH

C 8 H 7 BrO 3 EtOH

Br

A. Collet and J. Jacques, Bull. Soc. Chim.

Eph. 53

Eph. 54

Fr., 3330 (1973)

Cl

Fr., 3330 (1973) C 8 H 7 ClO 3

OH

EtOH

COOH

A. Collet and J. Jacques, Bull. Soc. Chim.

Eph. 55

A. Collet and J. Jacques, Bull. Soc. Chim.

OH Cl

COOH

Eph. 56

Fr., 3330 (1973) OH

EtOH

A. Collet and J. Jacques, Bull. Soc. Chim. Fr., 3330 (1973)

C 8 H 7 ClO 3

COOH

C 8 H 7 ClO 3

C 8 H 7 FO 2

F

EtOH

COOH

EtOH

Cl

A. Collet and J. Jacques, Bull. Soc. Chim.

Eph. 57

Eph. 58

Fr., 3330 (1973)

Farmaco, Ed. Sci., 27, 582 (1972) C 8 H 7 FO 3

OH

F

EtOH

COOH

A. Collet and J. Jacques, Bull. Soc. Chim.

Eph. 59

OH F

COOH

Eph. 60

Fr., 3330 (1973)

COOH

C 8 H 7 FO 3 EtOH

A. Collet and J. Jacques, Bull. Soc. Chim. Fr., 3330 (1973)

C 8 H 7 FO 3

OH

E. Bellasio, A. Trani and A. Sardi,

C8H8O3

OH

EtOH

COOH

Abs. EtOH

F

A. Collet and J. Jacques, Bull. Soc. Chim.

Eph. 61

Eph. 62

R. Roger, J. Chem. Soc., 1544 (1935)

Fr., 3330 (1973)

C8H12O2

H3COOC H

Eph. 63

EtOAc, Petrol. ether H

25:75 v/v%

W. von E. Doering and K. Sachdev, J. Am. Chem. Soc., 96, 1168 (1974)

© 2002 by CRC Press LLC

Cl

Cl

C 8 H 1 4 Cl 2 O 2 EtOAc

HOOC

Eph. 64

D. S. Acker and W. J. Wayne, J. Am. Chem. Soc., 79, 6483 (1957)

C 8 H 1 7 NO 2

HN

COOH

Et 2 O

H. Kotake, T. Saito and K. Okubo, Bull.

Eph. 65

N

COOH

C 8 H 1 7 NO 2

N

CBZ

EtOAc

EtOAc

H. Kotake, T. Saito and K. Okubo, Bull.

Eph. 68

Chem. Soc. Japan., 42, 1367(1969)

Chem. Soc. Japan., 42, 1367(1969)

C9H7F3O3

C9H8O3 COOH H

COOH

H

F3 C

J. R. E. Hoover, G. L. Dunn, D. R. Jakas, Eph. 70 L. L. Lam, J. J. Taggart, J. R. Guarini and L. Phillips, J. Med. Chem., 17, 34 (1974)

Eph. 69

OH

O

COOH

C9H8O5

D. G. Neilson, U. Zakir and C. M.

Eph. 71

Et2O

K. Harada and Y. Nakajama, Bull. Chem. Soc. Japan., 47, 2911 (1974) C 9 H 9 FO 3

OH COOH

EtOH

F

Eph. 72

Scrimgeour, j. Chem. Soc.C, 898 (1971)

A. Collet and J. Jacques, Bull. Soc. Chim. Fr., 3857 (1972)

C9H10O2 COOH

O

H 2 O, EtOH 10:90 v/v%

O

C 1 6 H 2 3 NO 5

COOH

H. Kotake, T. Saito and K. Okubo, Bull.

OH

Et 2 O

Chem. Soc. Japan., 42, 1367(1969)

COOH

Eph. 67

C 1 6 H 2 3 NO 5

H. Kotake, T. Saito and K. Okubo, Bull.

Eph. 66

Chem. Soc. Japan., 42, 1367(1969)

HN

CBZ

C9H10O3

O

EtOH, H2O

COOH

EtOH

25:75 v/v% R. Roger and D. G. Neilson, J. Chem.

Eph. 73

Eph. 74

Soc., 627 (1960)

OH COOH

Soc., 1519 (1962) C9H10O4 EtOH

OH O

COOH

C9H10O4 CHCl 3 , CCl4 40:60 v/v%

O Eph. 75

D. G. Neilson and D.A. V. Peters, J. Chem.

T. R. Emerson, D. F. Ewing, W. Klyne, D. G. Neilson, D. A. V. Peters, L. H. Roach and R. J. Swan, J. Chem. Soc., 4007 (1965)

© 2002 by CRC Press LLC

Eph. 76

D. G. Neilson, U. Zakir and C. M. Scrimgeour, J. Chem. Soc.C, 898 (1971)

OH COOH

C9H10O4

COOH

MeOH, H2O

C 9 H 1 1 NO 2

NH2

90:10 v/v%

O

D. G. Neilson, U. Zakir and C. M.

Eph. 77

K. Oki, K. Suzuki, S. Tuchida, T. Saito and

Eph. 78

Scrimgeour, J. Chem. Soc.C, 898 (1971)

H. Kotaka, Bull. Chem. Soc. Japan., 43, 2554 (1970)

COOH HN

C 1 7 H 1 7 NO 5 N COOH NO

CBZ

K. Oki, K. Suzuki, S. Tuchida, T. Saito

Eph. 79

C10H10N2O3 EtOAc

E. J. Corey, R. J. McCaully and H. S.

Eph. 80

and H. Kotaka, Bull. Chem. Soc. Japan.,

Sachdev, J. Am. Chem. Soc., 92, 2476

43, 2554 (1970)

(1970)

COOH

NH2

C 1 0 H 1 1 ClO 3

COOH

EtOH, H 2 O

O

C 1 0 H 1 2 BrNO 4 EtOH, Acetone 15:85 v/v%

40:60 v/v% H3CO

Cl

Br OH

A. Fredga, A. Kijellqvist and E.

Eph. 81

P. Crooij and J. Eliaers, J. Chem. Soc. C,

Eph. 82

Tornqvist, Arkiv Kemi, 32, 301 (1970) NHAc COOH

559 (1969)

C 1 2 H 1 6 BrNO 5

COOH

O

EtOH, Acetone

C10H12O3 Amyl-acetate

15:85 v/v% H3CO

Br OH

Eph. 83

P. Crooij and J. Eliaers, J. Chem. Soc. C,

Eph. 84

British Patent 1,030,389 (1966)

559 (1969) C 1 0 H 1 4 AsNO 5 COOH

C 1 0 H 1 5 NO 4

H N

H2O

COOH COOH AsO(OH)2 Eph. 85

C. S. Gibson and B. Levin, J. Chem. Soc., 2754 (1929)

© 2002 by CRC Press LLC

Eph. 86

W. Oppolzer and H. Andres, Tetrahedron Lett., 3397 (1978)

C10H16O3

HOOC

COOH

S

MeOAc

Benzene

O

S

M. Delepine and A. Willemart, Compt.

Eph. 87

C11H10O2S2

K. Pettersson, Arkiv Kemi, 7, 339 (1954)

Eph. 88

Rend., 211, 153 (1940) C11H12O2 Hexane

H

COOH

Acetone, MeOH

O

HO

P. H. Mazzocchi and R. S. Lustig, J. Am.

Eph. 89

H

N

Eph. 91

Chem. Comm., 27, 2702 (1962)

C11H16N2O2

COOH OH

EtOAc

N

H. Gustafsson, H. Ericsson and S.

33:67 v/v%

COOH L. Novak and M. Protiva, Coll. Czech.

Eph. 90

Chem. Soc., 97, 3714 (1975) COOH

C11H12O4

H

C11H20O3 Acetone

C. Beard, C. Djerassi, J. Sicher, F. Sipos

Eph. 92

Lindquist, Acta Chem., Scand., B28, 1069

and M. Tichy, Tetrahedron 19, 919 (1963)

(1974) C 1 2 H 1 3 NO 5

O O NHAc COOH

Eph. 93

MeOH, EtOH 40:60 v/v%

H. Nakamoto, M. Aburatani and M.

COOEt

C12H20O5S

COOH

Et 2 O

SAc

Eph. 94

Inagaki, J. Med. Chem., 14, 1021 (1971)

E. Walton, A. F. Wagner, F. W. Bachelor, L. H. Peterson, F. W. Holly and K. Folkers, J. Am. Chem. Soc., 77, 5144 (1955)

C12H22O2

H COOH

O

Benzene

C13H16O4 Benzene

O

COOH

Eph. 95

J. M. Walbrick, J. W. Wilson, Jr., and W. M. Jones, J. Am. Chem. Soc., 90, 2895 (1968)

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Eph. 96

G. Nomina, G. Amoiard and V. Torelli, Bull. Soc. Chim. Fr., 3664 (1968)

C13H18O3

COOH

C 1 4 H 1 8 ClNO 2

N

Benzene

O

COOH Cl

A. Fredga, T. Unge and R. Hakansson,

Eph. 97

Et 2 O

J. Borck, J. Dahm, V. Kopp, J. Kramer, G.

Eph. 98

Chemica Scripta, 4, 123 (1973)

Shorre, J. W. H. Hovy and E. Schorscher, U. S. Patent 3,669,956 (1972)

tBuOOC

N

Cl

C 1 4 H 1 9 NO 4

COOH

C 1 5 H 1 2 ClNO 3 N

Benzene, Hexane

O

COOH

abs. Et 2 O

20:80 v/v%

Eph. 99

H. Kinoshita, M. Shintani, T. Saito and H.

Eph. 100

Kotake, Bull. Chem. Soc. Japan., 44, 286

K. Undheim, P. Hamberg and B. Sjöberg, Acta Chem. Scand., 19, 317 (1965)

(1971) COOH

C15H14O2

C16H10N2O4

Acetone

H2O CO HN COOH C N H O

Eph. 101

K. Pettersson, Arkiv Kemi, 7, 339 (1954)

Eph. 102

R. Kuhn and H. J. Knackmuss, Chem. Ber., 96, 980 (1963)

OH

COOH

C16H14O4 H2O

C16H32O5

OH

HO OH

COOH H3CO

Eph. 103

G. Nomine and J. Cerede, French Patent

Eph. 104

1,205,651 (1960)

J. F. McGhie, W. A. Ross, J. W. Spence, F. J. James and A. Joseph, Chem. Ind. (London), 463 (1972)

COOH

C16H32O5

C17H12O2

OH

HO

Acetone, EtOH COOH

OH

Eph. 105

J. F. McGhie, W. A. Ross, J. W. Spence, F. J. James and A. Joseph, Chem. Ind. (London), 463 (1972)

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Eph. 106

A. Ebnöther, E. Jucker and A. Stoll, Helv. Chim. Acta, 48, 1237 (1965)

O

C17H14O3

O

C18H12O5

EtOH COOH

Eph. 107

COOH

EtOH, EtOAc

HOOC

E. Szarvasi, L. Fontaine and C.

Eph. 108

Letourneur, Bull. Soc. Chim. Fr., 3113

S. Hgishita and K. Kuriyama, J. Chem. Soc. Perkin 2, 59 (1978)

(1964) C18H18O4

C18H22O6 COOCH3 O

EtOH, H 2 O HOOC

Eph. 109

COOEt

35:65 v/v%

R. Buchan and M. B. Watson, J. Chem.

OH

H3CO

Eph. 110

Soc., 2465 (1968)

G. I. Kiprianov and L. M. Kutsenko, Zh. Obsch. Khim., 34, 3928 (1964)

COOH

C18H36O5

C20H22O4

OH

HO

EtOAc

COOEt

OH

EtOAc

COOH

Eph. 111

J. F. McGhie, W. A. Ross, J. W. Spence,

Eph. 112

F. J. James and A. Joseph, Chem. Ind.

L. Dreibelbis, H. N. Khatri and H. M. Walborsky, J. Org. Chem., 40, 2074 (1975)

(London), 463 (1972) OH OH COOH

C20H40O4

H3CO

CH2OH

C23H26O8

EtOH, H2O

H3CO

COOH

CH2Cl2

67:33 v/v% H3CO

OCH3 OCH3

Eph. 113

D. F. Ewing and C. Y. Hopkins, Can. J. Chem., 45, 1259 (1967)

E. Schreier, Helv. Chim. Acta, 46, 75 (1963)

C25H28N2O5

O

PhCH2N H OC O

Eph. 114

NCH2Ph H COOH

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OH

IPrOH

C6H10O3 H2O

O

O

M. Gerevcke, J. P. Zimmermann and W. Aschwanden, Helv. Chim. Acta, 53. 991 (1970)

Eph. 115

S. Bauer and S. Orszagh, Czech. Patent 88,066 (1958)

Eph. 116

C 9 H 1 1 NO 5

OH NH2

HO

C10H14O6 O

EtOH

O

iPrOH

COOH

HO

HOOC

B. Hegedus and A. Krasso, U. S Patent

Eph. 117

COOCH3

P. Newman, Optical Resolution Procedures

Eph. 118

3920728 (1975)

for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981 C 1 2 H 1 1 NO 4

O COOH N

EtOH

C 1 3 H 1 7 NO 5

COOH

O

NHAc

O

O

M. Bianchi, F. Barzaghi and F. Bonacina,

Eph. 119

O O C O

J. Med. Chem., 14, 1021 (1971)

C25H24O8

O

2.) EtOH

H. Nakamoto, M.Aburatani and M. Inagaki,

Eph. 120

Farmaco, Ed. Sci., 21, 121 (1966) O

1.) MeOH

C 6 H 1 2 SO 3

EtOAc

S O

COOH

Petroleum ether

O

COOH

Ph B. Zak, J. Stanek, M. Ledvinova, I. Eph. 122 Vesely, V. Votava, V. Kubelka, J. Palecek and J. Mostecky, Czech. Patent CS 248,946 (1988)

Eph. 121

O

1.) CH 2 Cl 2 2.) EtOH

HOOC

Eph. 123

C12H14O4

C13H20O5

O

O

J. Drabowicz, B. Dudziński, M. Mikolajczyk, M. W. Wieczorek and W. R. Majzner, Tetrahedron Asymmetry, 9, 1171 (1998)

W. Tochtermann, A.-K. Mattauch, M. Kasch, E.-M. Peters, K. Peters and H. G. von Schnering, Liebigs Ann. 317(1996)

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O

Eph. 124

COOH

EtOAc

R. Alajarin, J. J. Vaquero, J. AlvarezBuilla, M. Pastor, C. Sunkel, M. F. de CasaJuana, J. Priego, P. R. Statkow and J. SanzAparicio, I. Fonseca, J. Med. Chem., 38, 2830 (1995)

COOH

C 1 0 H 1 7 NO 4

H3CO

C 1 6 H 1 7 NO 4 S

EtOAc, Hexane BOC N H

EtOH COOH

70:30 v/v%

OH NH2

S

J. A. Zablocki, J. G. Rico, R. B. Garland,

Eph. 125

Eph. 126

O. Cervinka, V. Struzka, V. Dudek, J.

T. E. Rogers, K. Williams, L. A.

Belusa, V. Hruskova, Czech. Patent 265,

Schretzman, S. A. Rao, P. R. Bovy, F. S.

417, (1989)

Tjoeng, R. J. Lindmark, M. V. Toth, M. E. Zupec, D. E. McMackins, S. P. Adams, M. Miyano, C. S. Markos, M. N. Milton, S. Paulson, M. Herin, P. Jacqmin, N. S. Nicholson, S. G. Panzer-Knodle, N. F. Haas, J. D. Page, J. A. Szalony, B. B. Taite, A. K. Salyers, L. W. King, J. G. Campion and L. P. Feigen, J. Med. Chem., 38, 2378 (1995) C8H8O2

OH COOH

O

OCH3

EtOH or H2O

E. J. Valente, J. Zubkowski and D. S.

Eph. 127

C14H20O5

O

HOOC

Eph. 128

Eggleston, Chirality, 4 (8), 494 (1992)

W. Tochtermann, A. Mattauch, M. Kasch, E.-M. Peters, K. Peters and H. G. von Schnering, Liebigs Ann., 317 (1996)

HO

OCH3 H O

C15H24O6

C 1 1 H 1 3 Cl 2 O 4 P

Cl

OCH3

EtOH, H 2 O

Cl

HOOC

96:4 v/v% O

O

P O OH Eph. 129

W. Tochtermann, A. Mattauch, M. Kasch, E.-M. Peters, K. Peters and H. G. von Schnering, Liebigs Ann., 317(1996)

© 2002 by CRC Press LLC

Eph. 130

W. ten Hoeve, H. Wynberg, J. Org. Chem., 50, 4508 (1985)

C 1 1 H 1 3 Cl 2 O 4 P Cl O

Cl

EtOH, H 2 O O

96:4 v/v%

P O

OH

W. ten Hoeve, H. Wynberg, J. Org.

Eph. 131

Chem., 50, 4508 (1985)

Quinidine C4H8O4

OH

COOH

COOH

H2O

C 5 H 1 0 NO 2 EtOAc

OH

F. W. Bachelor and G. A. Miana, Can. J.

Quidi. 1

Quidi. 2

Chem., 47, 4089 (1969)

K. Freudenberg and W. Lwowski, Liebigs Ann. Chem.,592, 76 (1955) OH

C 6 H 1 1 NO 3 S N

COOH

O

Quidi. 3

COOH

EtOAc, MeOH

S

O2N

M. Matell, Acta Chem. Scand., 14, 677

Quidi. 4

H 2 O, EtOH 80:20 v/v%

A. Fredga and E. Andersson, Arkiv Kemi, Mineral. Geol., 14B, No. 38 (1941)

(1960)

COOH

C 8 H 7 NO 5

C8H10O4

COOH

EtOH

H 2 O, EtOH

O

COOH

C 9 H 7 Cl 3 O 3

Cl

80:20 v/v%

Cl

Cl

Quidi. 5

W. C. M. C. Kokke and F.A. Varkevisser,

Quidi. 6

J. Org. Chem., 39, 1535 (1974)

Sweden (1953)

C9H10O4

OH COOH

Ph. D. Thesis of Magnus Matell, Uppsala,

C 9 H 1 1 NO 2

NH2 COOH

MeOH

MeOH

HO

Quidi. 7

A. La Manna, G. Pagani, P. Pratesi and M. L. Ricciardi, Farmaco, Ed. Sci., 19, 506 (1964)

© 2002 by CRC Press LLC

Quidi. 8

S. G. Cohen and S. Y. Weinstein, J. Am. Chem. Soc., 80, 725 (1964)

O COOH

HN

C 1 0 H 1 1 NO 3

NO2

C10H4N2O8S2

COOH S

MeOH

EtOH

S COOH NO2 S. G. Cohen and S. Y. Weinstein, J. Am.

Quidi. 9

S. Gronowitz, Arkiv Kemi, 23, 307 (1965)

Quidi. 10

Chem. Soc., 80, 725 (1964) O HN H

C10H16N2O3S MeOH, Acetone

NH H S

C11H12N2O3

NH2 OH COOH

H

Benzene

N H

COOH

D. E. Wolf, R. Mozingo, S. A. Harris, R.

Quidi. 11

H. Rinderknecht, Helv. Chim. Acta, 47,

Quidi. 12

C. Anderson and K. Folkers, J. Am.

2403 (1964)

Chem. Soc., 67, 2100 (1945) HN CBZ

C19H18N2O6

OH

Benzene

COOH

C11H14O3

COOH

EtOH, H 2 O

O

50:50 v/v% N H

H. Rinderknecht, Helv. Chim. Acta, 47,

Quidi. 13

Quidi. 14

2403 (1964)

409 (1969) C12H14O2

COOH

A. Fredga and K. Olsson, Arkiv Kemi, 30,

COOH

HOOC

Et 2 O

M. S. Newman and J. Linsk, J. Org.

Quidi. 15

C12H14O4 MeOH

Quidi. 16

L. Westman, Arkiv Kemi, 12, 167 (1958)

Chem., 14, 480 (1949) HOOC HOOC

C13H16N2O5

O

abs. EtOH

N H

C14H6N4O12 NO2

O2N

EtOH

NO2 O2N

NO2

Quidi. 17

COOH

R. Adams and N. J. Leonard, J. Am. Chem. Soc., 66, 257 (1944)

© 2002 by CRC Press LLC

Quidi. 18

F. Bell and P. H. Robinson, J. Chem. Soc., 2234 (1927)

COOH

C 1 4 H 1 1 NO 4

C17H10N2O6

EtOH

EtOH HOOC

NO2

NO2

NO2

D. F. Detar and J. C. Howard, J. Am.

Quidi. 19

F. Bell and G. A. Dinsmore, J. Chem. Soc.,

Quidi. 20

Chem. Soc., 77, 4393 (1955)

3691 (1950)

C18H16O3

OH

C18H18O2

CHCl 3 , Acetone O

33:67 v/v%

O

B. D. West and K. P. Link, J.

Quidi. 21

Acetone COOH

K. Mislow, S. Hyden and H. Schaefer, J.

Quidi. 22

Heterocyclic Chem., 2, 93 (1965) O

Am. Chem. Soc., 84, 1449 (1962)

C 1 9 H 1 5 NO 6

O

O

Acetone, CHCl 3

Acetone, CHCl 3

OH

60:40 v/v% O

C. R. Wheeler and W. F. Trager, J. Med.

Quidi. 23

60:40 v/v%

NO2

O

O

C19H16O4

O

B. D. West, S. Preis, C. H. Schroeder and

Quidi. 24

Chem., 22, 1122 (1979)

K. P. Link, J. Am. Chem. Soc., 83, 2676 (1961)

C19H18O3

OH

abs. EtOH

COOH N

O

Quidi. 25

HOOC

O

N H

CHCl 3 , EtOH

H

O

B. D. West, S. Preis, C. H. Schroeder and

Quidi. 26

R. B. Woodward, M. P. Cava, W. D. Ollis,

K. P. Link, J. Am. Chem. Soc., 83, 2676

A. Hunger, H. U. Daeniker and K.

(1961)

Schenker, Tetrahedron, 19, 247 (1963)

COOH

C23H30N2O4

O

EtOH EtOOC

C20H18N2O4

NHAc H

N H

COOEt

O HOOC

C30H14O8 COOH O

EtOH

O

Quidi. 27

W. J. Cole, C. H. Gray and D. C. Nicholson, J. Chem. Soc., 4085 (1965)

© 2002 by CRC Press LLC

Quidi. 28

F. Bell and W. H. D. Morgan, J. Chem. Soc., 1963 (1950)

Nicholson, J. Chem. Soc., 4085 (1965)

Soc., 1963 (1950)

C30H18O4 COOH COOH

COOH

EtOH

C30H18O4 EtOH

COOH

F. Bell and D. H. Waring, J. Chem. Soc.,

Quidi. 29

F. Bell and D. H. Waring, J. Chem. Soc.,

Quidi. 30

1579 (1949) OPh

PhO

OPh OPh

PhO

OPh

2689 (1949) C50H34O10

COOH

EtOH

O. T. Schmidt and K. Demmler, Liebigs

J. W. E. Glattfield and J. W. Chittu, J. Am.

Quidi. 32

Ann. Chem., 586, 179 (1954) C30H18O4

Chem. Soc., 55, 3663 (1933) O

HO P

O O

COOH COOH

C 3 4 H 2 3 Br 2 O 6 P EtOAc

Br Br O O CH2Ph PhCH2

C. Koukotas and L. H. Schwartz, J.

Quidi. 33

H2O

OH

COOHCOOH

Quidi. 31

C4H8O4

OH

Chem. Soc. Chem. Comm., 1400 (1969)

Quidi. 34

E. Martinborough, T. M. Denti, P. P. Castro, T. B. Wyman, C. B. Knobler and F. Diederich, Helv. Chim. Acta, 78, 1037 (1995)

Cl

C 2 2 H 1 1 Cl F 3 O 4 MeOH H O

O

HOOC F3C

Quidi. 35

S. Stanchev, R. Rakovska, N. Berova and G. Snatzke, Tetrahedron Asymmetry, 6, 183 (1995)

© 2002 by CRC Press LLC

Quinine C 2 H 2 BrClO 2

Cl

H2O

COOH

Br

W. J. Pope and J. Read, J. Chem. Soc.,

Quin. 1

D

C 3 H 5 DFNO 2

COOH

F

MeOH, 2,4-

NH2

pentanedione

G. Gal, J. M. Chemerda, D. F. Reinhold and

Quin. 2

105, 811 (1914)

R. M. Purick, J. Org. Chem., 42, 142 (1977) C3H6O4

COOH

HO

EtOH

OH

E. Anderson, Amer. Chem. J., 42, 401

Quin. 3

C 3 H 6 O 4 Se

H. J. Backer and W. Van Dem, Rec. Trav.

Quin. 4

Chim., 48, 1287 (1929)

(1909) C 3 H 7 AsO 5

AsO3H2

EtOH

COOH

H. J. Backer and C. H. K. Mulder, Rec.

Quin. 5

PO3H2 H

O

COOH

EtOH

Beattie, British Patent 1,204,448 (1970) C 4 H 6 Cl 2 O 2 Cl Cl

A. McKenzie and H. J. Plenderleith, J.

Quin. 7

COOH

HOOC

OH

Acetone

D. J. Aberhart and L. J. Lin, J. Chem.

Quin. 9

MeOH, H 2 O

H. Scheibler and J. Magasanik, Chem.

HOOC

SeO2

Quin. 13

Y. Liwschitz, A. Singerman and Í. Wiesel,

Quin. 12

Isr. J. Chem., 6, 647 (1968) C 4 H 7 O 4 Se

© 2002 by CRC Press LLC

C4H8O3

OH

COOH

H2O

H. J. Backer and W. van Dam, Rec. Trav. Chim., 49, 482 (1930

COOH OH

Ber., 48, 1810 (1915 COOH

C 4 H 7 NO 5

NH2

50:50 v/v % Quin. 11

EtOH

Walker, J. Chem. Soc., 123, 2875 (1923)

C 4 H 7 ClO 2

COOH

C4 H6 O5

A. McKenzie, H. J. Plenderleith and N.

Quin. 10

Soc., Perkin 1, 2320 (1974) Cl

EtOAc

Chem. Prod. Res. Develop., 3, 14 (1964)

C4 H6 O3

COOH H

COOH

C. E. Glassick and W. E. Adcock, Ind. Eng.

Quin. 8

Chem. Soc., 1090 (1923) O

C3H7O4P MeOH

C 4 H 5 Cl 3 O 3

OH

H

H

B. G. Christensen, W. J. Leanza and T. R.

Quin. 6

Trav. Chim., 55, 594 (1936)

Cl3C

H2O

COOH

HO2Se

Quin. 14

H2O

H. T. Clarke, J. Org. Chem., 24, 1610 (1959)

C4H8O4

OH

COOH

COOH

H2O

C 4 H 9 AsO 5 H2O

AsO3H2

OH

F. W. Bachelor and G. A. Miana, Can. J.

Quin. 15

H. J. Backer and C. H. K. Mulder, Rec.

Quin. 16

Chem., 47, 4089 (1969)

Trav. Chim., 55, 594 (1936)

C 4 H 1 0 AsClO 3

Cl

H. J. Backer and C. C. Bolt, Rec. Trav.

COOH

H

(1964) C5H6O3

D. Dugat, M. Verny and R. Vessiere,

Quin. 19

COOH

HOOC

MeOH

OH

S

COOH

O

N H

(1969)

C5H8N2O4 MeOH, H 2 O

N H

O

H. Iwasaki, T. Kamiya, O. Oka and J.

Quin. 22

Ueyanagi, Chem. Pharm. Bull., 17, 866

Ueyanagi, Chem. Pharm. Bull., 17, 866 (1969)

H

C5H8N2O4

COOH

H

H

Acetone

R. G. Bergman, J. Am. Chem. Soc., 91,

Katsura, Bull. Chem. Soc. Japan, 35, 1149

© 2002 by CRC Press LLC

COOH

H2O

R. Kaneko, K. Wakabayashi and H.

(1962)

Acetone

7405 (1969) C5H6O3

O

C5H8N2O4

R. G. Bergman, J. Am. Chem. Soc., 91,

Quin. 24

7405 (1969)

Quin. 25

MeOH, H 2 O

(1969) COOH

O

CF3

HN

COOH

H. Iwasaki, T. Kamiya, O. Oka and J.

Quin. 23

C7 5 H 7 N 2 O 5 F 3

O

O

H

MeOH

S

O

Quin. 21

C5H6O4S2

M-O. Hedblom, Arkiv Kemi, 31, 489

Quin. 20

Tetrahedron, 27, 1715 (1971) NH2

Et2O

W. C. Agosts, J. Am. Chem. Soc., 86, 2683

Quin. 18

Chim., 54, 68 (1935) COOH

C5H4O4

H

C

H2O

AsO3H2 Quin. 17

HOOC

C5H8O2S EtOH

S

Quin. 26

G. Cleason and H-G. Jonsson, Arkiv Kemi, 28, 167 (1967)

COOH

C5H8O2S2

COOH

EtOH

C5H8O3 H2O

OH

S S G. Cleason, Arkiv Kemi, 30, 511 (1969)

Quin. 27

G. Nakaminami, M. Nakagawa, Sachiko

Quin. 28

Shioi, Y. Sugiyama, S. Isemura and M. Shibuya, Tetrahedron Lett., 3983 (1967) C5H8O3

COOH

OH

H2O

Acetone

O

O

O R. K. Hill and W. R. Schearer, J. Org.

Quin. 29

T. Kaneko, K. Wakabayashi and H. Kasura,

Quin. 30

Chem., 27, 921 (1962)

COOH

Quin. 31

Bull. Chem. Soc. Japan, 35, 1149 (1962)

C 5 H 9 BrO 2

Br

NH2

Acetone

HOOC

P. A. Levene, T. Mori, and L. A.

Quin. 32

COOH

SeO2

Acetone

W. Theilacker and G. Wendtland, Liebig's

Quin. 33

COOH

C5H10O3 H2O

HOOC

OH

OH

A. Tai and M. Imaida, Bull. Chem. Soc.

Quin. 35

A. Tai and M. Imaida, Bull. Chem. Soc.

Quin. 36

Japan, 51, 1114 (1978)

Japan, 51, 1114 (1978)

C13H10O3

O

COOH

H2O

Chim., 49, 482 (1930)

C5H10O3 EtOH

C 5 H 9 O 4 Se

H. J. Backer and W. van Dam, Rec. Trav.

Quin. 34

Ann. Chem., 570, 33 (1950)

HOOC

H2O

283, 31 (1948)

C 5 H 9 NO 4

COOH

C 5 H 9 NO 4

G. Hillman and A. Elies, Z. Physiol. Chem.,

Mikeska, J. Biol. Chem., 75, 337 (1927)

NO2

C5H8O3

C5H10O4

OH

COOH

Acetone

EtOH

OH

R. Brettle and N. Polgar, J. Chem. Soc.,

Quin. 37

Quin. 38

J. J. Sjolander, K. Folkers. E. A. Adelberg and E. L. Tatum, J. Am. Chem. Soc., 76,

664 (1959)

1085 (1954) C5H10O5

SO3H

COOH

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H2O

AsO3H2

COOH

C 5 H 1 1 AsO 5 H2O

H. J. Backer and D. van der Veen, Rec.

Quin. 39

Quin. 40

Trav. Chim., 55, 887 (1936)

Trav. Chim., 55, 594 (1936)

C 5 H 1 1 NO 2

NH2

C 5 H 1 1 NO 2

NH2

EtOH, H2O

COOH

H. J. Backer and C. H. K. Mulder, Rec.

EtOH, Et2O

COOH

25:75 v/v % E. Fischer and R. Groh, Liebigs Ann.

Quin. 41

Quin. 42

Chem., 383, 363 (1911)

Tetrahedron, 32, 2245

C 1 3 H 1 7 NO 5

CBZ

HN

EtOH, Et2O

COOH

D. R. Pilipauskas and K. D. Kopple,

Quin. 43

D. R. Pilipauskas and K. D. Kopple,

C 5 H 1 1 NO 2

COOH

H2N Quin. 44

Tetrahedron, 32, 2245(1976)

N

EtOAc

COOH

EtOAc

R. Adams and D. Fles, J. Am. Chem. Soc., 81, 4946 (1959)

C 1 3 H 1 3 NO 4

O

(1976)

AsO3H2

C 5 H 1 2 AsClO 3 H2O

Cl

O

R. Adams and D. Fles, J. Am. Chem.

Quin. 45

Quin. 46

Soc., 81, 4946 (1959)

Chim., 54, 68 (1935)

C6H6O4 HOOC H Quin. 47

HOOC

H2O

H

F. Feist, Liebegs Ann. Chem., 436, 125

Quin. 48

(1924)

HOOC

COOH COOH

COOH

C6H6O6 H2O

E. Buchner and R. von der Hide, Chem. Ber., 38, 3112 (1905)

C6H8O2

H

H. J. Backer and C. C. Bolt, Rec. Trav.

COOH

H2O

H

C6H8O4 H2O

COOH Quin. 49

M. Arai and R. J. Crawford, Cna. J.

Quin. 50

Chem., 50, 2158 (1972)

COOH

L. J. Goldsworthy, J. Chem. Soc., 124, 2012 (1924)

C6H8O4

COOH

H2O

EtOH, H 2 O

COOH Quin. 51

F. B. Kipping and J. J. Wren, J. Chem. Soc., 3246 (1957)

© 2002 by CRC Press LLC

C6H8O4

COOH Quin. 52

95:5 v/v %

C. G. Overberger and Y. Shimokawa, Macromolecule, 4, 718 (1917)

C6H8O4

COOH

COOH

EtOH, H 2 O

O

K. Mori, Tetrahedron, 31, 1381 (1975)

Quin. 53

EtOH

O

95:5 v/v %

O

C6H8O4

O

R. Adams and F. B. hauserman, J. Am.

Quin. 54

Chem. Soc., 74, 694 (1952)

COOH O

C6H8O4

COOH

C6H8O4S2

EtOH

S S

EtOH, H 2 O

O

50:50 v/v %

COOH

O. Cervinka and L. Hub, Coll. Czech.

Quin. 55

A. Fredga, Arkiv Kemi Mineral Geol., 12A,

Quin. 56

Chem. Comm., 33, 2927 (1968) S

No. 27 (1938)

C6H8O4S2

COOH

EtOH, H 2 O

S

Se Se

95:5 v/v %

COOH

C 6 H 8 O 4 Se 2

COOH

COOH

M-O. Hedblom. Swed. J. Agric. Res., 1,

Quin. 57

A. Fredga, Arkiv Kemi, Mineral Geol. 11B,

Quin. 58

43 (1971)

No. 15 (1933)

C6H8O2

O

F3C

COOH

CCl 4

C 6 H 9 NO 3 O

N

COOH

EtOH, Et2O 17:83 v/v %

Quin. 59

J. W. C. Crawford, J. Chem. Soc., 4280

Quin. 60

(1965)

HOOC

HOOC Quin. 61

HOOC

38, 312 (1955) C 6 H 9 NO 6

NH2

COOH

EtOAc

W. Marki, M. Oppliger, P. Thanei and R.

tBuOOC

tBuOOC

Quin. 62

HN

boc COOH

C 2 0 H 3 3 NO 9 EtOAc

W. Marki, M. Oppliger, P. Thanei and R.

Schwyzer, Helv. Chim. Acta, 60, 798

Schwyzer, Helv. Chim. Acta, 60, 798

(1977)

(1977) O

N N

H

Quin. 63

E. Hardegger and H. Ott, helv. Chim. Acta,

C6H10N2O3 MeOH, EtOAc

H. Völter and G. Helmchen, Tetrahedron Lett., 1251 (1978)

© 2002 by CRC Press LLC

C6H10O2

COOH Quin. 64

Acetone

S. Stallberg-Stenhagen, Arkiv Kemi Mineral Geol., 23A, No. 15 (1947)

C6H10O3

OH

OH

H2O O

E. T. Stiller, S. A. Harris, J. Finkelstein, J.

Quin. 65

A. Grussner, M. Gatzi-Fichter and T.

Quin. 66

Reichstein, Helv. Chim. Acta., 23, 1276

Chem. Soc., 62, 1785 (1940)

(1941)

C6H10O4

C6H10O4

COOH

EtOAc, Petroleum ether

L. A. Paquette and J. P. Freeman, J. Org.

COOH

HOOC

230 (1936)

C6H10O4S

COOH

COOH

MeOH

S

EtOH

H. Wren and J. Crawford, J. Chem. Soc.,

Quin. 68

Chem., 35, 2249 (1970)

C 6 H 1 0 O 4 Se MeOH

Se COOH

COOH

A. Fredga, Svensk Kem. Tids., 46, 10

Quin. 69

O

C. Keresztesy and K. Folkers, J. Am.

OAc

Quin. 67

MeOH

O

O

C6H10O3

Quin. 70

(1934)

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

C 6 H 1 0 O 4 Se

COOH

Se

COOH

C 6 H 1 1 BrO 2

Br

Acetone, H 2 O

COOH

Acetone

33:67 v/v % Quin. 71

A. Fredga, Arkiv Kemi Mineral Geol.,

Quin. 72

17A, No. 17 (1943) H2N

H

P. A. Levene, T. Mori, and L. A. Mikeska, J. Biol. Chem., 75, 337 (1927)

C 6 H 1 1 NO 2

C 7 H 1 1 NO 3

O HN

HOOC

H

HOOC

Quin. 73

A. Ichihara, K. Shiraishi and S.

Quin. 74

Sakamura, Tetrahedron Lett., 269 (1977) C 6 H 1 1 NO 2

H2N HOOC

H

EtOAc, EtOH

Tetrahedron Lett., 269 (1977)

K. Shiraishi, A. Ichihara and S. Sakamura, Agr. Biol. Chem., 41, 2497 (1977)

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C 7 H 1 1 NO 3

O

EtOAc, EtOH

HN HOOC

Quin. 75

A. Ichihara, K. Shiraishi and S. Sakamura,

Quin. 76

H

K. Shiraishi, A. Ichihara and S. Sakamura, Agr. Biol. Chem., 41, 2497 (1977)

C 6 H 1 1 NO 2 S 2 S

N

COOH

S

C 6 H 1 1 NO 2 S 2

COOH

EtOAc, MeOH

O

H2N

M. Matell, Acta Chem. Scand., 14, 677

Quin. 77

Quin. 78

(1960)

E. Fischer and F. Brauns, Chem. Ber., 47, 3181 (1914)

C 6 H 1 1 NO 3 S COOH

O

N

H2O

C6H12O2

EtOAc, MeOH

COOH

Acetone

S

M. Matell, Acta Chem. Scand., 14, 677

Quin. 79

Quin. 80

(1960)

Chem., 98, 1 (1932) C6H12O2

COOH

SH

Acetone

P. A. Levene and R. E. Marker, J. Biol.

Quin. 81

P. A. Levene and R. e. Marker, J. Biol.

COOH Quin. 82

Chem., 111, 299 (1935)

J. Biol. Chem., 75, 337 (1927) C6H12O3 COOH

EtOAc

OH

OH

G. Buchi, L. Crombie, P. J. Godin, J. S.

Quin. 83

Acetone

P. A. Levene, T. Mori, and L. A. Mikeska,

C6H12O3 COOH

C6H12O2S

Quin. 84

Kaltenbronn, L. S. Siddalingaiah and D.

H2O

H. Scheibler and A. S. Wheeler, Chem. Ber., 44, 2684 (1911)

A. Whiting, J. Chem. Soc., 2843 (1961) OH

COOH

C6H12O4

NH2

EtOH

COOH

C 6 H 1 3 NO 2 Acetone

OH

Quin. 85

D. H. G. Crout and D. Whitehouse, J.

Quin. 86

Chem. Soc., Frenkin 1,544 (1977 NHAc

COOH

W. A. H. Huffman and A. W. Ingersoll, J. Am. Chem. Soc., 73, 3366 (1951)

C 8 H 1 5 NO 2

C 6 H 1 3 NO 2

COOH

Acetone

EtOH

NH2

Quin. 87

W. A. H. Huffman and A. W. Ingersoll, J. Am. Chem. Soc., 73, 3366 (1951)

Quin. 88

T. Miyazawa, K. Takashima, Y. Mitsuda, T. Yamada, S. Kuwata and H. Watanabe, Bull. Chem. Soc. Japan., 52, 1539 (1979)

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C 6 H 1 4 AsClO 3

Cl AsO3H2

H2O

MeOH

S

T. Raznikiewicz, Acta Chem. Scand., 18,

Quin. 90

Chim., 54, 68 (1935)

467 (1961) C7H8O3S

OCH3 COOH

C7H8O3S

O

H. J. Backer and C. C. Bolt, Rec. Trav.

Quin. 89

COOH

C7H10O2

H

C

MeOH

EtOAc

COOH S T. Raznikiewicz, Arkiv Kemi, 18, 467

Quin. 91

Quin. 92

(1961)

L. Crombie, P. A. Jenkins and J. Roblin, J. Chem. Soc. Perkin 1, 1090 (1975)

C7H10O2 HOOC

C7H10O2

COOH

EtOAc W. von E. Doering and K. Sachdev. J.

Quin. 93

Acetone Quin. 94

Am. Chem. Soc., 97, 5512 (1975) COOH

C7H10O3

S. J. Goldberg and F-L. Lam. J. Org. Chem., 31, 241 (1966) C7H10O3

HOOC

abs. EtOH

COOH

O A. B. Arendaruk, E. I. Budovsky, B. P.

Quin. 95

Quin. 96

MeOH

Y. Inouye, S. Inamasu, M. Horiike, M.

Gommikh, M. Y. Karpeisky, L. I.

Ohno and H. M. Walborsky, Tetrahedron,

Kudryashov, A. P. Skoldinow, N. V.

24,

2907 (1968)

Smirnova, A. Y. Khorlin and N. K. Kochetkov, Zhur. Obsch. Khim., 27, 1312 (1957)

H2O COOH

A. Fredga and A. Sikström, Arkiv Kemi,

Quin. 97

C7H10O4S

C7H10O4

COOH

EtOH

HOOC Quin. 98

8, 433 (1955)

S

COOH

J. E. Némortin, E. Jonsson and A. Fredga, Arkiv Kemi, 30, 403 (1969)

C7H12O2

C 7 H 1 0 O 4 Se HOOC

Quin. 99

Se

COOH

A. Fredga and K. Styrman, Arkiv Kemi, 14, (1959)

© 2002 by CRC Press LLC

Acetone

H2O

COOH Quin. 100

B. Ackermark, Acta Chem. Scand., 16, 599 (1962)

C7H12O3

C7H12O3 COOH

HO

MeOH

D. S. Noyce and D. B. Denney, J. Am.

Quin. 101

COOH

O

H

H

Benzene

R. P. Zelinski, N. G. Peterson and H. R.

Quin. 102

Chem. Soc., 74, 5912 (1952)

Wallner, J. Am. Chem. Soc., 74, 1504 (1952)

C7H12O4

COOCH3

HOOC

COOH

S

H2O, Acetone

COOH

S. Stallberg-Stenhagen, Arkiv Kemi

EtOH, H 2 O 53:47 v/v%

90:10 v/v% Quin. 103

C7H12O4S

Quin. 104

M. Matell, Arkiv Kemi, 3, 129 (1951)

Mineral. Geol. 25A, No. 10 (1947) C7H12O4S2 HOOC

S

COOH

S

NH2

H 2 O, Acetone

COOH

55:45 v/v% Quin. 105

A. Fredga, Arkiv Kemi Mineral. Geol.

Quin. 106

H. Nohira, K. Ehara and A. Miyashita, Bull. Chem. Soc. Japan., 43, 2230 (1970)

C7H14O2

C7H14O2

Acetone Quin. 107

P. A. Levene and L. W. Bass, J. Biol.

COOH

Quin. 108

Chem., 70, 211 (1926)

COOH

Acetone

P. A. Levene, A. Rothen, G. M. Meyer and M. Kuna, J. Biol. Chem., 115, 401 (1936)

C7H14O3

OH

H 2 O, MeOH 30:70 v/v%

12A, No. 15 (1937)

COOH

C 7 H 1 3 NO 2

C7H14O3

O

MeOH, H2O

COOH

Acetone

30:70 v/v% Quin. 109

F. M. Hauser, M. L. Coleman, R. c.

Quin. 110

Huffman, F. I. Carroll, J. Org. Chem., 39,

J. W. Lewis and N. Polgar, J. Chem. Soc., 102 (1958)

3426 (1974) C 7 H 1 5 NO 2 H2N

Quin. 111

COOH

EtOAc

C. G. Overberger and G. M. Parker, J. Polymer Sci., A1, 6, 513 (1968)

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AsO3H2 COOH

Quin. 112

C 8 H 9 AsO 5 H2O

H. J. Backer and C. H. K. Mulder, Rec. Trav. Chim., 55, 594 (1936)

C 9 H 9 NO 3

NH2

COOH

EtOH

COOH

C8H10O3 EtOH, H2O 95:5 v/v%

HO

H

Quin. 113

A. A. W. Long, J. H. C. Nayler, U. S.

Quin. 114

O

K. Mori, Tetrahedron, 34, 915 (1978)

Patent 3,674,776 (1972) C8H10O3

COOH

C8H10O4

Acetone

Acetone

COOH

COOH

O Quin. 115

J. Dixon, B. Lythgoe, I. A. Siddiqui and J.

Quin. 116

Tideswell, J. Chem. Soc.C, 1301 (1971)

H

COOH Quin. 117

University (1965)

C8H12O2

H

Ph. D. Thesis of F. A. Mikulkski, Princeton

COOH

C8H12O4

EtOAc, Et 2 O 40:60 v/v%

C. D. Poulter, O. J. Muscio and R. J.

EtOAc HOOC

Quin. 118

Goodfellow, J. Org. Chem., 40, 139

R. Trave and L. Garanti, Gazz. Chim. Ital., 90, 612 (1960)

(1975)

C8H12O4

COOH

COOH

C 8 H 1 3 NO 3

EtOH

EtOH

CONH2

COOH Quin. 119

D. E. Applequist and N. D. Werner, J.

Quin. 120

Org. Chem., 28, 48 (1963)

Chim. Fr., 45, 293 (1929) C8H14O3

C8H14O2

H

EtOH

COOH

Quin. 121

M. M. G. Vavon and P. Peignier, Bull. Soc.

J. M. Walbrick, J. W. Wilson, Jr., and W.

HOOC

Quin. 122

M. Jones, J. Am. Chem. Soc., 90, 2895

OH

abs. EtOH

W. Adam and N. Duran, J. Am. Chem. Soc., 99, 2729 (1977)

(1968) OH

C8H14O3

COOH

COOH

H2O

H 2 O, EtOH

COOH Quin. 123

C. E. Wood and M. A. Comley, J. Chem. Soc., 125, 2630 (1924)

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C8H14O4

Quin. 124

50:50 v/v%

A. Fredga and U. Sahlberg, Arkiv Kemi Mineral. Geol., 18A, No. 16 (1944)

C8H14O4

COOH

H3COOC

Acetone

M. R. Cox, G. A. Ellestad, A. J.

Quin. 125

C8H14O4

Quin. 126

Hannaford, I. R. Wallwork, W. B.

H2O, EtOH

COOH

H3COOC

20:80 v/v% K. Kenyon and W. A. Ross, J. Chem. Soc., 3407 (1951)

Whalley and B. Sjöbereg, J. Chem. Soc., 7257 (1965)

COOH COOCH3

C8H14O4 EtOH, Et2O

40:60 v/v% Quin. 128

Soc. Chim. Fr., 45, 293 (1929) NH2 COOH

O

2073 (1957)

EtOH

Acetone

Quin. 130

P. A. Levene and R. E. Marker, J. Biol. Chem., 95, 1 (1932)

C8H16O2

C8H16O2

Acetone P. A. Levene, A. Rothen, G. M. Meyer

Quin. 131

C8H16O2

COOH

Liebigs Ann. Chem., 402, 364 (1914)

COOH

J. H. Hunt and D. McHale, J. Chem. Soc.,

C 8 H 1 5 NO 3

E. Fischer, A. Rohde and F. Brauns,

Quin. 129

EtOH, H2O

COOH

35:65 v/v%

M. M. G. Vavon and P. Feignier, Bull.

Quin. 127

C 8 H 1 5 NO 2

NH2

Acetone

COOH Quin. 132

and M. Kuna, J. Biol. Chem., 115, 401

P. A. Levene and R. E. Marker, J. Biol. Chem., 91, 687 (1931)

(1936)

COOH

C8H16O2

C8H16O2

Acetone

Acetone, H2O

COOH

50:50 v/v%

. Kenyon and B. C. Platt, J. Chem. Soc.,

Quin. 133

Quin. 134

633 (1939) COOH

Chem., 95, 1 (1932) C 9 H 7 Cl 3 O 3 H 2 O, EtOH

O Cl Cl

Cl

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P. A. Levene and R. E. Marker, J. Biol.

80:20 v/v%

O Cl

Cl

COOH

C 9 H 8 Cl 2 O 3 Acetone, H2O 56:44 v/v%

Ph. D. Thesis of Magnus Matell, Uppsala,

Quin. 135

M. Matell, Arkiv Kemi, 4, 473 (1952)

Quin. 136

Sweden (1953) COOH O Cl

C 9 H 8 Cl 2 O 3

C 9 H 9 NO 4

EtOAc

COOH

MeOH

Cl

O2N

Quin. 137

A. Fredga, Croat. Chem. Acta, 29, 313

F. Nerdel and H. Würgan, Liebigs Ann.

Quin. 138

(1957)

Br

Chem., 621, 34 (1959) C 9 H 1 0 Br 2 O 4

COOH COOH

COOH

Acetone

C9H10O2S EtOH

S

Br

Quin. 139

J. A. Berson, J. Am. Chem. Soc., 76,

Quin. 140

5748 (1954) OH

L. Lamberg and I. Hedlund, Arkiv Kemi, Mineral. Geol., 12A, No. 12 (1937)

C9H10O3

C9H10O3

O

abs. EtOH

COOH

COOH

EtOH, H 2 O 50:50 v/v%

Quin. 141

A. McKenzie and J. K. Wood, J. Chem.

Quin. 142

Soc., 828 (1919)

COOH OH

D. J. C. Pirie and I. A. Smith, J. Chem. Soc., 338 (1932)

C9H10O4

COOH

MeOH

SO3H

K. N. F. Shaw, M. D. Armstrong and A.

Quin. 144

McMillan, J. Org. Chem., 21, 1149 (1956)

SO3H

COOH

C9H10O5S

NH2

719 (1931)

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COOH

50:50 v/v%

C. H. K. Mulder, Rec. Trav. Chim., 50,

C. H. K. Mulder, Rec. Trav. Chim., 51, 174 (1932)

EtOH, H 2 O

Quin. 145

EtOH, H 2 O 50:50 v/v%

OH Quin. 143

C9H10O5S

C 9 H 1 1 NO 2 EtOH, H 2 O 90:10 v/v%

Quin. 146

E. Testa, Farmaco, Ed. Sci., 19, 895 (1964)

C 9 H 1 1 NO 2

COOH

NH2

H2O

NH2

D. J. Cram. L. K. Gaston and H. Jager, J.

Quin. 147

C 9 H 1 1 NO 3

OH

COOH

Quin. 148

British Patent 695,741 (1953)

Am. Chem. Soc., 83, 2183 (1961) H N

COOH

C 9 H 1 2 AsNO 5

C9H12O2

H2O

COOH

Acetone

H2O3As

C. S. Gibson, J. D. A. Johnson and B.

Quin. 149

Quin. 150

Levin, J. Chem. Soc., 479 (1929)

J. A. Berson, J. s. Walia, A. Remanick, S. Suzuki, P. Reynolds-Warnhoff and D. Willner, J. Am. Chem. Soc., 83, 3986 (1961)

COOH COOH

C9H12O4

C9H12O4

EtOH, H 2 O

Acetone

50:50 v/v%

COOH COOH

J. Dixon, B. Lythgoe, I. A. Siddiqui and J.

Quin. 151

Quin. 152

C9H12O4

O O C

H. M. Walboraky, L. Barash and T. C. Davis, Tetrahedron, 19, 2333 (1963)

Tideswell, J. Chem. Soc. C, 1301 (1971)

COOH

Acetone

EtOH, H2O

COOH

COOH

P. R. Bruck, R. D. Clark, R. S. Davidson,

Quin. 153

C9H12O4

Quin. 154

W. H. H. Günther, P. S. Littlewood and B.

37:63 v/v%

T. L. Dawson and G. R. Ramage, J. Chem. Soc., 3523 (1950)

Lythgoe, J. Chem. Soc., 2529 (1967)

COOH

C9H12O4

C9H16O2

COOH

EtOH, H2O

COOH

37:63 v/v%

T. L. Dawson and G. R. Ramage, J.

Quin. 155

HO O

Quin. 156

H. L. Goering and F. H. McCarron, J. Am. Chem. Soc., 80, 2287 (1958)

Chem. Soc., 3523 (1950) OH

Acetone

C 9 H 1 7 NO 5

H N

H2O COOH

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C9H18O2 COOH

Acetone

R. Kuhn and T. Wieland, Chem. Ber., 73,

Quin. 157

P. A. Levene and R. E. Marker, J. Biol.

Quin. 158

Chem., 95, 1 (1932)

971 (1940) C9H18O2 COOH

C9H18O2

COOH

Acetone, H 2 O

Acetone

50:50 v/v% P. A. Levene and R. E. Marker, J. Biol.

Quin. 159

M. Bianchi, P. Frediani, L. Lardicci and F.

Quin. 160

Chem., 95, 1 (1932)

Piacenti, Gazz. Chim. Ital, 104, 273 (1974) C 1 0 H 6 FeO 6

O

HOOC

Fe(CO3)3

F

OCH3 COOH

F

F

F

C10H7F5O3 Hexane, Acetone 50:50 v/v%

F

E. K. G. Schmidt, Angew. Chem. Internat.

Quin. 161

L. R. Pohl and W. F. Trager, J. Med.

Quin. 162

Edit., 12, 777 (1973)

Chem., 16, 475 (1973) C 1 0 H 9 NO 4

O2N COOH

C 1 0 H 1 0 ClNO 3

O

EtOH, H2O

OH

N O

W. H. Mills, H. V. Parker and R. W.

Quin. 163

Quin. 164

Prowse, J. Chem. Soc., 105, 1537 (1914)

Et2O Cl

D. B. Reisner, B. J. Ludwig, F. J. Steifel, S. Gister, M. Meyer, L. S. Powell and R. D. Sofia, Arzneim Forsh., 27, 760 (1977)

COOH

N S

EtOH

N

C10H10N2O5

C10H10N2O2S H N

O2N

COOH

H2O

O

A. Fredga, Acta Chem. Scand., B31, 869

Quin. 165

Quin. 166

(1977)

W. M. Colles and C. S. Gibson, J. Chem. Soc., 279 (1931)

C10H10O2 H

C10H10O3

O

EtOAc

C. G. Overberger and Y. Shimokawa,

Quin. 167

MeOH

H

COOH

H

COOH

Quin. 168

Macromolecules, 4, 718 (1971)

M. Ishihara, K. Yonetani, T. Shibai and Y. Tanaka, Int. Congr. Essent. Oila [Pap.] 7th 1977 (Pub. 1979) 7, 266

C10H10O4

H

H

COOH

COOH

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H COOH COOH

MeOH H

C10H10O4 EtOAc, MeOH

W. C. Agosta, J. Am. Chem. Soc., 86,

Quin. 169

Quin. 170

2638 (1964)

W. C. Agosta, J. Am. Chem. Soc., 86, 2638 (1964)

C 1 0 H 1 2 Br 2 O 4

Br Br

COOH COOCH3

Acetone

J. A. Berson, J. Am. Chem. Soc., 76,

Quin. 171

EtOH

Quin. 172

C10H12O3

OH COOH

C10H12O3

EtOH

J. Canceill, J. Gabard and J. Jacques, Bull.

Quin. 174

C10H12O3

OH

EtOH

COOH

Quin. 176

Testa, J. Med. Chem., 6, 29 (1963) OH COOH

J. M. Domagala and R. D. Bach, J. Org.

Acetone

G. Cignarella, E. Ocelli, G. Maffii and E.

50:50 v/v%

Chem., 44, 2429 (1979)

C10H12O3 COOH OH

EtOH, H 2 O

COOH OH

Soc. Chim. Fr., 231 (1968)

Quin. 175

D. F. DeTar and C. Weis, J. Am. Chem. Soc., 79, 3045 (1957)

4069 (1954)

Quin. 173

C10H12O2

COOH

A. McKenzie and A. Ritchie, Chem. Ber., 70, 23 (1937)

C10H12O3

C10H12O3 EtOH

EtOH, H 2 O

COOH

55:45 v/v%

H3CO E. W. Christie, A. McKenzie and A.

Quin. 177

Quin. 178

Chem., 23, 119 (1970)

Ritchie, J. Chem. Soc., 153 (1935) C10H12O3

O COOH

COOH O

EtOH, H 2 O

D. J. Cram and K. R. Opecky, J. Am.

Quin. 180

Chem. Soc., 81, 2748 (1959)

CN H Quin. 181

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25:75 v/v%

C. M. Bean, J. Kenyon and H. Phillips, J.

CN

MeOH

COOH

H M. Matsui, Y. Yamada and M. Nonoyama, Agr. Biol. Chem., 26, 351 (1962)

O

Chem. Soc., 303 (1936)

C 1 0 H 1 3 NO 2

HOOC

C10H12O5S Acetone, EtOAc

S

O

60:40 v/v% Quin. 179

D. J. Collins and J. J. Hobbs, Austr.J.

C 1 0 H 1 3 NO 2 MeOH, Et2O 55:45 v/v%

Quin. 182

J. Knabe and D. Strauss, Arch. Pharm. (Weinheim), 305, 54 (1972)

C 1 0 H 1 3 NO 2

H N

COOH

HO

Acetone

Acetone

Quin. 183

NH2

HO

COOH

M. P. Paradisi and A. Romeo, J. Chem.

C 1 0 H 1 3 NO 4

E. W. Tristram, J. Ten Broeke, d. F.

Quin. 184

Soc., Perkin 1,596 (1977)

Reinhold, M. Sletzinger, and d. E. Williams, J. Org. Chem., 29, 2053 (1964)

COOH

HO

C 1 2 H 1 5 NO 5 Acetone

NHAc

HO

Quin. 185

C10H16O2 H

H

EtOH

HOOC

E. W. Tristram, J. Ten Broeke, D. F.

I. G. M. Campbell and S. H. Harper, J. Sci.

Quin. 186

Food Agric., 3, 189 (1952)

Reinhold, M. Sletzinger, and D. E. Williams, J. Org. Chem., 29, 2053 (1964)

COOH

C10H16O2

H HOOC Quin. 187

S

EtOH

H

HOOC

I. G. M. Campbell and S. H. Harper, J.

Quin. 188

S

C10H16O6S3 MeOH, EtOAc

S

COOH

13:87 v/v%

A. Fredga, Chemica Scripta, 2, 47 (1972)

Sci. Food Agric., 3, 189 (1952) C10H18O2

COOH

Acetone, H2O

COOH Quin. 189

COOH

P. A. Levene and R. E. Marker, J. Biol.

CN COOH

Quin. 191

EtOH

90:10 v/v% Quin. 190

Chem., 97, 563 (1932) H

C10H18O4

H. Wren and H. Burns, J. Chem. Soc., 117, 266 (1920)

C 1 1 H 9 NO 2

C 1 1 H 1 1 NO 2 COOH CN

MeOH

E. W. Yankee, B. Spencer, N. E. Howe and D. J. Cram, J. Am. Chem. Soc., 95,

Quin. 192

MeOH

B. Loev, E. Macko and I. M. Fried, J. Med. Chem., 12, 854 (1969)

4220 (1973) C 1 1 H 1 1 NO 2 COOH CN

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MeOH

C 1 1 H 1 1 NO 2

CN COOH

MeOH

J. Knabe and D. Strauss, Arch. Pharm.

Quin. 193

D. J. Cram and P. Haberfield, J. Am.

Quin. 194

(Weinheim), 305, 54 (1972) OH

Chem. Soc., 83, 2354 (1961)

C 1 1 H 1 1 NO 3 MeOH

COOH

C 1 1 H 1 1 NO 3

O O

abs. Et 2 O

N O

N H

K. Ichihara and H. Nakata, Z. Physiol.

Quin. 195

D. B. Reisner, B. J. Ludwig, F. J. Steifel, S.

Quin. 196

Chem., 243, 244 (1936)

Gister, M. Meyer, L. S. Powell and R. D. Sofia, Arzneim. Forsch., 27, 760 (1977)

NH2

C11H12N2O2

COOH

MeOH

COOH

C13H14N2O3 MeOH

NHAc

N H

N H C. P. Berg, J. Biol. Chem., 100, 79

Quin. 197

C. P. Berg, J. Biol. Chem., 100, 79 (1933)

Quin. 198

(1933)

NH2

C11H12N2O2

HN CBZ

Acetone

COOH

N H

L. R. Overby and A. W. Ingersoll, J. Am.

Quin. 199

L. R. Overby and A. W. Ingersoll, J. Am.

Quin. 200

Chem. Soc., 82, 2067 (1960) NH2

Chem. Soc., 82, 2067 (1960) HN CBZ

C11H12N2O3 Benzene

COOH

HO

C19H18N2O6

COOH

HO

N H

Benzene

N H

A. J. Morris and M. D. Armstrong, J. Org.

A. J. Morris and M. D. Armstrong, J. Org.

Quin. 202

Chem., 22, 306 (1957)

COOH

Chem., 22, 306 (1957)

C11H12O2

C11H12O3S2

EtOH, H 2 O 56:44 v/v% Quin. 203

Acetone

COOH

N H

Quin. 201

C19H18N2O5

L. Westman, Arkiv Kemi, 12, 161 (1957)

MeOH, H 2 O

S O

Quin. 204

S

COOH

A. Fredga, Arkiv Kemi Mineral. Geol., 24B, No. 15 (1947)

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C11H12O2

C11H12O2

EtOH

EtOH, H 2 O 50:50 v/v%

HOOC

HOOC

COOH

L. Westman, Arkiv Kemi, 11, 431 (1957)

Quin. 205

Quin. 206

COOH

K. Kawazu, T. Fujits and T. Mitsui, J. Am. Chem. Soc., 81, 932 (1959)

C11H12O4

OH H

C 1 1 H 1 3 NO 3

NHCHO COOH

EtOH

O Quin. 207

H

20:80 v/v%

COOH G. Muller, G. Nominé and J. Warnant, U.

Quin. 208

S. Patent 2,952,682 (1960) COOH

H. Mizuno, S. Terashima and S. Yamada, Chem. Pharm. Bull., 19, 227 (1971)

C11H14O2

C11H14O2

Acetone COOH

Quin. 209

EtOH, H 2 O

Ph. D. Thesis of M. B. Bochner, Princeton

Quin. 210

University, Princeton, N. J. (1962)

C. Rüchardt and H. Trautwein, Chem. Ber., 98, 2478 (1965)

C11H14O2 MeOH

Et 2 O

C11H14O3 HO

COOH

H2O

HOOC

Quin. 211

C. S. Marvel, R. L. Frank and E. Prill, J.

Quin. 212

Am. Chem. Soc., 65, 1647 (1943) OH COOH

12, 823 (1957)

C11H14O3

C11H14O3

EtOH

CHCl 3 , Petroleum

O

Quin. 213

R. Fusco and E. Testa, Farmaco, Ed. Sci.,

M. Fileti, J. Prakt. Chem., 46, 560 (1892)

Quin. 214

COOH

J. W. Clark-Lewis and R. W. Jemison, Austr. J. Chem., 18, 1791 (1965)

© 2002 by CRC Press LLC

COOH

C11H14O4

O

EtOAc

H N

C 1 1 H 1 5 NO 2

COOH

MeOH, Acetone 15:85 v/v%

HO A. Collet and J. Jacques, Tetrahedron

Quin. 215

Quin. 216

Lett., 1265 (1978)

J. F. Klebe and H. Finkbeiner, J. Am. Chem. Soc., 90, 7255 (1968)

C11H16O4 H HOOC

Quin. 217

COOCH3

H

C11H18O2

H 2 O, Acetone

EtOH

COOH

13:87 v/v% M. Matsui and Y. Yamada, Agr. Biol.

Quin. 218

Chem., 27, 373 (1963)

CN COOH

L. Crombie, J. Crossley and D. A. Mitchard, J. Chem. Soc., 4957 (1963)

C 1 1 H 1 9 NO 2

C11H20O2

MeOH, H 2 O

Acetone

COOH Quin. 219

J. Knabe and H. Junginger, Pharmazie, 7,

Quin. 220

443 (1972)

P. A. Levene and R. E. Marker, J. Biol. Chem., 97, 563 (1932)

C11H20O3

COOH OH

HOOC

C12H8O4S3

COOH

Acetone

EtOH

S

S

S Quin. 221

C. Beard, C. Djerassi, J. Sicher, F. Sipos

Quin. 222

and M. Tichy, Tetrahedron 19, 919 (1963)

HOOC

CH2OH

S

Scripta, 11, 180 (1977)

C12H10O4S2 EtOH

A. Almqvist and R. Hakansson, Chem.

C 1 2 H 1 2 Br 2 O 2

H Br

COOH

abs. EtOH

S Br

Quin. 223

E. Wiklund and R. Hakansson, Chemica Scripta, 6, 174 (1974)

© 2002 by CRC Press LLC

Quin. 224

R. Adams and C. W. Theobald, J. Am. Chem. Soc., 65, 2383 (1943)

C 1 2 H 1 2 BrClO 3

H Br

Acetone

COOH

H3CO

COOH OCH3

R. Adams and R. S. Ludington, J. Am.

Quin. 226

Chem. Soc., 67, 794 (1945)

R. Adams and W. J. Gross, J. Am. Chem. Soc., 64, 1786 (1942)

C12H14N2O2S2

COOH

EtOH, H 2 O

S

S

EtOAc

Cl

Br

Quin. 225

C 1 2 H 1 2 Cl 2 O 3

H Cl

C12H12O2 EtOH

90:10 v/v%

N N H HOOC Quin. 227

W. H. Mills and B. C. Saunders, J. Chem.

Quin. 228

Soc., 537 (1931)

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

COOH

C12H14O2

SO2Ph

MeOH, H 2 O

COOH

C12H14O4S EtOH

67:33 v/v% Quin. 229

P. Newman, Optical Resolution

Quin. 230

Procedures for Chemical Compounds,

D. J. Cram and A. Ratajczak, J. Am. Chem. Soc., 90, 2198 (1968)

Volume 2. Opt.Res. Inf. Center, NY 1981 COOH

C12H16O2

C12H16O2 COOH

Acetone

EtOH, H 2 O 63:37 v/v%

Quin. 231

P. A. Levene and R. E. Marker, J. Biol.

Quin. 232

Chem., 93, 749 (1931)

G. Sörlin and G. Bergson, Arkiv Kemi, 29, 593 (1968)

C12H16O2 EtOH

C12H16O4

O

COOH

EtOH

O COOH Quin. 233

D. J. Cram, J. Am. Chem. Soc., 74, 2152 (1952)

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Quin. 234

A. M. Schercker, J. Org. Chem., 22, 33 (1957)

C12H22O2 Acetone

COOH

C 1 3 H 1 1 NO 5

NO2 COOH

EtOH

O

P. A. Levene and R. E. Marker, J. Biol.

Quin. 235

A. Khawam and E. V. Brown, J. Am.

Quin. 236

Chem., 97, 563 (1932)

Chem. Soc., 74, 5603 (1952)

C13H12O2

C 1 3 H 1 3 ClO 4

Cl

MeOH

COOH

COOH

O

B. Sjöberg, Arkiv Kemi, 9, 295 (1956)

Quin. 237

abs. EtOH

O

Quin. 238

R. G. Wilkinson, R. L. Fields and J. H. Boothe, J. Org. Chem., 26, 637 (1961)

COOH

C 1 3 H 1 4 BrClO 2

Cl

C 1 3 H 1 4 Cl 2 O 3 Cl

abs. EtOH

R. Adams and M. W. Miller, J. Am.

Quin. 240

Chem. Soc., 62, 53 (1940)

R. Adams and W. J. Gross, J. Am. Chem. Soc., 64, 1786 (1942)

C 1 3 H 1 5 ClO 2

H Cl

Acetone

Cl

Br

Quin. 239

COOH OCH3

C 1 3 H 1 5 NO 2

CN

EtOAc

COOH

EtOAc

COOH

Quin. 241

R. Adams and C. W. Theobald, J. Am.

Quin. 242

Chem. Soc., 65, 2383 (1943) OH COOCH3

R. Branchini, G. Casini, M. Ferappi and S. Gulinelli, Farmaco, Ed. Sci., 15, 734 (1960)

C13H16O6

COOH

Acetone

C13H18O2 EtOH, H 2 O

COOH O

Quin. 243

W. Heller and C. Tamm, Helv. Chim. Acta, 57, 1766 (1974)

© 2002 by CRC Press LLC

Quin. 244

J. B. Conant and G. H. Carlson, J. Am. Chem. Soc., 54, 4056 (1932)

C13H20O4

COOH H

COOH

C14H8F2O4

F

F

EtOH

Acetone

H COOH

HOOC G. Stork and F. H. Clarke, Jr., J. Am.

Quin. 245

W. Stanley, E. McMahon and R. Adams, J.

Quin. 246

Chem. Soc., 83, 3114 (1961) C14H8N2O8

HOOC HOOC

Am. Chem. Soc., 55, 706 (1933) C14H8N2O8

HOOC HOOC

EtOH, Light petroleum, Benzene

NO2

NO2O2N

G. H. Christie, A. Holderness and J.

Quin. 247

Quin. 248

Kenner, J. Chem. Soc., 671 (1926) HOOC

NO2

C14H8N2O8

HOOC

R. Kuhn and O. Albercht, Liebigs Ann. Chem., 465, 282 (1928) C 1 4 H 9 NO 6

HOOC HOOC

EtOH

EtOH NO2

O 2N

R. Kuhn and O. Albercht, Liebigs Ann.

Quin. 249

Quin. 250

Chem., 465, 282 (1928)

J. Canceill and J. Jacques, Bull. Soc.

Quin. 251

Quin. 252

Chim. Fr., 2727 (1973) COOH

R. Adams and J. B. Hale, J. Am. Chem. Soc., 61, 2825 (1939)

EtOAc

R. Adams and L. O. Binder, J. Am. Chem.

OH

EtOH, H2O 60:40 v/v%

COOH

Soc., 63, 2773 (1941)

C 1 4 H 1 1 NO 4

NO2

C 1 4 H 1 1 ClO 2

H

Cl

EtOH

COOH

F. Bell and P. H. Robinson, J. Chem. Soc., 2234 (1927)

C14H10O4

HOOC

Quin. 253

EtOH

NO2

COOH

C14H12O3 MeOH

Ph Quin. 254

A. Guarnieri, S. Burnelli, A. Andreani, I. Busacci, A. M. Barbaro and M. Gaiardi, Farmaco, Ed. Sci., 33, 761 (1978)

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COOH

H2N

C 1 4 H 1 3 NO 3 EtOH

C 1 4 H 1 3 NO 5

O 2N HOOC

EtOH, H2O 40:60 v/v%

HO O

J. H. C. Nayler, British Patent 1,267,936

Quin. 255

Quin. 256

(1972) COOH

A. Khawam and E. V. Brown, J. Am. Chem. Soc., 74, 5603 (1952)

C14H14O2

C14H14O3

COOH O

EtOAc

EtOH, H2O 50:50 v/v%

B. Sjöberg, Arkiv Kemi, 12, 573 (1958)

Quin. 257

COOH

Quin. 258

C14H14O3

H H SO2Ph

Acetone

O

M. Matell, Arkiv Kemi, 6, 251 (1953) C14H14O4S abs. EtOH

COOH

M. Janczewski and T. Bartnik, Polish J.

Quin. 259

Quin. 260

Chem., 42, 1253 (1968)

H

H COOH SO2Ph

U. Folli, D. Iarossi, F. Montanari and G. Torre, J. Chem. Soc., C, 1317 (1968)

C14H14O4S

C14H14O4S2

HOOC S

abs. EtOH

EtOH, H2O

S

50:50 v/v%

COOH U. Folli, D. Iarossi, F. Montanari and G.

