The Chemistry of C-Glycosides

TETRAHEDRON ORGANIC CHEMISTRY SERIES Series Editors: J E Baldwin, FRS & P D Magnus, FRS VOLUME 13 The Chemistry of C-...

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TETRAHEDRON ORGANIC CHEMISTRY SERIES Series Editors: J E Baldwin, FRS & P D Magnus, FRS

VOLUME 13

The Chemistry of C-Glycosides

Related Pergamon Titles of Interest

BOOKS Tetrahedron Organic Chemistry Series: CARRUTHERS: Cycloaddition Reactions in Organic Synthesis DEROME: Modern NMR Techniques for Chemistry Research GAWLEY: Asymmetric Synthesis* HASSNER & STUMER: Organic Syntheses based on Name Reactions and Unnamed Reactions PAULMIER: Selenium Reagents & Intermediates in Organic Synthesis PERLMUTTER: Conjugate Addition Reactions in Organic Synthesis SIMPKINS: Sulphones in Organic Synthesis WILLIAMS: Synthesis of Optically Active Alpha-Amino Acids WONG & WHITESlDES: Enzymes in Synthetic Organic Chemistry

JOURNALS

BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS

Full details of all Elsevier Science publications/free specimen copy of any Elsevier Science journal are available on request from your nearest Elsevier Science office

* In Preparation

The Chemistry of C-Glycosides DANIEL E. LEVY Glycomed Inc., California

and CHO TANG Sugen Inc., California

PERGAMON

U.K. U.S.A. JAPAN

Elsevier Science Ltd, The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, U.K. Elsevier Science Inc., 660 White Plains Road, Tarrytown, New York 10591-5153, U.S.A. Elsevier Science Japan, Tsunashima Building Annex, 3-20-12 Yushima, Bunkyo-ku, Tokyo 113, Japan

Copyright 91995 Elsevier Science Ltd All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic t a p e , mechanical, photocopying, recording or otherwise, without permission in writing from the publisher. First Edition 1995

Ubrary of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress

Bdtish Ubrary Cataloguing in Publication Data A catalogue record for this book is available from the British Library

ISBN 0 08 042080 X Hardcover ISBN 0 08 042081 8 Flexicover

Printed and Bound in Great Britain by BPC Wheatons Ltd, Exeter

CONTENTS

Acknowledgements

xi

Abbreviations

xiii

Chapter 1. Introduction 1

1

Organization of the Book 1.1 Definition and Nomenclature of C-Glycosides 0-Glycosides vs. C-Glycosides: Comparisons of Physical 1.2 Properties, Anomeric Effects, H-Bonding Abilities, Stabilities and Conformations 1.3 Naturally Occurring C-Glycosides 1.4 C-Glycosides as Stable Pharmacophores 1.5 Further Reading 1.6 References

4 7 10

22 22

29

Chapter 2. Electrophilic Substitutions 2

1 1

Introduction Anomeric Activating Groups and Stereoselectivity 2.1 2.2 Cyanation Reactions Cyanation Reactions on Activated Glycosides 2.2.1 2.2.2 Cyanation Reactions on Glycals Cyanation Reactions on Activated Furanosides 2.2.3 2.2.4 Cyanation Reactions with Metallocyanide Reagents 2.2.5 Other Cyanation Reactions 2.2.6 Cyanoglycoside Transformations Alkylation, Allenylation, Allylation and Alkynation 2.3 Reactions Use of Activated Glycosides and Anionic 2.3.1 Nucleophiles Use of Activated Glycosides and Cuprates 2.3.2 Use of Activated Glycosides and Grignard 2.3.3 Reagents Use of Activated Glycosides and Organozinc 2.3.4 Reagents Use of Modified Sugars and Anionic 2.3.5 Nucleophiles Lewis Acid Mediated Couplings with 2.3.6 Unactivated Olefins V

29 29 30 31 33 34 35 38 39 42 42 43 45 47 49

50

Lewis Acid Mediated Couplings of Glycosides and Silanes 54 Lewis Acid Mediated Couplings of Halo2.3.8 glycosides and Silanes 62 Lewis Acid Mediated Couplings of Nitro2.3.9 glycosides and Silanes 63 Lewis Acid Mediated Couplings of Glycals and 2.3.10 Silanes 64 C-Glycosidations with Organotin Reagents 67 2.3.11 C-Glycosidations with Organoaluminium 2.3.12 Reagents 70 71 Arylation Reactions Reactions with Metallated Aryl Compounds 73 2.4.1 Electrophilic Aromatic Substitutions with 2.4.2 Acetoxy, Trifluroacetoxy, and PNB Glycosides 74 Electrophilic Aromatic Substitutions on 2.4.3 Trichloroacetimidates 78 Electrophilic Aromatic Substitutions on 2.4.4 Haloglycosides 80 Electrophilic Aromatic Substitutions on Glycals 81 2.4.5 Intramolecular Electrophilic Aromatic 2.4.6 Substitutions 82 85 2.4.7 O-C Migrations Reactions with Enol Ethers, Silylenol Ethers and Enamines 89 2.5.1 Reactions with Enolates 89 2.5.2 Reactions with Silylenol Ethers 91 2.5.3 Reactions with Enamines 97 Nitroalkylation Reactions 98 Reactions with Allylic Ethers 101 Wittig Reactions with Lactols 104 2.8.1 Wittig Reactions 104 2.8.2 Horner-Emmons Reactions 108 2.8.3 Reactions with Sulfur Ylides 110 Nucleophilic Additions to Sugar Lactones Followed by Lactol Reductions 111 2.9.1 Lewis Acid-Trialkylsilane Reductions 111 2.9.2 Other Reductions 114 2.9.3 Sugar-Sugar Couplings 115 Nucleophilic Additions to Sugars Containing Enones 116 Transition Metal Mediated Carbon Monoxide Insertions 119 2.11.1 Manganese Glycosides 120 2.11.2 Cobalt Mediated Glycosidations 121 Reactions Involving Anomeric Carbenes 123 Reactions Involving Exoanomeric Methylenes 125 References 128

2.3.7

2.4

2.5

2.6 2.7 2.8

2.9

2.10 2.11

2.12 2.13 2.14

vi

Chapter 3. Nucleophilic Sugar Substitutions 3.

Introduction C Lithiated Anomeric Carbanions by Direct Metal 3.1. Exchange 3.1.1 Hydrogen-Metal Exchanges 3.1.2 Metal-Metal Exchanges 3.1.3 Halogen-Metal Exchanges 3.2. C, Lithiated Anomeric Carbanions by Reduction C1 Carbanions Stabilized by Sulfones, Sulfides, 3.3 Sulfoxides, Carboxyl and Nitro Groups 3.3.1 Sulfone Stabilized Anions Sulfide and Sulfoxide Stabilized Anions 3.3.2 Carboxy Stabilized Anions 3.3.3 3.3.4 Nitro Stablized Anions 3.4 References

,

Chapter 4. Transition Metal Mediated C-Glycosidations 4.

Introduction 4.1 Direct Coupling of Glycals and Aryl Groups 4.1.1 Arylation Reactions with Unactivated Aromatic Rings 4.1.2 Arylation Reactions with Metallated Aromatic Rings 4.1.3 Arylation Reactions with Halogenated Aromatic Rings Coupling of Substituted Glycals with Aryl Groups 4.2 Coupling of 7c-Ally1 Complexes of Glycals 4.3 4.4 Mechanistic Considerations 4.5 References

Chapter 5. Anomeric Radicals 5.

133 133 134 134 137 139 140 143 144 147 149 151 152 155

155 155 156 157 161 164 167 171 173 175

Introduction 5.1 Sources of Anomeric Radicals and Stereochemical Consequences 5.1.1 Nitroalkyl C-Glycosides as Raical Sources Radicals from Activated Sugars 5.1.2 5.2 Anomeric Couplings with Radical Acceptors 5.2.1 Non-Halogenated Radical Sources 5.2.2 Glycosyl Halides as Radical Sources 5.3 Intramolecular Radical Reactions 5.4 References vii

175 175 176 177 180 181 184 192 195

Chapter 6. Rearrangements and Cycloadditions 6.

Introduction 6.1 Rearrangementsby Substituent Cleavage and Recombination 6.1.1 Wittig Rearrangements 6.1.2 Carbenoid Rearrangements 6.2 Electrocyclic Rearrangements Involving Glycals 6.2.1 Sigmatropic Rearrangements 6.2.2 Claisen Rearrangements 6.3 Rearrangements from the 2-Hydroxyl Group 6.4 Bi molecular Cycloadditions 6.5 Manipulations of C-Glycosides 6.5.1 Knoevenagel Condensations 6.5.2 1,3-Dipolar Cycloadditions 6.6 References

Introduction 7.1 Wittig Reactions of Lactols Followed by Ring Closures 7.1.1 Base Mediated Cyclizations 7.1.2 Halogen Mediated Cyclizations 7.1.3 Metal Mediated Cyclizations 7.1.4 Comparison of Cyclization Methods 7.2 Addition of Grignard and Organozinc Reagents to Lactols 7.3 Cyclization of Suitably Substituted Polyols 7.3.1 Cyclizations via Ether Formations 7.3.2 Cyclizations via Ketal Formations 7.3.3 Cyclizations via Halide Displacements 7.3.4 Ring Cyclizations: A Case Study 7.4 Rearrangements 7.4.1 Electrocyclic Rearrangements 7.4.2 Ring Contractions 7.4.3 Other Rearrangements 7.5 Cycloadditions 7.6 Other Methods for the Formation of Sugar Rings 7.7 References

Chapter 8. Syntheses of C-Di and Trisaccharides 8.

197 198 198 199 201 201 202 204 206 206 207 208 210 211

Chapter 7. Sugar Ring Formations 7.

197

Introduction 8.1 Syntheses Reported in 1983

21 1 212 212 213 214 217 219 220 220 222 224 224 226 226 227 229 230 233 234 237 237 237

...

Vlll

8.2 Syntheses Reported in 1984 8.3 Syntheses Reported in 1985 8.4 Syntheses Reported in 1986 8.5 Syntheses Reported in 1987 8.6 Syntheses Reported in 1988 8.7 Syntheses Reported in 1989 8.8 Syntheses Reported in 1990 8.9 Syntheses Reported in 1991 8.10 Syntheses Reported in 1992 8.11 Syntheses Reported in 1993 8.12 Syntheses Reported in 1994 8.13 Trends of the Future 8.14 References

238 240 242 244 245 247 252 254 259 266 272 274 276

Index

279

Authors' Biographies

29 1

ix

This Page Intentionally Left Blank

ACKNOWLEDGEMENTS Brock, W. de Lappe (Information Services, Glycomed, Inc.) was instrumental in performing the necessary literature database searches for this work. John H. Musser (Vice President of Medicinal Chemistry, Glycomed, Inc.) reviewed this work in preparation for publicatiion clearance by Glycomed's intellectual property committee. Glycomed, Inc. (860 Atlantic Ave. Alameda, CA 94501) supported ongoing research efforts in the area of C-glycosides. The following figures were reproduced with the kind permission of the American Chemical Society" Figures 1.2.1 and 1.2.3 (Tse-Chang Wu, Peter G. Goekjian, Yoshito Kishi "Preferred Conformations of C-Glycosides. 1. Conformational Similarity of Glycosides and Corresponding C-Glycosides" The Journal of Organic Chemistry 1987, 52, 4819). Figures 1.2.2 (Yuan Wang, Peter G. Goekjian, David M. Ryckman, William H. Miller, Stefan A. Babirad, Yoshito Kishi "Preferred Conformations of C-Glycosides. 9. Conformational Analysis of 1, 4Linked Carbon Disaccharides" The Journal of Organic Chemistry 1992, 57, 482) Figure 8.11.2 (Toru Haneda, Peter G. Goekjian, Sung H Kim, Yoshito Kishi "Preferred Conformation of C-Glycosides. 10. Conformational Analysis of Carbon Trisaccharides" The Journal of Organic Chemistry 1992, 57, 482). The following figure was reproduced with the kind permission of the International Union of Pure and Applied Chemistry: Figure 1.2.4 (Yoshito Kishi "Preferred Solution Conformations of Marine Natural Product Palytoxin and of C-Glycosides and their Parent Glycosides" Pure and Applied Chemistry 1993, 65, 771). The following figure was reproduced with the kind permission of Academic Press: Figure 1.4.3 (Daniel E. Levy, Peng Cho Tang, John H. Musser "Cell Adhesion and Carbohydrates" Annual Reports in Medicinal Chemistry 1994, 29, 215). The following diagrams and the text from the bottom of page 53 through the middle of page 54 were reproduced with the kind permission of Elsevier Science Ltd, The Boulevard, Langford Lane, Kidlington OX5 1GB, UK: Scheme 2.3.17, Scheme 2.3.18, and Table 2.3.1 (Daniel E. Levy, Falguni Dasgupta, Peng Cho Tang "Synthesis of Novel Fused Ring C-Glycosides" Tetrahedron Asymmetry 1994, 5, 1937).

This Page Intentionally Left Blank

Abbreviations Ac

AIBN allyl-TMS 9-BBN Bn BSA Bz CBZ CN CSA DAHP DBU DIBAL DMF GDP LDA LTD4 m m-CPBA Me mMPM MOM Ms-C1 n bE NHS NMR nOe NPhth o

P PMB PNB p-Tol p-TolSC1 p-TsOH SAr sec

SPh TBDMS

acetyl 2,2 '-az obisis ob uty ronitrile allyl trimethylsilane 9-borabicyclo [3.3.1] nonane benzyl bis- trime thy 1silylac e timidate benzoyl benzyl carbamoyl cyano carnphorsulfonic acid 3-deoxy-D-arabino-heptulosonic acid7-phosphate 1,8-diazabicyclo [5.4.0] unclec-7-ene dehydroquinate diisobutyl aluminumhydride dimethyl formamide guanidine diphosphate lithium diisopropylamide leukotriene D4 meta meta-chloroperbenzoic acid methyl meta-methoxyphenylmethyl methoxymethyl methanesulfonyl chloride normal isocyano N-hydroxysuccinimide nuclear magnetic resonance nuclear Overhauser effect phthalimido ortho para para-methoxybenzyl para-nitrobenzoyl para-tolyl para-toluene chlorosulfide para-toluenesulfonic acid arylsulfide secondary phenylsulfido tert-butyl dimethylsilyl xiii

TBDPS tert THP TIPS TMS TMSCN TMSI TMSOTf Tr

tert-butyl diphenylsilyl tertiary tetrahydropyranyl triisopropylsilyl trimethylsilyl trimethylsilyl cyanide trimethylsilyl iodide trimethylsilyl triflate triphenylmethyl, trityl

xiv

C h a p t e r One

Introduction

O r g a n i z a t i o n of the b o o k This book is divided into eight chapters. Each of the first seven chapters centers a r o u n d a different class of reactions. The sections within each chapter define subsets of the reaction classes. For example, Chapter 2 deals extensively with electrophilic substitutions as a means of forming C-glycosides. However, each section within the chapter deals with methods used for the formation or introduction of specific groups at the C-glycosidic linkage. Chapter 8 is different from the first seven chapters. Instead of being divided into sections, it discusses the chronology of the evolution of C-di and trisaccharicle syntheses from 1983 through 1994. The final section speculates on the f u t u r e of C-glycoside c h e m i s t r y with r e s p e c t to new s y n t h e t i c methodologies. It is the hope of the authors that this book will serve as a comprehensive review of C-glycoside chemistry and a valuable reference tool.

1.1

D e f i n i t i o n a n d N o m e n c l a t u r e of C - G l y c o s i d e s

Carbohydrates have long been a source of scientific interest due to their a b u n d a n c e in n a t u r e a n d the s y n t h e t i c c h a l l e n g e s p o s e d by t h e i r polyhydroxylated structures. However, the commercial use of c a r b o h y d r a t e s has been greatly limited by the hydrolytic lability of the glycosidic bond. With the advent of C-glycosides, this limitation promises to be overcome thus paving the way for a new generation of carbohydrate-based products. C-glycosides occur when the oxygen atom of the exo-glycosidic b o n d is replaced by a carbon atom for any given O-glycoside. Additionally, for any furanose or pyranose, any exocyclic atoms linked to one or two etheral carbons tetrahedrally will be only carbon or h y d r o g e n and there will be at least one carbon and one OH group on the ring. In accordance with these statements, structural definitions of C and O-glycosides are illustrated in Figure 1.1.1. With the relatively m i n o r s t r u c t u r a l m o d i f i c a t i o n i n v o l v e d in the transition from O-glycosides to C-glycosides comes the more involved question of how to name these compounds. Figure 1.1.2 shows a series of C-glycosides with their c o r r e s p o n d i n g names. C o m p o u n d 1_ derives its name from the longest continuous chain of carbons. Since this is a seven carbon sugar, the name will be derived from heptitol. As the heptitol is cyclized between C2 and

2

Chapter I

Introduction

C6 it is designated as 2,6-anhydro. Finally, carbons 2-5 and carbons 6-7 bear the D-gulo and D-glycero configurations, respectively. By comparison, compound __4is a 2,6-anhydro heptitol bearing the D-glycero configuration at carbons 6-7. However, carbons 2-5 bear the D-ido configuration and the molecule is now designated as such. Figure 1.1.1

Definition of C-Glycosides O-Glycosides _~'~~

nOH

OR

/

n OH

C-Glycosides

I noH

Figure 1.1.2

n OH

Representative C-Glycosides and Their Nomenclature ~.. OAc

! OAc 3,4,5,7-Tet ra- O-acetyl-2,6-an hydro- 1-d eoxy- D-glyce ro-D-g u Io- heptitol C-glycero: C 6 and C 7 9 Anhydro: C2andC6 9 C s, C 4, C 3, C2: D-gulose stereochemistry 9 Heptitol: seven carbons (1-deoxy)

9

~.-OBn 2

OBn

OAc

1- O-Acetyl-2,6-an hyd ro-3,4,5,7-t etra- O-be nzyl- D-g lyce ro- D-g u Io-h eptit ol

Chapter 1

Introduction ~..OAc

3_

"OAc

~.ICN

5,6,7,9-Tet ra- O-acetyl-4,8-an hyd ro-2,3-d ideoxy- D-g lyce r- D-g u Io-n onan it rile

~OBn BnHN L 4_ ~1 2,6-An hyd ro-4,5,7-t ri- O-benzyl-3-(N-benzylam ino)- 1,3-d ideoxy- 1-iodoD-glycero-D-ido-heptitol ~.OAc A c O ~ s_

AcO

L.../cN

5,6,7,9-Tet ra- O-acety I-4,8-an hyd ro-2,3-d ideoxy- D-g lyce r- D-id o- n o n an it ri Ie

HO..~~O

,.~~OMe

_6

ON

Methyl-8,] 2-anhydro-6,7-dideoxy-D-glycero-D-gulo-a-D-gluco-tridecapyranoside or D-GIc-C-13-(1-6)-D-GIcOMe OAc

A c O ~

OAc

OAc ~oOc

_7

1,2,3,6-Tet ra- O-acetyl-4-deoxy-4- (3,4,5,7-tet ra- O-acetyl-2,6-an hydro- 1-deoxy- Dglyce ro- D-g u Io-heptitol- 1-yl)-ml3-D-galactopyran ose

Chapter I 1.2

Introduction

O-Glycosides vs. C-Glycosides: Comparisons of Physical Properties, Anomeric Effects, H-Bonding Abilities, Stabilities and Conformations

The s t r u c t u r a l and chemical similarities p r e v a l e n t b e t w e e n C a n d Oglycosides are illustrated in Table 1.2.1 and are summarized as follows. In light of the b o n d lengths, Van der Waal radii, electonegativities and b o n d rotational b a r r i e r s being very similar between O and C-glycosides, we find the largest difference between physical constants to be in the dipole moments. However, as minor differences do exist, the conformations of both O and C-glycosides are r e p r e s e n t e d by similar a n t i p e r i p l a n a r arrangements. These c o n f o r m a t i o n a l similarities are illustrated in Figure 1.2.1.

Table 1.2.1

Physical Properties of O and C-Glycosides

Bond Length Van der Waal Electrone8ativity Dipole Moment Bond Rotational Barrier H-Bonding Anomeric Effect Exoanomeric Effect Stability Conformation

O-Glycosides C-Glycosides O-C = 1.43 Angstroms O-C = 1.54 Angstroms O = 1.5 2 Angstroms O = 2.0 Angstroms O= 3.51 C= 2.35 C-O = 0.74D C-C = 0.3D CH3-O-CH3 = 2.7 CH3-CH3 = 2.88 kcals/mole kcals/mole Two None Yes No Yes No Cleaved by Acid and Stable to Acid a n d Enzymes Enzymes C1'-C2' antiperiplanar C I'-C 2' a n t i p e r i p l a n a r to 01-C1 to C1-C2

Perhaps the major difference between C and O-glycosides is found within chemical reactivities. Not only are C-glycosides absent of anomeric effects, they are also stable to acid hydrolysis and are incapable of forming hydrogen bonds. Within the realm of physical properties, O and C-glycosides exhibit similar coupling constants in their 1H NMR spectra. A s u m m a r y of the respective a v e r a g e c o u p l i n g c o n s t a n t s 1 is p r e s e n t e d in Figure 1.2.2 a n d specific illustrations2, 3 are shown in Figure 1.2.3. Regarding the study summarized in Figure 1.2.3, it was d e t e r m i n e d that as with O-glycosides, the C1'-C2, bond is antiperiplanar to the C1-C2 b o n d in the corresponding C-glycosides. Furthermore, C2 substituents were found to have no effect on C-glycosidic bond conformations and, considering 1,3-diaxial-like interactions, the C-aglyconic region will distort first. In summary, C-glycosides were f o u n d to be not conformationally rigid with conformations predictable based on steric effects. These conformations were shown to parallel those of corresponding (>glycosides thus suggesting potential uses for C-glycosides.

Chapter I

Figure 1.2.1

Introduction

C o n f o r m a t i o n s of O a n d C-Glycosides H

H

O-. R H

H R

H H

H

H

H2C~ R

~ - ~ O

\

R H

H

H

H

H

H

R

C o n f o r m a t i o n s a n d Coupling C o n s t a n t s

Figure 1.2.2

H1

H1 R

JHI,HS = 13 Hz JHI,HR = 3 Hz

O

s

JH1,HS = 3 Hz JH1,HR = 13 Hz

O H1

S

JHI,HS = 3 Hz JHI,HR = 3 Hz

O

H

H H1

R H1

JH1,HS = 12 Hz

JH1,HS = 3 Hz

JH1,HS = 3 Hz

JH1,HR - 3 Hz

JH1,HR = 12 Hz

JH1,HR = 3 Hz

6

Chapter i

Introduction

Kishi, et al.,4 d e m o n s t r a t e d t h a t "it is possible to p r e d i c t the conformational behavior around the glycosidic bond of given C-saccharides by placing the C1,-C2, bond antiperiplanar to the Ca-Cn bond and then focusing principally on the steric interaction around the non-glycosidic bond." This postulate was demonstrated, as shown in Figure 1.2.4, utilizing a d i a m o n d lattice to arrange the glycosidic conformations of the C-trisaccharide analogs of the blood group determinants.S,6

Figure 1.2.3

Literature Examples of Coupling Constants OH

OH

OH

o~,,,.. _

c ~,,,..~.,,,o. I~oA'~

~,~.,,,o

o.o.x

o.o.x

X=Y=N-H X-D,Y--N-H

X-Y-N=H X-N=H,Y=D

OH

OH

OH H t.