Quin. 261

Quin. 262

Torre, J. Chem. Soc., C, 1317 (1968)

21, 349 (1963)

C14H14O4S2

S

HOOC

COOH

Se Se

(1973)

50:50 v/v%

Quin. 264

S. Gronowitz and T. Frejd, Acta Chem. Scand., 26, 2279 (1972)

C14H16O2 Et 2 O C

EtOH, H 2 O

COOH

R. Hakansson, Chemica Scripta, 3, 177

Quin. 263

C 1 4 H 1 4 O 4 Se 2

COOH

EtOH, H 2 O

S

S. Gronowitz and R. Beselin, Arkiv Kemi,

COOH

C14H16O2 MeOH, H 2 O 67:33 v/v%

COOH

© 2002 by CRC Press LLC

Quin. 265

G. Kresze, W. Runge and E. Ruch,

P. Newman, Optical Resolution Procedures

Quin. 266

Liebigs Ann. Chem., 756, 112 (1972)

for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

C 1 4 H 1 7 NO 5

OH

COOH

EtOH

C14H18O2 EtOH

N COOH COOCH2Ph Quin. 267

G. Jollés, G. Poiget, J. Robert, B. Terlain

R. B. Barlow, F. M. Franks and J. D. M.

Quin. 268

and J-P. Thomas, Bull. Soc. Chim. Fr.,

Pearson, J. Med. Chem., 16, 439 (1973)

2252 (1965)

HO

C14H18O3

COOH

COOH

HO

EtOH

Quin. 269

R. B. Barlow, F. M. Franks and J. D. M.

C14H18O3 EtOH

French Patent 1,329,640 (1963)

Quin. 270

Pearson, J. Med. Chem., 16, 439 (1973) C15H12O2 COOH

COOH

Acetone, CHCl 3

C15H14O2 EtOH

83:17 v/v% Quin. 271

D. J. Cram and L. Gosser, J. Am. Chem.

M. Janczewski and W. Podkoscielny,

Quin. 272

Soc., 86, 5445 (1964) HO

COOH

Polish J. Chem., 39, 201 (1965) C15H14O3

OO

O

EtOH

E. W. Christie, A. McKenzie and A.

C15H14O4S2 abs. EtOH, Petroleum

S

HOOC

Quin. 273

O S

S

F. B. Kipping, J. Chem. Soc., 18 (1935)

Quin. 274

Ritchie, J. Chem. Soc., 153 (1935) C 1 5 H 1 5 NO 2 COOH

C 1 5 H 1 5 NO 2

MeOH

Abs. EtOH HN COOH

Quin. 275

H. Dahn, J. A. Garbarino and C. O'Murchu, Helv. Chim. Acta, 53, 1370 (1970)

© 2002 by CRC Press LLC

Quin. 276

Ph. D. Thesis of D. F. Zinkel, University of Wisconsin, Madison, Wis. (1961)

C15H15O5 NO2 COOH

COOH

EtOH, H 2 O

C 1 5 H 1 7 NO 4 EtOAc

O

45:55 v/v%

N

O

O

A. Khawam and E. V. Brown, J. Am.

Quin. 277

C. G. Overberger and G. M. Parker, J.

Quin. 278

Chem. Soc., 74, 5603 (1952)

COOH

plymer Sci., A1, 6, 513 (1968)

C15H20O2

O O S

abs. EtOH

B. Calas and L. Giral, Bull. Soc. Chim.

Quin. 279

Chem. Soc., 85, 1100 (1963) C 1 6 H 1 3 BrO 2

Br Ph

Ph Quin. 281 H

Ph HOOC

COOH Ph

H. M. Walborsky, L. Barash, A. E. Young Quin. 282 and F. J. Impastato, J. Am. Chem. Soc., 83, 2517 (1961)

H H

C 1 6 H 1 3 ClO 2

Cl

Ph

Ph

Abs. EtOH

D. J. Cram and A. S. Wingrove, J. Am.

Quin. 280

Fr., 2629 (1971) COOH

C15H22O4S COOH

N,N-dimethylformamide

H. M. Walborsky and A. E. Young, J. Am. Chem. Soc., 86, 3288 (1964)

C16H14O2

C16H14O3

EtOH

EtOAc

O COOH

Quin. 283

I. A. D'yakonov, M. I. Komendantov, F. Gui-siya and G. L. Korichev, Zh. Obsch. Kim., 32, 928 (1962)

COOHCOOH

Quin. 284

C. L. Bickel, J. Am. Chem. Soc., 60, 927 (1938)

C16H14O4

C 1 6 H 1 4 O 4 Se

EtOH

COOH

MeOH

Se

COOH

Quin. 285

F. Bell, J. Chem. Soc., 835 (1934)

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Quin. 286

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

COOH

C 1 6 H 1 5 BrO 2 EtOH

COOH

C 1 6 H 1 5 BrO 2 EtOH

Br

Br

H. R. Burjorjee, Kamakshi, B. K. Menon and D. H. Peacock, Proc. Ind. Acad. Sci., Sect. 1A, 407 (1934)

Quin. 287

COOH

Quin. 288

H. R. Burjorjee, Kamakshi, B. K. Menon and D. H. Peacock, Proc. Ind. Acad. Sci., Sect. 1A, 407 (1934)

C 1 6 H 1 5 ClO 2

COOH

EtOH

C 1 6 H 1 5 ClO 2 EtOH

Cl

Cl H. R. Burjorjee, Kamakshi, B. K. Menon and D. H. Peacock, Proc. Ind. Acad. Sci., Sect. 1A, 407 (1934)

Quin. 289

O

H. R. Burjorjee, Kamakshi, B. K. Menon and D. H. Peacock, Proc. Ind. Acad. Sci., Sect. 1A, 407 (1934)

C 1 6 H 1 6 ClNO 3 COOH

N

Quin. 290

COOH

EtOAc

C16H16O2 Acetone, H 2 O 50:50 v/v%

Cl

R. Adams and A. A. Albert, J. Am.

Quin. 291

Quin. 292

Chem. Soc., 64, 1475 (1942) COOH

W. Bleazard and E. Rothstein, J. Chem. Soc., 3789 (1958)

C16H16O2

COOH

HO

EtOH

C16H16O3 EtOH

Ph

M. Kawana and S. Emoto, Bull. Chem. Soc. Japan., 39, 910 (1966)

Quin. 293

Quin. 294

A. Guarnieri, S. Burnelli, A. Andreani, I. Busacci, A. M. Barbaro and M. Gaiardi, Farmado,Ed. Sci., 33, 761 (1978)

C16H16O3

OH COOH

C16H16O3 COOH

EtOH

EtOH

OH Ph

Ph Quin. 295

A. Guarnieri, G. Scapini, S. Burnelli and A. Andreani, Farmaco, Ed. Sci., 32, 324 (1977)

© 2002 by CRC Press LLC

Quin. 296

A. Guarnieri, S. Burnelli, L. Varoli, A. M. Barbaro and M. Gaidardi, Farmaco, Ed. Sci., 33, 992 (1978)

C16H16O3

OH COOH

C16H16O4S2

EtOH

EtOH S

O O S

Ph

COOH A. Guarnieri, S. Burnelli, A. Andreani, I.

Quin. 297

Quin. 298

F. B. Kipping, J. Chem. Soc., 1506 (1933)

Busacci, A. M. Barbaro and M. Gaiardi, Farmaco, Ed. Sci., 33, 761 (1978) O N

COOH

C 1 6 H 1 7 NO 3

C 1 6 H 1 9 ClO 2

EtOAc

Acetone, CH 3 CN 15:85 v/v%

Cl COOH

Quin. 299

R. Adams and A. A. Albert, J. Am.

Quin. 300

Chem. Soc., 64, 1475 (1942)

C. Noguchi, S. Kishimoto, I. Minamida and M. Obayashi, Chem. Pharm. Bull, 22, 529 (1974)

SO3H

HO3S

C17H14N2O8S2

C17H14O3

MeOH

Methyl-ethyl-ketone

O

N

N

CH2COOH Ph

O O

Quin. 301

H. Leuchs, E. Conrad and H.V.

Quin. 302

Katinszky, Chem. Ber., 55, 2131 (1922)

J.H. Brewster and R. T. Prudence, J. Am. Chem. Soc., 95, 1217 (1973)

C 1 7 H 1 5 BrO 2

HOOC

C17H18O3

CHCl 3

COOH OH

Br

Quin. 303

Ph

H. Keller, C. Krieger, E. Langer and H. Lehner, Liebigs Ann. Chem., 1296 (1977)

Quin. 304

A. Guarnieri, S. Burnelli, L. Varoli, A. M. Barbaro and M. Gaiardi, Farmaco, Ed. Sci., 33, 992 (1978)

HOOC

COOH

C18H16O4

C18H18O4

EtOH

EtOH

COOHCOOH

© 2002 by CRC Press LLC

Quin. 305

T. Sato, S. Akabori, M. Kainosho and K.

Quin. 306

Hata, Bull. Chem. Soc. Japan., 41, 218

H. E. Zimmerman and D. S. Crumrine, J. Am. Chem. Soc., 94, 498 (1972)

(1968) C18H18O4

COOHCOOH

C18H20O3

EtOH, H 2 O

COOH OH

50:50 v/v%

Ph Quin. 307

S. Gronowitz and J. E. Skramstead, Arkiv

Quin. 308

Kemi, 28, 115 (1967)

A. Guarneri, S. Burnelli, L. Varoli, A. M. Barbaro and M. Gaiardi, Farmaco, Ed. Sci., 33, 992 (1978) OCH3

C18H20O3 COOH

C18H20O4 Abs. EtOH

OH Ph

COOH

H3CO Quin. 309

A. Guarneri, S. Burnelli, L. Varoli, A. M.

Quin. 310

Barbaro and M. Gaiardi, Farmaco, Ed.

D. J. Collins and J. J. Hobbs, Aust. J. Chem., 23, 1605 (1970)

Sci., 33, 992 (1978) COOH

C18H22O3 MeOH

H3CO

C18H22O4S2

COOH S S

EtOH, H 2 O 50:50 v/v%

COOH

Quin. 311

J. Jacques and A. Horeau, Bull. Soc.

Quin. 312

Chim. Fr., 301 (1949)

Kemi, 28, 115 (1967)

OCH3

C19H20O2 Ph Ph

H COOH

S. Gronowitz and J. E. Skramstad, Arkiv

CHCl 3 , Hexane

Abs. EtOH

40:60 v/v% COOH

H3CO

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C19H22O4

H. E. Zimmerman, J. D. Robbins, R. D.

Quin. 313

D. J. Collins and J. J. Hobbs, Aust. J.

Quin. 314

McKelvey, C. J. Samuel and L. R. Sousa,

Chem., 23, 1605 (1970)

J. Am. Chem. Soc., 96, 4630 (1974) O

COOH

C20H16O8

O

COOH

EtOH

H3CO

OCH3

C21H22O7

H3CO

MeOH

H3CO

O HOOC

O O

J. E. Batterbee, R. S. Burden, L. Crombie

Quin. 315

G. Traverso, Farmaco, Ed. Sci., 16, 457

Quin. 316

and D. A. Whiting, J. Chem. Soc. C,

(1961)

2470 (1969)

C22H14O4 COOH COOH

EtOH, Et 2 O

R. Kuhn and O. Albrecht, Liebigs Ann.

Quin. 318

Soc., 1242 (1955)

Chem., 465, 282 (1928)

C22H14O4 COOH

EtOH

COOH COOH

50:50 v/v%

D. M. Hall and E. E. Turner, J. Chem.

Quin. 317

C22H14O4

C 2 2 H 1 9 NO 3

COOH

EtOH

EtOH

HOOC

HN

W. M. Stanley, J. Am. Chem. Soc., 53,

Quin. 319

Quin. 320

3104 (1931)

O

H. Wren and R. E. Burrows, J. Chem. Soc., 125, 1934 (1924)

C22H20O2

O

CH2OH

C22H22O8

abs. EtOH

O

COOH

Acetone

COOH Ph

H3CO

OCH3 OCH3

Quin. 321

S. M. Wong, H. P. Fischer and D. J.

Quin. 322

W. J. Gensler, C. M. Samour, S. Y. Wang

Cram, J. Am. Chem. Soc., 94, 2235

and F. Johnson, J. Am. Chem. Soc., 82,

(1971)

1714 (1960)

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C22H26O4

PhCH2O

C 2 3 H 2 1 NO 3

COOH

COOH

EtOAc

O

EtOH O

HN

N. Cohen, J. W. Scott, F. T. Bizzaro, R. J.

Quin. 323

Quin. 324

H. Wren and R.E. Burrows, J. Chem. Soc., 125, 1934 (1924)

Lopresti, W. F. Eichel and R. Saucy, Helv. Chim.Acta, 61, 837 (1978)

C24H18O4 COOH

Acetone

HOOC PhSO2

N

N

COOH

C25H26N2O4S2

SO2Ph

Acetone

HOOC

H. E. Harris, M. M. Harris, R. Z.

Quin. 325

Quin. 326

R. Adams and J. J. Tjepkema, J. Am. Chem. Soc., 70, 4204 (1948)

Mazengo and S. Singh, J. Chem. Soc. Perkin 2, 1059 (1974) COOH

C 2 6 H 2 1 NO 3

C 2 6 H 2 1 NO 3

COOH

abs. EtOH

Abs. EtOH HN

HN

Quin. 327

O

H. Wren and E. Wright, J. Chem. Soc.,

Quin. 328

136 (1929) O HOOC O

O

H. Wren and E. Wright, J. Chem. Soc., 136 (1929)

C30H14O8

C30H18O4

CHCl 3

COOH COOH

O COOH

Acetone

O

Quin. 329

R. Kuhn and O. Albercht, Liebigs Ann. Chem., 464, 91 (1928)

© 2002 by CRC Press LLC

Quin. 330

K. Lauer, R. Oda and M. Miyawaki, J. Prakt. Chem., 148, 310 (1937)

NH2

COOH

C 3 H 7 NO 2

COOH

NH

MeOH

C 8 H 1 3 NO 3 MeOH

O

Quin. 331

Ph. D. Thesis of Gunther Burger,

Quin. 332

University of Karlsruhe, West Germany

(1979)

(1979) H

C 6 H 9 NO 3 O

N H

Quin. 333

Ph. D. Thesis of Gunther Burger,

University of Karlsruhe, West Germany

COOH

C 6 H 9 NO 3 H

CH 3 CN

EtOH, H 2 O

COOH

20:80 v/v% S. M. Miller, U. S. Patent 4,161,600

Quin. 334

J. M. Walbrick, J. W. Wilson, Jr., and W. M. Jones, J. Am. Chem. Soc., 90, 2895

(1979)

(1968)

C 1 0 H 1 1 NO 4 COOH

C 1 1 H 9 NO 2 COOH

MeOH

O 2N

Quin. 335

T. T. Chu and C. S. Marvel, J. Am.

Quin. 336

Chem. Soc., 55, 2841 (1933)

CN N N

NO2

NO2

Acetone COOH

C. G. Overberger and D. A. Labianca, J.

Quin. 338

Org. Chem., 35, 1762 (1970)

C15H22O2 MeOH

C13H8N2O6 EtOH, H 2 O

CN Quin. 337

E. W. Yankee and D. J. Cram, J. Am. Chem. Soc., 92, 6329 (1970)

C12H16N4O4 COOH COOH

MeOH

CN

H

75:25 v/v%

R. Adams and J. B. Hale, J. Am. Chem. Soc., 61, 2825 (1939)

tBuOOC

tBuOOC

HN

COOCH2Ph

COOH

C 2 2 H 3 1 NO 8 EtOAc

COOH

Quin. 339

K. Yamashita, E. Nagano and T. Oritani, Agric.Biol. Chem., 44, 1441 (1980)

Quin. 340

W. Marki, M. Opplinger, P. Thanei and R. Schwyzer, Helv. Chim. Acta, 60, 798 (1977)

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HN

tBuOOC

COOCH2Ph

COOH

tBuOOC

C 2 2 H 3 1 NO 8

CH3COOC O COOH

EtOAc

MeOH H

N. T. Boggs, 3rd., B. Godlsmith, R. W.

Quin. 341

C15H14O6

Quin. 342

O

W. Tochtermann, T. Panitzsch, M. Petroll,

Gawley, K. A. Koehler and R. G. Hiskey,

T. Habeck, A. Schengler, C. Wolff, E.M.

J. Org. Chem., 44, 2262 (1979)

Peters, K. Peters and H. G. von Schnering, Eur. J. Org. Chem, 2651 (1998)

O

HO

C 3 4 H 2 3 Br 2 O 6 P

P

C 2 0 H 1 3 BO 2 O

EtOAc

O O

THF BH

O

Br Br O O CH2Ph PhCH2

E. Martinborough, T. M. Denti, P. P.

Quin. 343

Quin. 344

Z. Shan, G. Wang, B. Duan and D. Zhao, Tetrahedron Asymmetry, 7, 2847 (1996)

Castro, T. B. Wyman, C. B. Knobler and F. Diederich, Helv. Chim. Acta, 78, 1037 (1995) OCH3

OH NH

C10H12O3 COOH

EtOAc

benzoyl

C 1 7 H 1 7 NO 3 EtOAc, EtOH

COOH

90:10 v/v% Quin. 345

S. Mutti, C. Daubié, F. Decalogne, R.

Quin. 346

A. Olma, Polish J. Chem., 70, 1442 (1996)

Fourier, O. Montuori, P. Rossi, Synth. Comm., 26, 2349(1996) O O P P OH OH OH F

C 7 H 9 FO 3 P 2

C20H16O4

MeOH, Acetone

CH3Cl, MeOH HOOC

Quin. 347

R. Bau, P. -T. T. Pham, G. D. Duncan and C. E. McKenna, J. Med. Chem., 38, 1575 (1995)

© 2002 by CRC Press LLC

Quin. 348

COOH

M. Yamaguchi, H. Okubo and M. Hirama, Chem. Comm., 1771, (1996)

COOH

HO

CCl3

C 1 6 H 1 0 BrO 4

O

C 1 0 H 7 Cl 5 O 2

OAc

EtOH

Et2O

Cl

Br

Cl

Ciba Geigy AG, 91-310511/42, C91-

Quin. 349

Quin. 350

134482, CIBA 27.03.90

R. Wang, Z. li, X. Sun, Y. Chen, Lanzhou Daxue Xubeao, Ziran Kexueban, 27 , 132 (1999)

COOH

COOH

C6H8O4

C22H16O4

H2O, EtOH

CHCl 3 , MeOH

90:10 v/v%

HOOC

J.-J. Brunet, A. Herbowski and D.

Quin. 351

Quin. 352

Neibecker, Synth. Comm., 26, 483 (1996)

COOH

M. Yamaguchi, H. Okubo, M. Hirama, Chem. Comm., 1771 (1996)

Morphine COOH

Br

OH

C3H6O3

COOH

H2O

K. Freudenberg, Chem. Berl., 47, 2027

Morph. 1

OH

C 3 H 5 BrO 3

Morph. 2

H2O

K. Freudenberg and L. Markert, Chem. Ber., 60, 2447 (1927);

(1914)

J.C. Irvine, J. Chem. Soc., 89, 935 (1906); C.E. Wood, J.E. Such and F. Scarf, J. Chem. Soc., 600 (1923) Br

C 4 H 4 Br 2 O 4 COOH

HOOC

MeOH

H HOOC

O

COOH H

C4H4O5 MeOH, Acetone

Br

10:90 v/v %

A. McKenzie, J. Chem. Soc., 101, 1196

Morph. 3

Morph. 4

(1912) OH HOOC

(1925) COOH

C 4 H 5 ClO 5 COOH

R. Kuhn, F. Ebel, Chem. Ber., 58, 919

OH

EtOH

OH

Morph. 5

R. Kuhn and R. Zell, Chem. Ber., 59, 2514 (1926)

© 2002 by CRC Press LLC

Morph. 6

C4H8O3 H2O

P. A. Levene and H. L. Haller, J. Biol. Chem., 74, 343 (1927)

COOH NH2

H2O

E. Fischer and A. Mouneyrat, Chem. Ber.,

Morph. 7

COOH

C 4 H 9 NO 2

EtOH

S

G. Cleason and H-G. Jonsson, Arkiv Kemi,

Morph. 8

42, 2383 (1909) OAc

28, 167 (1967)

C6H10O4 COOH

H2O

K. Serck-Hanssen, Arkiv Kemi, 19, 83

Morph. 9

C 6 H 1 1 NO 3 S N

O

Morph. 10

M. Matell, Acta Chem. Scand., 14, 677

Cl

C 8 H 6 Cl 2 O 3

Morph. 12

Soc., 107, 1685 (1915)

MeOH

A. McKenzie and G.W. Clough, J. Chem. Soc., 93, 811 (1908) COOH

C8H14O3

COOH

C 8 H 7 ClO 2 COOH

MeOH

A. McKenzie and N. Walker, J. Chem.

OH

EtOAc, MeOH

(1960)

COOH

Morph. 11

COOH

S

(1961) Br

C5H8O2S

Se Se

H2 O

C 8 H 1 4 O 4 Se 2 H2 O

COOH

C. E. Wood and M. A. Comley, J. Chem.

Morph. 13

Morph. 14

Soc., 125, 2630 (1924)

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 2. Opt.Res. Inf. Center, NY 1981

COOH

O

C 9 H 7 Cl 3 O 3

Cl

H 2 O, EtOH

COOH

Cl

C 9 H 9 ClO 2 MeOH

80:20 v/v% Cl

Cl

Ph. D. Thesis of Magnus Matell, Uppsala,

Morph. 15

Morph. 16

Soc., 127, 82 (1925)

Sweden (1953) OH COOH

C9H10O3 H2O

© 2002 by CRC Press LLC

A. McKenzie and R. C. Strathern, J. Chem.

C9H10O3 COOH

HO

A. McKenzie and H. B. P. Humphries, J.

Morph. 17

M. Bougault, Ann. Chim., 25, 483 (1902)

Morph. 18

Chem. Soc., 97, 121 (1910) OH

C9H10O3 COOH

H2 O J. Owen and J. L. Simonsen, J. Chem.

Morph. 20

Soc., 1016 (1910)

COOH

C9H14O4

H2 O

A. McKenzie and G. W. Clough, J. Chem.

Morph. 19

HOOC HOOC

Soc., 1223 (1933) OH

C 1 0 H 1 1 NO 4

C10H12O3 COOH

H2O

H2 O

NO2 E. Fourneau and G. Sandulesco, Bull.

Morph. 21

J. A. Reid and E. E. Turner, J. Chem. Soc.,

Morph. 22

Soc. Chim. Fr., 41, 450 (1927) OH COOH

3694 (1950)

C10H12O4

COOH

H2O

C11H10O2S EtOH, H 2 O

S

80:20 v/v% E. W. Christie, A. McKenzie and A.

Morph. 23

Morph. 24

J. Sjöberg, Arkiv Kemi, 12, 565 (1958)

Ritchie, J. Chem. Soc., 153 (1935) OH

C11H14O3 COOH

Cl

COOH

O

EtOH

C 1 3 H 1 1 ClO 2 EtOH, H 2 O 30:70 v/v%

Morph. 25

M. Matell, Arkiv Kemi, 1, 455 (1949)

Morph. 26

M. Matell and S. Larsson, Arkiv Kemi, 5, 379 (1953)

HOOC HOOC

C 1 4 H 9 NO 6

HOOC

COOH

EtOH

C15H12O4 EtOH

NO2 Morph. 27

P. Berntsson and R. E. Carter, Acta Chem. Scand., 22, 2141 (1968)

© 2002 by CRC Press LLC

Morph. 28

D. Aziz and J. G. Breckenridge, Can. J. Res., 28B, 26 (1950)

O COOH

C 1 6 H 1 1 NO 4

C16H14O4

COOHCOOH

EtOH

N

EtOH

O

A. McKenzie and N. Walker, J. Chem.

Morph. 29

F. Bell, J. Chem. Soc., 835 (1934)

Morph. 30

Soc., 646 (1928) Ph

C17H10N2O6 EtOH HOOC

NO2

HOOC O

F. Bell and G. A. Dinsmore, J. Chem.

NH

R. Kuhn and F. Zumstein, Chem. Ber., 58,

Morph. 32

Soc., 3691 (1950) HOOC

H2O

Ph

NO2

Morph. 31

C18H16N2O6 O COOH

HN

COOH

1429 (1925) Br

C18H16O4 Acetone

HOOC

C 2 0 H 1 9 BrO 6

O

abs. EtOH, EtOAc 50:50 v/v% CH2COOH

O

L. V. Dvorken, R. B. Smyth and K.

Morph. 33

Morph. 34

Mislow, J. Am. Chem. Soc., 80, 486

D. W. Hill and R. Adams, J. Am. Chem. Soc., 53, 3453 (1931)

(1958)

C20H20O2 C(CH3)2

HOOC

C 2 2 H 1 7 NO 4

MeOH, H 2 O

N H

77:23 v/v%

R. Stoermer and H. Starck, Chem. Ber.,

Morph. 36

70, 479 (1937)

COOH

EtOH

C28H22O4 HOOC

COOH

HOOC

© 2002 by CRC Press LLC

A. McKenzie and N. Walker, J. Chem. Soc., 646 (1928)

C 2 4 H 1 2 Br 2 O 4 Br Br

O

HOOC

Ph

Morph. 35

EtOH

O

EtOH

Morph. 37

M. Crawford, R. A. M. MacKinnon and V.R. Supanekar, J. Chem. Soc., 2807 (1959)

© 2002 by CRC Press LLC

Morph. 38

F. Bell and D. H. Waring, J. Chem. Soc., 2689 (1949)

RESOLUTION OF BASES N-(1-naphtoyl)-(S)-tert-leucine C 6 H 1 5 NO i-PrOH

OH NH2

K. Drauz, W. Jahn, M. Schwarm, J. Chem.

1Nphtle. 1

Eur., 9, 838 (1995)

1-pyrrolidone carboxylic acid NH2

C7H17N Acetone

R. J. Dearborn and J. A. Stekol, U. S. Patent,

1Pyca. 1

2528267 (1950)

(-)-(2,3,4-trichlorophenyl)ethanesulfonic acid C 4 H 9 NO 2 S

SH COOH

H2N

T. Iwasaki, K. Kondo, T. Nakatani, R.

CIPES. 1

Yoshioka, U.S. Patent 5495012 (1996)

5,5-dimethyl-2-hydroxy-4-(dichlorophenyl)-1,3,2-dioxaphosphorinane-2-oxide NH2

C 1 5 H 1 7 NO MeOH

O

W. ten Hoeve, H. Wynberg, J. Org. Chem.,

24ClPho. 1

50, 4508 (1985)

(+)-2',4'-dichlorotartranilic acid H3CO

C 2 0 H 2 4 ClNO 2 S NCH3

H3CO

EtOAc

S

Cl

Dicltar. 1

T. A. Montzka, U. S. Patent, 3, 452, 086 (1969)

© 2002 by CRC Press LLC

2-(4-hydroxyphenoxy)propionic acid C10H11N2O4

NH2 OH

N

EtOH

O N

O Nissan Chem. Ind. KK., 91-023783/04, C91-

24hpa. 1

010168, NISC 17.07.89

4-(2-chlorophenyl)-5,5-dimethyl-2-hydroxy1,3,2-dioxaphposphorinane-2-oxide C 1 2 H 1 8 NO EtOH, H2O

HN

O

70:30 v/v% 2ClPho. 1

NH2

W. ten Hoeve, H. Wynberg, J. Org.

COOH

2ClPho. 2

W. ten Hoeve, H. Wynberg, J. Org. Chem., 50, 4508 (1985)

C 9 H 1 1 NO 2

COOH

S

EtOH, H2O

NH2

NH2

30:70 v/v% 2ClPho. 3

EtOH, H2O 50:50 v/v%

HO

Chem., 50, 4508 (1985)

COOH

C 8 H 9 NO 3

W. ten Hoeve, H. Wynberg, J. Org.

C 5 H 1 1 NO 2 S EtOH, H2O 66:34 v/v%

2ClPho. 4

Chem., 50, 4508 (1985)

W. ten Hoeve, H. Wynberg, J. Org. Chem., 50, 4508 (1985)

5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-1,3,2-dioxaphosphorinane-2-oxide NH2

C 1 5 H 1 7 NO EtOH, H2O

O

83:17 v/v% 2MePho. 1

NH2

W. ten Hoeve, H. Wynberg, J. Org.

COOH

2MePho. 2

W. ten Hoeve, H. Wynberg, J. Org. Chem., 50, 4508 (1985)

N-(2-naphtoyl)-(S)-tert-leucine C 6 H 1 5 NO OH

iPrOH

NH2

2Nphtle. 1

K. Drauz, W. Jahn, M. Schwarm, J. Chem. Eur., 9, 838 (1995)

© 2002 by CRC Press LLC

EtOH, H2O 55:45 v/v%

HO

Chem., 50, 4508 (1985)

C 8 H 9 NO 3

2'-nitrotartranilic acid C 1 4 H 2 1 NO 3

O O

NH N

EtOH, H 2 O 95:5 v/v%

N

C15H20N2O EtOH, H 2 O 90:10 v/v%

HO

OH 2Nitrt. 1

T. A. Montzka, T. L. Pindell and J. D.

T. Kametani, K. Kigasawa, M. Hiiragi, N.

2Nitrt. 2

Matiskella, J. Org. Chem., 33, 3993

Wagatsuma, O. Kusama and T. Uryu,

(1968);

Chem. Pharm. Bull., 24, 2563 (1976) C 1 5 H 2 1 NO 4

O O

C24H32N2

EtOH, H 2 O

NH

EtOH, H 2 O

N

95:5 v/v%

95:5 v/v% N

COOEt

2Nitrt. 3

T. Montzka, T. L. Pindell and J. D.

2Nitrt. 4

K. Natsuka, H. Nakamura, H. Uno and S. Umemoto, J. Med. Chem., 18, 1240 (1975)

Matiskella, J. Org. Chem., 33, 3993 (1968)

NH2

C 1 2 H 1 9 NO 2 EtOH, H 2 O

H3CO

EtOH, H 2 O

NH2

95:5 v/v%

OCH3 2Nitrt. 5

95:5 v/v%

OCH3

S. B. Martin, P. S. Callery, J. S. Zweig, A.

2Nitrt. 6

R. T. Standridge, H. G. Howell, J. A.

O'Brien, R. Rapoport and N. Castagnoli,

Gylys, R. A. Partyka and A. T. Shulgin,

Jr., J. Med. Chem., 17, 877 (1974)

J. Med. Chem., 19, 1400 (1976)

NH2

C13H23N EtOH, H 2 O 50:50 v/v%

2Nitrt. 7

C 1 3 H 2 1 NO 2

OCH3

O. Cěrvinka, A. Fábriová and J. Hajiček, Collect . Czech. Chem. Comm., 39, 1582 (1974)

© 2002 by CRC Press LLC

N-(3-carboxy-propionil-)-α α-phenylethylamine NH2

C8H11N Methylethylketone

E. Felder, D. Pitré, and S. Boveri, Helv.

3cpr. 1

Chim. Acta, 52, 329 (1969)

3-endo-benzamido-5-norbornene-2-endo-carboxylic acid C 1 0 H 1 5 NO

OH

EtOH, Et2O HN

12:88 v/v%

K. Saigo, Y. Okuda, S. Wakabayashi,

3enorb. 1

Chemistry Lett., 875 (1981)

3'-nitrotartranilic acid Ph

C 1 4 H 2 1 NO

OH

MeOH, H 2 O N

17:83 v/v% D. Fries and P. S. Portogese, J. Med. Chem.,

3Nitrt. 1

17, 990 (1974)

(+)-(1S)-2-Oxo-bornansulphonic acid C 2 4 H 2 8 FN 3 O 2 S O N

Acetone

O N

F S

Borns. 1

W. Aschwanden, E. Kyburz and P. Schönholzer, Helv. Chim. Acta, 59, 1245 (1976)

© 2002 by CRC Press LLC

d-4:6:4':6'-Tetranitrodiphenic acid C 2 3 H 3 0 ClN 3 O EtOH

N

HN H3CO N

Cl B. R. Brown and D. L. Hammick, J. Chem. Soc., 99 (1948)

Tnidp. 1

4-Chloro-tartranilic acid C 5 H 1 1 NO

OH

OH

C 5 H 1 1 NO

EtOH, H 2 O

N H

G. Lambrecht, Eur. J. Med. Chem. Chim. Ther., 11, 461 (1976)

4clta. 1

N H

90:10 v/v%

H. Sievertson, R. Dahlbom, R. Sandberg and B. Akerman, J. Med. Chem., 15, 1085 (1972)

4clta. 2

C 6 H 1 3 NO

OH

OH

EtOH,

EtOH, H 2 O

N

Methylethylketone

N

G. Lambrecht, Eur. J. Med. Chem., Chim. 4clta. 4 Ther., 11, 461 (1976)

4clta. 3

C 9 H 1 9 NO

95:5 v/v%

H. Sievertsson, R. Dahlbom. R. Sandberg and B. Ackerman, J. Med. Chem., 15, 1085 (1972)

C 7 H 1 3 NO

OH

EtOH

N 4clta. 5

G. Lambrecht, Arc. Pharm. (Weinheim, Ger.), 309, 235 (1976)

5,5-dimethyl -2-hydroxy-4-phenyl-1,3,2-dioxaphosphorinane-2-oxide Cl

C 1 4 H 1 4 Cl 2 N 2 EtOH, H2O

H2N

96:4 v/v% NH2

Cl

4PhPho. 1

© 2002 by CRC Press LLC

W. ten Hoeve, H. Wynberg, J. Org. Chem., 50, 4508 (1985)

R-(+)-6,6'-dinitrobiphenyl-2,2'-dicarboxylic acid C7H15N Et 2 O, EtOH

N H

R. K. Hill, T. H. Chan and J. A. Joule,

Dn6dp. 1

C 8 H 1 5 NO

Chim. Pays-Bas, 84, 385 (1965)

C 8 H 1 5 NO MeOH

O

H. C. Beyerman and L. Maat, Recl. Trav.

Dn6dp. 2

Tetrahedron, 21, 147 (1965)

N H

MeOH

N H

C 8 H 1 7 NO

HO H N

MeOH

O Dn6dp. 3

F. Galinovsky, G. Bianchetti and O. Vogl,

F. Galinovsky and H. Mulley, Monatsh.

Dn6dp. 4

Monatsh. Chem., 84, 1221 (1953)

Chem., 79, 426 (1948); L. Marion and W. F. Cockburn, J. Am. Chem. Soc., 71, 3402 (1949)

OH H N

Dn6dp. 5

C 8 H 1 7 NO

C 8 H 1 7 NO

HO

abs. EtOH

MeOH

N H H. C. Beyerman, L. Maat, J. P. Visser, J.

W. Gruber and K. Schlögl, Monatsh. Chem.

Dn6dp. 6

80, 499 (1949)

C. Craig, R. P. K. Chan and S. K. Roy, Recl. Trav. Cim. Pays-Bas, 88, 1012 (1969) C9H12N2

HN

C9H17N

H

MeOH

N H

N

Dn6dp. 7

E. Späth and F. Kesztler, Chem. Ber., 69,

MeOH, EtOAc 50:50 v/v%

H

E. Leete and R. A. Carver, J. Org. Chem.,

Dn6dp. 8

40, 2151 (1975)

2725 (1936) C10H12N2 MeOH N H

C10H20N2

H N H H

N H

EtOH, H 2 O 80:20 v/v%

N

Dn6dp. 9

E. Späth and F. Kesztler, Chem. Ber., 70, 704 (1937)

Dn6dp. 10

A. Garcia-Alvarez and Ribas-Marqués, An. R. Soc. Esp. Fis. Quim., Ser. B, 61, 573 (1965)

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C10H20N2

HH N H

N H Dn6dp. 11

C12H21N H

EtOH, H 2 O 96:4 v/v%

A. Garcia-Alvarez and Ribas-Marqués,

Acetone

N F. Bohlman and C. Arndt, Chem. Ber., 91,

Dn6dp. 12

An. R. Soc. Esp. Fis. Quim., Ser. B, 61,

2167 (1958)

573 (1965)

H N

OH

C 1 3 H 1 9 NO

C 2 6 H 2 9 NO 3

H3CO

MeOH

NH

Acetone, EtOH 50:50 v/v%

PhCH2O H3CO

Dn6dp. 13

C. Schöpf, W. Bundschuh, G. Dummer,

H. C. Beyerman, E. Buurman, L. Maat and

Dn6dp. 14

T. Kaufmann and R. Kress, Justus Liebigs

C. Olieman, Recl. Trav. Chim. Pays-Bas,

Ann. Chem., 628, 101 (1959)

95, 184 (1976)

9,7-di-d-bromocamphorsulphonate I

C 1 4 H 1 4 IN

H2N

EtOH

97Brsu. 1

A. Angeletti, Gazz. Chim. Ital., 63, 145 (1933)

Acetildibromo-L-tyrosine NH2

C8H11N

NH2

H2O

AcBr2t. 1

C9H13N H2O

H. D. DeWitt and A. W. Ingersoll, J. Am.

H. D. DeWitt and A. W. Ingersoll, J. Am.

AcBr2t. 2

Chem. Soc., 73, 5782 (1951)

Chem. Soc., 73, 5782 (1951)

N-Acetylleucine C 6 H 9 NS

C6H13N

MeOH

S

NH2

© 2002 by CRC Press LLC

N H

Acleu. 3

H. E. Smith, E. P. Burrows, M. J. Marks,

Acleu. 4

H. Eguster, Helv. Chim. Acta, 61, 921

Chem. Soc., 99, 707 (1977)

(1978)

C8H11N

NH2

H N

H2O

Acleu. 5

P. C. Wälchli, G. Mukherjee-Müller and C.

R. D. Linch and F-M. Chen, J. Am.

H. D. DeWitt and A. W. Ingersoll, J. Am.

Acleu. 6

Chem. Soc., 73, 5782 (1951)

C 8 H 1 7 NO

OH

Benzene

H. C. Beyerman, J. Eenshuistra, W. Eveleens and A. Zweistra, Recl. Trav. Cim. Pays-Bas, 78, 43 (1959)

C9H11N

C9H11N

H2O

H2O

NH2 Acleu. 7

NH2

V. Ghislandi and D. Vercesi, Boll. Chim.

Acleu. 8

Farm., 115, 489 (1976)

H. E. Smith and T. C. Willis, Tetrahedron, 26, 107, (1970)

C 9 H 1 2 ClN

C 9 H 1 2 ClN

Cl

H2O

Acleu. 9

NH2

Cl

NH2

H. E. Smith, E. P. Burrows and F-M.

Acleu. 10

Chen, J. Org. Chem., 40, 1562 (1975)

H2O

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

C 9 H 1 2 ClNO

OH NH2

NH2

H2O

C9H13N H2O

Cl

Acleu. 11

H. E. Smith, E. P. Burrows, J. D. Miano,

Acleu. 12

C. D. Mount, E. Sanders-Bush and F.

Ph.D. Thesis of D. F. Zinkel, Univetsity of Wisconsin (1961)

Sulser, J. Med. Chem., 17, 416 (1974) NH2

C9H13N

NH2

H2O

Acleu. 13

Ph.D. Thesis of D. F. Zinkel, Univetsity of Wisconsin (1961)

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C9H13N H2O

Acleu. 14

H. D. DeWitt and A. W. Ingersoll, J. Am. Chem. Soc., 73, 5782 (1951)

C10H15N

NH2

C10H19N H

MeOH

H2O

NH2 Acleu. 15

Y. Yamamoto, H. Shimoda, J. Oda and Y.

Acleu. 16

Inouye, Bull. Chem. Soc. Japan, 49, 3247

A. W. Ingersoll and H. D. DeWitt, J. Am. Chem. Soc., 73, 3360 (1951)

(1976) C11H17N

NH2

C13H19N

NH2

H2O

Acleu. 17

Ph.D. Thesis of M. E. Warren, Jr.,

MeOH

Acleu. 18

Sci., 26, 474, (1971)

Vanderbilt University, Tennessee (1963) C 1 8 H 2 1 NO 2 NH

V. Ghislandi and D. Vercesi, Farmaco, Ed.

C 1 9 H 2 1 NO 4

O NH

O

MeOH, Et2O

H3CO

50:50 v/v%

H3CO

H3CO OCH3

Acleu. 19

S. Teitel and J. P. O'Brien, Heterocycles,

Acleu. 20

2, 625 (1974)

J-I. Kunitomo, E. Yuge, Y. Nagai and K. Fujitani, Chem. Pharm. Bull., 16, 364 (1968)

C 2 0 H 2 2 D 3 NO 4

H3CO H3CO

D

NH D D

MeOH

H3CO

T. Kametani and M. Ihara, J. Chem. Soc.,

50:50 v/v%

Acleu. 22

H. Corrodi and E. Hardegger, Helv. Chim. Acta, 39, 889 (1956)

C, 1308 (1968) C 2 0 H 2 5 NO 4

H3CO H3CO H3CO

MeOH, Et2O

NH

H3CO H3CO H3CO

OCH3

Acleu. 21

C 2 0 H 2 5 NO 4

H3CO

NH

H3CO

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MeOH, Et 2 O

C21H26N2O3

N H H

abs. MeOH, Et 2 O

N H

H H3COOC OH

14:86 v/v%

A. R. Battersby, R. Binks, R. J. Francis,

Acleu. 23

Acleu. 24

L. Tőke, K. Honty and C. Szántay, Chem. Ber., 102, 3248 (1969)

D. J. McCaldin and H. Ramuz, J. Chem. Soc., 3600 (1964); E. BrochmannHanssen, C-H. Chen, C. R. Chen, H-C. Chiang, A. Y. Leung and K. McMurtrey, J. Chem. Soc., C, 1531 (1975) H3CO H3CO

H3CO

C29H40N2O4 N

MeOH, Et 2 O

H H

5:95 v/v%

H

H NH

H3CO

Acleu. 25

A. Brossi, M. Baumann and O. Schnider, Helv. Chim. Acta, 42, 1515 (1959); D. E. Clark, R. F. K. Meredith, A. C. Ritchie and T. Walker, J. Chem. Soc., 2490 (1962)

N-acetylserine C 6 H 1 4 ClNO NH2

EtOH, H 2 O 95:5 v/v%

Acser. 1

J. M. Gillingham, U. S. Patent, 3, 028, 430 (1962)

N-acetyl-L-tyrosine H N

C 1 2 H 1 7 NO MeOH, Et 2 O 30:70 v/v%

Atyr. 1

© 2002 by CRC Press LLC

R. Sarges, J. Org. Chem., 40, 1216 (1975)

D-alanine anilide C5H8O3

O Alaanil. 1

COOH

n-BuOH

S. Nakai, H. sato, T. Fujino, Jpn. Kokai Tokkyo Koho JP 08 59, 517 (1996)

5α α-andostran-17-one C8H9F3N2

CF3

EtOH, AcOH

NHNH2

Andos. 1

W. E. Pereira, Jr., M. Solomon and B. Halpern, Aust. J. Chem., 24, 1103 (1971)

D-arabonic acid C 1 0 H 1 5 NO

OH

MeOH HN Arab. 1

M. Tsuruga, S. Murakami, K. Kondo, S. Akabane, K. Washikita and T. Koshino, U. S. Patent, 3, 478, 101 (1969)

Aspartic acid NH2

C15H17N MeOH

Aspar. 1

Y. Suzuki, French Patent, 2, 044, 789 (1971)

Bile Acids NH2

C8H11N THF

Bilea. 1

K. Sada, T. Maeda, M. Miyata, Chem. Lett., 837, (1996)

© 2002 by CRC Press LLC

(-)-1,1'-binaphthalene-2,2'-dyl hydrogen phosphate N

C17H18N2

N

C 1 3 H 1 7 NO

OCH3

EtOH

MeOH, CH 2 Cl 2

N H

90:10 v/v%

O

BdyP. 1

S. H. Wilen, J. Z. Qi, P. G. Williard, J.

BdyP. 2

Org. Chem., 56, 485-487, (1991)

C. Comoy, C. Marot, T. Podona, M.-L. Baudin, L. Morin-Allory, G. Guillaumet, B. Pfeiffer, D.-H. Caignard, P. Renard, M.-C. Rettori, G. Adam, B. Guardiola-Lemaître, J. Med. Chem., 39, 4285-4298, (1996)

Binaphthyl-phosphoric acid C 6 H 1 4 ClNO

OH

C 1 8 H 2 1 NO 2 NH

IPrOH

HN

MeOH

H3CO H3CO

BinP. 1

R. Viterbo and J. Jacques, German Offen.

BinP. 2

2, 212, 660 (1972)

S. Teitel and J. P. O'Brien, Heterocycles, 2, 625 (1974)

C19H35N

C 1 0 H 1 5 NO

OH

MeOH, Acetone

N H

BinP. 3

Acetone

HN

10:90 v/v%

R. Viterbo and J. Jacques, British Patent,

BinP. 4

1, 360, 946 (1974)

360, 946 (1974) C 1 3 H 1 9 NO

O

R. Viterbo and J. Jacques, British Patent, 1,

C14H22N2O2

H N

1.) Acetone

Acetone N

BinP. 5

R. Viterbo and J. Jacques, British Patent, 1, 360, 946 (1974)

© 2002 by CRC Press LLC

O

BinP. 6

O

NH

2.) MeOH, Acetone

R. Viterbo and J. Jacques, British Patent, 1, 360, 946 (1974)

C15H24N2O3

H N

C 1 8 H 2 1 NO

Acetone O

O

MeOH

H N

NH

OH

OH

R. Viterbo and J. Jacques, British Patent,

BinP. 7

BinP. 8

1, 360, 946 (1974)

R. Viterbo and J. Jacques, British Patent, 1, 360, 946 (1974)

C 1 9 H 2 7 NO

C 1 4 H 2 1 NO

Acetone

N

HO

MeOH, CH 2 Cl 2

N

HO R. Viterbo and J. Jacques, British Patent,

BinP. 9

BinP. 10

W. Arnold, J. J. Daly, R. Imhof, E. Kyburz, Tetrahedron Lett., 24, 4, 343-346, (1983)

1, 360, 946 (1974)

3-Bromocamphor-10-sulphonic acid C 8 H 1 5 NO 2 N

C 2 3 H 3 0 ClN 3 O

N

Ethylene glycol

H2O

HO H HO

H

Cl

monoethyl ether, Acetone

HN

2:98 v/v% N H3CO

A. Stoll, A. Lindermann and E. Jucker, Helv. Chim. Acta, 36, 1506 (1953)

Br310su. 1

Br310su. 2

C 2 3 H 3 0 ClN 3 O 3

HO

OH

N

OCH3

F. A. Bacher, R. P. Buhs, J. C. Hetrick, W. Reiss and N. R. Trenner, J. Am. Chem. Soc., 69, 1534 (1947) O

EtOH, H 2 O

C 2 6 H 2 0 BO 2 EtOH

B

97:3 v/v%

HN

O N

Cl

Br310su. 3

G. J. Heeres, H. Wynberg, A. J. Nienhaus and G. J. P. A. Anders, Bioorg Chem., 4, 106 (1975)

© 2002 by CRC Press LLC

Br310su. 4

D. J. Owen, D. VanDerveer, G. B. Schuster, J. Am. Chem. Soc., 120, 1705 (1998)

d-3-Bromocamphor-8-sulphonic acid C4H7N H2O

NH2

A. Marszak-Fleury, Ann. Chim. (Paris),

Br38su. 1

M. G. Ettlinger, J. Am. Chem. Soc., 72,

Br38su. 2

4792 (1950) C4H11N

NH2

W.J. Pope and C. S. Gibson, J. Chem.

EtOH, Benzene NH2

50:50 v/v%

A. V. Robertson and B. Witkop, J. Am.

Br38su. 4

Soc., 101, 1072 (1912) OH

C5H8N2O

O N H

N

MeOH

OH

13, 656 (1958)

Br38su. 3

C 4 H 9 NO

NH2

Chem. Soc., 84, 1696 (1962)

C 5 H 1 3 NO

C6H14N2

H N

H2O

Acetone N H

Ph.D. Thesis of J. Clitherow, University

Br38su. 5

M. Matsumura, M. Awamura, T. Ishiguro,

Br38su. 6

E. Kitamura, Yakugaku Zasshi, 78, 338

of London (1961)

(1958) OH

N

C 6 H 1 5 NO EtOAc

K. B. Schowen, E. E. Smissman and W.

Br38su. 7

C 6 H 1 5 NO

OH

N

EtOAc

K. B. Schowen, E. E. Smissman and W. F.

Br38su. 8

F. Stephen, Jr., J. Med. Chem., 18, 292

Stephen, Jr., J. Med. Chem., 18, 292 (1975)

(1975)

O

N

C 8 H 1 3 NO

OH

H

H2O

OH

N

W. A. M. Davies, A. R. Pinder and I. G.

Br38su. 9

Br38su. 10

Morris, Tetrahedron, 18, 405 (1962)

O

C 8 H 1 3 NO

EtOH

A. J. Aasen, and C. C. J. Culvenor, J. Org. Chem., 34, 4143 (1969) C 8 H 1 3 NO

O

Acetone

Acetone

N Br38su. 11

C 8 H 1 5 NO 2

N T. Kunieda, K. Koga and S. Yamada, Chem. Pharm. Bull., 15, 337 (1967)

© 2002 by CRC Press LLC

Br38su. 12

T. Kunieda, K. Koga and S. Yamada, Chem. Pharm. Bull., 15, 337 (1967)

C9H11N

NH2

C 9 H 1 1 NS

EtOAc

H2O

N H

S

W. J. Pope and G. Clarke, J. Chem. Soc.,

Br38su. 13

Br38su. 14

85, 1330 (1904)

G. M. Bennett and W. B. Waddington, J. Chem. Soc., 1692 (1931)

C 9 H 1 3 NO

HN

OH

H2O

HO

H2O

HN

HO J. McL. Macdonald and E. Stedman, J.

Br38su. 15

Br38su. 16

Chem. Soc., 2513 (1932)

H. Legerlotz, German Patent, 543, 529 (1932)

C 9 H 1 5 NO

O

C 9 H 1 5 NO

O

butan-2-one

Acetone

N

N S. F. Mason, K. Schofield and R. J. Wells,

Br38su. 17

Br38su. 18

C9H17N

H

S. Yamada and T. Kunieda, Chem. Pharm. Bull., 15, 499 (1967)

J. Chem. Soc., C, 626 (1967)

C10H14N2

H N

H2O

N H H Br38su. 19

C 9 H 1 3 NO 2

H 2 O, EtOH

N H

L. Mascarelli and F. Nigrisoli, Gazz.

Br38su. 20

C. S. Gibson, J. Chem. Soc., 342 (1927)

Chim. Ital., 45, 106 (1915) C 1 1 H 1 4 ClNO

OH Cl

C11H15N

H2O

Br38su. 21

Y. H. Wu, R. F. Feldkamp and W. A.

Br38su. 22

W. J. Pope and E. M. Rich, J. Chem. Soc., 75, 1093 (1898)

Gould, U. S. Patent, 3, 118, 906 (1964) C11H15N

HO

N H

H2O

N H

H2O

N H

N H

C 1 1 H 1 7 NO 3 MeOH

H3CO OCH3

Br38su. 23

W. J. Pope and T. C. Beck, J. Chem. Soc., 91, 458 (1907)

© 2002 by CRC Press LLC

Br38su. 24

S. D. Brown, J. E. Hodgkins and M. G. Reinecke, J. Org. Chem., 37, 773 (1972)

NH2

H3C

I

C11H21N EtOH

C12H10I2N NH2

H2N

EtOH

I

Br38su. 25

A. A. Plentl and M. T. Bogert, J. Org.

Br38su. 26

Chem., 6, 669 (1941)

W. Theilacker, P. Braune and G. G. Strobel, Chem. Ber., 97, 880 (1964)

C 1 3 H 1 5 NO

O

C 1 3 H 1 7 NO

N

Acetone

H2O

N

HO Br38su. 27

S. Yamada and T. Kunieda, Chem.

Br38su. 28

Pharm. Bull., 15, 499 (1967)

H

C 1 2 H 2 3 NO

OH H

E. L. May and M. Takeda, J. Med. Chem., 13, 805 (1970) C14H14N4

H2N

MeOH

H2O

N N

N H

H2N Br38su. 29

J. S. Roberts and C. Thomson, J. Chem.

Br38su. 30

H N

C14H15N

C 1 4 H 2 1 ClN 2

EtOH, H 2 O

H2O

96:4 v/v%

Cl

Br38su. 31

C. S. Gibson and L. J. Simonsen, J.

Br38su. 32

Chem. Soc., 107, 1148 (1915)

O2 N

N H

NH

NH

H. C. Richards, R. F. Chambers, German Offen., 2, 221, 669 (1972) C14H21N3O2

1.) H 2 O

H2O

2.) Acetone

C. A. R. Baxter and H. C. Richards, J. Med. Chem., 14, 1033 (1971)

© 2002 by CRC Press LLC

N H

C14H21N3O2

3.) EtOAc

Br38su. 33

W. Theilacker and F. Baxmann, Justus Liebigs Ann. Chem., 581, 117 (1953)

Soc., Perkin Trans. 2, 2129 (1972)

NO2

Br38su. 34

N H

NH

H. C. Richards and R. F. Chambers, German Offen., 2, 221, 669 (1972)

C 1 5 H 1 7 NO

NH2 OH

C 1 5 H 2 1 NO

N

H2O

MeOH, H 2 O 70:30 v/v%

W. Stulmer and H-H. Frey, Arc. Pharm.

Br38su. 35

HO E. L. May and N. B. Eddy, J. Org. Chem.,

Br38su. 36

(Weinheim, Ger.), 286, 22 (1953)

24, 1435 (1959); S. E. Fullerton, E. L. May and E. D. Becker, J. Org. Chem., 27, 2144 (1962)

C16H20N2

NH2

C16H17N

H2O

H2O

NH

H2N

H. H. Richmond, E. J. Underhill, A. G.

Br38su. 37

W. Leithe, Chem. Ber., 67, 1261 (1934)

Br38su. 38

Brook and G. F. Wright, J. Am. Chem. Soc., 69, 937 (1947) N

C 1 7 H 2 1 NO 4

H OH

O

EtOAc, abs. EtOH

O

Acetone, H 2 O 8:92 v/v%

H2N

O

Br38su. 39

C16H20N2

NH2

H. King, J. Chem. Soc., 115, 476 (1919)

W. Theilacker and R. Hopp, Chem. Ber.,

Br38su. 40

92, 2293 (1959) O

C 1 7 H 1 6 FNO 2

O

iPrOAc

N

CF3 F3C

C17H16F6N2O

N

MeOH, H 2 O 43:57 v/v%

F

OH NH

Br38su. 41

R. J. Alabaster, A. W. Gibson, S. A. Johnson, J. S. Edwards. I. F. Cottrell, Tetrahedron Asymmetry, 8, 3, 447-450, (1997)

© 2002 by CRC Press LLC

Br38su. 42

F. I. Caroll and J. T. Blackwell, J. Med. Chem., 17, 210 (1974)

C 1 8 H 2 6 ClN 3

C 1 8 H 1 9 NO 2

abs. EtOH

H2O

N

Cl

HO

N

N

NH OH

B. Riegel and L. T. Sherwood, Jr., J. Am.

Br38su. 43

Br38su. 44

Chem. Soc., 71, 1129 (1949)

O

O

W. J. Pope and J. Read, J. Chem. Soc., 99, 2071 (1911)

C 1 9 H 1 9 NO 4

O

O

1.) AcOH, H 2 O, EtOH

C 1 9 H 1 7 NO 4 AcOH, H 2 O

57:10:33 v/v%

N

2.) H 2 O

N

H3CO

OH

O

E. Späth and W. Leithe, Chem. Ber., 63,

Br38su. 45

O

Br38su. 46

3007 (1930)

OCH3

H3CO

E. Späth and P. L. Julian, Chem. Ber., 64, 1131 (1931)

C 2 0 H 2 3 NO 4

NH2

H2O

Acetone, H 2 O 10:90 v/v%

H N

H3CO Br38su. 47

C20H16N2

NH2

OCH3 W. J. Pope and C. S. Gibson, J. Chem. Soc., 97, 2207 (1910)

© 2002 by CRC Press LLC

Br38su. 48

W. Theilacker and R. Hopp, Chem. Ber., 92, 2293 (1959)

O O

NCH3

H O

C 2 2 H 2 3 NO 7

C 2 1 H 2 7 NO

H2O

EtOH, H 2 O

H

80:20 v/v%

O

O

N

OCH3 OCH3

W. H. Perkin, Jr. and R. Robinson, J.

Br38su. 49

Br38su. 50

Chem. Soc., 99, 775 (1911) C26H24N2 THF, Et 2 O H N

Chem. Soc., 71, 2935 (1949) H3CO

C 2 2 H 2 7 NO 4 H2O

H3CO

55:45 v/v%

N H

E. E. Howe and M. Schletzinger, J. Am.

H

N

OCH3 OCH3

W. Stuhmer and G. Messwarb, Arch.

Br38su. 51

Br38su. 52

Pharm. (Weinheim, Ger.), 286, 221

H. Legerlotz, Arch. Pharm. (Weinheim, Ger.),256, 123 (1918)

(1953) H3CO

C 2 9 H 3 1 NO 7 N

H3CO

EtOH, H 2 O 70:30 v/v%

H3CO O

C26H36N2 H2O N H

H N

O

OCH3 OCH3

Br38su. 53

S. M. Kupchan, A. J. Liepa, V. Kameswaran and K. Sempuku, J. Am. Chem. Soc., 95, 2995 (1973)

H N

O

C10H12N2O EtOH

N H Br38su. 55

F. Malik, M. Hasan, K. M. Khan, S. Perveen, G. Snatzke, H. Duddeck, W. Voelter, Liebigs. Ann., 1861 (1995)

© 2002 by CRC Press LLC

Br38su. 54.

W. Stuhmer and G. Messward, Arch. Pharm. (Weinheim, Ger.), 286, 221 (1953)

Brucine C 1 6 H 1 5 NO 3

O N

1.) Acetone 2.) EtOH

H3CO

O

A. Kasahara, Nippon Kagaku Zasshi, 79, 339

Bruc. 1

(1958)

(-)-cis-2-benzamidocyclohexanecarboxylic acid C 1 4 H 1 4 Cl 2 N 2 Cl

N

EtOH, H2O

H2N

96:4 v/v%

N S. Negi, N. Minami, M. Matsukura, K. Sato,

Bzacy. 1

Jpn. Kokai Tokkyo Koho JP 07, 258, 215 (1995)

2-benzylamino-1-phenylethanol C6H9O3

OH

H2O O

O

S. Takeda, M. Takeda, K. Suzuki, M. Yuya,

BzaEt. 1

Jpn. Kokai Tokkyo Koho JP 02, 240, 073 (1990)

(S)-camphorsulphonic acid (benzenesulfonyl)hydrazone C 2 7 H 2 1 N 2 OP

O

C 2 8 H 2 3 N 2 OP

O

EtOAc

EtOAc

N

N N CSZ. 1

PPh2 X. Dai, A. Wong and S. C. Virgil, J. Org. Chem., 63, 2597 (1998)

© 2002 by CRC Press LLC

N CSZ. 2

PPh2 X. Dai, A. Wong and S. C. Virgil, J. Org. Chem., 63, 2597 (1998)

C 2 8 H 2 3 N 2 OP

O

EtOAc

N PPh2

N

X. Dai, A. Wong and S. C. Virgil, J. Org.

CSZ. 3

Chem., 63, 2597 (1998)

Benzylpenicillinic acid C 1 5 H 1 7 NO

OH

C 1 5 H 1 7 NO

OH

Et 2 O

H2O

HN Bzpen. 1

HN

W. B. Wheatley, W. E. Fitzgibbon and L.

V. V. Young, J. Am. Pharm. Assoc., 40,

Bzpen. 2

C. Cheney, J. Org. Chem., 18, 1564

261 (1951)

(1953)

Ca-lactate ester C 1 5 H 1 9 NO 4 EtOH, H2O

EtOOC

96:4 v/v%

COOH N H

P. Laurent, Eur. Pat. Appl. EP 680, 952

Calact. 1

(1995)

Camphoric acid C 7 H 1 7 NO

OH

HO

H

OH

Acetone

N

C 8 H 1 3 NO 2 EtOH

N Camp. 1

M. S. Raasch and W. R Brode, J. Am.

Camp. 2

Chem. Soc., 64, 1112 (1942)

Org. Chem., 27, 139 (1962)

C8H17N NH2

T. A. Geismann and A. C. Waiss, Jr., J.

NH2

MeOH

C9H13N EtOH, H 2 O 33:67 v/v%

Camp. 3

Ph.D. Thesis of K. F. Hoback, University of West Virginia (1955)

© 2002 by CRC Press LLC

Camp. 4

A. W. Ingersoll and F. B. Burns, J. Am. Chem. Soc., 54, 4712 (1932)

C 1 0 H 1 3 NO

O

abs. EtOH HN H. Takamtsu, Yakugaku Zasshi, 76, 1219

Camp. 5

C10H19N EtOH, H 2 O

N H

33:67 v/v% Ph.D. Thesis of H. J. Bulbrook, Iowa State

Camp. 6

(1956)

College (1935) C 1 1 H 1 5 NO

O

C14H15N

NH2

H2O

MeOH

N

P. Newman, Optical Resolution

Camp. 7

Ph.D. Thesis of K. F. Hoback, West

Camp. 8

Procedures for Chemical Compounds,

Wirginia University (1955)

Volume 1. Opt.Res. Inf. Center, NY 1979

N H

C15H18N2

H N

C 1 6 H 1 9 NO

OH NH2

EtOAc, dioxane 50:50 v/v%

K. R. Kopecky and T. Gillan, Can. J.

Camp. 9

50:50 v/v%

Camp. 10

Chem., 47, 2371 (1969)

Chem. Soc., 83, 3662 (1961) C 1 7 H 2 1 NO

Dioxane

OH

Camp. 11

B. M. Benjamin and C. J. Collins, J. Am.

C16H20N2O2

NH2 OH

MeOH, H 2 O

OH N

NH2

A. D. Thomsen and H. Lund, Acta Chem.

Camp. 12

Scand., 23, 3582 (1969)

and J. Jacques, Tetrahedron, 29, 4183

(+)-chlocyphos C 1 4 H 2 1 NO

OCH3

EtOH, H2O NH

75:25 v/v%

C. Sonesson, T. Barf, J. Nilsson, D. Dijkstra, A. Carlsson, K. Svensson, M. W. Smith, I. J. Martin, J. N. Duncan, L. J. King, H. Wikström, J. Med. Chem., 38, 1319 (1995)

© 2002 by CRC Press LLC

67:33 v/v%

M. Tramontini, L. Angiolini, C. Fouquey

(1973)

ChloP. 1

EtOH, H 2 O

Cinchonine C 1 5 H 1 3 NO 2

O

EtOH O NH2

Cincho. 1

A. Kasahara, Nippon Kagaku Zasshi, 79, 335 (1958)

2-(4-chloro-phenyl)carbamoyloxy-propionic acid C8H11N

NH2

HO H

E.Brown and M. Moudachirou,

Clplac. 1

Clplac. 2

Tetrahedron, 50, 10309 (1994)

H

Clplac. 3

E.Brown and M. Moudachirou,

NHAc

C 1 0 H 1 3 NO

NHCH3

E.Brown and M. Moudachirou,

Clplac. 4

Tetrahedron, 50, 10309 (1994)

E.Brown and M. Moudachirou, Tetrahedron, 50, 10309 (1994))

C10H15N

HN

Clplac. 5

NH2

Tetrahedron, 50, 10309 (1994)

C 1 0 H 1 5 NO

H

HO

C 9 H 1 3 NO

H

E.Brown and M. Moudachirou, Tetrahedron, 50, 10309 (1994)

(S,S)-2,3-dibenzoyloxysuccinic acid OH

O O 2N

DBzsuc. 1

C13H20N2O2 Acetone, H 2 O

NH

W. Fiedler, R. Eckardt, G. Faust, D. Lehmann, W. Pöpel, D. Lohmann, H.-J. Heidrich, H.-J. Jänsch, German Patent, DD 301 838 A7

© 2002 by CRC Press LLC

(+)-deoxycholic acid C 1 9 H 2 5 NO 2

O

C 1 8 H 2 3 NO 2

NH2

1.) EtOH, H 2 O

EtOH, H 2 O

46:54 v/v%

45:55 v/v% H3CO

NH2

OCH3

2.) MeOH, H 2 O 50:50 v/v%

O D. J. Collins and J. J. Hobbs, Aust. J.

Docha. 1

D. J. Collins and J. J. Hobbs, Aust. J.

Docha. 2

Chem., 23, 119 (1970)

Chem., 23, 119 (1970)

2,2'-Dihydroxy-1,1'-dinaphtyl-3,3'-dicarboxylic acid C14H21N EtOH

N

Dndc. 1

H. Gerlach and E. Huber, Helv. Chim. Acta, 51, 2027 (1968)

Diacetyl-d-tartaric acid C 1 1 H 1 5 NO 3

C 1 1 H 1 5 NO

O N

O

EtOAc

N

H 2 O, MeOH

HO OH H. Takamatsuo, Yakugaku Zasshi, 76,

Dactr. 1

Dactr. 1

H. Takamatsuo and Y. Minaki, Yakugaku Zasshi, 76, 1230 (1956)

1219 (1956) C 1 1 H 1 7 NO 3

HO

N

EtOH

C 1 3 H 1 9 NO 3 O

Acetone, H 2 O

OCH3

HO

OCH3

OH Dactr. 3

N

S. Ose, H. Takamatsu and Y. Minaki, Japanese Patent, 4417 (1958)

© 2002 by CRC Press LLC

Dactr. 4

S. Ose, H. Takamatsu and Y. Minaki, Japanese Patent, 4417 (1958)

C 1 7 H 1 9 NO

O

Acetone, H 2 O N

97:3 v/v%

H. Takamatsu, Yakugaku Zasshi, 71,

Dactr. 5

1219 (1956)

1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) C 2 1 H 1 7 NO 8

O O

Diethylketone

COOtBu

O

O

O N

O

K. Murakami, M. Ohashi, A. Matsunaga, I.

DBU. 1

Yamamoto, H. Nohira, Chirality, 5, 41-48, (1993)

α-fenilethylamine-hidrogen-succinate C 4 H 1 1 NO

OH

H2O

NH2

FEAsu. 1

E. Felder, D. Pitré and S. Boveri, Helv. Chem. Acta, 52, 329 (1969)

Glutamic acid OH NH2

C16H14O3

C 9 H 1 3 NO 2

OH

EtOAc

OH NH2

Ph.D. Thesis of F. Radke, Iowa State

Gluac. 1

College (1952) OH

Gluac. 2

© 2002 by CRC Press LLC

95:5 v/v%

V. D'Amato and R. Pagani, British Patent, 738, 064 (1955)

C 1 4 H 1 5 NO

OH

EtOH, H 2 O NH2

EtOH, H 2 O

50:50 v/v%

C 1 4 H 1 5 NO H2O

NH2

J. Weijlard, K. Pfister, 3rd, E. F.

Gluac. 3

Y. Yamakawa, Yakugaku Zasshi, 80, 295

Gluac. 4

Swanezy, C. A. Robinson and M. Tishler,

(1960)

J. Am. Chem. Soc., 73, 1216 (1951) C 1 5 H 1 7 NO

OH

EtOH, H 2 O

H

OH OH

50:50 v/v%

NH2

C 1 8 H 3 7 NO 2

NH2

H

1.) EtOH, H 2 O 67:33 v/v% 2.) EtOH, H 2 O 90:10 v/v%

H. H. MacDonald and R. J. Crawford,

Gluac. 5

D. Shapiro, H. Seagal and H. M. Flowers, J.

Gluac. 6

Can. J. Chem., 50, 428 (1972) C 1 8 H 3 9 NO 2

OH

Gluac. 8

Chem. Soc., 75, 5131 (1953); OH

Z. Physiol. Chem., 354, 169 (1973) NH2

NH2

EtOH, H 2 O

EtOH, H 2 O

95:5 v/v%

95:5 v/v%

B. Majhofer-Oreščanin and M. Proštenik,

Gluac. 10

Croat. Chem. Acta, 34, 161 (1962) NH OH 2

Chem. Acta, 32, 197 (1960) NH OH 2

C 2 0 H 4 3 NO 2

NH

O OH

EtOH, H 2 O

67:33 v/v%

67:33 v/v% Gluac. 12

C 1 5 H 2 3 NO 3

P. Newman, Optical Resolution Gluac. 14 Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

© 2002 by CRC Press LLC

B. Majhofer-Oreščanin and M. Proštenik, Tetrahedron, 12, 56 (1961) OH

C 1 4 H 1 5 NO

EtOH, H 2 O 83:17 v/v%

Gluac. 13

C 2 0 H 4 3 NO 2 OH

EtOH, H 2 O

Tetrahedron, 12, 56 (1961)

O

M. Munk-Weinert and M. Proštenik, Croat.

OH

B. Majhofer-Oreščanin and M. Proštenik,

Gluac. 11

C 2 0 H 4 3 NO OH

H

Gluac. 9

67:33 v/v%

W. Stoffel and K. Bister, Hoppe-Seyller's

C 2 0 H 4 3 NO

H

EtOH, H 2 O

OH NH2

67:33 v/v%

H. E. Carter and D. Shapiro, J. Am.

HO

C 1 8 H 3 9 NO 2

OH

EtOH, H 2 O

OH NH2

Gluac. 7

Am. Chem. Soc., 80, 1194 (1958)

NH2 K. Saigo, I. Sugiura, I. Shida and K. Tachibana, Bull. Chem. Soc. Jpn., 59, 2915 (1986)

NH2

C16H18N2 EtOH

N

R. Kunstmann, H. Gerhards, H. Kruse, M.

Gluac. 15

Leven, E. F. Paulus, U. Schacht, K. Schmitt and P. U. Witte, J. Med. Chem., 30, 798 (1987)

D-glucose C 3 H 9 NS

SH NH2

Gluco. 1

MeOH

J. R. Piper and T. P. Johnston, J. Org. Chem. 29, 1657, (1964)

(-)-diacetone-2-keto-L-gulonic acid C 1 6 H 1 7 NO 4

HO NH

HO

iPrOH

H3CO

C 1 8 H 1 9 NO 4 NH

H3CO

EtOH

O

HO

O

OH

Gulo. 1

S. Teitel, J. O'Brien and A. Brossi, J.

Gulo. 2

Med. Chem., 15, 845 (1972) C 1 9 H 2 3 NO 4

H3CO H3CO

NH

A. Brossi and S. Teitel, Helv. Chim. Acta, 54, 1564 (1971) C 2 0 H 2 5 NO 4

H3CO

iPrOH

H3CO H3CO

NH

1.) iPrOH 2.) MeOH

OCH3 OCH3

Gulo. 3

A. Brossi and S. Teitel, Helv. Chim. Acta, 54, 1564 (1971)

© 2002 by CRC Press LLC

H3CO Gulo. 4

W. J. Pope and S. J. Peachey, J. Chem. Soc., 73, 893 (1898)

H3CO

C 2 0 H 2 5 NO 5

H3CO NH

H3CO

EtOH

C 2 3 H 2 5 NO 3 iPrOH

H3CO

NH2

H3CO

OCH3 OCH3

Gulo. 5

O

A. Brossi and S. Teitel, Helv. Chim. Acta,

Gulo. 6

54, 1564 (1971)

A. Brossi and S. Teitel, J. Org. Chem., 35, 3559 (1970)

C 2 0 H 2 7 NO 4

H3CO NH

H3CO

C16H20N2O MeOH

EtOH H N

HO

NH2

OCH3 O

Gulo. 7

J. F. Blount, V. Toome, S. Teitel and A.

Gulo. 8

Brossi, Tetrahedron, 29, 31 (1973)

Benzyl N

O

R. I. Fryer, A. Boris, J. V. Earley and E. Reeder, J. Med. Chem., 20, 1268 (1977)

C14H20N2O2

OCH3

Acetone

C16H18N2O iPrOH

N H N H Gulo. 9

R. Fitzi and D. Seebach, ETH,

Gulo. 10

N G. P. Roth, M. Emmanuel and L. Tong, Tetrahedron Asymmetry, 8, 185(1997)

C8H11N

NH2

NH2

MeOH

OH

O2N

Gulo. 11

C. W. Den Hollander, W. Leimgruber and

C9H12N2O4

OH

Gulo. 12

EtOH, H 2 O 95:5 v/v%

C. W. Den Hollander, W. Leimgruber and

E. Mohacsi, U. S. Patent, 3, 682, 925

E. Mohacsi, U. S. Patent, 3, 682, 925

(1972)

(1972) C 1 0 H 1 5 NO

NH OH

© 2002 by CRC Press LLC

EtOAc

C12H13N NH2

Acetone

Gulo. 13

C. W. Den Hollander, W. Leimgruber, E.

C. W. Den Hollander, W. Leimgruber and

Gulo. 14

Mohacsi, U. S. Patent, 3, 682, 925 (1972)

E. Mohacsi, U. S. Patent, 3, 682, 925 (1972)

H3CO

NH

OCH3

C 1 6 H 1 7 NO EtOH, H 2 O

C 1 7 H 2 3 NO CH 3 CN

95:5 v/v% N H

Gulo. 15

C. W. D. Hollander, W. Leimgruber and

C. W. D. Hollander, W. Leimgruber and E.

Gulo. 16

E. Mohacsi, U. S. Patent, 3, 682, 925

Mohacsi, U. S. Patent, 3, 682, 925 (1972)

(1972) C 1 7 H 2 3 NO

N

NH

EtOH

H

H

Benzene

H3CO

HO

Gulo. 17

C 1 7 H 2 3 NO

C. W. D. Hollander, W. Leimgruber and

C. W. D. Hollander, W. Leimgruber and E.

Gulo. 18

E. Mohacsi, U. S. Patent, 3, 682, 925

Mohacsi, U. S. Patent, 3, 682, 925 (1972)

(1972)

Helicin C 1 4 H 1 5 NO

OH

NH2 Heli. 1

E. Erlenmeyer and A. Arnold, Justus Liebigs Ann. Chem., 337, 307 (1904)

Hydroxymethylene-d-camphor C5H10N2

N N

NH2 NH2

AcOH, H 2 O

C5H14N2 MeOH, H 2 O

50:50 v/v% Hycam. 1

R.J. Crawford, A. Mishra and R.J. Dummel, J. Am. Chem. Soc., 88, 3959 (1966)

© 2002 by CRC Press LLC

Hycam. 2

C. J. Dippel, Rec. Trav. Chim. Pays-Bas., 50, 525 (1931)

C6H14N2

H N

NH2

EtOH

C8H11N MeOH

N H

F. B. Kipping and W. J. Pope, J. Chem.

Hycam. 3

Hycam. 4

Soc., 1076 (1926)

A. P. Terent'ev, G. V. Panova, G. N. Koval' and O. V. Toptyigna, Zh. Obshch. Khim., 40, 1409 (197)

C8H18N2

H N

EtOH N H

Hycam. 5

F. B. Kipping, J. Chem. Soc., 1160 (1931)

(α αS)-(-)-p-Hydroxynorephedrine C 9 H 1 3 NO 2

OH NH2

H2O

HO

Hynep. 1

H. E. Smith, E. P. Burrows, P. L. Mobley, S. E. Robinson and F. Sulser, J. Med. Chem., 20, 978 (1977)

Isopropylidene glycerol NH2

C8H11N

NH2

MeOH

C 8 H 1 0 BrN MeOH

Br Iprgol. 1

M. Pallavicini, E.Valoti, L. Villa and O.

Iprgol. 2

M. Pallavicini, E.Valoti, L. Villa and O.

Piccolo, Tetrahedron Asymmetry, 7, 1117

Piccolo, Tetrahedron Asymmetry, 7, 1117

(1996)

(1996)

NH2

C8H10N2O2

NH2

MeOH

C12H13N iPrOH

O2N Iprgol. 3

M. Pallavicini, E.Valoti, L. Villa and O.

Iprgol. 4

M. Pallavicini, E.Valoti, L. Villa and O.

Piccolo, Tetrahedron Asymmetry, 7, 1117

Piccolo, Tetrahedron Asymmetry, 7, 1117

(1996)

(1996)

© 2002 by CRC Press LLC

C12H13N NH2

iPrOH

M. Pallavicini, E.Valoti, L. Villa and O.

Iprgol. 5

Piccolo, Tetrahedron Asymmetry, 7, 1117 (1996)

Quinine O

O

C 1 6 H 1 5 NO 2 1.) Acetone

O

1.) Acetone O

2.) EtOH

2.) EtOH

NH2

NH2

Quin. 1

C 1 6 H 1 5 NO 3

H3CO

A. Kasahara, Nippon Kagaku Zasshi, 79,

Quin. 2

339 (1958)

A. Kasahara, Nippon Kagaku Zasshi, 79, 339 (1958)

Lasalocid NH2

C7H17N

NH2

CH 2 Cl 2

C 8 H 1 0 BrN CH 2 Cl 2

Br Lasal. 1

J. W. Westley, R. H. Evans, Jr. and J. F.

Lasal. 2

Blount, J. Am. Chem. Soc., 99, 6057

J. W. Westley, R. H. Evans, Jr. and J. F. Blount, J. Am. Chem. Soc., 99, 6057 (1977)

(1977) NH2

C8H11N

C10H15N

N

CH 2 Cl 2

CH 2 Cl 2 , Hexane 20:80 v/v%

Lasal. 3

J. W. Westley, R. H. Evans, Jr. and J. F.

Lasal. 4

Blount, J. Am. Chem. Soc., 99, 6057

J. W. Westley, R. H. Evans, Jr. and J. F. Blount, J. Am. Chem. Soc., 99, 6057 (1977)

(1977)

NH2

C 1 1 H 1 7 NO 2

NH2

EtOH

C11H13N EtOH

OCH3 OCH3 Lasal. 5

J. W. Westley, R. H. Evans, Jr. and J. F. Blount, J. Am. Chem. Soc., 99, 6057 (1977)

© 2002 by CRC Press LLC

Lasal. 6

J. W. Westley, R. H. Evans, Jr. and J. F. Blount, J. Am. Chem. Soc., 99, 6057 (1977)

Malic acid C9H13N

NH2

NH2

EtOH

A. J. Little, J. M'Lean and F. J. Wilson, J.

Malac. 1

C9H13N EtOH

Malac. 2

M. E. Warren and H. E. Smith, J. Am. Chem. Soc., 87, 1757 (1965)

Chem. Soc., 336 (1940) C9H13N

NH2

H2O

C9H13N H2O

NH2 Ph.D. Thesis of Shoh-Chung Chen,

Malac. 3

Malac. 4

Polytechnic Institute of Brooklyn, New

G. A. Stenberg, Z. Phys. Chem., 70, 534 (1910)

York (1971) N

C 9 H 1 6 N 2 SO 2

O S

OH

H N

C10H15N NH2

iPrOH

EtOH, H 2 O 95:5 v/v%

J. A. Edwards, B. Berkoz, G. S Lewis, O.

Malac. 5

Malac. 6

Halpern, J. H. Fried, A. M. Strosberg, L.

D. J. Cram and E. McCarty, J. Am. Chem. Soc., 76, 5740 (1954)

M. Miller, S. Urich, F. Liu and A. P. Roszkowski, J. Med. Chem., 17, 200 (1974) C10H15N

NH2

H2O

H N

OH

C10H20N2O2

NH

EtOH

HO

Ph.D. Thesis of D. J. Severn, State

Malac. 7

Malac. 8

L. Bernardi, M. Foglio and A. Temperilli, J. Med. Chem., 17, 555 (1974)

University of New York at Stoney Brook (1969) C 1 7 H 1 4 ClNO EtOH, H 2 O

HO

C 1 7 H 1 4 ClNO EtOH, H 2 O

HO

95:5 v/v%

95:5 v/v%

NH2

NH2 Cl Cl

© 2002 by CRC Press LLC

F. E. Ray and W. A. Moomaw, J. Am.

Malac. 9

Malac. 10

Chem. Soc., 55, 749 (1933)

F. E. Ray and W. A. Moomaw, J. Am. Chem. Soc., 55, 749 (1933)

C17H26N2O

O N

EtOH

C 1 8 H 1 7 NO

N

NH2

W. B. Wright, Jr., H. J. Brabander and R.

Malac. 11

EtOH

H3CO

Malac. 12

A. Hardy, Jr., J. Org. Chem., 26, 476

F. E. Ray and W. A. Moomaw, J. Am. Chem. Soc., 55, 3833 (1933)

(1961) C19H26N2O2

N HO H3CO

C19H26N2O2

N

EtOH, H 2 O

Et 2 O,. MeOH

95:5 v/v%

94:6 v/v%

N

H. S. Mosher, R. Forker, H. R. Williams

Malac. 13

Malac. 14

H. E. Zimmerman, K. G. Hancock and G.

and T. S. Oakwood, J. Am. Chem. Soc.,

C. Licke, J. Am. Chem. Soc., 90, 4892

74, 4627 (1952)

(1968) C20H25N

N

abs. Et 2 O, MeOH

C 2 0 H 2 5 NO 3

H3CO N

EtO

Acetone, MeOH 92:8 v/v%

96:4 v/v%

HO H. E. Zimmerman, K. G. Hancock and G.

Malac. 15

Malac. 16

C. Licke, J. Am. Chem. Soc., 90, 4892

J. A. D. Jeffreys, J. Chem. Soc., 4451 (1956)

(1968) C 2 1 H 2 0 ClN

C11H17N NH2

MeOH

H2O

Cl

N

Malac. 17

A. Ebnöther, E. Jucker and A. Stoll, Helv. Chim. Acta, 48, 1237 (1965)

© 2002 by CRC Press LLC

Malac. 18

K. Saigo, M. Kai, N. Yonezawa, M. Hasegawa, Synthesis, 214 (1984)

C 1 1 H 1 6 BrN H2O

NH2 Br Malac. 19

K. Schwarzkopf, J. O. Metzger, W. Saak, S. Pohl, Chem. Ber./Recueil, 130, 1539 (1997)

Methyl hydrogen dibenzoyl-D-tartrate C10H21N Dimethylformamide

NH

V. V. Young, U. S. Patent, 3, 085, 110 (1963)

MeHDT. 1

L-menthyl-hydrogen phtalate C12H13N NH2

Benzene

R. R. Bottoms, U. S. Patent, 3, 000, 947

MeHph. 1

(1961)

l-menthoxy-acetic acid C 8 H 1 7 NO 2

OH

Acetone

OH

N

M. S. Raasch and W. R. Brode, J. Am. Chem.

Menta. 1

Soc., 64, 1112 (1942)

(-)-menthyl-N-aminocarbamate O

C 9 H 1 5 NO H2O

N MeaNc. 1

S. F. Mason, K. Schofield and R. J. Wells, J. Chem. Soc., C, 626 (1967)

© 2002 by CRC Press LLC

Menthylsulfuric acid C10H15N NH2

Mesu. 1

C10H15N

H2O

NH2

A. P. Terentyev and V. M. Potapov, Zh.

A. P. Terentyev and V. M. Potapov, Zh.

Mesu. 2

Obshch. Khim., 27, 1092 (1957)

Obshch. Khim., 27, 1092 (1957)

Menthol succinic ester C 1 0 H 1 5 NO

OH

n-butyl acetate HN D. L. Tabern, U. S. Patent, 2, 240, 318 (1941)

Mesuc. 1

N-acetyl-D-glutamic acid C 5 H 1 3 NO

OH N

iPrOH

T. Dhoi, T. Yu and F. Inoue, Japanese Patent

Acglu. 1

74-19252

N-acetylmethionine C 8 H 1 0 BrN

NH2

H2O

Toray Ind. Inc., 91-040116/06, C91-017253,

Nacmet. 1

TORA 22.05.89

N-acteyl-phenylalanine Br

Cl

C 1 9 H 1 7 Br 2 ClN 2 Acetone

N Br N H

Nacph. 1

F. G. Njoroge, A. G. Traveras, J. Kelly, S. Remiszewski, A. K. Mallams, R. Wolin, A. Afonso, A. B. Cooper, D. F. Rane, Y.-T. Liu,

© 2002 by CRC Press LLC

H2O

J. Wong, B. Vibulbhan, P. Pinto, J. Deskus, C. S. Alvarez, J. del Rosario, M. Connoly, J. Wang, J. Desai, R. R. Rossman, W. R. Bishop, R. Patton, L. Wang, P. Kirschmeier, M. S. Bryant, A. A. Nomeir, C.-C. Lin, M. Liu, A. T. McPhail, R. J. Doll and A. K. Ganguly, J. Med. Chem., 41, 4890 (1998)

N-acetyl-2-(p-methylphenyl)alanine NH2

C 8 H 1 0 BrN H2O

Br Toray Ind Inc., 91-040117/06, C91-017254,

NAcpma. 1

TORA 22.05.89

N-acetyl-(S)-tert-leucine C 6 H 1 5 NO iPrOH

OH NH2

K. Drauz, W. Jahn, M. Schwarm, J. Chem.

Nactle. 1

Eur., 9, 838 (1995)

N-Acetyl-L-tryptophan NH2

C8H11N EtOH, H 2 O 93:7 v/v%

L. R. Overby, J. Org. Chem., 23, 1393 (1958)

Nactry. 1

β-Naphtoxymethyl-acetic acid C 7 H 1 7 NO N OH

Napac. 1

E. Fourneau and I. Ribas, Bull. Sci. Pharmacol., 35, 273 (1928)

© 2002 by CRC Press LLC

Et 2 O

N-benzoyl-alanine C18H39N

NH2

Acetone

M. Munk-Weinert and M. Proštenik, Arhiv.

NBzal. 1

Kem. (Yugoslavia), 26, 89 (1954)

N-benzoyl-trans-2-amino-cyclohexane-carboxylic acid C 4 H 1 1 NO

OH

abs. n-Butanol

NH2

P. Newman, Optical Resolution Procedures

Nbzcy. 1

for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

N-benzyloxycarbonyl-phenylalanine-p-nitrophenyl ester C 1 1 H 1 7 NO 2

NH2

NH2

EtOAc

C 1 1 H 1 7 NO 2 EtOAc

OCH3 H3CO

OCH3 OCH3

NBzph. 1

F. A. B. Aldous, B. C. Barrass, K.

NBzph. 2

F. A. B. Aldous, B. C. Barrass, K.

Brewster, D. A. Buxton, D. M. Green, R.

Brewster, D. A. Buxton, D. M. Green, R.

M. Pinder, P. Rich, M. Skeels and K. J.

M. Pinder, P. Rich, M. Skeels and K. J.

Tutt, J. Med. Chem., 17, 1100 (1974)

Tutt, J. Med. Chem., 17, 1100 (1974)

N-benzyl-phenyl-glycine NH HN Nbpgly. 1

C5H12N2 H2O S. Nakai, H. Sato, (Toray Industries Inc.), Jpn. Kokai Tokkyo Koho JP 04 18, 084

© 2002 by CRC Press LLC

N-benzoyl-threonine C10H15N

C 1 8 H 2 9 NOS S

H2O HN

British Patent, 814, 339 (1959)

Nbzt. 1

OH

N

EtOH, H 2 O 95:5 v/v%

J. P. Long, F. P. Luduena, B. F. Tullar and

Nbzt. 2

A. M. Lands, J. Pharmacol. Exp. Ther., 117, 29 (1956) C 2 0 H 3 1 NO EtOH, H 2 O N

Nbzt. 3

95:5 v/v%

OH

J. P. long, F. P. Ludunea, B. F. Tullar and A. M. Lands, J. Pharmacol. Exp. Ther., 117, 29 (1956)

N-benzoyl-(S)-tert-leucine C 6 H 1 5 NO iPrOH

OH

NH2

K. Drauz, W. Jahn, M. Schwarm, J. Chem.

Nbztle. 1

Eur., 9, 838 (1995)

N-carbamoyl-valine H N

Ncval. 1

C6H12N2O

O NH2

French Patent 1, 559, 885 (1969), Chem. Ab. 72, 55890g (1970)

© 2002 by CRC Press LLC

N-Carbobenzoxy-L-alanine C 1 0 H 1 5 NO

OH

EtOAc HN Cbza. 1

L. R. Overby and A. W. Ingersoll, J. Am. Chem. Soc., 82, 2067 (1960)

N-formyl-(S)-tert-leucine C 6 H 1 5 NO iPrOH

OH NH2

Nftle. 1

K. Drauz, W.Jahn, M.Schwarm, J. Chem. Eur., 9, 838 (1995)

2-(4-nitro-phenyl)carbamoyloxy-propionic acid NH2

C8H11N

HO H

E. Brown and M. Moudachirou,

No2lac. 1

No2lac. 2

Tetrahedron, 50, 10309 (1994)

H

No2lac. 3

E. Brown and M. Moudachirou,

NHAc

C 1 0 H 1 3 NO

NHCH3

E. Brown and M. Moudachirou, Tetrahedron, 50, 10309 (1994) HN

No2lac. 5

NH2

Tetrahedron, 50, 10309 (1994)

C 1 0 H 1 5 NO

H

HO

C 9 H 1 3 NO

H

C10H15N

E. Brown and M. Moudachirou, Tetrahedron, 50, 10309 (1994)

© 2002 by CRC Press LLC

No2lac. 4

E. Brown and M. Moudachirou, Tetrahedron, 50, 10309 (1994)

N-p-nitrobenzoyl-L-glutamic acid H N

C16H12N2O

O

C 2 1 H 2 7 NO

NH2

BuOH

N

O

Npglu. 1

I. Tanaka, Y. Ohno, T. Okada and T.

Npglu. 2

Hino, German Offen. 1, 961, 180 (1970)

E. E. Howe and M. Tischler, U. S. Patent, 2, 644, 010 (1953)

C 2 1 H 2 7 NO IPrOH

N O

Npglu. 3

M. Schletzinger and M. Tischler, U. S. Patent, 2, 625, 564 (1953)

N-p-toluenesulfonylaspartic acid NH2

C3H10N2 H2O

NH2

S. Nakai, H. Sato, Jpn. Kokai Tokkyo Koho

Ptlas. 1

JP 04 18, 057(1992)

N-(p-toluol-sulphonyl)-phenyl-glycine NH

C5H12N2 H2O

HN

S. Nakai, H. Sato, (Toray Industries Inc.),

Nptspgly. 1

Jpn. Kokai Tokkyo Koho JP 04 18, 084

N-tosyl-L-phenylalanine C9H19N3O

HN NH N H

© 2002 by CRC Press LLC

O

MeOH

H. Murakami, S. Satoh, T. Tobiyama, K.

NtPhal. 1

Sakai and H. Nohira, Eur. Pat. Appl. EP 710, 652(1996)

d-oxymethylenecamphor C11H16N2

H N

AcOH, H 2 O, EtOH

N H Oxmc. 1

25:25:50 v/v%

C. S Gibson, J. H. nutland and J. L.

C11H17N Ligroin H2N

Oxmc. 2

J. W. E. Glattfield and C. N. Cameron, J. Am. Chem. Soc., 49, 1043 (1927)

Simonsen, J. Chem. Soc., 108 (1928) C11H17N

OH

AcOH, H 2 O, MeOH

Oxmc. 3

AcOH, MeOH

8:18:74 v/v%

H2N

J. W. E. Glattfield and C. H. Milligan, J. Am. Chem. Soc., 43, 2322 (1920)

NH2 Oxmc. 4

(1927)

C 1 8 H 3 9 NO 2 OH

EtOH, H 2 O

W. Stoffel and K. Bister, Hoppe-Seyller's Z.

PESAM. 1

Physiol. Chem., 354, 169 (1973)

(R,R)-2,3-di-(phenylaminocarbonyl)tartaric acid OCH3 OCH3

NH2 PhaTA. 1

C14H16N2O2

NH2 M. Cereghetti, R. Schmid, P. Schönholzer and A. Rageot, Tetrahedron Lett., 37, 5343 (1996)

© 2002 by CRC Press LLC

50:50 v/v%

J. Read and C. S. Steele, J. Chem. Soc., 910

(-)-PESAM ((-)-N-(1-phenylethyl)succinamic acid) NH OH 2

C 1 4 H 1 5 NO

(-)-1-phenylethanesulphonic acid C 8 H 9 2 NO 3

COOH

H2N

OH R. Yoshioka, O. Ohtsuki, T. Da-Te, K.

Phetsu. 1

Okamura and M. Senuma, Bull. Chem. Soc. Jpn., 67, 3012, (1994)

phenylethylsuccinic acid HO

NH2 OH

Phesuc. 1

C 1 5 H 1 7 NO 2 n-BuOH

M. C. Rebstock, C. D. Stratton and L. L. Bambas, J. Am. Chem. Soc., 77, 24 (1955)

(R)-phenylglycinamide C10H16O2 COOH

MeOH, H2O 67:33 v/v%

Phglya. 1

F. Faigl, E. Fogassy, L. Nagy, L. Csiz, I. Czudor and K. E. Kovacsne, PCT Int. Appl. WO 90 08, 126 (1990)

(R)-phenylglycine nitrile C10H16O2 COOH

MeOH, H2O 67:33 v/v%

Phglyn. 1

F. Faigl, E. Fogassy, L. Nagy, L. Csiz, I. Czudor and K. E. Kovacsne, PCT Int. Appl. WO 90 08, 126, (1990)

© 2002 by CRC Press LLC

d-phenylsuccinic acid C 1 6 H 1 9 BrN 2 N

C 1 6 H 1 9 ClN 2 N

abs. EtOH

abs. EtOH

N

N

Br

Cl

British Patent, 834, 984 (1960)

Phsuc. 1

Phsuc. 2

British Patent, 834, 984 (1960)

C16H20N2 abs. IPrOH

N N

British Patent, 834, 984 (1960)

Phsuc. 3

(-)-HO-p-C6H4OCHMeCO2H, 2-(4-hydroxyphenoxy)propionic acid C 9 H 1 1 NO

NH2 OH

Acetone

C11H13N3O3

NH2 OH

N

Acetone

O N

H. Matsumoto, Y. Obara, Jpn. Kokai

PhyPa. 1

PhyPa. 2

Tokkyo Koho JP 07, 215, 922, 922]

Nissan Chem. Ind KK. 91-023783, C91010168, NISC 17.07.89

(1995)

(+)-p-toluenesulfonylglutamic acid O

O S

O

O

C 1 9 H 2 3 NO 4 S

S

C11H12N2S

N

H2O

N

MeOH N

R. Howe, T. Leigh, B. S. Rao and A. H.

Tosug. 1

Tosug. 2

British Patent, 1, 169, 310 (1969)

Todd, J. Med. Chem., 19, 1074 (1976)

L-Pyrrolidoncarboxylic acid H N

C6H12N2O

O NH2

EtOH, H 2 O 95:5 v/v%

© 2002 by CRC Press LLC

NH2

C8H11N BuOH

M. Brenner and H. R. Rickenbacher,

Pyca. 1

R. J. Dearborn and J. A. Stekol, U. S.

Pyca. 2

Helv. Chim. Acta., 41, 181 (1958)

Patent, 2, 528, 267 (1950); A. Ault, "Organic Syntheses", Collect. Vol. V, Wiley, New York, N. Y. (1973), p. 932

NH2

C8H19N

C9H11N

BuOH

EtOH, MeOH 95:5 v/v% NH2

R. J. Dearborn and J. A. Stekol. U. S.

Pyca. 3

Pyca. 4

Patent, 2, 528, 267 (1950) CF3

F3C

J. H. Biel, Addn. 87, 352 to French Patent 1, 445, 453 (1966)

C 2 2 H 1 9 F 6 NO MeOH, Et 2 O 1:99 v/v%

HO

H N

F. I. Caroll and J. T. Blackwell, J. Med.

Pyca. 5

Chem., 17, 210 (1974)

Quinic acid NH

C 1 4 H 1 9 NO

NH

EtOH, H 2 O HO

96:4 v/v% B. F. Tullar, L. S. Harris, R. L. Perry, A.

Quiac. 1

C 1 5 H 2 1 NO EtOH, H 2 O

HO

Quiac. 2

K. Pierson, A. E. Soria, W. F. Wetterau

95:5 v/v% B. F. Tullar, L. S. Harris, R. L. Perry, A. K. Pierson, A. E. Soria, W. F. Wetterau and N.

and N. F. Albertson, J. Med. Chem., 10,

F. Albertson, J. Med. Chem., 10, 383

383 (1967)

(1967) C15H22N2O

H N

N

C 1 6 H 1 7 NO 2

HO

EtOH

NH

HO

MeOH

O

Quiac. 3

B. F. Tullar, J. Med. Chem., 14, 891 (1971)

Quiac. 4

E. Yamato, M. Hirakura and S. Sugasawa, Tetrahedron, Supplement 8, Part I, 129 (1966)

© 2002 by CRC Press LLC

H3CO

O

C 1 8 H 2 1 NO 2 NH

H3CO

MeOH

C 2 0 H 2 5 NO 3 N

H3CO

Acetone, MeOH 90:10 v/v%

HO

E. Yamato, M. Hirakura and S. Sugasawa,

Quiac. 5

J. A. D. Jeffreys, J. Chem. Soc., 4451

Quiac. 6

Tetrahedron, Suppl. 8, Part I, 129 (1966)

(1956)

(R,R)-tartaric acid monoanilide OH

C 1 4 H 1 6 FNO

N

EtOH, H2O

H

F

TAmani. 7

96:4 v/v%

S. Sólyom, G. Ábrahám, M. Szőllősy, I. Pallagi, E. Csuzdi, I. Ling, B. Vitális, K. Horváth, E. J. Horváth, L. G. Hársing Jr. and J. Kajtár, Heterocycles, 41, 6, (1995)

5-(+)-TAPA ((+)-α α-(2,4,5,7-tetranitro-9-fluor-enylideneaminooxy)propionic acid) CH3O

C15H21N3O THF, H 2 O

N HN

THF N

NH2

96:4 v/v%

F. I. Carroll, B. Berrang and C. P. Linn, J.

TAPA. 1

C16H23N3O

H3CO

HN

TAPA. 2

Med. Chem., 21, 326 (1978)

THF

Cl

F. I. Caroll, B. Berrang and C. P. Linn, J. Med. Chem., 21, 326 (1978)

C 2 5 H 2 8 Cl 4 N 2 O

Cl

NH2

N(n-C7H12)2 HO

C 3 0 H 4 2 BrNO Acetone

OH N Bu2N Cl

TAPA. 3

Br

Cl

F. I. Caroll, B. Berrang and C. P. Linn, J. Med. Chem., 21, 326 (1978)

© 2002 by CRC Press LLC

TAPA. 4

F. I. Caroll, B. Berrang and C. P. Linn, J. Med. Chem., 21, 326 (1978)

H2N

N

C18H18N4O2S

NH2

1.) AcOH

N O O S

2.) Dioxane

F. I. Carroll, B. Berrang and C. P. Linn, J.

TAPA. 5

Med. Chem., 21, 326 (1978)

(S)-2-(2,3,4-trichlorophenyl)ethanesulfonic acid N

N O N OH S

C13H15F2N4O2S CHCl 3

NH

F

F

TCPES. 1

H. Kawanishi, H. Morimoto, T. Nakano, T.Watanabe, K. Oda and K. Tsujihara, Heterocycles, 49, 181 (1998)

2-(3,4,5-trimethoxy-phenyl)carbamoyloxy-propionic acid NH2

C8H11N

HO H

E. Brown and M. Moudachirou,

Tmolac. 1

Tmolac. 2

Tetrahedron, 50 , 10309 (1994)

H

Tmolac. 3

NH2

E. Brown and M. Moudachirou, Tetrahedron, 50 , 10309 (1994)

C 1 0 H 1 5 NO

H

HO

C 9 H 1 3 NO

H

NHAc

C 1 0 H 1 3 NO

NHCH3

E. Brown and M. Moudachirou, Tetrahedron, 50 , 10309 (1994) HN

© 2002 by CRC Press LLC

C10H15N

Tmolac. 4

E. Brown and M. Moudachirou, Tetrahedron, 50 , 10309 (1994)

E. Brown and M. Moudachirou,

Tmolac. 5

Tetrahedron, 50 , 10309 (1994)

(+)-α α-methoxy-α α-trifluoromethylphenylacetic acid C 1 7 H 2 5 NO

N

Acetone HO

K. C. Rice and A. E. Jacobson, J. Med.

CF3Pha. 1

Chem., 19, 430 (1976)

10-Champhorsulphonic acid Cl

H2N

C 3 H 8 ClNO EtOH

OH

C4H8N2S HN

abs. EtOH

S

NH

R. Paul, R. P. Williams and E. Cohen, J.

Camps. 1

A. J. Little, J. M'Lean and F. J. Wilson, J.

Camps. 2

Org. Chem., 40, 1653 (1975) C 4 H 9 NO

NH2

C5H10N2

MeOH

OH

A. T. Bottini and V. Dev, J. Org. Chem.,

Camps. 3

Chem. Soc., 336 (1940)

Et 2 O

N N

A. Mishra and R. J. Crawford, Cam. J.

Camps. 4

27, 968 (1962); A. Kjaer, B. W.

Chem., 47, 1515 (1969)

Christensen and S. E. Ha, Acta Chem. Scand., 13, 145 (1959) C6H13N Benzene

C 6 H 1 4 ClN Cl

N

N H

H. Matsushita, Y. Tsujino, M. Noguchi,

Camps. 5

M. A. Davis, and S. O. Winthrop, German

Camps. 6

M. Saburi and S. Yoshikawa, Bull. Chem.

Patent 1, 290, 541 (1969)

Soc. Japan, 51, 201 (1978) C6H14N2

H N

Acetone

NH2 O

C 6 H 1 5 NO EtOAc

N H

Camps. 7

M. Matsumura, M. Awamura, T. Ishiguro, Camps. 8 E. Kitamura, Yakugaku Zasshi, 78, 338 (1958)

© 2002 by CRC Press LLC

W. R. Brode and I. J. Wernert, J. Am. Chem. Soc., 55, 1685 (1933)

C 7 H 1 1 NO

NH2

Ph.D. Thesis of G. R. Carlson, Michigan

Camps. 9

iPrOH, Acetone

H2O

O

N

Camps. 10

C 7 H 1 4 Cl 2 N 2 O MeOH, Acetone

O

N

H2N

Camps. 11

Cl

L. H. Sternbach an S. Kaiser, J. Am. Chem.

H

H H2N

NH2

C7H14N2 EtOH

20:80 v/v%

I. Aiko and T. Gono, Chem. Pharm. Bull.,

Camps. 12

5, 487 (1957)

S. E. Janson and Sir W. J. Pope, Proc. Roy. Soc. (London), A154, 53 (1936)

C7H15N N H

20:80 v/v%

Soc., 74, 2215 (1952)

State University (1971) Cl

C 7 H 1 3 NO

OH

N

abs. EtOH

OH

C7H16N2O

HO

Et 2 O, MeOH

N Camps. 13

M. S. Toy and C. C. Price, J. Am. Chem.

Camps. 14

Soc., 82, 2613 (1960) NH2

H. Singh and B. Razdan, Tetrahedron Lett., 3243 (1966)

C8H10N2O2

NH2

Et 2 O, H 2 O

C8H10N2O2 H2O

O2N

NO2 Camps. 15

F. Nerdel and H. Liebig, Chem. Ber., 87,

Camps. 16

221 (1954) NH2

Ph.D. Thesis of R. D. Bach, Massachussets Institute of Technology (1967)

C 8 H 1 1 NO

NH2

H2O HO

C. W. Moore, J. Chem. Soc., 99, 416

abs. EtOH, EtOAc 50:50 v/v%

HO

Camps. 17

C 8 H 1 1 NO 2

OH

Camps. 18

(1911)

T. Kappe and M. D. Armstrong, J. Med. Chem., 7, 569 (1964); J. van Dijk, V. G. Keizer, J. F. Peelen and H. D. Moed, Recl Trav. Chim. Pays-Bas, 84, 521 (1965)

OH HO

NH2

OH

© 2002 by CRC Press LLC

C 8 H 1 1 NO 3 H 2 O, MeOH

O

N

C 8 H 1 3 NO EtOH

K. Wismayr, R. Kilches, O. Schmid and

Camps. 19

Camps. 20

G. Zolls, German Patent 1, 247, 331

C. B. Page and A. R. Pinder, J. Chem. Soc., 4811 (1964)

(1967) C8H15N

H

C 9 H 1 1 NO

NH2 O

Acetone

H2O

N H H W. F. M. Van Bever, A. G. Knaeps, J. J.

Camps. 21

Camps. 22

M. Willems, B. K. F. Hermans and P. A.

B. M. Benjamin and C. J. Collins, J. Am. Chem. Soc., 83, 3662 (1961)

J. Janssen, J. Med. Chem., 16, 394 (1973) C 9 H 1 1 NO

O

H2O

NH2

C 9 H 1 1 NO

NH2

H2O

OH

P. Newman, Optical Resolution

Camps. 23

Camps. 24

Procedures for Chemical Compounds,

B. M. Benjamin and C. J. Collins, J. Am. Chem. Soc., 83, 3662 (1961)

Volume 1. Opt.Res. Inf. Center, NY 1979 C9H11N2O O N H

EtOH, Et 2 O 67:33 v/v%

N

H. McKennis, Jr., L. B. Turnbull, E. R.

Camps. 25

OH O2 N

Camps. 26

iPrOH

NH2

J. Controulis, M. C. Rebstock and H. M.

Bowmann and E. Wada, J. Am. Chem.

Crooks, Jr., J. Am. Chem. Soc., 71, 2463

Soc., 81, 3951 (1959)

(1949) C 9 H 1 3 NO

O NH2

12:88 v/v%

C 9 H 1 3 NO 2

OH NH2

EtOH, Et 2 O

J. Van Dijk and H. D. Moed, Recl. Trav.

Camps. 27

C9H12N2O4

OH

EtOH, H 2 O

HO

Camps. 28

Chim. Pays-Bas, 80, 573 (1961)

H. E. Smith, E. P. Burrows, P. L. Mobley, S. E. Robinson and F. Sulser, J. Med. Chem., 20, 978 (1977)

C 9 H 1 5 NO

N

Camps. 29

H

Acetone

N NH2OH

O S. F. Mason, K. Schofield and R. J. Wells, J. Chem. Soc., C, 626 (1967)

Camps. 30

EtOH, Et 2 O 23:77 v/v%

E. J. Corey, H. S. Sachdev, J. Z. Gougoutas and W. Saenger, J. Am. Chem. Soc., 92, 2488 (1970)

© 2002 by CRC Press LLC

C10H14N2O

C10H15N

C10H15N

EtOAc

AcOH, H 2 O

HN Ph.D. Thesis of M. S. Raaasch, The Ohio

Camps. 31

30:70 v/v%

H2N

Camps. 32

J. W. E. Glattfield and E. Wertheim, J. Am. Chem. Soc., 44, 2682 (1922)

State University (1941) C 1 0 H 1 5 NO

O NH2

C 1 0 H 1 7 NO

Et 2 O, EtOAc

OH

40:60 v/v% W. R. Brode and I. J. Wernert, J. Am.

Camps. 33

Acetone

N

Camps. 34

W. J. Pope, J. Chem. Soc., 75, 1105 (1898)

Chem. Soc., 65, 1685 (1933) C10H19N

S

C11H12N2S

N

CHCl 3

N

Diisobutyl ketone

N A. C. Cope, C. F. Howell and A.

Camps. 35

Camps. 36

Knowles, J. Am. Chem. Soc., 84, 3190

M. W. Bullock, J. J. Hand and E. Waletzky, J. Med. Chem., 11, 169 (1968)

(1962) C11H14N2

NH2

C11H14N2O

EtOH

MeOH

N

HN

O

N H

Camps. 37

British Patent, 911, 499 (1962)

Camps. 38

E. E. van Tamelen and J. S. Baran, J. Am. Chem. Soc., 80, 4659 (1958)

CN

O HO Camps. 39

NH2

C11H14N2O2 H2O

D. F. Reinhold, R. A. Firestone, W. A.

C11H15N EtOAc

N

Camps. 40

O. Červinka, A. Fábryová and F. Strejček,

Gaines, J. M. Chemerda and M.

Collect . Czech. Chem. Comm., 40, 3183

Sletzinger, J. Org. Chem., 33, 1209

(1975)

(1968)

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O N

C 1 1 H 1 5 NO

C11H17N

EtOAc

AcOH, H 2 O 50:50 v/v%

H2N

H. Takamatsuo, Yakugaku Zasshi, 76,

Camps. 41

Camps. 42

1219 (1956) NH2

Ph.D. Thesis of F. H. Thurber, University of Chicago, Illinois (1924)

C12H16N2

H N

H

O

CH 2 Cl 2 , Et 2 O

iPrOH

N

H

N H

W. C. Anthony, U. S. Patent, 3, 531, 573

Camps. 43

Camps. 44

(1970)

50:50 v/v%

G. Snatzke and G. Hajós, Heterocycles, 5, 299 (1976)

C12H17N

NH2

H2O

N H

C12H16N2O

C12H18N2 EtOH

N

M. Holtz and H. Müller, Chem. Ber., 33,

Camps. 45

Camps. 46

2842 (1901)

K. Hohenlohe-Ochringen and H. Bretschneider, Monatsh Chem., 96, 246 (1965)

C12H18N2O2

N O N

OH

Acetone

abs. EtOH

HN

HO

O

C 1 2 H 1 9 NO 3

OH Camps. 47

R. N. Booher, S. E. Smits, W. W. Tuner,

Camps. 48

Jr. and A. Pohland, J. Med. Chem., 20,

P. Pratesi, A. La Manna, G. Pagani and E. Grana, Farmaco, Ed. Sci., 18, 950 (1963)

885 (1977) OH

C 1 3 H 1 3 NO EtOH

N

Camps. 49

K. A. Thaker and U. S. Pathak, J. Indian Chem. Soc., 41, 555 (1964)

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OH

H2O

N

Camps. 50

C 1 3 H 1 3 NO

K. Löffler and H. Grunert, Chem. Ber., 40, 1342 (1907)

O

C13H16N2O

C 1 3 H 1 6 ClNO

Cl

abs. EtOH

N

NH

O

EtOH

N H

E. E. Smissman and G. Hite, J. Am.

Camps. 51

Camps. 52

Chem. Soc., 82, 3375 (1960)

J. Trojánek, Z. Koblicová and K. Bláha, Collect . Czech. Chem. Comm., 33, 2950 (1968)

O

C 1 3 H 1 7 NO 2

OH

EtOAc

N

C 1 4 H 1 0 Cl 5 N

Cl CCl3

H2N

CH 3 CN

Cl

Camps. 53

E. E. Smissman and G. Hite, J. Am.

Camps. 54

Chem. Soc., 82, 3375 (1960)

W. A. McBlain, R. W. Currie and F. H. Wolfe, Agricultural and Food Chemistry, 25, 59 (1977)

NH2

Br

C 1 4 H 1 2 BrN

NH2

Et 2 O, EtOH 88:12 v/v%

C 1 4 H 1 4 N 2 Br 2 Acetone

Br H2N

Br

Camps. 55

J. S. Fowler, J. Org. Chem., 37, 510

Camps. 56

(1972) H N

Chem. Soc., 57, 762 (1935) C14H15N

NH2

7:93 v/v%

G. Wittig and U. Thiele, Justus Liebigs Ann. Chem., 726, 1 (1969); R. Decamps, Bull. Soc. Chim. Belg., 33, 269 (1924); Y. Ogata and K. Takagi, J. Org. Chem., 35, 1642 (1970)

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C 1 4 H 1 5 NO

OH

MeOH, Et 2 O

Camps. 57

W. I. Patterson and R. Adams, J. Am.

EtOAc, CCl 4 43:57 v/v%

Camps. 58

I. G. Vasi and R. K. Desai, Indian J. Chem., Sect. B, 14B, 625 (1976)

C14H15N

OH NH2

C 1 5 H 1 5 NO

NH2

H2O

Pyridine

O

A. W. Ingersoll, J. Am. Chem. Soc., 50,

Camps. 59

Camps. 60

2264 (1928) N

S

O

R. Bognár, J. W. Clark-Lewis, A.Tőkés and M. Rákosi, Aust. J. Chem., 23, 2015 (1970)

C 1 2 H 1 7 FN 2 O 2 S

NH2

EtOH

NH

C15H17N H2O

O F N. Cohen, B. L. Banner, J. F. Blount, G.

Camps. 61

Camps. 62

Weber, M. Tsai and G. Saucy, J. Org.

Collins, J. Am. Chem. Soc., 83, 3654

Chem., 39, 1824 (1974)

(1961)

C 1 5 H 1 7 NO

NH2 HO

C 1 5 H 1 7 NO

OH

EtOH, H 2 O

H2O

50:50 v/v% B. M. Benjamin, H. J. Schaeffer and C. J.

Camps. 63

B. M. Benjamin, P. Wilder, Jr. and C. J.

NH2 Camps. 64

Collins, J. Am. Chem. Soc., 79, 6160

A. McKenzie and A. K. Mills, Chem. Ber., 62, 1784 (1929)

(1957) C15H18N2

N H

N

EtOH

O

Acetone, Et 2 O N

L. Novák and C. Szántay, Chem. Ber.,

Camps. 65

C15H22N2O2 NH

Camps. 66

102, 3959 (1969)

P. L. Julian and J. Pikl, J. Am. Chem. Soc., 57, 755 (1935)

C16H14N2

NH2

F H2N

H2O NH2 Camps. 67

M. S. Lesslie and E. E. Turner, J. Chem. Soc., 1512 (1929)

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O

C16H18F2N2 EtOAc

NH2 F Camps. 68

E. C. Kleiderer and R. Adams, J. Am. Chem. Soc., 53, 1575 (1931)

C16H19N N

C 1 6 H 1 9 NO

NH2

EtOAc

MeOH

O

Camps. 69

K. Ogiu, H. Fujimura and Y. Yamakawa,

H. Lettré, A. Mex and E. Ruhbaum, Hoppe-

Camps. 70

Yakugaku Zasshi, 80, 283 (1960) C 1 6 H 1 9 NO

OH NH2

O

H2O

25:75 v/v% C. J. Collins, M. M. Staum and B. M.

NH2 O

N. A. B. Wilson and J. Read, J. Chem. Soc.,

Camps. 72

Benjamin, J. Org. Chem., 27, 3525 (1962)

1120 (1935) H

C 1 6 H 1 9 NO 3 H2N

MeOH, Et 2 O O

C 1 6 H 1 9 NO 3

OH

EtOH, H 2 O

O

Camps. 71

Seyler's Z. Physiol. Chem., 289, 119 (1952)

C 1 6 H 2 1 NO 3 O

N

Acetone

OH

O

O

O

Camps. 73

E. Hardegger, E. Maeder, H. M. Semarne

G. Werner and K. Miltenberger, Justus

Camps. 74

Liebigs Ann. Chem., 631, 163 (1960)

and D. J. Cram, J. Am. Chem. Soc., 81, 2729 (1959) C 1 6 H 2 3 NO

N

O

C 1 6 H 2 7 NO 3

OH

1.) abs. EtOH

N

2.) Acetone

HO

3.) Et 2 O 4.) MeOH, Acetone

Camps. 75

E. L. May and M. Takeda, J. Med. Chem.,

O H. Hamano and S. Okuda, Chem. Pharm.

Camps. 76

13, 805 (1970)

O

Bull. 26, 833 (1978) C 1 8 H 2 9 NO 4

OAc

C17H21D2N2I

D

(CH3)2N

N D

N(CH3)3I

O Camps. 77

H. Hamano and S. Okuda, Chem. Pharm. Bull. 26, 833 (1978)

© 2002 by CRC Press LLC

Camps. 78

R. E. Carter and L. Dahlgren, Acta Chem. Scand., 24, 633 (1970)

N

C 1 7 H 2 3 NO 3

H

N

C 1 7 H 2 3 NO 3

H

EtOAc, EtOH

O

Acetone

O

O

O

OH

OH

M. Barrowcliff and F. Tutin, J. Chem.

Camps. 79

G. Werner and K. Miltenberger, Justus

Camps. 80

Soc., 95, 1966 (1909)

Liebigs Ann. Chem., 631, 163 (1960)

C 1 7 H 2 3 NO 3

H3CO

N

Et 2 O, Acetone

N

H3CO

C 1 7 H 2 4 ClNO

O

H

EtOAc

Cl H O

H. T. Openshaw and N. Whittaker, J.

Camps. 81

E. E. Smissman and J. L. Diebold, J. Org.

Camps. 82

Chem., 30, 4005 (1966)

Chem. Soc., 1461 (1963) N

C 1 7 H 2 5 NO

C 1 8 H 1 9 BrClN

Cl

abs. EtOH

Acetone, H 2 O Br

HO H2N

J. H. Ager, A. E. Jacobson and E. L. May,

Camps. 83

M. Oki, Bull. Chem. Soc. Jpn., 26, 161

Camps. 84

J. Med. Chem., 12, 288 (1969)

(1953)

C 1 8 H 2 3 NO

N

N

Acetone

HO

A. F. Casty and J. L. Myers, J. Pharm.

Camps. 85

C 1 8 H 2 3 NO

OH

EtOH, Acetone

Y. Yamakawa, Yakugaku Zasshi, 80, 298

Camps. 86

Pharmacol., 16, 455 (1964)

(1960)

C 1 8 H 2 5 ClN 2 O

C 1 8 H 2 9 NO 2 OH

1.) Methyletylketone Cl HN

O

2.) iPrOH N

H

N OH

H

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H2O

Camps. 87

W. F. M. Van Bever, A. G. Knaeps, J. J.

Camps. 88

H. Wieland, W. Koschara, E. Dane, J.

M. Willems, B. K. F. Hermans and P. A.

Renz, W. Schwarze and W. Linde, Justus

J. Janssen, J. Med. Chem., 16, 394 (1973)

Liebigs Ann. Chem., 540, 103 (1939) O

C19H17N

NH2

EtOH

C19H20N2O2 NH2

N

Acetone, MeOH

HO

Ph

Camps. 89

S. K. Hsü, C. K. Ingold and C. L. Wilson,

Camps. 90

J. Chem. Soc., 1778 (1935) H3CO NH2 H3CO H3CO

F. B. Block and F. H. Clarke, Jr., U. S. Patent, 3, 341, 538 (1967)

C 1 9 H 2 1 NO 5

C19H22N2

MeOH

MeOH

O

N

OH

N

Camps. 91

H. Corrodi and E. Hardegger, Helv. Chim.

Camps. 92

Acta, 40, 193 (1957)

A. L. Laings and M.-G. P. Stegen, U. S. Patent, 3, 202, 674 (1965) H N

C19H22N2O EtOH

N

N H H

Methyl-isobutyl

CN

O

H

C19H22N2O2

ketone

O

H O

Camps. 93

G. A. Swan, J. Chem. Soc., 1534 (1950)

Camps. 94

E. Haack, A. Hagedorn and K. Stach, British Patent, 1, 050, 838 (1966)

H3CO H3CO

C 1 9 H 2 3 NO 3 N

OH

H2O

C 1 9 H 2 5 NO N

abs. EtOH

HO

Camps. 95

J. Knabe and P. Horn, Arch. Pharm. (Weinheim, Ger.), 300, 547 (1967)

© 2002 by CRC Press LLC

Camps. 96

A. Pohland and H. R. Sullivan, J. Am. Chem. Soc., 77, 3400 (1955)

C20H16N2 NH2 H2N

Chlorbenzol, EtOH

C 2 0 H 1 7 NO 6

O H O

83:17 v/v%

N

30:70 v/v%

O O O

R. Kuhn and P. Goldfinger, Justus Liebigs

Camps. 97

Camps. 98

Ann. Chem., 470, 183 (1929)

H N

CH 2 Cl 2 , MeOH

H

O

W. Klötzer, S. Teitel and A. Brossi, Helv. Chim. Acta, 55, 2228 (1972)

C20H18N2

C20H19N

EtOH

EtOH, H 2 O 50:50 v/v%

NH2

N H

G. M. Bennettt and C. S. Gibson, J.

Camps. 99

Camps. 100

Chem. Soc., 123, 1570 (1923)

C. J. Collins, W. A. Bonner and C. T. Lester, J. Am. Chem. Soc., 81, 466 (1959)

C20H19N

C 2 0 H 2 7 NO

EtOH, H 2 O NH2

95:5 v/v%

N

H. E. Smith and T. C. Willis, Tetrahedron,

Camps. 101

EtOH HO

Camps. 102

26, 107 (1970)

NH2

CN

A. A. Shaikh and K. A. Thaker, J. Indian Chem. Soc., 45, 378 (1968)

C20H36N2O2

C 2 1 H 2 1 NO

EtOAc

EtOH, H 2 O NH2

H HO

92:8 v/v%

OH H HO

Camps. 103

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

© 2002 by CRC Press LLC

Camps. 104

A. McKenzie, A. K. Mills and J. R. Myles, Chem. Ber., 63, 904 (1930)

C21H24N2O

C21H24N2O

Acetone, EtOH

CN

Acetone

CN

45:55 v/v%

N

N

O

O

A. F. Casy and M. M. A. Hassan, J.

Camps. 105

Camps. 106

Chem. Soc., C, 683 (1966)

A. H. Beckett and A. F. Casy, J. Chem. Soc., 3076 (1957)

C21H26N2O4 O PhCOO

C 2 2 H 2 3 NO

EtOH, H 2 O

N

O

EtOAc

N OH

N

Camps. 107

I. Matuo and S. Ohki, U. S. Patent, 3, 850,

Camps. 108

921 (1974) H3CO

Chem. Soc., 52, 5056 (1930) C 2 2 H 2 7 NO 4 H2O

H3CO H

W. R. Brode and J. B. Littman, J. Am.

H2N

OPh SO2 OPh SO2

C24H20N2O6S2 abs. EtOH

N

NH2 OCH3 OCH3

Camps. 109

O. Haars, Arch. Pharm. (Weinheim, Ger.),

Camps. 110

243, 154 (1905)

NH2

Camps. 111

Soc., 2021 (1932) C24H21N

C24H33N

EtOH, H 2 O

Acetone

70:30 v/v%

C. L Arcus, J. Kenyon and S. Levin, J. Chem. Soc., 507 (1951)

© 2002 by CRC Press LLC

M. S. Leslie and E. E. Turner, J. Chem.

NH

Camps. 112

Addn. 88003 to French Patent, 1, 391, 213 (1966)

C28H28N2

C28H28N2

THF, Et 2 O

H N

33:67 v/v%

N H

Camps. 113

W. Stuhmer and G. Messward, Arch.

THF, Et 2 O

H N

Camps. 114

Pharm. (Weinheim, Ger.), 286, 221

N H

25:75 v/v%

W. Stuhmer and G. Messward, Arch. Pharm. (Weinheim, Ger.), 286, 221 (1953)

(1953) C32H38N2O8

C32H40N2O9

H3CO

MeOH

MeOH, CHCl 3

H N

N H H

N H

H

H H3CO H O C O H3CO

Camps. 115

H3CO OCH3

OCH3

L. Bláha, J. Weichet, J. Žvaček, S. Šmolik and B. Kákáč, Collect . Czech. Chem.

Camps. 116

SO2 H

R. B. Woodward, F. E. Bader, H. Bickel, A. J. Frey and R. W. Kierstead, Tetrahedron,

Comm., 25, 237 (1960)

H

25:75 v/v%

H H CH3OOC H H3CO H O C O H3CO

CH3OOC

H3CO

H N

2, 1 (1958)

C 9 H 1 7 NO 2 S

C 1 3 H 1 9 NO

N OH

Acetone

EtOH

N

Camps. 117

L. A. Paquette and J. P. Freeman, J. Org.

Camps. 118

Chem., 35, 2249 (1970)

B. D. Bhatt and K. A. Thaker, J. Inst. Chemists (India), 47, 92 (1975)

C 1 8 H 2 1 NO

C 1 7 H 1 7 BrClNO

Cl NH

EtOH

H3CO N

CH 3 CN, MeOH 80:20 v/v%

C OH

Br Camps. 119

B. D. Bhatt and K. A. Thaker, J. Inst. Chemists (India), 47, 92 (1975)

Camps. 120

S. Chumpradit, M.-P. Kung, J. J. Billings and H. F. Kung, J. Med. Chem., 34, 877 (1991)

© 2002 by CRC Press LLC

C 1 4 H 1 5 NO

C 6 H 1 5 NO OH

Toluene, MTBE

NH2

HO K. Drauz, W. Jahn and M. Schwarm, J.

Camps. 121

NH2 K. Saigo, I. Sugiura, I. Shida, K. Tachibana,

Camps. 122

Chem. Eur., 9, 838 (1995) C13H6F2N3O3

OH SO2CH3 F

N N

Bull. Chem. Soc. Jpn., 59, 2915 (1986) C9H16N2O

NHAc

Monochlorobenzene

1.) Acetone N

2.) iPrOH

N F

Camps. 123

Sumitomo Pharm Co., 91-008873/02,

Chiron Lab A/S, 91-117465/16, C91-

Camps. 124

C91-003891, SUMI 28.06.89

H

NH2

05042, CHIR- 15.09.89

C 1 5 H 1 5 NO

C 2 9 H 3 1 NO 4

HO

DMF, CH 2 Cl 2

Pyridine

O

8:92 v/v%

O

OH

O N

Camps. 125

A. L. Tőkés, Liebigs Ann. Chem., 89

Camps. 126

(1989)

S. Gauthier, B. Caron, J. Cloutier, Y. L. Dory, A. Favre, D. Larouche, J. Mailhot, C. Ouellet, A. Schwerdtfeger, G. Leblanc, C. Martel, J. Simard, Y. Mérand, A. Bélanger, C. Labrie and F. Labrie, J. Med. Chem., 40, 2117 (1997)

O S NH

C 7 H 9 NOS

H N

C 1 1 H 1 8 ClNO 2

Acetone

OH

HO Camps. 127

J. Brandt and H.-J. Gais, Tetrahedron Asymmertry, 8, 909 (1997)

Camps. 128

Cl Y. Ito, H. Kato, E. Koshinaka, S. Kurata, K. Morikawa, Eur. Pat. Appl. EP 420, 120, (Cl. C07C215/60), (1991)

© 2002 by CRC Press LLC

C13H15F2N3O3S

F OH N C C N

F

CHCl 3

N

C 2 1 H 2 2 OP

Ph + Ph P Ph

OH

MeOH, Et 2 O

SO2CH3

Camps. 129

N. Ohashi, H. Miyauchi and K. Shimago,

Camps.

K. Okuma, Y. Tanaka, H. Ohta and H.

Eur. Pat. Appl. EP 405, 502 (1991)

130

Matsuyama, Bull. Chem. Soc. Jpn., 66, 2623 (1993)

H

C 6 H 1 3 NO 2 COOH

NH2

Camps. 131

C18H27N

EtOH, H 2 O

Acetone

N

95:5 v/v%

J. Viret, H. Patzelt and A. Collet,

Camps.

M. A. Iorio, L. Tomassini, M. V. Mattson,

Tetrahedron Lett., 27, 5865 (1986)

132

C. George and A. E. Jacobson, J. Med. Chem., 34, 2615 (1991)

C18H27N Acetone

N

Camps. 133

C6H9N N H

M. A. Iorio, L. Tomassini, M. V. Mattson,

Camps.

G. V. Shustov, A. Rauk, Tetrahedron Lett.,

C. George, A. E. Jacobson, J. Med.

134

36, 31, 5449(1995)

Chem., 34, 2615 (1991)

Dibenzoyl-tartaric acid Cl

H2N OH

DBTA. 1

C 3 H 8 ClNO

CN

EtOH

E. Cohen and R. Paul, French Patent 2,

C4H8N2

NH2

MeOH

A. F. McKay, D. L Garmaise, R. Gaudry,

DBTA. 2

100, 788 (1972)

H. A. Baker, G. Y. Paris, R. W. Kay, G. E. Just and R. Schwartz, J. Am. Chem. Soc., 81, 4328 (1959) C4H9N

NH

DBTA. 3

MeOH

R. G. Kostyanovsky, I. M. Gella, V. I. Markov and Z. E. Samoljova, Tetrahedron, 30, 39 (1974)

© 2002 by CRC Press LLC

C6H13N MeOH, Acetone N H

DBTA. 4

20:80 v/v% W. Leithe, Monatsh. Chem., 50, 41 (1928)

C 6 H 1 3 NO

NH2

C6H15N

NH O

H. Horstman, H. Wollweber and K.

DBTA. 5

P. Karrer and P. Dinkel, Helv. Chim. Acta,

DBTA. 6

Meng, British Patent, 1, 031, 916 (1966) NH2

36, 122 (1953)

C6H15N

C6H15N

NH2

OH

EtOH, H2O 60:40 v/v%

P. Karrer and P. Dinkel, Helv. Chim.

DBTA. 7

A. Stoll, J. Peyer and A. Hofmann, Helv.

DBTA. 8

Acta, 36, 122 (1953)

Chim. Acta, 26, 929 (1943) C13H21N

OH

C 7 H 9 NO

EtOH, H2O

N

60:40 v/v% HN

OH

A. Stoll, J. Peyer and A. Hofmann, Helv.

DBTA. 9

O. Červinka, O. Bělovský and P.

DBTA. 10

Chim. Acta, 26, 929 (1943)

Pejmanová, Collect. Czech. Chem. Comm., 38, 1358 (1973)

OH

C7H13N

C 7 H 1 3 NO H2O

N

N R. G. Kostyanovsky, V. I. Markov and I.

DBTA. 11

A. Kalir, E. Sali and E. Shirin, Isr. J.

DBTA. 12

M. Gella, Tetrahedron Lett., 1301 (1972) OH +

N Cl Benzyl

C 1 4 H 1 9 NO

C 7 H 1 5 NO

O

H2O

A. Kalir, E. Sali and E. Shirin, Isr. J.

DBTA. 13

Chem., 9, 267 (1971)

N

L. Angiolini, P. C. Bizzarri and M.

DBTA. 14

Chem., 9, 267 (1971)

H

NH2 NHNH2

Acetone

Tramontini, Tetrahedron, 25, 4211 (1969) C7H15N3O

S

EtOH S

NH2 NH2

C7H18N2S2 H2O

H O DBTA. 15

W. L. F. Armarego and T. Kobayashi, J. Chem. Soc., C, 1597 (1970)

© 2002 by CRC Press LLC

DBTA. 16

F. P. Dwyer and T. E. MacDermott, J. Am. Chem. Soc., 85, 2916 (1966)

NH2

C 8 H 9 Cl 2 N

C8H9N

EtOH, H2O

MeOH NH2

95:5 v/v%

Cl Cl

R.W. Fuller, B. W. Roush, H. D. Snoddy

DBTA. 17

V. Ghislandi and D. Vercesi, Boll. Chim.

DBTA. 18

and B. B. Molloy, J. Med. Chem., 16, 106

Farm., 115, 489 (1976)

(1973) C 8 H 1 1 NO OH

N

C 8 H 1 1 NO

Acetone

Acetone

N OH

G. Fodor and E. Bauerschmidt, J.

DBTA. 19

G. Fodor and G. A. Cooke, Tetrahedron,

DBTA. 20

Heterocycl. Chem., 5, 205 (1968)

Suppl. 8, Part I, 113 (1966)

C 8 H 1 1 NO 2

OH NH2

C8H15N

MeOH

MeOH

N

OH

T. Kametani, S. Shibuya, H. Sugi and K.

DBTA. 21

N. J. Leonard and W. J. Middleton, J. Am.

DBTA. 22

Fukumoto, J. Heterocycl. Chem., 10, 451

Chem. Soc., 74, 5776 (1952)

(1973); T. Kametani, H. Sugi, H. Yagi, K. Fukumoto and S. Shibuya, J. Chem. Soc., C, 2213 (1970) OH H

C 8 H 1 5 NO

OH H

EtOH

N DBTA. 23

EtOH

N N. K. Kochetkov, A. M. Likhosherstov

DBTA. 24

N. K. Kochetkov, A. M. Likhosherstov and

and V. N. Kulakov, Tetrahedron, 25, 2313

V. N. Kulakov, Tetrahedron, 25, 2313

(1969)

(1969)

C 8 H 1 5 NO 2 N H HO

H

© 2002 by CRC Press LLC

OH

96:4 v/v%

G. Fodor an O. Kovács, J. Chem. Soc., 2341 (1953)

C 8 H 1 7 NO

H N

EtOH, H 2 O

HO

DBTA. 25

C 8 H 1 5 NO

Acetone, H 2 O 97.5:2.5 v/v%

DBTA. 26

C. Schöpf, E. Gams, F. Koppernock, R. Rausch and R. Walbe, Justus Liebigs Ann. Chem., 732, 181 (1970)

C 8 H 1 7 NO

OH N

Acetone

P. Newman, Optical Resolution

DBTA. 27

O

N

C 8 H 1 7 NO 2 EtOH

O

A. S. Angeloni, G. Gottarelli and M.

DBTA. 28

Tramontini, Tetrahedron, 25, 4147 (1969)

Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979 C 8 H 1 7 NO 2

O

O

EtOH

abs. EtOH

NH2

HN

Ph.D. Thesis of M. Broadhurst,

DBTA. 29

C8H20N2

HN

DBTA. 30

R. Ghirardelli and H. J. Lucas, J. Am. Chem. Soc., 79, 734 (1957)

University of california, Los Angeles (1973) H N

O

C9H11N3O NH2

C 9 H 1 2 ClN

Cl

Acetone, CHCl 3

EtOH, H 2 O

17:83 v/v%

95:5 v/v%

N H

NH2

G. H. Fisher and H. P. Schultz, J. Org.

DBTA. 31

DBTA. 32

Chem., 39, 635 (1974)

J. Org. Chem., 40, 1562 (1975)

C9H12N2O4

OH OH

H2O

NH2

O2N

J. Pratesi, Farmaco, Ed. Sci., 8, 41 (1953)

DBTA. 33

H. E. Smith, E. P. Burrows and F-M. Chen,

C9H13N abs. EtOH N

DBTA. 34

W. von E. Doering and V. Z. Pasternak, J. Am. Chem. Soc., 72, 143 (1950)

C9H15N

N

O

EtOH

Et 2 O

N

DBTA. 35

A. A. Bothner-By, R. S. Shutz, R. F.

DBTA. 36

C 9 H 1 7 NO

N. J. Leonard, R. C. Sentz and W. J.

Dawson and M. L. Solt, J. Am. Chem.

Middleton, J. Am. Chem. Soc., 75, 1674

Soc., 84, 52 (1962)

(1953)

© 2002 by CRC Press LLC

C10H11N

C10H13N

abs. EtOH

MeOH

N N H

G. Kohl and H. Pracejus, Justus Liebigs

DBTA. 37

DBTA. 38

Ann. Chem., 694, 128 (1966) O

Heterocyclic Chem., 13, 1053 (1976)

C 1 0 H 1 3 NO

H N

G. Bettoni, C. Cellucci and V. Tortolella, J.

C 1 0 H 1 5 NO

OH

EtOAc

EtOH N

DBTA. 39

H. Takamtsu, Yakugaku Zasshi, 76, 1219

DBTA. 40

(1956)

7468 (1960) C 1 0 H 1 5 NO 2

OH

C10H16N2

EtOH, H 2 O

HN

HO DBTA. 41

S. Ose and Y. Yoshimura, Japanese Patent

NHNH2

75:25 v/v%

S. Ose, H. Takamatsu and Y. Minaki,

DBTA. 42

D. J. Cram and J. S. Bradshaw, J. Am.

C 1 0 H 1 9 NO

C 1 0 H 2 3 NO

Acetone

N

75:25 v/v%

Chem. Soc., 85, 1108 (1963)

Japanese Patent, 4417 (1958)

O

EtOH, H 2 O

EtOH N OH

DBTA. 43

R. Andrisano, A. S. Angeloni, G.

DBTA. 44

Gottarelli, S. Marcocchi, B. Samori and

R. K. Hill, J. Am. Chem. Soc., 80, 1611 (1958)

G. Scapini, J. Org. Chem., 41, 2913 (1976)

N

S

MeOH

N

DBTA. 45

C11H12N2S

C11H14N2

NH2

MeOH

N H

F. Dewilde and G. G. Frot, British Patent,

DBTA. 46

British Patent, 911, 499 (1962)

1, 226, 253 (1971) C11H14N2O5

OH NH2 O 2N

COOEt

© 2002 by CRC Press LLC

C11H14N2O5

OH NH2

abs. EtOH O 2N

COOEt

abs. EtOH

British Patent, 725, 876 (1954)

DBTA. 47

HO

DBTA. 48

C 1 1 H 1 5 NO

NH2

British Patent, 725, 876 (1954)

HO

NH2

EtOH, H 2 O

G. Mohr, A. W. Frahm and F.

DBTA. 49

H2O

DBTA. 50

G. Mohr, A. W. Frahm and F.

Zymalkowsky, Justus Liebigs Ann.

Zymalkowsky, Justus Liebigs Ann. Chem.,

Chem., 756, 103 (1972)

756, 103 (1972)

C 1 1 H 1 5 NO

O N

C 1 1 H 1 5 NO 2

H3CO

Acetone

NH

HO L. D. Tomina, E. I. Klabunovskii, Y. I.

DBTA. 51

C 1 1 H 1 5 NO

DBTA. 52

CH 3 CN

S. Teitel, J. O'Brien, , W. Pool and A. Brossi, J. Med. Chem., 17, 134 (1974)

Petrov, A. D. Yuharsova and E. M. Cherkasova, Izv. Akad. Nauk SSSR, Ser. Khim., 1937 (1971) C 1 1 H 1 5 NO 2

HO NH

H3CO

CH 3 CN

S. Teitel, J. O'Brien, , W. Pool and A.

DBTA. 53

C 1 1 H 1 6 ClN

HN

Cl

DBTA. 54

MeOH

French Patent, 1, 528, 540 (1968)

Brossi, J. Med. Chem., 17, 134 (1974) C 1 1 H 1 6 Cl 2 N 2 O HO

Cl

C11H16N2O3 HO

N H

Cl

Cl

NH2

DBTA. 55

EtOH

Cl NO2

J. Keck, G. Kruger and R. Klaus, German

DBTA. 56

H N

C 1 1 H 1 7 NO

OH

MeOH, H 2 O

OH

70:30 v/v%

H. Hollweber, R. Hiltmann, H. Kaller and H-G. Kroneberg, French Patent, 1, 503, 517 (1967)

© 2002 by CRC Press LLC

L. Almirante and W. Murmann, J. Med. Chem., 9, 650 (1966)

Offen, 2, 212, 600 (1973)

DBTA. 57

N H

Acetone

H N

C 1 1 H 1 7 NO MeOH, H 2 O 70:30 v/v%

DBTA. 58

British Patent, 1, 043, 510 (1966)

OH

C 1 1 H 1 7 NO

H N

C 1 1 H 1 7 NO 3

OH

O

NH2

Acetone

H 2 O, Acetone 50:50 v/v%

O

L. D. Tomina, E. I. Klabunovskii, Y. I.

DBTA. 59

R. Baltzly and N. B. Mehta, J. Med. Chem.,

DBTA. 60

11, 833 (1968)

Petrov, L. A. Kretova, N. I. Kholdyakov, T. A. Antonova and F. M. Cherkasova, Izv. Akad. Nauk SSSR, Ser. Khim., 2181 (1971) C 1 1 H 1 8 NO 3 P

NH2 O P O O

C12H10N2O

N

O

MeOH

Acetone

H

H N

S. V. Rogozhin, V. A. Davankov and Y.

DBTA. 61

DBTA. 62

P. belov, Izv. Akad. Nauk SSSR, Ser.

G. Gottarelli and B. Samori, J. Chem. Soc., Perkin 2, 1971 (1972)

Khim., 955 (1973) C12H14N2 NH

C12H16F3N

EtOH

NH

abs. EtOH

N H

CF3 DBTA. 63

J. Trojánek, Z. Koblicová and K. Bláha,

DBTA. 64

L. G. Beregi, P. Hugon, J-C. Le Douarec

Collect . Czech. Chem. Comm., 33, 2950

and H. Schmitt, British Patent, 1, 078, 186

(1968)

(1967) C 1 2 H 1 6 F 3 NO

NH

C 1 2 H 1 7 NO

O

EtOAc

Acetone N

OH CF3 DBTA. 65

L. G. Beregi, P. Hugon, J-C. Le Douarec and H. Schmitt, French Patent, 1, 517, 587 (1968)

© 2002 by CRC Press LLC

DBTA. 66

A. Pohland, L. R. Peters and H. R. Sullivan, J. Org. Chem., 28, 2483 (1963)

C 1 2 H 1 7 NO

O

C 1 2 H 1 7 NO 2

H3CO

Acetone

EtOH

NH

H3CO N R. Anrisano, A. S. Angeloni, G.

DBTA. 67

Ph.D. Thesis of A. A Genenah, University

DBTA. 68

Gottarelli, S. Marzocchi, B. Samori and

of Minnesota (1972)

G. Scapini, J. Org. Chem., 41, 2913 (1976) N

C12H18N2O

OH

C 1 2 H 1 9 NO 3 HO

N H

N

Acetone, H2O 50:50 v/v%

HO

R. J. MacConaill and F. L. Scott,

DBTA. 69

OH

K. Wetterlin, J. Med. Chem., 15, 1182

DBTA. 70

Tetrahedron Lett., 2993 (1970)

(1972)

C13H14F3N

H N

abs. EtOH

abs. EtOH

N H

C 1 3 H 1 5 NO

O CF3

L. Beregi, P. Hugon and J. Claude, British

DBTA. 71

R. L. Clarke, B. F. Tullar and L. S. Harris,

DBTA. 72

Patent, 1, 121, 857 (1968) C 1 3 H 1 7 NO 2 O

N

J. Med. Chem., 5, 362 (1962) C 1 3 H 1 7 NO 4

N

O

Et2O, EtOH

O

Acetone, ligt petroleum

OCH3

O OCH3

M. Elander, L. Gawell and K. Leander,

DBTA. 73

G. Snatzke, G. Wollenberg, J. Hrbek, Jr., F.

DBTA. 74

Acta Chem. Scand., 25, 721 (1971)

Santavý, K. Bláha, W. Klyne and R. J. Swan, Tetrahedron, 25, 5059 (1969)

H N

C13H18N2

H N

abs. EtOH

N H

DBTA. 75

N

C14H20N2 abs. EtOH, EtOAc, Et 2 O 48:48:4 v/v%

J. D. Albright and H. R. Snyder, J. Am. Chem. Soc., 81, 2239 (1959)

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DBTA. 76

J.D. Albright and H. R. Snyder, J. Am. Chem. Soc., 81, 2239 (1959)

C 1 3 H 1 9 NO OH

H N

OH

C 1 3 H 1 9 NO

MeOH, H 2 O

MeOH, Acetone

80:20 v/v%

17:83 v/v%

N

M. M. Abdel-Monem, D. L. Larson, H. J.

DBTA. 77

DBTA. 78

C. Schöpf, W. Bundschuh, G. Dummer, T.

Kupferberg and P. S. Portoghese, J. Med.