X

Y

s.

X = Y = H , R = OH

~

H

~

OH

o.

OH

X

H

ol

Y

e.

OH

X = Y = H , R = OH X = H , Y = D , R = OH X=Y=R=H

OH

X

.

Y

OH

X = Y = H , R = OH X = D , Y = H , R = OH X=Y=R=H

= 10 - 12 Hz; Jl,x = 3 - 4 Hz for o~-isomer

O 1 - 0 1 - 0 1 , - 0 2, : 55" torsional angle (55 + 5" for methyl o~-glucopyranoside) ~

= 8 - 10 Hz; J1,Y = 2 - 5 Hz for 13-isomer

O1-C1-C1,-C 2, : -80" torsional angle (-70" for methyl I]-glucopyranoside)

In an NMR study of the conformations of C-glycofuranosides and Cglycopyranosides, Brakta, et ai.,7 d e m o n s t r a t e d that the 1H1,_2, coupling constants were limited in their abilities to define conformations. However, the

Chapter i

Introduction

7

HI, chemical shifts were shown to be more down field for the a anomers while the CI', and C5' chemical shifts were found to be more up field. Furthermore, the 1H-13C coupling constants for the anomeric protons were measured as larger for the a isomer. In light of all of this information, the nOe is the most diagnostic. When applied to H1, and H4, or Hs', no nOe exists for the a isomer while that for the 13isomer can be readily determined.

Figure 1.2.4

C - T r i s a c c h a r i d e of Blood G r o u p Determinants in D i a m o n d Lattice OH

H . . . . . . . ,,,,~CH3 o~,,...r~ HO~I jO

X H "O"

HO~,,]~Y HO,,,,'"k'...j.. 0 OMe

1.3

Naturally Occurring C-Glycosides

Figure 1.3.1

Aloins A a n d B

~ HO~ _

OH

_

.,.llOH HO

~~,

HJ

8,9_

~'CH2OH

8

Chapter 1

Introduction

While C-glycoside chemistry has recently attracted much attention, they were not invented by chemists. Many examples of C-glycosides have been isolated from nature. For example, in the structures represented in Figure 1.3.1 were isolated from Barbados aloe. These compounds, aloin A and aloin B, are collectively known as barbaloin make up the bitter and purgative principle of aloe.S-12

Figure 1.3.2

Carthamus tinctorius OH

HO/~ H

0

0

I

0

HO

~,

HO~O~H H

HO

/~ HOOH

HOH

II

II

0

OH OH H HO H H

SafflowerYellow B, 1_00 Oarthamustinctorius Figure 1.3.3

OH OH CH20H

(

OH

Trachelospermum

asiaticum

OH .g

.o-

O

oMe .

T

C"

T

1"I9

OH

-

-OMe

Chapter 1

Introduction

9

In 1984, a yellow pigment was isolated from the petals of C a r t h a m u s tinctorius. 13 The structure assigned to the isolate is shown in Figure 1.3.2 and contains an open-chain C-glycoside.

Figure 1.3.4

Asphodelus ramosus

H O ~

OH

O

OH 1:2: C-ct-rhamnopyranosyl 1__33:C-13-xylopyranosyl 1_44:C-13-antiaropyranosyl 15: C-o~-arabinopyranosyl 1__66:C-~-xylopyranosyl 1!: C-13-quinovopyranosyl

O% HO~,

OH n C h r y s o p o g o n aciculatis

Figure 1.3.5

HO

O

,% HO OH ~.,,tzOH HO

Aciculatin, 1__88

In 1986, the first naturally occurring lignan C-glycoside was isolated from T r a c h e l o s p e r m u m asiaticum (Figure 1.3.3). 14 A n o t h e r example of n a t u r a l l y o c c u r r i n g C-glycosides was r e p o r t e d in 1991 w h e n extracts of Asphodelus ramosus tubers were shown to posses ICs0 values of 4.5 p p m in the Artemia salina bioassay. Analysis of the extracts yielded the family of six new a n t h r a q u i n o n e - a n t h r o n e - C - g l y c o s i d e s shown in Figure 1.3.4.1s All six compounds share the same aglycone unit and differ only in the specific sugar attached. Again, in 1991, a flavone derived C-glycoside was i s o l a t e d from Chrysopogon aciculatis and shown to be cytotoxic to KB cells. Interestingly, this

10

Chapter 1

Introduction

compound, shown in Figure 1.3.5, was also shown to bind to DNA with a Kd of about 15 ~M.16 Considering the number of naturally occurring C-glycosides known, we cannot ignore the specific class of C-nucleosides. This class of compounds is particularly i m p o r t a n t due to the antibacterial, antiviral, and a n t i t u m o r properties of many of these molecules. Some examples of naturally occurring C-nucleosides are shown in Figure 1.3.6 and include pyrazofurin, showdomycin, oxazinomycin, formycin, and formycin B.17,18

Naturally Occurring C-Nucleosides

Figure 1.3.6 OH

O~NH

O OH

HO \

/

CONH2 OH

O'~-- NH

N/NH

Oxazinomycin, 19

O

Pyrazofurin, :20

Showdomycin, 21 ]~--- NH

NH2 OH

Ho*':

----

"*OH Formycin, 22

N

OH

HO

m

OH Formycin B, 23

1.4. C-Glycosides as Stable Pharmacophores With the fast paced development of the chemistry of C-glycosides, the pharmaceutical and biotechnology industries have recognized that C-glycoside analogs of biologically active c a r b o h y d r a t e s may be studied as stable pharmacophores. Currently, glycosides and saccharides are used in a variety of applications ranging from foodstuffs to components of nucleic acids and cell surface glycoconjugates. 19-24 Realizing the extent to which these types of compounds are involved in everyday life, the advantages of using C-glycosides as drug candidates become apparent. Included among these advantages are the facts that C-glycosides are stereochemically stable and that chiral starting materials are readily available (sugar units). Furthermore, C-glycosides as pharmacophores may yield novel enzyme inhibitors with structures that may

Chapter i

Introduction

11

be difficult or impossible to construct utilizing s t a n d a r d c a r b o h y d r a t e chemistry. The following Figures and Schemes illustrate the use of C-glycosides in biological systems. The biosyntheses and biodegradations of glycosides are accomplished by enzymes called glycosidases. In cases where the product of a glycosidation is mediating an undesired biological function, the utility of glycosidase inhibitors becomes apparent. Figure 1.4.1 shows a series of molecules designed to inhibit the specific activity of p-glucosidase (cellobiase).2s The assay used involves the cleavage of an O-nitrophenyl-p-D-glucoside with the above mentioned enzyme isolated from sweet almonds. 26 The biological activities of the illustrated synthetic compounds were compared to the activity of 1-deoxynojirimycin and the relevant Kis accompany the structures in Figure 1.4.1.

Figure 1.4.1

C-Glycosidic p-Glucosidase I n h i b i t o r s K i

.O -

OH ~'"O

p,

(p-glucosidase cellobiase)

NH3+CF3COO competitive, 7 X 105 M

OH

~

......OH _

+ NH3 CF3COO competitive, 7.6 X 10"3 M P.

OH

Ho'HH

competitive, 1.8 X 105M

OH

With the interest in glycosidase inhibitors, compounds lending insight to the structures and mechanisms of these enzymes have received much attention. Recently, Lehmann, et a1.,27 prepared a series of diastereotopic C-glycosides designed to be substrates for p-D-galactosidase. The premise was that in order to confirm this enzyme's mechanism of action, proposed from an extrapolation of lysozyme activity,28-31 the structural analysis of products resulting from the enzyme's effect on its substrates would be helpful. Therefore, the structures

12

Chapter i

Introduction

shown in Figure 1.4.2 were prepared and, as illustrated in Scheme 1.4.1, were shown to be substrates for p-D-galactosidase. 27

Figure 1.4.2

H

C-Glycosidic Substrates for p - D - G a l a c t o s i d a s e

H?c.OH

H?~IOH

o

HOH ' ~ ~ O ~

CN

CH3

HaC

Scheme 1.4.1

C-Glycosidic Substrates for p - D - G a l a c t o s i d a s e

H? ~--'OH

H?~IOH 13-Galactosidase pH = 6.8

-" H

O ~ O H

HOI With the encouraging results with synthetic p-D-galactosidase inhibitors, Lehmann, et al., 32 p r e p a r e d deuterated analogs. Utilizing the stereochemical outcome, the face of the substrate serving as the recipient of p r o t o n d o n a t i o n by the enzyme was determined. As shown in Scheme 1.4.2, a p r o t o n donating substituent in the binding site was found to induce reaction at the re face of the bound substrate. These findings were c o n s i s t e n t with the p r e v i o u s l y mentioned lysozyme model. Considering the rapid advancement of our understanding of the inhibition of c a r b o h y d r a t e binding proteins, there is still a t r e m e n d o u s need for more selective molecules. In the area of affinity labeling, diazoketones have f o u n d m u c h use. 33 With the irreversible n a t u r e of their b i n d i n g to respective enzymes, Myers, et al., 34 designed diazoketones into sugar derivatives. The general approach, shown in Scheme 1.4.3, was designed to create irreversible glycosidase inhibitors or suicide substrates. Inhibitors of the enzyme glycogen phosphorylase have been studied for their ability to lower blood glucose levels.35-37 In order to study the n a t u r e of the b i n d i n g of glucose derived substrates to glycogen p h o s p h o r y l a s e , the p r o d u c t shown in Scheme 1.4.4 38 was complexed to the enzyme and studied via x-ray crystallography. 39 Aside from demonstrating reasonable inhibitors, the

Chapter I

Introduction

13

conformations of C-glucosides bound to this particular enzyme were shown to exist in a skew boat conformation, S c h e m e 1.4.2

C-Glycosidic Substrates for ~-Galactosidase

H ( ~ ''OH

/O

O~

HO

Hko

.r'r'r'~O

reface

H

13-Galactosidase H O - ~ ~ ~ ~

H:~

.,,,,CH3 D

Scheme 1.4.3

OH

C-Glycosidic Affinity Labels for Carbohydrate Binding Proteins ~...-OAc

"~

OH Suicide substrate for glycosidases Affinity-labeling reagent

OAc

Scheme 1.4.4

OH

C-Glycosidic Glycogen Phosphorylase Inhibitors OBn

OH

OH

NHCOMe

ID

BnO"'. . . . .

OBn

"'OBn

HO"" . . . . .

"'OH

OH

Ki = 37 mM against glycogen phosphorylase

Glycosyltransferases assemble polysaccharides from their monomeric units by adding, to the growing carbohydrate chain, activated nucleotide

14

Chapter I

Introduction

sugars. 4o The chemistry of glycosyltransferases is well known 41-43 and is illustrated in the biosynthesis of sialyl LewisX, shown in Figure 1.4.3. 44 First, B1,4-galactosyltransferase forms the lactose scaffolding. Second, a-2,3sialyltransferase adds the sialic acid. Finally, the addition of fucose by a-l,3fucosyltransferase completes the synthesis.

Figure 1.4.3

The Biosynthesis of Sialyl Lewis x

O.~u I Yn

002. I

HO~oI/L"oH AcHN

~ c . ~HO ~

OH HO"'~OH

~ bj

~o"

F

a

~ ~ O.o._ ~ HC H)

O

o)

HO L...OH

The glycosidicbonds are formed by the corresponding 13-1,4-Galactosyltransferase b: o~-2,3-Sialyltransferase r ~-l,3-Fucosyltransferase

~.~c

(

glycosyltransferases in sequence and where specified:

OH

O H ~ O

a:

OH

OH

HO Figure 1.4.4

C-Glycosidic F u c o s y l t r a n s f e r a s e I n h i b i t o r s

O

re lo<

NH NH 2

L~

HO IOH

J= i -

GDP-L-Fucose O O II

..." HO

HO OH

II

o- o~ OH

OH X-

N HO,~~

O H 2, C 2 H 4

~

O

OH

C-GDP-Fucoseas FucosyltransferaseInhibitor

H2N

Chapter 1

Introduction

15

Since sialic acid and fucose are important in the binding interaction of sialyl Lewis x to the selectins,45-5o a reasonable conjecture is that removal of fucose from sialyl Lewisx will completely stop the binding of leukocytes to the endothelium. Furthermore, this may be accomplished by inhibiting the activity of ~-l,3-fucosyltransferase thus preventing the formation of sialyl Lewisx. Human ~-l,3-fucosyltransferases are found in milk, S1-S3 saliva, S4 and other specific cell lines.55-57 Through cloning studies, a role for an cz-l,3fucosyltransferase in cell adhesion was identified for the biosynthesis of sialyl Lewis x on neutrophils.58, 59 As these studies link ~-l,3-fucosyltransferase to cell adhesion and since the activated fucose species used by this enzyme is GDPL-fucose, Luengo, e t al., 6o prepared the C-glycoside analog of GDP-fucose shown in Figure 1.4.4. Scheme 1.4.5

C-Glycosidic Analogs of Lipid A a n d Lipid X

P" o O H O - ' ~ ~ ~ NH

Ph'~O--~'~ OH O0--~C02AIIyl 0 H Ph3P=CHCO2AIlyl NH

R

R

P" o O DBU

.,.,,,._ ,,,...-

HOIO~

CO2AIlyl

HoO o..,~

R

0==~

H

NHHO..-~"~..~-O

CH3(CH2)10HOI~'/ )

O=~

O==~

P\

(CH2)10CH3

HO

NH H O ~ O

O HN

CH3(CH2)lOHOI~' HO~ R CH3(CH2)I()- \ (CH2)loCH3

CO2H

Lipopolysaccharides or endotoxins are present in the cell walls of Gramnegative bacteria and are immunostimulants responsible for many pathological effects.61-69 Lipid A is the lipophilic terminal of endotoxins and lipid X is the

16

Chapter i

Introduction

reducing monosaccharide of lipid A. As the immunostimulatory effects of endotoxins are of interest, lipid A has been studied with the i n t e n t of eliminating the deleterious pathological effects.70-72 In fact, it was not until recently that lipid X was shown to posses some of the i m m u n o s t i m u l a t o r y effects present in lipid A.73-7s In 1991, Vyplel, et al., 76 reported the synthesis of C-glycosidic analogs of these two lipopolysaccharide subunits. The syntheses, summarized in Scheme 1.4.5, involve the use of Wittig methodology in order to effect the C-glycosidation. The results of this study d e m o n s t r a t e d the feasibility of replacing the anomeric phosphate groups on these lipids with Cglycosidic carboxylic acid units as well as retaining at least three lipid units on any given analog in order to retain immunostimulatory activity. Endotoxic potential appeared to not be changed in the transition to C-glycosides. Scheme 1.4.4

C-Glycosidic Ligands for e-c01i Receptors

OBn

OBn 70~

BnO~"" y

*OMe

"OBn ~OBn TMSOTf BnO~"" T OBn OBn

/

OBn

r~

1. 9-BBN, H202 2. Ms-CI ID 3. Bu4NN3 4. H2/Pd(OH)2

NH2 NHS-Biotin.._

BnO\~"" ~ / "OBn OBn

OH

o

NH HO~"" y

"wOH OH

Pathogenic organisms are known to use carbohydrate receptors such as lectins to bind to cell surfaces. 77-79 Type I pili, a type of proteinaceous appendage, are found on the surface of Escherichia coli80 and contain receptors capable of binding to a-linked mannosides.81-83 In 1992, Bertozzi, et al.,S4 Prepared new C-mannosides that bind to Escherichia coli receptors and are able

Chapter I

Introduction

17

to target proteins to this organism. A specific synthesis, shown in Scheme 1.4.6, began with the p e r - b e n z y l a t e d O-methylmannoside shown. The initial Cglycosidation was accomplished on t r e a t m e n t with allyltrimethylsilane and trimethylsilyl triflate giving the C-mannoside in high yield with the a a n o m e r favored at a ratio of 15 : 1. Elaboration of this c o m p o u n d to the aminopropyl mannoside was accomplished via conversion of the allyl group to an alcohol on t r e a t m e n t with 9-BBN followed by an oxidative workup. The alcohol was then mesylated and the mesylate was displaced with azide. Simultaneous reduction of the azide to the amine and removal of the benzyl groups was accomplished utilizing a palladium hydroxide mediated catalytic hydrogenation. Once formed, the a m i n o p r o p y l m a n n o s i d e was coupled with biotin. This product was shown to totally block the bacterial m e d i a t e d a g g l u t i n a t i o n of yeast cells at a concentration of 7 mM. It is interesting that this c o m p o u n d is 9.6 times more active than the parent methyl-~-D-mannopyranoside.SS,86

C-Glycosidic Polymers as Inhibitors of Influenza Virus

S c h e m e 1.4.5

AcHN~2H

HOf i II ~

I

OH

NaCNBH3

OH

pH = 7

AcHN ---O 002%

~

~'~O

OH

OH

18

Chapter i

Introduction

Sialic acids are found t e r m i n a t i n g cell-surface g l y c o p r o t e i n s a n d glycolipids.87-89 Pathogens use sialic acid a-glycosides in order to attach to cells p r i o r to infection. This process is m e d i a t e d by lectins, a class of glycoproteins.77,90, 91 Among the most studied of these glycoproteins is influenza hemagglutinin.92-94 Recently, the ability of this protein to attach to erythrocytes has been inhibited by polyvalent sialic acid derivatives.95-100 In 1992, Nagy, eta/., 101 reported the preparation of new carbohydrate materials resistant to neuraminidase, the enzyme present on the surface of influenza virus 92 responsible for cleavage of the hydrolyzable O-sialoside linkage of previously tested compounds. The fact that the newly reported compounds, p r e p a r e d as shown in Scheme 1.4.5, are C-glycosides and, thus, resistant to neuraminidase explains their ability to inhibit the in vitro infectivity of the influenza virus.

Scheme 1.4.6 Cl/ MeO2C

C-Glycosidic Hemagglutination Inhibitors

r,,,,.~HAc

HO2C/ r~ HAc 1. HSCH2CH2NH2"HCI/AICV/hv 2. N-Acroyloxysuccinimide/Et3N

~-OAc I-OAc "OAc

H2NCO-.~ HO2C/

i-~NHAc Acrylamide/AICV/hv

o

I-OH i-0".

Neu5Ac '~--Neu5Ac /.~..-OCNH 2 H2NCO" 'k~...~OCNH2 Neu5Ac~--~ "~, ~OCNH 2 poly(5-co-acrylamide)

The compounds of the present study were prepared from the C-allyl sialic acid derivative described by Paulsen et a/.lO2 and Vasella, et al. lo3 The ethyl ester of this compound was converted to the amide, shown. Completion of the synthesis involved reductive amination to the illustrated glucose based polymer thus giving the product. In one particular instance, the starting materials were combined to yield a product containing approximately 30% of the sialic acid analog. This polyvalent C-sialoside inhibited infection by influenza virus with an IC50 of 0.2~M. The polymeric nature of the above example is advantageous in that many pathogen-host cell interactions are of a polyvalent nature.104 The rational behind this relates to the much stronger binding observed when a series of weaker interactions are acting in unison. In 1993, Whitesides, et al.,105 took advantage of this phenomenon and reported a study complimentary to Nagy's

Chapter i

Introduction

19

work utilizing a glucose-based polymer. The approach of the Whitesides study is shown in Scheme 1.4.6 and involves the preparation of sialic acid substituted acrylamide polymers. C-Glycosides as LTD4 Antagonists

Figure 1.4.5

OH

HO2C(CH2)nS...."

I0H

CO2H

.....jCsHll

",,Jill

SR

CH3(CH 2

Leukortiene D4 SR = cysteinylglycine Scheme 1.4.7

CO2H

n=2,3

Preparation of C-Glycosides as LTD4 Antagonists

HO... HOllo

O

HO...,,

1. AcOH/HBr OH 2. Zn, AcOH

TBDPSO

-.,,,ll

\

o

/

1. Allyltrimethylsilane

~

2.NaOMe

HO

3. TBDPS-CI 4. 9-BBN, H202

Swern OH 2.1. Ag20, NaOH, EtOH 3. (Me)2C(OMe)2,p-TsOH

O

HO o "'""'\ 1. Cystein/Homocystein Methyl Ester 2. KOH

1. m-CPBA 2. Swern CO2Me 3. H2C=PPh3

HO2C(CH2)nS%;

.,,1111~ CH3(CH 2

CO2Me

_OH

> CH3(CH2)1 2 / ~

..,,,,I~

CO2H

n=2,3 Beginning with the C-allyl sialoside described in Scheme 1.4.5, elaboration to the extended chain analog was accomplished by first treating with aminoethanethiol under radical conditions and then acylating the resulting amine with N-acroyloxysuccinimide. This compound was then added to

Chapter 1

20

Introduction

polyacrylamide under radical forming conditions to obtain the final product. These new compounds, compared to the corresponding O-glycosidic analogs, showed approximately the same activities in inhibiting influenza induced agglutination with Kis ranging from 0.2 to 0.4 ~M. Many other approaches have been reported for the preparation of stable C-glycosidic pharmacophores. Among these is the synthesis of the leukotriene antagonists shown in Figure 1.4.5.106 This work, shown in Scheme 1.4.7, involves the initial acetylation and dehydration of D-xylose giving the illustrated glycal. Treatment with allyltrimethylsilane gave a C-allyl glycoside. Further elaboration via deacetylation, silylation, and hydroxylation utilizing 9BBN/H202 yielded the alcohol, shown. The alcohol was then oxidized to the corresponding methyl ester and the silyl group was removed. Conversion of the double bond to an epoxide on treatment with m-CPBA was followed by a Swern oxidation of the secondary alcohol followed by a Wittig reaction, thus providing the illustrated olefin. The synthesis was completed by opening the epoxide with cysteine or homocysteine esters followed by hydrolysis to the corresponding carboxylic acid. Once synthesized, these compounds were shown to inhibit the leukotriene D4 induced contractions of guinea pig ileum in vitro.

Scheme 1.4.8

Early Steps in the Shikimate Pathway

CH2OPO3H2

CH2OPO3H2

HO co H -HOo- OO H. O

OPO3H2

O ~ ~

OH

COH OH

DAHP

DHQ

The shikimate pathway is utilized by plants to form aromatic amino acids, lo7-1o9 In this bioprocess, shown in Scheme 1.4.8, D - e r y t h r o s e - 4 phosphate is combined with phosphophenylpyruvate giving 3-deoxy-Darabino-heptulosonic acid-7-phosphate (DAHP). The next step utilizes DHQ synthase to convert DAHP to dehydroquinate (DHQ).