Kaufmann and R. Kress, Justus Liebigs

Chem., 15, 494 (1972)

Ann. Chem., 628, 101 (1959)

OH

N

C 1 3 H 1 9 NO

N

Tetrahydrofurane

C 1 3 H 1 9 NO Acetone

O L. Dall'Asta and A. Pedrazzoli, Chem.

DBTA. 79

DBTA. 80

Therap., 2, 441 (1967)

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

C 1 3 H 1 9 NO 2

N

COOCH3

EtOAc O

N

R. N. Boher, S. E. Smits, W. W. Turner,

DBTA. 81

Acetone

NH

O

C13H20N2O2

DBTA. 82

G. Jollés, G. Poiget, J. Robert, B. Terlain

Jr. and A. Pohland, J. Med. Chem., 20,

and J-P. Thomas, Bull. Soc. Chim. Fr.,

885 (1977)

2252 (1965) C 1 3 H 2 1 NO

OH N

C 1 3 H 2 1 NO

NH

EtOH

OH

EtOH, H 2 O 60:40 v/v%

DBTA. 83

L. Angiolini, P. Costa Bizzari and M.

DBTA. 84

Tramontini, Tetrahedron, 25, 4211 (1969)

A. Stoll, J. Peyer and A. Hofmann, Helv. Chim. Acta, 26, 929 (1943) CN

C 1 4 H 1 7 NO abs. EtOH

MeOH

N

O

CN

NH

DBTA. 85

C14H18N4 N

R. L. Clark, B. F. Tullar and L. S. Harris, J. Med. Chem., 5, 362 (1962)

© 2002 by CRC Press LLC

DBTA. 86

J. T. Broeke, A. W. Douglas and E. J. J. Grabowski, J. Org. Chem., 41, 3159 (1976)

O

C 1 4 H 1 9 NO

C 1 4 H 1 9 NO

abs. EtOH

Acetone

N

N

DBTA. 87

H. Takamtsuo, Yakugaku Zasshi, 76,

O

Ph.D. Thesis of J. R. Soares, Columbia

DBTA. 88

1219 (1956)

University, New York (1971) C 1 4 H 1 9 NO 2

C14H20N2O

H N

Acetone

O

O

N

iPrOH

N H

O DBTA. 89

P. Newman, Optical Resolution

DBTA. 90

B. F. Tullar, J. Med. Chem., 14, 891 (1971)

Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

OH

C 1 4 H 2 1 NO

C 1 4 H 2 1 NO

MeOH

MeOH, H 2 O

N

N

DBTA. 91

P. S. Portogese, Z. S. D. Gomaa, D. L.

DBTA. 92

OH H. C. Beyerman, W. Eveleens and Y. M. F.

Larson and E. Shefter, J. Med. Chem., 16,

Muller, Recl. Trav. Chim. Pays-Bas, 75, 63

199 (1973)

(1956); H. C. Beyerman, J. Eenshuistra and W. Eveleens, Recl. Trav. Chim. Pays-Bas, 76, 415 (1957)

N

DBTA. 93

C 1 4 H 2 1 NO

C 1 4 H 2 1 NO

EtOH, H 2 O

MeOH, H 2 O

33:67 v/v%

56:44 v/v%

OH

C. Schöpf, G. Dummer, W. Wüst and R.

N

DBTA. 94

OH H. C. Beyerman, J. Eenshuistra, W.

Rausch, Justus Liebigs Ann. Chem., 626,

Eveleens and A. Zweistra, Recl. Trav.

134 (1959)

Chim. Pays-Bas, 78, 43 (1959)

© 2002 by CRC Press LLC

C 1 4 H 2 1 NO

C 1 4 H 2 1 NO HN

iPrOH, H 2 O

abs. EtOH

50:50 v/v%

N

O

OH

C. Schöpf, G. Dummer and W. Wüst,

DBTA. 95

DBTA. 96

Justus Liebigs Ann. Chem., 626, 134

R. L. Clarke, B. F. Tullar and L.S. Harris, J. Med. Chem., 5, 362 (1962)

(1959) C 1 4 H 2 1 NO 3

H3CO

O

N

H3CO

OH

EtOH NH

N H

HO

A.R. Battersby, R. Binks, T.P. Edwads, J.

DBTA. 97

DBTA. 98

Chem. Soc., 3474 (1960)

T. Leigh and L. H. Smith, British Patent, 1, 270, 723 (1972)

C 1 5 H 1 5 NO

NH2

C14H22N2O3

O

C 1 5 H 2 1 NO

MeOH

O

N

O

R. Bognár, J. W. Clark-Lewis, A. L.

DBTA. 99

Tőkés and M. Rákosi, Aust. J. Chem., 23,

DBTA. 100

R. J. MacConaill and F. L. Scott, Tetrahedron Lett., 2993 (1970)

2015 (1970) C 1 5 H 2 1 NO N

O

DBTA. 101

C 1 5 H 2 1 NO

Acetone

P. Newman, Optical Resolution

O

DBTA. 102

EtOH, H2O

N

H. H. Takamtsu and Y. Minaki, Yakugaku Zasshi, 76, 1230 (1956)

Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979 C 1 5 H 2 1 NO

OH

EtOH, H 2 O 53:47 v/v%

N

© 2002 by CRC Press LLC

HO

O

N

C 1 5 H 2 1 NO 2 MeOH, H 2 O 67:33 v/v%

DBTA. 103

K. H. Bell and P. S. Porthogese, J. Med.

K. Miura, Yakugaku Zasshi, 62, 217 (1942)

DBTA. 104

Chem., 16, 589 (1973) C 1 5 H 2 1 NO 2 Methylethylketone

C 1 5 H 2 1 NO 4

CH3O NH

CH3O

COOEt

COOEt N

DBTA. 105

G. Lambrecht and E. Mutschler, Arch.

A. R. Pattersby, R. Binks and T. P.

DBTA. 106

Pharm., 308, 676 (1975) C 1 5 H 2 3 NO

OH

Edwards, J. Chem. Soc., 3474 (1960) C 1 5 H 3 3 NO

OH N

Acetone

abs. EtOH

N

DBTA. 107

M. Tramontini, L. Angiolini, C. Fouquey

J. L. Coke and A. B. Richon, J. Org. Chem.,

DBTA. 108

and J. Jacques, Tetrahedron, 29, 4183

41, 3516 (1976)

(1973) C 1 6 H 1 7 NO 3

HO HO

NH

C16H19N

1.) Benzene, Et 2 O

NH2

Acetone, MeOH 89:11 v/v%

2.) Benzene 3.) EtOH, Et 2 O

HO

4.) EtOH 5.) MeOH

DBTA. 109

D. H. R. Barton, D. S. Bhakuni, G. M.

S. M. Pines, J. M. Chemerda, M. A.

DBTA. 110

Chapman and G. W. Kirby, L. J. Haynes

Kozlowski, L. M. Weinstock, P. Davis, B.

and K. L. Stuart, J. Chem. Soc., C, 1295

Handelsman, V. J. Grenda and G. W.

(1967)

Lindberg, J. Med. Chem., 10, 725 (1967)

C 1 6 H 2 1 NO 2

HN

C 1 6 H 2 3 NO 2

O

Acetone

Acetone N

COOEt DBTA. 111

G. Satzinger, W. Herrman and M. Herrman, German Patent, 2, 132, 562 (1973)

© 2002 by CRC Press LLC

DBTA. 112

British Patent, 1, 062, 137 (1967)

C 1 6 H 2 5 NO 2

OCH3

C 1 6 H 2 5 NO

EtOAc

Acetone OH

OH

N

N

K. Flick and E. Frankus, U. S. Patent, 3,

DBTA. 113

DBTA. 114

M. Tramontini, L. Angiolini, C. Fouquey and J. Jacques, Tetrahedron, 29, 4183

830, 934 (1974)

(1973) C17H19N

C 1 7 H 1 9 NOS CHCl 3 , Acetone

EtOH N H

H N OH S

DBTA. 115

C. G. Overberger, J. G. Lombardino and

DBTA. 116

R. G. Hiskey, J. Am. Chem. Soc., 79,

J. R. Geigy, French Patent, 1, 205, 878 (1960)

6430 (1957) H3CO

C 1 7 H 1 9 NO 3 NH

HO

HO

1.) Benzene, Et 2 O

C 3 1 H 3 1 NO 3

H3CO NH

Benzyl-O

1.) Benzene, Et 2 O

2.) Benzene

2.) Benzene

3.) EtOH, Et 2 O

3.) EtOH, Et 2 O

4.) EtOH

Benzyl-O

4.) EtOH

5.) MeOH DBTA. 117

D. H. R. Barton, D. S. Bhakuni, G. M.

5.) MeOH DBTA. 118

D. H. R. Barton, D. S. Bhakuni, G. M.

Chapman, G. W. Kirby, L. J. Haynes and

Chapman, G. W. Kirby, L. J. Haynes and

K. L. Stuart, J. Chem. Soc., C, 1295

K. L. Stuart, J. Chem. Soc., C, 1295 (1967)

(1967) C 1 7 H 2 1 NO 2 H3CO

C 1 7 H 2 3 NO

N

MeOH

MeOH H HO

H3CO HN

DBTA. 119

J. Knabe and R. Dorr, Arch. Pharm. (Weinheim, Ger.), 306, 784 (1973)

© 2002 by CRC Press LLC

DBTA. 120

M. Gates and W. G. Webb, J. Am. Chem. Soc., 80, 1186 (1958)

C 1 7 H 2 5 NO

C 1 8 H 1 8 Cl 3 N

Acetone

O

1.) Acetone, Et 2 O

N

42:58 v/v% N

2.) Acetone, MeOH

Cl

80:20 v/v%

Cl Cl DBTA. 121

C. F. Huebner, U. S. Patent, 3, 252, 996

DBTA. 122

British Patent, 1, 049, 965 (1966)

(1966)

OCH3

HN

C 1 8 H 2 1 NO 2

C 1 8 H 2 1 NO 2

CH 3 CN

1.) CH 3 CN

O

O

HN

2.) iPrOH

OCH3

DBTA. 123

S. Teitel, J. O'Brien, W. Pool and A.

DBTA. 124

Brossi, J. Med. Chem., 17, 134 (1974) C 1 8 H 2 1 NO 2

HO NCH3

H3CO

S. Teitel, J. O'Brien, W. Pool and A. Brossi, J. Med. Chem., 17, 134 (1974)

H3CO

NH

Acetone, n-hexane

C 1 8 H 2 1 NO 3 EtOH

H3CO

HO

OCH3 DBTA. 125

T. Kametani, S. Takana, F. Sasaki and K.

DBTA. 126

Yamaki, Chem. Pharm. Bull., 16, 20

Wildman and D. T. Bailey, J. Org. Chem.,

(1968)

35, 1100 (1970) C 1 8 H 2 1 NO 3

HN

H3CO HO O

DBTA. 127

O

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

© 2002 by CRC Press LLC

C 1 8 H 2 1 NO 4

HO

Acetone

O

A. Brossi, G. Grethe, S. Teitel, , W. C.

NH

Acetone

H3CO DBTA. 128

D. H. R. Barton, R. B. Boar and D. A. Widdowson, J. Chem. Soc., C, 1213 (1970)

C 3 2 H 3 3 NO 4

Benzyl-O NH

H3CO Benzyl-O

C 1 8 H 2 1 NO 4

H3CO

Acetone

MeOH, Et 2 O

NH

HO HO

H3CO

H3CO DBTA. 129

D. H. R. Barton, R. B. Boar and D. A.

A. R. Battersby, R. Southgate, J. Staunton

DBTA. 130

Widdowson, J. Chem. Soc., C, 1213

and M. Hirst, J. Chem. Soc., C, 1052 (1966)

(1970) C 3 2 H 3 3 NO 4

H3CO

NH

Benzyl-O Benzyl-O

C 1 8 H 2 3 NO

N

MeOH, Et 2 O

MeOH

H

H3CO H3CO

DBTA. 131

A. R. Battersby, R. Southgate, J. Staunton

M. Gates and W. G. Webb, J. Am. Chem.

DBTA. 132

Soc., 80, 1186 (1958)

and M. Hirst, J. Chem. Soc., C, 1052 (1966) OH

C 1 8 H 2 3 NO 2

H N

C 1 8 H 2 3 NO 3

HN

EtOAc

EtOH, H 2 O

O

95:5 v/v% H3CO

DBTA. 133

British Patent, 1, 158, 775 (1969)

DBTA. 134

OCH3

OCH3

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

C 1 8 H 2 3 NO 3

HO

N

H3CO

Et 2 O

C 1 8 H 2 5 NO 2

H3CO H3CO

Acetone, Et 2 O

N H

H3CO

DBTA. 135

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

© 2002 by CRC Press LLC

DBTA. 136

A. Mondon and P-R. Seidel, Chem. Ber., 104, 2937 (1971)

C 1 9 H 1 9 NO 2

H3CO N

H3CO

MeOH

H3CO

C 1 9 H 2 0 ClNO 2 NH

H3CO H

MeOH, Et 2 O

H

Cl

J. Knabe and H. Powilleit, Arc. Pharm.

DBTA. 137

DBTA. 138

(Weinheim, Ger.), 303, 37 (1970) C 1 9 H 2 1 ClN 2 S

S Cl

A. Brossi and F. Burkhardt, Helv. Chim. Acta, 44, 1558 (1961) C 1 9 H 2 3 NO 4

H3CO

EtOH

N

HO H3CO

N

EtOAc

N

HO DBTA. 139

J. O. Jilek, K. Šindelář, J. Pomikáček, O. Horešoský, K. Peltz, E. Svátek, B. Kakáč,

DBTA. 140

A. R. Battersby, T. H. Brown and J. H. Clements, J. Chem. Soc., 4550 (1965)

J. Holubek, J. Metyšová and M. Protiva, Collect . Czech. Chem. Comm., 38, 115 (1973) H3CO N

Benzyl-O H3CO

C 3 3 H 3 5 NO 4

C19H24N2

EtOAc

1.) EtOH N H H

2.) MeOH N

Benzyl-O

H

DBTA. 141

A. R. Battersby, T. H. Brown and J. H.

DBTA. 142

OCH3

G. C. Morrison, W. A. Cetenko and J. Shavel, Jr., J. Org. Chem., 31, 2695 (1966)

Clements, J. Chem. Soc., 4550 (1965) S

H

C 1 9 H 2 4 N 2 OS

N

MeOH

Acetone, iPrOH

N

C 1 9 H 2 5 NO 2

83:17 v/v%

O O

N

DBTA. 143

G. Tokár, G. Krasznai and J. Somló, Hungarian Patent, 155, 314 (1969)

© 2002 by CRC Press LLC

DBTA. 144

M. Sasamoto, Chem. Pharm. Bull., 8, 324 (1960)

N

C 1 9 H 2 5 NO 3

C 1 9 H 2 5 NO 2 MeOH

HO

1.) MeOH

N

H

2.) iPrOH, H 2 O

H3CO OCH3

DBTA. 145

HO

M. Gates and G. Tschudi, J. Am. Chem.

DBTA. 146

Soc., 78, 1380 (1956) N N

K. Wetterlin, J. Med. Chem., 15, 1182 (1972)

C19H26N2O

C 1 9 H 3 1 NO

H N H

1.) Acetone

HO

DBTA. 147

3.) ETOH

OH

1.) EtOH OH

2.) iPrOH

T. Kametani, K. Kigasawa, M. Hiiragi, N.

2.) EtOAc

H

DBTA. 148

Wagatsuma, O. Kusama and T. Uryu,

S. Hagishita and K. Kuryama, Chem. Pharm. Bull., 24, 1724 (1976)

Chem. Pharm. Bull., 24, 2563 (1976) H3CO N

H3CO

C 2 0 H 2 4 ClNO 2

H3CO

Acetone, Et 2 O

H3CO

Cl

DBTA. 149

C 2 0 H 2 4 ClNO 2 N

MeOH, Et 2 O

Cl

A. Brossi, H. Besendorf, B. Pellmont, M.

DBTA. 150

Walters and O. Schnider, Helv. Chim.

A. Rheiner, Jr. and A. Brossi, Helv. Chim. Acta, 45, 2590 (1962)

Acta, 43, 1459 (1960) H3CO

C20H24N2O4 N

H3CO

Acetone

C 2 0 H 2 5 NO 4

H3CO HO H3CO

N

MeOH

H3CO NO2

DBTA. 151

M. Walter, H. Besendorf and O. Schnider, Helv. Chim. Acta, 46, 1127 (1963)

© 2002 by CRC Press LLC

DBTA. 152

B. K. Cassels and V. Deulofeu, Tetrahedron, , Suppl. 8, Part II, 485 (1966)

H3CO

C 2 7 H 2 9 NO 5

H3CO

MeOH

H3CO

N

Benzoyl-O H3CO

MeOH OCH3

H3CO

DBTA. 153

C 2 0 H 2 5 NO 5

NH2 O

OCH3

B. K. Cassels and V. Deulofeu,

DBTA. 154

W. Wiegrebe, HG. M. Stephan, J. Fricke

Tetrahedron, , Suppl. 8, Part II, 485

and U. P. Schlunegger, Helv. Chim. Acta,

(1966)

59, 949 (1976) H

C 2 0 H 2 6 ClNO 2 EtOH, H 2 O

H N

H3CO

C20H26N2O2 NH

Acetone, MeOH 80:20 v/v%

H

90:10 v/v% HO

OCH3 Cl

DBTA. 155

A. Rheiner, Jr. and A. Brossi, Helv. Chim.

DBTA. 156

British Patent, 1, 280, 202 (1972)

Acta, 45, 2595 (1962) OCH3

C20H24N2O2

H3CO

MeOH, Et 2 O

N

H3CO

C 2 1 H 2 5 NO 4 OCH3

Et

MeOH,EtOAc

N

H3COOC H3CO OCH3

DBTA. 157

A. Brossi, M. Baumann, F. Burkhardt, R.

DBTA. 158

Richle and J. R. Frey, Helv. Chim. Acta,

A. C. Barker and A. R. Battersby, J. Chem. Soc., C, 1317 (1967)

45, 2219 (1962) C 2 1 H 2 6 ClNO EtOH, Et 2 O

N H H

N

MeOH

25:75 v/v%

O OH Cl

C22H28N2O3

N

H H3COOC O

DBTA. 159

A. Ebnöther and H-P. Weber, Helv. Chim. Acta, 59, 2462 (1976)

© 2002 by CRC Press LLC

DBTA. 160

C. Szántay and M. Bárczai-Beke, Chem. Ber., 102, 3963 (1969)

C 2 3 H 2 3 NO 2

NH

C23H26N2O2

MeOH

MeOH

N

H O

O-Benzyl O-Benzyl

N O

P. Pratesi, A. LaManna and E. Grana,

DBTA. 161

DBTA. 162

I. van Wijngaarden, Life Sci., 8, 517 (1969)

Farmaco. Ed. Sci., 19, 529 (1964) OH

C 2 4 H 2 7 NO EtOH

C 2 7 H 2 9 NO 4

H3CO

MeOH

N

PhCH2O

N

AcO

R. Riemschneider, K. Brendel and J.

DBTA. 163

DBTA. 164

Takei, Justus Liebigs Ann. Chem., 665,

T. Kametani and H. Yagi, Chem. Pharm. Bull., 15, 1283 (1967)

43 (1963) AcO

C 2 7 H 2 9 NO 4 N

H3CO

H3CO

C 2 7 H 3 1 NO 4

Acetone

EtOAc H3CO H

O

OCH2Ph

T. Kametani, S. Takano, F. Sasaki and K.

DBTA. 165

G. V. Parry and J. Staunton, J. Chem. Soc., C, 210 (1968)

C29H38N2O4 N

EtOH

H

C29H40N2O4

H3CO H3CO

N

N

H3CO

MeOH, EtOAc

H

H

H3CO

DBTA. 167

A. R. Battersby, D. M. Foulkes, M. Hirst,

Yamaki, Chem. Pharm. Bull.,16, 20

H H3CO

DBTA. 166

(1968) H3CO H3CO

N

H3CO

H

H

H NH

H3CO

H. T. Openshaw and N. Whittaker, J. Chem. Soc., 1461 (1963); A. R. Battersby and J. C. Turner, J. Chem. Soc., 717 (1960)

© 2002 by CRC Press LLC

DBTA. 168

M. Barash, J. M. Osbond and J. C. Wickens, J. Chem. Soc., 3530 (1959)

C29H40N2O4

H3CO N

H3CO

EtOH

H H

H3CO

C 3 3 H 3 5 0 NO 4

H3CO N

PhCH2O

50:50 v/v%

H

H

MeOH, Et 2 O

H3CO

NH

OCH2Ph

H3CO

E. E. van Tamelen, P. E. Aldrich and J. B.

DBTA. 169

DBTA. 170

Hester, Jr., J. Am. Chem. Soc., 81, 6214

A. R. Battersby, D. M. Foulkes and R. Binks, J. Chem. Soc., 3323 (1965)

(1959) NH2

C 3 3 H 3 5 0 NO 4

H3CO

EtOAc

N

PhCH2O

C5H12N2O

NH2 O

MeOH

H3CO OCH2Ph

A. R. Battersby, M. Hirst, D. J. McCaldin,

DBTA. 171

DBTA. 172

British Patent, 1, 271, 470

R. Southgate and J. Staunton, J. Chem. Soc., C, 2163 (1968) H H N

C8H16N2

NH2

C10H12F3N

EtOH, H 2 O N H H

MeOH

50:50 v/v% CF3

DBTA. 173

E. Brill and H. P. Schultz, J. Org. Chem.,

DBTA. 174

28, 1135 (1963) HO

N H

Cl

V. W. Jacewicz, British Patent, 1, 413, 033 (1975)

C 1 0 H 1 4 Cl 2 N 2 O

C 1 1 H 1 4 Cl 2 N 2 O HO

EtOH

N H

abs. EtOH

Cl

DBTA. 175

Cl

Cl

NH2

NH2

British Patent, 1, 394, 542 (1975)

© 2002 by CRC Press LLC

DBTA. 176

British Patent, 1, 394, 542

C 1 1 H 1 6 BrClN 2 O HO

Cl

C 1 1 H 1 6 Cl 2 N 2 O HO

N H

EtOH Cl

Br

EtOH

Cl NH2

NH2

DBTA. 177

N H

British Patent, 1, 394, 542 (1975)

DBTA. 178

British Patent, 1, 394, 542 (1975)

C 1 2 H 1 6 Cl 2 N 2 O

HO

EtOH

N H

Cl

C 1 2 H 1 8 Br 2 N 2 O HO

Br

Cl

Br NH2

NH2 DBTA. 179 HO

British Patent, 1, 394, 542 (1975)

DBTA. 180

C 1 2 H 1 8 Cl 2 N 2 O HO

N H

EtOH

Cl

Cl

NH2

DBTA. 181

British Patent, 1, 394, 542 (1975)

C 1 2 H 1 8 Cl 2 N 2 O

N H

Cl

EtOH

N H

EtOH

Cl NH2

British Patent, 1, 394, 542 (1975)

DBTA. 182

British Patent, 1, 394, 542 (1975)

C 1 3 H 1 8 Cl 2 N 2 O HO

EtOH

N H

Cl

C 1 3 H 2 0 Br 2 N 2 O HO

Cl

Cl

Cl NH2

NH2

DBTA. 183

EtOH

N H

British Patent, 1, 394, 542 (1975)

DBTA. 184

British Patent, 1, 394, 542 (1975)

C 1 4 H 2 1 NO

OH O

1.) EtOH, H 2 O 99:1 v/v% O

O

N H

C14H22N2O3 EtOH

NH

2.) Benzene

N

DBTA. 185

J. A. Christensen and R. F. Sguires, U. S. Patent, 3, 912, 745 (1975)

© 2002 by CRC Press LLC

DBTA. 186

T. Leigh and L. H. Smith, British Patent, 1, 270, 723 (1972)

C16H22N2O3

C 2 0 H 2 7 NO 2

N

EtOH

HO

N H

OH

DBTA. 187

N H

Acetone, MeOH HO

O

43:57 v/v%

O

S. Yoshizaki, Y. Manabe, S. Tamada, K.

DBTA. 188

Nakagawa and S. Tei, J. Med. Chem., 20,

Y. Lambert, J-P. Daris, I. Monković and A. W. Pircio, J. Med. Chem., 21, 423 (1978)

1103 (1977) C 2 0 H 2 7 NO 2

N H O

H3CO

C21H28N2O3

H

MeOH

N H

CH 2 Cl 2 , MeOH

N

89:11 v/v%

H3COOC OH DBTA. 189

Y. Lambert, J-P. Daris, I. Monković and

DBTA. 190

A. W. Pircio, J. Med. Chem., 21, 423

C. Szántay, L. Szabó and G. Kalaus, Tetrahedron, 33, 1803 (1977)

(1978) C23H28N2O3 HO

EtOH

N H

C 2 4 H 2 5 NO 4 HN

EtOH, H 2 O O

O

DBTA. 191

N H

O

S. Yoshizaki, Y. Manabe, S. Tamada, K.

95:5 v/v%

O

O O

DBTA. 192

S. F. Dyke, R. G. Kinsman, P. Warren and

Nakagawa and S. Tei, J. Med. Chem., 20,

A. W. C. White, Tetrahedron, 34, 241

1103 (1977)

(1978)

© 2002 by CRC Press LLC

C33H27N6O2

AcNH

C4H8N2O3

CONH2

MeOH

EtOH H2 N

COOH

N

N N

N

NHAc

DBTA. 193

A.Tatibouët, M. Demeunynck, C. Arnaud,

DBTA. 194

A. Andraud, A. Collet and J. Lhomme,

R. Soós, E. Fogassy, J.Gressay, A. Erdélyi, Hungarian Patent, 165115 (1974)

Chem. Comm., 161 (1999) C 1 4 H 1 9 NO EtOH

NH H O

C34H36O2S2P2

S Ph2PO

EtOAc, CHCl 3 86:14 v/v% POPh2

S

DBTA. 195

I. Reiners and J. Martens, Tetrahedron

DBTA. 196

Asymmetry, 8, 277 (1997)

T. Benincori, E. Brenna, F. Sannicoló, L. Trimarco, P. Antognazza, E. Ceasrotti, F.Demartin and T. Pilati, J. Org. Chem., 61, 6244(1996)

H3CO

DBTA. 197

H NH2

H

C 1 6 H 1 7 NO

H3CO

H N

EtOH, iPrOH 40:60 v/v%

F. Claudi, G. M. Cingolani, A. Di

H

DBTA. 198

C 1 6 H 1 7 NO EtOH, iPrOH 40:60 v/v%

F. Claudi, G. M. Cingolani, A. Di Stefano,

Stefano, G. Giorgioni, F. Amenta, P.

G. Giorgioni, F. Amenta, P. Barili, F.

Barili, F. Ferrari and D. Giuliani, J. Med.

Ferrari and D. Giuliani, J. Med. Chem., 39,

Chem., 39, 4238 (1996)

4238 (1996)

© 2002 by CRC Press LLC

C 2 1 H 2 2 NO 2 H

EtOAc

N

O-Benzyl H3CO

EtOAc, MeOH

H3CO

H3CO

C 3 3 H 3 5 NO 5

50:50 v/v%

H3CO

H3CO

HN

Benzyl-O

J. L. Neumeyer, Y. Gao, N. S. Kula and

DBTA. 199

DBTA. 200

E. McDonald, R. Ramage, R. N.

R. J. Baldessarini, J. Med. Chem., 34, 24

Woodhouse, E. W. Underhill, L. R. Wetter

(1991)

and A. R. Battersby, J. Chem. Soc., Perkin Trans.1, 2979 (1998) C13H16N2

N NH

C14H17N Acetone

EtOH

N

A. A. Cordi, J.-M. Lacoste, F. Le Borgne,

DBTA. 201

DBTA. 202

Y. Herve, L. Vaysse-Ludot, J.-J.

Charles K.-F- Chiu, Synth. Comm., 26, 577 (1996)

Descombes, C. Courchay, M. Laubie and T. J. Verbeuren, J. Med. Chem., 40, 2931 (1997) N

COOCH3 Cl

C 1 3 H 1 8 ClNO 2 MeOH

H

A. P. Kozikowski, G. L. Araldi, J. Boja,

DBTA. 203

H H3CO

DBTA. 204

NH2 H

EtOH, iPrOH 62:38 v/v%

F. Claudi, G. M. Cingolani, A. Di Stefano,

W. M. Meil, K. M. Johnson, J. L. Flippen-

G. Giorgioni, F. Amenta, P. Barili, F.

Anderson, C. George, E. Saiah, J. Med.

Ferrari, D. Giuliani, J. Med. Chem., 39,

Chem., 41, 1962 (1998)

4238 (1996)

C 2 2 H 2 6 ClFN 2 N N

Cl

C 1 4 H 1 4 Cl 2 N 2

NH2

C12H18N2

1.) EtOAc 2.) EtOAc, MeOH

N

F

DBTA. 205

K. P. Bogeso, J. Arnt, K. Frederiksen, H. M. Numata, H. Mizuguchi, S. Fujimori, DBTA. 206 O. Hansen, J. Hyttel, H. Pedersen, J. Med. Jpn. Kokai Tokkyo Koho JP 07, 330, 732, Chem., 38, 4380 (1995) (1995)

© 2002 by CRC Press LLC

C34H52N2O2 O

CN

C 1 8 H 2 3 NO 2

HO

iPr2O, iPrOH 94:6 v/v%

O

N

N

HO

O. Ehrmann, H. Nagel, Ger. Offen. DE 4,

DBTA. 207

DBTA. 208

234, 000 (1994)

V. Ghislandi, O. Azzolina, S. Collina, E. Paroli, L. Antonilli, G. Giusepetti and C. Tadini, Chirality, 6, 389 (1994)

NO2

C20H24N4O6 CH3CN

H EtOOC

C40H34O2P2

Ph2OP POPH2

COOEt N H S HN C NH2

Boehringer Biochem, 90-255591/34, C90-

DBTA. 209

DBTA. 210

110627, BOEF 17.02.89

P. J. Pye, K. Rossen, R. A. Reamer, N. N. Tsou, R. P. Volante and P. J. Reider, J. Am. Chem. Soc., 119, 6207 (1997)

H

POPh2

1.) EtOAc, CHCl 3 Ph2OP

DBTA. 211

2.) EtOAC, Toluene

H

H N

C40H34O2P2

U. Matteoli, V. Beghetto, C. Schiavon, A.

N O

DBTA. 212

Scrivanti and G. Menchi, Tetrahedron

C27H25F3N2O COOCH2Ph CF3

W. Hermann, J. Kleinschroth, K. Steiner, Eur. Pat. Appl. EP 385, 423 (1990)

Asymmetry, 8, 1403 (1997) C 1 7 H 2 3 NO 4

N O HO HO

DBTA. 213

Ph + Ph P Ph

C 2 1 H 2 2 OP OH

MeOH, Et 2 O

O

C. S. Zheng and J. X. Xie, Yaoxue Xuebao, 26 96 (1991)

DBTA. 214

K. Okuma, Y. Tanaka, H. Ohta and H. Matsuyama, Bull. Chem. Soc. Jpn., 66, 2623 (1993)

© 2002 by CRC Press LLC

C 1 6 H 1 5 Cl 2 FN 2 S

Cl Cl

N

F

C11H18N2O

OH

CH 2 Cl 2 HN

H2N

N S

DBTA. 215

W. Heitmann, H. Liepmann, U. Mätzel, Boehringer Ingelheim, 91-327060/45, C91DBTA. 216 H. Zeugner, A. M. Fuchs, H. Krähling, M. 141220, BOEH 04.05.90 Ruhland, F. Mol and M. Th. M. Tulp, Eur. J. Med. Chem., 23, 249(1988) C14H20N2O

N H

DBTA. 217

O

C15H22N2O

iPrOH

N

NH

EtOH

O NH

K. Nemák, M. Ács, Zs. M. Jászay, D.

DBTA. 218

K. Nemák, M. Ács, Zs. M. Jászay, D.

Kozma and E. Fogassy, Tetrahedron, 52,

Kozma and E. Fogassy, Tetrahedron, 52,

1637 (1996)

1637 (1996) C16H24N2O

N

O

C14H20N2O

IPrOH

N

K. Nemák, M. Ács, Zs. M. Jászay, D.

DBTA. 220

K. Nemák, M. Ács, Zs. M. Jászay, D.

Kozma and E. Fogassy, Tetrahedron, 52,

Kozma and E. Fogassy, Tetrahedron, 52,

1637 (1996)

1637 (1996) C15H22N2O

N

iPrOH

NH

NH

DBTA. 219

O

O

C15H19F3N2O

iPrOH

N NH

O

iPrOH

NH

F3 C DBTA. 221

K. Nemák, M. Ács, Zs. M. Jászay, D.

DBTA. 222

K. Nemák, M. Ács, Zs. M. Jászay, D.

Kozma and E. Fogassy, Tetrahedron, 52,

Kozma and E. Fogassy, Tetrahedron, 52,

1637 (1996)

1637 (1996)

© 2002 by CRC Press LLC

C16H21F3N2O EtOH

O

N

C16H18F2N2

H N

MeOH N

NH F

F3 C

DBTA. 223

F

K. Nemák, M. Ács, Zs. M. Jászay, D.

DBTA. 224

R. E. Johnson, P. J. Silver, R. Becker, N. C.

Kozma and E. Fogassy, Tetrahedron, 52,

Birsner, E. A. Bohnet, G. M. Briggs, C. A.

1637 (1996)

Busacca, P. Canniff, P. M. Carabateas, C. C. Chadwick, T. D'Ambra, R. L. Dundore, J.-S. Dung, A. M. Ezrin, W. Gorczyca, P. G. Habeeb, P. H. Douglas S. Krafte, G. M. Pilling, B. O'Connor, M. T. Saindane, D. C. Schegel, G. P. Stankus, J. Swestock and W. A. Volberg, J. Med. Chem., 38, 2551 (1995) C 1 7 H 1 9 NO 2

COOEt

EtOH

C 1 3 H 1 7 NO 3

O

H3CO NH

H3CO

DBTA. 225

NH2

D. Mondeshka, I. Angelova, B. Stensland,

DBTA. 226

R. E. Mewshaw, K. L. Marquis, X. Shi, G.

P.-E. Werner and C. Ivanov, Acta Chem.

McGaughey, G. Stavk, M. B. Webb, M.

Scand., 46, 54 (1992)

Abou-Gharbia, T. Wasik, R. Scerni, T. Spangler, J. A. Brennan, H. Mazandarani, J. Coupet and T. H. Andree, Tetrahedron, 54, 7081 (1998)

O,O'-di-p-toluoyltartaric acid C 6 H 1 4 ClNO N H

Cl

OH

iPrOH

C 8 H 1 3 NOS MeOH

S

OH

N H DPTA. 1

L. H. Smith, British Patent, 1, 269, 776 (1972)

© 2002 by CRC Press LLC

DPTA. 2

J. M. Barker, D. J. Byron and P. R. Huddleston, J. Chem. Soc., C, 2813 (1969)

C 8 H 1 7 NO Abs. EtOH

N

C 8 H 1 7 NO 2

H HO H

OH

N

J. Renz, J. P. Bourquin and G. Gamboni,

DPTA. 3

H. Bolinger and C. H. Eugster, Helv. Chim.

DPTA. 4

Acta, 54, 2704 (1971)

British Patent, 873, 316 (1961) OH

C 9 H 1 1 Cl 2 NO MeOH, H 2 O

NH2

Cl

80:20 v/v%

Cl

E. Sandrin and S. Guttmann, French

DPTA. 5

C9H12N2O2

N

EtOH. Et 2 O

N

O

H. Link and K. Bernauer, Helv. Chim.

DPTA. 6

Acta, 55, 1053 (1972)

C 1 0 H 1 5 NO

C11H12N2S

S N

MeOH

N

N

H. G. Leemann and S. Fabbri, Helv.

O

O

Patent, 2, 125, 484 (1972)

DPTA. 7

iPrOH

H

O

French Patent, 2, 041, 445 (1971)

DPTA. 8

Chim. Acta, 42, 2696 (1959) C 1 1 H 1 7 NO 3

HO

N H

EtOH

IPrOH, H 2 O HN

50:50 v/v% HO

OH

O. Thoma and K. Zeile, U. S. Patent, 3,

DPTA. 9

J. J. Fauley and J. B. LaPidus, J. Org.

DPTA. 10

Chem., 36, 3065 (1971)

341, 594 (1967) C 1 2 H 1 7 NO 3

H3CO NH

H3CO

N

OH

A. R. Battersby and T. P. Edwards, J.

DPTA. 11

E. Jucker, A. Ebnöther and J-M. Bastian,

DPTA. 12

Chem. Soc., 1214 (1960)

French Patent, 1, 529, 080 (1968)

C 1 3 H 1 9 NO 3 O

O O

C 1 3 H 1 7 NO EtOH

EtOH

HO

DPTA. 13

C 1 2 H 1 7 NO

OH

OH

Cl

EtOH

MeOH N

NH

R. Howe, T. Leigh, B. S. Rao and A. H. Todd, J. Med. Chem., 19, 1074 (1976)

© 2002 by CRC Press LLC

C 1 3 H 2 0 ClNO

DPTA. 14

L. H. Smith, British Patent, 1, 269, 776 (1972)

C13H20N2O

H N

NH O

EtOH, H 2 O

C 1 3 H 2 1 NO 2 EtOH, H 2 O

NH

95:5 v/v%

C. Tegner and N-E. Willman, Acta Chem.

DPTA. 15

OH O

67:33 v/v%

R. Howe, British Patent, 1, 069, 343 (1967)

DPTA. 16

Scand., 15, 1180 (1961) C 1 4 H 1 2 ClNS

S Cl

MeOH, EtOAc

Et 2 O

O

50:50 v/v%

NH2

D. T. Witiak, J. Med. Chem., 19, 40

DPTA. 17

C 1 4 H 1 5 NO

H. G. Leemann and S. Fabbri, Helv. Chim.

DPTA. 18

Acta, 42, 2696 (1959)

(1976) C14H18N4

C 1 4 H 2 1 NO

EtOH

MeOH

OH

N HN HN DPTA. 19

N

N

G. Bormann and F. Troxler, Swiss Patent

D. S. Fries and P. S. Potogese, J. Med.

DPTA. 20

Chem., 19, 1155 (1976)

529, 702 (1972) Cl

C 1 4 H 2 2 ClNO EtOH

N

L. H. Smith, British Patent, 1, 269, 776

DPTA. 22

(1972)

H. Gerlach, Helv. Chim. Acta, 49, 2481 (1966)

C 1 5 H 1 9 NO OH

C 1 5 H 1 6 DNO EtOAc

N H

OH

DPTA. 21

OH

D

C 1 5 H 1 9 NO N

MeOH, H 2 O

Acetone

61:39 v/v% HN

O DPTA. 23

R. Howe, British Patent, 1, 024, 643 (1966)

© 2002 by CRC Press LLC

DPTA. 24

A. E. Wick, P. A. Bartlett and D. Dolphin, Helv. Chim. Acta, 54, 513 (1971)

C 1 5 H 2 1 NO OH

OH O

MeOH, H 2 O 90:10 v/v%

HN

C 1 5 H 2 3 ClN 2 O 3 EtOH

NH

O Cl

N

K. H. Bell and P. S. Porthogese, J. Med.

DPTA. 25

DPTA. 26

Chem., 16, 589 (1973)

L. H. Smith, J. Med. Chem., 19, 1119 (1976)

C 1 5 H 2 3 NO

OCH3

NH2

iPrOH

C 1 6 H 1 5 NO 3 MeOH

O

N

O O

J. F. Cavalla and A. C. White, British

DPTA. 27

DPTA. 28

S. Kobayashi, M. Kihara, T. Hashimoto and T. Shingu, Chem. Pharm. Bull., 24 716

Patent, 1, 012, 008 (1965)

(1976)

C 1 6 H 1 7 NO 3

O

C 1 6 H 1 8 ClNO 2

HO

EtOH

O

NH2

MeOH, EtOAc

N

O

O Cl H. Irie, S. Uyeo and A. Yoshitake, J.

DPTA. 29

DPTA. 30

Chem. Soc., C, 1802 (1968)

W. S. Saari, French Patent, 2, 013, 693 (1970)

C16H18N4O

O H2NHN

C 1 6 H 1 9 ClN 2

MeOH

EtOH, H 2 O

N

N H

43:57 v/v%

N Cl

N H

DPTA. 31

A. Stoll and A. Hofmann, Helv. Chim.

DPTA. 32

J. H. Hunt, J. Chem. Soc., 2228 (1961)

Acta, 26, 922 (1943) C 1 6 H 1 9 NO 2

O OH HN

MeOH, H 2 O 15:85 v/v%

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C 1 6 H 2 1 NO 2

O OH HN

MeOH

R. Howe, British Patent, 1, 069, 343

DPTA. 33

R. Howe, British Patent, 1, 069, 343 (1967)

DPTA. 34

(1967) C 1 6 H 2 1 NO 2

OH

C16H25N

MeOH, H 2 O HN

Acetone

N

64:36 v/v%

HO

R. Howe, British Patent, 1, 024, 643

DPTA. 35

DPTA. 36

(1966)

Am. Chem. Soc., 79, 5558 (1957) C 1 7 H 1 7 NO 2

N

EtOH, H 2 O

NH

H3CO

1.) EtOH, Et 2 O 2.) EtOH, MeOH

HO

O E. W. Warnhoff and P. Reynolds-

DPTA. 38

Warnhoff, Can. J. Chem., 51, 2338 (1973)

NH

D. S. Bhakuni, S. Statish and M. M. Dhar, Tetrahedron, 28, 1093 (1972)

C 3 1 H 3 1 NO 3

Benzyl-O H3CO

C 1 7 H 1 9 NO 3

HO

95:5 v/v%

O

DPTA. 37

K. Biemann, G. Büchi and B. H. Walker, J.

C 1 7 H 2 1 NO 3

OH

1.) EtOH, Et 2 O 2.) EtOH, MeOH

Benzyl-O

MeOH O

N

H3CO

D. S. Bhakuni, S. Statish and M. M. Dhar,

DPTA. 39

DPTA. 40

Tetrahedron, 28, 1093 (1972) C 1 7 H 2 3 NO 4 Acetone O

T. Kametani, M. S. Premila and K. Fukumoto, Heterocycles, 4, 1111 (1976) C 1 8 H 2 1 NO 3

H3CO N

HO

MeOH, EtOAc 20:80 v/v%

O

O HO

DPTA. 41

H N

Y. Sato, Y. Kobayashi, T. Nagasaki, T. Oshima, S. Kumakura, K. Nakayama, H. Koike and H. Takagi, Chem. Pharm. Bull., 20, 905 (1972)

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HO

DPTA. 42

H. Yamaguchi, Yakugaku Zasshi, 78, 678 (1958)

C 1 8 H 2 1 NO 3

H3CO

MeOH

N

HO

HO

C 1 8 H 2 1 NO 3

H3CO

Acetone

N

H3CO

HO

DPTA. 43

T. Kametani and H. Yagi, Chem. Pharm.

H. Yamaguchi, C. Tanaka and F. Nagatani,

DPTA. 44

Bull., 15, 1283 (1967) NH

O

Yakugaku Zasshi, 82, 552 (1962)

C 1 8 H 2 5 NO 2 1.) Et 2 O

OH

H3CO HO

2.) EtOH

C 1 9 H 1 8 D 3 NO 4 N D D

MeOH

D OCH3 OH

DPTA. 45

R. Howe, British Patent, 1, 069, 343

DPTA. 46

(1967)

C, 191 (1968) C 1 9 H 2 1 NO 4

H3CO

T. Kametani and M. Ihara, J. Chem. Soc.,

NH

Acetone

H3CO

C 1 9 H 2 1 NO 4 MeOH

HO

O N

H3CO OCH3 HO

DPTA. 47

T. Kametani and S. Shibuya, Yakugaku

DPTA. 48

Zasshi, 87, 196 (1967) H3CO

T. Kametani and M. ihara, J. Chem. Soc., C, 2010 (1966)

C 3 3 H 3 3 NO 4

C 1 9 H 2 1 NO 4

HO

MeOH

Benzyl-O

OCH3

N

H3CO

N

EtOH

H3CO Benzyl-O

DPTA. 49

OH

OCH3

T. Kametani and M. ihara, J. Chem. Soc., C, 2010 (1966)

© 2002 by CRC Press LLC

DPTA. 50

Ph.D. thesis of W. Erhardt, University of Minnesota (1974)

C19H22N2O5

H3CO NH

H3CO O2N

Acetone

C 1 9 H 2 3 NO 3

H3CO

EtOH

N

H3CO

HO

H3CO C. Ferrari and V. deulofeu, Tetrahedron,

DPTA. 51

DPTA. 52

18, 419 (1962)

D. G. Farber and A. Giacomazzi, An. Asoc. Quim. Argent., 58, 133 (1970)

C20H19N3

N

C20H21N N

EtOH

1.) Acetone 2.) MeOH, Et 2 O

N N

DPTA. 53

14:86 v/v% R. P. Ryan, W. G. Lobeck, Jr., C. M.

DPTA. 54

Combs and Y-H. Wu, Tetrahedron, 12,

A. Ebnöther, E. Jucker and A. Stoll, Helv. Chim. Acta, 48, 1237 (1965)

2325 (1971) HO

C 2 0 H 2 3 NO 4

H3CO

Acetone N

C 2 0 H 2 5 NO 4

H3CO NH

H3CO H3CO

MeOH

H3CO H3CO

DPTA. 55

OCH3

T. Kametani, M. Takeshita and S. Takano,

DPTA. 56

H. Corrodi and E. Hardegger, Helv. Chim. Acta, 39, 889 (1956)

J. Chem. Soc., Perkin Trans. 1, 2834 (1972) C 2 0 H 2 5 NO 5

H3CO NH

H3CO

C20H26N2

1.) Acetone

Acetone N

2.) MeOH H3CO

OCH3

N

OCH3

DPTA. 57

T. Kametani, H. Sugi and S. Shibuya, Tetrahedron, 27, 2409 (1971)

© 2002 by CRC Press LLC

DPTA. 58

R. Jacob and M. Messer, British Patent, 900, 352 (1962)

H3CO

C 2 0 H 3 1 NO 2 N

EtOH, EtOAc

MeOH, Et 2 O

H3CO

10:90 v/v%

HO C H

H3CO

L. L. Skaletzky, B. E. Graham and J.

67:33 v/v%

N

OCH3 DPTA. 59

C 2 1 H 2 5 NO 4

DPTA. 60

OCH3

British Patent, 866, 394 (1961)

Szmuszkovicz, J. Med. Chem., 12, 977 (1969) C 2 1 H 2 5 NO 5

OCH3 H3CO

EtOH

N

N

H3CO

C 2 1 H 2 6 N 2 OS

S OCH3

Acetone

N

H3CO OH

DPTA. 61

R. W. Doskotch, J. D. Phillipson, A. B. Ray and J. L. Beal, J. Org. Chem., 36, 2409 (1971)

S

DPTA. 62

O

C21H26N2S2

S

Acetone

N

J-P. Bourquin, G. Schwarb, G. Gamboni, R. Fischer, L. Ruesch, S. Guldimann, V. Theus, E. Schenker and J. Renz, Helv. Chim. Acta, 42, 259 (1959)

O

C 2 1 H 2 7 ClN 2 O 3 EtOH

Cl

HN

OH NH

N

DPTA. 63

J. Renz, J-P. Bourquin and G. Gamboni,

DPTA. 64

British Patent, 873, 316 (1961) C 2 1 H 2 7 NO 4

H3CO

1.) EtOAc

N

H3CO

L. H. Smith, British Patent, 1, 269, 775 (1972) C 2 1 H 2 7 NO 5

H3CO N

HO

MeOH

2.) EtOAC, Acetone 70:30 v/v%

H3CO OCH3 DPTA. 65

Ph.D. Thesis of W. Erhardt, University of Minnesota (1974)

H3CO

OCH3 OH

DPTA. 66

A. R. Battersby, R. B. Brandbury, R. B. Herbert, M. H. G. Munro and R. Ramage, J. Chem. Soc., Perkin 1, 1394 (1974)

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CF3

F3C

C 2 2 H 1 9 F 6 NO MeOH

C 2 2 H 2 7 NO 4

H3CO

1.) CH 3 CN

H3CO

2.) Et 2 O, CH 2 Cl 2

N

H H C OH

20:80 v/v% 3.) Et2O

NH

OCH3

H3CO

F. I. Caroll and J. T. Blackwell, J. Med.

DPTA. 67

DPTA. 68

Chem., 17, 210 (1974)

H. Bruderer, J. Metzger, A. Brossi, J. J. Daly, Helv. Chim. Acta, 59, 2793 (1976)

C 2 2 H 2 7 NO 4

H3CO

C22H28N2O2

CH 3 CN

H3CO H

H3CO

O

N

N H

DPTA. 70

P. Newman, Optical Resolution Procedures

J. Daly, Helv. Chim. Acta, 59, 2793

for Chemical Compounds, Volume 1.

(1976)

Opt.Res. Inf. Center, NY 1979 C 2 2 H 3 1 NO 2

OH O

EtOAc

C 2 3 H 2 7 NO 2 MeOH

HO N

NH

O

R. Howe, British Patent, 1, 069, 343

DPTA. 71

OH

OCH3

H. Bruderer, J. Metzger, A. Brossi and J.

DPTA. 69

Acetone

N

DPTA. 72

(1967)

L. H. Smith, British Patent, 1, 136, 918 (1968)

C 2 4 H 2 4 IN EtOH I

N

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C 2 4 H 2 5 NO 3

H3CO PhCH2O

HO

NH

Acetone

D. C. Remy, K. E. Rittle, C. A. Hunt, P.

DPTA. 73

DPTA. 74

T. Kametani, K. Sakurai, S. Kano and H. Iida, Yakugaku Zasshi, 87, 822 (1967)

S. Anderson, B. H. Arison, E. L. Engelhardt, R. Hirschman, B. V. Clineschmidt, V. J. Lotti, P. R. Buntig, R. J. Ballentine, N. L. Papp, L. Flataker, J. J. Witoslawski and C. A. Stone, J. Med. Chem., 20, 1013 (1977) C25H32N2O6 1.) Acetone

N H

2.) MeOH, Acetone

C 2 6 H 2 8 BrNO 3

H3CO N

HO

MeOH, Et 2 O

N

H

H

CH3OOC H H3CO H

Br OCH2Ph

OAc

R. B. Woodward, F. E. Bader, H. Bickel,

DPTA. 75

DPTA. 76

A. R. Battersby, R. B. Herbert, L. Mo and F. Šantavý, J. Chem. Soc., C, 1739 (1967)

A. J. Frey and R. W. Kierstead, Tetrahedron, 2, 1 (1958) C 2 7 H 3 1 NO 4

PhCH2O

C27H32N2O4

H3CO

Acetone

H3CO

N

H3CO

MeOH

N

H3CO H3CO

OCH3

T. Kametani, M. Takeshita and S. Takano,

DPTA. 77

DPTA. 78

J. Chem. Soc., C, 2834 (1972) H3CO

Br

NH2 OCH2Ph

C 2 9 H 3 4 BrNO 5 N

H3CO

Acetone

T. Kametani, M. Ihara, K. Fukumoto and H. Yagi, J. Chem. Soc., C, 2030 (1969) C 3 2 H 3 2 BrNO 3

H3CO N

PhCH2O

Acetone

H3CO H3CO

OCH2Ph

PhCH2O Br

DPTA. 79

T. Kametani, Y. Satoh and K. Fukumoto, J. Chem. Soc., Perkin1, 2160 (1972)

© 2002 by CRC Press LLC

DPTA. 80

T. Kametani, Seiichi Takano and K. Masuko, Yakugaku Zasshi, 86, 976 (1966)

H3CO

C 3 3 H 3 3 NO 4 MeOH

PhCH2O

C 3 4 H 3 7 NO 5

H3CO NH

PhCH2O

CH 3 CN

N

H3CO PhCH2O

DPTA. 81

OCH3 OCH2Ph

OCH3

T. Kametani, M. Takemura, M. Ihara, K.

A. Brossi, J. O'Brien and S. Teitel, Helv.

DPTA. 82

Chim. Acta, 52, 678 (1969)

Takahashi and K. Fukumoto, J. Am. Chem. Soc., 98, 1956 (1976) H3CO H3CO

C34H52N2O4 NH H

C 9 H 1 1 Cl 2 NO

NH2

EtOH

MeOH, H 2 O 80:20 v/v%

OH H3CO

H NH

Cl Cl

H3CO

DPTA. 83

A. A. Genenah, T. O. Soine and N. A.

E. Sandrin and S. Guttman, British Patent,

DPTA. 84

Shaath, J. Pharm. Sci., 64, 62 (1975) C 1 2 H 1 7 NO 2

H3CO HO

DPTA. 85

N

C 1 8 H 2 9 NO 2

OH O

EtOH

N

J. M. Bobbitt, I. Noguchi, H. Yagi and K.

E. Ferrero, L. Manzoni, L. Dall'Asta and A.

DPTA. 86

H. Weisgraber, J. Org. Chem., 41, 845

Pedrazzoli, Arzneim-Forsch., 23, 1596

(1976)

(1973) C 1 9 H 2 3 NO 2

H3CO PhCH2O

1, 377, 787 (1974)

N

C 2 1 H 2 0 IN

EtOH

EtOH I

N

DPTA. 87

J. M. Bobbitt, I. Noguchi, H. Yagi and K. H. Weisgraber, J. Org. Chem., 41, 845 (1976)

© 2002 by CRC Press LLC

DPTA. 88

D. C. Remy, K. E. Rittle, C. A. Hunt, P. S. Anderson, B. H. Arison, E. L. Engelhardt, R. Hirschman, B. V. Clineschmidt, V. J. Lotti, P. R. Buntig, R. J. Ballentine, N. L. Papp, L. Flataker, J. J. Witoslawski and C. A. Stone, J. Med. Chem., 20, 1013 (1977)

C 2 1 H 2 0 IN

C 2 5 H 2 4 F 3 NS

EtOH

Benzene SCF3

OCH3 N

N

D. C. Remy, K. E. Rittle, C. A. Hunt, P.

DPTA. 89

DPTA. 90

D. C. Remy, K. E. Rittle, C. A. Hunt, P. S.

S. Anderson, E. L. Engelhardt, B. V.

Anderson, B. H. Arison, E. L. Engelhardt,

Clineschmidt and A. Scriabine, J. Med.

R. Hirschman, B. V. Clineschmidt, V. J.

Chem., 20, 1681 (1977)

Lotti, P. R. Buntig, R. J. Ballentine, N. L. Papp, L. Flataker, J. J. Witoslawski and C. A. Stone, J. Med. Chem., 20, 1013 (1977)

OH

H N

C 2 8 H 4 1 NO 2

C23H18N2

EtOH

Acetone

O

N N H

DPTA. 91

H

M. T. Cox, S. E. Jaggers and G. Jones, J.

DPTA. 92

Med. Chem., 21, 182 (1978)

E. Tálas, J.Margitfalvi, D. Machytka and M. Czugler, Tetrahedron Asymmetry, 9, 4151 (1998)

C17H17N EtOAc

H N

HN

C16H25N2 1.) EtOH 2.) EtOH, EtOAc

H DPTA. 93

N

J. G. Cannon, R. Raghupati, S. T. Moe, A.

5:95 v/v% DPTA. 94

P. Stjernlöf, M. Gullme, T.Elebring, B.

K. Johnson and J. P. Long, J. Med.

Andersson, H. Wikström, S. Lagerquist, K.

Chem., 36, 1316 (1993)

Svensson, A.Ekman, A. Carlsson and Staffan Sundell, J. Med. Chem., 36, 2059 (1993)

© 2002 by CRC Press LLC

C16H24N2

H N

HN

EtOH

H P. Stjernlöf, M.D. Ennis, L.O. Hansson,

DPTA. 95

EtOH

H

O

F

C 6 H 1 5 NOS

N

S

E. Teodori, F. Gualtieri, P. Angeli, L.

DPTA. 96

R. L. Hoffman, N. B. Ghazal, S. Sundell,

Brasili, M. Giannella and M. Pigini, J. Med.

M. W. Smith, K. Svensson, A.Carlsson

Chem., 29, 1610 (1986)

and H. Wikström, J. Med. Chem., 38, 2202- (1995) OH

C 2 5 H 2 7 FN 2

Ph

MeOH

C 2 7 H 2 8 ClN OH

Cl

MeOH

N N

N Ph

F

T. Gizur, I. Péteri, K. Harsányi and E.

DPTA. 97

T. Gizur, I. Péteri, K. Harsányi and E.

DPTA. 98

Fogassy, Tetrahedron Asymmetry, 7 1589

Fogassy, Tetrahedron Asymmetry, 7 1589

(1996)

(1996) C22H23N

C 1 9 H 2 9 NO 3

O

MeOH

EtOH EtOOC

N N S. T. Philips, T. de Paulis, B. M. Baron, B. W. Siegel, P. Seeman, H. H. M. Van Tol, H.-C. Guan and H. E. Smith, J. Med. Chem., 37, 2686 (1994)

DPTA. 99

DPTA. 100

J. A. Werner, L. R. Cerbone, S. A. Frank, J. A. Ward, P. Labib, R. W: Tharp-Taylor and C. W. Ryan, J. Org. Chem., 61, 587 (1996) O

C20H33N2O

OH N

abs. EtOH

C24H33N3O2 CH3CN

N

N H H3CO

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H N

N

DPTA. 101

G. E. Boswell, R. W. McNutt, D. G.

DPTA. 102

I. A. Cliffe, C. I. Brightwell, A. Fletcher, E.

Bubacz, A. O. Davis and K.-J. Chang, J.

A. Forster, H. L. Mansell, Y. Reilly, C.

Heterocyclic Chem., 32, 1801 (1995)

Routledge and A. C. White, J. Med. Chem., 36, 1509 (1993) O

C 7 H 1 5 NO

COOH

H2O

N

C 1 9 H 2 2 FN 3 O 3 MeOH

N

OH

DPTA. 103

F N

HN

M. Acs, E. Fogassy and T. Szili, Hung.

DPTA. 104

HU 61, 278 (1992)

F. Tafusa, H. Yamashita, H. Miyamoto and M. Tominaga, Jpn. Kokai Tokkyo Koho JP 04, 295, 474 (1992)

C18H19N

H DPTA. 105

C17H17N

N

H

J. G. Cannon, R. Raghupathi and S. T.

DPTA. 106

Moe, J. Med. Chem., 36, 1316 (1993)

N

J. G. Cannon, R. Raghupathi and S. T. Moe, J. Med. Chem., 36, 1316 (1993)

C14H18N2

HN

C12H16N2

N

N

EtOH

N DPTA. 107

P. Stjernlöf, M. Gullme, T. Elebring, B.

DPTA. 108

W. Glassco, J. Suchocki, C. George, B. R.

Andersson, H. Wikström, S. Lagerquist,

Martin and E. L. May, J. Med. Chem., 36,

K. Svensson, A. Ekman, A. Carlsson and

3381 (1993)

S. Sundell, J. Med. Chem., 36, 2059(1993) C 1 2 H 1 7 NO 3 H2N

COOCH3

OH

MeOH

H N

C 1 7 H 1 8 NO

OH

DPTA. 109

Y. Gao and C. M. Zepp, U.S. Patent 5, 399, 765 (1995)

DPTA. 110

L. Björk, B. B. Höök, D. L. Nelson, N.-E. Andén and U. Hacksell, J. Med. Chem., 32, 779 (1989)

© 2002 by CRC Press LLC

C11H18N2O

OH

C18H20N2

H H N

EtOH, H 2 O

HN

H2N

37:63 v/v%

H

H2N Boehringer Ingelheim, 91-327060/45,

DPTA. 111

DPTA. 112

C91-141220, BOEH 04.05.90

R. Kunstmann, H. Gerhards, H. Kruse, M. Leven, E. F. Paulus, U. Schacht, K. Schmitt and P. U. Witte, J. Med. Chem., 30, 798 (1987)

C19H21N

C14H16N2

EtOAc

H3CO H

EtOH

NH2

N

NH2 J. G. Cannon, P. T. Flaherty, U. Ozkutlu

DPTA. 113

DPTA. 114

J. W. Clader, J. G. Berger, R. E. Burrier, H.

and J. P. Long, J. Med. Chem., 38, 1841

R. Davis, M. Domalski, S. Dugar, T. P.

(1995)

Kogan, B. Salisbury and W. Vaccaro, J. Med. Chem., 38, 1600 (1995)

Mandelic acid NH2

C 5 H 1 3 NO

C7H15N

EtOAc, abs EtOH

OH

N H

75:25 v/v% A. Kjaer and H. Thomsen, Acta Chem.

Mac. 1

Mac. 2

Scand., 16, 591 (1962)

L. Maat and H. C. Beyerman, Recl. Trav. Chim. Pays-Bas, 92, 156 (1973)

C8H17N MeOH

N

Mac. 3

C 9 H 1 1 NO

J. Cymerman Craig and A. R. Pinder, J. Org. Chem., 36, 3648 (1971)

N H Mac. 4

Benzene, MeOH 92:8 v/v%

E. J. Corey, R. J. McCaully and H. S. Sachdev, J. Am. Chem. Soc., 92, 2476 (1970)

© 2002 by CRC Press LLC

OH

O

C 9 H 1 1 NO H 2O

NH2

C 9 H 1 1 NO 2

O

EtOAc, EtOH

O NH2

H. Takamatsuo, Yakugaku Zasshi, 76,

Mac. 5

75:25 v/v%

J. B. Stenlake, D. D. Breimer, G. A. Smail,

Mac. 6

1219 (1956)

A. Stafford and W. C. Bowman, J. Pharm. Pharmacol., 20, Suppl. 82S (1968)

NH2

Mac. 9

NH2

EtOAc

H. Takamtsu, Yakugaku Zasshi, 76, 1219

H2O

294 (1931)

C 1 0 H 1 3 NO

H N

C9H13N3

F. Bobeck, Justus Liebigs Ann. Chem., 487,

Mac. 8

Chim. Pays-Bas, 80, 573 (1961)

O

NH2

N H

iPrOH J. Van Dijk and H. D. Moed, Recl. Trav.

Mac. 7

NH

C 9 H 1 3 NO

O

C10H15N EtOH

J. Van. Dijk, V. G. Kreizer and H. D.

Mac. 10

(1956)

Moed, Recl. Trav. Chim. Pays-Bas, 82, 189 (1963) OH

C10H15N EtOH, Et 2 O

H N

C 1 0 H 1 5 NO EtOH, H 2 O

HN

13:87 v/v% Mac. 11

Ph.D. Thesis of M. S. Raaasch, The Ohio

95:5 v/v% R. H. F. Manske and T. B. Johnson, J. Am.

Mac. 12

State University (1941)

OH

C 1 0 H 1 5 NO 4 S NH2

Br

N

EtOH HN

O

Mac. 13

M. C. Rebstock and L. L. Bambas, J. Am.

Mac. 14

Chem. Soc., 77, 186 (1955)

Cl

C 1 1 H 1 3 ClN 2 O

OH N HN

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C 1 1 H 1 3 BrN 2 O

OH

OH

S O

Chem. Soc., 51, 1906 (1929)

67:33 v/v%

D. G. Neilson, I. A. Khan and R. S. Whitehead, J. Chem. Soc., C, 1853 (1968)

OCH3

C11H15N Et 2 O

EtOH, EtOAc 67:33 v/v%

EtOH, EtOAc

NH2

D. G. Neilson, I. A. Khan and R. S.

Mac. 15

J. D. McDermed, G. M. McKenzie and H.

Mac. 16

S. Freeman, J. Med. Chem., 19, 547 (1976)

Whitehead, J. Chem. Soc., C, 1853 (1968)

C 1 1 H 1 7 NO OH

N H

EtOAc

A. Stoll, J. Peyer and A. Hofmann, Helv.

Mac. 17

S. Ose and Y. Yoshimura, Yakugaku

Mac. 18

Zasshi, 78, 687 (1958)

C12H16N2O N

HN

EtOAc

N

Chim. Acta, 26, 929 (1943) OH

C 1 1 H 1 7 NO

OH

C12H16N2O2

OH

O

N

EtOH, light petroleum

EtOAc, Acetone

HN

50:50 v/v% D. G. Neilson, I. A. Khan and R. S.

Mac. 19

D. G. Neilson, I. A. Khan and R. S.

Mac. 20

Whitehead, J. Chem. Soc., C, 1853 (1968)

OH

H N

Whitehead, J. Chem. Soc., C, 1853 (1968)

C 1 2 H 1 7 NO

C 1 2 H 1 9 NO

EtOH, H 2 O

NH

O

95:5 v/v% J. J. Fauley and J. B. LaPidus, J. Org.

Mac. 21

iPrOH, Et 2 O 20:80 v/v%

T. Kralt, H. H. Haeck and H. A.

Mac. 22

Chem., 36, 3065 (1971)

Peperkamp, Recl. Trav. Chim. Pays-Bas, 85, 607 (1966)

OH

C 1 3 H 1 9 NO OCH3

C 1 3 H 2 1 NO 3 EtOH, H 2 O

MeOH HN

HO

NH2

90:10 v/v% OH

Ph.D. Thesis of A. E. Weber, University

Mac. 23

Mac. 24

M. J. Mardle, H. Smith, B. A. Spicer and R. H. Poyser, J. Med. Chem., 17, 513 (1974)

of Washington (1974)

C 1 4 H 1 3 NO

NH2

C 1 4 H 1 9 NO N

EtOH

Acetone, MeOH

O

90:10 v/v% HO

Mac. 25

A. McKenzie and N. Walker, J. Chem. Soc., 646 (1928)

© 2002 by CRC Press LLC

Mac. 26

H J. H. Ager, A. E. Jacobson and E. L. May, J. Med. Chem., 12, 288 (1969)

C 1 4 H 2 1 NO

C15H15N

MeOH

EtOH, H 2 O

OCH3 NH2

OCH3

96:4 v/v% NH2

Ph.D. Thesis of A. E. Weber, University

Mac. 27

Mac. 28

of Washington (1974)

512 (1976)

C15H17N3O2S O

EtOH

O S

N H

R. Haller and U. Busser, Arch. Pharm., 309,

O

C15H19N3O3 MeOH

N O

NH NH2

O

N N

Mac. 29

D. F. Ewing and D. G. Neilson, J. Chem.

Mac. 30

N

H-J. Kessler, C. Rufer and K. Schwarz, Eur. J. Med. Chem.-Chim. Ther., 11, 19 (1976)

Soc., C, 390 (1966)

C 1 5 H 2 1 NO

C 1 5 H 2 1 NO N

EtOH, Acetone

Acetone

72:28 v/v%

HO

HO Mac. 31

J. H. Ager, A. E. Jacobson and E. L. May,

Mac. 32

J. Med. Chem., 12, 288 (1969)

C 1 5 H 2 1 NO N

Acetone, MeOH 10:90 v/v%

E. L. May and M. Takeda, J. Med. Chem., 13, 805 (1970)

H3CO

C 1 5 H 2 3 NO 3 1.) MeOH

H3CO

H3CO

H2N

HO

2.) Benzene, iPrOH 90:10 v/v%

Mac. 33

M. E. Rogers and E. L. May, J. Med. Chem., 17, 1328 (1974)

© 2002 by CRC Press LLC

Mac. 34

Ph.D. Thesis of A. E. Weber, University of Washington (1974)

C17H19N

N

iPrOH

abs. EtOH, Acetone

HO

50:50 v/v%

NH2

R. Carnmalm, T. DePaulis, N. E.

Mac. 35

C 1 7 H 2 5 NO

E. L. May and N. B. Eddy, J. Med. Chem.,

Mac. 36

9, 851 (1966)

Stjernström and S. B. Ross, Acta Pharm. Suecica, 13, 485 (1976)

OAc

H N

C 1 7 H 2 7 NO 4

C 1 8 H 2 1 NO

EtOH

H N

Et 2 O OCH3

O

OH L. Bláha and J. Weichet, Czech. Patent,

Mac. 37

P. Newman, Optical Resolution Procedures

Mac. 38

152, 096 (1974)

for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

N

C 1 9 H 2 1 NO MeOH, iPrOH

C 1 9 H 2 3 NO 3

H3CO N

H3CO

EtOH

HO

HO M. Dexter, U. S. Patent, 3, 417, 094

Mac. 39

M. P. Cava and A. Afzali, J. Org. Chem.,

Mac. 40

40, 1553 (1975)

(1968)

H3CO

OH

C 1 9 H 2 3 NO 4 N

HO

O

CH 3 CN

C19H24N2O4 1.) MeOH

HN

2.) EtOH

O

H3CO OH

H2N O

Mac. 41

P. Sohar and E. F. Schoenwaldt, U. S. Patent, 3, 894, 027 (1975)

Mac. 42

J. Augstein, D. A. Cox, A. L. Ham, P. R. Leeming and M. Snarey, J. Med. Chem., 16, 1245 (1973)

© 2002 by CRC Press LLC

OH

F

C 2 0 H 2 1 F 2 NO

C 2 0 H 2 3 NO

Acetone

N

1.) iPrOH OH

2.) EtOH

N F

E. J. Warawa, N. J. Mueller and R. Jules,

Mac. 43

N. Yokoyama, F. B. Block and F. H.

Mac. 44

J. Med. Chem., 17, 497 (1974)

C 2 0 H 2 3 NO N

H Ph

Clarke, J. Med. Chem., 13, 488 (1970)

H N

HO

C 2 7 H 3 3 NO 3

abs. EtOH

EtOH, H 2 O 90:10 v/v% OCH2Ph OCH2Ph

M. Dexter, U. S. Patent, 3, 417, 094

Mac. 45

M. J. Mardle, H. Smith, B. A. Spicer and R.

Mac. 46

H. Poyser, J. Med. Chem., 17, 513 (1974)

(1968) OH

C 1 0 H 1 5 NO 2 NH2

C 1 1 H 1 5 NO

OCH3

abs. EtOH

Et 2 O

NH2

O H. Bruderer, French Patent, 1, 569, 369

Mac. 47

Mac. 48

S. Freeman, J. Med. Chem., 19, 547 (1976)

(1969)

O

J. D. McDermed, G. M. McKenzie and H.

C 1 5 H 1 7 NO

O

abs. EtOH

OH

C 1 7 H 2 5 NO 2

NH

iPrOH

N W. A. Gregory, British Patent, 1, 245, 502

Mac. 49

Mac. 50

British Patent, 1, 215, 751 (1970)

(1971)

O

OH

C 1 7 H 2 7 NO 2

NH

EtOAc

C18H26N2O

OCH3

Et 2 O N H

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British Patent, 1, 215, 751 (1970)

Mac. 51

J. D. McDermed, G. M. McKenzie and H.

Mac. 52

S. Freeman, J. Med. Chem., 19, 547 (1976)

C18H26N2S S

N

O

Et 2 O

OH

C 1 8 H 2 9 NO 2

NH

iPrOH

N

I. Jirkovsky, L. G. Humber, K. Voith and

Mac. 53

G. Härtfelder, H. Lessenich and K. Schmitt,

Mac. 54

M-P. Charest, Arzneim-Forsch., 27, 1642

British Patent, 1, 215, 751 (1970)

(1977)

C 1 3 H 1 5 NOS CH 3 CN

NH2

NH

S O

T. Nishi, K. Nakajima, Y. Iio, K.

Mac. 55

C 9 H 1 1 NO

O

EtOH, H 2 O 95:5 v/v%

M. Brisander, P. Caldirola, A. M.

Mac. 56

Ishibashi and T. Fukazawa, Tetrahedron

Johansson and U. Hacksell, J. Org. Chem.,

Asymmetry, 9, 2567 (1998)

63, 5362 (1998)

O

C 1 6 H 1 7 NO NH

C19H23N

EtOH, H 2 O

1.) Et 2 O, EtOH N H

95:5 v/v%

75:25 v/v% 2.) EtOAc

Mac. 57

M. Brisander, P. Caldirola, A. M.

Durif, M.-T. Averbuch and J.-L. Pierre,

Chem., 63, 5362 (1998)

Tetrahedron Lett., 39, 2565 (1998)

NH2

C11H17N iPrOH

C13H18N2O2 O O

Mac. 59

J. Einhorn, C. Einhorn, F. Ratajczak, A.

Mac. 58

Johansson and U. Hacksell, J. Org.