Figure 1.4.6

C-Glycosidic Tetrazole DAHP Analogs CH2OPO3H2

CH2OPO3H2N"--N ,, H 0 ----~--~-~"-~-~~ ..N NH

N"

\

/NH

N~---'N I

Chapter I Scheme 1.4.9

21

C-Glycosidic Tetrazoles

AcO" ~

AcO----~ OAc NaN~NH4C'= A c O . ~ " ~ I"O A c O ~

0Ac

~co:--~~l.o A c O ~ C N

N--'-N /~ ~'~ ..N NH

Peptidoglycan Lipid-Bearing Monomer

Figure 1.4.7

~.OH HO

Introduction

OH 0

0

NHAc I -ACHNI

o= I

II

Peptide

I

~'l

"-J rA

0/% L

O/~O ~

Scheme 1.4.10

-I

O~p.~O~p.~O I

~ ~'~,

~

L

C-Glycosidic Transglycosylase Inhibitor

P,~~o

H2C=PPh3 79%

B n O ~ OBn OH

1. Hg(CF2CO2)2,_ 2. KCI/12 80%

P"~o~O BnO~ . . . - ~ ~

NHAc

P"'~o~ r

OH -

~OI

OH

B n O ~ OBn

BnO L

~..OH

"J

CO2H

O\B/O~/X'-,.c~

"

.1~)

22

Chapter I

Introduction

As the shikimate pathway is essential to the biology of plants, it has been identified as a potential target for herbicides. 110 As potential inhibitors of DHQ synthase, Wightman, eta/., 111 prepared the C-glycosidic tetrazole DAHP analogs shown in Figure 1.4.6. The key synthetic step, represented in Scheme 1.4.9, involved the conversion of cyanoglycosides to tetrazoles on t r e a t m e n t with sodium azide and ammonium chloride. 112 Transglycosylasell3 is a penicillin-binding protein responsible for the connection of lipid-bearing carbohydrate-based monomers to peptidoglycan. This process is i m p o r t a n t in that the proliferation of bacteria requires polymerization of the peptidoglycan carbohydrate chain 114 in addition to the processing of the peptide backbone. Referring to the s t r u c t u r e of the peptidoglycan monomer unit, represented in Figure 1.4.7, Vederas, et al., lls p r e p a r e d a C - p h o s p h o n a t e disaccharide as a potential i n h i b i t o r of the transglycosylase induced peptidoglycan polymerization. The key step in the preparation of the inhibitor is shown in Scheme 1.4.10 and involves the elaboration of the glucose derivative, shown, to the olefin on reaction with methylenetriphenylphosphorane. Once the olefin was isolated, the C-glycoside was obtained via mercury mediated cyclization followed by oxidation of the mercury with iodine. Further elaboration of the resulting iodide gave the desired C-phosphate disaccharide shown.

1.5

Further Reading

This chapter introduced the nomenclature, physical properties, chemistry, and potential uses of C-glycosides. Through specific examples and detailed analyses of synthetic strategies, this book will endeavor to explore the various chemical reactions associated with C-glycosides as well as methods for their preparation. In addition to the present compilation, n u m e r o u s review articles 116-122 have been written that cover a wide range of subjects regarding C-glycosides. Although this book is meant to be extensive in its treatment of the subject, it is not exhaustive. Therefore, for more detailed treatments of the topics presented herein, the reader is referred to the cited references.

1.6 0

.

3. 4. .

6.

References Wang, Y.; Goekjian, P. G.; Ryckman, D. M.; Miller, W. H.; Babirad, S. A.; Kishi, Y. J. Org. Chem. 1992, 57, 482. Wu, T. C.; Goekjian, P. G.; Kishi, Y. J. Org. Chem. 1987, 52, 4819. Goekjian, P. G.; Wu, T.-C.; Kishi, Y. J. Org. Chem. 1991, 56, 6412. Wang, Y.; Goekjian, P. G.; Ryckman, D. M.; Kishi, Y. J. Org. Chem. 1988, 53, 4151. Hanecla, T.; Goekjian, P. G.; Kim, S. H.; Y-dshi, Y. J. Org. Chem. 1992, 57, 490. Kishi, Y. Pure & Appl. Chem. 1993, 65, 771.

Chapter i

D

So 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.

Introduction

23

Brakta, M.; Farr, R. N.; Chaguir, B.; Massiot, G.; Lavaud, C.; Anderson, W. R.; Sinou, D.; Daves, G. D. Jr. J. Org. Chem. 1993, 58, 2992. Grun, M.; Franz, G. Pharmazie 1979, 34, H. 10, 669. Auterhoff, H.; Graf, E.; Eurisch, G.; Alexa, M. Arch. Pharm. (Weinheim, Get.) 1980, 313, 113. Graf, E.; Alexa, M. Planta Med. 1980, 38, 121. Rauwald, H.-W. Arch. Pharm. (Weinheim, Get.) 1982, 315, 769. Rauwald, H.-W.; Roth, K. Arch. Pharm. (Weinheim, Get.) 1984, 317, 362. Takahashi, Y.; Saito, K.; Yanagiya, M.; Ikura, M.; Hikichi, K.; Matsumoto, T.; Wada, M. Tetrahedron Lett. 1984, 25, 2471. Abe, F.; Yamauchi, T. Chem. Pharm. Bull. 1986, 34, 4340. Adinolfi, M.; Lanzetta, R.; Marciano, C. E.; Parrilli, M.; Giuliu, A. D. Tetrahedron 1991, 47, 4435. Carte, B. K.; Carr, S.; DeBrosse, C.; Hemling, M. E.; Mackenzie, L.; Often, P.; Berry, D. Tetrahedron 1991, 4 7, 1815. Buchanan, J. G.; Wightman, R. H. Prog. Chem. Org. Nat. Prod. 1984, 44, 243. Humber, D. C.; Mulholland, K. R.; Stoodley, R. J. J. Chem. Soc. Perkdn Trans. 1 1990,283. Schmidt, R. R. Angew. chem. 1986, 98, 213. Schmidt, R. R. Angew. chem. Int. Ed. Engl. 1986, 25, 212. Schmidt, R. R. Pure Appl. Chem. 1989, 61, 1257. Paulson, H. Angew. chem. 1990, 102, 851. Paulson, H. Angew. chem. In t. Ed. Engl. 1990, 29, 823. Hakomori, S. J. Biol. Chem. 1990, 265, 823. Schmidt, R. R.; Dietrich, H. Angew. Chem. Int. Ed. Engl. 1991, 30, 1328. Lehmann, J.; Ziser, L. Carbohydr. Res. 1989, 188, 45. Fritz, H.; Lehmann, J.; Schlesslmann, P. Carbohydrate Res. 1983, 113, 71. Hehre, E. J.; Genghoff, D. S.; Sternlicht, H.; Brewer, C. F. Biochemistry 1977, 16, 1780. Flowers, H. M.; Sharon, N. Adv. Enzymol. 1979, 48, 30. Blake, C. C. F.; Johnson, L. N.; Meir, G. A.; North, A. T. C.; Phillips, D. C.; Sarma, V. R. Proc. R. Soc. (London), Set. B 1967, 167, 378. Phillips, D. C. Sci. Am. 1966, 215, 78. Lehmann, J.; Schlesselmann, P. Carbohydrate Res. 1983, 113, 93. Sinott, M.L. CRC Crit. Rev. Biochem. 1982, 12, 327. Myers, R. W.; Lee, Y. C. Carbohydrate Res. 1986, 152, 143. Martin, J. L.; Veluraja, K.; Ross, K.; Johnson, L. N.; Fleet, G. W. J.; Ramsden, N. G.; Bruce, I.; Orchard, M. G.; Oikonomakos, N. G.; Papageorgiou, A. C.; Leonidas, D. D.; Tsitoura, H. S. Biochemistry 1991, 30, 10101. Acharya, K. R.; Stuart, D. I.; Varvil, K. M.; Johnson, L. N. Glycogen Phosphorylase b, World Scientific Press, Singapore, 1st ed. 1991. Martin, J. L.; Johnson, L. N.; Withers S. G. Biochemistry 1990, 29, 10745.

24 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.

Chapter 1

Introduction

Pougny, J.-P.; Nassr, M. A. M.; Sinnay, P. J. Chem. Soc., Chem. Commun. 1981, 375. Watson, K. A.; Mitchell, E. P.; Johnson, L. N.; Son, J. C.; Bichard, C. J.; Fleet, G. W. J.; Ford, P.; Watkin, D. J.; Oikonomakos. J. Chem. Soc. Chem. Comm. 1993, 654. Paulson, J. C.; CoUey, K.J.J. Biol. Chem. 1989, 264, 17615. Kornfeld, R.; Kornfeld, S. Annu. Rev. Biochem. 1985, 54, 631. Sadler, J. E. Biology o f Carbohydrates 1984, 2, 87. Basu, S.; Basu, M. Glycoconjugates 1982, 3, 265. Lowe, J. B.; Stoolman, L. M.; Nair, R. P.; Larsen, R. D.; T.L. Berhend, T. L.; Marks, R. M. Cell 1990, 63, 475. Berg, E. L.; Robinson, M. K.; Mansson, 0.; Butcher, E. C.; Magnani, J. L. J. Biol. Chem. 1991, 265, 14869. Tyrrell, D.; James, P.; Rao, N.; Foxall, C.; Abbas, S.; Dasgupta, F.; Nashed, M.; Hasegawa, A.; Kiso, M.; Asa, D.; Kidd, J.; Brandley, B. K. Proc. Nat/. Acad. Sci. USA. 1991, 88, 10372. Polley, M. J.; Phillips, M. L.; Wayner, E.; Nucelman, E.; Kinghal, A. K.; Hakomori, S.; Paulson, J. C. Proc. Natl. Acad. Sci. USA. 1991, 88, 6224. Imai, Y.; Singer, M. S.; Fennie, C.; Lasky, L. A.; Rosen, S. D. J. Cell Biol. 1991, 113, 1213. Stoolman, L. M.; Rosen, S. D. J. Cell Biol. 1983, 96, 722. True, D. D.; Singer, M. S.; Lasky, L. A.; Rosen, S. D. J. Cell Biol. 1990, 111, 2757. Prieels, J. P.; Monnom, D.; Dolmans, M.; Beyer, T. A.; Hill, R. L. J. Biol. Chem. 1981 256, 10456. Johnson, P. H.; Watldns, W. M. Biochem. Soc. Trans. 1982, 10, 445. Eppenberger-Castori, S.; Lotscher, H.; Finne, J. Glycoconjugate jr. 1989, 8, 264. Johnson, P. H.; Yates, A. D.; Watkins, W. M. Biochem. Biophys. Res. Commun. 1981, 100, 1611. Holmes, E. H.; Levery, S. B. Arch. Biochem. Biophys. 1989, 274, 633. Kukowska-Latallo, J. F.; Larsen, R. D.; Nair, R. P.; and Lowe, J. B. Genes Dev. 1990, 4, 1288. Stroup, G. B.; Anumula, K. R.; Kline, T. V.; Caltabiano, M. M. Cancer Res. 1990, 50, 6787. Macher, B. A.; Holmes, E. H.; Swiedler, S. J.; Stults, C. L. M.; Srnka, C. A. Glycobiology 1991, 1,6. Kuijpers, T.W. Blood 1993, 81,873. Luengo, J. I.; Gleason, J.G. Tetrahedron Lett. 1992, 33, 6911. Galanos, C.; L~deritz, O.; Rietschel, E. T.; Westphal, 0.; Brade, H.; Brade, L.; Freudenberg, M.; Schade, U.; Imoto, M.; Yoshimura, H.; Kusumoto, S.; Shiba, T. Eur. J. Biochem. 1985, 148, 1. Homma, J. Y.; Matsura, M.; Kanegasaki, S.; Kawakubo, Y.; Kojima, Y.; Shibukawa, N.; Kumazawa, Y.; Yamamoto, A.; Tanamoto, K.; Yasuda, T.;

Chapter 1

63.

64.

65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85.

In troduct3"on

25

Imoto, M.; Yoshimura, H.; Kusomoto, S.; Shiba, T. J. Biochem. 1985, 98, 395. Kotani, S.; Takada, H.; Tsujimoto, M.; Ogawa, T.; Harada, K.; Mori, Y.; Kawasaki, A.; Tanaka, A.; Nagao, S.; Tanaka, S.; Shiba, T.; Kusumoto, S.; Imoto, M.; Yoshimura, H.; Yamamoto, M.; Shimamoto, T. Infect. Immun. 1984, 45, 293. Kotani, S.; Takada, H.; Tsujimoto, M.; Ogawa, T.; Takahashi, I.; Ikeda, T.; Otsuka, K.; Shimauchi, H.; Mashimo, J.; Nagao, S.; Tanaka, A.; Harada, K.; Nagaki, K.; Kitamura, H.; Shiba, T.; Kusumoto, S.; Imoto, M.; Yoshimura, H. Infec. Immun. 1985, 49, 225. Kusumoro, S.; Yamamoto, M.; Shiba, T. Tetrahedron Lett. 1984, 25, 3727. Galanos, C.; Rietschel, E. T.; Liideritz, O.; Westphal, O.; Kim, Y. B.; Watson, D. W. Eur. J. Biochem. 1975, 54, 603. Levin, J.; Poore, T. E.; Zauber, N. P.; Oser, R. S. N. Engl. J. Med. 1970, 283, 1313. Galanos, C.; Liideritz, O.; Rietschel, E. T.; Westphal, O. In International Review o f Biochemistry, Biochemistry o f Lipids, II; Goodwin, T. W., Ed.; University Park Press: Baltimore, MD 1977; Vol. 14, pp239-335. Takahashi, I.; Kotani, S.; Takada, H.; Tsujimoto, M.; Ogawa, T.; Shiba, T.; Kusumoto, S.; Yamamoto, M.; Hasegawa, A.; Kiso, M.; Nishijima, M.; Harada, K.; Tanaka, S.; Okumura, H.; Tamura, T. Infect. Immun. 1987, 65, 57. Nakamoto, S.; Takahashi, T.; Ikeda, K.; Achiwa, K. Chem. Pharm. Bull. 1987, 35, 4517. Kumazawa, Y.; Matsura, M.; Maruyama, T.; Kiso, M.; Hasegawa, A. Eur. J. Immunol. 1986, 16, 1099. Lasfargues, A.; Charon, D.; Tarigalo, F.; Ledu, A. L.; Szabo, L.; Chaby, R. Cell Immunol. 1986, 98, 8. Nishijima, M.; Amano, F.; Akamatsu, Y.; Akegawa, K.; Tokunaga, T.; Raetz, C. R. H. Proc. Natl. Acad. Sci. USA 1985, 82, 282. Amano, F.; Nishijima, M.; Akamatsu, Y. J. Immunol. 1986, 136, 4122. Sayers, T. J.; Macher, I.; Chung, J.; Kugler, E. J. Immunol. 1987, 138, 2935. Vyplel, H.; Scholz, D.; Macher, I.; Schindlmaier, K.; Schutze, E. J. Med. Chem. 1991, 34, 2759. Sharon, N.; Lis, H. Science 1989, 246, 227. Sharon, N.; Lis, H. Lectins, Chapman and Hall, London, 1989. Mirelman, D. Microbial Lectins and Agglutins: Properties and Biological Activity, D. Mirelman, Wiley-Interscience, Sons, New York, 1986. Clegg, S.; Gerlach, G. F. J. Bacteriol. 1987, 169, 934. Firon, N.; Ofek, I.; Sharon, N. Infection and Immunity 1984, 43, 1088. Firon, N.; Ofek, I.; Sharon, N. Carbohydr. Res. 1983, 120, 235. Ofek, I.; Mirelman, D.; Sharon, N. Nature 1977, 265, 623. Bertozzi, C.; Bednarski, M. Carbohydrate Res. 1992, 223, 243. Esdat, Y.; Ofek, I.; Yashouv-Gan, Y.; Sharon, N.; Mirelman, D. Biochem. Biophys. Res. Commun. 1978, 85, 1551.

26 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.

Chapter 1

Introduction

Firon, N.; Ofek, I.; Sharon, N. Biochem. Biophys. Res. Commun. 1982, 105, 1426. Cornfield, A. P.; Schauer, R. Occurrence of Sialic Acids. In Sialic Acids; Chemistry, Metabolism and Function; Schauer, R., Ed.; Springer-Verlag Publishing Co.: New York, 1982; Vol. 10, pp 5-39. McGuire, E.J. Biological Roles of Sialic Acid; Rosenberg, A., Schengrund, C.L., Eds.; Plenum Publishing Co.: New York, 1976. Sharon, N. The Sialic Acids. In Complex Carbohydrates; Addison-Wesley Publishing Co.: London, 1975; pp142-154. Ruigrok, R. W. H.; Andr6, P. J.; Hoof Van Huysduynen, R. A. M.; Mellema, J. E. J. Gen. Virol. 1985, 65, 799. Markwell, M. A. K. Viruses as Hemagglutinins and Lectins. In Microbial Lectins and Agglutinins: Properties and Biological Activity;, Mirelman, E., Ed.; Wiley Series in Ecological and Applied Microbiology; WileyInterscience Publication, John Wiley and Sons Publishing Co.: New York, 1986; pp 21-53. Wiley, D. C.; Skehel, J. J. Annu. Rev. Biochem. 1987, 56, 365. Weis, W.; Brown, J. H.; Cusack, S.; Paulson, J. C.; Skehel, J. J.; Wiley, D. C. Nature 1988, 333, 426. Sauter, N. K.; Bednarski, M. D.; Wurzburg, B. A.; Hanson, J. E.; Whitesides, G. M.; Skehel, J. J.; Wiley, D. C. Biochemistry 1989, 28, 8388. Spaltenstein, A.; Whitesides, G. M. J. Am. Chem. Soc. 1991, 113, 686. Glick, G. D.; Knowles, J. R. J. Am. Chem. Soc. 1991, 113, 4701. Sabesan, S.; Duus, J. O.; Domaille, P.; Kelm, S.; Paulson, J. C. J. Am. Chem. Soc. 1991, 113, 5865. Gamain, A.; Chomik, M.; Laferriere, C. A.; Roy, R. Can. J. Microbiol. 1991, 37,233. Byramova, N. E.; Mochalova, L. V.; Belyanchikov, I. M.; Matrosovich, M. N.; Bovin, M. V. J. Carbohydr. Chem. 1991, 10, 691. Matrosovich, M. N.; Mochalova, L. V.; Marinina, V. P.; Byramova, N. E.; Bovin, M.V. FEBS Lett. 1990, 272, 209. Nagy, J. O.; Wang, P.; Gilbert, J. H.; Schaefer, M. E.; Hill, T. G.; Gallstrom, M. R.; Bednarski, M. D. J. IVied. Chem. 1992, 35, 4501. Paulsen, H.; Matschulat, P. Liebigs Ann. Chem. 1991,487. Wallimann, K.; Vasella, A. Helv. Chim. Acta 1991, 74, 1520. Matrosovich, M. N. FEBS Lett. 1989, 252, 1. Sparks, M. A.; Williams, K. W.; Whitesides, G. M. J. IVied. Chem. 1993, 36, 778. Sabol, J.; Cregge, R.J. Tetrahedron Lett. 1989, 30, 6271. Weiss, U.; Edwards, J. M. The Biosynthesis o f Aromatic Compounds, Wiley, New York, 1980. Ganem, B. Tetrahedron 1978, 34, 3353. Dewick, P. M. Nat. Prod. Rep. 1992, 9, 153. Kishmore, G. M.; Shah, D. M. Ann. Rev. Biochem. 1988, 57, 627.

Chapter 1

Introduction

27

111. Buchanan, J. G.; Clelland, A. P. W.; Johnson, T.; Rennie, R. A. C.; Wightman, R. H. J. Chem. Soc. Perkin Trans. 1 1992, 2593. 112. Farkas, I.; Szab6, I. F.; Bognfir Carbohydr. Res. 1977, 56, 404. 113. Taku, A.; Stuckey, M.; Fan, D. P. J. Biol. Chem. 1982, 257, 5018. 114. Van Heijenoort, Y.; Leduc, M.; Singer, H.; Van Heijenoort, J. J. Gen. Microbiol. 1987, 133, 667. 115. Qjau, L.; Vederas, J. C. J. Org. Chem. 1993, 58, 3480. 116. Herscovici, J.; Antonakis, K. Stud. Nat. Prod. Chem. 1992, 10, 337. 117. Postema, M. H.D. Tetrahedron 1992, 48, 8545. 118. Daves, G. D. Jr. Acc. Chem. Res. 1990, 23, 201. 119. Carbohydr. Res. 1987, 1 71. Special Issue for C-Glycosides. 120. Hacksell, U.; Daves, G. D. Jr. Progress in Medicinal Chemistry 1985, 22, 1. 121. Hanessian, S.; Pernet, A. G. Adv. Chem. Biochem. 1976, 33, 111. 122. Carbohydrate Chemistry, Specialist Periodical Reports, Royal Chemical Society 1968-1990, Vol. 1-24, Sections on C-Glycosides.

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C h a p t e r Two

2

Electrophilic Substitutions

Introduction

One of the most widely used methods for the formation of C-glycosides involves electrophilic species derived from the sugar component. Some representative examples, shown in Figure 2.0.1, include oxonium compounds, lactones, enones, carbenes, and enol ethers. Once formed, nucleophiles can be induced to react with these reactive species thus providing t r e m e n d o u s diversity in the types of C-glycosides accessible. This chapter focuses on various approaches made use of in the formation of C-glycosides via the addition of nucleophiles to carbohydrate-derived electrophiles.

Figure 2.0.1

Examples of Electrophilic Substitutions

~0~ ~~Nucleophile

__oyx X = LeavingGroup,OH

4) O

2.1

A n o m e r i c Activating Groups and Stereoselectivity

When considering the formation of C-glycosides by electrophilic substitution, several direct comparisons can be made to the similar reactions 29

Chapter 2

30

E1ectrophilic Substitutions

utilized in the preparation of O-glycosides. Specifically, any activating group that is good enough for the formation of O-glycosides may be used in the p r e p a r a t i o n of C-glycosides. This rational arises from the fact t h a t Cglycosidations via electrophilic substitution proceed t h r o u g h m e c h a n i s m s similar to those observed in the corresponding O-glycosidations. Additionally, since C-glycoside technology generally utilizes slightly m o r e s t r i n g e n t conditions, less reactive groups such as OAc and OTMS may also be used. One particular advantage to this chemistry is noted by the fact that heavy metal reagents are not required for the formation of C-glycosides. Furthermore, this chemistry is widely applicable to both benzyl and acetate protected sugars. One concern applicable to all aspects of organic chemistry is the question of the stereochemical outcome of reactions. In the case of C-glycosides, since no a n o m e r i c effect exists, the s t e r e o c h e m i s t r y is c o m p l e t e l y d i c t a t e d by stereoelectronic effects. Additionally, it should be noted that neighboring group participation is not a p r e d o m i n a n t factor. The major consequence of these observations is that axially (a) substituted C-glycosides are far more accessible than the corresponding equatorial (13)isomers.

2.2

Cyanation Reactions

Direct cyanations to sugars or sugar derivatives, represented in Figure 2.2.1, effect one carbon extensions. The resulting nitriles are then available for a number of further reactions including cycloadditions, hydrolyses to acids, and reduction to aminomethyl groups. Unfortunately, there are no stereospecific methods available for these reactions.

Figure 2.2.1

Example of Cyanation Reactions

~

X

~

CN

In addition to the formation of anomeric nitriles, similar chemistry allows for the formation of anomeric isocyanides. Requirements for these reactions include utilizing acetates, halides, and imidates as activating groups. Some Lewis acids used to effect these transformations include SnC14, TMSOTf, TMSCN, Et2A1CN, and HgCN. Additionally, both benzylated and acetylated sugars may be used.

Chapter 2 2.2.1

E1ectrophilic Substitutions

31

Cyanation Reactions on Activated Glycosides

Among the most basic of methods for the formation of C-cyanoglycosides involves the reaction of 1-O-acetoxyglycosides with TMSCN. Examples of this reaction, shown in Scheme 2.2.1,1,2 incorporate the use of both benzyl and acetyl protected sugars. Where benzylated sugars were used, the results provided a 1 : 1 ratio of anomers. However, when mannose pentaacetate was used, the only isolated c o m p o u n d possessed the a configuration. This observation can be explained by the involvement of the adjacent acetate group as illustrated in figure 2.2.2. The result of this intermediate is apparent in that the approach of nucleophiles is only possible from the a face. Scheme 2.2.1

C y a n a t i o n s of 1-O-Acetoxyglycosides

~,,,.OBn BnO.----~.~~ 0

~,...,.OBn TMSCN

B n O ~ C N 40% BnO +

~,,...OBn BnO

OAc

50% AcO'-'--k OAc

AcO'm-k OAc

TMSON

,,F ,.OEtt OAc Figure 2.2.2

BnO' CN

.,.co 51%

lq

CN

Cyanations with Acetate Participation

I AcO~~ O . ~ CN

In a d d i t i o n to a c e t a t e s as g l y c o s i d i c a c t i v a t i n g g r o u p s , trichloroacetimidates are useful. This activating group is advantageous in the formation of C-cyanoglycosides as d e m o n s t r a t e d by the n e a r exclusive

. . . .

32

Ch, apter, 2,,, E1ectrophj!~c Substitutions

formation of the e anomer coupled with an 87% isolated yield. This specific example, shown in Scheme 2.2.2 was reported by Schmidt, et al.,3 and utilized the a-trichloroacetimidate of 2,3,4,6-tri-O-benzyl glucose available from the reaction of trichloroacetonitrile with the protected glucose.

Scheme 2.2.2 .

.

.

.

.

.

.

.

Cyanations of Trichloroacetimidates .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

~.OBn

B~

TMSCN TMSOTf BnO CN

CCI3 Scheme 2.2.3 .

.

.

.

.

.

.

.

.

Cyanations of Fluoroglycosides .

.

.

.

.

.

.

.

.

.

.

~....OBn

.

~.-OBn

Bn

BF3"OEt2

F Scheme 2.2.4

BnOCN

Cyanations of Fluoroglycosides

~...~OBn

~10Bn

Boo--O, BnO-~~~

TMSCN

BF3*OEt~

BnO F

BnBO~

~...OBn BoO~ " ~ - ~ 0

B o O ~ C N

BnO CN Equivalents of BF3"OEt2

%~

0.05 1.0

30 100

BnO

13 70 0

%

As a final example of specific glycosidic activating groups utilized for the preparation of cyanoglycosides, fluoroglycosides are addressed. In the formation of C-glycosides, fluoride is a formidable activating groups. More examples utilizing this activating group are addressed later. For now, the reaction shown in Scheme 2.2.3 provides an excellent introductory example.

Chapter 2

Electrophilic Substitutions

33

Utilizing an anomeric mixture of fluoroglucosides, Nicolau, et al., 4 induced a reaction with TMSCN catalyzed by borontrifluoride etherate thus providing the desired cyanoglycosides. The reaction provided a 90% isolated yield containing a 3 : 1 ratio of anomers favoring the ~ configuration. This anomeric preference appears to be d e p e n d e n t on the a m o u n t of Lewis acid used in the reaction. Specifically, in an example r e p o r t e d by Araki, et al.,S shown in Scheme 2.2.4, 0.05 equivalents of borontrifluoride etherate effected a 3 : 7 ratio of anomers favoring the 13configuration. However, when 1.0 equivalent of the catalyst was used the only identified product possessed the ~ configuration. 2.2.2

Cyanation Reactions on Glycals

Where the direct use of glycosides is widely useful, glycals have provide more c o m p l i m e n t a r y and, in m a n y cases, more stereoselective results. For example, as shown in Scheme 2.2.5, Grynkiewicz, et a1.,6 converted tri-O-acetyl glucal to the illustrated cyanoglycoside. The reaction proceeded in a 79% yield with only one p r o m i n e n t isomer. In a similar reaction, shown in Scheme 2.2.6, Nicolau, et aL, 7 accomplished a stereoselecrive cyanation reaction beginning with a 1-methyl substituted glycal. This reaction proceeded in an 82% yield with an additional 11% accounted for in the isolation of the corresponding isocyanide. S c h e m e 2.2.5

C y a n a t i o n s of Glycals

OAc

OAc TMSCN

Ac

BF3~

"

O.~.,,,,~CN

AcO~,,'' 79%

OAc

Scheme 2.2.6

Cyanations of Glycals OAc

OAc

~ I Ac OAc

CN

TMSCN ,,,.,..--

TiCI4

AcO\,,,'' 82%

Chapter 2

34

Scheme 2.2.7

E1ectrophilic Substitutions

A r y l s u l f o n i u m Glycals

OBn

OBn

OBn ,,CI

~'

p-TolSCI

SAr

OBn

BnO~""y

"'q/+Ar

.,,~xS

,.

[Bn(

OBn

BnO ~ O ~ . . TMSCN 88% "~

O SnCI4

Bn

BnO\~""

-

OBn

_

CN > 19 : 1, one pot procedure works well with enol ethers

""/SAr OBn

In one final example involving glycals, arylsulfonium compounds are shown to be useful intermediates. As illustrated in Scheme 2.2.7, Smolyadova, et al.,8 formed arylsulfonium compounds on treatment of glycals with p-toluene chlorosulfide. The addition proceeded stereoselectively allowing for an SN2 ring opening of the sulfonium ring yielding a C-l-cyano-2-arylsulfide glycoside in 88% yield. The stereochemical outcome resulted in a 19 : 1 bias towards the isomer. 2.2.3

Cyanation Reactions on Activated Furanosides

Scheme 2.2.8

Cyanations of Furanoses OBz

OBz

~

Until now, only the chemistry regarding the addition of TMSCN to pyranose sugars has been discussed. Such chemistry is, however, easily applicable to the corresponding furanose forms. These reactions have been demonstrated with benzoyl protected furanoses catalyzed by borontrifluoride etherate (Scheme 2.2.8) 2 and with benzyl protected sugars catalyzed by trityl perchlorate (Scheme 2.2.9).9 In this second example, the anomeric ratio was shown to be solvent dependent with the a isomer favored by 93% when ether

Chapter 2

E1ectrophilic Substitutions

35

was used. Dimethoxyethane, on the other hand, allowed 37% of the product mixture to obtain the ~ configuration. As with acetoxy furanosides, reactions with trimethylsilyl cyanide have also been applied to fluoro furanosides. These reactions, illustrated in Scheme 2.2.10,5 unlike those mentioned above, produced high yields of 1 : 1 anomeric ratios even when run at -78~

Cyanations of Furanoses

Scheme 2.2.9

o oAc

OBn

OBn TMSCN

.---

~ , ~ C N

TrCIO4 BnO

BnO"~'"

OBn

;~"OBn

Solvent

Yield (%)

od13

Dimethoxyethane

97

63/37

Diethyl Ether

93

93/7

Cyanations of Furanoses

Scheme 2.2.10 OBn

OBn O

F

TMSCN ~ BF3,OEt2

CN (::z " 13= 1 "1

,,,,__

BnO"~""

2.2.4

;~'OBn

-78"C 90%

.e" BnO"~

"'~'OBn

Cyanation Reactions with Metallocyanide Reagents

TMSCN is not the only reagent useful for the formation of cyanoglycosides. Complimentary and, perhaps, equally i m p o r t a n t is the use of a l u m i n u m reagents. As applied to pyranose sugars, Grierson, et al.,lO demonstrated that the stereochemical outcome of the cyanation reaction with diethylaluminum cyanide was temperature dependent. Thus, as shown in Scheme 2.2.11, at room temperature, a mixture of a and ~ isomers were formed while, at reflux, the predominant isomer possessed the a configuration. The use of aluminum reagents is also applicable to fluoroglycosides as demonstrated by the example shown in Scheme 2.2.12. Nicolau, et el., 4 added d i m e t h y l a l u m i n u m cyanide to the illustrated fluoroglucoside. When

Chapter 2

36

ElectrophilicSubstitutions

borontrifluoride etherate was used t o catalyze the reaction, a 96% yield was obtained with a 10 19 ratio of anomers favoring the ~ configuration. Scheme 2.2.11

Glycal Cyanations with Et2A1CN

OAc

OAc

OAc .,,,~CN

Et2AICN ,._ r.t. 92% p._

AcOrn'" y

AcO~~ ,"',

AcOrn" 60"40

OAc OAc

OAc Et2AICN reflux

O.).,,,~C N ,..._

AcOrn,'"

Ac OAc Fluoroglycoside Cyanations with Me2A1CN

Scheme 2.2.12

BnO

~OBn

~..--OBn O

Me2AICN,._

BnO~~BnOO

BF3-OEt2

BnO~ CN

F

Fluoroglycoside Cyanations with Et2A1CN

Scheme 2.2.13

0~0

o o FNc o O CN

.,,~ F Et2AICN

+

54%

7

"

3

Chapter 2 Scheme 2.2.14

Electrophilic Substitutions

37

Fluoroglycoside Cyanations with Et2A1CN

O

O

7r

FEt2AICN

O

~176

84%

9

~176 :

1

Regarding the use of a l u m i n u m r e a g e n t s in the t r a n s f o r m a t i o n of f l u o r o g l y c o s i d e s to c y a n o g l y c o s i d e s , Drew, et a/., 11 d e m o n s t r a t e d the compatibility of acetonide protecting groups with this technology. As shown in Scheme 2.2.13, utilizing d i e t h y l a l u m i n u m cyanide, the bis-acetonide of the i l l u s t r a t e d a - f l u o r o m a n n o s i d e was c o n v e r t e d to a 7 : 3 m i x t u r e of the ~isocyanoglycoside a n d the ~-cyanoglycoside, respectively. F u r t h e r m o r e , as shown in Scheme 2.2.14, similar results were o b s e r v e d utilizing f u r a n o s e analogs. Mercuric Cyanide Cyanoglycosidations

S c h e m e 2.2.15

~... OAc

Aco--'x-o AcO ~

Br NPhth

~... OAc

. lc.l

%O

c. NPhth

The p r e v i o u s two e x a m p l e s are useful if the d e s i r e is to f o r m isocyanoglycosides. With respect to the formation of cyanoglycosides, the yields are poor; however, if no other m e t h o d s apply, these examples are d e e m e d useful. Another low yielding reaction which deserves mention is the conversion of bromoglycosides to cyanoglycosides via the in situ formation of mercuric cyanide. 12 The reaction, shown in Scheme 2.2.15, proceeded in only a 12% yield but, clue to the ease of f o r m a t i o n of bromoglycosides, p r o v i d e s a u n i q u e addition to the available methodology.

Chapter 2

38

2.2.5

E1ectrophilic Substitutions

Other Cyana tion Reactions

Scheme 2.2.16

Vinyligous Lactone Cyanations with Acetone Cyanohydrin

~S) AcO" O~

~C-'~CN.~ I ~S)'"r iPraNEt [AcO" O~ t1,,,,.... .,,,CN

NaBH4

OH 64% Scheme 2.2.17

~~O ~.,,~CN

+

AcO

CeCl3

1 j

AcO" ~" OH 15% n

Vinyligous Lactone Cyanations with Acetone Cyanohydrin

OAc

OAc

m

~

AcOrn,'" O

N

I•

r

iPr2NEt

O..~CN

Ac(

O

OAc

ON+

NaBH4

OAc

,,..._

CeCI3

AcO~,~," OH 60%

AcO~,,'' _ OH 20%

C-Cyanoglycosides are accessible from a number of starting materials other than glycosides and glycals. In concluding this section, the formation of cyanoglycosides from vinyligous lactones is explored. As shown in Scheme 2.2.16, Tatsuta, et a1.,13 formed 2-deoxy cyanoglycosides utilizing acetone

Chapter 2

Electrophilic Substitutions

39

cyanohydrin and Hiinig's base. Following hydride reduction of the resulting ketone, a mixture of the 3-hydroxy isomers were isolated. As illustrated by comparing the results shown in Scheme 2.2.16 with those illustrated in Scheme 2.2.17, the stereochemistry of the initial cyanation is dependent upon the stereochemistry of the starting material. Furthermore, the formation of the opposite 3-hydroxy configurations following hydride reduction is noted. Cyanoglycoside Transforma Lions

2.2.6

Hydride Reduction of Cyanoglycosides

Scheme 2.2.18

~.-OBn

~...OBn

LiAIH4 v

BnO~

CH2NH2

CN C-Glycosidic Acids and Amides from Nitriles

Scheme 2.2.19

OAc

OAc

I"/O~.. CN AcO~" y

TiCI4/AcOH

~/O

~ . . GONH2

AcO~" y

"'/OAc OAc

""'/OAc OAc

OH

NaOH

~"O ~.. CO2H

,,,,..--

HO~" y

""//OH OH

With the variety of methods available for the p r e p a r a t i o n of cyanoglycosides, a brief discussion of the versatility of these compound is warranted. To begin, as shown in Scheme 2.2.18, cyanoglycosides are easily reduced to the corresponding aminomethylglycosides on treatment with lithium

Chapter 2

40

Electrophilic Substitutions

a l u m i n u m hydride. 1 This reaction is effected without epimerization a t the glycosidic position.

Scheme 2.2.20

Diazoketones f r o m Cyanoglycosides

~.OAc

OH

HBr/AcOH p._

CN

H

CONH2 OH

OAc

~NO2/CH2CI2 OH

OH

1._..,CICO2Me/NMMH O ~ COCHN2 2. CH2N2 OH

CO2H OH

The hydrolysis of nitriles to amides is applicable to Gcyanoglycosides. As shown in Scheme 2.2.19, BeMiller, et al., 14 utilized titanium tetrachloride in acetic acid to effect the conversion of a peracetylated C-cyanogalactoside to its corresponding primary amide. This transformation was effected in an 80% yield. Furthermore, base hydrolysis of the nitrile provides a clean conversion to the carboxylic acid.iS Thus through the methods already m e n t i o n e d , extensions with standard organic techniques allow the formation of a wide variety of useful functional groups. Illustrating the versatility of C-cyanoglycoside nitrile derivatives, Myers, et al., 15 formed a diazoketone from the peracetylated C-cyanoglucoside shown. The reaction sequence, illustrated in Scheme 2.2.20, involved the initial hydrolysis of the nitrile to the corresponding primary amide. Subsequent hydrolysis afforded the carboxylic acid. On conversion of the acid to a mixed carbonic a n h y d r i d e followed by t r e a t m e n t with diazomethane, the desired diazoketone was obtained. Among the most useful of synthetic transformation available to nitriles is the ability to form unnatural amino acids. An early example of the application of this technology to the formation of C-glycosyl amino acids was reported by Igolen, et al. 16 As shown in Scheme 2.2.21, the cyanofuranoside was converted to the c o r r e s p o n d i n g a l d e h y d e t h r o u g h initial f o r m a t i o n of an N,N'd i p h e n y l e t h y l e n e d i a m i n e 1 7 , 1 8 followed by acid hydrolysis. Utilizing S-~methylbenzylamine, benzoic acid, and tert-butyl isocyanate, application of the Ugi c o n d e n s a t i o n l9 afforded the easily separable diastereomeric mixture, shown. Completion of the synthesis was then applied to the s e p a r a t e d diastereomers via debenzylation on treatment with formic acid followed by acid hydrolysis of the resulting amides.

Chapter 2 Scheme 2.2.21

~

Electrophilic Substitutions

41

C-Glycosyl Amino Acids OTol

OTol

Ox-,~CN 1. PhHN~ N H P h 2. Dowex50 (H+)

,,..

TolO

~ ~ 'cH~ To,d Benzoic Acid tert-Butyl Isocyanate S-~-Methylbenzylamine

Chromatography

Ph

~

OTol

~

NmCOPh

OTol

CONHtBu

Told

N---COPh

..,,, CONHtBu

TolO

11" Conc. FormicAcid

1. Conc. FormicAcid 2. 6N HCI OTol

NH 2 /~il~

2. 6N HCI OTol

CO2H

NH 2 / ~ J " , , = l CO2H

# To iO,~"

Figure 2.2.3

TolO

C-Glycosidic Heterocycles f r o m Nitriles

O. cN

OCH2R'

N H Bz p-Tol H CMe 2

Many Heterocyclic Compounds

R'

Heterocycles

H Bz p-Tol Bz PNB

Triazoles Xanthines Benzoxazoles

Chapter 2

42

Electrophilic Substitutions

As a final tribute to the versatility of cyanoglycosides, Poonian, et al., 2o and E1 Khadem, et al., 21 demonstrated that a wide variety of heterocycles may be derived from these compounds. Particularly interesting is the variety of compatible protecting groups including benzoyl, p-nitrobenzoyl, and acetonides. These observations are summarized in Figure 2.2.3 and the reader is referred to the original text for structural and experimental details.

2.3

Alkylation, Allenylation, Allylation and Alkynation Reactions

Concerning C-glycoside chemistry, in general, alkylation, allenylation, allylation, and alkynation reactions, generally illustrated in Figure 2.3.1, are among the most useful methods for preparative scales. Furthermore, they tend to yield the most valuable synthetic intermediates in that different functional groups of various lengths are easily obtained. As for the carbohydrate starting materials, many different glycosidic activating groups are useful in conjunction with a variety of Lewis acids. These reactions proceed well in many solvents including acetonitrile, nitromethane, and dichloromethane. Finally, b o t h benzylated and acetylated sugars may be used and the p r e d o m i n a n t products bear the a configuration.

Figure 2.3.1

~.~.X

~~,,~R

Examples of Alkylations, etc.

D,

R = alkyl, allyl, allenyl, alkynyl

2.3.1

Use of Activated Glycosides and Anionic Nucleophiles

As early as 1974, Hanessian, et al., 22 d e m o n s t r a t e d the use of anion chemistry in the preparation of C-glycosides. As shown in Scheme 2.3.1, abromo-tetra-O-acetyl-D-glucose was treated with the anions of diethylmalonate and dibenzylmalonate yielding two distinct C-glycosides. In the case of the dibenzyl analog, debenzylation followed by t r e a t m e n t with the Meerwein reagent gave a p r o d u c t identical to that formed from d i e t h y l m a l o n a t e . Furthermore, clecarboxylation of the diacid gave the corresponding carboxylic acid which, when subjected to a modified Hunclsdiecker reaction23 yielded the illustrated [~-bromopyranoside. Subsequent treatment of this bromide with sodium acetate in dimethylformamide gave the known ~-acetoxymethyl-Cglycoside thus demonstrating the accessibility of B anomers. One additional

Chapter 2

Electrophilic Substitutions

43

reaction d e m o n s t r a t i n g the feasibility of f u r t h e r functionalizing these Cglycosides i n v o l v e d the a b r o m i n a t i o n of the p r e v i o u s l y d e s c r i b e d monocarboxylic acid.

Scheme 2.3.1

C-Glycosides via Anionic Nucleophiles

~..-OAc Aco O, AcO~ AcOBr

CH2(CO2Et)2 Nail

I

CH2(CO2Bn)2 NaH

I

EtO3+BF4"

~..OAc CH(CO2Bn)2 Pd/C H2

ACOc~ AcO

~.....OAc A c O . - - ~ . ~ , , , , ~ Br AcO I aOAc DMF

~...-OAc

C~ AcO

2.3.2

~...OAc AcO..---k-..~.~O AcO.-~~~~ CH(CO2Et)2 AcO

X.--OAc

AcO---~-~O AcO~~~,-.AcO

CH(GO2H)2

1

~.....OAc A c O ~ c o 2 H AcO SOCI2,Br2 MeOH

......OAc AcO~O\ I~r A c O ~ c o 2 H

AcO

Use o f Activated Glycosides and Cuprates

Similar C-glycosidations are available via cuprate chemistry. For example, as shown in Scheme 2.3.2, Bihovsky, et ai.,24 utilized a variety of cuprates in the p r e p a r a t i o n of a-C-methylglycosides. The yields were relatively poor when acetate protecting groups were used. However, substantial i m p r o v e m e n t s in the yields were observed with methyl and benzyl protecting groups. In all cases, the a anomer was favored in ratios as high as 20 : 1. Additional examples of the applicability of o r g a n o c u p r a t e s to the preparation of C-glycosides were reported by Bellosta, et al.25 His work, shown in Scheme 2.3.3, illustrated the selective formation of both a and ~ anomers

Chapter 2

44

Electrophilic Substitutions

through the appropriate epoxides. Furthermore, an explanation of the regioselectivity of this reaction was addressed through the stereoelectronic interactions represented in Figure 2.3.2. In light of the promise demonstrated by this work, the difficulty in obtaining the required 1,2-epoxysugars is noted. Scheme 2.3.2

C-Glycosidations via Cuprate Nucleophiles

OR

OR ( ).

,,Me

~,Br

Me2CuLi

""OR

R

RO,~..~..,,,,,O R OR

OR Me Bn Ac Scheme 2.3.3

(%)

Yield

R

46

4O 8

C-Glycosidations vta Cuprate Nucleophiles

v,-OAc

~.OAc

AC2c~~~O x

1. Organocuprate= A c O ~ O 2. Acetylation A c O ~ R O OAc R = Me 66% Me2CuLi R = Ph 23% Ph2CuLi ~ .OBn OAc ~.-OBn .

Me2CuLi Ph2CuLi

R = Me

90%

R = Ph

70%

R

In an earlier example of the applicability of cuprate chemistry to Cglycosidations, Bellosta, et ai.,26 stereospecifically prepared epoxides from protected glucals (Scheme 2.3.4). Unfortunately, as shown in the previous example, the use of acetate protecting groups instead of benzyl protecting

Chapter 2

Electrophilic Substitutions

groups generally resulted in lower yields. improved through the use of mixed cuprates.

Figure 2.3.2

45

These observations were not

Regioselectivity of Cuprate Additions to Sugar-Derived Epoxides

A B

B' \

H

O ] CH2OAc H

C.H2OAc

.

o

OAc

C-Glycosidations via Cuprate Nucleophiles

Scheme 2.3.4

OAc

OAc

(

1. Organocuprate 2. Acetylation

Ac

AcO"" y OAc

Me2CuLi MeCuCNLi Ph2CuLi

R=Me R=Me

R=Ph

OBn

65.5% 25% 25% OBn

O

,,,R

Organocuprate

Bn

2.3.3

oRAc

OAc

() O

Bn OBn

~)

Me2CuLi Ph2CuLi

R = Me

R = Ph

~OH OBn

90%

70%

Use of Activated Glycosides and Grignard Reagents

Complimentary to the use of cuprates, Grignard reagents have found a useful place in the technology surrounding C-glycosidations. As shown in Scheme 2.3.5, Shulman, et al., 27 utilized allyl and vinyl Grignard reagents to

Chapter 2

46

Electrophilic Substitutions

give ~-C-glycosides in modest yields. Subsequent epoxidation of these products provided potential glucosidase inhibitors. In a later report, Hanessian, et ai.,28 confirmed the above results and postulated the intermediate epoxide, shown in Scheme 2.3.6, as an explanation of the stereoselectivity of this chemistry.

Scheme 2.3.5

C-Glycosidations via Grignard Reagents

~..OAc

~.....OAc 1. ExcessAllylorVinyl magnesium bromide A O A O c O ~ _ _ ~ ~ 2. Acetylation

ACOc~ AcO Br

R = Allyl or Vinyl > 40% yield

AcO

~...OAc

COc

Glucosidase Inhibitor

AcO

Scheme 2.3.6

C-Glycosidations via Grignard Reagents

~...OBn gngO~

~...OBn Ally,orVinyl BnBO~ magnesiumbromide~

R

AcO 13r

R = Allyl or Vinyl > 81% yield

HO

F oBn] /

]

Scheme 2.3.7

C-Glycosidations via Grignard Reagents

OBn

M e O ~

0.,~..,,,,~

OMe

OBn

~ MgBr

.....