K. Saigo, M. Kai, N. Yonezawa and M. Hasegawa, Synthesis, 214 (1984)

Mac. 60

MeOH H

N NH H

D. Giardina, M. Crucianelli, R. Romanelli, A. Leonardi, E. Pogessi and C. Melchiorre, J. Med. Chem., 39, 4602 (1996)

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H2N

NH2

C9H13N MeOH

C9H13N

HO

EtOH

OCH3

Mac. 61

K. Sakai, Y. Hashimoto, K. Kinbara, K.

Mac. 62

A. Sudo and K. Saigo, Tetrahedron Asymmetry, 7, 2939 (1996)

Saigo, H.Murakami and H. Nohira, Bull. Chem. Soc. Jpn., 66, 3414 (1993)

C 6 H 1 5 NO OH

C20H23N Et 2 O, EtOH

IPrOH

NH2

Mac. 63

N H

K. Drauz, W. Jahn and M. Schwarm, J.

Mac. 64

Chem. Eur., 9, 838 (1995)

75:25 v/v%

J. Einhorn, C. Einhorn, F. Ratajczak, A. Durif, M.-T. Averbuch and J.-L. Pierre, Tetrahedron Lett., 39, 2565 (1998) NH2

C 1 4 H 1 5 NO

C8H11N H 2O

EtOH HO

Mac. 65

NH2

K. Saigo, I. Sugiura, I. Shida, and K.

Mac. 66

Tachibana, Bull. Chem. Soc. Jpn., 59,

S. Larsen and H. Lopez de Diego, J. Chem. Soc. Perkin Trans. 2, 469 (1993)

2915 (1986)

C 2 1 H 3 0 NO 4 Et2O

COOEt HN

tBuCOCH2 N

NH2

CH3CN

N O

N

O

Mac. 67

C20H22N4O2

O

G. Liu, Jr. K. J. Henry, B. G. Szczepankiewicz, M. Winn, N. S. Kozmina, S. A. Boyd, J. Wasicak, T. W. von Geldern, J. R. Wu-Wong, W. J. Chiou, D. B. Dixon, B. Nguyen, K. C. Marsh and T. J. Opgenorth, J. Med. Chem., 41, 3261 (1998)

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Mac. 68

G. Semple, H. Ryder, M. Ohta and M. Staoh, Synth. Comm., 26 (4), 721 (1996)

COOCH3 NH2

C13H14N2O2

C19H23N H2N

1.) EtOH

EtOH

2.) MeOH N

O J. Matsubara, K. Otsubo, S. Morita, T.

Mac. 69

Mac. 70

A. Port, A. Virgili and C. Jaime, Tetrahedron Asymmetry, 7, 1295 (1996)

Ohtani, Y. Kawano and M. Uchida, Heterocycles, 43, 133(1996)

H OH N

NH2

C 1 5 H 1 5 NO 3

C 9 H 1 3 NO

MeOH

MeOH

O

O

OCH3

I. Lantos, J. Flisak, L. Liu, R. Matsuoka,

Mac. 71

Mac. 72

K. Sakai, Y. Hashimoto, K. Kinbara, K.

W. Mendelson, D. Stevenson, K.

Saigo, H. Murakami and H. Nohira, Bull.

Tubman, L. Tucker, W.-Y. Zhang, J.

Chem. Soc. Jpn., 66 , 3414(1993)

Adams, M. Sorenson, R. Garigipati, K. Erhardt and S. Ross, J. Org. Chem., 62, 5385 (1997) NH2

C13H14N2

C11H17N iPrOH

N NH2

R. C. Griffith, R. J. Murray and M.

Mac. 73

Mac. 74

Balestra, PCT Int. Appl. WO 93 20, 052

K. Saigo, M. Kai, N. Yonezawa and M. Hasegawa, Synthesis, 214, (1984)

(1993) H N

C5H12N2

C 9 H 1 2 ClN

Acetone

Cl

N H

Mac. 75

A. Takebayashi, N. Murakami and H. Nohira, Jpn. Kokai Tokkyo Koho JP 04, 360, 877, (1992)

© 2002 by CRC Press LLC

Mac. 76

NH2

MeOH

M. Mori and M. Kawashima, Jpn. Kokai Tokkyo Koho JP 04 18, 058 (1992)

C 1 1 H 1 5 NO

C13H22N2O2 O

NH2

O H

A. Sudo and K. Saigo, Tetrahedron

Mac. 77

NH H

N

OH

Mac. 78

Asymmetry, 7, 2939 (1996)

D. Giardiná, M. Crucianelli, R. Romanelli, A. Leonardi, E. Poggesi and C. Melchiorre, J. Med. Chem., 39, 4602 (1996)

O

N

C8H16N2O

C 1 1 H 1 5 NO

Acetone

EtOH

N H

H2N

R. Fitzi, D. Seebach, ETH 1998

Mac. 79

Mac. 80

OH

A. Sudo and K. Saigo, Tetrahedron Asymmetry, 6, 2153 (1995)

HO

C 1 5 H 2 1 NO

HO

C 1 6 H 2 3 NO

MeOH, Acetone

MeOH, Acetone

N

N

S. Shiotani, T. Kometani, T. Nozawa, A.

Mac. 81

S. Shiotani, T. Kometani, T. Nozawa, A. Kurobe and O. Futsukaichi, J. Med. Chem.,

Chem., 22, 1558(1979)

22, 1558(1979)

COOH

O

Mac. 82

Kurobe and O. Futsukaichi, J. Med.

C 1 8 H 2 0 FN 3 O 4

H

H 2O

C19H21N N

N

F

H

N

O

iPrOH, EtOAc, Et 2 O 25:25:50 v/v%

N

Mac. 83

Hoechst AG, DE-3639465, 88-141358

Mac. 84

R. Kunstmann, H. Gerhards, H. Kruse, M. Leven, E. F. Paulus, U. Schacht, K. Schmitt and P. U. Witte, J. Med. Chem., 30, 798 (1987)

© 2002 by CRC Press LLC

C21H25N H

N

C10H20N2

N

iPrOH NH2

H

R. Kunstmann, H. Gerhards, H. Kruse, M.

Mac. 85

B. R. de Costa and L. Radesca,

Mac. 86

Heterocycles, 31, 10, 1837 (1990)

Leven, E. F. Paulus, U. Schacht, K. Schmitt and P. U. Witte, J. Med. Chem., 30, 798 (1987)

Tartaric acid O

H2N O

NH

C 3 H 8 ClN NH2

H2O

C.H. Stammer, A. N. Wilson, C. F.

Tarta. 1

Cl

C3H6N2O2

H2O

E. Aberhalden and E. Eichwald, Chem.

Tarta. 2

Ber., 51, 1312 (1918)

Spencer, F. W. Bachelor, F. W. Holly and K. Folkers, J. Am. Chem. Soc., 79, 3236 (1957) OH

OH

C 3 H 9 NO NH2

+

NH2 benzyl

EtOH, Et 2 O

EtOH, Et 2 O

O

6:94 v/v%

C 1 0 H 1 5 NO

O

6:94 v/v%

O2N

R. L. Clark, W. H. Jones, W. J. Raich and

Tarta. 3

R. L. Clark, W. H. Jones, W. J. Raich and

Tarta. 4

K. Folkers, J. Am. Chem. Soc., 76, 3995

K. Folkers, J. Am. Chem. Soc., 76, 3995

(1954)

(1954)

OH

C 3 H 9 NO

OH

NH2

NH2

C 3 H 9 NO OH

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H 2O

H 2O

R. H. Sullivan, U. S. Patent 3, 116, 332

R. L. Clark and W. H. Jones, U. S. Tarta. 6 Patent 2, 646, 445 (1953)

Tarta. 5

C 3 H 9 NO NH2

(1963)

HN

benzyl

OH

C 1 0 H 1 5 NO H 2O

A. Stoll, J. Peyer and A. Hofmann, Helv.

Tarta. 7

A. Stoll, J. Peyer and A. Hofmann, Helv.

Tarta. 8

Chim. Acta, 26, 929 (1943) NH2

NH2

C3H10N2 NH2

C3H10N2 NH2

H 2O

F. P. Dwyer, F. L. Garvan and A.

Tarta. 9

Chim. Acta, 26, 929 (1943)

M. Gulotti, A. Pasini, P Fantucci, R. Ugo

Tarta. 10

Shulman, J. Am. Chem. Soc. , 81, 290,

and R. D. Gillard, Gazz. Chim. Ital., 102,

(1959)

855 (1976)

NH2

C4H7N

C4H11N

NH2

H2O A. Lindquist, B. Ringdahl, U. Svensson

Tarta. 11

H 2O

H2O K. R. Kopecky, P. M. Pope and J. A. Lopez

Tarta. 12

and R. Dahlbom, Acta Chem. Scand.,

Sastre, Can. J. Chem., 54, 2639 (1976)

B30, 517 (1976)

C4H11N

NH2

OH NH2

H2O W. Leithe, Chem. Ber., 63, 800 (1930); H.

Tarta. 13

C 4 H 1 1 NO H2O

D. Pitré and E. B. Grabitz, Chimia, 23, 399

Tarta. 14

E. Smith, S. L. Cook and M. E. Warren,

(1969); A. Kjaer and B. W. Christensen,

Jr., J. Org. Chem, 29, 2265 (1964); B.

Acta Chem. Scand., 16, 71 (1962)

Halpern and J. W. Westley, Chem. Comm., 34 (1967) NH2

C 4 H 1 1 NO

OH

NH2

C4H12N2 NH2

EtOH, MeOH,H 2 O 90:5:5 v/v%

F. H. Dickey, W. Ficett and H. J. Lucas, J.

Tarta. 15

80:20 v/v% Tarta. 16

Am. Chem. Soc., 74, 944 (1952) NH2

E. Balieu, P. M. Boll and E. Larsen, Acta Chem. Scand., 23, 2191 (1969) NH2

C4H12N2 abs. EtOH

NH2

Tarta. 17

F. H. Dickey, W. Ficett and H. J. Lucas, J. Am. Chem. Soc., 74, 944 (1952)

H 2 O, EtOH

NH2

Tarta. 18

C4H12N2 EtOH, H 2 O 33:67 v/v%

M. Gullotti, A. Pasini, P. Fantucci, R. Ugo and R. D. Gillard, Gazz. Chim. Ital., 102, 855 (1972); E. Strack and H. Schwaneberg, Chem. Ber., 67, 1006 (1934)

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C5H9N NH2

C5H9N

EtOH, H 2 O

EtOH, H 2 O

NH2

90:10 v/v% B. Rigdahl and R. Dahlbom, Acta Chem.

Tarta. 19

96:4 v/v% W. Kirmse, A. Engelmann and J. Heese,

Tarta. 20

Scand., B30, 812 (1976)

NH2

Chem. Ber., 106, 3073 (1973)

C5H11N

C5H11N N H

H2O

M. Vogel and J. D. Roberts, J. Am. Chem. Tarta. 22 Soc., 88, 2262 (1966)

Tarta. 21

HO

H

C 5 H 1 1 NO

H

N

abs. EtOH, EtOAc

abs. EtOH P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

OH

C 5 H 1 1 NO abs. EtOH

NH2

40:60 v/v% P. D. Armstrong and J. G. Cannon, J.

Tarta. 23

M. Godchot and M. Mousseron, Bull. Soc.

Tarta. 24

Med. Chem., 13, 1037 (1970)

C 5 H 1 1 NO O NH2

O

S

MeOH

NH2

S. Tatsuoka and M. Honjo, Yakugaku

Tarta. 26

(1971) NH2

C 5 H 1 2 N 2 OS NH2

MeOH

E. J. Cragoe, Jr., U. S. Patent, 3, 577, 409

Tarta. 25

Chim. Fr., 51, 1270 (1939)

Zasshi, 73, 357 (1953)

C5H13N

C5H13N

MeOH

MeOH, Acetone NH2

Ph.D. Thesis of D. W. Reger, Rutgers

Tarta. 27

R. H. Holm, A. Chakravorty and G. O.

Tarta. 28

Dudek, J. Am. Chem. Soc., 86, 379 (1964)

University, new Jersey, (1970) OH

N

OH

C 5 H 1 3 NO

C 5 H 1 3 NO

N

EtOH, H 2 O 95:5 v/v%

Tarta. 29

Ph.D. Thesis of J. Clitherow, University of London (1961)

© 2002 by CRC Press LLC

Tarta. 30

M. M-L. Chan and J. B. Robinson, J. Med. Chem., 17, 1057 (1974); R. T. Major and H. T. Bonett, J. Am. Chem. Soc., 57, 2125 (1935); K. B. Schowen, E. E. Smossman and W. F. Stephen, Jr., J. Med. Chem., 18, 292 (1975)

NH2

C 5 H 1 3 NO OH

H2O

NH2

F. Barrow and G. W. Ferguson, J. Chem.

Tarta. 31

OH

Soc., 410 (1935) NH2

C 6 H 9 NO NH2

MeOH

A. P. Terentev, R. A. Gracheva and L. F.

Tarta. 33

C6H11N abs. EtOH

B. Ringdahl and R. Dahlbom, Acta Chem.

Tarta. 34

Titova, Zh. Obsch. Khim., 34, 513 (1964)

Scand., B30, 993 (1976) Cl

C6H11N EtOH, iPrOH

NH2

H 2 O, EtOH

F. Barrow and G. W. Ferguson, J. Chem.

Tarta. 32

Soc., 410 (1935)

O

C 5 H 1 3 NO

NH2

C 6 H 1 2 ClN abs. EtOH

50:50 v/v% B. Ringdahl and R. Dahlbom, Acta Chem.

Tarta. 35

M. Mousseron and P. Froger, Bull. Soc.

Tarta. 36

Scand., B30, 812 (1976)

Chim. Fr., 843 (1947)

C6H13N N H

H2O

abs. EtOH N H Ph.D. Thesis of H. Bulbrook, Iowa State

Tarta. 37

C6H13N

G. E. McCasland and S. Proskow, J. Am.

Tarta. 38

College (1935)

Chem. Soc., 78, 5646 (1956)

C6H13N

C6H13N

N H

W. Leithe, Monatsh. Chem., 50, 41

Tarta. 39

H 2O

N H

Tarta. 40

(1928); R. G. Kostyanovsky, I. M. Gella,

G. Bettoni, R. Perrone and V. Tortorella, Gazz. Chim. Ital., 102, 196 (1972)

V. I. Markov and Z. E. Samoljova, Tetrahedron, 30, 39 (1974)

N H

Tarta. 41

C6H13N

NH2

C 6 H 1 3 NO

EtOH, H2O

OH

EtOH

95:5 v/v% T. Masamune, M. Takasugi and A. Murai, Tetrahedron, 27, 3369 (1971)

© 2002 by CRC Press LLC

Tarta. 42

M. Godchot and M. Mousseron, Bull. Soc. Chim. Bull. Soc. Chim. Fr., 51, 1277 (1932)

C 6 H 1 3 NO MeOH

O

NH2

C6H14N2

NH2

H 2O

NH2 Tarta. 43

R. P. Zelinski, N. G. Peterson and H. R.

Tarta. 44

R.G. Asperger and C. F. Liu, Inorg. Chem.,

Wallner, J. Am. Chem. Soc., 74, 1504

4, 1492 (1965); M. Gullotti, A. Pasini, P.

(1952)

Fantucci, R. Ugo and R. D. Gillard, Gazz. Chim. Ital., 102, 855 (1972); F. M. Jaeger and L. Bijkerk, Z. Anorg. Allg. Chem., 233, 97, (1937) NH2

C6H15N NH2

Tarta. 45

MeOH

Ph.D. Thesis of D. W. Reger, Rutgers

MeOH Tarta. 46

University, New Jersey (1970) NH2

B. Halpern and J. W. Westley, J. Chem. Soc., Chem. Comm., 34 (1966) NH2

C6H15N MeOH

Tarta. 47

R. A. Johnson, H. C. Murray and L. M.

C6H15N

C6H15N MeOH

Tarta. 48

Reineke, J. Am. Chem. Soc., 93, 4872

R. H. Mazur, J. Org. Chem., 35, 2050 (1970); R. H. Holm, A. Chakravoty and G. O. Dudek, J. Am. Chem. Soc., 86, 379

(1971)

(1964) NH2

NH2

C6H15N MeOH

Tarta. 49

R. A. Johnson, H. C. Murray and L. M.

C6H15N MeOH

Tarta. 50

Reineke, J. Am. Chem. Soc., 93, 4872

R. H. Mazur, J. Org. Chem., 35, 2050 (1970); R. H. Holm, A. Chakravoty and G. O. Dudek, J. Am. Chem. Soc., 86, 379

(1971)

(1964)

C6H15N NH2

Tarta. 51

EtOH, H2O

OH

95:5 v/v%

H. E. Smith and H. E. Ensley, Can. J. Chem., 49, 2902 (1971)

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N

C 6 H 1 5 NO EtOH, H2O 96:4 v/v%

Tarta. 52

G. H. Cocolas, E. C. Robinson and T. C. Spaulding, J. Pharm. Sci, 60, 1749 (1971)

OH

C 6 H 1 5 NO

NH2 O

C 7 H 9 NO

abs. EtOH

MeOH N

W. R. Brode and I. J. Wernert, J. Am.

Tarta. 53

H. McKennis, Jr., L. B. Turnbull and E. R.

Tarta. 54

Chem. Soc., 55, 1685 (1933)

OH

Bowman, J. Biol. Chem., 239, 1215 (1964) OH

C 7 H 9 NO

C 7 H 9 NO

MeOH N

N H. McKennis, Jr., L. B. Turnbull and E.

Tarta. 55

O. Červinka, O. Bělovský and P.

Tarta. 56

R. Bowman, J. Biol. Chem., 239, 1215

Pejmanová, Collect. Czech. Chem. Comm.,

(1964); H. McKennis, Jr., L. B. Turnbull,

38, 1358 (1973)

E. R. Bowman and C. N. Lukhard, J. Biol. Chem., 241, 1878 (1966) NH2

NH2

C7H10N2

C7H10N2

EtOH, H 2 O

EtOH, H 2 O

N

N

95:5 v/v% H. E. Smith, L. J. Schaad, R. B. Banks, C.

Tarta. 57

Tarta. 58

95:5 v/v% H. E. Smith, L. J. Schaad, R. B. Banks, C.

J. Wiant and C. F. Jordan, J. Am. Chem.

J. Wiant and C. F. Jordan, J. Am. Chem.

Soc., 95, 811 (1973); K. Michelsen, Acta

Soc., 95, 811 (1973)

Chem. Scand., A28, 428 (1974) NH2

NH2

C7H10N2 MeOH

N

C7H10N2 H 2 O, MeOH

N

78:22 v/v% H. E. Smith, L. J. Schaad, R. B. Banks, C.

Tarta. 59

Tarta. 60

J. Wiant and C. F. Jordan, J. Am. Chem.

Ph.D. Thesis of M. Broadhurst, University of California at Los Angeles (1973)

Soc., 95, 811 (1973) OH N

NH2

C 7 H 1 3 NO

C7H14N2O2 OH

abs. EtOH

NHAc Tarta. 61

R. Adams, S. Miyano and D. Fleš, J. Am. Chem. Soc., 82, 1466 (1960)

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Tarta. 62

abs. EtOH, H 2 O, Acetone

R. Vince and S. Daluge, J. Med. Chem., 17, 578 (1974)

NH2

C7H15N

C7H15N H 2O N H

M. Mousseron and P. Froger, Bull. Soc.

Tarta. 63

O. Engels, Chem. Ber., 33, 1087 (1900)

Tarta. 64

Chim. Fr., 843, (1947)

C7H15N

C7H15N

N H

H. Ripperger, K. Schreiber and F. J. Sych,

Tarta. 65

H 2O

N H

A. Gunther, Chem. Ber., 31, 2134 (1898)

Tarta. 66

J. Prakt. Chem., 312, 471 (1970)

C 7 H 1 5 NO

OH

EtOH

N H

Tarta. 68

Soc., C, 248 (1969) OH

Tarta. 69

M. Mousseron and R. Granger, Bull. Soc. Chim. Fr., 850 (1947)

C 7 H 1 5 NO NH2

HO NH2

abs. EtOH

M. Mousseron and R. Granger, Bull. Soc.

Tarta. 70

M. Mousseron and R. Granger, Bull. Soc. Chim. Fr., 850 (1947) NH2

C7H15N abs. EtOH

Tarta. 71

C7H17N MeOH

NH2

M. Mousseron and R. Granger, Bull. Soc.

Tarta. 72

Chim. Fr., 850 (1947)

Ph.D. Thesis of D. W. Reger, Rutgers University, New Jersey (1970)

C7H17N NH2

Tarta. 73

C 7 H 1 5 NO abs. EtOH

Chim. Fr., 850 (1947)

HO

abs. EtOH

N H

OH

J. B. Kay and J. B. Robinson, J. Chem.

Tarta. 67

C 7 H 1 5 NO

MeOH

P. Newman, Optical Resolution Tarta. 74 Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

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C7H17N NH2

D. C. Iffland and N. T. Buu, J. Org. Chem., 32, 1230 (1967)

NH2

C8H8N2

H2 N

EtOAc, light Petroleum

C8H18N2O3S

S

H2O

N O

O O

Tarta. 75

D. G. Neilson and D. F. Ewing, J. Chem.

Tarta. 76

Soc., C, 393 (1966) NH2

R. Heymes and G. Amiard, French Patent 1, 492, 854 (1968) NH2

C 8 H 1 0 BrN MeOH

Br

Tarta. 77

C 8 H 1 0 ClN MeOH

Cl

G. Gottarelli and B. Samori, J. Chem.

Tarta. 78

Soc., (B), 2418 (1971) NH2

G. Gottarelli and B. Samori, J. Chem. Soc., (B), 2418 (1971) NH2

C8H10N2O2 H2O

C8H11N MeOH

O 2N

Tarta. 79

A. P. Terentyev and V. M. Potapov, Zh.

Tarta. 80

A. Ault, J. Chem. Ed., 42, 269 (1965)

Obshch. Khim.., 27, 1092 (1957) OH

OH

C 8 H 1 1 NO

C 8 H 1 1 NO

EtOH NH2

Tarta. 81

NH2

J. Read and I. G. M. Campbell, J. Chem.

Tarta. 82

Soc., 2682 (1930)

H2O

A. L. Green, R. Fielden, D. C. Bartlett, M. J. Cozens, R. J. Eden and D. W. Hills, J. Med. Chem., 10, 1006 (1967)

NH2 OH

OH

C 8 H 1 1 NO H2O

NH2

HO

C 8 H 1 1 NO 3 H2O

OH

Tarta. 83

H. Reilen, L. Knöpfle and W. Sapper,

Tarta. 84

B. F. Tullar, British Patent, 656, 500 (1951)

Justus Leibigs Ann. Chem., 534, 247 (1938) NH2 NH2

C8H12N2 H2O

C8H12N2 MeOH, Et2O

N NH2

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H. Reihlen, E. Weinbrenner and G. V.

Tarta. 85

N. B. Chapman and J. F. A. Williams, J.

Tarta. 86

Hessling, Justus Liebigs Ann. Chem.,

Chem. Soc., 2797 (1953)

494, 143 (1932); M. Gullotti, A. Pasini, P. Fantucci, R. Ugo and R. D. Gillard, Gazz. Chim. Ital., 102, 855 (1972)

NHAc N

C10H14N2O

C15H19N2O2S

MeOH, Et2O

Acetone

N. B. Chapman and J. F. A. Williams, J.

Tarta. 87

N. B. Chapman and J. F. A. Williams, J.

Tarta. 88

Chem. Soc., 2797 (1953)

Chem. Soc., 2797 (1953)

C8H13N EtOH, EtOAc

N

OH S

A. M. Likhosherstov, A. M. Kritsyn and

EtOH N H

33:67 v/v% Tarta. 89

C 8 H 1 3 NOS

J. M. Barker, D. J. Byron and P. R.

Tarta. 90

N. K. Kochetkov, Zh. Obshch. Khim., 32,

Huddleston, J. Chem. Soc., C, 2813 (1969)

2377 (1962) HO

C 8 H 1 3 NOS NH

EtOH

N HO

C 8 H 1 3 NO 2 O

H 2O

S J. M. Barker and P. R. Huddleston, J.

Tarta. 91

J. Gadamer and F. Hammer, Arch. Pharm.

Tarta. 92

Chem. Soc. Perkin Trans. 1, 1200 (1973)

(Weinheim, Ger.), 259, 110 (1921)

C8H15N

C8H15N

H2O

N

K. Löffler and G. Friedrich, Chem. Ber.,

Tarta. 93

42, 107 (1909)

Tarta. 94

K. Löffler and G. Friedrich, Chem. Ber., 42, 107 (1909)

H

C8H15N

N

EtOAc, EtOH 67:33 v/v%

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H2O

N

C8H15N N

H2O

N. J. Leoonard, and D. L. Felley, J. Am.

Tarta. 95

K. Löffler and E. Grosse, Chem. Ber., 40,

Tarta. 96

Chem. Soc., 72, 2537 (1950)

OH

N

1333 (1907)

C 8 H 1 5 NO

C 8 H 1 5 NO

abs. MeOH

MeOH

N H

E. R. Atkinson and D. D. McRitchie, J.

Tarta. 97

OH

B. Langström, Chem. Scr., 5, 170 (1974)

Tarta. 98

Org. Chem., 36, 3240 (1971)

C 8 H 1 5 NO 2

N

H2O

HO H HO

Tarta. 100

2341 (1953)

N NH2

EtOH

T. O. Soine, W. S. Hanley, N. A. Saath and A. A. Genanh, J. Pharm. Sci., 64, 67 (1975)

C8H16N2

C8H17N

MeOH

H2O NH2

G. Bulteau, French Patent 1, 528, 014

Tarta. 101

Tarta. 102

(1968)

J. V. Braun and E. Anton, Chem. Ber., 60, 2438 (1927)

C8H17N H 2O

N H

Tarta. 103

C8H16N2

H

G. Fodor an O. Kovács, J. Chem. Soc.,

Tarta. 99

CN

N

J. Cymerman Craig and A. R. Pinder, J.

C8H17N H 2O

N H

Tarta. 104

J. D. Granger, Chem. Ber., 30, 1060 (1897)

Org. Chem., 36, 3648 (1971)

N H

Tarta. 105

C8H17N

C8H17N

H 2O

H 2O N H

W. Sobecki, Chem. Ber., 41, 4103 (1908)

Tarta. 106

L. Levy and R. Woffenstein, Chem. Ber., 28, 2270 (1895)

C8H17N N

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H 2O

C8H17N N

H 2O

K. Löffler and F. Thiel, Chem. Ber., 42,

Tarta. 107

Tarta. 108

132 (1909)

Chem Comm., 19, 930 (1954)

C8H17N

H N

A. Šilhánková, D. Doskočilová, J. Beran

Tarta. 110

Comm., 32, 3221 (1967)

Chem., 732, 181 (1970)

C 2 2 H 2 7 NO 2

OH

EtOH

C 8 H 1 7 NO

H N

abs. EtOH

benzoyl

C. Schöpf, E. Gams, F. Coppernock, R.

Tarta. 112

Rausch and R. Walbe, Justus Liebigs Ann. Chem., H N

M. Mousseron and R. Granger, Bull. Soc. Chim. Fr., 850 (1947)

732, 181 (1970)

C 8 H 1 7 NO

C 8 H 1 7 NO

EtOH, Acetone

EtOH, Acetone

80:20 v/v% Tarta. 113

C. Schöpf, E. Gams, F. Coppernock, R. Rausch and R. Walbe, Justus Liebigs Ann.

O

OH

M. Mousseron and R. Granger, Bull. Soc.

HO

Tarta. 114

Chim. Fr., 850 (1947)

90:10 v/v%

N H

M. Mousseron and R. Granger, Bull. Soc. Chim. Fr., 850 (1947)

C 8 H 1 7 NO

C8H19N NH2

EtOH HO

EtOH

OH

and M. Ferles, Collect, Czech. Chem

benzyl N

Tarta. 111

C 8 H 1 7 NO

H 2O

N

Tarta. 109

R. Lukěs and J. Jizba, Collect, Czech.

1.) MeOH 2.) EtOH

NH2

3.) H 2 O Tarta. 115

M. Mousseron and R. Granger, Bull. Soc.

Tarta. 116

Chim. Fr., 850 (1947) NH2 O

C9H11N

EtOH, H 2 O

EtOH

W. R. Brode and I. J. Wernert, J. Am. Chem. Soc., 65, 1685 (1933)

© 2002 by CRC Press LLC

Soc., 456 (1944)

C 8 H 1 9 NO

60:40 v/v% Tarta. 117

F. G. Mann and J. W. G. Porter, J. Chem.

NH2

Tarta. 118

C. Kaiser, B. M. Lester, C. L. Zirkle, A. Burger, C. S. Davis, T. J. Delia and L. Zirngibl, J. Med. Chem., 5, 1243 (1962)

Cl

C 9 H 1 1 NO

C 9 H 1 2 ClN

H2O

NH2

H2O NH2

OH

Tarta. 119

E. Dornhege, Jusus Liebigs Ann. Chem.,

Tarta. 120

743, 42 (1971)

I. B. Johns and J. M. Burch, J. Am. Chem. Soc., 60, 919 (1938) D

C 9 H 1 2 ClNO NH2

Cl

EtOH

C 9 H 1 2 DN iPrOH, H 2 O

NH2

91:9 v/v% Tarta. 121

P. Newman, Optical Resolution

Tarta. 122

Procedures for Chemical Compounds,

R. L. Foreman, F. P. Siegel and R. G. Mrtek, J. Pharm. Sci., 58, 189 (1969)

Volume 1. Opt.Res. Inf. Center, NY 1979 NH2

OH

C 9 H 1 2 FNO

F

C9H12N2O NHNH2

EtOH

EtOH

OCH3

Tarta. 123

C. Rufer, H. Biere, H. Ahrens, O. Loge

Tarta. 124

and E. Schröder, J. Med. Chem., 17, 708

D. H. Peacock, J. Chem. Soc., 103, 669 (1913)

(1974) OH OH O2 N

Tarta. 125

OH

C9H12N2O4

OH

H2O

NH2

O2 N

H. Ikeda and H. Ikeda, J. Sci. Res. Inst.

Tarta. 126

(Tokyo), 45, 8 (1951)

NH2

Tarta. 127

EtOH, H 2 O 97:3 v/v%

J. Kucera, Collect. Czech. Chem. Comm., 20, 968 (1955)

C9H13N NH2

C9H12N2O4

C9H13N NH2

EtOH

W. Leithe, Chem. Ber., 65, 660 (1932)

Tarta. 128

EtOH

O. Yu. Magdison and G. A. Garkusha, Zh. Obshch. Khim., 11, 339 (1941)

C9H13N NH2

C9H13N

iPrOH, H 2 O

MeOH NH2

91:9 v/v% Tarta. 129

D. Blackburn an G. Burghard, J. Pharm. Sci., 54, 1586 (1965)

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Tarta. 130

H. Biere, C. Rufer, H. Ahrens, O. Loge and E. Schröder, J. Med. Chem., 17, 716 (1974)

C9H13N NH2 CH3O

Tarta. 131

EtOH, H 2 O

NH2

C 9 H 1 3 NO H2O

HO

95:5 v/v% R. D. Guthrie and J. L. Hedrick, J. Am.

Tarta. 132

J. Van Dijk, V. G. Kreizer, J. F. Peelen and

Chem. Soc., 95, 2971 (1973); H. O.

H. D. Moed, Recl. Trav. Chim. Pays-Bas,

Bernhard, I. Kompiš, S. Johne, D. Gröger,

84, 521 (1965)

M. Hesse and H. Smitd, Helv. Chim. Acta, 56, 1266 (1973) OH

Tarta. 133

OH

C 9 H 1 3 NO NH2

C 9 H 1 3 NO NH2

EtOH

W. N. Nagai and S. Kanao, Justus Liebigs

Tarta. 134

MeOH

M. J. Kalm, J. Org. Chem., 25, 1929 (1960)

Ann. Chem., 470, 157 (1929) OH

OH

C 9 H 1 3 NO NH2

C 9 H 1 3 NO

H2O

abs. EtOH HN

Tarta. 135

W. N. Nagai and S. Kanao, Justus Liebigs

Tarta. 136

Ann. Chem., 470, 157 (1929)

G. P. Men'shikov and G. M. Borodina, Zh. Obshch. Khim., 17, 1569 (1947), (Chem. Ab. 42, 2245 (1948)) OH

C 9 H 1 3 NO HN

Tarta. 137

C 9 H 1 3 NO 2

HO

OH

MeOH

EtOH NH2

B. Lindeke. E. Anderson and U. Paulsen,

Tarta. 138

British Patent, 396, 951 (1932)

Acta Chem. Scand., B30, 789 (1976) OH

CH3O

Tarta. 139

NH2

EtOH, H 2 O

HN

HO

75:25 v/v%

S. M. albonico, A. M. Kuck and V. Deulofeu, J. Chem. Soc., C, 1372 (1967)

© 2002 by CRC Press LLC

OH

C 9 H 1 3 NO 2

C 9 H 1 3 NO 3 MeOH

OH

Tarta. 140

F. Flächer, Hoppe-Seyler's Physiol. Chem., 58, 189 (1909)

NH2

C9H14N2 NH2

MeOH

W. Froentjes and K. M. Dijkema, Recl.

Tarta. 141

H N

C9H14N2 NH2

H2O

J-P. Fourneau, Bull. Soc. Chim. Fr., 11, 141

Tarta. 142

Trav. Chim. Pays-Bas, 62, 723 (1943)

(1944)

C9H14N2

H N

NH2

C9H14N2 NHNHCH3

H2O

EtOH, H 2 O 95:5 v/v%

J-P. Fourneau, Bull. Soc. Chim. Fr., 11,

Tarta. 143

141 (1944); J. Bernstein and K. A. Losee,

S. Selzer, J. Am. Chem. Soc., 94, 829

U. S. Patent, 3, 060, 192 (1962)

(1971)

H

C9H17N MeOH, Et 2 O

N H H

C 9 H 1 7 NO MeOH

N

50:50 v/v%

A. Popovici, C. F. Geschickter, E. L. May

Tarta. 145

A. Tsolis, S. G. Mylonakis, M. T. Nieh and

Tarta. 144

O

F. Galinovsky, G. Bianchetti and O. Vogl,

Tarta. 146

and E. Mosetting, J. Org. Chem., 21, 1283

Monatsh. Chem., 84, 1221 (1953)

(1955)

C9H19N

C 9 H 1 9 NO

H N

H2O

N

Tarta. 147

OH

R. Lukes and M. Smetacková, Collect .

H2O

Tarta. 148

Czech. Chem. Comm., 6, 231 (1934)

OH

Chim. Fr., 850 (1947) OH

C 9 H 1 9 NO

NHCH3

M. Mousseron and R. Granger, Bull. Soc.

CCl3

Acetone

C 1 0 H 1 2 Cl 3 NO EtOH

N

Tarta. 149

M. Mousseron and R. Granger, Bull. Soc. Chim. Fr., 850 (1947)

Tarta. 150

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

© 2002 by CRC Press LLC

OH NH2 O2 N

COOCH3

C10H12N2O5

C10H13N

MeOH

EtOH

H H H2N

Tarta. 151

A. Hajos and J. Kollonitsch, Acta. Chim.

Tarta. 152

Acad. Sci., Hung., 17, 449 (1958)

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

C10H13N

C10H13N

H2O

H2O

NH2

Tarta. 153

NH2

G. Tattersall and F. S. Kipping, J. Chem.

Tarta. 154

J. W. Harris, J. Chem. Soc., 115, 61 (1919)

Soc., 83, 918 (1903); G. Tattersall, J. Chem. Soc., 85, 169 (1904) NH2

NH2

C10H13N H2O

C10H13N Acetone, H 2 O 50:50 v/v%

Tarta. 155

V. Ghislandi and D. Vercesi, Farmaco,

Tarta. 156

Ed. Sci., 26, 474 (1971)

A. G. Davies, E. E. Edwin and J. Kenyon, J. Chem. Soc., 250 (1956)

C10H13N

C10H13N N H

Tarta. 157

NH

EtOH

F. Morlacchi, V. Losacco and V.

Tarta. 158

H2O

W. Leithe, Monatsh Chem., 53, 956 (1929)

Tortorella, Gazz. Chim. Ital., 105, 349 (1975)

C 1 0 H 1 4 ClN Cl

NH2

MeOH, H 2 O 67:33 v/v%

Tarta. 159

C10H14N2

French Patent, 1, 528, 540 (1968)

N

N Tarta. 160

A. Pictetand A. Rotschy, Chem. Ber., 37, 1225 (1904)

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H2O

NH2

C10H14N2 NH2

C10H14N2

H2O

NH2 NH2 Tarta. 161

E. Eidenbenz, Chem. Ber., 74, 1798

Tarta. 162

E. Bamberger, Chem. Ber., 23, 291 (1890)

(1941)

H N

C10H14N2

C10H15N

H2O

NH2

N H Tarta. 163

C. S. Gibson, J. Chem. Soc., 342 (1927)

Tarta. 164

EtOH

O. Červinka, E. Kroupová and O. Bělovský, Collect . Czech. Chem. Comm., 33, 3551 (1968)

NH2

C10H15N

C10H15N

EtOH

EtOH NH2

Tarta. 165

A. P. Terent'ev, G. V. Panova, G. N.

Tarta. 166

Koval' and O. V. Toptyigna, Zh. Obshch.

D. J. Cram and E. McCarty, J. Am. Chem. Soc., 76, 5740 (1954)

Khim., 40, 1409 (1970) NH2

C10H15N

C10H15N NH2

H2O

Tarta. 167

O. Červinka, V. Dudek and L. Hub,

P. Newman, Optical Resolution Procedures

Collect . Czech. Chem. Comm., 35, 724

for Chemical Compounds, Volume 1.

(1970)

Opt.Res. Inf. Center, NY 1979

C10H15N

C10H15N

H2O

H 2 O, EtOH

H2N Tarta. 169

Tarta. 168

MeOH

H2N P. W. B. Harrison, J. Kenyon and J. R. Sepherd, J. Chem. Soc., 658 (1926)

© 2002 by CRC Press LLC

Tarta. 170

95:5 v/v% Ph.D. Thesis of H. Meislich, Columbia University, New York (1950)

OH

OH

C 1 0 H 1 5 NO

C 1 0 H 1 5 NO H2O

MeOH HN

HN

W. N. Nagai and S. Kanao, Justus Liebigs

Tarta. 171

E. Späth and R. Göhring, Monatsh Chem.,

Tarta. 172

Ann. Chem., 470, 157 (1929) OH

41, 319 (1920)

C 1 0 H 1 5 NO

C 1 0 H 1 5 NO

O

MeOH

EtOH

NH2

NH2

Ph.D. Thesis of M. S. Raasch, The Ohio

Tarta. 173

W. R. Brode and I. J. Wernert, J. Am.

Tarta. 174

State University (1941)

OH

Chem. Soc., 65, 1685 (1933) OH

C 1 0 H 1 5 NO 2

C 1 0 H 1 5 NO 2

EtOH

EtOH, H 2 O

N

HN

95:5 v/v% OH

OH British Patent, 396, 951 (1933)

Tarta. 175

H. Bretschneider, Monatsh Chem., 80, 517

Tarta. 176

(1949)

OH

C 1 0 H 1 5 NO 2

O

Acetone NH2

C 1 0 H 1 5 NO 2 S NH2

MeOH

OH

S

O R. Howe, E. H. P. Young and A. D.

Tarta. 177

R. A. Cutler, R. J. Stenger and C. M. Suter,

Tarta. 178

Ainley, J. Med. Chem., 12, 998 (1969) H3COOC

O N

J. Am. Chem. Soc., 74, 5475 (1952) OH

C 1 0 H 1 5 NO 3

N

H2O HO

S. P. Findlay, J. Org. Chem., 22, 1385

A. La Manna, A. Campiglio, Faramaco, Ed.

Tarta. 180

(1957) NH2

Sci., 14, 317 (1959)

C10H19N

H

MeOH, EtOH

C10H19N N

H

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iPrOH, H 2 O 80:20 v/v%

OH

Tarta. 179

C 1 0 H 1 5 NO 3

EtOH, MeOH

J. Read and R. A. Storey, J. Chem. Soc.,

Tarta. 181

B. Witkop, J. Am. Chem. Soc., 71, 2559

Tarta. 182

2770 (1930) OH

(1949) COOCH3

C 1 0 H 1 9 NO

H

C 1 0 H 1 9 NO 2 MeOH, Acetone

EtOH

N

N H

K. Winterfeld amd C. Heinen, Justus

Tarta. 183

P. Newman, Optical Resolution Procedures

Tarta. 184

Liebigs Ann. Chem., 578, 171 (1952)

for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

OH

NH2

C 1 0 H 2 1 NO

H N

abs. EtOH

M. Mousseron and R. Granger, Bull. Soc.

Tarta. 185

MeOH

Ph.D. Thesis of D. W. Reger, Rutgers

Tarta. 186

Chim. Fr., 850 (1947)

University, New Jersey (1970) H N

C11H12N2O

N

C11H14N2 Et 2 O, MeOH

MeOH

N OH

NH2

E. Späth, F. Kuffner and N. Platzer,

Tarta. 187

C10H23N

20:80 v/v%

V. M. Potapov, A. P. Terent'ev, M. N.

Tarta. 188

Chem. Ber., 68, 1384 (1935)

Preobrazhenskaya and N. N. Suvorov, Zh. Obshch. Khim., 33, 2702 (1963)

NH S

C11H14N2S

N

C 1 1 H 1 5 Cl 2 NO

HO

N H

abs. EtOH

EtOH, EtOAc 33:67 v/v%

Cl Cl

Tarta. 189

K. Koczka and G. Fodor, Acta. Chim. Acad. Sci. Hung., 13, 89 (1957)

Tarta. 190

P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1. Opt.Res. Inf. Center, NY 1979

N H

C11H15N

C11H15N

abs. EtOH

H2O H2N

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Tarta. 191

Ph.D. Thesis of H. J. Bulbrook, Iowa

Tarta. 192

State College (1935) NH2

Tarta. 193

Soc., 81, 574 (1902)

NH2

C11H15N

EtOH, H 2 O

96:4 v/v%

78:12 v/v%

G. Seidl and R. Husigen, Chem. Ber., 97,

NH2

Tarta. 194

H N

C 1 1 H 1 5 NO

L. Cook and E. J. Fellows, German

Tarta. 196

Ausleg., 1, 131, 227 (1962)

N O

C11H16N2 H2O

N H

15:85 v/v% Tarta. 195

G. Seidl, R. Husigen and J. H. M. Hill, Tetrahedron, 20, 633, (1964)

H 2 O, iPrOH

O

C11H15N

EtOH, H 2 O

249 (1964) O

F. S. Kipping and A. E. Hunter, J. Chem.

C. S Gibson, J. H. nutland and J. L. Simonsen, J. Chem. Soc., 108, (1928)

C11H16N2O2

C11H17N

NH2

EtOH

Tarta. 197

abs. EtOH

N

O

A. N. Dey, J. Chem. Soc., 1057 (1937)

Tarta. 198

M. Shibasaki, T. Sato, N. Ohasi, S. Terashima and S. Yamada, Chem. Pharm. Bull., 21, 1868 (1973) OH

C11H17N N

C 1 1 H 1 7 NO MeOH, Et 2 O

MeOH N

Tarta. 199

S. Senoh and I. Mita, Yakugaku Zasshi,

Tarta. 200

Ann. Chem., 470, 157 (1929)

72, 1096 (1952) OH

N

Tarta. 201

C 1 1 H 1 7 NO

C 1 1 H 1 7 NO NH O

H2O

W. N. Nagai and S. Kanao, Justus Liebigs Ann. Chem., 470, 157 (1929)

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W. N. Nagai and S. Kanao, Justus Liebigs

MeOH, Acetone 33:67 v/v%

Tarta. 202

R. V. Heinzelman, J. Am. Chem. Soc., 75, 921 (1953)

OH

HN

HO

OH

C 1 1 H 1 7 NO 3

C 1 1 H 1 7 NO 3

N

MeOH

EtOH

HO OH

Tarta. 203

OCH3

A. M. Lands, F. P. Ludunea and B. F.

Tarta. 204

Tullar, J. Pharmacol. Exp. Ther., 111, 469

A. La Manna and V. Ghislandi, Farmaco, Ed. Sci., 14, 323 (1959)

(1954) COOCH3 O

N

H

C 1 1 H 1 7 NO 3 MeOH

S. P. Findlay, J. Org. Chem., 23, 391

Tarta. 206

(1958)

Acetone

N

H

Tarta. 205

C 1 1 H 2 1 NO

OH

J-C. Jallageas and E. casadevall, C. R. Hebd. Seances Acad. Sci.., Ser. C, 269, 1141 (1969)

H2N

C12H13N NH2

Tarta. 207

H2O

MeOH

R. R. Bottoms, U. S. Patent, 2, 996, 545

Tarta. 208

N H

NH2

C12H13N3 NH

A. Fredga, B. Sjöberg and R. Sandberg, Acta Chem. Scand., 11, 1609 (1957)

(1961)

N

C12H13N

C12H16N2O2

CN

abs. n-PrOH

H2O

H3CO OCH3 Tarta. 209

G. C. Habermehl and W. Ecsy,

Tarta. 210

Heterocycles, 5, 127 (1976)

C12H17N H2O

N

Tarta. 211

M. Holtz and H. Müller, Chem. Ber., 33, 2842 (1901)

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A. Hagedorn, F. Braun and W. Güthlein, German Patent, 1, 274, 586 (1968)

C 1 2 H 1 7 NO 2

H3CO

H3CO

Tarta. 212

NH

H2O

E. Späth and F. Dengel, Chem. Ber., 71, 113 (1938)

H3CO

C 1 2 H 1 7 NO 3 NH

H3CO

C12H18N2

MeOH, Et 2 O

MeOH, Acetone

NH

OH

N H Tarta. 213

A. Brossi and F. Burkhardt, Helv. Chim.

Tarta. 214

Acta, 44, 1558 (1961)

W. F. M. Van Bever, C. J. E. Niemegeers and P. A. J. Janssen, J. Med. Chem., 17, 1047 (1974)

NH2

OH

C12H19N iPrOH, EtOH,

C 1 2 H 1 9 NO H2O

HN

Acetone 47:6:47 v/v% Tarta. 215

A. G. Mohan and R. T. Conley, J. Org.

Tarta. 216

British Patent, 1, 043, 510 (1966)

Chem., 34, 3259 (1969) OH

C 1 2 H 1 9 NO

HN

H2O

C 1 2 H 1 9 NO NH

O

H 2 O, iPrOH 7:93 v/v%

Tarta. 217

O

H. Wollweber, R. Hiltmann, H. Kaller and

Tarta. 218

T. Kralt, H. H. Haeck and H. A.

H-G. Kroneberg, French Patent, 1, 503,

Peperkamp, Recl. Trav. Chim. Pays-Bas,

517 (1967)

85, 607 (1966)

NH2

C 1 2 H 1 9 NO 2

H3CO

MeOH

H3CO

NH2

C 1 2 H 1 9 NO 3 EtOH

OCH3

O Tarta. 219

R. Howe, British Patent, 1, 018,

Tarta. 220

113(1966)

F. A. B. Aldous, B. C. Barrass, K. Bewster, D. A. Buxton, D. M. Green, R. M. Pinder, P. Rich, M. Skeels and K. J. Tutt, J. Med. Chem., 17, 1100 (1974)

NH2

H3CO

H3CO

OCH3

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C 1 2 H 1 9 NO 3 EtOH

OH

H N

C 1 2 H 2 3 NO abs. EtOH

F. A. B. Aldous, B. C. Barrass, K. Bewster, D. A. Buxton, D. M. Green, R. M. Pinder, P. Rich, M. Skeels and K. J. Tutt, J. Med. Chem., 17, 1100 (1974)

Tarta. 221

H

C 1 2 H 2 3 NO

N

C 1 2 H 2 7 NO N

MeOH, Acetone OH

H

D

Tarta. 224

abs. EtOH

A. Casadevall, E. Casadevall and M. Mion, Bull. Soc. Chim. Fr., 4498 (1968) NH2

C13H8D5N

D

OH

50:50 v/v%

L. Mion, A. Casadevall and E. Casadevall, Bull. Soc. Chim. Fr., 2950 (1968)

Tarta. 223

M. Mousseron and R. Granger, Bull. Soc. Chim. Fr., 850 (1947)

Tarta. 222

C 1 3 H 1 2 BrN H2O

EtOH, light D NH2 D

petroleum

Br

D

G. R. Clemo and A. McQuillen, J. Chem.

Tarta. 225

Tarta. 226

Soc., 808 (1936) NH2

G. R. Clemo, C. Gardner and R. Raper, J. Chem. Soc., 1958 (1939) NH2

C 1 3 H 1 2 ClN

C 1 3 H 1 2 IN

H2O Cl

H2O I

G. R. Clemo, C. Gardner and R. Raper, J.

Tarta. 227

Tarta. 228

Chem. Soc., 1958 (1939)

C13H15N

90:10 v/v% Tarta. 229

Chem. Soc., 1958 (1939) O

C 1 3 H 1 6 ClNO NH

Acetone, H 2 O

N

H. Fritz and E. Stock, Justus Liebigs Ann.

Acetone

Cl

Tarta. 230

Chem., 721, 82 (1969)

NH2

G. R. Clemo, C. Gardner and R. Raper, J.

T. W. Hudyma, S. W. Holmes, I. R. Hooper, German Offen, 2, 062, 620 (1970)

C 1 3 H 1 7 FeN

C13H17N

MeOH

abs. EtOH

Fe

H2N Tarta. 231

A. Ratajczak and H. Zmuda, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 22, 261 (1974); A. Ratajczak and H. Zmuda, Rocz. Chem., 49, 215 (1975)

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Tarta. 232

C. J. Collins, Z. K. Cheema, R. G. Werth and B. M. Benjamin, J. Am. Chem. Soc., 86, 4913 (1964); H. E. Smith and T. C. Willis, Tetrahedron, 26, 107 (1970)

O

C 1 3 H 1 7 NO N

C13H18N2O

Acetone

EtOH H N

O NH2

Ph.D. Thesis of J. R. Soares, Columbia

Tarta. 233

Tarta. 234

University, New York (1971)

Ph.D. Thesis of J. R. Soares, Columbia University, New York (1971)

C13H19N

C13H19N H N

EtOH

EtOH

N

Ph.D. Thesis of H. Meislich, Columbia

Tarta. 235

Tarta. 236

A. Ladenburg, Chem. Ber., 37, 3688 (1904)

University, New York (1950)

C 1 3 H 1 9 NO OH

C 1 3 H 1 9 NO

Acetone, MeOH

Acetone, MeOH

OH

50:50 v/v%

96:4 v/v%

N

N

Ph.D. Thesis of D. L. Larson, University

Tarta. 237

Tarta. 238

of Minnesota (1969)

M. M. Abdel-Monem, D. L. Larson, H. J. Kupferberg and P. S. Portoghese, J. Med. Chem., 15, 494 (1972)

H N

C 1 3 H 1 9 NO 3

O

N

N

EtOH

C13H21N3 EtOH, Et 2 O

OCH3 OCH3

S. Ose, H. Takamatsu and Y. Minaki,

Tarta. 239

Tarta. 240

French Patent, 1, 491, 596 (1967)

Japanese Patent, 4417 (1958)

C13H21N3O3

HO

N H

MeOH

F

C 1 4 H 1 1 Cl 3 FN CCl3

NHCONH2 OH

NH2

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EtOH

C. Kaiser, D. F. Colella, M. S. Schwartz,

Tarta. 241

Tarta. 242

E. Garvey and J. R. Wardell, Jr., J. Med.

W. C. Sagar, R. E. Monroe and M. J. Zabik, J. Agr. Food Chem., 20, 1176 (1972)

Chem., 17, 49 (1974) Cl

NH2

C 1 4 H 1 1 Cl 4 N CCl3

Br

EtOH

C 1 4 H 1 2 BrN EtOH

NH2

W. C. Sagar, R. E. Monroe and M. J.

Tarta. 243

Tarta. 244

J. S. Fowler, J. Org. Chem., 37, 510 (1972)

Zabik, J. Agr. Food Chem., 20, 1176 (1972) Br H2N

Cl H2N

C 1 4 H 1 4 BrN abs. EtOH

A. Angeletti, Gazz. Chim. Ital., 65, 819

Tarta. 245

abs. EtOH

Tarta. 246

(1935) Cl

A. Angeletti, Gazz. Chim. Ital., 62, 376 (1932)

Cl

H2N

C 1 4 H 1 4 ClN

NO2O2N

C 1 4 H 1 4 Cl 2 N 2 NH2

EtOH, H 2 O

C14H14N2O2 abs. EtOH

96:4 v/v% W. Kuhn and R. Rometsch, Helv. Chim.

Tarta. 247

Tarta. 248

Acta, 27, 1080 (1944)

J. T. Melillo and K. Mislow, J. Org. Chem., 30, 2149 (1969); S. Sako, Bull. Chem. Soc. Japan, 9, 393 (1934)

C14H15N

C14H15N

H2O

H2O

NH2

NH2

R. Söderquist, J. Prakt. Chem., 101, 293

Tarta. 249

Tarta. 250

(1921) OH

D. Pitré and L. Fumagalli, Farmaco, Ed. Sci., 17, 130 (1962)

C 1 4 H 1 5 NO

C 1 4 H 1 5 NO

abs. EtOH NH2

© 2002 by CRC Press LLC

MeOH HO

NH2

E. Erlenmeyer and A. Arnold, Justus

Tarta. 251

Tarta. 252

Liebigs Ann. Chem., 337, 307 (1904); J.

A. Lespagnol, J. Cheymol and J. Soleil, Bull. Soc. Chim. Fr., 480, (1947)

Read, I. G. M. Campbell and T. V. Barker, J. Chem. Soc., 2305 (1929)

C14H16N2

NH2

C14H16N2

NH2

EtOH, H 2 O NH2

96:4 v/v%

I. Lifschitz, J. G. Bos, Recl. Trav. Chim.

Tarta. 253

H 2 O, EtOH NH2 Tarta. 254

M. Gullotti, A. Pasini, P. Fantucci, R. Ugo

Pays-Bas, 59, 173 (1940); F. Vögtle and

and R. D. Gillard, Gazz. Chim. Ital., 102,

E. Goldschmitt, Chem. Ber., 109, 1

855 (1972)

(1976) H2N

C14H16N2

C14H17N

abs. EtOH

H 2 O, Acetone N

NH2

Tarta. 255

J. Meisenheimer and M. Horing, Chem.

Tarta. 256

Ber., 60, 1425 (1927); W. Dethloff and H.

50:50 v/v%

S. J. Daum, M. D. Aceto and R. L. Clarke, J. Med. Chem., 16, 667 (1973)

Mix, Chem. Ber., 82, 534 (1949) NH

C 1 4 H 1 9 NO

C 1 4 H 1 9 NO 2

H2O

EtOH

HO

N H

Tarta. 257

B. F. Tullar, L. S. Harris, R. L. Perry, A.

Tarta. 258

COOEt

F. Bergel, A. L. Morrison, A. R. Moss and

K. Pierson, A. E. Soria, W. F. Wetterau

H. Rinderknecht, British Patent, 574, 061

and N. F. Albertson, J. Med. Chem., 10,

(1945)

383 (1967)

C 1 4 H 2 1 NO HN

O

EtOH, H 2 O 95:5 v/v%

© 2002 by CRC Press LLC

C 1 4 H 2 1 NO NH2

OCH3

1.) MeOH

OCH3

2.) iPrOH

R. L. Clarke, B. F. Tullar and L.S. Harris,

Tarta. 259

Ph.D. Thesis of A. E. Weber, University of

Tarta. 260

J. Med. Chem., 5, 362 (1962)

Washington (1974) OH

C14H22N2O

H N

C 1 4 H 2 3 NO 4 S

HO

N

H2O

O

EtOH HN O S O

Tarta. 261

N. I. Kudryashova and N. V. Khromov-

C. Kaiser, M. S. Schwartz, D. F. Colella

Tarta. 262

Borisov, Zh. Obshch. Khim., 30, 4035

and J. R. Wardell, Jr., J. Med. Chem., 18,

(1960)

674 (1975)

H N

O

C14H24N2O

H O

NH2

C 1 5 H 1 3 NO 2 EtOH

EtOH O

N H

Tarta. 263

D. Bovet and G. B. M. Bettolo, German

Tarta. 264

Patent, 944, 950 (1956)

H. E. Hennis and C. Wang, J. Org. Chem., 34, 1907 (1969)

C15H15N NH

Tarta. 265

NH2

H2O

W. Leithe, Monatsh Chem., 53, 956

H2O

Tarta. 266

(1929) H N

P. A. Levene, L. A. Mikeska and K. Passoth, J. Biol. Chem., 88, 27 (1930)

C15H17N

OH

H2O

H. Fujimura and Y. Yamakawa, Yakugaku Zasshi, 80, 286 (1960)

Tarta. 268

75:25 v/v%

B. M. Benjamin, P. Wilder, Jr. and C. J. Collins, J. Am. Chem. Soc., 83, 3654 (1961)

© 2002 by CRC Press LLC

C 1 5 H 1 7 NO EtOH, H 2 O

NH2

Tarta. 267

C15H17N

C 1 5 H 1 7 NO

NH2

C 1 5 H 1 7 NO

H2O

MeOH, Et 2 O,

NH2

O

OH

Petrolether 55:10:35 v/v%

R. Quelet and E. Frainnet and C. R. Herb.

Tarta. 269

W. Stulmer and H-H. Frey, Arc. Pharm.

Tarta. 270

Seances Acad. Sci., Ser. C, 236, 492

(Weinheim, Ger.), 286, 22 (1953)

(1953)

C 1 5 H 1 7 NO

C15H18N2

EtOH N

K. A. Thakar and U. S. Pathak, J. Indian

Tarta. 271

Tarta. 272

Chem. Soc., 41, 555 (1964)

C 1 5 H 1 9 NS

N

N H

OH

J. Pospišek, Z. Koblicová, J. Trojánek and K. Bláha, Chem. Ind. (London), 25 (1969)

Cl

HN

MeOH

C 1 5 H 2 0 ClNO 1.) abs. EtOH

O

Si

H

2.) EtOH, H 2 O

NH2 Tarta. 273

EtOH

83:17 v/v%

D. Terunuma, T. Okada, T. Araki and H.

Tarta. 274

British Patent, 1, 133, 302 (1968)

Nohira, Chem. Lett., 675 (1975) NH

C 1 5 H 2 1 NO

C 1 5 H 2 1 NO

H2O

HO

Acetone, EtOH N

Tarta. 275

B. F. Tullar, L. S. Harris, R. L. Perry, A.

O

Tarta. 276

K. Pierson, A. E. Soria, W. F. Wetterau

50:50 v/v%

Ph.D. thesis of J. R. Soares, Columbia University, New York (1971)

and N. F. Albertson, J. Med. Chem., 10, 383 (1967)

C15H22N2O

O N N H

© 2002 by CRC Press LLC

C 1 5 H 2 3 NO H

EtOH, Et 2 O

Acetone, Et 2 O

N O

95:5 v/v%

T. Kobayashi, Justus Liebigs Ann. Chem.,

Tarta. 277

M. Kotake, I. Kawasaki, S. Matsutani, S.

Tarta. 278

536, 143 (1938); F. J. Dale and B.

Kusumoto and T. Kaneko, Bull. Chem. Soc.

Robinson, J. Pharm. Pharmacol., 22, 889

Jpn., 35, 1494 (1962)

(1970) H3CO

C 1 5 H 2 3 NO 2 OH O NH

Acetone, H 2 O

MeOH

H3CO

99:1 v/v%

A. Brändstrom, H. Corrodi, U. Junggren

Tarta. 279

C 1 5 H 2 3 NO 3

H3CO

H2N

Ph.D. Thesis of A. E. Weber, University of

Tarta. 280

and T-E. Jönsson, Acta Pharm. Suec., 3,

Washington (1974)

303 (1966) O

C15H23N2O N

EtOH

N

French Patent, 1, 491, 596 (1967)

Tarta. 281

C15H24N2O

H N

N

H2O

O

Tarta. 282

N. I. Kudryashova, and N. V. KhromovBorisov, Zh. Obshch. Khim., 30, 4035 (1960)

C15H24N2O

H N

N O

H 2 O, EtOH

HO H3CO

C 1 5 H 2 5 NO 3 N H

H2O

56:44 v/v% OCH3

Tarta. 283

N. I. Kudryashova, and N. V. Khromov-

Tarta. 284

Borisov, Zh. Obshch. Khim., 30, 4035

R. Baltzly and N. B. Mehta, J. Med. Chem., 11, 833 (1968)

(1960) O

C 1 5 H 2 5 NO 3 HO H3CO

N H

C 1 6 H 1 5 NO 5 O

H2O H2N

MeOH, EtOH 10:90 v/v%

OH

OCH3

O O Tarta. 285

R. Baltzly and N. B. Mehta, J. Med. Chem., 11, 833 (1968)

© 2002 by CRC Press LLC

Tarta. 286

J. Read and I. G. M. Campbell, J. Chem. Soc., 2674 (1930)

Cl

C 1 6 H 1 7 ClN 2 NH H N

EtOH

C 1 6 H 1 7 Cl 2 N MeOH

NH2

Cl

Cl

H. Ott, G. E. Hardtmann, M. Denzer, A. J.

Tarta. 287

Tarta. 288

S. H. Pines, J. M. chemerda, M. A.

Frey, J. H. Gogerty, G. H. Leslie and J. H.

Kozlowski, L. M. Weinstock, P. Davis, B.

Trapold, J. Med. Chem., 11, 777 (1968)

Handelsman, V. J. Grenda and G. W. Lindberg, J. Med. Chem., 10, 725 (1967)

Cl

OH

C 1 6 H 1 9 ClN 2 O

C 1 6 H 1 9 NO NH2

abs. EtOH

50:50 v/v%

O N

N

Tarta. 289

EtOH, H 2 O

British Patent, 905, 993 (1962)

Tarta. 290

B. M. Benjamin and C. J. Collins, J. Am. Chem. Soc., 83, 3662 (1961)

OH

OH

C 1 6 H 1 9 NO

NH2

C 1 6 H 1 9 NO NH2

EtOH, H 2 O

EtOH, H 2 O

50:50 v/v% Tarta. 291

B. M. Benjamin and C. J. Collins, J. Am.

Tarta. 292

Chem. Soc., 83, 3662 (1961) O

Benjamin, J. Org. Chem., 27, 3525 (1962) NH2

C 1 6 H 1 9 NO 3 EtOAc, MeOH,

HO NH2

C16H20N2 MeOH

EtOH H2N

O

Tarta. 293

C. J. Collins, M. M. Staum and B. M.

J. Read and I. G. M. Campbell, J. Chem. Soc., 2674 (1930)

Tarta. 294

C. G. Overberger, N. P. Marullo and R. G. Hiskey, J. Am. Chem. Soc., 83, 1374 (1961)

© 2002 by CRC Press LLC

OCH3 NH2

O

C16H20N2O2 EtOH

NH2

C16H20N2O2 H2O

H2N

H3CO

NH2

O

H. Musso and W. Steckelberg, Justus

Tarta. 295

Tarta. 296

Liebigs Ann. Chem., 693, 187 (1966)

F. Vögtle and E. Goldschmitt, Chem. Ber., 109, 1 (1976)

C 1 6 H 2 1 NO N

C 1 6 H 2 1 NO NH

1.) H 2 O

HO

MeOH

2.) EtOH, H 2 O 90:10 v/v% G. Hayashi, M. Takeda, H. Kugita, N.

Tarta. 297

HO

Tarta. 298

Sugimoto and H. Fujimura, Chem. Pharm.

J. Hellerbach, G. Grussner and O. Schnider, Helv. Chim. Acta, 39, 429 (1956)

Bull., 11, 489 (1963)

C 1 6 H 2 1 NO NH2

HO

MeOH

H3CO H3CO

C 1 6 H 2 1 NO 3 N H

H

Acetone

O

M. E. Freed, J. R. Potoski, G. L. Conklin

Tarta. 299

Tarta. 300

and S. C. Bell, J. Med. Chem., 19, 560

H. T. Openshaw, N. C. Robson and N. Whittaker, J. Chem. Soc., C, 101 (1969)

(1976)

Si

C 1 6 H 2 1 NSi

C 1 6 H 2 1 NSi

MeOH

MeOH

NH2

Si

D. Terunuma, T. Okada, T. Araki and H.

Tarta. 301

Tarta. 302

Nohira, Chem. Lett., 675 (1975)

NH2

D. Terunuma, T. Okada, T. Araki and H. Nohira, Chem. Lett., 675 (1975)

C 1 6 H 2 1 NSi MeOH Si

NH2

© 2002 by CRC Press LLC

C 1 6 H 2 3 NO HO

NH2

MeOH

Tarta. 303

D. Terunuma, T. Okada, T. Araki and H.

Tarta. 304

Nohira, Chem. Lett., 675 (1975)

M. E. Freed, J. R. Potoski, G. L. Conklin and S. C. Bell, J. Med. Chem., 19, 560 (1976)

NH2

HO

C 1 6 H 2 3 NO MeOH

H3CO

C 1 6 H 2 3 NO 4 N

H3CO

Acetone

COOEt

Tarta. 305

M. E. Freed, J. R. Potoski, G. L. Conklin

Tarta. 306

G. Snatzke, G. Wollenberg, J. Hrbek, Jr., F.

and S. C. Bell, J. Med. Chem., 19, 560

Santavý, K. Bláha, W. Klyne and R. J.

(1976)

Swan, Tetrahedron, 25, 5059 (1969)

O

N

N

C16H25N3O

C17H15N

EtOH

EtOH, H 2 O

N

95:5 v/v%

H2N

Tarta. 307

H. Wollweber, R. Hiltman, F. Hoffmeister

Tarta. 308

and H-G. Kroneberg, British Patent, 1,

S. Berlingozzi, Gazz. Chim. Ital., 50, 56 (1920)

089, 706 (1967) CF2CF2Ph H N

C 1 7 H 1 5 NO EtOH, H 2 O

HO

EtOH

95:5 v/v%

H2N

Tarta. 309

C17H17F4N

M. Betti, Gazz. Chim. Ital., 36, 392

Tarta. 310

(1906)

M. E. Christy, C. D. Colton, M. Mackey, W. H. staas, J. B. Wong, E. L. Engelhardt, M. Torchiana and C. A. Stone, J. Med. Chem., 20, 421 (1974)

N

O

C17H19N

C 1 7 H 1 9 NO 2

MeOH

EtOH HO

Tarta. 311

H. Richter and B. Acksteiner, German Patent, 1, 098, 511 (1961)

© 2002 by CRC Press LLC

Tarta. 312

N

H. Takamatsu and Y. Minaki, Yakugaku Zasshi, 76, 1230 (1956)

C 1 7 H 2 0 ClNO

C17H21N N

1.) Acetone

Cl

2.) EtOH, Et 2 O

OH

2.) H 2 O

67:33 v/v%

N

A. Markovac.Prpic, D. Fles and M.

Tarta. 313

1.) MeOH

Y. Yamakawa, Yakugaku Zasshi, 80, 292

Tarta. 314

(1960)

Milohnoja, Croat. Chem. Acta., 32, 209

(1960) OH

C 1 7 H 2 1 NO

N

N

COOCH3

C 1 7 H 2 1 NO 4

H OOCPh

H2O

H2O

H

British Patent, 318, 488 (1930)

Tarta. 315

R. Wilstätter, O. Wolfes and H. Mäder,

Tarta. 316

Justus Liebigs Ann. Chem., 434, 111

(1923)

H

N

COOCH3 OOCPh

C 1 7 H 2 1 NO 4

C17H22N2 N

H2O

EtOH, H 2 O

HN

H

Tarta. 317

95.5 v/v%

R. Wilstätter, O. Wolfes and H. Mäder,

Tarta. 318

P. S. Porthogese and D. L. Larson, J.

Justus Liebigs Ann. Chem., 434, 111

Pharm. Sci., 53, 302 (1964); A. F. Casy and

(1923)

M. M. A. Hassan, J. Pharm. Pharmacol., 19, 17 (1967)

C17H23N N H

1.) H 2 O 2.) Acetone

Tarta. 319

K. Harasawa, Yakugaku Zasshi, 77, 172

C 1 7 H 2 3 NO

N H HO

Tarta. 320

(1957)

O. Schnider and A. Grüssner, U. S. Patent, 2, 676, 177 (1954)

C 1 7 H 2 3 NO N

H2O

H

HO

C 1 7 H 2 3 NO N

H2O

H3CO

H

EtOH, H 2 O 90:10 v/v%

© 2002 by CRC Press LLC

K. Harasawa, Yakugaku Zasshi, 77, 172

Tarta. 321

Tarta. 322

(1957)

G. Hayashi, M. Takeda, H. Kugita, N. Sugimoto and H. Fujimura, Chem. Pharm. Bull., 11, 489 (1963)

H3CO

C 1 7 H 2 3 NO

Et NH2

C 1 7 H 2 3 NO O

MeOH

EtOH

N

Tarta. 323

M. E. Freed, J. R. Potoski, G. L. Conklin

Tarta. 324

I. Jirovsky, L. G. Humber and R.

and S. C. Bell, J. Med. Chem., 19, 560

Noureldin, Eur. J. Med. Chem., Chim.

(1976)

Ther., 11, 571 (1976)

NH

C 1 7 H 2 3 NO 2

OH

Ph

EtOOC

C 1 7 H 2 3 NO 2

N

MeOH

H3CO

Acetone, H 2 O 98.5:1.5 v/v%

Tarta. 325

I. Monković, H. Wong, A. W. Pircio, Y.

Tarta. 327

G. Satzinger, W. Herrmann and M.

G. Perron, I. J. Pachter and B. Belleau,

Herrmann, German Ausl., 1, 923, 247

Can. J. Chem., 53, 3094 (1975)

(1970)

C 1 7 H 2 5 NO H3CO

Tarta. 326

C 1 7 H 2 5 NO

H3CO

NH2

MeOH

NH2

M. E. Freed, J. R. Potoski, G. L. Conklin

Tarta. 328

MeOH

M. E. Freed, J. R. Potoski, G. L. Conklin

and S. C. Bell, J. Med. Chem., 19, 560

and S. C. Bell, J. Med. Chem., 19, 560

(1976)

(1976)

N

N

C 1 7 H 2 5 NO

C18H12N2 EtOH

abs. EtOH HO

N Tarta. 329

K. C. Rice and A. E. Jacobson, J. Med. Chem., 19, 430 (1976)

© 2002 by CRC Press LLC

Tarta. 330

M. Crawford and I. F. B. Smyth, J. Chem. Soc., 4133 (1952)

N

C18H12N2

C18H19N

EtOH

EtOH, H 2 O 70:30 v/v%

N

NH2

M. Crawford and I. F. B. Smyth, J. Chem.

Tarta. 331

B. S. E. Carnmalm, T. DePaulis, S. B. Ross

Tarta. 332

Soc., 4133 (1952)

and N-E. Stjernstrom, German Offen. 2, 227, 844 (1973) COOCH3 H OH N

C18H21N Acetone

C 1 8 H 2 1 NO 5 Acetone

HO OH

N British Patent, 1, 142, 030 (1969)

Tarta. 333

A. Hajos and P. Sohar, Acta Chim. Acad.

Tarta. 334

Sci. Hung., 53, 295 (1967)

C 1 8 H 2 3 NO

C 1 8 H 2 3 NO 3

N

Acetone

Acetone, EtOH OH

H

N

50:50 v/v%

H3CO OH O

Tarta. 335

A. H. Beckett and A. F. Casy, J. Chem.

Tarta. 336

Soc., 900 (1955) H N O

O

N

3052 (1954)

C18H25N5O5 OH

N

N

D. Elad and D. Ginsburg, J. Chem. Soc.,

C 1 8 H 2 5 NO N

H2O

MeOH

N OH

H3CO

OH

Tarta. 337

K. H. Klinger, U. S. Patent, 3, 398, 150

Tarta. 338

K. Vogler, U. S. Patent, 2, 744, 112 (1956)

(1968) N H3CO

C 1 8 H 2 5 NO MeOH

H3CO

C 1 8 H 2 5 NO 3 N

H3CO HO

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Acetone H

O. Schnider, A. Brossi and K. Vogler,

Tarta. 339

V. Prelog, A. Langermann, O. Rodig and

Tarta. 340

Helv. Chim. Acta, 37, 710 (1954)

M. Ternbah, Helv. Chim. Acta, 42, 1301 (1959)

C 1 8 H 2 7 NO

C18H28N2O H N

1.) Acetone, MeOH N

IPrOH

N O

78:22 v/v% 2.) iPrOH

O

W. F. Munch, Jr., U. S. Patent, 3, 511,

Tarta. 341

Tarta. 342

B. F. Tullar, J. Med. Chem., 14, 891, (1971)

846 (1970) NH2

C 1 8 H 2 9 NO 3 S S

N

O OH

H2O

EtOH Ph

O

Tarta. 343

C19H17N

J. P. Long, F. P. Luduena, B. F. Tullar and

Tarta. 344

A. M. Lands, J. Pharmacol. Exp. Ther.,

S. K. Hsü, C. K. Ingold and C. L. Wilson, J. Chem. Soc., 1778 (1935)

117, 29 (1956)

C 1 9 H 1 9 NO 3

O O

N

1.) abs. EtOH

C 1 9 H 1 9 NO 3

O N

O

2.) EtOH, H 2 O

2.) EtOH, H 2 O 95:5 v/v%

H3CO

Tarta. 345

95:5 v/v%

E. Schittler, Helv. Chim. Acta, 15, 394

OCH3

Tarta. 346

(1932); F. Fatils, G. Wagner and E. Adler,

F. Fatils, G. Wagner and E. Adler, Chem. Ber., 77, 686 (1944)

Chem. Ber., 77, 686 (1944) O O

C 1 9 H 1 9 NO 3

O

abs. EtOH

O

N

C 1 9 H 1 9 NO 4 N

MeOH

HO

H3CO

H3CO

Tarta. 347

G. Barger and E. Schittler, Helv. Chim. Acta, 15, 381 (1932)

© 2002 by CRC Press LLC

Tarta. 348

I. Kikkawa, Yakugaku Zasshi, 79, 1244 (1959)

C 1 9 H 2 1 NO 2

OCH3 H3CO

1.) EtOH, EtOAc N

C 1 9 H 2 1 NO 4 H3CO

NH

Acetone

O

2.) EtOH, EtOAc, Hexane

H3CO OCH3

W. S. Saari and S. W. King, J. Med.

Tarta. 349

T. Kametani and S. Shibuya, J. Chem. Soc.,

Tarta. 350

Chem., 16, 171 (1973) H3CO

C 1 9 H 2 2 ClNO 2

C19H22N2

MeOH

Acetone, H 2 O

NH

H3CO

5565 (1965)

N

CN

94:6 v/v%

Cl

A. Brossi, H. Besendorf, B. Pelmonnt, M.

Tarta. 351

CN

Walter and O. Schnider, Helv. Chim.

S. Buck, J. Am. Chem. Soc., 70, 4194

Acta, 43, 1459 (1960)

(1948)

N

C19H22N2

C19H22N2

Acetone, H 2 O

Acetone, H 2 O

91:9 v/v%

A. Pohland, F. J. Marshall and T. P.

Tarta. 353

A. A. Larsen, B. F. Tullar, B. Elpern and J.

Tarta. 352

N

CN

97:3 v/v%

E. Walton, P. Ofner and R. H. Thorp, J.

Tarta. 354

Carney, J. Am. Chem. Soc., 71, 460

Chem. Soc., 648 (1949)

(1949)

C19H22N2

C 1 9 H 2 2 N 2 OS

EtOH, H 2 O CN

N

MeOH

S

95:5 v/v%

N O N

Tarta. 355

A. A. Larsen and B. F. Tullar, U. S. Patent, 2, 773, 901 (1956)

© 2002 by CRC Press LLC

Tarta. 356

J. Krapcho, C. F. Turk and J. J. Piala, J. Med. Chem., 11, 361 (1968)

H3CO

C19H22N2O2 NH

H3CO

MeOH

C 1 9 H 2 3 NO 3 N

H3CO

1.) Et 2 O

OH

2.) MeOH

H3CO NO2

M. Walter, H. Besendorf and O. Schnider,

Tarta. 357

Tarta. 358

Helv. Chim. Acta, 46, 1127 (1963) HO

C 1 9 H 2 3 NO 5 NH

HO H3CO

G. Greth, M. Usković and A. Brossi, J. Org. Chem., 33, 2500 (1968)

C19H24N2

N

EtOH, CHCl 3

EtOH, H 2 O

N

40:60 v/v%

H3CO OCH3

British Patent, 1, 173, 719 (1969)

Tarta. 359

N H H

Tarta. 360

C19H24N2

S

MeOH

N

N

H

French Patent, 1, 216, 929 (1960)

OCH3

iPrOH

N

H

A. Le Hir, R. Goutarel and M-M. Janot,

Tarta. 361

Tarta. 362

Bull. Soc. Chim. Fr., 1091 (1952) S

C19H24N2S

N

MeOH

R. M. Jacob and J. G. Robert, U. S. Patent, 2, 837, 518 (1958)

C 1 9 H 2 5 NO 2 N O

N

Tarta. 363

C 1 9 H 2 4 N 2 OS

1.) EtOH 2.) Acetone, EtOH

O

J. D. Grenzer, M. N. Lewis, F. H. McMillan and J. A. King, J. Am. Chem. Soc., 75, 2506

© 2002 by CRC Press LLC

(1953)

Tarta. 364

M. Sasamoto, Chem. Pharm. Bull., 8, 980 (1960)

OH

C 1 9 H 2 5 NO 4

C 1 9 H 2 9 NO

O

EtOH

HN

O

EtOH OH N

OH

R. Howe, British Patent, 1, 024, 643

Tarta. 365

Tarta. 366

(1966) H3CO

N

D. W. adamson and W. M. Duffin, British Patent, 750, 156 (1956)

C 2 0 H 2 1 NO 4

H3CO

abs. EtOH

H3CO

C 2 0 H 2 1 NO 4 N

abs. EtOH

H3CO

O O

O O

Tarta. 367

R. D. Haworth, W. H. Perkin, Jr., and J.

Tarta. 368

Z. Kitasato and I. Shishido, Justus Liebigs Ann. Chem., 527, 176 (1937)

Rankin, J. Chem. Soc., 29, (1926)

OH

C 2 0 H 2 1 NO 4

O N

O

H2O

C 2 0 H 2 3 NO 2 EtOH

O

H3CO OCH3

N

Tarta. 369

J. Gadamer and F. Kuntze, Arch. Pharm.

Tarta. 370

(Weinheim, Ger.), 249, 598 (1911)

M. E. Christy, C. C. Boland, J. G. Williams and E. L. Engelhardt, J. Med. Chem., 13, 191 (1970)

O

Ph

O Ph

C 2 0 H 2 3 NO 2 MeOH

NH

H3CO H3CO

C 2 0 H 2 3 NO 3 N

abs. EtOH

H3CO

Tarta. 371

W. R. Hardie, J. Hidalgo, I. F. Halverstadt and R. E. Allen, J. Med. Chem., 9, 127 (1966)

© 2002 by CRC Press LLC

Tarta. 372

K. Goto, R. Inaba and H. Nozaki, Justus Liebigs Ann. Chem., 530, 142 (1937)

H3CO

C 2 0 H 2 3 NO 4 N

HO H3CO

EtOH

C 2 0 H 2 3 NO 4 N

H3CO HO

J. Gadamer, Arch. Pharm. (Weinheim,

Tarta. 374

Ger.), 249, 669 (1911)

Ph.D. Thesis of W. Erhardt, University of Minnesota (1974) N

C20H24N2 Acetone, EtOH

N

C20H24N2O2 Benzene, H 2 O

H3CO O

50:50 v/v% N

Tarta. 375

EtOH

H3CO

H3CO Tarta. 373

H3CO

HN

C. F. Huebner, U. S. Patent, 3, 060, 186

Tarta. 376

R. B. Woodward and W. E. Doering, J. Am. Chem. Soc., 67, 860 (1945)

(1962)

C 2 0 H 2 5 NO

C 2 0 H 2 5 NO

EtOH

Acetone, H 2 O OH

97:3 v/v%

N

N

OH Tarta. 377

R. P. Mull and R. H. Mizzoni, French

Tarta. 378

Patent, 1, 491, 362 (1967) H3CO H3CO H3CO

C 2 0 H 2 5 NO 4 N

abs. EtOH

(1967) H3CO H3CO H3CO

C 2 7 H 2 9 NO 5 N

abs. EtOH

Benzoyl-O

HO

Tarta. 379

W. Veldkamp, U. S. Patent, 3, 317, 380

B. Frydman, R. Bendisch and V. Deulofeu, Tetrahedron, 4, 342 (1958)

© 2002 by CRC Press LLC

Tarta. 380

B. Frydman, R. Bendisch and V. Deulofeu, Tetrahedron, 4, 342 (1958)

H3CO N

H3CO HO

C 2 0 H 2 5 NO 4

H3CO

abs. EtOH

H3CO Benzoyl-O

H3CO

Tarta. 381

C 2 7 H 2 9 NO 5 N

abs. EtOH

H3CO

B. Frydman, R. Bendisch and V.

Tarta. 382

Deulofeu, Tetrahedron, 4, 342 (1958)

N N

B. Frydman, R. Bendisch and V. Deulofeu, Tetrahedron, 4, 342 (1958)

C20H26N2

C20H26N2

EtOH, H 2 O

EtOH

40:60 v/v% N

NH2 Tarta. 383

C. F. Huebner and M. J. Allen, French

Tarta. 384

Patent, 1, 216, 929 (1960)

N OH

R. H. Mizzoni and R. P. Mull, French Patent, 1, 458, 076 (1966)

C 2 0 H 2 7 NO

C 2 0 H 2 7 NO

EtOH, H 2 O

EtOH OH

96:4 v/v%

N Tarta. 385

A. F. Casy and M. M. A. Hassan, J. Med.

Tarta. 386

Chem., 11, 601 (1968) N OH

Tarta. 387

Chem. Soc., 45, 378 (1968) N

C 2 0 H 2 7 NO 2

HO

MeOH, Acetone 25:75 v/v%

I. Monković, H. Wong, A. W. pircio, Y. G. Perron, I. J. Pachter and B. Belleau, Can. J. Chem., 53, 3094 (1975)

© 2002 by CRC Press LLC

A. A. Shaikh and K. A. Thaker, J. Indian

C 2 0 H 2 7 NO 2 OH

MeOH

HO

Tarta. 388

M. Saucier, J-P. DavisY. Lambert, I. Monković, J. Med. Chem., 20, 676 (1977)

O S O

C 2 0 H 2 7 NO 2 S

C 2 0 H 3 1 NO

Acetone

EtOH

B,. F. Tullar, W. Wetterau and S. Archer,

Tarta. 389

Tarta. 390

J. Am. Chem. Soc., 70, 3959 (1948)

N H

C20H36N2 H

OH

N

N

D. W. Adamson, and W. M. Dufin, British Patent, 750, 156 (1956)

HO

OH

C 2 0 H 4 1 NO 2

H NH2

EtOH

EtOH, H 2 O

H

95:5 v/v%

N

P. L. Southwick, J. A. Vida and D. P.

Tarta. 391

Tarta. 392

Mayer, J. Org. Chem., 29, 1429 (1964)

N

B. Majhofer-Oreščanin and M. Proštenik, Croat. Chem. Acta, 34, 161 (1962)

C21H18N2

H3CO

H2O

H3CO

NH

C 2 1 H 2 1 NO 6 N H O

MeOH

H

O O O

H. L. Snape, J. Chem. Soc., 77, 778

Tarta. 393

Tarta. 394

(1900); I. Lifschitz and J. G. Bos, Recl.

W. M. Whaley and M. Meadow, J. Chem. Soc., 1067 (1953)

Trav. Chim. Pays-Bas, 58, 638 (1939) O N

O O

C 2 1 H 2 5 NO 3 H 2 O, Acetone

C 2 1 H 2 5 NO 4

H3CO N

H3CO

EtOH

0.5, 99.5 v/v% H3CO OCH3 Tarta. 395

F. P. Doyle, Beecham Phammaceuticals, Betchwort, Surrey, England

© 2002 by CRC Press LLC

Tarta. 396

Ph.D. Thesis of W. Erhardt, University of Minnesota (1974)

H3CO

H3CO

C 2 1 H 2 5 NO 4 N

H3CO H3CO

OCH3

EtOH

C 2 1 H 2 5 NO 4 EtOH

N

H3CO H3CO OCH3

Tarta. 397

J. M. Gulland and R. D. Haworth, J.

Tarta. 398

Chem. Soc., 131, 1834 (1928)

Kier, J. Pharm. Sci., 56, 973 (1967)

C 2 1 H 2 7 NO

C 2 1 H 2 7 NO

Acetone

PrOH

N

O

Tarta. 399

M. J. Martell, Jr., T. O. Soine amd L. B.

N

O

W. R. Brode and M. W. Hill, J. Org.

Tarta. 400

Chem., 13, 191 (1948)

A. A. Larsen, B. F. Tullar, B. Elpern and J. S. Buck, J. Am. Chem. Soc., 70, 4194 (1948)

C 2 1 H 2 7 NO

C 2 1 H 2 7 NO

H2O

H2O

N

O

Tarta. 401

HN

A. A. Larsen, B. F. Tullar, B. Elpern and

Tarta. 402

J. S. Buck, J. Am. Chem. Soc., 70, 4194

OH

Y. Kasuya, Yakugaku Zasshi, 78, 509 (1958)

(1948)

C 2 1 H 2 7 NO

H3CO

EtOH

H3CO

HO

C 2 1 H 2 7 NO 5 N H

abs. EtOH

OH

N

OCH3 OCH3

Tarta. 403

S. O. Winthrop, M. A. Dawis, G. S. Myers, J. G. Gavin, R. Thomas and R. Barber, J. Org. Chem., 27, 230 (1962)

© 2002 by CRC Press LLC

Tarta. 404

J-L. Ferron and P. L'Ecuyer, Can. J. Chem., 33, 352 (1955)

H3CO

C 2 1 H 2 7 NO 5

C 2 1 H 2 9 NO 2

NCH3

H3CO H3CO

MeOH

N OH HO

H3CO

OH

J. Gadamer, Arch. Pharm. (Weinheim,

Tarta. 405

M. Saucier, J-P. Daris, Y. Lambert, I.

Tarta. 406

Monković and A. W. Pircio, J. Med. Chem.,

Ger.), 249, 669 (1911)

20, 676 (1977)

C 2 1 H 2 9 NO 2 N

C 2 2 H 2 7 NO 2

MeOH

H 2O

N O

OH

HO

HO

I. Monković, H. Wong, A. W. Pircio, Y-

Tarta. 407

H. Wieland, W. Koschara and E. Dane,

Tarta. 408

G. Perron, I. J. Pachter and B. Belleau,

Justus Liebigs Ann. Chem., 473, 118

Can. J. Chem., 53, 3094 (1975)

(1929)

C 2 2 H 2 7 NO 3 Acetone

N

O N

O

C 2 2 H 2 7 NO 3 Acetone

O

O

O

O

Tarta. 409

F. P. Doyle, M. D. Mehta, G. S. Sach, R.

F. P. Doyle, M. D. Mehta, G. S. Sach, R.

Tarta. 410

Ward and P. S. Sherman, J. Chem. Soc.,

Ward and P. S. Sherman, J. Chem. Soc.,

578 (1964)

578 (1964)

C22H28N2O

C 2 3 H 2 9 NO

1.) MeOH, Et 2 O H

O HN

H2N

Tarta. 411

7:93 v/v%

O

2.) H 2 O

R. Riemschneider and H. Kampfer, Justus Liebigs Ann. Chem., 665, 35 (1963)

© 2002 by CRC Press LLC

EtOH N

Tarta. 412

M. Erlenbach and A. Sieglitz, British Patent, 685, 616 (1953)

NH2

C 2 3 H 2 9 NO 2

O N H

n-PrOH

C24H24N2O EtOH, Et 2 O

H

N O

O

M. Erlenbach and A. Sieglitz, British

Tarta. 413

R. Riemschneider and A. Rook, Monatsh.

Tarta. 414

Patent, 685, 616 (1953) H N

Chem., 92, 1227 (1961)

C24H27N

C 2 4 H 2 9 NO

MeOH, H 2 O

MeOH

H

H

60:40 v/v%

N HO

H. Maske, E. Lindner and H. Ott, German

Tarta. 415

Tarta. 416

Patent, 1, 115, 263 (1961)

L. G. Humber, F. T. Bruderlein and K. Voith, Molecular Pharm., 11, 833 (1975)

N

C 2 4 H 3 1 NO 1.) iBuOH 2.) H 2 O

N

C 2 4 H 3 3 NO 2 OH

HO

MeOH

H

O

H

Tarta. 417

M. Erlenbach and A. Sieglitz, British Patent, 685, 616 (1953)

Tarta. 418

M. Menard, P. Rivest, B. Belleau, J-P. Daris and Y. G. Perron, Can. J. Chem., 54, 429 (1976)

C25H27N

C25H28N2O

Acetone

MeOH HO

N

N N

Tarta. 419

R. P. Mull and R. H. Mizzoni, British Patent, 1, 142, 030 (1969)

© 2002 by CRC Press LLC

Tarta. 420

H. E. Zaugg, R. J. Michaels, H. J. Glenn, L. R. Swett, M. Freifelder, G. R. Stone and A. W. Weston, J. Am. Chem. Soc., 80, 2763 (1958)

C 2 5 H 3 1 NO

H3CO

MeOH

H3CO

C 2 6 H 2 8 BrNO 4 NH

H

H

MeOH

Br

N HO

OCH3 OCH2Ph

L. G. Humber, F. T. Bruderlein and K.

Tarta. 421

Tarta. 422

Voith, Molecular Pharm., 11, 833 (1975) H3CO

Y. Inubushi, Y. Masaki, S. Matsumoto and F. Takami, J. Chem. Soc., C, 1547 (1969)

C 2 6 H 2 8 BrNO 4 NH

H3CO

C 2 6 H 2 9 NO 2

EtOH

Br

O

O

N

MeOH

OCH3 OCH2Ph

Tarta. 423

E. Fujita, A. Sumi and Y. Yoshimura,

Tarta. 424

Chem. Pharm. Bull., 20, 368 (1972)

C 3 0 H 4 2 BrNO

W. J. Houlihan, French Patent, 1, 467, 524 (1967)

NH2

C 6 H 1 3 NO 2 COOCH3

MeOH, H 2 O

MeOH

N HO

70:30 v/v%

Br

Tarta. 425

D. E. Pearson and A. A. Rosenberg, J.

Tarta. 426

Med. Chem., 18, 523 (1975) NH2

Tarta. 427

Ph.D. Thesis of N. A. Porter, Harvard University, Cambridge, Massachusetts (1965)

© 2002 by CRC Press LLC

(1970)

C10H24N2 H2O

NH2

H. Jensen, German Offen. 1, 807, 495

C11H15N H2O

N H

Tarta. 428

A. Ottolino and V. Tortorella, Gazz. Chim. Ital., 105, 935 (1975)

O

H N

C13H16N2O2

C17H25N3O

MeOH

O

N

Et 2 O

N O

N

H2N R. Dziemian and N. Finch, U. S. Patent, 3,

Tarta. 429

Tarta. 430

944, 671 (1976) O N

O

G. Feo, M. Giannangeli, D. Piccinelli and P. Sale, Farmaco. Ed. Sci., 26, 370 (1971)

C 1 8 H 1 7 NO 2

C 1 8 H 1 9 NOS

abs. EtOH

MeOH, H 2 O OH

N

90:10 v/v%

S

L. Marion and V. Grassie, J. Am. Chem.

Tarta. 431

Tarta. 432

Soc., 66, 1290 (1944)

A. W. Ruddy and T. J. Becker, U. S. Patent, 2, 837, 525 (1958)

C 2 2 H 2 3 NO

C 2 6 H 2 3 NO N

MeOH, Et 2 O,

O

Petrolether

OH

HN

EtOH, Benzene 50:50 v/v%

55:10:35 v/v%

W. Stuhmer and H-H. Frey, Arch. Pharm.

Tarta. 433

Tarta. 434

(Weinheim, Ger.), 286, 22 (1953)

Ph.D. Thesis of J. B. Littman, The Ohio State University (1930)

C 1 8 H 2 2 ClN 5 O N O

N

HN

Tarta. 435

EtOH N

C4H12N2 H2N

NH2

H 2 O, MeOH

Cl

NH

M. Gianangeli, N.Cazzola, M.R. Luparini,

Tarta. 436

M.G. Scaros, P. K. Yonan, S. A. Laneman

M. Magnani, M. Mabilia, G. Picconi, M.

and P. N. Fernando, Tetrahedron

Tomaselli and L. Baiocchi, J. Med.

Asymmerty, 8, 1501 (1997)

Chem., 42, 336(1999)

© 2002 by CRC Press LLC

N

COOCH3 OH

C 1 1 H 1 7 NO 3

C 1 3 H 1 2 ClN NH2

EtOH

Cl Z. Chen, S. Izenwasser, J. L. Katz, N.

Tarta. 437

C. J. Opalka, T. E. D'Ambra, J. J. Faccone,

Zhu, C. L. Klein and M. L. Trudell, J.

G. Bodson and E. Cossement, Synthesis,

Med. Chem., 39, 4744 (1996)

766 (1995)

HO CH2Ph HO

Tarta. 438

C 2 3 H 3 1 NO 3

C17H13N2S

MeOH

MeOH

N

N N

S

HO

Tarta. 439

B. L. Chenard, J. Bordner, T. W. Butler,

Tarta. 440

D. Xu, P. G. Mattner, A. Kucerovy, K.

L. K. Chambers, M. A. Collins, D. L. De

Prasad and O. Repic, Tetrahedron

Costa, M. F. Ducat, M. L. Dumont, C. F.

Asymmetry, 7, 747 (1996)

Fox, E. E. Mena, F. S. Menniti, J. Nielsen, M. J. Pagnozzi, K. E. G. Richter, R. T. ronau, I. A. Shalaby, J. Z. Stemple and W. F. White, J. Med. Chem., 38, 3138 (1995) Cl

C 1 9 H 2 2 ClNO

Cl

C 2 0 H 2 4 ClNO

Acetone

Acetone OH

OH

N

N

Tarta. 441

S. Stanchev, R. Rakovska, N. Berova and

Tarta. 442

S. Stanchev, R. Rakovska, N. Berova and

G. Snatzke, Tetrahedron Asymmetry, 6,

G. Snatzke, Tetrahedron Asymmetry, 6,

183 (1995)

183 (1995)

© 2002 by CRC Press LLC

NH2 H OCH3

C 1 2 H 1 9 NO

C13H18N2

EtOH, H 2 O

EtOH

60:40 v/v% HN

Tarta. 443

M. Wang, S. Z. Liu, J. Liu and B. F. Hu,

N A. A. Cordi, T. Persigand and J.-P.

Tarta. 444

J. Org. Chem., 60, 7364 (1995)

Lecouvé, Synth. Comm., 26, 1585 (1996)

H N

C14H16N2

C6H13N H2O

H2N NH2

Tarta. 445

S. Pikul and E. J. Corey, Org. Synth, 71,

D. Doller, R. Davies and S.

Tarta. 446

22 (1993)

Chackalamannil, Tetrahedron Asymmetry, 8, 1275 (1997)

C13H16N2 HN

EtOH N

Tarta. 447

A. A. Cordi, T. Persigand and J.-P.

C33H34O2P2 Ph Ph P O

Ph P Ph O

K. Yamamoto, M. Myazawa, S. Momose

Tarta. 448

Lecouvé, Synth. Comm., 26, 1585 (1996)

and M. Funahashi, Jpn. Kokai Tokkyo Koho JP 05, 306, 292, (1993)

C21H2N2O

H2N

C11H16N2 MeOH

Acetone N

N N

Tarta. 449

OH

Hoechst AG., 91-102910/15, C91044153, FAHR 22.09.89

Tarta. 450

T. Hojo, T. Yokoyama, K. Nakazono and M. Okada, Jpn. Kokai Tokkyo Koho JP 02, 218, 664(1990)

© 2002 by CRC Press LLC

O

C 2 1 H 2 7 NOW

C 1 7 H 1 6 ClNO 3 MeOH

1.) Acetone Cl

2.) MeOH, Acetone

N

OH

OH

W

N H

Hoechst AG, Ger. Offen. DE 3, 931, 554, (Cl. C07D233/64), (1991)

Tarta. 451

O

O

D. M. Floyd, S. D. Kimball, J. Krapcho, J. Das, C. F. Turk, R. V. Moquin, M. W. Lago, K. J. Duff, V. G. Lee, R. E. White, R. E. Ridgewell, S. M. Moreland, R. J. Brittain, D. E. Normandin, S. A. Hedberg and G. G. Cucinotta, J. Med. Chem., 35, 756 (1992)

Tarta. 452

O

C 2 3 H 2 7 ClN 2 O 4 MeOH

C 1 8 H 1 6 F 3 NO 3 MeOH

F3C

Cl

OH

OAc N H

N O

O

N

D. M. Floyd, S. D. Kimball, J. Krapcho, J. Tarta. 454 Das, C. F. Turk, R. V. Moquin, M. W. Lago, K. J. Duff, V. G. Lee, R. E. White, R. E. Ridgewell, S. M. Moreland, R. J. Brittain, D. E. Normandin, S. A. Hedberg and G. G. Cucinotta, J. Med. Chem., 35, 756 (1992)

Tarta. 453

O

D. M. Floyd, S. D. Kimball, J. Krapcho, J. Das, C. F. Turk, R. V. Moquin, M. W. Lago, K. J. Duff, V. G. Lee, R. E. White, R. E. Ridgewell, S. M. Moreland, R. J. Brittain, D. E. Normandin, S. A. Hedberg and G. G. Cucinotta, J. Med. Chem., 35, 756 (1992) OCH3

C24H27F3N2O4 MeOH

F3C

H3CO OAc N O

C 1 8 H 2 1 NO 4 S EtOH, H2O

S OH

95:5 v/v%

NH2 COOCH3

N

Tarta. 455

D. M. Floyd, S. D. Kimball, J. Krapcho, J. Tarta. 456 Das, C. F. Turk, R. V. Moquin, M. W. Lago, K. J. Duff, V. G. Lee, R. E. White, R. E. Ridgewell, S. M. Moreland, R. J. Brittain, D. E. Normandin, S. A. Hedberg and G. G. Cucinotta, J. Med. Chem., 35, 756 (1992)

© 2002 by CRC Press LLC

J. Das, D. M. Floyd, S. D. Kimball, K. J. Duff, M. W. Lago, J. Krapcho, R. E. White, R. E. Ridgewell, M. T. Obermeier, S. Moreland, D. McMullen, D. Normandin, S. A. Hedberg and T. R. Schaeffer, J. Med. Chem., 35, 2610 (1992)

C17H26N2O N

O NH

Tarta. 457

C18H28N2O

EtOH, H2O

O

N

NH

96:4 v/v%

K. Nemák, M. Ács, Zs. M. Jászay, D.

K. Nemák, M. Ács, Zs. M. Jászay, D.

Tarta. 458

Kozma and E. Fogassy, Tetrahedron, 52,

Kozma and E. Fogassy, Tetrahedron, 52,

1637 (1996)

1637 (1996)

C12H16N2O N H

Tarta. 459

O NH

EtOH, H2O

C16H24N2O O

N HN

75:25 v/v%

K. Nemák, M. Ács, Zs. M. Jászay, D.

EtOH, H2O 96:4 v/v%

K. Nemák, M. Ács, Zs. M. Jászay, D.

Tarta. 460

Kozma and E. Fogassy, Tetrahedron, 52,

Kozma and E. Fogassy, Tetrahedron, 52,

1637 (1996)

1637 (1996)

C13H15F3N2O N H

O

C17H23F3N2O

EtOH

O

N

NH

NH

F3C Tarta. 461

iPrOH

EtOH, H2O 75:25 v/v%

F3C K. Nemák, M. Ács, Zs. M. Jászay, D.

Tarta. 462

K. Nemák, M. Ács, Zs. M. Jászay, D.

Kozma and E. Fogassy, Tetrahedron, 52,

Kozma and E. Fogassy, Tetrahedron, 52,

1637 (1996)

1637 (1996)

HO

C 1 6 H 2 3 NO

H N

MeOH

C12H17N2

N H N

Tarta. 463

S. Shiotani, T. Kometani, T. Nozawa, A.

Tarta. 464

G. A. Brine, P. A. Stark, Y. Liu, F. I.

Kurobe and O. Futsukaichi, J. Med.

Carroll, P. Singh, H. Xu and R. B.

Chem., 22, 1558 (1979)

Rothman, J. Med. Chem., 38, 1547 (1995)

© 2002 by CRC Press LLC

C12H18N2

H N

MeOH, Acetone

HN Tarta. 465

Z,-X. Wang, Y.-C. Zhu, W.-Q. Jin, X.-J. Chen, J. Chen, R.-Y. Ji and Z.-Q. Chi, J. Med. Chem., 38, 3652 (1995)

© 2002 by CRC Press LLC

Appendix 2 Commercially Produced Resolving Agents and Optically Active Industrial Products That May Be Eligible as Resolving Agents C. KASSAI AND D. KOZMA The following compilation is intended to give information to collegues who intend to elaborate industral scale resolutions about potential sources of resolving agents. We tried to list as many as possible optically active compounds which are produced on an industrial scale. The list is not complete and it cannot be guarateed that the company indicated is still producing or marketing the compound. Names of companies may also have changed. Purpose of the list to give information not to promote any of the products listed. Our work was not supported by any of the companies. The well known major companies producing and/or marketing ﬁne chemicals were not included in our list, since their catalogues are readily available or and information about their products can also be retrieved on the internet. Structure of the data base: 1) 2) 3) 4)

Names and internet address of companies List of abbreviations Alphabetically ordered list of optically active acids produced on an industrial scale Alphabetically ordered list of optically active bases produced on an industrial scale

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Su

lier

A'inomoty Cv, Inc. Amano Pharmaceutical Co . BASF Bios nth International Austin Bochrin~cr [n =clhcim KG Calaire Chimic s.a . Caller Chemical Com an Ccl~=cne Co . Chernetall Chemical Products lnc. Chcmcx Chiron Laboratories Chiroscicncc Ltd . ~h155p Co . Daiccl Chemical Industries C~ . DSM Dynamic Nobel Aktien esellschaft Eastman Fine Chemicals EGiS Co . Elan Inc. EMS-Dottikon AG Ex ansia Fine Dr anics Ltd. Finetech Ltd. Genx me Pharmaceuticals Kancka Cor oration Kin chem lnc. Chemie Linz Ges.m .h .H . Lonza Ltd. L ondell A.H . Marks & Co . Ltd . Ma ro Industries Mitsubishi Co, Na asc & Co . Ltd. Nippvn Chemical Industrial Co . Ltd. Nutraswcct Oxford As mmet Ltd. Peboc Ltd. Rccordati S . .A . ReximIDe ussa Sanafi-S nlhelabo Sc . racor Sumitomo Co . ~

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Internet address of Suppliers Internet address Htt :Ilwww .a'inornoto .com I-itl :Ilwww .amano-cn~ mc .co .' 1 Htt :Ilwww .basf.com Htt :Ilwww .b os nth.com Httpalaustinchcmical .com Htt :Ilwww .intcrchcm .comlim actlsu Htt :Ilwww .callcr .com Htt :Ilwww .cel =er~c,com Httpalwww.chemetall,corn

liersitefcalsite .htm

Htt :Ilwww .chemexindustries.com Htl :Ilwww .chiron.com Htt . :~lwww .chiroscicnce .cvm Htt :~I«~ww.chcmical-mctal .co,~ 1'cslcom an ICIC02$ .html f ltlpalwww.chemical-metal .co.jpljcslcompanylDIDD03 .htm 1 Htt :Ilwww .dsm .com, Htt :Ilwww .dsm- rou .com Httpalwww.dynatnit-nobel.cotn Htt :Ilwww .socma .comlmarket laceleastman .html Htt :Ilwww .c =is .h u Htt :Ilwww .elan-chemical .com Htt :Ilwww .socma,comlmarket lacelcms .html Htl :Ilwww .socma .cotnlmarket lacelcx ansia.html I-itt :Ifwww .fincor anicsco .coral Htt :Ilwww .technion,ac .iiltechnionldimotechl~netech,html Htt :Ilwww . enx me .com Htt :Ilwww .chcmical-rnctal .co.' 1'cslc0m an IKJKD14.htm1 Htt :Ilkin chem .com Htt :Ilwww .wk.or.atlawlatcltai eilEn lishIDSMChemie .htm Htt :Ilwww .lonza .com Htt :Ilwww .l ondell .com Htl :Ilwww .ahmarks .cotn f itt :Ilwww .ma ro .com Htt :Ilwww .mitsubishi .co. Htt :Ilwww .na asc.com Httpalwww.chemical-mctal .c v .jpljeslcompany11~11N 107.htm1 I-itt :Ilwww .nutraswcct .com Htt :Ilwww .oai .co,ukl Htt :Ilwww .eastman .comlfinecheml ebdiv.htm Htt :Ilwww .rccordati .it Htt :Ilwww .de ussa-huels .deldhlindex .htm Htt :Ilwww .sanoii.com Htt :Ilwww .se racor .co m Httpalwww.sumitomo-chem,co.jpl

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Appendix 3 Chiral Selective Chromatographic Analysis Z. Juvancz and G. Seres LIST OF ABBREVIATIONS AND SYMBOLS Ac ACN AGP BGE c CAPS Cbz CD CE CEC CHES CSP DAD DEA Dnb Dns EOF FSOT G GC HPLC i.d. iPrOH k¢ K LC MEKC MeOH MES MS n PrOH R

Acetic acid Acetonitrile a1-Acid glycoprotein Background electrolyte Concentration 3-(Cyclohexylamino) propanesulfonic acid Carbobenzyloxy derivative Cyclodextrin Capillary electrophoresis Capillary electrochromatography 2-(Cyclohexylamino)ethanesulfonic acid Chiral stationary phase Diode array detector Diethylamine Dinitrobenzoyl derivative Dansyl derivative Electroosmotic flow Fused silica open tubular column Free energy Gas chromatography High performance liquid chromatography Internal diameter Isopropanol Capacity factor Distribution coefficient Liquid chromatography Micellar electrokinetic chromatography Methanol 2-(N-Morpholino)ethanesulfonic acid Mass spectrometer Number of theoretical plates Propanol Universal gas constant

© 2002 by CRC Press LLC

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CRC Handbook of Optical Resolution via Diastereomeric Salt Formation

Rs SFC SDS T TAPS tBuOH TBDMS TEA TEAOH TFA tR TRIS wh a m

ABBREVIATION

Resolution value Supercritical fluid chromatography Sodium dodecyl sulfate Temperature 3-[N-Tris(hydroxymethyl)methylamino]propanesulfonic acid tert-Butanol tert-Butyldimethylsilyl Triethylamine Triethanolamine Trifluoroacetic acid Retention time Tris(hydroxymethyl)aminomethane Peak width at half height of peak Chromatographic selectivity Electrophoretic mobility OF

GAS CHROMATOGRAPHIC CHIRAL STATIONARY PHASES (A3.2)

2,3-diAc-6-TBDMS-b-CD 2,3-diAc-6-TBDMS-g-CD 2,6-diMe-3-Pe-b-CD 2,6-diMe-3Pe-g-CD 2,3-diMe-6TBDMS-b-CD 2,3-diMe-6-TBDMS-g-CD 2,6-diPe-3-butyryl-g-CD PerMe-b-CD PerMe-g-CD PerPe-a-CD

ABBREVIATION

OF

2,3-Diacetyl-6-tert-butyldimethylsilyl-b-CD 2,3d-Diacetyl-6-tert-butyldimethylsilyl-g-CD 2,6-Dimethyl-3-pentyl-b-CD 2,6,-Dimethyl-3-pentyl-g-CD 2,3-Dimethyl-6-tert-butyldimethylsilyl-b-CD 2,3-Dimethyl-6-tert-butyldimethylsilyl-g-CD 2,6 Dipentyl-3-butyryl-g-CD Permethylated-b-CD Permethylated-g-CD Perpentylated-a-CD

CHIRAL AGENTS

CM-a-CD CM-b-CD CM-g-CD HP-a-CD HP-b-CD HP-g-CD MA-b-CD 2,3-Ac-6-5-b-CD 2,3-Me-6-S-b-CD Me-b-CD PerMeMA-b-CD PerMe-b-CD Pho-a-CD Pho-g-CD S-b-CD S-g-CD SBE-b-CD SPE-b-CD QA-b-CD TEA-b-CD 18C6H4 © 2002 by CRC Press LLC

IN

CAPILLARY ELECTROPHORESIS (A3.5)

Carboxymethylated-a-CD Carboxymethylated-b-CD Carboxymethylated-g-CD (2-Hydroxy)propyl-a-CD (2-Hydroxy)propyl-b-CD (2-Hydroxy)propyl-g-CD Mono(6-amino-6-deoxy)-b-CD 2,3-Acetyl-6-sulfato-b-CD 2,3-Dimethyl-6-sulfato-b-CD Randomly methylated-b-CD Permethylated 6-monoamino-b-CD Permethylated-b-CD a-CD phosphate g-CD phosphate Sulfated-b-CD Sulfated-g-CD Sulfobutylether-b-CD Sulfopropylether-b-CD 2-Hydroxypropyltrimetylammonium-b-CD 2-Hydroxy-3-trimethylammoniumpropyl-b-CD 18-Crown-6-tetracarboxylic acid

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A3.1 GENERAL ASPECTS OF CHIRAL SELECTIVE CHROMATOGRAPHY The goal of this appendix is to provide some guidelines and several literature references for the chiral selective analysis of resolved compounds with focus on basic and acidic enantiomers. The theoretical background of chromatography is discussed only to the extent that is necessary for adaptation or development of chiral selective methods. Those selectors (or their analogs) are emphasized that are commercially available. General guidelines for the development of new methods are presented. Literature data were collected and selected according to the main topic of this book. Only the special features of chiral chromatography are discussed here. This appendix is a good start, but reading other books about these topics is strongly recommended. The basic and practical 1 2 knowledge of gas chromatography (GC), supercritical fluid chromatography (SFC), liquid chro3 4 matography (LC), and capillary electrophoresis (CE) has been presented elsewhere. Monographs 5–7 8 9,10 11–13 and reviews dedicated to chiral selective GC, SFC, LC, and CE also give more detailed information.

A3.1.1 ADVANTAGES

OF

CHROMATOGRAPHY

IN

CHIRAL ANALYSIS

The checking of enantiomer purity of resolved compounds requires accurate, robust and highly reproducible analytical methods with broad linearity ranges. Several methods (chromatography, polarimetry, NMR, ORD, etc.) have been applied for the determination of enantiomer ratio. Considering rigorous demands by authorities (e.g., Ref. 14), only chromatography is a completely suitable method for determining the enantiomer ratio, especially for the detection of small impurities. Chromatographic methods offer the following advantages: 1. 2. 3. 4. 5. 6. 7.

Accuracy over 99.9 e.e. No interference with matrix components There is no requirement for high purity of the chiral separation agent Very small samples are necessary Determination of several enantiomeric pairs in a single run Fast analysis Online coupling with MS or NMR permits structure identification

Chromatographic detectors have a linear range over more than three orders of magnitude. Peak areas of enantiomers are measured independent of each other, thus allowing precise determination for all components. These two factors offer unique possibilities for the exact determination of e.e., 15,16 even beyond 99%. Chromatographic methods can separate not only the enantiomers from each other, but also the main product from the other components, such as by-products, residues of reagents, starting materials, 17 etc. Well-chosen chromatographic parameters create a disturbance-free retention window, in which the peaks of enantiomers do not co-elute with other components. Purity requirements of used chiral selective agents are low; even a chiral selective agent of 70% e.e. is appropriate for the determination of 99.9% enantiomer ratio in the direct way of chromatography. Chiral impurities of separation media do not disturb the quantitative determinations; they only reduce the chiral selectivity of the chromatographic system. The sample requirement of various chromatographic analyses is in the femtogram (fg) to microgram (mg) range. Chromatographic methods can also separate diastereomers of molecules having more than one 18,19 chiral center. Combinatorial synthetic methods, becoming increasingly popular, also require the simultaneous separation of several enantiomeric pairs. © 2002 by CRC Press LLC

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Very fast, chiral chromatographic procedures, taking as little as 8 sec, have been reported. Direct injection of reaction media without sample purification is also well-known in the chromatographic literature, providing good opportunities for process analysis. Note that polarimetry and circular dichroism give only one signal for two enantiomers; therefore, the exact determination of e.e. values beyond 99% is impossible. Matrix components can also seriously disturb measurements and the such determinations require pure standards. Determinations of e.e. values >99% by NMR have been occasionally claimed. Exact NMR measurements, however, require expensive instrumentation and special solvents; they are rather time-consuming and matrix components may interfere with exact determinations. Moreover, in the case of high e.e. values, the shift reagents used must be very pure (>99.9%). Chromatographic methods provide separations, but little structural information. Chromatographic systems can, however, be coupled online to structure identification instruments (MS, NMR, IR, and DAD), creating hyphenated systems. The information gained by these instruments avoids 21 misinterpretations of eluted peaks. There are two approaches to chromatographic chiral separations. The direct chromatographic method separates the enantiomers via transient diastereomeric associations between the chiral selector and the selectand. The enantioselective agents can be either a stationary or a mobile phase. Association and dissociation processes are fast. With the indirect method, enantiomers are first converted to a pair of stable (mostly covalently bound) diastereomers by reaction with a chiral reagents (derivatization), followed by analysis on achiral chromatographic media. Indirect methods have several disadvantages: they require high-purity derivatization agents and fast and complete reactions. Also, sample discrimination can occur during derivatization and chromatography, and the diastereomers may can elicit different detector responses. This appendix only deals with direct methods.

A3.1.2 BASICS

OF

CHROMATOGRAPHY

The separation of two adjutant peaks is characterized by their resolution value (Rs). The Rs value is a function of various chromatographic parameters: 1 ( a – 1 ) k¢ R s = --- n ◊ ----------------- -----------------a ( k¢ + 1 ) 4

(A3.1.1)

where the n is the number of the theoretical plates representing the efficiency of the system, a is the chromatographic selectivity (in this case, chiral selectivity) representing the relative retention of the peaks, and the k¢ is the capacity factor representing the ratio of the resident time of compounds in the stationary and mobile phases. In the general practice the resolution value is calculated from: t R2 – t R1 R s = 1.17 ------------------------W h2 + W h1

(A3.1.2)

where tr1 and tr2 are the retention times of the peaks, and Wh2 and Wh1 are the peak widths measured at half height. A baseline separation of peaks of Rs = 1.5 is sufficient for the determination of exact areas of symmetrical peaks of the same magnitudes. Peaks having a perfect Gaussian shape, but differing 22 by more than three orders of magnitude in their area need an Rs value >1.5. Because chromatographic peaks in chiral separations rarely have a perfect shape, Rs values >1.5 must be selected. Peaks are usually asymmetric with tailing, probably caused by adsorption effects (e.g., silanol 15,22–25 effect) or overloading. Due to this asymmetry, instead of the peak height, peak area is the base of quantification. In chiral separation, to avoid co-elution of minor peaks with the tail of major © 2002 by CRC Press LLC

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629

peaks, it is advisable to elute the minor component first and thereby avoid uncertainty in peak area 25,26 determination. 5 Chiral selectivity (a) can be expressed thermodynamically using the Gibbs-Helmholtz equation : – DRS ( DG ) ln a = --------------------------RT

(A3.1.3)

where DRS symbol refers to the difference of interaction free energy between the enantiomers, DG the energy difference of the solutes between the stationary and mobile phases, T is the temperature, and R the universal gas constant. Even 0.1 kJ/M energy difference is enough for the chiral separations 26 in the case of high-efficiency chromatographic methods. Equation (A3.1.3) provides the thermodynamic basis for a general observation in chiral chromatography: chiral selectivity increases exponentially with decreasing temperature. Therefore, it is recommended that the operating temperature be kept low if efficiency and analysis time permit. During chromatography processes, not only enantioselective interactions take place between selector and selectands, but also achiral interactions. The latter are known to diminish chiral selectivity, because achiral interactions compete with chiral ones for the solute molecules. For example, the well-known silanol effect (interactions with the remaining silanol groups of support) decreases the 23 selectivity of the stationary phase.

A3.1.3 PHYSICAL BASIS

OF

CHIRAL SELECTIVE CHROMATOGRAPHY 27–29

The majority of direct enantiomer separations can be deduced from the three-point model. According to this theory, the chiral selector and selectand need at least three simultaneous interactions to make differentiation between enantiomers. Of course, the interaction sites can be other 30 than point-type interactions. Charge-transfer interactions between two aromatic ring systems or inclusion in the selector cavity can function as interaction points. Even the repulsive effect of a 28 bulky group can act as an interaction. A given selector can establish three-point interactions with only enantiomers, the groups of which can interact with the groups of selectors (acid-base, H-bond donor-acceptor, etc.) and have a close fit from a steric point of view. A rigid structure (selector, selectand, or both) can produce high chiral selectivity because only one of the enantiomers has a tight fit to the selectand. On the other hand, selectors with a rigid structure have a rather narrow band of selectivity because they can create 7 a close fit only with a limited set of compounds. Flexible selectors show moderate selectivity, but are capable of chiral recognition toward a broad spectrum of enantiomers. The very broad selectivity range of cyclodextrins is partly due to their flexible structure. The rigid structure of metalcontaining chiral complexes are more selective than cyclodextrins, but with a much lower number 15 of enantiomers.

A3.1.4 COMPARISON OF VARIOUS CHROMATOGRAPHIC MODES IN CHIRAL ANALYSIS Various types of interactions play a role in chiral recognition. Intermolecular forces involved in chiral recognition are polar/ionic, p-p, dipole-dipole, hydrogen bonding, dispersion (hydrophobic), repulsive, and shape-selective interactions. During method development, the analyst can manipulate these intermolecular forces by choosing suitable stationary and mobile phases. For example, a nitro group containing enantiomer having a p-acid structure can easily be separated on a p-base stationary phase. The various types of chromatographic modes favor different types of interactions (Table A3.1.1). GC works with the weakest interactions, while ionic forces important in CE are the strongest interactions. © 2002 by CRC Press LLC

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TABLE A3.1.1 Interactions Dominant in Various Chromatographic Modes Interaction Type Dispersion p-p Dipole-dipole H-bond Ionic Repulsive Shape selective

GC

SFC

HPLC

CE

++++ ++ + +

+++ ++ ++ ++

+ ++

++ ++

++ +++ +++ +++ ++ +++ ++

+ ++ ++ +++ ++++ ++ +++

Note: The number of + signs shows the importance of a given interaction.

TABLE A3.1.2 Advantages of Various Chiral Chromatographic Modes Chromatographic Mode Feature Efficiency Low analysis temperature Stationary phase variability Mobile phase variability Detectability Speed of analysis Elaboration level of technique

GC

SFC

LC

CE

++++ + ++

+++ +++ + + +++ ++ +

++ ++++ +++ +++ +++ + ++++

++++ ++++ + ++++ ++ ++++ ++

++++ ++++ ++++

Note: The number of + signs shows the goodness of a given feature.

In addition to chiral recognition forces, some other parameters must be considered when trying to find the ideal chromatographic mode. The advantages of various chiral selective chromatographic modes are summarized in Table A3.1.2. GC and CE are the most efficient; that is, even millions of theoretical plates can be achieved. These methods are appropriate for baseline separations of enantiomers having only a = 1.01 values (~0.1 kJ/M). LC can produce the same resolutions for enantiomers having at least a = 1.2 values. LC enables the widest choice of chiral stationary phases. Theoretically, all of the stationary phases that are applied in LC can be used in CE in CEC mode, but the CEC techniques have not been developed as yet. The dissolving power of the mobile phase significantly influences the selectivity of a chromatographic system. From this point of view, the most versatile technique is CE followed by LC. The nature of the mobile phase has a certain influence on selectivity in SFC, but none in GC. Owing to selective detectors (ECD, NPD), GC is the most sensitive mode. MS is most developed with GC. Sensitive detectors (UV, fluorescent) applied in LC, SFC, and CE require chromophore groups that are absent in many enantiomers. The small diameters of CE columns offer only limited detectability because of the short optical path length (50 to100 mm) possible in on-column detection. The high permeability of the mobile phase offers high mobile phase velocity, resulting in fast 20 analysis in GC. Owing to a combination of high efficiency and fast mass transfer, CE also proves 31 to be a fast method. © 2002 by CRC Press LLC

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GC and LC are the oldest methods; therefore, their instrumental backgrounds are the most developed. They have been routinely used for decades, offering well-developed methodological know-how and established working conditions with an enormous number of applications. The most 11 dynamically developing branch of chiral chromatography is CE. Of course, the choice of chromatographic mode is influenced not only by the character of the separable enantiomers, but also by the availability instruments. Sometimes, special requirements restrict the choice of method to be used. For example, fast analysis can be crucial in process control: in this case the GC or CE is ideal. On the other hand, LC may be the choice if robustness and the automation of the method are crucial for laboratories working under GLP conditions.

A3.1.5 ROLE

OF

SAMPLE DERIVATIZATION

IN

CHIRAL CHROMATOGRAPHY

Achiral derivatization of the analytes can change their polarity (volatility), chiral recognition, and 32 detectability features. For example, an acidic functional group is optimal for CE analysis (highly polar, less volatile), but the methyl esters of acids (low polarity improved volatility) are excellent for GC analysis. Chiral recognition of selectors can be improved with appropriate derivatization of selectands. Dansyl (Dns) derivatives of amino acids are well separated on Pirkle-type chiral 30 stationary phases (CSPs), and the cyclic derivatives of diols and amino alcohols fit well the 5,18 structure of cyclodextrin-based CSPs. Moreover, Dns derivatives of amino acids improve not only selectivity, but also their detectability. The retention shift of enantiomers resulting from derivatization may enable the avoidance of co-elution with matrix components.

REFERENCES 1. R.L. Grob, Modern Practice of Gas Chromatography, John Wiley & Sons Inc. (1995). 2. T. Berger and K. Anton, Eds., Packed Column Supercritical Fluid Chromatography, Marcel Dekker, New York (1997). 3. L.R. Sneyder, J.L. Glajch, and J.J. Kirkland, Practical HPLC Method Development, John Wiley & Sons Inc. (1997). 4. K.D. Altria, Capillary Electrophoresis Guidebook. Principles, Operation and Applications (Methods in Molecular Biology), Humana Press (1996). 5. W.A. König, The Practice of Enantiomer Separation by Capillary Gas Chromatograpy, Hüthig, Heidelberg (1987). 6. W.A. König, Gas Chromatographic Enantiomer Separation with Modified Cyclodextrins, Hüthig, Heidelberg (1992). 7. Z. Juvancz and P. Petersson, J. Mirocol. Sep., 8, 99 (1996). 8. Z. Juvancz and K.E. Markides, LC/GC Int., 5, 44 (1992). 9. S. Allenmark, Chromatographic Enatioseparation: Methods and Applications, Ellis Horwood (1991). 10. G. Subramanian, A Practical Approach to Chiral Separations by Liquid Chromatography, VCH Publisher (1994). 11. B. Chankvetadze, Capillary Electrophoresis in Chiral Analysis, John Wiley & Sons (1997). 12. G. Gübitz and M.G. Schmid, J. Chromatogr. A., 792, 179 (1997). 13. K. Verleysen and P. Sandra, Electrophoresis, 19, 2798 (1998). 14. Department of Health and Human Service of USA Food and Drug Administration’s Policy Statement for the Development of New Stereoisomeric Drugs, Fed. Reg., 57, 2 May, 102 (1992). 15. V. Schurig, J. Chromatogr., 441, 135 (1988). 16. K.D. Altria, M.M. Rogan, and D.M. Goodall, Chromatographia, 38, 637 (1994). 17. Z. Juvancz, K.E. Markides, and L. Jicsinszky, J. Microcol. Sep., 11, 716 (1999). 18. Z. Juvancz, K. Grolimund, and V. Schurig, J. Microcol. Sep., 5, 459 (1993). 19. H. Wan and L.S. Blomberg, Electrophoresis, 18, 943 (1997). 20. V. Schurig and H. Grosenick, J. Chromatogr. A., 666, 617 (1994). 21. M. Manschreck and M. Mintas, Angew. Chem., 92, 490 (1980). 22. I.R. Snyder, J. Chromogr. Sci., 10, 200 (1972). © 2002 by CRC Press LLC

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632 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.

A3.2

CRC Handbook of Optical Resolution via Diastereomeric Salt Formation M. Petersen, J. Chromatogr., 505, 3 (1990). M.A. Nussbaum, Electrophoresis, 20, 2664 (1999). V.R. Meyer, LC-GC Int., 7, 94 (1994). V. Schurig, J. Chromatogr. A., 666, 111 (1994). C.E. Dalgliesh, J. Chem. Soc., 3940, (1952). V.R. Meyer and M. Rais, Chirality, 1, 167 (1989). V.A. Davankov, V.R. Meyer, and M. Rais, Chirality, 2, 208 (1990). W.H. Pirkle, C.G. Welsh, and M.H. Hyun, J. Chromatogr., 607, 126 (1992). A. Aumatell and A.Guttman, J. Chromatogr. A., 717, 229 (1995). K. Blau and J.M. Halket, Eds., Handbook of Derivatives for Chromatography, John Wiley & Sons (1993).

CHIRAL SELECTIVE GAS CHROMATOGRAPHY

A3.2.1 CHARACTERIZATION

OF

GC

Gas chromatography is the best technique for the separation of volatile, apolar and moderately polar enantiomers. Several less-volatile chiral compounds are also appropriate for GC analysis after derivatization. Compounds lacking UV or fluorescent activity are also frequently analyzed by GC, although their volatility would suggest LC, SFC, or CE. The usefulness of GC is well-demonstrated 1,2 3,4 5 by ª20000 chiral separations done with GC. Two books, several reviews, and a database dealing with chiral GC have been published. A3.2.1.1 Special Features of GC As has been shown (Section A3.1.4, Table A3.1.2), the prominent advantage of GC is its high efficiency, short analysis time, good detectability, well-established instrumentation and solid theoretical background. Its weak points are the passive role of the mobile phase in selectivity and often high analysis temperatures. A3.2.1.2 Special Features of GC in the Chiral Analysis Retention times in GC are primarily determined by non-selective interactions; therefore, chiral selectivity values (a) rarely exceed 2. The high efficiency of GC columns, however, frequently compensates for moderate selectivity. The low viscosity of the mobile phase allows the use of long (up to 100 m) open tubular columns, realizing more than 1 million theoretical plates. This means 3 that even a values of 1.01 to 1.03 may be enough for baseline separation in GC. The elevated analysis temperature required for less-volatile enantiomers result in diminished selectivity but is compensated for by the high efficiency of columns. Achiral derivatization, mostly in the case of acids and amines has great importance in chiral-selective GC by producing more volatile analytes, allowing lower analysis temperatures and giving undistorted peaks.

A3.2.2 COLUMNS In chiral-selective GC, fused silica open tubular (FSOT, capillary) columns are used almost exclusively, with column lengths between 10 and 50 m. In case of high selectivity values (a > 1.1), columns less than 5 m in length may be sufficient. The recommended inner diameter (i.d.) of the columns is between 0.1 and 0.32 mm. Smalldiameter columns (0.1 mm i.d.) offer very high efficiency but moderate loadability. Chiral columns are more susceptible to overloading than achiral columns because only some of the interaction sites of CSPs have chiral recognition features. Even samples of a few tenths of a nanogram can overload 6 0.1-mm i.d. columns, causing significant peak broadening and sharply reducing resolution values. The use of 0.1-mm i.d. columns, which can separate enantiomers having an a value of 1.01 are © 2002 by CRC Press LLC

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recommended only up to 10 to 20 e.e. The loadability of normal, 0.2 to 0.25-mm i.d. columns can secure baseline separation for enantiomers having an a value of 1.03, even in the case of e.e. 99.9.

A3.2.3 MOBILE PHASES For the mobile phase (carrier gas), H2 and He are recommended. The nature of the mobile phase influences both speed and efficiency of the analysis, but is indifferent from the point of view of selectivity. The speed of analysis is highest using H2 because it has the highest permeability. Considering GC/MS coupling and fire regulations, however, He may be preferred. The purity of the carrier gas (free of O2 and H2O) is more important for CSPs than for apolar silicone stationary phases. The use of gas purifiers and their regular replacement is highly recommended. Daily change of the septum is also advisable because any leak through the septum results in O2 contamination.

A3.2.4 CHIRAL-SELECTIVE STATIONARY PHASES A3.2.4.1 Requirements for Chiral-Selective Stationary Phases in GC An up-to-date chiral-selective stationary phase (CSP) must be highly efficient, selective, thermally stable, and chemically inert. Owing to the moderate selectivity of CSPs, highly efficient columns are a necessity. Only those CSPs can exceed the 3000 plates/meter values, which contain highly efficient silicone 4 7 polymers. A good CSP is the result of a compromise. Using an apolar, achiral matrix (silicone polymer), increasing the percentage and rigidity of the chiral component has both advantages and disadvantages. Efficient CSPs can be mixtures of an achiral silicone polymer and chiral molecules, or the chiral functionality can be chemically bonded to the silicone matrix. Some older CSPs (cyclodextrin derivatives) are undiluted, molten chiral compounds but have moderate selectivity, and several of 8–10 these CSPs have been reintroduced as mixtures with silicone matrices. It has been proven both theoretically and practically that the chiral selectivity of CSPs shows 11 a leveling-off curve as a function of the percentage of the chiral component. Therefore, there is no reason to increase this above 50%. On many occasions, 15 to 25% chiral content is enough for most separations. It is very important to preserve the low temperature working range of CSPs by using a low chiral content. CSPs with a chemically bonded chiral component (e.g., Chirasil-Val, Chirasil-Dex CB) offer higher selectivity and efficiency as well as broader operation temperature ranges than their mixed analogs. A3.2.4.2 Cyclodextrin-Based CSPs Cyclodextrins (CDs) have become the most popular CSPs shortly after their introduction in capillary 12 5 GC. More than two thirds of chiral GC separations were done on CD-based CSPs. CDs are cyclic 13 oligosaccharides with 6 (a-CD), 7 (b-CD), and 8 (g-CD) glucose units. Native CDs have no melting points because they decompose before melting. Various derivatives of CDs, however, become liquid at moderate temperatures. The working range of CDs (liquid state) can be expanded 3,14–16 by dissolving them in silicone matrices. For example, the melting point of permethylated bCD is 150∞C, but its 10% solution in OV-1701, an achiral silica stationary phase, can be used even at room temperature. Enantiomers having no functional groups have been separated on CD-based CSPs. Moreover, 17 they can recognize not only central, but also planar and axial chirality and chiral centers with 2 heteroatoms. The broad recognition range of CDs arises from their structure: several different chiral 4 centers, differently substituted groups, and a chiral recognition mechanism based on induced fit. © 2002 by CRC Press LLC

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In contrast, owing to their flexible structure, CDs show only moderate selectivity. The variety of the sources of their chiral recognition ability makes chiral selectivity features unpredictable. Sometimes, more than one chiral recognition mechanism is involved in the separation of enanti18 omers. Elution reversal within a homologous series of g-lactones has provided some evidence for the coexistence of more than one chiral recognition mechanism. The ring size of CDs has a very loose correlation with the size of separated chiral compounds. 19 Several enantiomers were separated on CDs of all ring sizes, and branched alkane enantiomers 20 (smallest compounds) were separated on a derivative of g-CD. CDs substituted with polar groups (acetyl, trifluoroacetyl, and butyryl) show, in general, higher selectivity toward polar 21 enantiomers than CDs with apolar (methyl, pentyl) substitution. H-bond-type interactions can play a role in chiral recognition; therefore polar enantiomers 22 (acids, alcohols) frequently show higher selectivity than their derivatives. Consequently, if the volatility of analytes allows, it is better to analyze them without derivatization. In contrast to other CSPs, CDs also show selectivity toward enantiomers with a chiral center 4,23 not adjacent to the functional groups. Because CDs are natural products, their antipodes are not available. Elution reversal of enantiomers, important in the determination of high e.e., can sometimes be achieved by changing the cavity size or substitution pattern of CDs.19,20 Permethylated b-CD shows the broadest selectivity spectrum and therefore has been used most 4 14 frequently in CSPs. It is marketed either as a mixture with moderately polar silicones or in a 22,24,25 chemically bonded form (Chirasil-Dex CB). The bonded version has higher efficiency, selectivity, 25 and broader temperature working range than the mixed versions. A typical application is shown in Fig. A3.2.1. The high selectivity of Chirasil-Dex, a CSP having chemically anchored selectors, is apparent. The efficiency of the columns is high using only a 0.1-mm i.d. column and a thin film of CSP. Owing to proper derivatization, the peaks show perfect shape coming from a well-chosen derivative of enantiomer. For details, see the procedure described after Fig. A3.2.3. The only difference was that the reagent was acetic anhydride instead of trifluoroacetic anhydride. The importance of CDs derivatized in 6-O positions with tert-butyldimethylsilyl (TBDMS) groups is rapidly growing; they have become the second most important class of CD-based CSPs. 15,26 16,27 Both acyl and alkyl substituted versions in the remaining 2-O and 3-O positions with different 19,28 ring sizes are current. The achiral silicone matrix content is in the 50 to 80% range. Recently, several silyl derivatives of CDs have been introduced as chiral components. Some of them showed unique, but rather narrow selectivity spectra. An example is shown in Fig. A3.2.2. The low chiral content and apolar silicone matrix allow the analysis of the low-molecularweight acid without derivatization. The mixed CSPs show a high efficiency. Acyl (acetyl, trifluoroacetyl, butyryl, etc.) substituted derivatives in 3-O positions (other positions alkylated) of CDs are also frequently used, primarily for the analysis of polar enantiomers in 8,23 mixed or undiluted forms. Peralkylated versions of CDs other than methyl are also frequently applied in mixed, undiluted, 9,21,29 and chemically bonded forms. A3.2.4.3 Amino Acid-Based CSPs These CSPs are excellent for the separation of vicinal, bifunctional enantiomers having H-bond 1,30,31 donor abilities even after derivatization. They are excellent for the chiral analysis of amino acids (except proline), aminoalcohols, and hydroxy- and haloacids. Successful chiral separations have been achieved with enantiomers other than cited, but their applications have shrunk with the introduction of CD based CSPs. The rigid structure of the chiral part limits their recognition potential, primarily toward analytes having functional groups in a-positions to the chiral center. Isopropylesters of N-trifluoroacetyl amino acids are the most frequently used derivatized forms on 32,33 these CSPs. Cyclic derivatives also show high selectivity. Changing the chirality of the amino acid enables retention reversal of R and S enantiomers. © 2002 by CRC Press LLC

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635

FIGURE A3.2.1 Chiral separation of N-acetyl-2-methylindane. Conditions: 10 m ¥ 0.1 mm i.d. fused silica open tubular column, coated with Chirasil-Dex (df = 0.15 m m); oven temperature 160∞C; carrier gas H2. (From Z. Juvancz, K. Grolimund, V. Schurig, J. Microcol. Sep., 5, 549 (1993). With permission.)

Chirasil-Val, a chemically bonded valine-tert-butylamide containing silicone polymer is 1,31 appropriate for enantiomer separation of all essential amino acids in a single run. It is highly recommended for chiral analysis of amino acids (with the exception of proline) because resolution values are high and the derivatization of them is well-developed and simple. Chiral 2,22 separation of proline, however, is recommended on CD-based CSPs. A typical example is shown in Fig. A3.2.3. The well-designed, chemically bonded CSP offers good selectivity (baseline separation even for proline) and fast analysis. The traditional, commercialized versions of Chirasil-Val have less favorable characteristics. The applied derivatives are best suited to CSPs producing separation of not only enantiomers, but owing to the carefully adjusted temperature program, complete separation of various amino acids also. N-trifluoroacetyl propylester derivatives (frequently used in Chirasil-Val-type CSPs) can be 31,35 prepared as follows. The amino acid sample (5 mg) was dissolved in 3 N HCl in propanol (20 ml), heated in the sealed vial (0.5 h, at 100∞C), and dried in an N2 stream. The residue was dissolved © 2002 by CRC Press LLC

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FIGURE A3.2.2 Chirospecific differentiation of tropic acid. Conditions: 30 m ¥ 0.23 mm i.d. open tubular -1 glass column coated with 20% 2,3-diAc-6-TBDMS-g-CD in SE-52 (0.25 mm df), carrier gas H2, 50 cm s , -1 temperature programmed from 165∞C at 2∞C min . (From B. Maas, A. Dietrich, V. Karl, A. Kaunzinger, D. Lehman, T. Köpke, and A. Mosandl, J. Microcol. Sep., 5, 421 (1993). With permission.)

in CH2Cl2 (20 ml), mixed with trifluoroacetic anhydride (4 ml), and heated again in a sealed vial (0.5 h, at 40∞C), followed evaporation in an N2 stream. Finally, the residue was dissolved in CH2Cl2. The same reaction parameters can be applied using isopropanol, acetic anhydride, or pentafluoropropionic anhydride. XE-60-Val-a-pea silicone polymer contains a modified XE-60 silicone matrix substituted with 1 a valine-a-phenylethylamide side chain. Two chiral centers of side chain enhance the chiral recognition capability of this CSP. Selectivity of XE-60-L-Val-(S)-a-pea is comparable to that of Chirasil-Val. Its diastereomer, XE-60-L-Val-(R)-a-pea shows reduced selectivity toward amino 1 acids, but high selectivity toward cyclic derivatives of amino alcohols, diols, and acetylated amines. Several other types of chemically bonded, highly efficient, and selective CSPs have been published. For example, CSPs containing metal complexes coordinated to chiral terpenoic compounds 35 efficiently separate g-lactones, aliphatic secondary alcohols, and rigid cyclic compounds. The naphthylethyl amide containing silicone polymers are Pirkle-type CSPs with high selectivity for 36 7 aromatic compounds. Mixtures of a silicone matrix with cellulose derivatives of chiral molecules, 37 and CSP containing amides of trans-1,2-cyclohexyldiamine were also introduced into GC. Unfortunately, these CSPs are not yet commercially available. © 2002 by CRC Press LLC

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FIGURE A3.2.3 Gas chromatogram of N(O)-trifluoroacetyl-n-propyl amino acid ester enantiomers on a capillary column (15 m × 0.25 mm) coated with an improved version of Chirasil-Val (0.14 µm); carrier gas He (45 cm/sec); column temperature: 85°C, hold for 2 min, heated to 100°C at 3°/min, to 120°C at 6°/min, and 210°C at 8°/min. In each case, the D-enantiomer is eluted first, except for 4-hydroxyproline. (From I. Abe, T. Nishiyama, and H. Frank, HRC, 17, 9 (1994). With permission.)

A3.2.5 ANALYSIS TEMPERATURE Analysis temperature has an important influence on selectivity in GC. As shown earlier [Eq. (A3.1.3) in Section A3.1.2], selectivity sharply increases with decreasing temperature. Elution of compounds of low volatility requires elevated temperature, sometimes above 200°C, which may also cause 22,35 Decreasing the analysis temperature by derivatization of sample degradation and racemization. analytes is discussed in Section A3.2.6. An effective way of reducing analysis temperature is to use, instead of undiluted chiral selectors, 4,14 a CSP containing the chiral selector dissolved in an apolar silicone matrix. Lower analysis temperature entails longer retention times; which can be compensated, however, by taking a shorter column. For example, at lower temperatures, a 50-m-long column could be replaced by a 2-m column without 8,38 impairing resolution. On the other hand, the required vapor pressure of the analytes and efficiency loss of some CSPs (solidification) at low temperature set a lower limit for analysis temperature.

A3.2.6 ACHIRAL DERIVATIZATION The achiral derivatization of the analytes can change their polarity (volatility), chiral recognition, and detectability. 34 In chiral GC practice, the most important effect of derivatization is increased volatility. In this way, the analysis temperature can be kept low to achieve high selectivity. In the majority of © 2002 by CRC Press LLC

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cases, the most volatile derivatives proved to give the best selectivities. Also, derivatives that are well-suited to chiral recognition mechanisms of CSP can improve resolution For example (and in contrast to CD-based CSPs), on amino acid-based CSPs, isopropyl esters of amino acids show 30 better selectivity than the more volatile methyl esters. Derivatization reactions must be fast and should give homogeneous and thermostable products. It is advisable to use volatile agents and side-product-free reactions to avoid disturbing peaks. In several cases, an evaporation or extraction step is necessary to eliminate disturbing compounds. Carboxylic acids and phenols are usually converted to methyl esters and methyl ethers, respec22,34 tively. For methylation, diazomethane is recommended. For methanol with acid catalysis (BF3, HCl) is also suitable. Efficient chiral recognition may require esterification with other alcohols when the appropriate alcohols are reacted with the analytes using acid catalysis. Alcohols, amines, and phenols are easily acylated using acyl and perfluoroacyl anhydrides in aprotic solvent with base catalysis (TEA, pyridine). The most frequently used reagents are acetic anhydride, trifluoroacetic acid anhydride, and pentafluoropropionic acid anhydride. Cyclic derivatives of 1,2- and 1,3-functionalized compounds frequently show high selectivity. From 1,2- and 1,3-diols phosgene produces cyclic carbonates, oxazolidine-2-ones from 2-amino 22,32,33 These cyclic derivatives are alcohols, and 1,3-dioxolane-2,4-diones from 2-hydroxy acids. 2,22,33 well-suited to both amino acid and cyclodextrin based CSPs. Silyl derivatives are less popular in chiral chromatography. Several derivatives (Dns, Dnb, antranyl, etc.) of chiral selective LC cannot be used in GC because their considerable molecular weight requires high analysis temperature, or their thermolability results in thermal decomposition under GC conditions.