ZnCl2 Bn

BnO"'

OBn

OBn

Chapter 2

E1ectrophilic Substitutions

47

Grignard reagents are useful nucleophiles capable of effecting reactions on compounds stable to other types of nucleophiles. For example, the alkynation reaction shown in Scheme 2.3.7 proceeded in a 70% yield with complete retention of the a configuration.29 However, when lithium and organocopper reagents were used, no reaction was observed. An additional feature of this reaction is the demonstration of the utility of glycosidic esters as viable leaving groups in the formation of C-glycosides via nucleophilic substitutions.

Scheme 2.3.8

C-Glycosidations via Grignard Reagents

R.__~O"'h/sO2Ph

O

R'MgBr ,.

R' n = 0, 1

R.___ ~

ZnBr2

tC H

OAc

OAc O.

,,,~SO2Ph

PhMgBr

O

ZnBr2

Ac

Ph

Ac

With the incorporation of new leaving groups in C-glycoside methodology, the versatility of the b e n z e n e s u l p h o n y l group m u s t be m e n t i o n e d . As illustrated in Scheme 2.3.8, a variety of nucleophiles may be coupled with both furanose and pyranose compounds.a0 In all cases, the yields exceed 70%. This observation, coupled with the ready availability of glycosidic sulphones, 31-34 illustrates the general usefulness of this technology.

2.3.4

Use of Activated Glycosides and Organozinc Reagents

Scheme 2.3.9

C-Glycosidations via

Organozinc Reagents

AcO'~~.,, O"~ BrZnCa2co2tBu,.. AcO~k~O~ ....,~r cO2tBu (z:13=2:1 A~

T

TMSOTf -

AoO'~''" '''~

OAc

The previous two examples are the result of zinc modified Grignard reagents. However, the direct use of organozinc compounds is also known in

Chapter 2

48

Electrophilic Substitutions

the field of C-glycosidations. As shown in Scheme 2.3.9, Orsini, et al.,3s reacted acetylated glycals with tert-butoxycarbonylmethylzinc bromide. In the case of tri-O-acetyl glucal, the reaction gave a 49% yield with a 2 19 ratio favoring the anomer.

Scheme 2.3.10

C-Glycosidations via Organozinc Reagents

.,,,,

TBDMS

Et2Zn, CH212 TBDMSO

OBn

(z'~=94"6

OBn ( )~.

SPh

(

Et2Zn,CH212 Bn

/

o~'~ = 72"28

'"*OBn

Bn

''"0 Bn

OBn

OBn

OAc

OAc ()

Ac

SPh "'/OAc

OAc

(

Me2Zn,CH212= Ac

OAc

Although the use of organozinc reagents resembling Grignard reagents has been fruitful, the use of simpler reagents such as diethylzinc has, in many cases, effected higher yields. For example, as shown in Scheme 2.3.10, Kozikowski, et al., 36 formed C-ethylglycosides from thioglycosides. In the cases of t-lyxose and D-glucose derivatives, the p r e d o m i n a n t p r o d u c t possessed the a configuration presumably resulting from an axial addition. An interesting observation was noted in that all reactions proceeded well when silyl groups, ketals, and benzyl protecting groups were used. However, the use of acetate groups facilitated the formation of the illustrated 1 , 2 - O - i s o p r o p y l i d e n e derivative on treatment with dimethylzinc. The mechanism postulated for the f o r m a t i o n of this c o m p o u n d is shown in Scheme 2.3.11 a n d involves displacement of the sulfide by the neighboring acetate forming a stabilized

Chapter 2

Electrophilic Substitutions

49

carbocation. Subsequent transfer of a methyl group from dimethylzinc gives the observed product. C-Glycosidations via Organozinc Reagents

Scheme 2.3.11

AcO--7 AcO-~7

AcO-~7

AcO--~,O

~c~oC~

Me2Zn SPh CH212-AcOQ ~ ~ r '

AoO-7"-J~P Me2ZnAcO

AcO

2.3.5

Use of Modified Sugars and Anionic Nucleophiles

Scheme 2.3.12

C-Glycosidations via Organolithium Reagents

OMOM

OMOM

/O-.~OBnOOH2L, ~~/. 60% ~ ~o~o ~-- ~ ~o~o~-: Scheme 2.3.13

OH

oO' ~~.

1. H+

~-

OBn2"He'Pd/C

HO~''

~

.......

1. LiC-CR 2. 0.1NHCI

OTs NaOMe

..5/--d......

.

, OH

C-Glycosidations via Organolithium Reagents

0//" / O ~

OH

or

~0~

0/''' ......

"~F

Chapter 2

50

E1ectrophilic Substitutions

With all the anionic nucleophiles mentioned thus far as reagents useful for the preparation of C-glycosides, organolithium compounds have yet to be discussed. While these compounds can be used similarly to other nucleophiles, some of their most interesting chemistry is the result of reactions with modified carbohydrates such as the ribose-derived lactone shown in Scheme 2.3.12. Treatment of this compound with benzyloxymethyllithium gave the alkylated hemiacetal. Furthermore, after removal of the MOM groups, the c o m p o u n d spontaneously rearranged to the illustrated pyranose form.37 Although the isolated product is a ketose sugar, it bears some properties in common with Cglycosides and, as will be discussed later, can be converted to a true C-glycoside under reductive conditions. C-Glycosidations via

Scheme 2.3.14

Organogrignard Reagents

~....OBn

~.....OBn Allylmagnesium . bromide

BnO Triethylsilane BF3oOEt2, CH3CN 76%, 10:1

BnO B

~1OBn O n ~ BnO

+

OH

~..-OBn BnO"-'k' ' - ~ 0 BnO ~ ~ . ~ . ~ , . ~ BnO

A ~C02E t

Another excellent example demonstrating the utility of organolithium compounds in the formation of C-glycosides from modified carbohydrates was reported by Koll, et al.38 This study, shown in Scheme 2.3.13, involves the addition of a lithium acetylide to a C-glycosyl oxetane. The result was the extension of a pre-existing C-glycosyl side chain. A final example regarding the C-glycosidation of modified sugars is shown in Scheme 2.3.14 and involves reaction of the illustrated lactone with allylmagnesium bromide. The r e s u l t i n g alcohol was s u b s e q u e n t l y deoxygenated utilizing triethylsilane in the presence of a Lewis acid thus giving a 76% yield of the illustrated [3-anomer.39 It should be noted that by applying this methodology to the hemiacetals shown in Scheme 2.3.12 true C-glycosides can be obtained.

2.3.6

Lewis Acid Mediated Couplings with Unactivated 01efins

Anionic nucleophiles provide valuable and versatile routes to the preparation of C-glycosides. However, the most extensively used technologies

Chapter 2

Electrophilic Substitutions

51

lie within the chemistry of Lewis acid mediated reactions of carbohydrates with u n s a t u r a t e d h y d r o c a r b o n s and derivatives thereof. In the next series of examples, reactions of sugars and sugar derivatives with olefins, silyl olefins, stannyl olefins, and aluminum olefins are discussed. C-Glycosidations with 1-Hexene

Scheme 2.3.15

OAc

OAc SnCI4 1 -Hexene

75%

BnO

OAc

CI

BnO

Scheme 2.3.16

OBn

BnO

OBn

OBn

C-Glycosidations with Olefins

OAc

OAc SnCI4

+

....

..,,,,,~ ~ O H

OH

AcO""" OAc

AcO~'''

79%

OAc

AcO"" OAc

85% O

An early example of the reaction of protected furanoses with olefins is shown in Scheme 2.3.15. In this study, Cupps, et aL, 4o utilized tin tetrachloride

Electrophilic Substitutions

Chapter 2

52

to effect the formation of a 75% yield of the illustrated C-glycoside. This reaction showed little anomeric selectivity. Additionally, the chloride, shown, was identified as a b y p r o d u c t arrising from the i n t e r m e d i a t e carbocation.

C-Glycosidations with Olefins

Scheme 2.3.17

\

2--o BnO'"'"
BnO

BnO

OBn _-

r--o BnO.,,'.~

OBn

~

+

-

BnO,,,"

BnO

BnO

~j-- CH2CBH5

C-Glycosidations with Olefins

Scheme 2.3.18

BnO

+ ~,,.._~

BnO

0 /OAc

BnO

d

TMSOTf

~

BnO

d

OBn

BnO

~/OTf

BnO

/ d

BnO

BnO

.,,,111

BnO

BnO

%

BnO

/.,,,,hi /

4

OBn

OBn

BnO

~

OBn

TfO"

Chapter 2

Electrophilic Substitutions

53

Where the previous reaction involved the use of an u n a c t i v a t e d olefin, this was apparently not the source of the lack of stereochemical induction. This is illustrated by work r e p o r t e d by Herscovici, et a1.,41,42 shown in Scheme 2.3.16, where several unactivated olefins were successfully used to produce aC-glycosides in good to excellent yields.

Table 2.3.1 Entry

A

C-Glycosidations with Olefins

Sugar

Olefin

kk

BnO....7 BnO

/

0

BnO~oAc

Product

Yield

BnO~ 0 TMSOTf

BnOl'"" k

) ....,,,

74%

Bn0#' ~C)'~

BnOBnO BnO~

Lewis Acid

BnO--~__O ) .... "'l

TMSOTf ~

)

BnO~._ BnO 7

TMSOTf

~nO--~

~/O~,

Bn

/

76%

21%

c

D

OBn'••

OAc Bn

)

OBn

~ OBn

!

71%

TMSOTf

or BF3"OEt2

a..

~n~

~O~."

!

OAc Bn

C;

SnC14

BnO.,,,.~-O

78%

In a final example demonstrating the utility of unfunctionalized olefins, Levy, et al., 43 r e p o r t e d a novel a d a p t a t i o n in which the formed C-glycoside cyclizes to an adjacent oxygen with loss of a benzyl group. As shown in Scheme 2.3.17, 1-O-acetyl-2,3,4-tri-O-benzyl-L-fucose was treated with isobutylene and an excess of TMSOTf giving the illustrated fused ring C-glycoside. This reaction p r o c e e d e d in >70% yield in b o t h m e t h y l e n e chloride a n d acetonitrile. Additionally, b o r o n t r i f l u o r i d e e t h e r a t e could also be used. The p r o p o s e d mechanism, shown in Scheme 2.3.17, involves the initial elimination of the

Chapter 2

54

E1ectrophilic Substitutions

acetate to form an oxonium ion. This species then undergoes a Prins-type 44 reaction with the olefin giving a tertiary carbocation. Finally, s p o n t a n e o u s c y c l i z a t i o n with loss of a b e n z y l cation gives the o b s e r v e d p r o d u c t . Interestingly, although cyclization relies on the loss of a benzyl group, attempts to induce the formation of acyclic C-glycosides failed a n d no reaction was observed utilizing acetate protecting groups. In exploring the generality of this reaction, the 1-O-acetyl-tetra-O-benzyl analogs of D-glucose, D-galactose, and D-mannose, were studied. In all three cases, borontrifluoride etherate was found to be too weak a Lewis acid to effect this reaction and TMSOTf was required. The reactions of these compounds with TMSOTf and isobutylene are summarized in Table 2.3.1. An additional example with L-fucose and methylene cyclohexane is also included therein. When comparing the data presented in Table 2.3.1, the anomalous results observed in the case of D-mannose (Entry C) can be explained as shown in Scheme 2.3.18. The initial cz-C-glycosidation gives a tertiary carbocation. The anomeric preference for the addition places the newly formed b o n d trans to the 2-benzyloxy group. The high strain associated with a 6-5 trans-fused ring system disfavors attack by the oxygen of the neighboring group allowing the triflate anion to add to the tertiary carbocation. As cis-fused t e t r a h y d r o f u r a n - t e t r a h y d r o p y r a n ring systems are found in the halichrondrins, 4s the herbicidins, 46-48 and octosyl acid, 49 this simple onepot p r e p a r a t i o n d e m o n s t r a t e s unique advantages over previous a p p r o a c h e s utilized to target these classes of compounds.S0, sl

2.3.7

Lewis Acid Mediated Couplings of Glycosides and Silanes

While the use of u n p r o t e c t e d olefins has p r o v e n f r u i t f u l in the p r e p a r a t i o n of C-glycosides, the most commonly utilized technology involves the use of silyl c o m p o u n d s . Reactions involving the coupling of s u g a r derivatives with allyl and acetylenic silanes has been initiated with a n u m b e r of Lewis acids as well as a wide variety of glycosidic activating groups. The first of these to be addressed is the acetate activating group. An early r e p o r t demonstrating the generaliW of Lewis acid m e d i a t e d Cglycosidations with allylsilanes was reported by Giannis, et ai.,52 and is shown in Scheme 2.3.19. In this study, allylations were catalyzed by borontrifluoride etherate utilizing either dichloroethane or acetonitrile as solvents. As observed, no stereoselectivity was noted with dichloroethane. However, the more polar acetonitrile, capable of coordinating to intermediate oxonium ions, i n d u c e d fairly high selectivity. An additional reaction d e m o n s t r a t e d the applicabiliW of this technology to disaccharides. In a later report, similar observations were noted in the reaction of penta-O-acetyl-D-galactose with allyltrimethylsilane in n i t r o m e t h a n e utilizing b o r o n t r i f l u o r i d e e t h e r a t e as the catalyst (Scheme 2.3.20). 14

Chapter 2

Electrophilic Substitutions

55

C-Glycosidations with A11ylsilanes

Scheme 2.3.19

~.....OAc

~OAc ~ ACOco OAc OAc

COc~

BF3.OE,52equ, , v3.equiv~ Allyltrimethylsilane,

AcO L oc'p=l "1 o~'~=95"5 AcO ~.OAc

72% 81%

Dichloroethane,50~C, 6 hr. Acetonitrile, 4~C, 48 hrs.

"~

AcO. ~ O A c A c O ~

A c O ~ AcO [ 78% o~'~=1"1 "~] 80% o~" 13=95"5 jOAc OAc

OAc OAc Dichloroethane,50~C, 6 hr. Acetonitrile, 4~C, 48 hrs.

CO~co-

~OAc OAc

o-- 3t o Ac

68%

Acetonitrile, 4~C, 48 hrs.

OAc

~..OAc

AcO'~~~1'~O~

~(D

I ~..,,A '_ OAc u c

O

A c O ~

OAc ....

UAc

AoO~~~O

AcO Acetonitrile, 20~C, 48 hrs.

A)c~

AcO L

6Ac~OAc 55%

o~" 13= 99" 1

OAc

OAc (

)T

OAc Allyltrimethylsilane BF3*OEt2,CH3NO2 /'"'~OAc Ac

OAc

~]

~......OAc

C-Glycosidations with Allylsilanes

Scheme 2.3.20

Ac

o~'13=4"1

( /

OAc

''"OAc

55%

"~

Chapter 2

56

Electrophific Substitutions

With respect to the related trifluoroaceoxy glycosides, comparable Cglycosidation results were observed. Additionally, as shown in Scheme 2.3.21, the reaction exhibited a similar preference for formation of a anomers.S3 Scheme 2.3.21

C-Glycosidations with Allylsilanes

~-OBn

~.OBn 1. Trifluoroacetic anhydride

BnOno~~Bn~ OH 2.

Allyltrimethylsilane 3. BF3,,OEt2

BnO [ 8s%

Scheme 2.3.22

OBn [~Oy

C-Glycosidations with Allylsilanes

OBn OAc

Allyltrimethylsilane,.~ TrCIO4

BnO"~"

Scheme 2.3.23

;:~'OBn

BnO OBn 90%,cx'~= 100"0

C-Glycosidations with Allylsilanes

TBDMSO

TBDMSO ~

Allyltrimethylsilane ~. ZnBr2, 86%

oXo ~"

With the usefulness of the chemistry described in the previous three schemes, it is important to note that similar reactions are applicable to furanose sugars. As shown in Scheme 2.3.22, Mukaiyama, et ai.,9 effected the illustrated r e a c t i o n b e t w e e n allyltrimethylsilane and an acetate activated ribose derivative. Utilizing trityl perchlorate as a catalyst, the reaction proceeded in 90% yield with total a selectivity. Concurrently, a similar reaction was reported with a 1 - m e t h y l - l - a c e t o x y furanoside.S4 This reaction, shown in Scheme 2.3.23, not only demonstrates that high stereoselectivity can be obtained with

Chapter 2

E1ectrophilic Substitutions

57

1-substituted sugars, it also illustrates the compatibility of acetonides and silyl ethers as protecting groups when zinc bromide is used as a Lewis acid. Scheme 2.3.24

C-Glycosidations with

~.-OBn

~..OBn

BnO~)pN B

Scheme 2.3.25

Allylsilanes

Allyltrimethylsilane BF3-OEt2, CH3CN 79%

(x'13=10"

BnO [ ~

1

C-Glycosidations with Allylsilanes

OPNB TMS~ BF3~

CH3CN j"

PNBO

O

PNBO

%.

84%

T M S ~ BF3*OEt2, CH3CN D,

O

PNBO

90%

With the current discussion of the acetate activating group used in the preparation of C-glycosides, the chemistry of 1-O-p-nitrobenzoyloxy glycosides deserves mention. Perhaps one of the earliest examples of the use of 1-O-p-nitrobenzoyloxy (PNB) glycosides as substrates for C-glycosidations was reported by Lewis, et al. 39 In the cited report, the PNB glycoside, shown in Scheme 2.3.24, was reacted with allyltrimethylsilane utilizing borontrifluoride etherate as a catalyst to yield the desired a-C-glycoside. This initial reaction, from its good yield and preference for the a anomer, demonstrated the utility of this activating group applied to pyranose sugars thus setting the stage for further exploration. Shortly after publication of the previous example, Acton, et al.,SS reported the reactions shown in Scheme 2.3.25. In this study, the high yielding Cglycosidations were utilized in the preparation of anthracycline C-glycosides via Diels-Alder methodology. In the examples reported, high a selectivity was achieved utilizing borontrifluoride etherate in acetonitrile.

Chapter 2

58

Electrophilic Substitutions

C-Glycosidations with Allylsilanes

S c h e m e 2.3.26

NO 2

OBn

OBn

(

T M S ~ ID

Bn( ()~~ ,.

Bn

BF3K]Et2, CH3CN

"OBn OBn

OBn O

O

O

45%

OBn IP

90~C, Toluene

Bn

~".,,,,,0 Bn ~.,~7OBn

Scheme 2.3.2 7

OBn

80%

C-Glycosidations with Allylsilanes NO 2

OBn

OAc

>-/.'' ~

TMS/[~j..

)

( "~ ....

D,

OAc

BF3-OEt2, CH3CN

Bn(

Bn

/ ~ " " 0 B0

/''OBn OBn

OBn NO2 OBn

OAc

74% ~'13=10"1

OBn

TMS..]~~/

(

BF3K)Et2, CH3CN Bn

~

OBn

~OB 0

Bn OBn

n 81% r 10"1

A similar reaction, reported by Martin, et al.,S6 is shown in Scheme 2.3.2 6. However, several differences are apparent in comparing this reaction to the earlier example. Initially, the fact that the previous example is applied to an amino sugar becomes obvious. However, the more important observation is the fact that the amino sugar is also a 2-deoxygenated sugar. The result is an

Cha.pte r 2

Electrophilic Substitutions

59

electron deficient sugar compared to the glucose analog shown in scheme 2.3.26. It is, in fact, this observation that may account for the somewhat lower yield reported for this analogous C-glycosidation. As with the previous example, a Diels-Alder reaction was used to further derivatize this C-glycoside. Scheme 2.3.28 .

.

.

.

.

.

.

.

.

.

OPNB

C-Glycosidations with P .r o p. a r.g y .l s i l a n e s . ~ O

O TMS

Bn

O

o

BF3.OEt2

BnO~

~'] """" y "'OBn OPMB OBn

Scheme 2.3.29

CH3CN o 10: 1,70%

BnO~ ' l ' ' ' * " ~ " " OPMB

y

'"~OBn OBn

C-Glycosidations with Allylsilanes

~1OBn L TMS~

B'B~ BnOJO.~NH

ZnCl2

~...-OBn ~-

BnBO~ BnO [

ccla Scheme , 2.3.30

C-Glycosidations with Allylsilanes . . . . . . . . . . . . . . . .

OBn

LcO/o

OBn

~'13=1o"1

/

~nO"" ~O~n R = Me, PNB

TMS~

OBn

/

OBn

TMSOTf or

BF3oOEt2

~nO"~' ~O~n > 90%,(x'13= 4" 1

In addition to extended allylsilanes, acetate substituted allylsilanes are useful reagents for C-glycosidations. As shown in Scheme 2.3.27, PNB activated glucose a n d m a n n o s e d e r i v a t i v e s were t r e a t e d w i t h 1-acetoxy-

Chapter 2

60

Electrophilic Substitutions

allyltrimethylsilane. 57 Utilizing borontrifluoride etherate as the catalyst, high yields of ~-C-glycosides were obtained. The use of these c o m p o u n d s is a p p a r e n t as hydrolysis of the acetate groups readily liberates a l d e h y d e s available for further elaboration. Where allyl groups are readily incorporated as C-glycosides, p r o p a r g y l groups are equally useful. As shown in Scheme 2.3.28, Babirad, et ai.,58 used propargyltrimethylsilane to produce the desired allene. The yield was reported at 70% with an anomeric ratio of 10 : 1 favoring the ~ anomer. Interestingly, when identical reaction conditions were applied to the ~ isomer of the starting C-disaccharide, no reaction was observed. These results were c o m p a r a b l e to results observed for corresponding reactions with allylsilanes d e m o n s t r a t i n g a useful v e r s a t i l i t y in the types of C-glycosidations a v a i l a b l e f r o m silyl compounds.

Scheme 2.3.31

OR L~O"~

C-Glycosidations with Allylsilanes

OR OMe

TMS~ SnCI4

RoI

RO~ :"~OR R = p-chlorobenzyl Scheme 2.3.32

OR L~O"~

78%, o~: [3= 1 : 1

C-Glycosidations with Allylsilanes

OMe

~~...SiMe2CI

OR L~O"~

SnCI4

I

RO~ ~'OH R = p-chlorobenzyl

Me2

OR

OR 58%

Ro"

OMe

Ro" 5

:

1

Chapter 2

Electrophilic Substitutions

61

Any discussion involving the preparation of C-glycosides from acetate and PNB a c t i v a t e d s u g a r s w o u l d not be c o m p l e t e w i t h o u t m e n t i o n of the electronically similar trichloroacetimidate activating group. As m e n t i o n e d in section 2.2, trichloroacetimidates are easily prepared on reaction of hemiacetals with trichloroacetonitrile. The resulting activating g r o u p is s u b s e q u e n t l y displaced by silyl activated nucleophiles u n d e r Lewis acid catalysis. As shown in Scheme 2.3.29, Hoffman, et ~.,3 exploited this chemistry in the preparation of C-glucosides utilizing allyltrimethylsilane

Scheme 2.3.33 OH

C-Glycosidations with Allylsilanes

~

OTMS

( ).

H

.,,,~OM e

"

( i..

,,~OM e

BSA ~ Silylation

"""OH

TMS

'"~OTMS

OH

OTMS OH

( ).

,,~R

EtsSiH/TMSOTf or TMSOTf/Allyltrimethylsilane

R = H or Allyl

""'OH

H OH

General Method for Many Sugars

Moving from the chemistry of esters as glycosidic activating groups, Om e t h y l g l y c o s i d e s have been shown to be extremely useful. As shown in Scheme 2.3.30, Nocotra, et al.,S9 utilized b o t h PNB activated a n d m e t h o x y a c t i v a t e d f u r a n o s i d e s as s u b s t r a t e s for C - g l y c o s i d a t i o n s . This s t u d y d e m o n s t r a t e d essentially identical results for both of these activating groups with yields exceeding 90% a n d a 4 : 1 p r e f e r e n c e for the ~ a n o m e r s . Furthermore, no change in the results were observed when alternating between trimethylsilyl triflate and borontrifluoride etherate as Lewis acid catalysts. Although the above results a p p e a r useful for the p r e p a r a t i o n of Cfuranosides, these reactions are not always this specific. As shown in Scheme 2.3.31, Martin, et al.,6o a t t e m p t e d a similar reaction with the simpler furanose shown. A l t h o u g h a g o o d yield was a c h i e v e d for this r e a c t i o n , the stereochemical outcome p r e s e n t e d a 1 : 1 mixture of anomers. However, as shown in Scheme 2.3.32, when intramolecular delivery of the allyl group was effected, the reaction yielded a 5 : 1 mixture favoring the ~ anomer. Thus, this approach is a potentially useful route to ~-C-glycosides.

Chapter 2

62

Electrophilic Substitutions

In a demonstration that unprotected sugars may be utilized as substrates for C-glycosidations, Bennek, et aL, 61 utilized BSA as an in situ silylating reagent in the p r e p a r a t i o n of C-pyranosides. Subsequent t r e a t m e n t with either triethylsilane or allyltrimethylsilane in the presence of TMSOTf gave either the deoxy sugar or the allyl glycoside shown in Scheme 2.3.8. This procedure, shown in Scheme 2.3.33, was shown to be a general method applicable to many sugars. Scheme 2.3.34

C-Glycosidations with Allylsilanes

~....OBn ~.....OBo

.I~T

BOOn~

TMSOTforTMSI~ BnOI~

> 90%

R = OMe, CI

BnO [ Y R ' = H, Br, Me

R'

Before changing to a discussion of halogens as glycosidic activating groups, a final example of the use of O-methylglycosides deserves mention. This specific example highlights the ability to prepare C-glycosides bearing vinyl halides in addition to simple and alkyl substituted olefinic substituents. 62 The cited publication reports applicability to a variety of sugars of which, glucose is shown in Scheme 2.3.34. These examples, like those heretofore mentioned proceed with high ~ selectivity. Furthermore, as a lead into the discussion of haloglycosides as C-glycosidation substrates, chloroglycosides were equally as effective in these reactions. Lewis Acid Mediated Couplings of Haloglycosides and Silanes

2.3.8

Scheme 2.3.35

C-Glycosidations with Allylsilanes

~...-OBn BnO~ O BnO~ BnO

TMS~

=

~...OBn BnO- ' ~ ~ " O\

BF3,OEt2

F

BnO

95%, (~: [3> 20 : 1 Haloglycosides, already discussed under cyanation reactions, are useful substrates for C-glycosidations utilizing both allylsilanes and silyl enol ethers.

Chapter 2

Electrophilic Substitutions

63

As shown in Scheme 2.3.35, Nicolau, et al., 4 utilize the fluoroglucoside shown and effected the formation of a variety of C-glycosides. The example shown proceeded in high yields with excellent stereoselectivity. Similar results, shown in Scheme 2.3.36, were observed by Araki, et al. 63 Scheme

2.3.36

C-Glycosidations with Allylsilanes

OBn ~~/O~F

TMS~

OBn ~,. O.,

.

BF3"OEt2

BnO,~-" ;~..OBn

2.3.9

Bn0~" "~,.0Bn 93%, o~:13= 100:0

Lewis Acid Mediated CoupBngs o f Nitroglycosides and Silanes

Scheme 2.3.37

C-Glycosidations with Allylsilanes

OBn ~][/O...,,,,\ X

TMS~

~.

OBn ~,~....O.~..,,,,,~ R

BF3*OEt2

BnO,~

BnO~" y

"q/N 3

OBn

"''/N3 OBn

Results

OMe OAc ONO 2

No Reaction Very

Slow,R = CH 2

4 0 % Yield, R = O after ozonolysis, ~ : 13 = 5 : 1

Presently, several classes of anomeric activating groups have been discussed. Additionally many more have been reported. However, no further discussions regarding the formation of alkyl, olefinic, or acetylenic Cglycosidations is planned except for the contents of Scheme 2.3.37. This scheme, presenting work reported by Bednarski, et at., 64 is intended to present a final activating group in comparison to some already discussed. As the three groups shown in this report increase in their electronegativities from methoxy to acetoxy to nitro, their reactivities also increase. This is advantageous as applied to the azidosugar shown. Similar results were observed utilizing propargyl trimethylsilane. The take-home lesson is that if C-glycosidations fail,

Chapter 2

64

Electrophilic Substitutions

changing to more electronegative anomeric activating groups may, in fact, allow the induction of otherwise difficult reactions.

Lewis Acid Mediated Couplings of G1ycals and Silanes

2.3.10

Anomeric activating groups provide useful means for the preparation of C-glycosides from naturally occurring sugars. However, glycals have been extremely useful substrates in their complimentarity to sugars. Additionally, they have been used to demonstrate versatility not directly available from other sugar derivatives. In a very nice example of the utility of allylsilanes and silylacetylenes in C-glycoside chemistry, Ichikawa, et al.,6s d e m o n s t r a t e d a preference for the a anomer in all cases. The results, shown in Scheme 2.3.38, included a demonstration that a characteristic nOe can be used to confirm the stereochemical outcome of the reaction with bis-trimethylsilylacetylene. Scheme

2.3.38

C-Glycosidations with Allylsilanes a n d Related C o m p o u n d s

OAc

OAc 69.7 Allyltrimethylsilane "BF3~ D

AcO~'"

~

(74.2)

O.)..,,,,,,,~-.~..~ 85%,0~'13= 96"4

Ac OAc

OAc

OAc BistrimethylsilylacetyleneTiCl4

AcO~""

/TMS O.) ......., ~ S

Ac OAc

Several Steps lID Oe ~

With the advent of glycal chemistry being incorporated into C-glycoside technology came a host of new compounds previously difficult to prepare. As shown in Scheme 2.3.39, this statement is supported by a report by Stutz, et a1.,66 in which a C-linked disaccharide was prepared by the direct coupling of an

Chapter

2

Electrophilic Substitutions

65

allylsilane modified sugar with a glycal. While this example is not intended to be representative of the state of C-disaccharide chemistry, it does illustrate an extreme regarding the usefulness of glycals. C - G l y c o s i d a t i o n s w i t h Allylsilanes

Scheme 2.3.39

TMS_

II

J~

O .,,,~OMe

"BnO~.,,,OBnACO,,,,,...

OAc

OBn

OMe

BF3,OEt2 AcO"" ~~

OAc

"'OBn

BnO~*~ OBn

Scheme 2.3.40

C - G l y c o s i d a t i o n s w i t h Allylsilanes

OAc

OAc

Nucleophile TiCI4

R

AcO"""

Ac

OAc Nucleophile

R

TMSCH2CH=CH2 TMSC8CCH3

Scheme 2.3.41

Yield (%)

CH2CH=CH2

75

C8CCH3

79

C - G l y c o s i d a t i o n s w i t h Allylsilanes

OAc OAc

()

"~ ~ Ac

Allyltrimethylsilane BF3,OEt2 OAc

OAc

75%

"

0

Chapter 2

66

Electrophilic Substitutions

As simple glycals are substrates for C-glycosidations, so are 1-substituted glycals. An example of C-glycosidations on substituted glycals was reported by Nicolau, et ai.,7 and is illustrated in Scheme 2.3.40. In this study, reactions with a l l y l t r i m e t h y l s i l a n e and m e t h y l t r i m e t h y l s i l y l a c e t y l e n e were explored. Utilizing titanium tetrachloride as the catalyst, yields in excess of 75% were obtained and the products exhibited the stereochemistry shown. As with 1-substituted glycals, 2-substituted glycals are known to be useful substrates for C-glycosidations. In these cases, the final products are enones. As shown in Scheme 2.3.41, Ferrier, eta]., 67 demonstrated the utility of these reactions by effecting the formation of a 75% yield of the product shown. The reaction proceeded utilizing borontrifluoride etherate as a catalyst and displayed a preference for the a anomer. The specific reaction was successfully used in the preparation of trichothecene-related compounds. Further examples of the utility of 2-acetoxyglycals as C-glycosidation substrates were reported by Tsukiyama, et al., 68 and are illustrated in Scheme 2.3.42. This study demonstrated the highly stereospecific high yielding nature of these reactions. Furthermore, the generality of these reactions was demonstrated in their application to a variety of silylated acetylenes.

Scheme 2.3.42

C-Glycosidations with Silylacetylenes

OAc

OAc .0

(

Ac

)"i ~

OAc

,,,,j.'I'M S

Bistrimethylsilylacetylene SnCI4, -78~

OAc

Unstable

OAc

..TMS

NaBH4/CeCI3

'"'OH

50%

Before leaving the subject of C-glycosidations utilizing s i l y l a t e d nucleophiles, the reaction described in Scheme 2.2.7 deserves revisiting. In this report, Smolyadova, et al.,8 formed arylsulfonium compounds on treatment of glycals with p-toluene chlorosulfide. These compounds were then treated with cyanating reagents to form C-cyanoglycosides. However, as shown in Scheme 2.3.43, a l l y l t r i m e t h y l s i l a n e was also reacted with these a r y l s u l f o n i u m compounds allowing the formation of C-allylglycosides with high [5 selectivity. Interestingly, when acetate protecting groups were used, a substantial loss of stereoselectivity was observed with a minor decrease in the yield.

Chapter 2

Electrophilic Substitutions

67

A l l y l a t i o n s via A r y l s u l f i d e s

S c h e m e 2.3.43

m

OBn

OBn

OBn

O p-TolSCI

SnCI4

BnO""'

BnO""' y OBn

+ SAr

Bn

-"SAr

OBn

OBn OBn (

TMS~

>19:1

79%

Bn OBn OAc

OAc

~ I

66%

-

Ac

(i

~~

13:(z=3:2

Ac OAc

OAc

Thus far, the n u c l e o p h i l e s d i s c u s s e d as viable r e a g e n t s for Cglycosidations have c e n t e r e d a r o u n d silylated c o m p o u n d s . However, no discussion of C-glycosides would be complete without addressing the variety of nucleophiles available for the formation of such compounds. Therefore, the r e m a i n d e r of this section will focus on non-silylated reagents and, specifically, tin and aluminum-derived nucleophiles.

2.3.11

C-Glycosidations with Organotin Reagents

Allyltin reagents are useful reagents for the p r e p a r a t i o n of C-glycosides. Specifically, their versatility is noted in their ability to produce either a or ~ Cglycosides depending upon the reaction conditions used. As shown in Scheme 2.3.44, Keck, et al., 69 initiated such reactions on p h e n y l s u l f i d e activated pyranose and furanose sugars. Aside from yields exceeding 80% in all cases, specific stereochemical consequences were observed. For example, utilizing p y r a n o s e sugars as C-glycosidation substrates, p h o t o c h e m i c a l initiated Cglycosidations f a v o r e d the f o r m a t i o n of the a a n o m e r while Lewis acid mediated reactions favored the 1~. Similar results were observed for furanose

Chapter 2

68

F.lectrophilic Substitutions

sugars. However, an important deviance is the lack of stereospecificity observed under photolytic reaction conditions. C-Glycosidation via Allyltin Reagents

Scheme 2.3.44

S Ph

O

Bu3Sn"~

TBDMSO

= TBDMSO

Catalyst

Yield (%)

(x" 13

Photochemical BF3oOEt2

87 99

92"8 1 "99 OR

OR

l..fo

.....,,sp. Bu3Sn.4.

Catalyst

Yield (%)

Photochemical BF3.OEt 2 Photochemical BF3.OEt 2

8O 79 91

R CH2OCH2Ph TBDMS

~

AcO

~^,, "~"

CI Bu3Sn~ CO2Et

AcO

1 "99 40"60 59" 41

C-Glycosidation via Allyltin Reagents

Scheme 2.3.45

AcO

Complex Mixture

Photolysis

AcO

OAc

Aco\ I Y"\

~

_~

AcO 60%, o~'~ = 1 19

-~COeEt

Chapter 2

Electrophilic Substitutions

69

Although anomeric selectivity is generally difficult to observe, photolytic reaction conditions have found tremendous utility in the preparation of anomeric mixtures of C-glycosides derived from sialic acid and related compounds. As shown in Scheme 2.3.45, Nagy, et al., 7o induced such a reaction to obtain a 60% yield of the desired product mixture. Additional examples of these reactions were reported by Waglund, et al., 71 and are illustrated in Scheme 2.3.46. C-Glycosidation via Allyltin Reagents

Scheme 2.3.46

AcO

AcO Ac...,O~,,,, O~c AcO~~~.,..~

Ac

Bu3Sn-~ SPh

Photolysis

AcO"~-~r,~~~__

SPh ..,,,,',002,Me

O

~

CO2Me 30%, o~'13= 1 19 O

CO2Me

Oq

....

"o

Bu3Sn~

"1

C_O2Me

Photolysis

4_0

4-~ 30%, o~'13= 9" 1

Scheme 2.3.47

C-Glycosidation via AceWlenic Tin Reagents

OBn

OBn )..

,,~Br

~ ....

Bn(

(~ '"OBn OBn

( R~SnBu3," ZnCI2, CC[ 4

Bn

::iiii,O,n OBn

R=Ph 61% 49% R = n-C6H13 R = H3CCOCH 2 44%

70

Chapter 2

Electrophillc Substitutions

The chemistry of aUyltin compounds, with the exception of photochemical reactions, is analogous to that of allylsilanes and translates to the use of acetylenic tin reagents. As a final illustration of the utility of tin reagents to the formation of C-glycosides, the use of acetylenic tin reagents, shown in Scheme 2.3.47, is addressed. In the cited report, Zhai, et aL, 72 observed the formation of ~-C-acetylenic glycosides in good yields. The reactions were catalyzed by zinc chloride and run in carbon tetrachloride. Although the yields were not optimal, the v e r s a t i l i t y a n d applicability of this t e c h n o l o g y is n o t e d in its complimentarity to techniques discussed thus far.

2.3.12

C-Glycosidations with Organoaluminum Reagents

Complimentary to the chemistry of tin nucleophiles utilized in the formation of C-glycosides is the related chemistry s u r r o u n d i n g a l u m i n u m nucleophiles. The more common examples of this chemistry is applied to haloglycosides as glycosidation substrates. Thus, as shown in Scheme 2.3.48, Tolstikov, et/tl., 73 treated 2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl bromide with a variety of aluminum reagents effecting the formation of C-glycosides in good yields with demonstrated versatility in stereoselectivity. Specifically, no advantageous stereoselectivity was observed utilizing a trimethylsilylacetylene reagent, a selectivity was observed with ethyl and naphthyl reagents, and selectivity was observed utilizing tri-n-butyl aluminum.

Scheme 2.3.48

C-Glycosidation via Aluminum Reagents

OBn

OBn (~

,,,,Br ""

( RAIEt2 D,

'"*OBn

Bn

Bn

OBn

~..,~) oRBn OBn

R

Yield (%)

~ : 13

TMS---C~--~-C 1-Naphthyl CH3CH2

64 48 57

62:38 100:0 90 : 10

(C4Hs)3AI

63

8:92

Additional examples of the utility of aluminum reagents are taken from a report by Posner, et ai.,74 and are illustrated in Scheme 2.3.49. As shown, utilizing both saturated and unsaturated nucleophiles, good to high yields were

Chapter 2

Electrophilic Substitutions

71

obtained on reaction with fluorofuranosides. Additionally, all reactions demonstrated a preference for a selectivity. However, similar reactions, applied to the fluoropyranoside, shown in Scheme 2.3.50, produced high yields with substantially lower anomeric selectivity. Thus, combined with the examples of Scheme 2.3.48, these results clearly demonstrate the utility of organoaluminum reagents for the preparation of C-glycosides.

Scheme 2.3.49

C-Glycosidation via Aluminum Reagents

O

Oo__

O

F

R2AIR'

R

R'

Yield (%)

(x" 13

CH3CH2 C~--C---.nC6H13

79 85

> 20" 1 > 20" 1

H2C ' ~ ' ~ ~ nC6H1

68

> 20" 1

CH3CH2 CH3CH2 \ CH2 Scheme 2.3.50

C-Glycosidation vta Aluminum Reagents

~...OBn ~....-OBn BnO L ~ BnO

85%, (x .13= 2.6 .1 nC6H13

2.4

A r y l a t i o n Reactions

In comparison to the reactions described in the previous section, arylation reactions, related to allylation reactions and illustrated in Figure 2.4.1, can be

Chapter 2

72

Electrophilic Substitutions

more c o n v e n i e n t and versatile. For example, in most cases, Friedel-Crafts m e t h o d o l o g y applies. Additionally, not only is the conversion from O to Cglycosides feasible, but both a and 13anomers are accessible. Before exploring the various preparations of C-arylglycosides, it should be n o t e d t h a t an a d d e d feature of these c o m p o u n d s is the ease with which s t e r e o c h e m i s t r y can be assigned. Specifically, a r e p o r t by Bellosta, et a1.,75 showed that C-arylglucosides and C-arylmannosides exhibited characteristic differences in their chemical shifts and C-H coupling constants. As shown in Figure 2.4.2, the C1 carbon of the a anomers consistently a p p e a r e d down field from the 13anomers. Additionally, the coupling constants of the a anomers were approximately 10 Hz smaller than those for the ~ anomers.

Example of Arylation Reactions

Figure 2.4.1 .

~

X R = Aryl

C-Arylglycoside Chemical Shifts and Coupling Constants

Figure 2.4.2

OAc

OAc ()

( ~'~...

Ac

Ac

OAc C1:6 = 72.91 ppm, JC,H

=

156 Hz

OAc

~''OAc

OAc C1:6 = 80.22 ppm, JC,H = 144 Hz OAc

() , Ac OAc C1:6 = 75.57 ppm, JC, H

Ac -"

150 Hz

(

i

"OAc

OAc C1:6 = 78.09 ppm, JC,H = 140 Hz

Chapter 2

E1ectrophilic Substitutions

73

Reactions with Metallated Aryl Compounds

2.4.1

In beginning a discussion of the chemistry surrounding the preparation of C-arylglycosides, let us recall the work illustrated in Scheme 2.3.48 where Tolstikov, et at., 73 treated 2,3,4,6-tetra-O-benzyl-~-D-glucopyranosyl bromide with a variety of aluminum reagents effecting the formation of C-glycosides in good yields with demonstrated versatility in stereoselectivity. One particular example from this report involved the use of 1-naphthyl-diethylaluminum. This particular reaction, in spite of its 48% yield, exhibited total ~ selectivity. Observations of the ability of arylaluminum species forming C-glycosides have also been noted with heterocyclic aromatic species. As shown in Scheme 2.4.1, Macdonald, et al., 76 utilized furanyl-diethylaluminum in the formation of Cfuranylglycosides. The remarkable observation noted was the ability of this reagent to effect reaction with retention of the anomeric configuration of the starting sugar. Similar results were also observed with the corresponding pyrrole compound.

Scheme 2.4.1

C-Glycosidation via Aluminum Reagents

O

OBn

OBn ()

F

~.O/~ AIEt 2

()

45~176

Bn

Bn

""'OBn

Bn

OBn

OBn IE]: (:x,= 2.5 : 1 OBn

Bn

OBn

() OBn

I,'I,,OlI'Bn F

62%

BnO'*"'

''"OBn OBn (:x.: 13= 3 : 1

Aryltin reagents have been used similarly to arylaluminum compounds for the preparation of C-glycosides. Particularly applied to reactions with furanose glycals, Daves, et a1.,77,78 carried our the reactions shown in Schemes 2.4.2 and 2.4.3. Utilizing palladium acetate to mediate the couplings between glycals and aryltributyltin compounds, B anomeric selectivity was observed in poor to good yields.

74

Chapter 2

Scheme 2.4.2

Electrophilic Substitutions

C-Glycosidation via Tin Reagents

CHOCHOo.)

OMe

CH3OCH20 ~OMe Pd(OAc)270% ~,~O,~.~~~ /

TIPSOd

TIPSO

Bu3Sn

Scheme 2.4.3

C-Glycosidation via Tin Reagents OMe ,,%

OR

Pd(OAc)2 Bu3Sn

TIPSO4r O OMe ,,%

R CH2OMe TIPS

RO.~ 2.4.2

Yield(%) 66 28

\ OTIPSO Electrophilic Aromatic S u b s t i t u t i o n s Trifluoroacetoxy, and PNB Glycosides

with

Acetoxy,

Although the use of aluminum and tin reagents have provided fruitful approaches to the preparation of C-arylglycosides, the majority of this chemistry centers around reactions utilizing Lewis acid catalysis. Of particular importance are reactions proceeding via electrophilic aromatic substitution. This type of chemistry has been widely applied to a sugars bearing a variety of

Chapter 2

Electrophilic Substitutions

75

activating groups. One particular example, shown in Scheme 2.4.4, involves the coupling of an acetate activated ribofuranose with 1-methylnaphthalene. This reaction, reported by Hamamichi, et al.,79 proceeded in 79% with the formation of the a anomer comprising only 8.3% of the product mixture. Scheme 2.4.4

C-Glycosidation via Electrophilic Aromatic Substitutions

OBz L~oy

OBz

~

O

OAc SnCI4

BzO*""

~*"OBz 79%Yield,8.3%c~anomer C-Glycosidation via Electrophilic Aromatic Substitutions

S c h e m e 2.4.5

OR OAc L~Oy AcO --"

OAc

SnCI4 ~:~=1 "1

OAc

O OR -% R

AcI

0 AcO

Me TIPS

(%) 6O 87

Yield

76

Chapter 2

E1ectrophilic Substitutions

Additional examples utilizing acetate activating groups were reported by Daves, et a1.,80,81 and are related to the reaction shown in Scheme 2.4.3. The cited reactions, illustrated in Scheme 2.4.5 proceeded in good yields with low anomeric specificity. However, with the ease of separation of the anomers, functional yields could be obtained on exposing the undesired isomer to tin chloride thus forming a 1 : 1 anomeric mixture ready for separation. The compounds shown in this example were used in the development of synthetic strategies to the preparation of the antibiotics gilvocarcin, ravidomycin, and chrysomycin shown in Figure 2.4.3.