A3.2.7 INSTRUMENTAL Most up-to-date GC instruments can be used with open tubular columns even of 0.1 mm i.d. The sensitivity of FID (flame ionization detection) is sufficient for the quality control of resolutions, but MS and IR detectors also offer structural information. Virtually every column manufacturer sells permethylated b-CD containing CSPs in mixed forms. Its chemically bonded version (Chirasil-Dex CB) is also available. A broad range of CDbased stationary phases are customized. Most CSPs are mixtures of CD derivatives and silicone polymers, but Lipodex and Chiraldex CSPs are undiluted CD derivatives. Upon request, Lipodex CSPs can also be delivered in mixed forms. Brand names (prefix of CSPs) and the producers of CD-based CSPs are as follows: Lipodex and Hydrodex, Macherey-Nagel; BGB, BGB Analytik AG; Chirasil-Dex,Varian; Rt-DEX, Restek; DEX, Supelco; Chiraldex, ASTEC, FS-Cyclodex, CS-Chromatographie Service; Megadex, Mega. Chirasil-L-Val, the chemically bonded valine containing CSPs, are available from Varian, Alltech, and Macherey-Nagel. The R version and XE-60-L-Val-(S)-a-pea is product of Varian.

A3.2.8 APPLICATIONS Several examples of chiral-selective GC separations are collected in Table A3.2.1. Abbreviations for chiral selectors are in the list of symbols (page 611). OV-1701, PS 268, and SE-52 are achiral silicone polymer stationary phases. The present compilation is, of course, not comprehensive, but the authors have tried to give a representative collection, concentrating on acidic and basic enantiomers. The data in Table A3.2.1 show the characteristic features of separations. Several chiral separations of acids and amines were omitted because they were performed on outdated or commercially unavailable CSPs. Lipodex CSPs were included because their improved mixed versions are commercially available. “Analyzed form” suggests the recommended derivatization for the given CSP. The lengths of columns and analysis temperatures are only guidelines. The producers of columns were listed in Section A3.2.7. © 2002 by CRC Press LLC

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TABLE A3.2.1 Chiral Separations with GC Name of the Analyte (Analyzed Form)

Column (m ¥ mm)

Alkyl branched acids

30 ¥ 0.23

Alkyl branched acids (methyl ester) Bicyclo[2.2.1]hept-5-encarbocyclic acid (methyl ester) cis/trans-Chrysanthemic acids (free acids) cis/trans-Chrysanthemic, permethrinic, deltamethrinic acids (alkyl esters) Citramallic acid (methyl ester) Dichlorprop (methyl ester)

30 ¥ 0.23 40 ¥ 0.25

10 ¥ 0.1 10 ¥ 0.1

10 ¥ 0.25 10 ¥ 0.1

Dichlorprop (methyl ester)

20 ¥ 0.25

Dichlorprop, Fenoprop, Mecoprop (methyl ester) Fenoprofen, Flurbiprofen, Ibuprofen (methyl ester) 2-Hydroxy-, 3-hydroxy-acids (methyl ester)

8 ¥ 0.25 8 ¥ 0.25 30 ¥ 0.23

2-Hydroxy-, 3-hydroxy-acids (methyl ester) 2-Hydroxy-, 3-hydroxy- acids (TFA, methyl ester) 2-Hydroxy-acids (1,3-dioxolane-2,4-diones)

15 ¥ 0.25

Jasmonic acid (methyl ester)

2 ¥ 0.25

Jasmonic acid (methyl ester)

25 ¥ 0.25

Juvenile hormone I (methyl ester) Lactic acid (methyl ester)

8 ¥ 0.25 10 ¥ 0.25

Lipoic acid (methyl ester)

25 ¥ 0.25

50 ¥ 0.25 35 ¥ 0.25

Stationary Phase (Product Name) Acids 15% 2,3-diMe-6TBDMS-b -CD + PS-268 (b -Dex 325, BGB-172, Hydrodex b-6TBDM) 17% 2,3-diMe-6-TBDMS-g-CD + SE-52 (g-Dex 325) 10%PerMe-b -CD + OV-1701 (Chirasil-Dex CB, Hydrodex b -PM) Chemically bonded (Chirasil-Dex CB, Chemically bonded (Chirasil-Dex CB,

30% PerMe-b-CD Hydrodex b-PM) 30% PerMe-b-CD Hydrodex b-PM)

80% 2,6-diPe-3-butyryl-g-CD + OV-1701 (diluted Lipodex E) Chemically bonded 30% PerMe-b-CD (Chirasil-Dex CB, Hydrodex b-PM) 15% PerMe-b -CD + OV-1701 (Chirasil-Dex CB, Hydrodex b-PM)

50% 2,6-diMe-3Pe-b -CD + OV-1701 (Hydrodex b -3P) 50% 2,6-diMe-3Pe-b -CD + OV-1701 (Hydodex-b -3P) 30% 2,3-diMe-6TBDMS-b -CD + SE-52 (b -Dex 325, BGB-172, Hydrodex b -6TBDM) 50% 2,6-diMe-3Pe-b-CD + OV-1701 (Hydrodex b -3P) 100% 2,6-diPe-3-butyryl-g-CD (Lipodex E) Chemically bonded valine phenylethylamide (XE-60-L-Val-(R)-a-Pea) 10% PerMe-b-CD + OV-1701 (Chirasil-Dex CB, Hydrodex b-PM) 50% 2,6-diMe-3Pe-b -CD + OV-1701 (Hydrodex b -3P) 50% 2,6-diMe-3-Pe-b -CD + OV-1701 (Hydrodex-b -3P) Chemically bonded 40% 2,6-diPe-3butyryl-g-CD (diluted Lipodex E) 50% 2,6-diPe-3-butyryl-g-CD + OV-1701 (diluted Lipodex E)

Analysis Temperature (∞∞C)

Ref.

90∞C(5 min)Æ 1.5∞C/minÆ230∞C

28

80∞C(5 min)Æ 1.5∞C/minÆ230∞C 105∞C

28 46

110∞C

22

90–160∞C

22

100∞C

41

130∞C

22

60∞C(1 min)Æ 20∞C/minÆ 100∞CÆ 2∞C/minÆ140∞C 110∞C

47

120∞CÆ 1∞C/minÆ160∞C 80–150∞C

10 10 27

110∞CÆ 1∞C/minÆ170∞C 80–170∞C

10 23

100–150∞C

32

100∞C(3min)Æ 5∞C/minÆ130∞C 160∞C

38

120∞C

40

80∞C

48

155∞C

41

9

(Continued) © 2002 by CRC Press LLC

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TABLE A3.2.1 Chiral Separations with GC (continued) Name of the Analyte (Analyzed Form)

Column (m ¥ mm)

2-Methylbutananoic acid (propyl ester) MCPP (methyl ester)

25 ¥ 0.23

2-Methyldecanoic-, 2-methyldodecanoic-acids (methyl ester) 2-Methyl-3-oxabutanoic acid (ethyl ester) 1-Methyl-2-oxo-cyclohexane carboxylic acid (methylester) Permethrinic acids (methyl ester) 2-Phenyllactic acid (methyl ester) 2-Phenylpropionic acid (methyl ester) Tropic acid (methyl ester)

33 Amino acids (N-TFA amide, isopropyl ester?) 20 Amino acids (N-TFA amide, propyl ester?)

20 ¥ 0.25

Stationary Phase (Product Name) 50% 2,3-Ac-6-TBDMS-b-CD + OV-1701 (b-DEX 225, BGB-174) 15% PerMe-b-CD + OV-1701 (Chirasil-Dex CB, Hydrodex b-PM)

Analysis Temperature (∞∞C)

Ref.

80∞C

26

60∞C(1 min)Æ 20∞C/minÆ 100∞CÆ 2∞C/minÆ140∞C 120∞C

47

10

25 ¥ 0.25

50% 2,6-diMe-3Pe-b-CD + OV-1701 (Hydrodex b-3P)

10 ¥ 0.25

60% 2,6-diPe-3-butyryl-g-CD + 0V-1701 (diluted Lipodex E) 50% 2,6-diMe-3-Pe-b-CD + OV-1701 (Hydrodex-b-3P)

85∞C

41

75∞C

40

50% 2,6-diMe-3Pe-g-CD + OV-1701 (Hydrodex b-3P) 50% 2,6-diMe-3-Pe-b-CD + OV-1701 (Hydrodex-b-3P) 50% 2,6-diMe-3-Pe-b-CD + OV-1701 (Hydrodex-b-3P) 20% 2,3-Ac-6-TBDMS-g-CD + SE-52 (g-DEX 225, BGB-175)

110∞C

10

135∞C

40

105∞C

40

165∞CÆ 2∞C/minÆ200∞C

28

120∞CÆ 3∞C/minÆ160∞C 85∞C(2 min)Æ 120∞CÆ 3∞C/minÆ 185∞CÆ210∞C 80∞C

23

175∞C

22

120∞CÆ 3∞C/minÆ160∞C 110∞C

23 22

60∞C

41

100∞C

22

60∞C

46

120∞CÆ1∞C/min

40

25 ¥ 0.25

25 ¥ 0.25 25 ¥ 0.25 25 ¥ 0.25 75 ¥ 0.23

50 ¥ 0.25 50 ¥ 0.27

Baclofene (N-TFA amide, methyl ester) Baclofene (lactame)

10 ¥ 0.25

N-methylamino acids (N-TFA amide, methylester) Proline (N-TFA amide, methylester)

50 ¥ 0.25

2-Aminopentane (N-TFA amide) Deprenyl

10 ¥ 0.25

2,5,-Dihydro-2-isopropyl3,6,-dimethoxypyrazine Ketamine (N-TFA amide)

40 ¥ 0.25

10 ¥ 0.1

10 ¥ 0.1

10 ¥ 0.1

8 ¥ 0.25

Amino Acids 100% 2,6-diPe-3-butyryl-g-CD (Lipodex E) Chemically bonded valinetercbutylamide (Chirasil-Val)

35% 2,6-diPe-3-butyryl-g-CD + OV-1701 (diluted Lipodex E) Chemically bonded 30% PerMe-b-CD (Chirasil-Dex CB, Hydrodex b-PM) 100% 2,6-diPe-3-butyryl-g-CD (Lipodex E) Chemically bonded 30% PerMe-b-CD (Chirasil-Dex CB, Hydrodex b-PM) Amines 60% 2,6-diPe-3-butyryl-g-CD + OV-1701 (diluted Lipodex E) Chemically bonded 30% PerMe-b-CD (Chirasil-Dex CB, Hydrodex b-PM) 10% PerMe-b-CD + OV-1701 (Chirasil-Dex CB, Hydrodex b-PM) 50% 2,6-diMe-3-Pe-b-CD + OV-1701 (Hydrodex-b-3P)

31

8

(Continued) © 2002 by CRC Press LLC

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TABLE A3.2.1 Chiral Separations with GC (continued) Name of the Analyte (Analyzed Form)

Column (m ¥ mm)

Mefenorex

8 ¥ 0.25

Methamphetamine (N-TFA amide) 2-Methylindane (N-Ac amide) Methoxyphenamine (N-TFA amide) 1-Phenyethylamine (TFA amide) Tocainide (N-pentafluoropropionylamide) Viloxazin

30 ¥ 0.25

Alprenolol (oxazolidine)

10 ¥ 0.1

Metoprolol (oxazolidine)

10 ¥ 0.1

Propranolol (oxazolidine)

10 ¥ .25

Ethosuximide

8 ¥ 0.25

Ethotoin

25 ¥ 0.25

Gluthetimide

10 ¥ 0.1

Hexobarbital

25 ¥ 0.25

5-Isobutylhydantoin

4.5 ¥ 0.25

10 ¥ .0.1 18 ¥ 0.25 10 ¥ 0.25 25 ¥ 0.3 8 ¥ 0.25

Mephenytion

4.5 ¥ 25

Methylphenidate

10 ¥ 0.1

Mesuximide

25 ¥ 0.25

3-Methyl-3-phenylsuccinimide

10 ¥ 0.1

© 2002 by CRC Press LLC

Stationary Phase (Product Name) 50% 2,6-diMe-3-Pe-b-CD + OV-1701 (Hydrodex-b-3P) 20% PerMe-g-CD + SPB-35 (g-DEX 120) Chemically bonded 30% PerMe-b-CD (Chirasil-Dex CB, Hydrodex b-PM) 50% 2,6-diMe-3-Pe-b-CD + OV-1701 (Hydrodex-b-3P) 50% 2,6-diPe-3-butyryl-g-CD + OV-1701 (diluted Lipodex E) Chemically bonded valinetercbutylamide (Chirasil-Val) 50% 2,6-diMe-3-Pe-b-CD + OV-1701 (Hydrodex-b-3P) Aminoalcohols Chemically bonded 30% PerMe-b-CD (Chirasil-Dex CB, Hydrodex b-PM) Chemically bonded 30% PerMe-b-CD (Chirasil-Dex CB, Hydrodex b-PM Chemically bonded 20% 2,3-diMe6TBDMS-b-CD (b-Dex 325, BGB-172, Hydrodex b-6TBDM) Other Compounds 50% 2,6-diMe-3-Pe-b-CD + OV-1701 (Hydrodex-b-3P) 50% 2,6-diPe-3-butyryl-g-CD + OV-1701 (diluted Lipodex E) Chemically bonded 30% PerMe-b-CD (Chirasil-Dex CB, Hydrodex b-PM) 50% 2,6-diMe-3-Pe-b-CD + OV-1701 (Hydrodex-b-3P) 50% 2,6-diMe-3-Pe-b-CD + OV-1701 (Hydrodex-b-3P) 60% 2,6-diPe-3-butyryl-g-CD + OV-1701 (diluted Lipodex E) Chemically bonded 30% PerMe-b-CD (Chirasil-Dex CB, Hydrodex b-PM) 50% 2,6-diPe-3-butyryl-g-CD + OV-1701 (diluted Lipodex E) Chemically bonded 30% PerMe-b-CD (Chirasil-Dex CB, Hydrodex b-PM)

Analysis Temperature (∞∞C)

Ref.

119∞C

40

90∞CÆ1∞C/min

44

160∞C

22

120∞C

40

95∞C

41

190∞C

50

130∞C

40

160∞C

22

170∞C

22

160∞C

51

110∞C

40

190∞C

41

180∞C

22

180∞C

9

140∞C

40

150∞C

8

130∞C

22

190∞C

41

170∞C

22

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A3.2.9 METHOD DEVELOPMENT Before experimenting, a careful check of published data is very useful. Several data collections are available dealing with chiral GC separations, providing guidelines or ready recipes for the separa1,2 tions of interest. Books on chiral GC, and the data in “Collection of Enantiomer Separation 26,27,39–41 Factors” in HRC should be checked first. Catalogs and booklets of column producers can 42–45 also be useful. Some column manufacturers offer not only columns, but also method develop5 ment. The CHIRBASE/GC database refers to approximately 20,000 separations. Adaptation of published data to other enantiomers is questionable, foremost with CD-based CSPs. A slight modification of the analyte structure can result in totally different selectivity. The optimal method would be to start development with a 1-mg/ml sample of about 20% e.e. The retention order of isomers can easily be established in this way. In the case of enantiomer ratios >90%, an Rs value of ~0.8 can remain unrecognizable and side products can be misinterpreted as the minor enantiomer. A 10 to 15-m long, 0.1-mm i.d. column with thin-film (0.1 mm) CSP is well-suited for preliminary experiments. Other parameters include: (1) injection, 1 m l volatile organic solvent; split, 1:100–200; (2) carrier gas H2 (70 cm/sec); (3) temperature program: isothermic at 50∞C (2 min) followed by 2∞C/min up to maximum operational temperature of CSP. Of course, the temperature program can be started at a higher temperature (e.g., analysis of enantiomers having a boiling point above 200∞C at 120∞C) and stop earlier. If no resolution is observed, other CSPs or a derivative of the analytes should be tested. In the case of some resolutions (Rs > 0.7), the following step is an isothermal run. Adjust the analysis temperature to 20∞C less than the elution temperature of enantiomers in the programmed run. A further decrease in the analysis temperature results in a steep improvement in resolution. In general, an Rs value of 2.5 is sufficient for transferring the method to broader i.d. columns and higher e.e. values. Columns with 0.2 to 0.32-mm i.d. with thicker films (0.2 to 0.3 mm) have moderate efficiency, but their increased capacity helps to avoid overloading. Alcohols and carboxylic acids can be measured without derivatization if they elute below 150 to 200∞C and show no peak tailing. GC analysis of amines and hydroxy acids (at least in the carboxyl function) regularly need derivatization. A permethylated b-CD containing CSP should be the first choice or, if possible, its chemically bonded version (Chirasil-Dex CB). If the first CSP is not good enough, the following CD containing CSPs (CDs with silicone matrix) are recommended in this order: 2,3 diacetyl-6-TBDMS b-CD; 2,3-dimethyl-6-TBDMS b-CD; 2,3-dimethyl-6-TBDMS g-CD; 3-butyryl-2,6-dipentyl-g-CD; 3-pentyl2,6-dimethyl-b-CD; 3-trifluoroacetyl-2,6-dimethyl-b-CD. The use of undiluted CD derivatives is sometimes also successful, but their efficiency and lifespan are rather moderate. Chirasil-Val is recommended for the analysis of amino acids—except for proline. Analysis of proline is recommended for a CD-based CSP. Amino alcohols, as well as 1,2- and 1,3-diols can be well separated on a XE-60-L -Val-(S)-a-pea CSP in cyclic derivative forms.

REFERENCES 1. W.A. König, The Practice of Enantiomer Separation by Capillary Gas Chromatograpy, Hüthig, Heidelberg (1987). 2. W.A. König, Gas Chromatographic Enantiomer Separation with Modified Cyclodextrins, Hüthig, Heidelberg (1987). 3. V. Schurig, J.Chromatogr. A, 666, 111 (1994). 4. Z. Juvancz and P. Petersson, J. Microcol. Sep., 8, 99 (1996). 5. B. Koppenhoefer, A. Nothdurft, J. Pierot-Sanders, P. Piras, C. Popescu, C. Roussel, M. Stiebler, and U. Trettin, Chirality, 5, 213 (1993). © 2002 by CRC Press LLC

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Chiral Selective Chromatographic Analysis 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51.

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Z. Juvancz, K. Grolimund, and V. Schurig, HRC, 16, 202 (1993). E. Francotte, K. Grolimund, and Z. Juvancz, Chirality, 5, 232 (1993). I. Hardt and W.J. König, Microcol. Sep., 5, 35 (1993). I. Hardt and W.A. König, J. Chromatogr. A., 666, 611 (1994). W.A. König and B. Gehrcke, HRC, 16, 175 (1993). M. Jung, D. Schmalzing, and V. Schurig, J. Chromatogr., 552, 43 (1991). Z. Juvancz, G. Alexander, and J. Szejtli, HRC, 10, 105 (1987). J. Szejtli and T. Osa, Eds., Methods in Comprehensive Supermolecular Chemistry, Vol. 3, Cyclodextrins, Elsevier (1997). V. Schurig and H.-P. Nowotny, J. Chromatogr., 441, 155 (1988). A. Dietrich, B. Maas, V. Karl, P. Kreis, D. Lehmann, B. Weber, and A. Mosandl, HRC, 15, 176 (1992). A. Dietrich, B. Maas, W. Medder, V. Karl, A. Kaunzinger, and A. Mosandl, HRC, 15, 590 (1992). B. Maas, A. Dietrich, and A. Mosandl, HRC, 17, 109 (1992). C. Bicchi, G. Artuffo, A. D’Amato, G. Pellegrino, A. Galli, and M. Galli, HRC, 15, 701 (1991). C. Bicchi, G. Artuffo, A. D’Amato, G. Pellegrino, A. Galli, and M. Galli, HRC, 15, 701 (1991). W.A. König, D. Ichlen, Y. Runge, I. Pforr, and A. Krebs, HRC, 13, 702 (1990). W.A. König, S. Lutz, P. Evers, and J. Knabe, J. Chromatogr., 503, 256 (1990). Z. Juvancz, K. Grolimund, and V. Schurig, J. Microcol. Sep., 5, 459 (1993). W.A. König, R. Krebber, and P. Mischnick, HRC, 12, 732 (1989). V. Schurig, D. Schmalzing, U. Mühleck, M. Jung, M. Schleimer, P. Mussche, C. Duvekot, and J.C. Buyten, HRC, 13, 713 (1990). Z. Juvancz, D. Schmalzing, G.J. Nicholson, and V. Schurig, HRC, 10, 105 (1987). B. Maas, A. Dietrich, and A. Mosandl, HRC, 17, 169 (1994). B. Maas, A. Dietrich, and A. Mosandl, HRC, 17, 109 (1994). B. Maas, A. Dietrich, V. Karl, A. Kaunzinger, D. Lehmann, T. Köpke, and A. Mosandl, J. Microcol. Sep., 5, 421 (1993). W.A. König, C. Fricke, Y. Seritas, B. Momeni, and G. Hochenfeld, HRC, 20, 55 (1997). B. Koppenhoefer, and E. Bayer, in J. Chromatogr. Library, Vol. 32, 1, Brunner, F. (Ed.) (1985). I. Abe, T. Nishiyama, and H. Frank, HRC, 17, 9 (1994). W.A. König, E. Steinbach, and K. Ernst, J. Chromatogr., 301, 129 (1984). O. Gyllenhaal and J. Vessman, J. Chromatogr., 435, 259 (1988). K. Blau and J.M. Halket (Eds.), Handbook of Derivatives for Chromatography, John Wiley & Sons (1993). V. Schurig, J. Chromatogr., 441, 135 (1988). Z. Juvancz, J.S. Bradshaw, S.K. Aggarwal, C.A. Rouse, B.J. Tarbet, K.E. Markides, and M.L. Lee, Enantiomer, 3, 89 (1998). Z. Juvancz, K.E. Markides, P. Petersson, D.F. Johnson, J.S. Bradshaw, and M.L. Lee, J. Microcol. Sep., (submitted). M. Lindström, HRC, 14, 765 (1991). W.A. König, HRC, 16, 312 (1993). W.A. König, HRC, 16, 338 (1993). W.A. König, HRC, 16, 569 (1993). Chiraldex Capillary GC Columns, ASTEC (1996). J. Zeeuw and N. Vonk, Applications of Fused Silica Capillary Columns for the Separation of Non Derivatized Chiral Compounds by GC, Chrompack P1118 (1997). Bulletin 877, Chiral Cyclodextrin Capillary Columns, Supelco (1998). Guide to the Analysis of Chiral Compounds by GC, Restek, 1996. H.-P. Nowotny, D. Schmalzing, D. Wistuba, and V. Schurig, HRC, 12, 383 (1989). F. Sanchez-Rasero, M.B. Matallo, G. Dios, E. Romero, and A. Pena, J. Chromatogr. A., 799, 355 (1998). H. Grosenick and V. Schurig, J. Chromatogr. A., 761, 181 (1997). H. Frank, G.J. Nicholson, and E. Bayer, J. Chromatogr. Sci., 15, 174 (1977). O. Gyllenhaal, B. Lamm, and J. Vessman, J. Chromatogr., 411, 285 (1987). J. Dönecke, C. Paul, W.A. König, L. Svensson, O. Gyllenhaal, and J. Vessman, J. Microcol. Sep., 8, 495 (1996).

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A3.3

CRC Handbook of Optical Resolution via Diastereomeric Salt Formation

CHIRAL SELECTIVE SUPERCRITICAL FLUID CHROMATOGRAPHY

A3.3.1 CHARACTERIZATION

OF

SFC 1–4

Supercritical fluid chromatography (SFC) is a good technique for enantiomer separations. Mediumpolarity enantiomers with moderate molecular weight (200 to 800) or thermolabile structures are dedicated for SFC analysis. Chiral SFC separations can substitute normal-phase LC, primarily with shorter analysis time and higher selectivity. Chiral SFC can also be more advantageous than GC if the GC analysis temperature is above 180 to 220∞C. A3.3.1.1 Special Features of SFC 4,5

The pressure and temperature of the mobile phase are near their critical points. If these parameters of the mobile phase are below the critical value, some authors call it subcritical fluid chromatog6 raphy; but from a practical point of view, the two regions do not differ significantly. Most packed4 column chiral separations have been performed in the subcritical region. A crucial requirement for the mobile phase is that it must be a single phase. A unique feature of SFC is that the solvating power of the mobile phase increases with the elevation of its density (pressure) without significant change in polarity. Near the critical point, the solvating power of the mobile phase forms an S-shaped curve as a function of pressure. Similar to GC, the low viscosity and high permeability of the mobile phase offer fast analysis 7,8 and high efficiency. Analysis times as short as 2 min have been reported for chiral SFC. The low viscosity of the mobile phase allows the use of open tubular columns up to 20 m in length, achieving 5 more than 100,000 theoretical plates. On the other hand, similar to LC, the mobile phase in SFC has solvating power with tunable 4,5,8,9 polarity and selectivity features. A3.3.1.2 Special Features of SFC in Chiral Analysis The features of SFC, including fast analysis, high efficiency, low analysis temperature, and a wide 2–4 variety of detectors, make it an attractive alternative for chiral analysis. SFC employs low analysis temperatures even for high-molecular-weight compounds, thus offering high chiral selectivity. Even 10 a values of 6.44 with Rs 25.5 have been achieved with this technique. Due to the high efficiency of long columns in SFC, it is possible to separate enantiomers with a selectivity value of 1.04. Enantiomers of acids and amines were separated without derivatization in SFC, unlike in GC practice where these functional groups generally require derivatization. Using a pressure gradient, the elution power of SFC can be increased without changing the selectivity of system, thus achieving rapid chiral separations. The selectivity of an SFC system can be tuned with organic modifiers 4 9 (additives), even with a modifier gradient.

A3.3.2 COLUMNS 4,5

In SFC, both packed and open tubular columns can be used. For chiral SFC, packed columns are better. The low viscosity (pressure drop) and high permeability of the mobile phase allows longer 4,11 columns than HPLC. The length of packed columns ranges from 15 cm to more than 1 m. On several occasions, standard HPLC columns have been connected in a row for chiral SFC analysis. Back-pressure regulation of packed columns permits an optimum flow rate during the entire analysis, even when using pressure or modifier gradients. The loadability of packed columns is high, which 12,13 Several chiral packed columns are commercially available is important in the case of extreme e.e. as HPLC columns.

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645 3,5

Open tubular columns have 50 to 100 mm i.d. and 5 to 15 m length and offer high efficiency, but they have limited loadability, long analysis time, and complicated, poorly automatizable instrumentation. No chiral open tubular columns are on the market for SFC. Therefore, when experience with capillary column preparation is lacking, the use of a packed column is recommended for chiral SFC.

A3.3.3 MOBILE PHASES The high permeability of mobile phases results in not only several times faster analysis, but also quicker equilibration of the system (after gradient or eluent change) in SFC than in LC. In chiral SFC applications, only carbon dioxide-based mobile phases have been used thus far. In addition to low viscosity and high permeability, CO2 has low toxicity and price. It is common to add polar organic modifiers (1 to 40%) to CO2 in packed-column chiral SFC. These modifiers not only increase the dissolving power of the mobile phase, but also influence its selectivity and deactivate the adsorptive sites of the support. The most frequently used modifier is 9,10 1,4,8,12,14,15 7 methanol. Other alcohols (e.g., ethanol, isopropanol), and sometimes dioxane and aceto16 nitrile, are also used. Chiral selectivity shows a maximum as a function of modifier concentra1,16,17 9 tion. The use of modifier gradients is a very effective way of chiral selective method development. Support passivation effects of modifiers are often enhanced with co-modifiers (0.1 to 2%). Comodifier passivation is very important in the case of monomeric chiral stationary phases and ionizable analytes. Adsorption of basic compounds can be eliminated with volatile organic amines (e.g., 9,10,12,14 triethylamine, propylamine, isopropylamine) and adsorption of acids with volatile acids (e.g., 8–10 acetic, trifloroacetic). Simultaneous applications of both acidic and basic co-modifiers offer a 9 general passivation effect. Chiral selectors as mobile-phase additives have been used by applying N-benzoxycarbonylglycyl18 19 L-proline chiral ion-pairing agent and partially methylated b-cyclodextrin. 2 In general, a values are lower in SFC than in GC at the same operating temperature, caused by the solvent sphere around the analytes and stationary phase. There is no general rule regarding the chiral selectivity shift between the LC and SFC, but frequently much higher selectivity is 1–4,12,14 measured in SFC than in LC. The active role of CO2 has been observed in chiral recognition 12,14 interactions on several occasions. For example, aminoalcohols create transient complexes with CO2, which can contribute to the chiral recognition mechanism of some CSPs.

A3.3.4 STATIONARY PHASES Almost every type of chiral stationary phase (CSP) introduced in GC and LC practice has been used in SFC. The mobile phases in SFC are relatively weak; therefore, the disturbing silanol effect is more pronounced in SFC, mostly in the case of monomeric CSPs. This and higher loadability explain the advantages of polymeric CSPs over monomeric ones. Polymeric CSPs consist of silica particles covered with polymeric chiral molecules. The multilayer polymeric materials prevent interactions between the surface and analytes. A3.3.4.1 Polysaccharide-based CSPs In SFC practice, the most frequently used CSPs are variously derivatized polysaccharides (amylose, 4,9,13–17,20–22 cellulose). Several derivatives are on the market. Their selectivity covers a broad range. 13,20 Complete separation of molecules with more than one chiral center has also been reported. The active role of CO2 in the chiral recognition of aminoalcohols and other enantiomers has also been 14 reported using cellulose-based CSPs, achieving higher selectivity than in LC. Their multilayer character allows high sample loadability, thus offering both the exact determination of e.e. and 13,17 Moreover, these polysaccharide CSPs are the most frequently used preparative-scale applications. in LC practice and thus LC methods are transferable to SFC. An application is illustrated in Fig. A3.3.1.

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FIGURE A3.3.1 Separation of the acids (A) Ibuprofen and (B) Flurbiprofen enantiomers on a Chirapak AD [amylose (3,5-dimethylphenylcarbamate)] column by SFC. Conditions: (A) Column; flow rate, 2 ml/min; mobile phase, 5% methanol in carbon dioxide; outlet pressure, 100 bar; oven temperature, 35∞C; injection volume, 0.5 ml; detection at 220 nm. Conditions for (B) are the same except the mobile phase was 20% methanol in carbon dioxide. (From W.H. Wilson, Chirality, 6, 216 (1994). With permission.)

In SFC, a Chirapak AD CSP is much more efficient than in normal-phase LC. Temperature and methanol content of the mobile phase had significant impact on the resolution of Ibuprofen. Rs values were at a maximum at 35∞C and 5% methanol. At lower temperature, selectivity increased but efficiency decreased. Variation of pressure, however, did not cause significant change in resolution. A change from methanol to ethanol produced only a minor improvement, but the use of isopropanol almost totally destroyed the separation of Flurbiprofen. Polymeric CSPs allowed the analysis of free acids without an acidic additive. A3.3.4.2 Pirkle-type CSPs Pirkle, brush-type CSPs have been frequently applied for separating compounds having aromatic 1,4,7–12,23 groups. Analytes having p-acidic or p-basic groups need their complementary CSPs. On several occasions, derivatization of analytes (e.g., by dansyl or dinitrobenzoyl groups) introduce aromatic functional groups, thus improving chiral recognition and detectability. The most versatile CSP is Whelk-O 1. It shows selectivity toward both p-acidic and p-basic 4,23 analytes because Whelk-O 1 has both electron-rich and -poor aromatic groups. It can separate chiral acids, alcohols, ketones, epoxides, esters, ethers, carbamates, amines, sulfoxides, and sulfonamides functionalized enantiomers. The poly-Whelk-O 1 is the improved version of Whelk-O 1, in 4,8,10 which the chiral recognition units of Whelk-O 1 are attached to a silicone backbone. The polymeric © 2002 by CRC Press LLC

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Chiral Selective Chromatographic Analysis

structure provides higher efficiency and loadability, improved selectivity, and a well-passivated system. Moreover, on poly-Whelk-O 1, analysis is faster. Tyrosine-containing Pirkle-type CSPs are very selective toward enantiomers of b-blocker 12,24 aminoalcohols. They form a transient complex with carbon dioxide, contributing to the chiral recognition mechanism of these CSPs. CSPs containing trans-1,2-diaminocyclohexane as the chiral group also show p-acid Pirkletype character. They are excellent for the separation of aminoalcohols in oxazolidine derivative form because the twisted structure of the CSP shows high enantioselectivity toward these cyclic 7,11 derivatives. A3.3.4.3

Other Types of CSPs 9,25,26

Recently, CSPs containing macrocyclic antibiotics have been introduced in SFC. These chiral selective agents were originally designed for working with an aqueous mobile phase, but they also perform well in CO2 media. Their high chiral selectivity can be attributed to the presence of several chiral centers in a single molecule. These CSPs require high modifier content to compensate for the strong interactions of chiral centers with silanols. 1,27,28 A A cyclodextrin-containing brush-type CSP was also applied in packed-column SFC. strong silanol effect and poor loadability prevent its broad application. Silica particles were encapsulated into derivatized cyclodextrin-containing silicone polymers, which opens the door for appli29 cation of this highly favored chiral selector in SFC. 2,3 Several papers in the literature deal with open tubular column SFC coated with various CSPs. Most of these CSPs were originally developed for GC purposes and after immobilization they were applied in SFC. The commercial market, however, does not offer any capillary SFC columns coated with CSP.

A3.3.5

INSTRUMENTATION 30

Several vendors offer SFC instruments for packed columns. Berger Instruments (Berwyn, PA) has further developed the previously commercialized Hewlett-Packard HP G 1205 apparatus. Sensar Larson-Davis (Provo, UT) followed the line of Dionex and Lee Scientific, offering instruments for both packed and open tubular column SFC. Gilson (Middleton, WI) sells a very flexible system with pressure, composition, and temperature gradient abilities. Well-trained chromatographers can, however, assemble an isocratic SFC instrument from an HPLC or SFE piston pump and GC oven in their own labs. The mobile phase consists of high-purity (at least 99.9%) CO2 and HPLC-quality modifiers, which are generally delivered by piston pumps. Cooling of the pumps is necessary. Injections are made through a rotary valve. All up-to-date instruments use back-pressure regulators to keep the flow optimal during gradients. Most frequently, a UV detector is employed. Precise adjustment of the parameters requires microprocessor control in the case of gradient runs.

A3.3.6

APPLICATIONS

Table A3.3.1 shows a collection of data for successful chiral SFC separations. Most were performed on the recommended, commercially available CSPs analyzing acidic and basic enantiomers. Some separations are shown on more than one CSP to enable comparison among CSPs. The results achieved on poly-Whelk-O 1 are also cited in Table A3.3.1 because these results are only slightly better than those achieved on Whelk-O 1.

A3.3.7

METHOD DEVELOPMENT

The first step in method development is to find an analogous case in chiral SFC, GC, and/or HPLC 2–4, 8,9 literature. © 2002 by CRC Press LLC

Column (mm)

Analysis Temperature (∞C)

Abscisic acid

250 ¥ 4.6

40

Dichlorprop

550 ¥ 0.18

25

Dichlorprop

650 ¥ 0.18

35

Fenoprofen

250 ¥ 4.6

30

Flurbiprofen (naphthylenemethylamide) Flurbiprofen

150 ¥ 1.2

50

250 ¥ 4.6

25

Flurbiprofen

250 ¥ 4.6

35

Ibuprofen

250 ¥ 4.6

35

Ibuprofen

250 ¥ 4.6

25

Mandelic acid

250 ¥ 4.6

30

Naproxene

250 ¥ 4.6

25

Alanine (Cbz )

250 ¥ 4.6

40

Mobile Phase Composition (v:v:v) Acids CO2:iPrOH:TFA (92:8:0.4) CO2:MeOH:TEA (70:30:0.7) CO2:MeOH:TEA (69:29:1) a Composition gradient CO2:dioxane:MeOH (70:15:15) CO2:iPrOH:Ac (90:10:0.2) CO2:MeOH (80:20) CO2:MeOH (95:5) CO2:iPrOH:Ac (90:10:0.2) a Composition gradient CO2:iPrOH:Ac (90:10:0.2) Amino Acids CO2:iPrOH:TFA (92:8:0.4)

Inlet Pressure (bar)

Stationary Phase (Product Name)

Ref.

200

p-acid/base (Whelk-O 1)

23

250

Macrocyclic antibiotic (Riscotecin)

26

250

Macrocyclic antibiotic (Vancomycin)

25

200

Amylose tris(3,5-dimethylphenylcarbamate) (Chirapak AD) 3,5-Dinitrobenzoyl derivative of (R,R)-1,2diaminocyclohexane Polymeric p-acid/base (Poly-Whelk-O 1)

9

100 200 100 100 200 200

Amylose tris(3,5-dimethylphenylcarbamate) (Chirapak AD) Amylose tris(3,5-dimethylphenylcarbamate) (Chirapak AD) Polymeric p-acid/base (Poly-Whelk-O 1)

7 4, 8 15 15 4, 8 9

200

Cellulose tris(3,5-dimethylphenylcarbamate) (Chiracel OD) Polymeric p-acid/base (Poly-Whelk-O 1)

200

p-Acid/base (Whelk-O 1)

23

4, 8

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Name of the Analyte (Analyzed Form)

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© 2002 by CRC Press LLC

TABLE A3.3.1 Chiral Separations with SFC

40

Valine (Dnb, methyl ester)

250 ¥ 4.6

30

a-Arylethylamines (acetamides) Lormethazepam

250 ¥ 4.6

27

250 ¥ 4.6

30

Amines CO2:MeOH (90:10) a Composition gradient

Lormethezapam

250 ¥ 4.6

30

Composition gradient

Meditominide Mianserin

250 ¥ 4.6 250 ¥ 4.6

30 30

Oxazepam

250 ¥ 4.6

30

Oxazepam

250 ¥ 4.6

30

Composition gradient CO2:MeOH:TEA (70:30:0.5) CO2:MeOH:ACN:DEA (70:10:20:0.5) a Composition gradient

Thalidomide

250 ¥ 4.6

40

Thalidomide

650 ¥ 0.18

35

Verapamil

250 ¥ 4.6

5

Alprenolol (oxazolidine)

150 ¥ 1.2

50

Alprenolol Metoprolol

250 ¥ 4.6 250 ¥ 4.6

30 30

Metoprolol

650 ¥ 0.18

35

CO2:iPrOH:TFA (92:8:0.4) CO2:MeOH (90:10)

200

p-Acid/base (Whelk-O 1)

23

150

Naphthylethylcarbamoylated b-cyclodextrin (Cyclobond I 2000RN)

28

200

Polymeric p-acid/base (Poly-Whelk-O 1)

10

200

9

150

Amylose tris(3,5-dimethylphenylcarbamate) (Chirapak AD) Cellulose tris(3,5-dimethylphenylcarbamate) (Chiracel OD) p-Base (Chirex3022) Cellulose tris(3,5-dimethyl-phenylcarbamate) (Chiralcel AD) Cellulose tris(3,5-dimethylphenylcarbamate) (Chiralcel OD) Amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD) Macrocyclic antibiotic (Ristocetin)

26

200

Macrocyclic antibiotic (Vancomycin)

25

250

p-Acid/base (Whelk-O 1)

23

180

3,5-Dinitrobenzoyl derivative of (R,R)-1,2diaminocyclohexane Macrocyclic antibiotic (Chirobiotic T) Cellulose tris(3,5-dimethylphenylcarbamate) (Chiracel OD) Macrocyclic antibiotic (Vancomycin)

7

a

200

a

200 200

CO2:MeOH:TFA (75:25:0.1) CO2:MeOH:TEA (69:30:1) CO2:ACN:TEA (75:25:0.1) Aminoalcohols CO2:dioxane:MeOH (70:15:15) a Composition gradient a Composition gradient CO2:MeOH:TEA (69:29:1)

200 200

200 200 200

9 9

16 9

9 9 25 (Continued )

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250 ¥ 4.6

Chiral Selective Chromatographic Analysis

© 2002 by CRC Press LLC

Phenylalanine (Cbz)

649

Column (mm)

Analysis Temperature (∞∞C)

Pindolol

500 ¥ 3.2

27

Propranolol

500 ¥ 3.2

27

Hexobarbital

250 ¥ 4.6

30

Hexobarbital Coumachlor Warfarin

250 ¥ 4.6 250 ¥ 4.6 250 ¥ 4.6

30 40 25

Warfarin

250 ¥ 4.6

Warfarin

250 ¥ 25.4

a

Mobile Phase Composition (v:v:v)

Inlet Pressure, (bar)

CO2:EtOH:propylamine (79:20:1) CO2:EtOH: propylamine (79:20:1)

200

Tyrosine containing p-acid (ChyRoSine)

12

200

Tyrosine containing p-acid (ChyRoSine)

12, 24

200

Amylose tris(3,5-dimethylphenylcarbamate) (Chirapak AD) Macrocyclic antibiotic (Chirobiotic V) Macrocyclic antibiotic (Ristocetin) Polymeric p-acid/base (Poly-Whelk-O 1)

9

Other Enantiomers a Composition gradient a

200 150 200

30

Composition gradient CO2:MeOH:TFA (75:25:0.1) CO2:iPrOH (90:10) a Composition gradient

25

CO2:iPrOH:Ac (75:25:0.5)

253

200

Composition gradient: CO2:MeOH:TEA:TFAA (95:5:0.1:0.1) for 5 min gradient to 30% MeOH at 5%/min rate.

Stationary Phase (Product Name)

Cellulose tris(3,5-dimethylphenylcarbamate) (Chiracel OD) p-Acid/base (Whelk-O 1)

Ref.

9 26 8 9 23

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Name of the Analyte (Analyzed Form)

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TABLE A3.3.1 Chiral Separations with SFC (continued)

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FIGURE A3.3.2 Separation of Felodipin enantiomers on Chirapak AD [amylose (3,5-dimethylphenylcarbamate)] with modifier gradient. Conditions: column, 25 cm ¥ 4.6 mm packed with Chirapak AD (10 mm); pressure, 200 bar; mobile phases: CO2-based mixtures with 0.1% trifluoroacetic acid and triethylamine. (A) Fast gradient (5% methanol (5 min) to 30% at 5%/min); (B) slow gradient (5% methanol (5 min) to 30% at 1%/min); (C) isocratic (5% methanol). (From A. Medvedovici, P. Sandra, L. Torbio, and F. David, J. Chromatogr. A, 785, 159 (1997). With permission.)

The use of a polymeric CSP is favored. If there is no clue in the literature, test Chiracel OD and/or Chirapak AD. Among monomeric CSPs, Whelk-O 1 and vancomycin are recommended. Use of a 25 cm ¥ 4.6 mm i.d. commercially packed column is best for beginning, with analysis temperature of 30∞C, using as mobile phase CO2 :methanol (90:10), and a flow rate of 2 ml/min 16 at 200 bar pressure. Addition of 0.5% trifluoroacetic acid or 0.5% diethylamine is also recommended in the case of acidic and basic enantiomers, respectively. After 5 min of isocratic run, 5%/min of the modifier gradient, up to 30%, should be added. If no resolution is observed, changing the modifier to isopropanol or ethanol would be the next step. An example is shown in Fig. A3.3.2. The fast gradient resulted in moderate resolution, which was improved using a slower gradient or an isocratic run. Adding 0.1% triethylamine to the eluent was necessary for good peak shape of the underivatized basic compound. On the other hand, the 0.1% trifluoroacetic acid (acid composition of general mobile phases) did not disturb the analysis. In the case of no separation, test runs on other CSPs can be proposed in the same manner. If resolution is observed with a modifier gradient, the methods can adapted to isocratic conditions by © 2002 by CRC Press LLC

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taking half of the modifier content as compared to gradient elution. Resolution can be further improved by fine-tuning the modifier composition, pressure, and the analysis temperature. When in need of a second pump and a modifier gradient cannot be realized, one should begin method development with a pressure gradient. An isobar period of 2 min at 100 bar should be followed by a 5 bar/min pressure gradient up to 400 bar using the starting mobil phase of gradient method. In case of successful resolution, the next step should be an isobar analysis with a pressure of 15 bar less than the elution pressure in the previous run. Fine-tuning of separation can be achieved by adjusting the type and percentage of modifier, analysis temperature, and pressure of the mobile phase. LC methods can be transferred to SFC. Doubling the modifier concentration is recommended when changing from n-hexane to CO2.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

P. Macaudiére, M. Caude, R. Rosset, and A. Tambute, J. Chromatogr. Sci., 27, 583 (1989). Z. Juvancz and K.E. Markides, LC/GC Intern., 5, 44 (1992). P. Petersson and K.E. Markides, J. Chromatogr. A, 666, 381 (1994). T. Berger and K. Anton (Eds.), Packed Column Supercritical Fluid Chromatography, Marcel Dekker, New York (1997). M.L. Lee and K.E. Markides (Eds.), Analytical Supercritical Fluid Chromatography and Extraction, Chromatography Conferences Inc., (1990). T.L. Chester, Anal. Chem., 69, 165A (1997). F. Gasparrini, D. Misti, and C. Villani, HRC, 13, 182 (1990). G.J. Terfloth, W.H. Pirkle, K.G. Lynam, and E.C. Nickolas, J. Chromatogr. A, 705, 185 (1995). A. Medvedovici, P. Sandra, L. Torbio, and F. David, J. Chromatogr. A, 785, 159 (1997). W.H. Pirkle, L.J. Brice, and J. Terfloth, J. Chromatogr. A, 753, 109 (1996). F. Gasparrini, Proc. II Eur. Symp. Anal. SFC and SFE, 73 (1992). N. Bargman-Leyder, D.E. Thiebaut, F. Vergne, A. Begos, A. Tambute, and M. Caude, Chromatographia, 39, 673 (1994). K. Yaku, K. Aoe, N. Nishimura, T. Sato, and F. Morishita, J. Chromatogr. A, 785, 185 (1997). K. Anton, J. Eppinger, L. Freerikson, E. Francotte, T.A. Berger, and W.H. Wilson, J. Chromatogr. A, 666, 395 (1994). W.H. Wilson, Chirality, 6, 216 (1994). A. Kot, P. Sandra, and A. Venema, J. Chromatogr. Sci., 32, 439 (1994). M. Villeneuve and R.J. Anderbergg, J. Chromatogr. A, 826, 217 (1998). W. Stauer, M. Schindler, G. Schill, and F. Erni, J. Chromatogr., 447, 287 (1988). A. Salvator, E. Varesio, J.L. Veuthey, and M. Dreux, Proc. 9th Int. Symp. Cyclodextrins, Santiago de Compostela, 613 (1998). L. Siret, P. Macaudiére, N. Bargmann-Leyder, A. Tambute, M. Caude, and E. Gougeon, Chirality, 6, 440 (1994). R.M. Smith and L. Ma., J. Chromatogr. A, 785, 179 (1997). J. Whatley, J. Chromatogr. A, 697, 251 (1995). A.M. Blum, K.G. Lynmann, and E.C. Nicolas, Chirality, 6, 302 (1994). S.C. Bargman-Leyder, D. Bauer, A.Tambute, and M. Caude, Anal. Chem., 67, 952 (1995). J. Donnecke, L. Svensson, O. Gyllenhaal, K.-E. Karlsson, A. Karlsson, and J. Vessman, J. Microcol. Sep., 11, 521 (1999). L.A. Svensson and P.K. Owens, Analyst, 125, 1037 (2000). P. Macaudiére, M. Caude, R.Rosset, and A. Tambute, J. Chromatogr., 405, 135 (1987). K.L. Williams, S.A. Sander, and S. Wise, J. Chromatogr. A, 746, 91 (1996). Y. Shen, Z. Chen, N.L. Owen, W. Li, J.S. Bradshaw, and M.L. Lee, J. Microcol. Sep., 8, 249 (1996). B. Erickson, Anal. Chem., 69, 683A (1997).

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A3.4

CHIRAL SEPARATION BY LIQUID CHROMATOGRAPHY

Conventional liquid chromatography, efficient in non-chiral separations, cannot be applied to the resolution of enantiomers. Chiral high-performance liquid chromatography (HPLC) can be realized using chiral selectors. A chiral selector can be an optically active chiral molecule or a chiral polymer, dissolved in the mobile phase or immobilized on the surface of a stationary phase. Due to the inadequate enantiomeric purity and high cost of chiral mobile phase additives, this appendix deals only with chiral stationary phases. Diastereomeric interaction with a chiral analyte enables chiral stationary phases (CSPs) to distinguish enantiomers. In HPLC applications, a chiral stationary phase must be bound to an inert and mechanically stable silica or polymeric resin matrix.

A3.4.1 CHIRAL STATIONARY PHASES

IN

LIQUID CHROMATOGRAPHY

Chiral stationary phases can be classified according to the mechanism of their interaction with the 1 solute. Wainer proposed the following scheme for their classification : 1. Type I CSPs resolve enantiomers by establishing three-point attractive interactions with the solute by hydrogen bonding, p-p electron coupling, and dipole-dipole stacking. 2. Chiral discrimination by Type II CSPs involves a combination of attractive interactions and inclusion complexing. In general, these are linear polysaccharide derivatives. 3. Type III CSPs are based on a special solute interaction with chiral cavities to form inclusion complexes. A variety of structurally different stationary phases belong to this group, including cyclodextrins and cyclodextrin derivatives, macrocyclic antibiotics, crown ethers, and non-cellulosic helical polymers. 4. Type IV CSPs form diastereomeric metal complexes with chiral analytes by means of a chiral ligand exchange chromatographic (CLEC) mechanism. 5. Type V CSPs are proteins; interactions with the solute are a combination of hydrophobic forces and hydrogen bonding. A3.4.1.1 Brush-type (Pirkle) Stationary Phases 2

Pirkle developed special chiral selectors based on charge-transfer complexation and simultaneous hydrogen bonding. They are of Type I in Wainers classification. The structure of these 3 phases strictly corresponds to Dalgliesh’s three-point simultaneous fit model. Accordingly, the stereoselective group in Pirkle phases always contains a p-basic naphthyl or p-acidic dinitrobenzoyl ring substituted with two hydrogen-bonding moieties. Strong three-point interaction enables chiral separation. Naphthyl amino acid derivatives such as 2-naphthylalanine or 1-naphthylleucine, all bonded covalently to silica, are p-donor phases. To fit to such Pirkle phases, the analytes should contain a p-acceptor group such as dinitrobenzoyl. p-Acid derivatization can easily be accomplished with a wide range of alcohols, amines, and carboxylic acids by introducing 3,5-dinitrobenzoyl, 3,5-dinitroanilide, 3,5-dinitrophenylurea, or 3,5-dintrophenylcarbamate-groups. Derivatized amino alcohols, a4 amino acids, aminophosphonates, carboxyl acids, alcohols, imides, and amines can be successfully resolved on a p-base Pirkle column. Another group of brush-type stationary phases is based on the reciprocality concept of the three-point recognition mechanism. These are p-acceptor phases having N-(3,5-dinitrobenzoyl)phenylglycine or N-(3,5-dinitrobenzoyl)leucine charge-transferring aromatic sites. These p-acidic columns are capable of separating compounds containing p-donor aromatic rings. Chiral separations 5 of bis-2-naphthol atropisomers and analogs are the best examples of this recognition mechanism.

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A wide range of structures can be resolved after p-basic derivatization, such as imides, amino 6 alcohols, arylacetamides, hydantoins, 2-carboalkoxyindolines, barbiturates, and benzodiazepi7 nones. Naphthoyl chloride and other appropriate reagents (e.g., naphthylurea) can be used for 8 derivatization. In the case of (±)-ephedrine, oxazolidine derivation was successful. In mixed brush-type stationary phases, both p-acid and p-basic groups are attached to a polymeric matrix; therefore, these phases form a chiral cleft. Examples for mixed stationary phases are a-Burke-1, Whelk-O and SS-Whelk-O1. For successful separation an aromatic group or a hydrogen-bonding group attached to the chiral center is necessary. A3.4.1.2 Linear Polysaccharides Polysaccharides and their derivatives offer a combination of attractive interactions and inclusion complexing to produce a chiral separation. According to the Wainer classification, they are Type II chiral selectors. Polysaccharide phases possess a linear polymeric structure. By means of inclusion complexation, this host–guest molecular arrangement leads to special polar, p-p interactions. There are different cellulose-based stationary phases, including pure microcrystalline cellulose triacetate, silica coated with cellulose triacetate, cellulose tribenzoate, cellulose tribenzyl ether, cellulose tricinnamate, cellulose trisphenylcarbamate- and cellulose tris-(3,5-dimethylphenyl carbamate). Separation of chiral aliphatic compounds can be performed on cellulosic phases. Aromatic moieties can strengthen the interaction but are not essential for chiral recognition. Because water hydrolyzes cellulosic phases, solvents of reduced polarity must be applied, typically 0 to 100% hexane-alcohol mixtures both in normal and reverse phase mode. These phases are commonly used in normal phase mode using hexane-ethanol and hexane-iPrOH mixtures. Chlorinated solvents must be avoided because they may elute cellulose from the silica support. Recently, a stable version of a tris-(3,5-dimethylphenylcarbamate)-based CSP (Chiralcel-ODR) was developed, which is devoted to reverse phase applications using a 0.5 M perchlorate buffer to prevent dissolution of the stationary phase. Another Type II stationary phase is amylose-coated silica. Amylose, having a predominantly helical structure, is the linear a-D-glucan component of starch. Amylose columns, namely silica-based amylose tris-(3,5-triphenylmethylcarbamate) and amylose (S)-1-methylbenzylcarbamate stationary phases show different selectivities as compared to cellulose. Amylose columns are preferentially chosen to resolve atropisomers with polar 9 substituents. Mobile phases used for amylose columns are generally the same as those used in common normal phase liquid chromatography, except for chlorinated solvents. Good results have also been obtained with pure ethanol as the mobile phase. A3.4.1.3 Cyclodextrins Cyclodextrin CSPs include chiral cavities; thus, they are definitely of Type III according to Wainer’s classification. Cyclodextrins are cyclic oligosaccharides containing a-(1,4) linked D-glucopyranose units. a-, b-, and g-cyclodextrins, contain 6, 7, and 8 glucopyranose units, respectively. The shape of cyclodextrins is a truncated conic with an inner cavity; the diameter of the cavity is proportional to the number of glucopyranose units. In cyclodextrins, secondary hydroxyl groups (OH-2 and -3) line the mouth of the cavity, and a primary 6-hydroxyl group is at the bottom of the cone. Apolar glycosidic oxygens make the cavity hydrophobic and ensure inclusion complexing of the hydrophobic parts of solutes. Interactions between the polar region of a solute and secondary hydroxyls at the mouth of the cavity, combined with the hydrophobic interactions within the cavity, provide a unique two-point fit and lead to chiral recognition. © 2002 by CRC Press LLC

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Cyclodextrins, covalently attached to silica gel by Armstrong’s process, provide stable sta11 tionary phases. Selectivity of a cyclodextrin phase is dependent on the size of the analytes and is based on a simple fit-unfit geometrical parameter. a-Cyclodextrin includes small aromatic molecules, whereas b-cyclodextrin incorporates both naphthyl groups and substituted phenyl groups. Enantiomers that 12–14 contain an aromatic ring can be separated by reverse phase inclusion complex formation. An additional attractive dipole-dipole stacking can be introduced using cyclodextrin columns in normal phase, or in nonaqueous reverse-phase chromatography (polar organic mode). A3.4.1.4 Modified Cyclodextrins A number of modified cyclodextrin structures have been developed, which have expanded the range of applicable operation modes and eligible analytes. Thus, various achiral and chiral substituents 15 were attached to the secondary alcoholic groups. Chiral analogs are (S)-2-hydroxypropyl and (S)16 or (R)-1-naphthylethylcarbamate derivatized cyclodextrins. 1-Naphthylethylcarbamate columns are analogous to naphthyl brush-type stationary phases, but they operate both in polar water-based reverse-phase solvent systems and in normal phase. Acetylated cyclodextrins are analogous to acetylated cellulose but can only be used in reverse phase. Another achirally substituted b-cyclodextrin is the 3,5-dimethylphenylcarbamate derivative, which can be applied in both reverse and normal phase mode. Furthermore, it is an alternative stable derivative in coated cellulose applications. Several chiral separations operate under both normal phase and reverse phase conditions, often resulting in a reverse of the elution order. A3.4.1.5 Chiral Crown Ethers Because, by definition, crown ethers form a cavity, stationary phases containing crown ethers all belong to Type III, according to the Wainer classification. 17 Similar to cyclodextrins, crown ethers contain oxygen atoms within the cavity. The cyclic structure that contains apolar ethylene groups between oxygens forms a hydrophobic innner cavity. 18 Crown ethers can be immobilized on the silica surface to form chiral HPLC phases. Chiral 18-crown-6 type stationary phases separate primary amines by means of a special coordination complex, wherein the nitrogen atom in the analytes must be present as a tetrahedral ammonium salt coordinating with the oxygen atoms in the ring system. Chiral crown ether derivatives are available in both (+) and (-) forms, which allows one to invert the elution order (e.g., in trace analysis). A3.4.1.6 Macrocyclic Antibiotics 19

Macrocyclic antibiotics can be immobilized on silica to form Type III chiral CSPs. Vancomycin and teicoplanin are cyclic glycopeptides with multiple chiral centers and a cup-like inclusion region to which a flapping sugar cover is attached. Similar to protein chiral selectors, the amphoteric cyclic glycopeptides consist of peptide and carbohydrate binding sites by which multimodal possibilities are generated in addition to inclusion complexation. The 18 chiral centers in the vancomycin molecule offer a complex cyclodextrin-like chiral environment. In contrast to the single cavity of cyclodextrins, vancomycin consists of three pockets, resulting in a more complex inclusion of appropriate guest molecules. The attractive forces are p-p interactions, hydrogen bonding, ionic interactions, and dipole stacking. A carboxylic acid and a secondary amine group sit on the rim of the cup and can take part in ionic 20 interactions. Vancomycin columns operate in reverse, polar, and normal phase modes. Teicoplanin 21 has 20 chiral centers, 3 sugar groups, and 4 fused rings. There is an acidic group at one end of the peptide cup and a basic one at the other end; both may be involved in ionic interactions. The sugar groups are arranged in three flaps that can be folded to enclose a molecule in the peptide cup. © 2002 by CRC Press LLC

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Crown ether or ligand exchange applications can be replaced by a teicoplanin column offering a very useful alternative to separate all amino acids using ethanol-water or methanol-water mobile reverse phases. Selectivity can be increased with an excess of organic modifier. A3.4.1.7 Helical Polymers Poly-(triphenylmethylmethacrylate) and poly-(diphenyl-2-pyridylmethylmethacrylate) contain a tunnel-like structure. The triphenylmethyl and pyridylmethyl groups attached to the helical polymer backbone offer a propeller-like chiral environment. Such optically active artificial polymers are 22 widely used for the separation of several racemates. A3.4.1.8 Ligand Exchange 23

Chiral ligand exchange chromatography, first developed by Davankov, separates enantiomers by formation of diastereomeric metal complexes. Stationary phases of chiral ligand exchange chromatography are classified as Type IV CSPs. Such methods are primarily used for separation of amino acids, but are also employed when the analyte contains an electron-donating nitrogen, sulfur, or oxygen atom, or p-electron-donating double bonds. Most applications use grafted L-proline and a metal ion incorporated in a coordination sphere. The metal ion occupies a central position in 24 complexation as an appropriate coordination center. Most often, the central atom is Cu(II); but in some special cases, the Co(III), Cr(III), and Pt(IV) ions are used as outer-sphere complexing agents. Forming three-dimensional ternary diastereomeric copper complexes they may separate amino acids. Water stabilizes the complex in an axial coordination position. Due to the different stabilities of mixed diastereomeric chelate complexes, chiral separation can be observed. 25 26 Chiral amino-acid-copper complexes can be bound to silica or to a polymeric support. Another 27,28 approach is to graft L-proline onto polystyrene resins. A3.4.1.9 Proteins 29

Enantioselective separation on protein CSPs was first developed and reported by Hermansson. Separation mechanisms of protein CSPs rely on a unique combination of hydrophobic and polar interactions by which the analytes are oriented to a chiral surface. According to Wainer’s classification, they are of Type V. Several proteins have been used as chiral stationary phases, including human a-acid glycoprotein (AGP), human serum albumin (HSA), bovine serum albumin (BSA), and ovomucoid protein (OVM). Protein CSPs are widely used in various applications. Human a-acid glycoprotein (orosomucoid, isoelectric point 2.7) is a stable acidic polypeptide consisting of 181 amino acids, contains two disulfide bridges and 40 sialic acid residues. It is covalently bound to silica, giving a reversephase column. Certain structures have enhanced affinities for the protein stationary phase; e.g., when the chiral center is part of or near a cyclic moiety. The chiral center must be next to a hydrogen-bonding site 30 and the maximum distance between the ring and the polar group is three carbon atoms. 31,32 Human serum albumin (MW 69,000, isoelectric point 4.8 ) and bovine serum albumin (MW 66,000, isoelectric point 4.7) are two closely related protein stationary phases. The mechanism of chiral recognition has not yet been elucidated. In special cases, a reversal of elution order has been observed on different stationary phases. Ovomucoid (OVM, MW 55,000) is an acidic glycoprotein. Its single-chain structure includes 33 186 amino acids and 9 disulfide bridges in 3 distinct domains. Miwa was the first to create an 34 effective CSP based on ovomucoid protein. A particularly useful development in the field of drug analysis is a cellobiohydrolase-based 35 CSP. Cellobiohydrolase (CBH) is a stable enzyme that can be immobilized onto 5-mm spherical silica particles. This chiral stationary phase is especially efficient for the direct separation of a © 2002 by CRC Press LLC

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36

broad range of basic drugs. Any CBH column can be used in the reversed phase mode with pH 4.0 to 7.0 phosphate or acetate buffers using 2-propanol and acetonitrile organic modifiers. Chiral selectivity is best when the analytes contain one or more nitrogen atoms and also hydrogen-bondforming phenol, alcohol, carbonyl, amine, or ester groups.

A3.4.2 INSTRUMENTATION Chiral separations require simple isocratic chromatographic equipment. Considering that the selectivity is often as small as 1.05, one must routinely ensure the best resolution by minimizing extra column volume. The connecting tubes should be of the smallest bore size commercially available (0.05 in.) and minimum length. To achieve maximum efficiency, the particle size of the stationary phase should not be more than 5 mm. Sample load in chiral chromatography is usually very low; therefore, the instrument should be equipped with an appropriate injector of not more than 5 ml capacity and zero dead volume. In chiral method development, pumps and detectors need not be of the highest quality; however, with the aim of detecting trace chiral impurities, they are recommended to secure low baseline noise. Detectors applied in chiral HPLC are typically UV absorbance instruments, but there are other special chiral detectors that can be applied, especially in research. A circular dichroism detector is useful for simultaneous detection of enantiomers in partially resolved peaks. Chiral separations using a polarimeter detector were often referred to in early works; but due to their low sensitivity and strong temperature dependence, this method has been superseded. Electrochemical detectors can be used for sensitive assays of electroactive chiral compounds, especially in presence of complex matrices.

A3.4.3 METHOD DEVELOPMENT The development of a suitable enantioselective method should be based on the structure of particular analytes (Tables A3.4.1, A3.4.2, and A3.4.3). The application of Type I CSPs is restricted to those molecules that possess a special structure to form a direct solute:CSP complex. Such compounds are lactams, succinimides, sulfoxides, and sulfides. Because of a relatively small number of pelectron-rich or p-electron-deficient molecules, chiral derivatization with naphthoyl or dinitrobenzoyl groups is particularly important in resolving amines and aminoalcohols on a brush-type Pirkle phase. b-Blockers can easily be enantio-separated on a-1-Burke phase with ammonium acetate containing 37 an ethanol/dichloromethane binary organic solvent mixture. Derivatization on Pirkle phases is generally achiral so that it does not lead to the well-known problems emerging in quantitation of any enantiomer ratio. Mixed brush-type phases have much wider applicability than the original Pirkle phases and 77 mixed phases recognize a broad range of analytes, including naproxen and abscisic acid. Mobile phases involved in Pirkle-type chiral chromatography are common apolar organic solvents (i.e., those used in normal phase HPLC), generally hexane mixed with ethanol or 2-propanol organic modifiers, or ternary mixtures of dichloromethane:ethanol:methanol. For separation of atropisomers or aliphatic chiral compounds with a ring structure, Type II cellulose CSPs appear to be successful. When the center of chirality is adjacent to a carbonyl group, cellulose tribenzoate can be used as the stationary phase. Cellulose tricinnamate CSPs show outstanding resolving power for barbiturates. Cellulose tris-phenylcarbamate-based CSPs are very successful in the separation of polar molecules. Molecules with asymmetries on a chiral plain, such as disubstituted cyclopropanes, can be separated on an amylose CSP. In the case of atropisomers, amylose is also the favorite CSP in enantio-separation. The cellulose tris-phenylcarbamate stationary phase offers exceptional separations, with reso38 lution values above 25 in some cases. If the molecule contains both aromatic and polar hydrogene bonding parts and the apolar part fits the cavity, some believe that cyclodextrin (CD) is the best choice for enantio-separation. Solute size is important in complexation. a-CD is suitable for analytes with a single aromatic ring, whereas © 2002 by CRC Press LLC

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TABLE A3.4.1 Examples of Separations of Chiral Amines by HPLC Analyte Amines

CSP

Methaqualone

Cellulose triacetate Polymethacrylate Cellulose triacetate Teicoplanin a Cellulose TPMC Vancomycin CBH CBH S-NEC-bcyclodextrin b-Cyclodextrin

Oxazepam Praziquantel Proglumide Oxazepam Gluthethimide Phenylethanolamine Epinephrine Tropicamide Methamphetamine Ephedrine Deprenyl a

Mobile Phase Composition (v:v:v)

Selectivity Factor ( )

Ref.

EtOH:H2O (76.8:23.2)

1.51

63

Hexane:dioxane:EtOH:ACN (80:17:2:1) MeOH

1.17 3.41

65 66

MeOH:1%TEAA; pH 4.1 (20:80) Hexane:EtOH (85:15) ACN:18 mM ammonium nitrate; pH 7.0 2-PrOH:10 mM Na3PO4; pH 6.0 (5:95) 2-PrOH:10 mM Na3PO4; pH 6.5 (5:95) ACN:1%TEAA; pH4.5 (30:70)

1.4 4.56 1.17 1.40 1.62 1.22

500 mM TEA in neat water; pH adjusted to 3.5 with H2SO4

1.11 1.08 1.26

67 68 69 70 71

TPMC = triphenylmethyl carbamate.

TABLE A3.4.2 Examples of Separations of Chiral Aminoalcohols by HPLC Analyte Aminoalcohols Metoprolol

CSP Burke-type Pirkle phase

Oxprenolol Pronethalol Propranolol Pindolol Bufuralol Teratolol Devrinol Alprenolol

b-Cyclodextrin Teicoplanin CBH

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Mobile Phase Composition (v:v:v) Dichloromethane:ethanol (19:1) containing 0.5 g/l ammonium acetate Dichloromethane:ethanol (19:1) containing 0.5 g/l ammonium acetate Dichloromethane:ethanol (19:1) containing 0.5 g/l ammonium acetate Dichloromethane:ethanol (19:1) containing 0.5 g/l ammonium acetate Dichloromethane:ethanol (19:1) containing 0.5 g/l ammonium acetate Dichloromethane:ethanol (19:1) containing 0.5 g/l ammonium acetate Can:MeOH:AcOH:TEA (95:2:0.4:0.2) MeOH:1%TEA; pH 4.1 (20:80) 2-Propanol:10 mm phosphate; pH 6.8 (0.5:99.5)

Selectivity Factor ()

Ref. 72

1.00 1.13 1.39 1.30 1.93 1.08 1.10 8.30

73 47 74

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TABLE A3.4.3 Examples of Separations of Chiral Acids by HPLC

Analyte Acids

CSP

Mobile Phase Composition (v:v:v)

Selectivity Factor ( )

Ref.

Abscisic acid Flurbiprofen Tropic acid Baclofen Fenoprofen Ibuprofen Cyclohexyl phenylacetic acid Cyclohexyl phenylglycolic acid

Whelk-O 1 Teicoplanin Teicoplanin Teicoplanin Polymethacrylate b-Cyclodextrin b-Cyclodextrin b-Cyclodextrin

Hexane:iPrOH:AcOH (80:20:0.5) MeOH:1%TEAA; pH 4.1 (20:80) MeOH:1%TEAA; pH 4.1 (20:80) MeOH:ACN:TEA:AcOH (545:455:2:2) ACN:H2O:AcOH (80:20:0.5) ACN:1%TEAA; pH 7.5 (30:70) ACN:1%TEAA; pH 4.2 (35:65) ACN:1%TEAA; pH 4.2 (35:65)

1.39 1.10 1.10 1.20 1.10 1.09 1.70 1.60

75 47 47 47 76 77 78

Aspartame diketopiperazine

Crown ether

2-Propanol:0.01 M perchloric acid (1.5:98.5)

1.10

79

molecules with naphthyl groups can easily be separated on a b-CD CSP. The use of g-CD CSP for 39 bulky molecules is particularly efficient. Native cyclodextrin columns operate in both reverse and normal phase mode; in addition, they are suitable for special polar organic mode operation. In reverse phase mode, the recognition interactions take place in water. Triethylamine acetate and, rarely, triethylamine phosphate have proved to be very good buffers. Citrate can also be used, especially for acidic structures. Ammonium nitrate buffers can be applied to reduce strong inclusion. The recommended pH range is 4 to 7. Increased buffer concentration enhances hydrophobic interactions. The most common organic modifiers in reverse phase mode are methanol and acetonitrile. The influence of pH on hydrogen bonding is illustrated by the reverse phase separation of ibuprofen 40 on b-cyclodextrin CSP. No separation was observed at pH 7.0, whereas full resolution can be achieved at pH 4.1. Amino acids must be separated on native CDs at low pH to suppress ionization of the carboxyl groups and enhance the protonation of amine groups. 41 Polar organic mode separation can be achieved in the absence of water with a special mobile phase consisting of acetonitrile, up to 10% methanol, up to 0.5% acetic acid, and 0.5% triethylamine 42 as organic modifiers. To achieve separation, the analytes must include an aromatic ring and at least two hydrogen-bonding groups, one of them close to the ring. Acetonitrile fits the hydrophobic cavity and separation occurs on the surface by means of hydrogen bonding between the polar groups of the analyte and secondary alcoholic hydroxyl groups of the CD. The bulky planar aromatic ring of the analytes serves as an orientating group, positioning the molecule to contact the CD properly. Ionization and thus chiral separation can efficiently be controlled by the ratio between triethylamine and acetic acid. This is to be varied until a desirable interaction is attained. Polar organic mode will distinguish between some underivatized chiral molecules such as b-blockers that 43 are difficult to separate with aqueous mobile phases. Amino acid enantiomers can be separated by means of derivatizing them with FMOC, CBZ, dansyl, or AQC (Waters AccuTag, aminoquinoline 44 succinimidyl carbamate) reagent. Acetylated b- and a-CD columns are employed in normal or reverse phase mode. The size of the CD rim is extended with the attached acetyl groups providing a further orientation for an optimum fit of some bulky guest molecules. Compounds separated on an acetylated b-CD phase 45 include scopolamine, atropine, homatropine, and cocaine, phenylephrine, epinephrine, and ephedrine. In the case of epinephrine, the aromatic ring is merged so deeply into the cavity that the

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hydrogen bonding at the mouth of the cavity is weakened. Addition of a strong sodium nitrate buffer weakens inclusion and thus enhances the separation. (S)- or (R)-1-naphthylethylcarbamate b-cyclodextrin derivatives are analogous to naphthyl Pirkle-type columns, but chiral recognition can take place in parallel with inclusion complexing. It is stable in both normal and reverse phase solvents and it is also stable in pure iPrOH or MeCN. 46 This column is particularly useful for 3,5-dinitrobenzoyl derivatives. With cyclodextrin (S)- or (R)-2-hydroxypropylether, separations rely on extended hydrogenbonding interactions. Chiral centers between rigid substituents must be adjacent to an aromatic moiety, or must involve a hydrogen-bonding group. Enantioselectivity is better if the chiral center is situated between two adjacent p-systems. These columns must be used in reverse phase mode. Amino acid derivatives, methyl esters, and peptides can be separated on teicoplanin CSP in polar 47 organic mode using MeCN:MeOH:HOAc:TEA (46:54:2:2 volume ratio) as a typical mobile phase. Normal phase separations on macrocyclic antibiotic CSPs are also possible with hexane:ethanol mobile phases. Organic acids can easily be separated on teicoplanin CSP using reverse phase mode and low pH to maximize retention. Vancomycin columns separate amines, amides, neutral molecules, and esters but are less selective for acidic molecules. In reverse phase mode, an aqueous triethylamine:acetate buffer, THF, acetonitrile, or methanol can be applied as modifiers. Optimum selectivity can be achieved with acetonitrile and THF. Pure methanol or ethanol mobile phases have also yielded good separations in some cases. Normal phase operation is possible using hexane:ethanol mobile phases. Vancomycin chiral columns have very high loading capacity and can therefore be used in preparative applications. 48 Crown ethers separate cationic forms of primary amines and amino acids by means of inclusion complexation using reverse phase mode. For efficient complexation, a strong acidic mobile phase (generally 10 mM to 0.1 M perchloric acid) protonates the analytes. Moreover, addition of perchloric acid results in enhanced hydrophobicity of the guest molecule and therefore it prompts inclusion. In the case of amino acids and a-chiral carboxylic acids, which are able to form a complex with transition metals, the first choice is a Type IV ligand exchange CSP. Analyte concentrations are in a broad range (0.05 to 20 mM). Hydroxy acids, like lactic, atrolactic, and phenyllactic acids, 49 can be separated on a hydroxyproline CSP with Cu(II) ions. The use of CLEC is primarily limited to a-amino acid separations, but aminoalcohols such as catecholamines can be chromatographed 50,51 in the form of their Schiff-base derivatives as a monodentate ligand at weakly acidic pH. Slow 52 complexation can be avoided by working at elevated temperatures. To avoid any loss of copper, the separation temperature must be of 50∞C or higher. Type-V protein CSPs are recommended when the enantiomers contain excess charge. The best chiral resolution can be obtained with small organic molecules. Several chiral analytes have been 53,54 55 56 separated on MeGP columns, for example, b-blockers, acidic drugs such as ibuprofen, and 57 basic drugs such as lignocain and bupivacain. Most commonly used mobile phases are phosphate buffers of pH 4-7 with a low percentage of organic modifiers, preferebly iPrOH. If this does not work, then MeCN, EtOH, MeOH, or THF should be used as the second choice. The modifier induces a reversible change in the protein structure. A change in pH has a crucial effect on the selectivity, especially in case of amines. Lower pH will diminish the negative charge on the protein that causes amines to be less retained. A lower content of organic modifier results in sharper peaks, and thus 58 enantioselectivity improves. A good starting point is a 10 mM sodium acetate buffer at pH 4.5 for amines and aminoalcohols. With acids, method development generally starts with 10 mM phosphate buffer at pH 7.0. OVM CSP was investigated to resolve several acidic, basic, and neutral chiral analytes with 59 different mobile phases involving primary secondary and tertiary alcohols. The human serum albumin stationary phase has proved to be particularly useful in separating 60 benzodiazepine enantiomers using octanoic acid in the mobile phase. In protein-CSP-based chiral chromatography, mobile phase modifiers enhance selectivity or resolution. Charged modifiers can © 2002 by CRC Press LLC

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be used where organic modifiers have failed. Octanoic, decanoic, and butyric acids and dimethyloctylamine can be applied to improve the separation of acidic analytes in AGP chromatography. For example, the theoretical plate number in the separation of the acidic drug ibuprofen can be 61 elevated ten times, with a three-times reduction in k. Uncharged additives, such as ethylene glycol, 1-butanol, and 2-butanol, have also been used. Charged additives can change protein structure irreversibly; their application may damage the column. Micellar chromatography on an AGP column with the nonionic surfactant Tween-20 has been 62 reported to provide efficient chiral separation of aromatic amines and aminoalcohols. The major drawback of protein phases is their very low capacity. For maximum resolution, only about 0.5 µg (about 4 to 6 nM) analyte can be injected into an analytical column. Maximum flow rates on an AGP column of 4-mm i.d. are about 1.5 ml/min.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

I.W. Wainer, Drug Stereochemistry, Marcel Dekker, New York, 141 (1993). W.H. Pirkle and D.W. House, J. Org. Chem., 44, 1957 (1979). C.E. Dalgliesh, J. Chem. Soc., 3940 (1952). W.H. Pirkle, D.W. House, and J.M. Finn, J. Chromatogr., 192, 143 (1980). W.H. Pirkle and J.L. Schreiner, J. Org. Chem., 46, 1488 (1981). W.H. Pirkle, J.M. Finn, J. Schreiner, and B.C. Hamper, J. Am. Chem. Soc., 103, 3964 (1981). W.H. Pirkle and A. Tsipouras, J. Chromatogr., 29, 291 (1984). Q. Yang, Z.P. Sun, and Y. Ling, J. Chromatogr., 477, 208 (1988). H. Hess, G. Burger, and H. Musso, Angew. Chem., 90, 645 (1978). T.J. Ward and D.W. Armstrong, J. Liq. Chromatography., 9, 407 (1986). U.S. Patent 4539399 (1985). D.W. Armstrong, Y.I. Han, and S.M. Han, Anal. Chim. Acta, 208, 275 (1988). C.A. Chang, Q. Wu, and D.W. Armstrong, J. Chromatogr., 354, 454 (1986). T.E. Beesley, Am. Lab., 78, 87 (1985). A.M. Stalcup, S. Chang, D.W. Armstrong, and J. Pitha, J. Chromatogr., 513, 181 (1990). D.W. Armstrong, C.D. Chang, and S.H. Lee, J. Chromatogr., 539, 83 (1991). C.J. Pedersen, J. Am. Chem. Soc., 89, 2495 (1967). K. Kimura, M. Nakajima, and T. Shono, Anal. Lett., 13, 741 (1980). D.W. Armstrong, Y. Tang, S. Chen, Y. Zhou, and C. Bagwell, Anal. Chem., 66, 1473 (1994). H.Y. Aboul-Enein and V. Serignese, Chirality, 10, 358 (1998). D.W. Armstrong, Y. Liu, and K.H. Ekborg-Ott, Chirality, 7, 474 (1995). Y. Okamoto, S. Honda, I Okamoto, and S. Murata., J. Am. Chem. Soc., 103, 6971 (1981). V.A. Davankov, Advances in Chromatography, Vol. 18, Marcel Dekker, New York, 139 (1980). V.A. Davankov, J.D. Navratil, and H.F. Walton, Ligand Exchange Chromatography, CRC Press, Boca Raton, FL (1988). C. Corradini, F. Federici, M. Sinibaldi, and A. Messina, Chromatographia, 18, 459 (1984). V.A. Davankov, Y.A. Zolotarev, and A.B. Tevlin, Bioorganich. Khim., 4, 1164 (1978). B. Lefebre, R. Audebert, and C. Quivoron, Isr. J. Chem., 15, 69 (1979). B. Lefebre, R. Audebert, and C. Quivoron, J. Liquid Chromatogr., 1, 761 (1978). J. Hermansson, J. Chromatogr., 269, 71 (1983). J. Hermansson, Chromatographia, 24, 520 (1987). J. Hermansson, J. Chromatogr., 609, 163 (1992). I. Fitos et al., Chirality, 11, 115 (1999). I. Kato, J. Scrode, W.J. Kohr, and M. Laskowski, Biochemistry, 26, 193 (1987). T. Miwa, T. Miyakawa, M. Kayano, and Y. Miyake,Y., J. Chromatogr., 408, 316 (1987). P. Erlandsson, J. Am. Chem. Soc., 112, 4573 (1990). J. Hermansson, J. Chromatogr. A, 687, 174 (1994). W.H. Pirkle and J.A. Burke, J. Chromatogr., 557, 174 (1991). Y. Okamoto and K. Hatada, J. Chromatogr., 448, 454 (1988).

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39. A.M. Stalcup, H.L. Jin, and D.W. Armstrong, J. Liq. Chromatogr., 13, 473 (1990). 40. G. Geisslinger, K. Dietzel, D. Lowe, O. Schuster, G. Lachman, G. Rau, and K. Brune, J. Chromatogr., 491, 139 (1989). 41. S.C. Chang, G.L. Reid III, S. Chen, C.D. Chang, and D.W. Armstrong, Trends Anal. Chem., 12, 144 (1993). 42. J. Zukowski, M. Pawlowska, M. Nagatkina, and D.W. Armstrong, J. Chromatogr., 629, 169 (1993). 43. D.W. Armstrong, S. Chen, C. Chang, and S. Chang, J. Liq. Chromatogr., 15, 545 (1992). 44. M. Pawlowska, S. Chen, and D.W. Armstrong, J. Chromatogr., 641, 257 (1993). 45. D.W. Armstrong, S.M. Han, and Y.I. Han, Anal. Biochem., 167, 261 (1987). 46. D.W. Armstrong, M. Hilton, and L. Coffin, LC-GC Magazine, 9, 646 (1991). 47. A. Berthod, C. Liu, C. Bagwell, and D.W. Armstrong, J. Chromatogr. A, 731, 123 (1996). 48. T. Shinbo, T. Yamaguchi, K. Nishimura, and M. Sugiura, J. Chromatogr., 405, 145 (1987). 49. G. Gübitz, J. Liq. Chromatogr., 9, 519 (1986). 50. C.H. Shieh, B.L. Karger, J.L. Neumeyer, L.R. Gelber, and B. Feibush, J. Chromatogr., 406, 383 (1987). 51. L.R. Gelber, B.L. Karger, J.L. Neumeyer, and B. Feibush, J. Am. Chem. Soc., 106, 7729 (1984). 52. Y.A. Zolotarev, N.F. Myasodeov, V.I. Penkina, O.V. Petrenik, and V.A. Davankov, J. Chromatogr., 207, 231 (1981). 53. G. Schill et al., J. Liq. Chromatogr., 9, 641 (1986). 54. J. Hermansson, J. Chromatogr., 298, 67 (1984). 55. A. Ceccato, J. Chromatogr. A, 760, 193 (1997). 56. G. Fornasini, Chirality, 9, 297 (1997). 57. I. Abraham et al., J. Chromatogr. B, 703, 203 (1997). 58. J. Hermansson, J. Chromatogr. A, 694, 57 (1995). 59. I.W. Wainer, J. Iredale, and A.-F. Aubry, Chromatographia, 31, 329 (1991). 60. P.J. Hayball, J. Chromatogr. B, 662, 128 (1994). 61. T. Noctor, G. Felix, and I.W. Wainer, Chromatographia, 31, 55 (1991). 62. D. Haupt, C. Pettersson, and Westerlund, J. Chromatogr., 5, 224 (1993). 63. A.M. Rizzi, J. Chromatogr., 513, 195 (1990). 64. M. Krause and R. Galensa, J. Chromatogr., 441, 417 (1988). 65. S. Huenig and N. Klaunzer, J. Chromatogr., 481, 387 (1989). 66. C.B. Ching, B.G. Ling, E.J. Lee, and S.C. Ng, J. Chromatogr., 634, 215 (1993). 67. N. Bergmann-Leyder, M. Tambuté, and M. Caude, Chirality, 7, 311 (1995). 68. H.Y. Aboul-Enein and V. Serignese, Chirality, 10, 358 (1998). 69. J. Hermansson and A. Grahn, J. Chromatogr., 687, 42 (1994). 70. K. Williams, L. Sander, and L. Wise, J. Chromatogr. A, 746, 91 (1996). 71. K. Lemr, D. Jirovsky, and J. Seveik, J. Liq. Chromatogr., 19, 3173 (1996). 72. W.H. Pirkle and J.A. Burke, J. Chromatogr., 557, 173 (1991). 73. G. Felix, C. Cachau, A. Thienpontand, and M. Soulard, Chromatographia, 42, 583 (1996). 74. P. Erlandsson, I. Marle, and L. Hannson, J. Am. Chem. Soc., 112, 4574 (1990). 75. C.J. Welch, Chirality, 5, 569 (1993). 76. N. Oi, Y. Matsumoto, H. Kitahara, and H. Miyazaki, Bunsi Kagaku, 35, 312 (1986). 77. G. Geisslinger, K. Dietzel, D. Loew, G. Lachmann, and K. Brune, J. Chromatogr., 491, 139 (1989). 78. K.G. Feitsma, J. Bosman, B.F.H. Denth, and R.A. De Zeuw, J. Chromatogr., 333, 59 (1985). 79. S. Motellier and I.W. Wainer, J. Chromatogr., 516, 365 (1990).

A3.5

CHIRAL SEPARATION BY CAPILLARY ELECTROPHORESIS

A3.5.1 SPECIAL FEATURES

OF

CAPILLARY ELECTROPHORESIS (CE)

A3.5.1.1 Characterization of Capillary Electrophoresis 1,2

Capillary electrophoresis (CE) has unique advantages in the analysis of ionizable compounds, but it can also separate neutral compounds using ionized selectors. CE offers very high efficiency, fast analysis, low analysis temperature, and a broad variability of mobile and stationary phases (see Section A3.1.4, Table A3.1.2). In chiral CE, aqueous and non-aqueous based buffers and an extremely broad © 2002 by CRC Press LLC

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spectrum of chiral additives can be used. Instrumentation of CE is still in its infancy, but shows fast development. In electrophoresis, ionized species move toward oppositely charged electrodes. The physical basis of separation is the different electrophoretic mobility ( m) of different compounds. The electrophoretic mobility of compounds increases with increasing ionization degree and decreasing radius. Migration of ions can be accelerated by a stronger electric field and lower viscosity of buffer. An increase in the electric field, however, results in faster migration, but only to a certain limit. Above a certain current, frictional collision among migrating ions and buffer molecules produces excessive heat (Joule heating), causing bubble formation, a shutdown of electrical current, and finally stopped flow. Introduction of capillaries into electrophoresis has opened new perspectives. The high surface area of the capillary as compared to the volume of buffer offers effective Joule heat dissipation, keeping the temperature of the buffer low. Capillary electrophoresis works upto 30-kV, providing excellent efficiency and fast analysis. The most frequently used capillaries are made of fused silica, having negatively charged silanol groups on its surface. Silanol groups attract positively charged buffer components, creating a positively charged layer. This positively charged layer moves toward the cathode, dragging the entire volume of the buffer, producing a s.c. electroosmotic flow (EOF). The speed of EOF is often larger than the migration speed of analyzed ions, offering detection of both cations and anions at the catodic end. Moreover, EOF creates a flat flow profile, which gives higher efficiency than the laminar flow profile of pressure-driven systems. EOF can be adjusted by pH, reversed in direction with cationic 3,4 5,6 surfactants, or eliminated using coated capillaries (e.g., polyacrylamide). Some unwanted effects can cause a drop in efficiency. If the conductivity of the solute zone differs significantly from the conductivity of buffer, broad distorted peaks are observed. The reason for this is electrodispersion; unbalanced electric fields at solute boundaries create diffuse, spreading zones. The efficiency of the system can be preserved by a balanced conductivity of analytes and 7,8 buffer components (mobility matching). 2,9 Adsorption of analytes on the column wall is another unwanted effect. Adsorption of analytes can be suppressed using a well-designed buffer with high ionic strength, organic additives, or 4,5,10 deactivation of the column wall by a permanent or dynamic coating. The volume of the capillary is very small; therefore, even a 1-nl sample can cause some loss 1,11 in efficiency. A good injection technique, “stacking” (shrink the initial band), makes possible the analysis of 10- to 70-nl samples without significant loss in efficiency. The initial band of the sample can be focused very simply by injecting the sample in running buffer diluted ten times. Quantitative measurements of CE are based on peak areas instead of peak heights because overloading and electrodispersion frequently cause asymmetric peaks. To obtain correct quantitative 12 data, peak areas are divided by their migration times because the speed of the individual analytes is not the same in the detector. In CE, as contrasted with general chromatographic practice, compounds with a slow migration speed spend a longer time in the detection window than fast migrating ones; therefore, slower migrating compounds give relatively larger signals. A3.5.1.2 Characterization of Chiral-Selective CE During the 1990s, CE has became the most dynamically developing technique for chiral separations. More than 10,000 chiral separations have already performed with this technique, despite the fact 13 that the first chiral CE separation was published in 1985. One book, several reviews (e.g., 14, 15), and special issues of scientific journals (e.g., Electrophoresis, Vol. 18/6, Vol. 20/13; J. Chromatogr. A, Vol. 792, Vol. 875) were dedicated to chiral-selective CE. Basically, CE is not a chromatographic technique, but enantiomer separations with CE always also include chromatographic processes. Partitioning of enantiomers between the chiral selectors © 2002 by CRC Press LLC

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and background electrolyte (BGE) is necessary for chiral recognition. This is the reason why chiral-selective CE is categorized as capillary electrokinetic chromatography (EKC) and shows a 16 lot of similarities to micellar electrokinetic chromatography (MEKC). The chiral selectors are usually dissolved in the buffer, creating pseudo-stationary phases. The disperse character of chiral selectors provides high efficiency, caused by drastically reduced resistance to mass transfer in the stationary phase. This is why protein-based chiral selectors in CE dispersed, pseudo-CSP show a much higher efficiency than real CSPs in LC. Moreover, other than in chiral capillary GC, no axial diffusion is required for the analytes to interact with the chiral selectors on the column wall. Fast migration, EOF-induced flat flow profile, and dispersed chiral selectors make it possible to achieve several hundred thousand theoretical plates in a 50-cm column. CE will probably supersede LC in the future in the majority of chiral separations. 17 The mobility difference of two enantiomers (Dm) can be expressed by : [ c ] ( m f – mc ) ( K S – K R ) D m = ------------------------------------------------------------------------------------2 1 + [c](K R + K S) + (1 + K RK S)[c ]

(A3.5.1)

where [c] is the concentration of the chiral selector; mf and mc are the mobility of analytes in free and complexed (diastereomeric associations) forms, respectively; KS and KR are stability (partition) constants of enantiomers with the chiral selector. This approach postulates that both enantiomers have the same speed in both the free (mf) and associated states (mc). The difference of the interaction energies of R and S enantiomers (non-equal partition ratio, KS π KR) is not enough for chiral separations in CE. It is also necessary that there should be a mobility difference between the free and diastereomeric association forms of molecules (mf π mc). This means that the neutral enantiomers cannot be separated with neutral selectors because the migration speed of enantiomers is equal to 13,15,17 EOF in both free and associated forms. Separation of neutral enantiomers generally requires 18 19 charged selectors or a combination of a neutral selector with a charged achiral agent. Equation (A3.5.1) has some important consequences. The migration difference has an optimum 17,20 as a function of the concentration of chiral selectors, which was empirically demonstrated. Namely, the concentration of selectors is first order in the numerator, but it is the square in the denominator. This equation also shows that an oppositely charged selector and selectand produce a large mobility difference because the mf and mc have opposite increments. That is, the length of columns increases virtually because mobility increments of analytes are opposite in the free and 33 associated states. Note that the mobility differences sometimes do not closely correlate with resolution values 7–9 because adsorption and electrodispersion are disregarded. Derivatization also plays role in chiral selective CE, although the high polarity of acidic and 21 basic enantiomers is favorable in CE. CE applies similar derivatives as LC to improve the detectability of analytes. Considering the high efficiency of CE and the broad variety of selectors, derivatization in CE is of minor importance in improving selectivity. A3.5.1.3 Special Techniques in Chiral-Selective CE A3.5.1.3.1 Counter-Current Method Several chiral selectors (proteins, macrocyclics, alkaloids, etc.) have strong UV absorbance, dis10,22–26 simulating the signal of analytes. The counter-current technique overcomes this problem. This technique uses coated capillaries to eliminate the EOF and analyze oppositely charged analytes and selectors. Before injection, the capillary is filled under pressure with the chiral selector and the reservoirs of the electrodes do not contain chiral selectors. After injection, during analysis, ionic chiral selectors move toward the injector end. These UV-active selectors move away from the detector window before the analytes reach the detector because selectors and selectands move in opposite directions. Of course, separation length is shorter than the distance of injector and detectors, © 2002 by CRC Press LLC

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but the high selectivity of these selectors compensates for this loss of separation length. In some applications, only part of the capillary is filled or short bands of the chiral selector are used, (partial 24 filling technique). A3.5.1.3.2 Reversal of Migration Order Because in the case of high e.e., tailing of the major peak can overlap the minor peak, it is essential that the minor peak should come first (Section A3.1.2). An entire chapter focuses on reversing of 13 migration order of enantiomers in the book on chiral CE. CE offers many more methods other than chromatographic modes to invert the migration order of enantiomers, including: 27

1. The simplest method is to change the chirality of the chiral selector. This is possible with synthetic selectors (e.g., camphorsulfonic acids, amino acids containing micelles, or ligand exchangers). 2. Using a selector with opposite selectivity is a frequently used technique. Finding such selector pairs is based on a trial-and-error method, but several such combinations have 3,9,28,29 been published. 3. Changing the ionization state of selector or selectand by shifting the pH of BGE can also 6,30,31 lead to reversal of the migration of enantiomers. For example, the migration direction of the diastereomeric associate is different when the selector is charged than when it is neutral. 6,32 4. Elimination or reversal of EOF also resulted in migration reversal on several occasions. 5. An increase in the concentration of chiral selector can produce migration reversal without 3 EOF. The less strongly bound cationic enantiomer elutes first at the cathodic end using a small concentration of anionic selector. The strongly bound enantiomers migrate first to the anodic end using high concentration of selector. 33 6. Addition of an achiral surfactant also results in migration reversal. Migration of selector can drastically change if the selector becomes part of a micelle. One of these methods can result in migration of the minor enantiomer first in the case of high e.e., but the adjustment of ionic strength of BGE (background electrolyte) is also important to avoid 7,8 peak distortion by electrodispersion. Reversal of migration order sometimes also results in a reversal of migration direction of enantiomers, which necessitates that the polarity of the electric source be reversible to be able to change the polarity of the electric source. A3.5.1.3.3 Capillary Electrochromatography in Chiral Analysis Capillary electrochromatography (CEC) is a hybrid technique of CE and LC that is just gaining 34 ground in chiral CE. CEC has real stationary phases and the flow of mobile phase is generated by EOF. CEC columns are generally fused silica tubes (0.1 to 0.32 mm i.d.) packed with particles. CEC offers much higher efficiency than LC because it is compatible with a particle size even as low as 0.5 mm, but is less efficient than CE. Analysis of neutral enantiomers and high capacity are also advantages of CEC. The chiral selector can be dissolved in the buffer or as a CSP. Commercial 35 columns with achiral ODS particles can separate enantiomers, using a cyclodextrin-containing buffer. 36 Other types of capillary electrophoresis (i.e., capillary isotachophoresis and capillary gel 37 electrophoresis ) have been applied to chiral separations, but these techniques have minor importance in enantiomer-selective analysis.

A3.5.2 COLUMNS Lengths of columns are in the 10- to 100-cm range. The total length of the column (the distance between electrodes) and the effective length of columns (distance from injection point to detector) are different. Very fast analysis can be done with 5- to 7-cm effective lengths, injecting the sample © 2002 by CRC Press LLC

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from the opposite “detector” end. Inner diameters of columns are between 0.025 and 0.1 mm. A decrease in the column i.d. results in a reduction of current and better heat dissipation, allowing 40 higher electric power. In CE fused silica columns are typically used. Reproducibility of silanol content of column wall and elimination of adsorbed contaminants requires a washing cycle after each run. Some applications 5,6,23 (e.g., counter-current technique, migration reversal, protein selectors, etc.) use acrylamide or 10 methylcellulose coated columns to eliminate EOF and adsorption.

A3.5.3 BACKGROUND ELECTROLYTES The majority of chiral separations use 20- to 100-mM concentrations of aqueous BGEs. A high buffer concentration reduces the EOF and the adsorption of analytes on the column wall, but it produces high conductivity with Joule heating. Several applications adapt the generally used LC buffer additives: phosphate, borate, acetate, and citrate anions, potassium, sodium, ammonium, and lithium cations. The use of low-conductivity organic and zwitterionic buffers (e.g., TRIS, MES, CAPS, and TAPS) offers higher efficiency because their heat generation is less. The choice of the background 7,8 buffer according mobility matching helps to eliminate the efficiency loss due to electrodispersion (Section A3.5.1.1). Borate and phosphate ions give complexes with some types of analytes (e.g., sugars, diols, catecholamines), which can either improve or impair the selectivity of chiral 41,42 selectors. 43 Strong basic BGE components (e.g., alkyl ammonium salts) and high concentrations of basic 3 chiral selectors can cause reversal of EOF in the anodic direction. These compounds also prevent the adsorption of basic enantiomers on the column wall. Several nonionic polymers have also been 44 applied to gain better peak shapes via decreased adsorption. During one analysis, only a few microliters of buffer pass the capillary; however, buffer reservoirs must be of 0.1 to 1.0 ml volume to keep the buffer composition constant during the runs. Due to depletion of buffer caused by electrochemical reactions, replenishment of the buffer after 3 to 15 analyses is necessary. 45 Organic modifiers (5 to 40%) are frequently applied as buffer additives. Such modifiers exert multiple, sometimes opposite effects. Organic modifiers reduce the EOF and the adsorption of 1 analytes on the column wall, but increase their solubility in BGE. They can compete with the 9,46 analytes for the interaction sites of the chiral selector. According to the concentration, both the organic modifier and the selector mobility difference of enantiomers can increase or decrease. Application of organic modifiers is often crucial when using macrocyclic or protein-based 23,47,48 selectors. Methanol is used most frequently, but the addition of other alcohols and acetonitrile 49,50 has also been noted. 4,27,51 CE based on nonaqueous buffers is a recently introduced tool in chiral CE. Buffers based on organic solvents can overcome several solubility and decomposition electrodispersion problems. Native cyclodextrins show many times higher solubility in dimethylformamide than in water-based buffers. Methanol, acetonitrile, dimethylformamide, N-methylformamide, formamide, dimethylsulfoxide, and dimethylacetamide have been used as solvents of BGE.

A3.5.4 CHIRAL SELECTORS In CE, a very broad spectrum of chiral selectors have been applied. Minute selector consumption of CE allows the use of even very expensive selectors. The high efficiency of CE results in baseline separations with selectors having only moderate selectivity (a = 1.01). Fast analyses enables rapid method development. The pH value of BGE determines the ionized state of ionizable chiral selectors and analytes. Enantiomers with chiral selectivity in their ionized states can be separated within a broad pH range © 2002 by CRC Press LLC

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(e.g., acids above their pKa values) using neutral selectors. On the other hand, enantiomers showing selectivity in their neutral states can be separated only in a narrow pH range (around their pKi) 52 using neutral selectors. In the latter instance, the neutral states of enantiomers show selectivity and their ionized states mobility other than EOF. These statements imply that the separation of enantiomers must be tested at two pH values using neutral selectors. Acidic enantiomers, for example, can be separated at their pKa and at least 2 pH units higher than their pKa values. Separation of enantiomers showing chiral recognition in their neutral state need very careful adjustment of parameters because a small change in pH can result in a large shift in their separation. Charged selectors have some advantages over neutral ones. Analyzing enantiomers having opposite charges to the selector, as discussed in Section A3.5.1.2, results in virtual column elonga17, 18 tion. Charged selectors can separate neutral enantiomers over a broad pH range. Moreover, they can show more than one chiral recognition feature, depending on their ionization state, which 6,53 further expands their applicability. On the other hand, charged selectors increase the conductivity of the buffer; therefore, they cannot be used at high concentrations. A3.5.4.1 Cyclodextrin-based Selectors Cyclodextrins (CDs) are the most frequently used chiral selectors in CE because they exhibit a 14,15,54,55 56 CDs are cyclic oligosachharides ; they are briefly discussed very broad selectivity spectrum. in Section A3.2.4.2. A large number of variously derivatized CDs, including both ionized and neutral ones, have been introduced for chiral CE. Most are mixtures of statistically substituted isomers, differing from each other in their degree of substitution and substitution pattern. The various isomers have different chiral recognition features and therefore the selectivity spectrum of these derivatives is very broad. On the other hand, the statistical substitution pattern results in poor producer-to-producer, even batch-to-batch reproducibility. Recently, some uniform CD derivatives were introduced, securing 57–59 good reproducibility but a narrower selectivity range. CDs have low or moderate UV absorbency and they act not only as chiral selectors, but also as solubizers. A wide variety of CDs is available at relatively low cost and there is plentiful information regarding their application. A3.5.4.1.1 Neutral Cyclodextrins 13

Native cyclodextrins were the first to be introduced to CE. The selectivity of native CDs is 13,60,61 significantly influenced by their ring size. The use of native CDs has recently declined because they have moderate selectivity and solubility in water-based buffers. Methyl-substituted CDs have a flexible structure, giving a broad recognition spectrum, and 53,55 their solubility is high. Some methylated CDs, such as 2,6-di-O-methyl-b-CD (DIMEB) and 2,3,6-tri-O-methyl-b-CD (PerMe-b-CD) are homogeneous derivatives having a regular substitution pattern. The most often used methylated CDs, however, are randomly substituted Me-b-CD, con62 sisting of a large number of isomers with substitution degrees around 1/3 to 2/3. Me-b-CD has 53,63 a broader recognition spectrum than uniform derivatives, but poor reproducibility. 64–68 (S )-(2-Hydroxy)propyl-CDs (HP-CDs) are rather important selectors in chiral CE. The (2-hydroxy)propyl-substituents include a chiral center; thus, extra chiral recognition sites have been introduced. They have a flexible structure and the product is a mixture of isomers; therefore, they have a broad chiral selectivity spectrum. HP-CDs are not only good selectors, but also excellent solubilizers toward both apolar and polar compounds. Their solubility in water (>100 mM ) is high. The degree of substitution of HP-CDs varies, according to producers, from 2 to 6. Some vendors offer them with different substitution degrees. For example, Cyclolab sells HP-b-CD with 3, 4.8, and 6.3 degrees of substitution. © 2002 by CRC Press LLC

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A3.5.4.1.2 Negatively Charged CDs 13,15,18,55

Several acidic and basic CDs have been introduced to chiral CE. Sulfate-substituted CDs 28,58,59,69–76 are very versatile separation agents, gaining high popularity in the late 1990s. Sulfate groups can be joined directly to CD (sulfate, sulfato) or via an alkyl spacer (sulfo ethers). Currently, the most used chiral selector is the sulfobutyl ether of b-CD (SBE-b-CD), but other 28,76 ring sizes with same groups have also been succesfully applied. Sulfoethyl- and sulfopropyl2,72 ethers have also been introduced but they rarely show any advantage over SBE-b-CD. Sulfate groups attached directly to CD also proved effective and are frequently used as chiral recognition 30,58,59,72–78 agents. The selectivity of sulfate-substituted CDs depends greatly on the degree of substitution and the 71,73 length of the alkyl spacer. Even reversal of the migration order of enantiomers was observed between SBE-b-CDs substituted to a different degree. Uniform derivatives of sulfate-substituted CDs have been prepared to avoid the batch-to-batch inconsistency of selectors and to limit electrodispersion. In these uniform derivatives, sulfate groups were attached to each primary hydroxyl group 58 59 (position 6-O) and the other groups (positions 2- and 3-O) have acetyl or methyl substituents. The strong acidity of sulfo and sulfate groups guarantees the ionized state of selectors in the entire useful pH range (2 to 12). SBE-b-CD is a very effective chiral selector, sometimes only at less than 61,77 1 mM concentration or only a short band13,78 of it is sufficient for baseline separation. Sulfate derivatives are primarily used for separation of basic and neutral enantiomers, but they also work with 77 acidic enantiomers. The addition of an organic modifier to BGE is frequently useful. The high conductivity of these selectors causes increased electrodispersion, which can be compensated for by 7,8 a well-balanced BGE. 3,6,9,29,30,53,79,80 Carboxy-substituted CDs are also popular chiral selectors in CE. Carboxymethylsubstituted b-CDs (CM-b-CDs) have been applied most frequently; but others, such as carboxyethyl-6, 9, 29, 53 and succinyl-substituted b-CDs,6, 30 have also proved to be successful chiral separator agents. Carboxy-substituted CDs with other ring sizes (a and g ) have been successfully 29 applied. The conductivity of carboxy-substituted CDs is moderate; therefore, they can be used in high concentration (up to 30 mM) without difficulty. An example is shown in Fig. A3.5.1 The electropherogram in Fig. A3.5.1 effectively demonstrates the ability of CE to separate not only a single pair of enantiomers, but several of them, as well as to separate the main and side products. A high concentration of CM-a-CD was necessary to avoid co-migration of EOF and ortho-isomers. The selected pH was the result of a compromise between chiral selectivity toward the main and by-products. 80 The selectivity spectra of CM-b-CDs from different sources deviate significantly, caused by their different degrees of substitution and random substitution patterns. Carboxyl functions change their ionization state at pH values between 3 and 5; therefore, they cannot be used for the separation of neutral enantiomers in this region. A change in their ionization 6,9,29 state can modify their chiral recognition features. They are highly soluble in water-based BGEs and their charges cause only a moderate conductivity increase (Joule heat) at elevated concentrations. Application of organic modifiers is not so common with CM-b-CDs as with sulfate-derivatized CDs. They are excellent for the separation of basic and neutral enantiomers, but that of acidic enantiomers has been also occasionally reported. 9,29,53,81,82 CDs with phosphate substitution have also been developed with noticeable results. 82 Their highly substituted versions are adsorbed on the column wall at low pH. This can be completely eliminated by increasing the pH, decreasing the concentration of phosphated CD, or 9,29,82 These CDs have a rather broad selectivity spectrum with adding an organic modifier. multimodal character. Some enantiomers have been separated with phosphated CDs of all three 9,82 ring sizes, proving that chiral recognition by CDs is not necessarily an inclusion phenomenon. Their chiral recognition capability can change with pH, according to whether they are in a singly 53 or doubly ionized state. Several basic and neutral enantiomers have been separated with these agents. © 2002 by CRC Press LLC

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FIGURE A3.5.1 Simultaneous chiral separation of metoprolol and its ortho and meta by-products. Conditions: column, 37 cm (30-cm effective length) ¥ 50 mm, bare fused silica; 15 mM CM-a-CD; BGE, 100 mM phosphate; pH 4.9; potential, 25 kV; detection, 214 nm; temperature, 15∞C. (From Z. Juvancz, K.E. Markides, and L. Jicsinzky, J. Microcol. Sep., 11, 716 (1999). With permission.)

A3.5.4.1.3 Positively Charged CDs 3,4,57,70,83–86

Various CDs with amine functions have frequently been used. Quaternary ammonium 3,84,86 group containing derivatives have a charged state over the entire useful pH range. The most 83 frequently used derivative is 2-hydroxypropyl-trimethylammonium-b-CD (QA-b-CD). It is multisubstituted and has a strong basic character; therefore, EOF reversal was observed in the high © 2002 by CRC Press LLC

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FIGURE A3.5.2 Optimized separation of phenoxy acids. Conditions: column, 57 cm ¥ 0.05 mm i.d. FSOT; background buffer, 40 mM boric:acetic and phosphoric acid buffer (Britton-Robinson, 1:2:2), 15 mM PMeMAb-CD, pH 6.5; potential, 30 kV; detection, 202 nm; temperature, 25∞C. (From R. Ivanyi, L. Jicsinszky, and Z. Juvancz, Chromatographia, 53, 69, 2001. With permission.) 3

concentration range. The unbalanced EOF caused deviation in the migration times of enantiomers. 85 Monofunctionalized CD derivatives — mono-(6-amino-6-deoxy)-b-CD (MA-b-CD) or the 57 recently introduced permethylated 6-monoamino-b-cyclodextrin (PMeMA-b-CD) — do not cause EOF reversal. Due to its high degree of methylation, PeMA-b-CD is a good solubizer, exhibiting both chemical and EOF stability. This selector is capable of chiral recognition in both the charged and neutral state. Amine-substituted CDs are excellent for the separation of acidic and neutral 57,84 enantiomers, but some examples have also been published for basic enantiomers. One application is illustrated in Fig. A3.5.2. The parameters in Fig. A3.5.2 were optimized not only for chiral separations, but also for the separation of various herbicides. The pH (6.5) of BGE keeps both selectors and selectands ionized, giving pseudo-elongation of the column. Monosubstitution of PMeMA-b-CD allows for the use of selectors at high concentration, and makes the use of organic additives and a coated column unnecessary. A3.5.4.1.4 Combination of CDs 15,87

40,80–91

and research papers, a buffer containing two types of CDs According to literature reviews frequently provides improved separation. In general, one neutral and one charged CD are combined. The synergistic effect of two chiral selectors is based on different mechanisms. Chiral recognition by both CDs is not necessary for better separation. For example, a neutral CD is responsible for the chiral recognation of a neutral pair of enantiomers, and a charged one lacking chiral recognition 90 causes a migration speed other than EOF for the neutral species of the enantiomer. © 2002 by CRC Press LLC

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671

A3.5.4.2 Macrocyclic Chiral Selectors Chiral separations with macrocyclic antibiotics represent the most dynamically developing branch 47,92 33,49,50,93–95 of enantioselective CE. Since 1994, several reviews and papers have demonstrated the 50 advantages of such selectors; even an Rs value of 38 could be achieved using 1.2 mM teicoplanin. Macrocyclic antibiotics show high enantioselectivity because they have multiple chiral centers (e.g., 38 in vancomycin) and basket-like twisted shapes. They contain several ionizable groups of different type (i.e., a set of different pK values) and can establish strong electrostatic interactions. They are used at 0.1 to 5 mM concentrations, except for rifamycins, which are used up to 30 mM. Selectivity depends significantly on the pH of BGE because chiral recognition features change with 93 ionization state. Moreover, some of their members show chemical stability over a certain pH 49 49,50,94 range. The addition of organic modifiers usually improves their efficiency and selectivity. Amino groups containing macrocycles can lose their resolution power due to adsorption on the column wall, which can be compensated using a coated capillary, low concentration of selectors, 33,49,92 and/or adding organic modifiers. Macrocyclic antibiotics exhibit significant UV absorbance. Detectability problems can be solved by counter-current methods (Section A3.5.1.3.1) or low concentrations of selectors, indirect detection, and a well-chosen detection wavelength. Among macrocyclic selectors, vancomycin (a glycopeptide) is most widely used. It is excellent for the separation of acidic enantiomers, but separation of neutral enantiomers has also been reported. It has a limited stability; therefore, the pH of BGE must be kept between 4 and 7. Vancomycin shows strong adsorption to the column wall, which can be eliminated using a coated capillary or by adding 49,92,93 SDS (sodium dodecyl sulfate), a micelle-forming agent. Teicoplanin is also a glycopeptide and equally suitable for the separation of acidic enantiomers. 49,50 Owing to its long hydrocarbon tail, it is prone to micelle formation, thus impairing selectivity. To avoid micelle formation, a low concentration of the selector or adding organic modifier is recommended. A few percent of acetonitrile improves separation with teicoplanin, but alcohols cause precipitation. An application is shown in Fig. A3.5.3. The high ACN content was necessary to avoid micelle formation. TRIS-based buffer provided low conductivity and good solubility. Other derivatives (e.g., Dns) of peptides showed less selectivity than FMOC. Ristocetin A, a glycopeptide, is also effective for the separation of acidic enantiomers; but, in 47,49 general, analysis time is much shorter than with vancomycin. Ristocetin A has a good pH stability and the broadest selectivity spectrum among the macrocyclics tested thus far, but its high price hinders its popularity. 95 Avoparcin, also a glyopeptide, shows the best pH stability among macrocyclic antibiotics. To avoid self-association of selectors and adsorption on the column wall, the addition of organic modifiers is advantageous. Its chiral recognition characteristics are most compatible with acidic enantiomers. Rifamycin B and Rifamycin SV are ansa compounds (a fused ring system spanned by an aliphatic bridge) and are applied at much higher concentrations (5 to 50 mM) than other glycopep92 tides. They require high organic modifier content to avoid aggregation. Because of their high UV absorbance, counter-current or indirect UV methods are recommended for detection. Rifamycin B is appropriate for the separation of basic compounds, and rifamacin SV of acidic and neutral compounds. A3.5.4.3 Miscellaneous Chiral Selectors 24,48

Practically all the protein selectors that have been used in chiral LC have also been tested in CE. Proteins show much higher efficiency in CE than in HPLC because they are in the dissolved form in CE. © 2002 by CRC Press LLC

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FIGURE A3.5.3 Electroferograms of 9-fluorenylmethylchloroformate (FMOC) derivatized peptides. Conditions: column, 67 cm (46.5 cm effective length) ¥ 25 mm, bare fused silica; 1.2 mM teicoplanin +40% ACN; BGE, 25 mM TRIS/phosphate; pH 6.25; potential, 30 kV; detection, 254 nm; temperature, 25∞C. (From H. Wan and L.S. Blomberg, Electrophoresis, 18, 943 (1997). With permission.)

Proteins are applied at <1 mM concentrations or in a counter-current mode. Even a 1-cm 24 long cellobiohydrolyse plug was sufficient for the baseline resolution of some chiral molecules. The pH of BGE can be very critical because the ionization state of proteins influences their chiral recognition abilities; in addition, at extreme pH values, they become denatured. Use of coated capillaries is essential because proteins show strong adsorption to silica surface. Addition of few percentage of organic modifiers can improve the resolution, but in a high percentage cause denaturation. 25 56 96 Bovine serum albumin (BSA), human serum albumin (HSA), and Avidin is suitable for the separation of acidic enantiomers, and a1-acid glycoprotein (AGP) is recommended for the 10,44,97 separation of basic compounds. Cellobiohydrolyse is primarily used for the separation of basic enantiomers. 98–101 Several chiral ionic and neutral surfactants have been introduced to CE working within 16 micellar electrokinetic chromatography (MEKC) conditions. There are neutral micelles, which are only appropriate for the separation only of ionized enantiomers, and charged micelles for the separation of neutral and charged molecules. The concentration of constituents of micelles must be above the critical micelle concentration (CMC) and the analysis temperature above the Craft point.

© 2002 by CRC Press LLC

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Bile acids show rather high selectivity for acidic, neutral, and basic enantiomers because their voluminous rigid structures offer good chiral recognation. Synthetic chiral micelles (alkyl100 substituted sugars and amino acids) are effective chiral separation agents. The use of non-cyclic 101 35,101 oligo- and polysaccharides has been reviewed and discussed in research papers, but it is much less useful than cyclodextrins. The crown ether 18-crown-6 tetracarboxylic acid (18C6H4) is a useful chiral selector for primary 102 amines and its use in CE, as reported in a review and several research papers (e.g., Refs. 103 to 105). The pH of BGE must be adjusted to ensure that the selectands are positively charged and the selector is negatively charged. 27 106 Ion-pair forming chiral agents, camphorsulfonic acid (both R and S), and quinine can be used under nonaqueous CE conditions.

A3.5.5 INSTRUMENTATION There are several complete, automated CE instruments with various detectors on the market. The instruments available from Agilent and Beckman are well-designed, highly automated, and offer reproducible measurements. Prince Inc. sells a modular instrument that allows for the tailor-made arrangement of units. The power source of instruments goes up to 30 kV. Efficient cooling of the capillary is essential, and polarity switching is required for several migration order and EOF reversal methods and for injection on the detection end. The simplest injection method is pressure-forced injection, when injection time and pressure regulate the volume of the sample. Fused silica open tubular columns of 10- to 100-cm lengths and 25- to 100-mm i.d. are common. Bare silica tubes need pretreatment before use to create silanol groups on the surface. Before the initial use of a capillary, preconditioning steps are recommended: 0.1 M NaOH wash for 1 hr, followed by 30 min wash with distillated water. A polyamide coating can be easily made in the 5,6,32 lab to eliminate EOF. UV detection is the standard, but laser fluorescence and MS detections have also been reported. The outer polyamide coating can be burned off with micro burner over a length of 1 to 2 cm, creating a window for UV detection. Extended path-length detectors (bubble, Z cells) to improve the sensitivity are on the market. The data rate in CE must be at least 5 to 10 Hz because the peaks are very narrow. Several firms offer a broad range of chiral selectors. Some of them (e.g., Cyclolab, ASTEC, Regis, Beckman, etc.) sell purified selectors and starter kits for chiral CE purposes. It is recommended that one buy directly from the producers because they can better guarantee “order-to-order” consistency. According to producers, several derivatized cyclodextrins show significant deviations in their selectivity.63,71,73,80 It is very important to use totally deionized water (18 MW) and pass the buffer through a 0.45-mm polymer filter. Between the runs, the following general regeneration steps are recommended: distilled water, 1 min; 0.1 M NaOH, 2 min; distilled water, 2 min; running buffer, 3 min. The composition of buffer shifts during analysis, as a result of ion transport and chemical reactions at/on the electrodes. These unwanted side effects necessitate regular replenishment of the buffer (every 3 to 12 analyses) and the cleaning of the electrodes at least every week.

A3.5.6 APPLICATIONS Table A3.5.1 shows several examples of the chiral CE separation of acidic and basic compounds, offering an excellent starting point for method development. Analysis temperatures were omitted because analyses were mostly carried out at 15 to 25∞C. Values for electric power are also missing because, for the most part, they depend on the instrument and do not influence selectivity.

© 2002 by CRC Press LLC

Name of Analyte (Analyzed Form)

1,1¢-Binaphtyl-2.2¢-diyl hydrogen phosphate 2-(3-Chlorphenoxy)-propionic acid Dichlofop, Dichlorprop, Fenoprop, Haloxyfrop Dichlorprop Fenoprofen Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen Flurbiprofen, Ketoprofen, Indoprofen Haloxyprop Ibuprofen

37 ¥ 50

Acids 5 mM SBE-b-CD + 15 mM PerMeb-CD 2.5 mg/ml CM-b-CD + SBE-b-CD

pH

Background Buffer

Ref.

3

100 mM TEAOH/phosphate

89

5.5

100 mM TEAOH/phosphate

89

2 mM Ristocetin 6 mM Vancomycin (partialy filling) 25 mM PerMe-b-CD 15 mM QA-b-CD

7.0 5

100 mM phosphate + 30% iPrOH 75 mM Britton-Robinson

49 93

4.65 7.5

110 85

31.5 ¥ 50

30 mM PerMe-b-CD

5.0

50 mM Acetate 10 mM TRIS/acetic acid in formamide 100 mM MES

111

37 ¥ 50 45.5 ¥ 50 37 ¥ 50

2 mM Vancomycin + 30 mM SDS 40 mg/ml SBE-b-CD 5 mM SBE-b-CD + 30 mM PerMe-b-CD 15 mM PMeMA-b-CD 20 mM MA-b-CD + 10 mM PerMe-b-CD 0.4 mM Avoparcin 15 mM PMeMA-b-CD 15 mM PMeMA-b-CD 15 mM 2,3-Ac-6-S-b-CD 5 mM MA-b-CD

7 7 3

50 mM Phosphate 25 mM Phosphate 100 mM TEAOH/phosphate

33 69 54

6.5 2.3

40 mM Britton-Robinson 34 mM Phosphate

57 89

6 6.5 6.5 2.5 4.75

95 57 57 59 85

0.5 mM Avidin

4.0

50 mM Phosphate 40 mM Britton-Robinson 40 mM Britton-Robinson 25 mM Phosphate 30 mM Acetic acid/ 15 mM imidazole 50 mM Phosphate

43 ¥ 50 (methylcellulose coated) 25 ¥ 50 33 ¥ 50 (polyacrylamide coated) 50 ¥ 75 31 ¥ 50

Flurbiprofen, Ibuprofen, Pirprofen Naproxen

50 ¥ 50 30 ¥ 50

Naproxen cis-Permethrinic acid Phenoxy propionic acids 2-Phenylpropionic acid Phenyllactic acid

33 50 50 39 30

Vanillomandelic acid

Chiral Selector

¥ ¥ ¥ ¥ ¥

50 50 50 25 50

31.5 ¥ 50 (polyacrylamide coated)

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CRC Handbook of Optical Resolution via Diastereomeric Salt Formation

Carprofen

Column Effective Length ¥ i.d. (cm ¥ mm)

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TABLE A3.5.1 Examples of Chiral Separations with Capillary Electrophoresis

23.5 ¥ 50

80 mM b-CD

Nonaqueous

Phenyalanine, Tryptophane, Tyrosine Phenyalanine, Tryptophane, Tyrosine Triptophaneamide

50 ¥ 75 52 ¥ 75 50 ¥ 50 (polyvinyl alcohol coated)

40 mM a-CD 19.7 mM S-g-CD 10 mM 18C6H4 + 5 mM CM-b-CD

1-Aminoindane Atropine Brompheniramine Chlorpheniramine Chlorpheniramine Cyclodine Diltiazem Dimetinden

19 ¥ 25 50 ¥ 75 74 ¥ 50 21 ¥ 50 21 ¥ 50 30 ¥ 50 50 ¥ 50 30 ¥ 75 (polyacrylamide coated) 20 ¥ 50 (methylcellulose coated) 30 ¥ 50 30 ¥ 50 50 ¥ 50 52.4 ¥ 75 27.5 ¥ 50 56 ¥ 50 55.4 ¥ 50

Disopyramide Disopyramide Disopyramide Duloxetine Ketamine Metaclazepam Methamphetamine 3,4-Methylenedioxyamphetamine

Amines 30 mM 2,3-Me-6-S-b-CD 5 mM S-b-CD 1 mM SPE-b-CD 18 mg/ml b-CD 1 mg/ml CM-b-CD 10 mM QA-b-CD 50 mM Sodium taurocholate 2% CM-b-CD 0.5 mM AGP (partially filling) 20 mM MA-b-CD 7 mM Pho-g-CD 2.5 mM Me-b-CD 2% S-b-CD (partial filling) 45 mM HP-a-CD 16 mM HP-b-CD 10 mM HP-b-CD

2.5–6.0 6 2.5 2.1 6.25

2.5 2.5 7.8

50 mM Phosphate/acetate 50 mM Phosphate 10 mM TRIS/citrate 100 mM TEAOH/phosphate 25 mM TRIS/phosphate +40% ACN 10 mM NaCl in N-methylformamide 100 mM Phosphate 37 mM TEA/phosphate 40 mM TRIS

31 95 105 112 50

60 74 100

Nonaqueous 10 7 3.0 3.0 4 7 2.7

Acidic MeOH 50 mM TAPS 20 mM Borate/phosphate 100 mM TEAOH/phosphate 100 mM TEAOH/phosphate 50 mM Acetate 20 mM Phosphate/borate 20 mM citrate

113 72 70 30 30 83 94 6

3.97

50 mM Acetate

10

2.4 2.4 4.0 3.8 2.5 3.5 2.5

100 mM Phosphate 100 mM Phosphate 50 mM TRIS/phosphate 10 mM Phosphate 100 mM Phosphate 118 mM TRIS/phosphate 50 mM Phosphate

53 53 62 78 68 65 66

51

675

(Continued )

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Amino Acids 3.0–40 mM HP-b-CD 0.4 mM Avoparcin 10 mM 18C6H4 50 mg/ml HP-b-CD 1.2 mM Teicoplanin

Chiral Selective Chromatographic Analysis

© 2002 by CRC Press LLC

24.5 ¥ 50 33 ¥ 50 50 ¥ 50 40 ¥ 50 46.5 ¥ 25

Amino acids (Dns) 52 Amino acids (N-3,5-dinitrobenzoyl) Amino acids, di- and tripeptides Aspartyl tripeptides Di-tripeptides (FMOC, AEOC derivatives) Glutamic acid (dansyl derivatives)

Name of Analyte (Analyzed Form)

Remoxipride Tetryzoline Thalidomide Tocainide Tocainide Tocainide Trimipramine Verapamil

Clenbuterol Clenbuterol, Ephedrine Ephedrine Labetol Metaproterenol Metoprolol

Chiral Selector

pH

Background Buffer

Ref.

45 mM HP-g-CD

2.5

100 mM Phosphate

64

0.2 mM AGP

4.0

50 mM Acetate

97

27.5 ¥ 50 (polyacrylamide coated) 40 ¥ 50 (polyacrylamide coated) 30 ¥ 50 43 ¥ 50 (polyacrylamide coated) 30 ¥ 50 50 ¥ 50 50 ¥ 50 31 ¥ 50 44 ¥ 50

45 mM HP-b-CD 20 mg/ml QA-b-CD

2.5 3.0

100 mM Phosphate 50 mM Phosphate

67 3

7.5 mM Pho-g-CD 20 mM CM-g-CD 30 mM PerMe-b-CD 1 mM QA-b-CD 25 mM PerMe-b-CD

6.8 5.0 2.4 8.2 3.0

100 mM Phosphate 50 mM Phosphate 50 mM Phosphate 50 mM TRIS 100 mM TEA/phosphate

29 29 29 70 114

37 ¥ 50

Aminoalcohols 15 mM Me-b-CD

54 101 6

45 ¥ 50 30 ¥ 75 (polyacrylamide coated) 40 ¥ 50 7 ¥ 50 (polyacrylamide coated) 56 ¥ 50

3

25 mM N-Dodecoxycarbonylvaline 1.5% CM-b-CD

8.8 5.8

100 mM TEOH/phosphate 100 mM CHES/TEA 20 mM Phosphate

10 mg/ml S-b-CD 30 mM Me-b-CD

6.0 2.5

30 mM Phosphate 25 mM Phosphate

75 38

30 mM Camphorsulfonic acid

nonaquous

1 M AC in ACN + 0.2 mM Tween 20

27

CRC Handbook of Optical Resolution via Diastereomeric Salt Formation

Oxomemazine

Column Effective Length ¥ i.d. (cm ¥ mm)

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TABLE A3.5.1 Examples of Chiral Separations with Capillary Electrophoresis (continued)

15 mM CM-a-CD

4.9

100 mM Phosphate

9

30 ¥ 50 50 ¥ 50 50 ¥ 50

15 mM Pho-a-CD 20 mM Rifamycin B 0.8 mM Cellobiohydrolase I (1-cm long plug) 25 mM Me-b-CD 7.4 mM Me-b-CD 5 mM CM-b-CD + 8 mM RAMEB

8.3 7.0 5.0

100 mM Phosphate + 5% MeOH 100 mM Phosphate 20 mM Phosphate

9 94 24

2.5 3 3

50 mM Phosphate 50 mM Phosphate 12 mM TRIS/phosphate

39 20 91

9.3 6.3

100 mM TRIS + 50 mM borate 50 mM Phosphate

42 23

6.5

40 mM Britton-Robinson

57

2% S-b-CD (partial filling) 0.25 mM Avidin

3.8

10 mM Phosphate

78

6.0

96

5 mM SBE-b-CD + 40 mM PerMe-b-CD

3

50 mM Phosphate + 10% tetrahydrofuran 100 mM TEAOH/phosphate

Picumeterol Propanolol Propanolol

8.5 ¥ 50 50 ¥ 75 20 ¥ 75 (polyacrylamide coated)

3-Benzyloxy-1,2,-propanediol Loxiglumide

50 ¥ 50 35.5 ¥ 0.05 (polyacrylamide coated) 50 ¥ 50

Phenprocoumon Warfarin

52.4 ¥ 75

Warfarin

31.5 ¥ 50 (polyacrylamide coated) 37 ¥ 50

Warfarin

Miscelleneous Enantiomers 1.8% b-CD 3 mM Vancomycin (counter-current) 15 mM PMeMA-b-CD

54

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30 ¥ 50

Chiral Selective Chromatographic Analysis

© 2002 by CRC Press LLC

Metoprolol and its by-products Metoprolol Norphenyephrine, Terbutaline Oxprenolol

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A3.5.7 METHOD DEVELOPMENT The publications mentioned at the beginning of Section A3.5 and the data in Table A3.5.1 should be consulted to find existing methods or analogs for certain compounds. The literature suggests 54,65,107–109 some systematic methods for method development using a set of CDs. Data referring to randomly substituted selectors should be treated with caution. Selectivity of randomly substituted selectors under the same name but coming from different sources can drastically differ. Moreover, the literature frequently does not specify the exact degree of substitution nor the exact substitution pattern of the used selectors. Previous knowledge concerning UV spectra, solubilities, and pK values of analytes before the 108 first test run obtained either from literature or from preliminary experiment is very important. The estimation of analyte pK values is possible by performing CE runs without chiral selectors at various pH values (3, 5, 7, 9). Migration times other than EOF show the ionized state of analytes. Britton-Robinson buffer (20 mM acetic acid 20 mM phosphoric acid 20 mM boric acid adjusted to the appropriate pH with 0.2 M NaOH) is the recommended BGE for the estimation of pKi. Poorly soluble samples can precipitate, causing clogging of the capillary. The solubility of analytes can improve by adding organic modifiers, and several selectors also act as solubizers. Neutral selectors have narrower selectivity spectra, but at much lower prices than charged selectors. Therefore, method development should begin with neutral CDs. Methods using neutral selectors require that the analyte be ionized; thus, buffer pH should be at least >pKa + 1 for acidic enantiomers and 0.9 (semi-separated peaks), further optimization with the same selector is recommended. If the Rs value is between 0.7 and 1.0, selectors with same the substitution pattern, but of different ring size, can be tested. Resolution failing, the next neutral selectors to be tried should be 15 mM HP-b-CD and thereafter 15 mM Me-b-CD. When none of the neutral CDs exhibit chiral separation, ionizable CDs become the nextappropriate candidates. Basic analytes are tested with 5 mM acidic selectors in the following order: CM-b-CD, SBE-b-CD, Pho-g-CD. For acidic enantiomers, the best chiral selector is 10 mM PMeMA-b-CD. Concentration optimization of the chiral selector is recommended in 2- to 5-mM increments. The effect of organic modifiers should be tested first with 5% methanol and, when effective, with 10% methanol. When methanol does not work, the same procedure should be repeated with acetonitrile. Fine adjustment of pH should be done in steps of 2 pH units and followed by smaller increments. Using organic buffers (TAPS, MES, TRIS, CAPS, etc.) can also improve resolution by decreasing conductivity and increasing the solubility of the buffer. Peak deformation can be compensated by diluting the sample or by properly adjusting the 7,8 conductivity of the buffer to avoid electrodispersion. Tailing of peaks may indicate adsorption of analytes onto the column wall, which can be eliminated by the use of a coated capillary or by adding neutral detergents. Programs have also been worked out for the optimization of analysis parameters 65,104 if some resolution had been observed. Joule heating does not decrease efficiency in the linear range of the power-current curve. To avoid Joule heating, the current should be kept below 90 mA. Using chiral selectors other than CDs is recommended on the basis of literature sources. 47,92 Vancomycin was used for acidic enantiomers and rifamycin B for basic enantiomers. The combination of two selectors is an effective enantiomer separation method, but requires certain 54 skills in chiral CE.

REFERENCES 1. R. Weinberger, Practical Capillary Electrophoresis, Academic Press, New York (1993). 2. K.D. Altria, Capillary Electrophoresis Guidebook. Principles, Operation and Applications (Methods in Molecular Biology), Humana Press (1996). © 2002 by CRC Press LLC

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Chiral Selective Chromatographic Analysis 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56.

679

G. Schulte, B. Chankvetadze, and G. Blaschke, J. Chromatogr. A, 771, 259 (1997). F. Wang and M.G. Khaledi, J. Chromatogr. A, 875, 277 (2000). S.J. Hjerten, Chromatogr., 347, 191 (1985). T. Schmitt and H. Engelhardt, Chromatographia, 37, 475 (1993). Y.Y. Rawjee, R.L. Williams, and G. Vigh, Anal. Chem., 66, 3777 (1994). R.L. Williams and G. Vigh, J. Chromatogr. A, 730, 273 (1996). Z. Juvancz, K.E. Markides, and L. Jicsinszky, J. Microcol. Sep., 11, 716 (1999). A. Amini, C. Petterson, and D. Westerlund, Electrophoresis, 18, 950 (1997). A. Huang, M.J. Gordon, and R. Zare, Anal. Chem., 60, 1837 (1988). K. Altria, Chromatographia, 35, 177 (1993). B. Chankvetadze, Capillary Electrophoresis in Chiral Analysis, John Wiley & Sons, New York (1997). G. Gübitz and M.G. Schmid, J. Chromatogr. A, 792, 179 (1997). K. Verleysen and P. Sandra, Electrophoresis, 19, 2798 (1998). J. Vindevogel and P. Sandra, Introduction to Micellar Electrokinetic Chromatography, Huthig (1992). S.A.C. Wren and R.C. Rowe, J. Chromatogr., 603, 235 (1992). B. Chankvatadze, J. Chromatogr. A, 792, 269 (1997). Ph. Schmidt, A.W. Garrison, D. Freitag, and A. Kettrup, J. Chromatogr. A, 792, 419 (1997). S.A.C. Wren and R.C. Rowe, J. Chromatogr., 635, 113 (1993). H.A. Bardelmeijer, H. Lingeman, C. de Ruiter, and W.J.M. Underberg, J. Chromatogr. A, 807, 3 (1998). T.J. Ward, C. Dann, and A.P. Brown, Chirality, 8, 77 (1996). C. Desidero and S. Fanali, J. Chromatogr. A, 807, 37 (1998). M. Hedeland, R. Isaksson, and C. Petterson, J. Chromatogr. A, 807, 297 (1998). D. Eberle, R. Hummel, and R. Khun, J. Chromatogr. A, 759, 185 (1997). R. Vespelec, V. Sustacek, and P. Bocek, J. Chromatogr., 638, 255 (1993). I. Bjornsdottir, S.H. Hansen, and S. Terabe, J. Chromatogr. A, 745, 37 (1996). M. Jung and E. Francotte, J. Chromatogr. A, 755, 81 (1996). Z. Juvancz, R. Ivanyi, L. Jicsinszky, and K.E. Markides, J. Microcol. Sep., 13, 62 (2001). B. Chankvetadze, G. Pintore, N. Burjenadze, D. Bergenthal, D. Strickmann, R. Cerri, and G. Blaschke, Electrophoresis, 19, 2101 (1998). A. Rizzi and L. Kremser, Electrophoresis, 20, 2715 (1999). T. Schmitt and H. Engelhardt, J. Chromatogr. A, 697, 561 (1995). K.L. Rundlett and D.W. Armstrong, Anal. Chem., 67, 2081 (1995). M.M. Robson, M.G. Cikalo, P. Myers, M.R. Euerby, and K.D. Bartle, J. Microcol. Sep., 9, 357 (1997). Y. Deng, J. Zhang, T. Tsuda, P.H. Yu, A.A. Boulton, and R.M. Cassidy, Anal. Chem., 70, 4586 (1998). J. Snopek, I. Jelinek, and E. Smolkova-Keulemansova, J. Chromatogr., 609, 1 (1992). A. Guttman and N. Cooke, J. Chromatogr. A, 685, 155 (1994). A. Aumatell and A. Guttman, J. Chromatogr. A, 717, 229 (1995). K.D. Altria, M.A. Kelly, and B. Clark, Chromatographia, 43, 153 (1996). M.A. Nussbaum, Electrophoresis, 20, 2664 (1999). M. Stefansson and M. Novotny, J. Am. Chem. Soc., 115, 11573 (1993). A. Bunke, M.G. Schmid, and G. Gübitz, J. Chromatogr. A, 761, 269 (1997). C. Quang and M.G. Khaledi, HRC, 17, 99 (1994). I. Bjornsdottir and S.H. Hansen, Chirality, 7, 219 (1995). K. Sarmini and E. Kenndler, J. Chromatogr. A, 792, 3 (1997). S.A.C. Wren and R.C. Rowe, J. Chromatogr., 609, 363 (1992). D.W. Armstrong and U.B. Nair, Electrophoresis, 18, 2331 (1997). D.K. Lloyd, A.F. Aubry, and E. de Lorenzi, J. Chromatogr. A, 792, 349 (1997). M.P. Gasper, A. Beretold, U.B. Nair, and D.W. Armstrong, Anal. Chem., 68, 2501 (1996). H. Wan and L.S. Blomberg, Electrophoresis, 18, 943 (1997). I. Valko, H. Siren, and M.-L. Riekkola, LC/GC Int., 10, 190 (1997). Y.Y. Rawjee and G. Vigh, Anal. Chem., 66, 619 (1994). Z. Juvancz, K.E. Markides, and L. Jicsinszky, Electrophoresis, 18, 1002 (1997). M. Fillet, P. Hubert, and J. Crommen, J. Electrophoresis, 19, 2834 (1998). S. Fanali, J. Chromatogr. A, 875, 89 (2000). J. Szejtli and T. Osa, Eds., Methods in Comprehensive Supermolecular Chemistry, Vol. 3, Cyclodextrins, Elsevier (1997).

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0019_frame_Appendix3.fm Page 680 Thursday, August 9, 2001 2:09 PM

680 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107.

CRC Handbook of Optical Resolution via Diastereomeric Salt Formation R. Ivanyi, L. Jicsinszky, and Z. Juvancz, Chromatographia, 53, 166 (2001). J.B. Vincent, D.M. Kirby, T.V. Nguyen, and G. Vigh, Anal. Chem., 69, 4419 (1997). H. Cai and G. Vigh, J. Microcol. Sep., 10, 293 (1998). P. Dzygiel, P. Wieczorek, and J.A. Jönsson, J. Chromatogr. A, 792, 297 (1997). B. Chankvetadze, G. Endresz, and G. Blaschke, J. Chromatogr. A, 700, 43 (1996). E.C. Rickard, R.J. Bopp, D.J. Skanchy, K.L. Chetwyn, B. Pahlen, and J.F. Stobaugh, Chirality, 8, 108 (1996). A. Salvador, E. Varesio, M. Dreux, and J.-L. Veuthey, Electrophoresis, 20, 2670 (1999). B. Koppenhoefer, U. Epperlein, Y. Xiaofeng, and L. Bingcheng, Electrophoresis, 18, 924 (1997). E. Varesio, J.-Y. Gauvrit, R. Longeray, P. Lanteri, and J.-L. Veuthey, Electrophoresis, 18, 931 (1997). M. Lanz, R. Brenneisen, and W. Thormann, Electrophoresis, 18, 1035 (1997). L. Bingcheng, Z. Xiaofeng, U. Epperlein, M. Schwierskott, R. Schlunk, and B. Koppenhoefer, HRC, 21, 215 (1998). B. Koppenhoefer, U. Epperlein, R. Sclunk, Y. Xiaofeng, and L.J. Bingcheng, J. Chromatogr. A, 793, 153 (1998). C. Desidero, C.M. Polcaro, and S. Fanali, Electrophoresis, 18, 227 (1997). H. Jakubetz, M. Juza, and V. Schurig, Electrophoresis, 18, 897 (1997). I.S. Lurie, N.G. Odeneal, T.D. McKibben, and J.F. Casale, Electrophoresis, 19, 2918 (1998). M. Wedig and U. Holzgrabe, Electrophoresis, 20, 1555 (1999). P. Morin, M. Dreux, S. Usse, M.C. Viaud, and G. Guillaumet, Electrophoresis, 20, 2630 (1999). K. Verleysen, T. Van den Bosch, and P. Sandra, Electrophoresis, 20, 2650 (1998). S.L. Tamasier-Karolak, M.-A. Stenger, and A. Bommart, Electrophoresis, 20, 2656 (1998). E. Francotte, L. Brandel, and M. Jung, J. Chromatogr. A, 792, 379 (1997). C. Desidero and S. Fanali, J. Chromatogr. A, 716, 183 (1995). A.M. Stalcup and K.H. Gahm, Anal. Chem., 69, 1360 (1996). S. Sabah and G.K.E. Scriba, J. Chromatogr. A, 833, 261 (1999). J. Szeman, K. Ganzler, and A. Salgo, J. Chromatogr. A, 728, 423 (1996). Y. Tanaka, M. Yanagava, and S. Terabe, HRC, 19, 421 (1996). Z. Juvancz, K.E. Markides, and L. Jicsinszky, J. Microcol. Sep., 5, 89 (1991). A. Bunke and T. Jira, J. Chromatogr. A, 798, 275 (1998). F. Wang and M.G. Khaledi, Electrophoresis, 19, 2095 (1998). F. Lelievre, P. Gareil, and A. Jardy, Anal. Chem., 69, 385 (1997). F. Wang and M.G. Khaledi, J. Chromatogr. A, 817, 121 (1998). I.S. Lurie, J. Chromatogr. A, 792, 297 (1997). M. Fillet, P. Hubert, and J. Crommen, Electrophoresis, 18, 1013 (1997). M. Fillet, B. Chankvetadze, J. Crommen, and G. Blaschke, Electrophoresis, 20, 269 (1999). F. Lelievre, P. Gareil, Y. Bahaddi, and G. Galons, Anal. Chem., 69, 393 (1997). K.A. Assi, B.J. Clark, and K.D. Altria, Electrophoresis, 20, 2723 (1998). C. Desidero and S. Fanali, J. Chromatogr. A, 807, 37 (1998). C. Desidero, C.M. Polcaro, P. Padiglioni, and S. Fanali, J. Chromatogr. A, 781, 503 (1997). D.W. Armstrong, K.L. Rundlett, and G.L. Reid III, Anal. Chem., 66, 1690 (1994). K.H. Ekborg-Ott, G.A. Zientara, J.M. Schneiderheinze, K. Gahm, and D.W. Armstrong, Electrophoresis, 20, 2438 (1999). Y. Tanaka, N. Matsubara, and S. Terabe, Electrophoresis, 15, 848 (1994). A. Amini and D. Westerlund, Anal. Chem., 70, 1425 (1998). H. Nishi, T. Fukuyama, M. Matsuo, and S. Terabe, J. Chromatogr., 515, 233 (1990). E. Szoko, J. Gyimesi, Z. Szakacs, and M. Tarnai, Electrophoresis, 20, 2574 (1999). Y. Mechref and Z. El Rassi, Electrophoresis, 18, 912 (1997). A.G. Peterson, E.S. Ahuja, and J.P. Foley, J. Chromatogr. B, 683, 15 (1996). R. Khun, D. Riester, B. Fleckenstein, and K.H. Weismuller, J. Chromatogr. A, 716, 371 (1995). H. Nishi, K. Nakamura, and T. Sato, J. Chromatogr. A, 757, 225 (1997). K. Verleysen and P. Sandra, J. Microcol. Sep., 11, 37 (1999). M. Schmid and G. Gubitz, J. Chromatogr. A, 709, 81 (1995). A.M. Stalcup and K.H. Gahm, J. Microcol. Sep., 8, 145 (1996). A. Guttman, S. Brunet, and N. Cooke, LC/GC, 14, 32 (1996).

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Chiral Selective Chromatographic Analysis 108. 109. 110. 111. 112. 113. 114.

681

N. Roos, K. Ganzler, J. Szeman, and S. Fanali, J. Chromatogr. A, 782, 257 (1997). J.C. Reijenga, B.A. Inglese, and F.M. Everaerts, J. Chromatogr. A, 772, 19 (1997). A. W. Garrison, P. Schmitt, D. Martens, and A. Ketrupp, Environ. Sci. Technol., 30, 2449 (1996). S. Fanali and Z. Aturki, J. Chromatogr. A, 694, 297 (1995). S. Sabah and G.K.E. Scriba, J. Microcol. Sep., 10, 255 (1998). M. Tacker, P. Glukhovskly, H. Cai, and G. Vigh, Electrophoresis, 20, 2794 (1999). I. Bechet, P. Paques, M. Fillet, P. Hubert, and J. Crommen, Electrophoresis, 15, 818 (1994).

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