Figure 2.4.3

C-Glycosidic Antibiotics

R OH

Antibiotic Gilvocarcin V

OMe OMe

.o

H3 Ravidomycin I NMe2 AcO HO

0

~l

HO Scheme 2.4.6

Chrysomycin HO

C-Glycosidation via Electrophilic Aromatic Substitutions

~..OBn

~ . . . O B n

1. Trifluoroacetic Anhydride

OBn OH 2. ~ ] ~ O M e 3. BFa,OEt2

B~O ~0

OMe OBn

50% Yield, One Pot

Chapter 2

E1ectrophilic Substitutions

77

Related to the acetate activating group is the more labile trifluoroacetate group. In a reaction between methylphenol and 1-trifluoroacetoxy-2,3,4,6tetra-O-benzyl-D-glucopyranose, shown in Scheme 2.4.6, Allevi, et al., s3 observed the formation of a 50% yield of the ~ coupled product. This reaction actually proceeded through a one pot process in which the trifluoroacetate was formed followed by introduction of the nucleophile and addition of the Lewis acid. In spite of the relatively low yield, the ease of this chemistry and selectivity for the ~ anomer illustrates its usefulness. C-Glycosidation via Electrophilic Aromatic Substitutions

Scheme 2.4.7

OBn

RO.~~OR ( ,~~-..,,,,~X

OBn =

R'O.~~OR' () ~

Lewis Acid

Bn

'"*OBn

Bn

OBn X = OCOCF3,3,5-Dinitrobenzoate

OBn

Lewis Acid

R

R'

Yield (%)

(~ : 13

BF3.OEt2, 5 min. BF3.OEt2, 5 min. ZnBr2, 15 min.

Me TMS TMS

Me H H

81 95 67

0 : 100 100 : 0 0 : 100

C-Glycosidation via Electrophilic Aromatic Substitutions

Scheme 2.4.8

OMe MeOi ~ ' ~ O M e

OBn ( )..

OBn

OBn M e O ~ ~

"/OMe

,~xOCOCF 3

'"OBn

Bn

OMe

BF3*OEt2 59%

Bn

(~) OBn

In a subsequent study regarding the a and B selectivity of electrophilic aromatic substitutions, Cai, et a/.,82,83 demonstrated that, in addition to aromatic

Chapter 2

78

Electrophilic Substitutions

ring substituents, selectivity is also related to the Lewis acid used. The study, illustrated in Scheme 2.4.7, demonstrated a complete reversal in selectivity when the Lewis acid was changed from borontrifluoride etherate to zinc chloride. Unlike the previous example where only the trifluoroacetate activating group was used, the anomeric position on the sugars in these examples were also activated with the 3,5-dinitrobenzoate group. As a final example utilizing the trifluoroacetate anomeric activating group, Schmidt, et al., 84 coupled 1,2,3-trimethoxybenzene with the glucose derivative shown. As illustrated in Scheme 2.4.8, this reaction proceeded with high selectiviW giving the product in 59% yield. This reaction was utilized in the preparation of C-glycosidic bergenin analogs.

2.4.3

Electrophilic Aromatic Substitutions on Trichloroacetimidates

Scheme 2.4.9

C-Glycosidation via Electrophilic Aromatic Substitutions

OMe ~.....OBn r~ ~OMe ~......OBn BnO~O\ BnO~~'~

BnO~~~~...~, OBn

I OMe

OMe OBnMeO.~

MeO~OM e

OMe

OMe

BnB~ OBn

CCI 3

OTMS ~~]XOTMS

OMe

~...OBn t~ OH Bn O n ~ " OBn OH

In one of the earliest demonstrations of C-arylation chemistry, Schmidt, et a1.,85 utilized easily prepared trichloroacetimidates to prepare the products shown in Scheme 2.4.9. In all cases, the ~ anomer was the preferred product.

Chapter 2

Electrophilic Substitutions

79

An interesting observation is the demonstrated ability to utilize both alkyl and silyl phenolic protecting groups. Furthermore, in an extension of this work to heterocyclic substrates, a variety of furans were utilized.86 The results from this study, shown in Scheme 2.4.10, exhibited a strong preference for formation of the a anomer as opposed to the observations shown in Scheme 2.4.9. C-Glycosidation via Electrophilic Aromatic Substitutions

Scheme 2.4.10

~....OBn

~10Bn

BnO---V O BnO-~~~

oy.

BnOI

/

CCI 3

Scheme 2.4.11

R = H, Me, CH2OBn Only Isomer

ZnCI2. Et20

R

C-Glycosidation via Electrophilic Aromatic Substitutions

Ph OBn L()

~~0~--

..,,,,,O .,,,9

BnO"" ~ / OBn

CCI3 NH

"~OBn

Ph

Ph

H

OBn BF3~

()

,,

63%

Bn OBn

As a final example illustrating the versatility of trichloroacetimidates in the preparation of C-glycosides, Schmidt, et al., 87 reported coupling the glucose analog, shown, with 2,3-diphenylindole and related compounds. Although the reaction, shown in Scheme 2.4.11, proceeded with no anomeric selectivity, the 63% yield included none of the N-glycosidation product which might have formed and subsequently undergone an N-C migration. Interestingly, some Nglycosidation was observed when the glucose was activated with an anomeric acetate group.

80

Chap ter 2

E1ectrophilic Substitutions

Electrophilic Aromatic Substitutions on Haloglycosides

2.4.4

As a c e t a t e a n d r e l a t e d activating g r o u p s have b e e n useful in the f o r m a t i o n of C-arylglycosides, so have halides. In the first of two examples introducing the usefulness of this technology, Matsumoto, et ai.,88 published a r e p o r t on a zirconicene dichloride-silver perchlorate complex as a p r o m o t e r of Friedel-Crafts reactions in the preparation of C-glycosides. The reaction studied is shown in Scheme 2.4.12 and some of the results are s u m m a r i z e d in Table 2.4.1. In this study, the first three runs proceeded with glycosidation occurring at C4, exclusively. Runs 4-6 proceeded with glycosidation occurring at C1, and runs 7-10 followed routes similar to the first three runs. What is i m p o r t a n t to note is the control over the anomeric configuration of the product. For example, where r u n 4 p r o c e e d e d with high B selectivity using 5 e q u i v a l e n t s of the catalyst, w h e n only 0.2 equivalents were used, the selectivity was reversed giving high ~ selectivity. T a b l e 2.4.1

Run

Aryl-H OMe

MeO.

C-Glycosidation via Electrophilic Aromatic Substitutions Lewis Acid Reaction Time Yield (%) Equivalents 5.0 2.0 0.3

20 min 45 min 2 hr

96 91 79

O" 100 1"12 2"1

5.0 2.0 0.2

30 min 30 min 15 hr

77 58 40

1"13 2"1 21"1

5.0 2.0 0.2

20 min 20 min 75 min

59 64 50

O" 100 O" 100 O" 100

OMe

OMe

Scheme 2.4.12

C-Glycosidation via Electrophilic Aromatic Substitutions F

Meg.oMe

OMe

Aryl

CP2ZrCI2-AgCIO4 Me MeO

OMe OMe

Chapter 2

Electrophilic Substitutions

81

In the second example of the utiliW of glycosyl halides as substrates for the formation of C-arylglycosides, Allevi, et al., 89 d e m o n s t r a t e d conditions utilizing silver triflate as the catalyst. This study, summarized in Scheme 2.4.13, p r o c e e d e d in only 40% yield with total ~ selectivity. Thus, the developing trend, compared to that in the formation of C-allylglycosides is that C-arylglycosidations have a tendency to allow the formation of p r o d u c t mixtures highly enriched with ~ anomers. C-Glycosidation via Electrophilic Aromatic Substitutions

Scheme 2.4.13

OMe ~OBn

~.,.OBn B n O ~ O \

BnO---.~~

Silver Triflate

OBn

BnOI CI

2.4.5 Scheme 2.4.14

f

MeO

Electrophilic Aromatic Substitutions on Glycals C-Glycosidation via Electrophilic Aromatic Substitutions

OAc

k.

oAc

oAc 0

=

+

0

SnCI4

"'"

AcO"" OAc

Ac R= H R = OMe

Ac (Literature) Only Isomer

Only Isomer (Literature)

o~ Isomer: J4' 5'= 5.8 to 6.6 Hz and Less Dextrarotatory 13Isomer: J4',5' = 8.8 to 9.1 Hz, nOe Between H1 and H5 and More Dextrorotatory

To this point, all examples for the formation of C-aryl glycosides utilized Friedel-Crafts type conditions with a propensity for selectively producing [3 anomers. These reactions were all directed at sugars bearing glycosidic activating groups. However, in 1988, Casiraghi, et al., 90 d e m o n s t r a t e d the

Chapter 2

82

Electrophilic Substitutions

selective accessibility of both a and ~ anomers directed by the nature of aromatic ring substitution. This study was applied to tri-O-acetylglucal and is illustrated in Scheme 2.4.14. Additionally, the NMR results defining coupling constants and nOe observations characteristic of each anomer are also shown. As stated, "in the D-series, for a given anomeric pair the more dextrorotatory member having J4,5 of 8.7-10 Hz and relevant positive nOe between H1 and H5 should be assigned as ~-D, whilst the other displaying a J4,5 value in the range of 3-9 Hz and no nOe between H1 and H5 is to be named a-D."

Scheme 2.4.15

C-Glycosidation via Electrophilic A r o m a t i c Substitutions

OAc

o,c

0-3 O,

BF3K3Et2

AcO*"" T OAc

54%

Ac

In one additional example of the formation of C-arylglycosides from glycals, Ichikawa, et al.,6s illustrated the applicability of this chemistry to heterocyclic aryl species. Specifically, as shown in Scheme 2.4.15, tri-O-acetoxy glucal was treated with furan and borontrifluoride etherate. The result was a 54% yield of the desired C-furanoglycoside as a 1 : 1 anomeric mixture. 2.4.6

In tramolecular Electrophilic Aromatic Substitutions

Scheme 2.4.16

C-Glycosidation v i a Intramolecular

Electrophilic A r o m a t i c Substitutions

OBn

OBn ......

r

'~ Bn

BnO#":

%'O

As electrophilic aromatic substitutions have provided access to Carylglycosides via intermolecular reactions, similar technology is available for effecting the intramolecular delivery of the aromatic species. For example, utilizing the fluorofuranoside shown in Scheme 2.4.16, Araki, et al.,91 achieved

Chapter 2

E1ectrophilic Substitutions

83

f o r m a t i o n of an 83% yield of the bicyclic p r o d u c t on t r e a t m e n t with borontrifluoride etherate. C - G l y c o s i d a t i o n via Intramolecular Electrophilic Aromatic Substitutions

Scheme 2 . 4 . 1 7

OMe / Me

0

o

OMe

= 85%

.. ^,"

",.,,..,.....J

Meu

u

MeO

OMe

~

MeOd

0 " ~ OMe 9

OMe

MeO

0

OMe

"~3

SnCI4

=

46%

OMe

,."

",

MeO OBn LO

~ O M e ,,,,OMe

Bn

0 OBn

~.~T~ ~

OBn OMe

8o%

Bn OBn

Similar results, observed by Martin, et al., 92 in analogous tin chloride mediated reactions with O-methylglycosides. These reactions, shown in Scheme 2.4.17, illustrate the applicability of this chemistry no only to both furanose and pyranose sugars, but also to 2-O-benzyl and 2-O-benzoylated sugars. In all applicable cases, a detectable a m o u n t of the c o r r e s p o n d i n g regioisomer was formed. It is interesting to note that in one case, a double C-glycosidation was observed.93 This reaction, shown in Scheme 2.4.18, proceeded in 63% overall

Chapter 2

84

Electrophilic Substitutions

yield with opening of the furanose ring. The resulting product contained a cisfused bicyclic ring system core. In all examples of this technology, the possibilities for further derivitization are apparent through hydrogenation of the benzylic ethers or hydrolysis of the analogous esters. Scheme 2.4.18

C-Glycosidation via Intramolecular Electrophilic Aromatic Substitutions

OmMPM

0~

OMe mMPMO

r

0

~ O M e

SnCI4

mMPMO*"

m~~O.O": "-,,0

l

MeO MeO

o.~--/~/~ .,: ..,,,,,o

~

H O ~ X , . ~ OmMPM

Scheme 2.4.19

C-Glycosidation via Intramolecular Electrophilic Aromatic Substitutions

OBn

OBn

i,,,.......~o~..o~ BnO~

OMe

~*OBn

~.o~,~~o,o I,,,,......~,o) ..... BnO~

'"'0

R = H, Me, Ac

As the methoxy anomeric activating group has been useful in intramolecular C-glycosidations, so has the acetoxy group. As shown in Scheme

Chapter 2

E1ectrophilic Substitutions

85

2.4.19, Anastasia, et al., 94 utilized borontrifluoride etherate to effect this reaction on furanose sugars. In this study, the methoxy group was shown to be equally as useful as the acetoxy group. Furthermore, the free hydroxyl group can be used.

2.4. 7

O-C Migrations C-Glycosidation via O-C Migrations

Scheme 2.4.20

MeO

MeO

OAc

HO~-~~-OMe 78 yo Ac O~"

=

OAc

OAc

+

OAc

O ~...,,,,O

Oy

Ac

Ac 80

"

HO

OAc BF3"OEt2 .. 76% r

O

OMe

(x'13 = 42"58

Ac

Scheme 2.4.21

C-Glycosidation via O-C Migrations

OAc

AcO"""

AcO,,,,..,......~ , OAc R

Yield (%)

o~" 13

H OMe

63 82

29"1 100 19

20

O

Chapter 2

86

Scheme 2.4.22

Electrophilic Substitutions

C-Glycosidation

v/a

O-C Migrations

OAc HO BzO ~''....

+

=

OBz

O BzO

Lewis Acid

Yield ( % )

B F 3 . O E t 2, r.t. SnCI4, -25=C CpHfCI2-AgCIO 4, -150C

75 99 99

~

9[3

1 "4 1 14 9 1 10 9

. _

OBz

Moving away from electrophilic aromatic substitutions as a means of f o r m i n g C-arylglycosides, p e r h a p s the most notable r e a c t i o n is the O-C migration. This reaction is proposed to proceed through initial formation of an O-glycoside. This O-glycoside then rearranges, in the presence of Lewis acids, to a C-glycoside. Direct evidence for the O-glycoside intermediates was provided by Ramesh, et al.9s As shown in Scheme 2.4.20, para-methoxyphenol was coupled with the glycal, shown, to give the O-glycoside as a mixture of anomers. Regardless of the stereochemical outcome of the initial O-glycosidation, all s t e r e o c h e m i s t r y at the anomeric c e n t e r was lost on f o r m a t i o n of the Cglycoside.

Scheme 2.4.23

C-Glycosidation

.....

v/a

O-C Migrations

HO +

BzO"" OBz

BzO*"

Lewis Acid

Yield ( % )

~ : 13

BF3,OEt 2, r.t. SnCI4, -40~ CpHfCI2-AgCIO4,-15~

94 88 98

0:100 0 : 100 0:100

.. I

OBz

Chapter 2

;

TMSOTf-AgCIO4

OR

RO"

OH

R

X

Yield (%)

OR cz:13

Bz H H

OH OMe OH

99 90 99

1:70 1 : 15 1 :> 99

~~.~

X

R O""

87

C-Glycosidation via O-C Migrations

Scheme 2.4.24

RO

Electrophilic Substitutions

_L-(3R

OR

.X .X

RO"'

,,.

RO"" NMe2 OR

The study just cited was not the first example of O-C migrations. Rather, it was i n t e n d e d to introduce the reaction through a mechanistic insight. Early examples of this reaction were noted using phenolic salts. An excellent example is contained in a report by Casiraghi, et al. 96 As shown in Scheme 2.4.21, a glycal derivative was treated with bromomagnesium phenoxide derivatives. In the two examples shown, the yields were quite good a n d the a n o m e r i c preference of this reaction favored the cz configuration. Subsequent research further s u p p o r t e d these observations. 97 This result is a nice contrast to the 13 selectivity observed utilizing electrophilic aromatic substitution reaction to effect the formation of C-arylglycosides. As glycals have been useful substrates for O-C migrations, so have electron deficient 2-deoxy sugars which undergo more facile C-glycosidations. As shown in Schemes 2.4.22 and 2.4.23, Matsumoto, et al., 98 d e m o n s t r a t e d that these s u b s t r a t e s are easily reacted with 2 - n a p h t h o l utilizing Lewis acid catalysts. Under these conditions, formation of C-naphthylglycosides readily occurred. It should be n o t e d that utilizing b o r o n t r i f l u o r i d e e t h e r a t e as a catalyst allowed for the isolation of small amounts of O-glycosides from the reaction mixtures. The stereoselectivity of these reactions was shown to be influenced by the Lewis acid used as well as by steric effects. These results

Chapter 2

88

Electrophilic Substitutions

were confirmed by Toshima, et a1.,99,100 and d e m o n s t r a t e d to be general to a variety of protected and u n p r o t e c t e d sugars. The results, shown in Scheme 2.4.24, also illustrate that the relative reaction conditions are easily applied to unactivated glycosides.

C-Glycosidation

Scheme 2.4.25

WaO-C

Migrations

OBn BnO ,~

I~o H

0Y OAc

CP2HfCl2-AgCIO4

Bnd-"

HO

BnO//~o\

Bn

,r

~b,O

OBn

%

BnO

Bn

So far, the only examples of O-C migrations have applied to p y r a n o s e sugars or derivatives thereof. However, it should be noted that such reactions are applicable to furanose sugars. One p a r t i c u l a r example, r e p o r t e d by Matsumoto, et al., lol was used in the total synthesis of gilvocarcin M. The specific reaction, shown in Scheme 2.4.25, utilized the acetoxy a c t i v a t e d f u r a n o s i d e shown. Treating this c o m p o u n d with the phenol a n d using the hafnocene dichloride-silver perchlorate complex as the Lewis acid, the desired C-arylglycoside was obtained in 87% yield with the a anomer favored in a ratio of 8 : 1.

Scheme 2.4.26

C-Glycosidation vta O-C Migrations

MeO OMe H3C

BZOz~

H3C\

OH OMe CP2HfCI2-AgClO4 86%

~

BzO..-..-~.~.~O //

HO

OMe OMe N-",/~~~,, /

I MeO

In examining these examples of O-C migrations, it should be noted that while the phenolic units in these illustrations are relatively simple, this c h e m i s t r y has been applied to m u c h more complex systems. An excellent illustration of this statement is contained in a report by Matsumoto, et al., loa

Chapter 2

Electrophilic Substitutions

89

targeting the total synthesis of the vineomycins. The key reaction, shown in Scheme 2.4.26, involves the application of O-C migration chemistry to the anthracene analog shown. The substrate was the 2-deoxyfluoropyranoside shown and the Lewis acid was the hafnocene dichloride-silver perchlorate complex. The desired reaction proceeded in 86% yield with high ~ selectivity thus illustrating that O-C migrations are not necessarily specific for a given anomer. Furthermore, with the versatility contained within arylglycosidations, in general, the p r e p a r a t i o n of increasingly more complex targets becomes significantly more general. 2.5

Reactions with Enol Ethers, Silylenol Ethers and Enamines

Figure 2.5.1

Examples of Reactions with Silylenol Ethers and Related Compounds

~,~

X

Y = Enol Ether or Enamine

As arylations are complimentary to allylations, condensations of sugars with silylenol ethers and related c o m p o u n d s is directly analogous to condensations with allylsilanes. Consequently, the use of enol ethers, silylenol ethers, and enamines in C-glycoside chemistry, illustrated in Figure 2.5.1, provide avenues to additional functionalities on the a d d e d groups. The incorporation of these compounds onto carbohydrates is accomplished through relatively general methods. The products are usually of the ~ configuration. However, the ~ isomers are accessible through epimerization. In all cases except those involving glycals, benzylated sugars are preferred. Finally, the advantage of being able to run these reactions at low temperature is offset by the need to activate the anomeric position in all cases. 2.5.1

Reactions with Enolates

The need for anomeric activation when utilizing enol ethers and related nucleophiles can be misleading. Examples have been reported illustrating the ability to couple anionic nucleophiles with unactivated sugars. For example, as shown in Scheme 2.5.1, Gonzales, et al.,lO3 c o u p l e d b a r b i t u r a t e s with glucosamine to give ~-C-glycosyl barbiturates. Furthermore, as shown in Scheme 2.5.2, Yamaguchi, et al.,104 combined the illustrated unactivated 2deoxy sugar with a keto-diester to give the isolated ~-C-glycoside.

Chapter 2

90

E1ectrophilic Substitutions

C-Glycosidations via Enolates

Scheme 2.5.1

I

~

HO--~~, HO~

OH 0

/

o ~HO-~~ -y~o Ho~~--~~~~

8,%

H2N

H2N

OH

~r O

C-Glycosidations via Enolates

Scheme 2.5.2 OMOM

O

OMOM

CO2Et

EtO2C CO2Et,, Piperidine. HOAc

MOMO~,'''

CO2Et

48%

MOMO~,,,'

OMOM

Scheme 2.5.3

OMOM

Mechanism of C - G l y c o s i d a t i o n s via Enolates O

OMOM

OMOM .OH

EtO2C

CO2Et

9 CO2Et

Piperidine, HOAc 48%

MOMO~,,'''

CO2Et

MOMO~,,,'

OMOM

OMOM m

OMOM

O~'~//~'CO2Et Et

MOMOe'" OMOM

Chapter 2

Electrophilic Substitutions

91

The reactions illustrated in Schemes 2.5.1 and 2.5.2 do not proceed through direct glycosidation pathways. Instead, as shown in Scheme 2.5.3, the nucleophiles adds to the aldehyde of the open sugar. The resulting ~,~unsaturated carbonyl compounds recyclize via 1,4-addition of a hydroxyl group allowing axial orientation of the extended unit. The resulting products are the illustrated ~-C-glycosides.

Reactions with Silylenol Ethers

2.5.2

C-Glycosidations with Silylenol Ethers

Scheme 2.5.4

OBn

OBn O

BnO

OAc

Nucleophile TrCIO4

OBn

R

BnO*"

Nucleophile

R

TMSO

Yield (%)

~" 13

H2"'\""

R'= tBu

93

99 " 1

'R

R'= Ph

97

100 09

93

96"4

?= O

R'

7OBn

'-CH

?=o

'-- OTMS

C-Glycosidations with Silylenol Ethers

Scheme 2.5.5

TMSO

OBn

~

O'~OAc

r

OBn

OBn

SnCI4

RO~'" CH2Ph CH2CH2SCH 3 CH2CH2StBu CH2CH2S(O)CH3

Yield (%)

o:" 13

95 46 44 92

82 : 18 42:58 32:68 68:32

Chapter 2

92

Electrophilic Substitutions

Moving to more conventional glycosidation methods, a variety of anomeric activating groups have been utilized in the direct coupling of silylenol ethers with sugars. As shown in Scheme 2.5.4, Mukaiyama, et al.,9 reported such reactions with a variety of silylenol ethers. Utilizing the acetate activated ribose derivative, shown, the reactions were catalyzed by trityl perchlorate and run in dimethoxyethane. In all cases, the yields exceeded 90% and, unlike the above mentioned couplings with enolates, the a anomer was overwhelmingly the predominant isomer.

Scheme 2.5.6

C-Glycosidations with Silylenol Ethers

~...OBn ~.-OBn 1. Trifluoroaceticanhydride= B n O ~ O BnO O 2. Nucleophile BnO B n O - ~ ~ B n ~ OH 3. BF3oOEt2 BnO One Pot Reaction Nucleophile

TMSO~ R'

R

H2C 'R

Yield (%)

O

R'= tBu R'= Ph

50 75

(~ :

o~only o~only

In a study by Narasaka, et al.,10s,lo6 the variability of the reaction of 2deoxyribose with silylenol ethers was addressed. As shown in Scheme 2.5.5, the yields, as well as the anomeric ratios, are dependent upon the nature of the protecting group used on the 3-hydroxyl group possibly reflecting steric effects. Consequently, the best results were obtained utilizing benzyl groups. As with previously discussed C-glycosidation methods, the use of trifluoroacetoxyglycosides is complimentary to the use of acetoxyglycosides. In conjunction with couplings to silylenol ethers, Allevi, et aL, 53 reported the study summarized in Scheme 2.5.6. The reported results showed that good to high yields are available with high a selectivity. These results are in agreement with those reported for the corresponding acetoxyglycosides. In comparing acetates and trifluoroacetates, electronically similar trichloroacetimidates must be examined as anomeric activating groups in coupling reactions with silylenol ethers. As m e n t i o n e d in section 2.2, trichloroacetimidates are easily p r e p a r e d on reaction of hemiacetals with trichloroacetonitrile. The resulting activating group is subsequently displaced by a variety of nucleophiles under Lewis acid catalysis. As shown in Scheme 2.5.7, Hoffman, et al., 3 exploited this chemistry in the preparation of a variety of C-glucosides utilizing silylenol ethers. Haloglycosides, already discussed with respect to other C-glycosidation reactions, are useful substrates for coupling with silylenol ethers. As shown in

Chapter 2

Electrophilic Substitutions

93

Scheme 2.5.8, Nicolau, et al., 4 utilize the fluoroglucoside shown and effected the formation of a variety of C-glycosides. The example shown proceeded in high yield. However, the stereoselectivity of the reactions mentioned in this report were relatively low. This does not reflect upon the general utility of this chemistry as will be illustrated in the following example. Scheme 2.5.7

C-Glycosidations with Silylenol Ethers

~10Bn ~.~OBn BnOl

O.~NH

Nucleophile ZnCI2

BnO

R

CCl 3

Nucleophile

~'~

R

OTMS H

OTMS

0

O

OTMS

H 2 C ~

Scheme 2.5.8

4"1

Not determined

C-Glycosidations with Silylenol Ethers

OTMS ~.OBn

~-OBn Bo0--~-.~.~ 0

B n O ~ BnO

BF3=OEt2 95%

BnO

e'p=2"l

0

In the application of C-glycosidation techniques via addition of silylenol ethers to fluoroglycosides, Araki, et a1.,63,107 explored their applicability to furanose sugars. As shown in Scheme 2.5.9, although comparable results were

Chapter 2

94

Electrophilic Substitutions

obtained using allyltrimethylsilane, substantial improvements over Nicolau's results were observed utilizing the silylenol ether shown. Thus, fluorofuranosides form C-glycosides on reaction with silylenol ethers in yields exceeding 90% and exhibit high anomeric preferences for the a configuration. C-Glycosidations with Silylenol Ethers

Scheme 2.5.9 OBn

OTMS

OBn

94'6o/o

BnO"#

"~OBn oc:13=20:1

Scheme 2.5.10 C-Glycosidations with Silylenol Ethers ~....OBn

~10Bn Nucleophile AgOTf

BnOI Cl Nucleophile TMSO

R'

)

Bn

O n ~ BnO

R

'R

R'= tBu R'= Ph

Yield (%)

ct:15

83 88

oconly ~ only

With the ability to make use of fluoroglycosides as C-glycosidation substrates, chloroglycosides have been comparably useful. As shown in Scheme 2.5.10, Allevi, et al.,S9 condensed silylenol ethers with 2,3,4,6-tetra-O-benzyl-aD-glucopyranosyl chloride. Silver triflate was utilized as the Lewis acid catalyst. In the examples studied, the yields exhibited were consistently greater than 80%. Furthermore, complete a selectivity was observed. Subsequent research reported by Allevi, et a1.,53,108 demonstrated the feasibility of combining steroidal silylenol ethers with chloroglycosides to give ~-C-glycosides. The results of this study are illustrated in Scheme 2.5.11. Furthermore, as these reactions consistently exhibited high ~ selectivity, conditions for epimerization to the 13isomers were demonstrated. As expected, this transformation proceeded easily on treatment with base. As with arylation reactions, intramolecular delivery of silylenol ethers is a viable approach to the formation of C-glycosides. An interesting example,

Chapter 2

Electrophilic Substitutions

95

r e p o r t e d by Craig, et al., 109 d e m o n s t r a t e d the formation of a c/s-fused oxetane from an i n t r a m o l e c u l a r enol ether. The activating g r o u p used in this reaction was the p h e n y l s u l f i d e g r o u p . Additionally, the f o r m a t i o n of o n l y one stereoisomer was observed. The reaction described and its stereoselectivity is rationalized in Scheme 2.5.12.

Scheme 2.5.11

C-Glycosidations with Silylenol E t h e r s

OBn

8H17 TMSO

BnO"" ~ " "'OBn OBn AgOTf,75%

BnO BnO

O/~

.......'

"

~

/ C8H!7

KOH/MeOH 85%

BnJ Bn'O O / / ' ~ BnO--~O

BnO,,,....(k~ BnJ

~

/

8H17

Bn~) O' / ' ~ ' ~

)••,,,

cH2COOMe

BnO BnO '''' ~

"' '"'OBn

OBn

NaOMe/MeOH~ BnO 85%

BnO~,''' ~

/ '"'OBn OBn

As activated sugars are capable of reacting with silylenol ethers to form C-glycosides, so are glycals. In 1981, Fraser-Reid, et al., 110 showed t h a t in addition to forming a-O-glycosides from the glycals the same glycals will form a-C-glycosides w h e n treated with silylenol ethers. F u r t h e r m o r e , analogous to w o r k p r e v i o u s l y d e s c r i b e d , the a a n o m e r s were easily c o n v e r t e d to the

Chapter 2

96

E1ectrophilic Substitutions

corresponding B isomers on treatment with base. These results are illustrated in Scheme 2.5.13 and summarized in Table 2.5.1.

Scheme 2.5.12 C-Glycosidations with Silylenol Ethers

O

,nOZ'Z'"0' ',u OBn

AgOTf/Mol.Sieves 50%

BnO

OTBDMS

u

OBn

/H~

,OTBDMS

o . , j .... .,,2' 5+ / \

T B D M S O + u~ ' H

Scheme 2.5.13

O ......""r ~ t B .....'"0

H

tBu

C-Glycosidations with Silylenol Ethers

OAc

[- OAc

i~,,'

OAc ~0. ROHD, y

0+ ~

BF3oOEt~

AcO"'

-]

c

q'"

,,~OR

Ac

OAc

OTMS H2C~"ph

Mino/[~Major

OAc O Ac

Ph.,

tBuOK

OAc I~,~/O__...,,,,,,,~/ Ph

-r ]

;r

AoO,,,,..'~,j

o

Continuing with glycals, Kunz, et ai.,111 not only demonstrated their ability to condense with silylenol ethers, condensations with enamines were also

Chapter 2

Electrophilic Substitutions

97

explored. As shown in Scheme 2.5.14, the titanium tetrachloride m e d i a t e d condensation proceeded in 90% yield with exclusive formation of the [~ anomer. Alternately, w h e n the e n a m i n e was used, exclusive 1,4-addition led to the p r o d u c t shown. As with the silylenol ether, the enamine p r o d u c e d solely the [~ anomer. However, the isolated yield of 28% was substantially lower.

Table 2.5.1 Solvent

C-Glycosidations with Silylenol Ethers ~.~ Catalyst T/oC t/h

,

CH2C12 CH2C12 CH2C12 CH2C12 THF THF THF CH3(N CH3(N

BF3.OEt2 BF3.OEt2 A1C13 CF3SO3SiMe3 BF3.OEt2 A1C13 A1C13 BF3.OEt2 AlCl3

Scheme 2.5.14

-40 to 0 -78 -40 to 0 23 -40 to 23 -40 to 0 23 -45 to 0 -45 to 10

4:1

0.5 2.5 1.0 0.3 5.0 18 36 0.75 1.0

99 <1 92 75 <1

7:3 7:3

7"3 4 :1

77 <1 97

C-Glycosidations with Silylenol Ethers and Enamines

OAc

Ac

~ Yield

~

TMSO

(

,l oA c

"@

OAc

o

TiCI4

O

OAc

90%

OAc

r

",ss

Ac

O

2.5.3

28%

Reactions with Enamines

In a final example of the applicability of enol e t h e r analogs to the synthesis of C-glycosides, Allevi, et a1.,112 explored a variety of e n a m i n e s

Chapter 2

98

ElectrophilicSubstitutions

utilizing silver triflate as a catalyst. This study differed from that previously discussed in that the sugar is a glycosyl chloride and the enamines are conjugated to carbonyl functionalities. The results, shown in Scheme 2.5.15, are unlike those in the previous example thus demonstrating a propensity for the formation of a anomers. Furthermore, in all cases, the yields observed were approximately 85%. Thus, the conjugated enamines used in this report appear to have general applicability in condensations with glycosyl halides. Scheme 2.5.15

C-Glycosidations with Enamines

OBn

OBn L.

Bn '

~ (

,,,CI

//1~./CO2 Me

'"OBn

AgOTf/Mol.Sieves 85%

o,,i

COCH 3 ( ) \ ,**L "" CO2Me

~~}

I1,

/""OBn

Bn

OBn

OBn OBn MeO.~l.~

CO2Me

COCH2OMe (

)-

,**L

85% Bn

/''"OBn OBn

OBn (

85% Bn

'~""'**~COPh /'"0

Bn

OBn

2.6

N i t r o a l k y l a t i o n Reactions

The formation of nitroalkyl glycosides, illustrated in Figure 2.6.1, is limited in scope and few examples have been reported. The problems associated with this reaction involve the acidity of n i t r o m e t h y l groups. Specifically, after formation of the C-glycoside, nitromethyl anions are easily

Chapter 2

E1ectrophilic Substitutions

99

formed. F u r t h e r m o r e , when acetate protecting groups are used, n i t r o n a t e s readily form. The few examples illustrated in this section are m e a n t to convey the relatively limited accessibility of these compounds.

Figure 2.6.1

Example of Nitroalkylation Reactions

~.~X

Scheme 2.6.1

=

~ ~ J 4 ~

NO2

Nitroalkylation Reactions

H2NO2

2-Hydroxypyridine

",,,

69 ~

/

OH

OH

Ph~O~

-O

Fe(0)/CO2 54%

y

HO-..~-~~CH2NH2

OH

OH

Scheme 2.6.2

Nitroalkylation Reactions

OH

OAc O

~,,-.-

AcO

OH

1. CH3NO2 = 2. Ac20

......~

~,

...

OAc

NO2

Acd

-

"~

One specific example illustrating the utility of n i t r o a l k y l a t i o n s was r e p o r t e d by Drew, et a1.,113 and is shown in Scheme 2.6.1. In this report, a benzylidine protected glucose analog was converted in a 69% yield to a ~-C-

Chapter 2

100

E1ectrophilic Substitutions

glycoside. Subsequent reduction of the nitro group gave the c o r r e s p o n d i n g a m i n o m e t h y l derivative suitable for f u r t h e r functionalization. It should be noted that a potential side reaction arises from nitromethane adding, via a 1,4addition, to the intermediate olefin. Applied to furanose sugars, Koll, et al., 114 reported the analogous reaction shown in Scheme 2.6.2.

Synthesis of 1-Deoxy-l-Nitrosugars

Scheme 2.6.3

B n O ~ BnO

BnBo

BnO'~ NH2OH BnO~-

-OH

Bno~NOH

OH

BnO

? N+

O2N~CHO

BnO"'~

"

B n ~O

r BnO NO2 ozone

BnO

BnO

Nitroalkylation Reactions

Scheme 2.6.4

•.•"•

NO2

O

NO2

?"~ O NO2 ~~.NO2 ~ ' ~ O ' ......,,,, tBuOK,light= . ~ ~ I~NO2 85%

O~.O

Ox .

NO2

CH3NO2D. 'BuOK,Jight

72%

d

~

O.~.O

NO2

Related to nitroalkylsugars are 1-deoxy-l-nitrosugars. These c o m p o u n d s are relatively easy to prepare via oximes. As shown in Scheme 2.6.3, Vasella, et ai.,115,116 effected this transformation via addition of an aldehyde to the oxime, shown. S u b s e q u e n t t r e a t m e n t with ozone gave an anomeric mixture of the desired 1-deoxy- 1-nitrosugar in 73% overall yield.

Chapter 2

ElectrophilicSubstitutions

101

The utility of 1 - d e o x y - l - n i t r o s u g a r s was f u r t h e r d e m o n s t r a t e d by Vasella, eta/., 117 in a study of nitroalkylation reactions. The study, summarized in Scheme 2.6.4, involved the addition of n i t r o m e t h a n e a n d 2-nitropropane. The reactions proceeded in excess of 70% yield. Further studies of the utility of nitrosugars will be discussed later in the formation of C-disaccharides.

2.7

Reactions with Allylic Ethers

Figure 2,7.1

Example of Reactions with Allylic Ethers c.o

Scheme 2.7.1

Reactions of Glycals w i t h Allylic Ethers

""

~

AC

OAc

,,,,,,.... 0 ZnBr2

OAc (

)

OAc

CHO

Ac

82%

OAc

=AcO~

I I

R=Si

~CHO 81%

Unlike nitroalkylation reactions, the use of allylic ethers as reagents in Cglycoside c h e m i s t r y has p r o v e n to be s u b s t a n t i a l l y m o r e useful. These reactions, illustrated in Figure 2.7.1 and alluded to in Scheme 2.3.16,41, 42 show a p r o p e n s i t y for ~ selectivity and are able to provide additional a s y m m e t r i c centers. These reactions, however, procede in an SN2'-like fashion and are limited to glycals. Consequently, a wide variety of deoxy sugar derivatives are available. Although, as shown in Scheme 2.3.16, the chloride was the p r o d u c t observed in the reaction of tri-O-acetyl glucal with an allylic alcohol, one can envision the abiliW of this type of condensation to yield carbonyl c o m p o u n d s if the double b o n d could be kept intact. This has been accomplished utilizing O-

Elec trophilic Substitutions

Chapter 2

102

silyl protected allylic alcohols. An early example, shown in Scheme 2.7.1, was reported by Herscovici, et al., 118 and demonstrates applicability to various glycals. As shown, in Scheme 2.7.2, the mechanism of these transformations involves formation of the carbocation followed by the evolution of its equilibrium with the illustrated O-glycoside. As the carbocation reacts with the allylic ether, the reaction is driven to provide the desired product. S c h e m e 2.7.2

AcO'

Reactions of Glycals with Allylic Ethers

= -2

OAc

S c h e m e 2.7.3

1

+,.j

A c O ~ " ~0"

. O.

AcO~"

~,,,,.. O CHO =A c O ~

Reactions of Glycals with Allylic Ethers

0 ...,,,,,,,~ ~0

AcO"'

OAc M u l t i p l e Steps

AcO"" "

=.

66%

H

0

In later reports, Herscovici, et al., 119 demonstrated the applicability of this technology to more complex allylic ethers. The example shown in Scheme 2.7.3 was utilized in an enantiospecific naphthopyran synthesis.

Chapter 2

Electrophilic Substitutions

103

In a final example, summarized in Scheme 2.7.4, Herscovici, et al., 120 utilized several silyl ethers in reactions with various glycals to prepare the products shown. In the same report, a study was carried out involving the use of deuterated allylic ethers. This experiment, shown in Scheme 2.7.5, was designed to prove the involvement of a pinacole-type mechanism in the transformation. The 1,2-deuteride shift supported this hypothesis. Scheme 2.7.4

Reactions of Glycals with Allylic Ethers

,',,,,,,....0

.~,.OR

AcO~"" "~., =_. _ ~OAc

ZnBr2

72%, 6:4 -

OAc

OAc ...~OR

AcO~]e ~

i,,,,,,....~ "~

60%, 3:1 ZnBr2

53%, 1:1 ZnBr2 and PhCHO

I R=Si I Scheme 2.7.5

OHC...~.

Reactions of Glycals with Allylic Ethers

~ .OR D D

~

i,,,,,.....0~~o

D

AcO"" " " r f ~OAc ~

OAc ~

f § D "~OR " " " ' . ~~~ ~ " ~ O D

I R = Si I

Chapter 2

104

Electrophilic Substitutions

The fact that ketones, aldehydes, and geminal diacetates are readily available from these reactions illustrate their complementarity to reactions with allylsilanes. Specifically, the equivalency of allylic ethers to homoenolates allows for the formation of c o m p o u n d s extended by one c a r b o n unit as c o m p a r e d to the products of couplings with enolate equivalents already discussed.

2.8

Wittig Reactions with Lactols

Where the use of allylic ethers provides c o n v e n i e n t routes to the formation of ketones and aldehydes, the Wittig reaction, as illustrated in Figure 2.8.1, may be utilized in the formation of ester functionalized C-glycosides. This approach is either a or ~ selective and works with benzylated, acetylated, and unprotected sugars. A particular advantage is that reaction intermediates can be intercepted and utilized. Furthermore, glycosidic activation is not required for this type of reaction.

Figure 2.8.1

Example of Wittig Reactions with Sugars Wittig

2.8.1

. ~ ~ O OR

=

Wittig Reactions Wittig Reactions with Lactols

Scheme 2.8.1

OH O

3

R = p-nitrobenzoyl

r.....C02Et =~

F

3

RO 54%

CO2Et +

RO 15%

In 1981, Acton, eta/., 121 performed the reaction shown in Scheme 2.8.1 to give a 3 : 1 ratio of anomeric esters. Shortly thereafter, Nicotra, et aL, 122 r a n a similar reaction, shown in Scheme 2.8.2, and studied the 13C chemical shifts of the resulting a and ~ anomers. This study yielded an easy m e t h o d for the assignment of the anomeric stereochemistry with the anomeric carbon of the

Cha ter 2

Electro hilic Substitutions

105

anomer possessing a chemical shift of approximately 33 ppm and that of the anomer possessing a chemical shift of approximately 37 ppm. Scheme 2.8.2

W__ittig Reactions with Lactols

6 Hz J1,1'13= 10 Hz O ~ 33.84 ppm Jl,l'(x =

H O ~ AcHN

OH

~.-OAc

A~o~

Ph'"~O"~ OH ~

Wittig

AcHN L 50% -~ CO2Et ~-OBn 33.2ppm BnO-'-'t"--.%-.~O B n O ~ ~

/

AcO L....__ _ GO2Et

AcO L...CO2Et ~..--OAc 37,27ppm AcO~O / AcO. ~ - ~ ~ - . ~ AcO CO2Et Scheme 2.8.3

33 74 . ppm

~-OBn 37 61 ppm BnO--'-'k"-.-.~.~O / " BnO-..-.~~~~ AcO CO2Et

Mechanism of Wittig Reactions with Lactols

H O ~

AcHN

0.01MNaOEt=

P:CHCO P e, o OH

OH

-

O H ~

=-

o

H O ~ c o

Et

AcHN E:Z=3:I

~ ~ , ~ ~ ~-CO2Et

2

O, AcHN

1 /

/ / /

CO2Et

Time

0~:13

/

15 min

9:1

|

Chapter 2

106

ElectrophilicSubstitutions

The mechanism of Wittig reactions applied to lactols is illustrated in Scheme 2.8.3 in a reaction reported by Giannis, et al. 12s As shown, the Wittig reagent reacts with the aldehyde of the straight-chain form of the sugar. The free 5-hydroxyl group then adds to the resulting a,~-unsaturated ester u n d e r basic conditions giving the products shown. Furthermore, the anomeric ratio of the p r o d u c t mixture is d e p e n d e n t upon the time of exposure to base thus demonstrating the ability to convert the a anomer to the ~ anomer. It is notable that the mechanism of this reaction resembles that of nitroalkylation reactions shown in Scheme 2.6.1. In the cited report, the reaction shown was used in the synthesis of a potential ~-D-hexosaminase A inhibitor. Wittig Reactions with Lactols

Scheme 2.8.4

BnO.~~ ( )

.OH

BnO~'' " ~ ~',~,OBn OBn BnO'~'.~ ( ) T OH

BnO~ Zn dust, BrCH2CO2Me PPh3

() ~ C 0 2 M e

BnO"' ~ / ''"OBn OBn 64% BnO C02Me

,,..._

BnO"

~

~'"~OBn

BnO"

BnO~''' ~ OBn OBn

'"'OBn

OBn 75%

OBn

BnO~... ( ~ O H

~ j

BnO~

( I~~-~'~C02Me

Bn0""' ~ ~ "OBn OBn 49%,I :I

With the utility of Wittig reagents in the formation of C-glycosides, it is i m p o r t a n t to mention work reported by Dheilly, et al., 124 in which benzyl p r o t e c t e d glucose, galactose, and m a n n o s e were t r e a t e d with m e t h y l bromoacetate, zinc dust, and triphenylphosphine. The procedure described was reported by Shen, et al., 12s as a one-pot formation and application of Wittig reagents. The original report utilized this methodology in transformations regarding aromatic and aliphatic aldehydes. As shown in Scheme 2.8.4, applying this methodology to protected sugars provides C-glycosidic esters in good yields. In all cases except for mannose, the reaction proceeded with selectiviW. The lack of selectivity for the mannose case may be attributed to steric effects. Furanose sugars have also been utilized as substrates for Wittig reactions. As shown in Scheme 2.8.5, Fraser-Reid, et al., 126 applied this methodology to

Chapter 2

Electrophilic Substitutions

107

m a n n o s e derivatives. The reactions p r o c e e d e d with b o t h the S - O - t r i t y l protected compound (reacted with carbomethoxymethylene t r i p h e n y l p h o s p h o r a n e ) and the free S-hydroxyl analog (reacted with acetonyl t r i p h e n y l p h o s p h o r a n e ) . In both cases, as m e n t i o n e d in previous examples, a kinetic a n d a t h e r m o d y n a m i c p r o d u c t was observed. F u r t h e r m o r e , on t r e a t m e n t with 10 mM sodium methoxide, the t h e r m o d y n a m i c isomer became more prominent.

Wittig Reactions with Lactols

Scheme 2.8.5 OTr

OTr

CO2Me

Ph3P=GHCO2MeD.

OH

COMe

~O.~OHph3P=CHCOMe" ~O~

~176

CO2Me

+

Kinetic OH

OTr

Thermodynamic OH

COMe

+ ~.~O.~ ......,,,,I

~176

~176

NaO Me

Ki netic

Therm odynam ic

None 10 mM

7 1

3 4

Scheme 2.8.6

W i t t i g - T y p e Reactions with Sugar Lactones

--~o--~ ~ ~

~176

O---m

CCI4/(NMe2)3P 79%

CI

Chapter 2

108

Electrophilic Substitutions

Although outside the scope of this discussion, Wittig-type reactions have been utilized in transformations involving sugar lactones. As shown in Scheme 2.8.6, Chapleur, et al., i2y induced the reaction between the protected sugar, shown, and hexamethylphosphorus triamide-tetrachloromethane to give the desired dichloro olefin in 79% yield. This example is important in the illustration that phosphorus chemistry is capable of providing avenues to a wide variety of desirable functional groups important in the preparation of Cglycosides. Further illustrations involving Horner-Emmons methodology are discussed below.

Horner-Emmons Reactions

2.8.2 Scheme 2.8.7

H o r n e r - E m m o n s Reactions with Lactols

BnO~... ( OBHn BnO~,,,"~ OBn BnO'~~ 9 0 ~ CO2Me

(MeO)2POCH2CO2Me Nail, THF, 50 ~ C

BnO~"~"" T

"~OBn OBn

B n O ~ . .1s OBn

B n O ~''' ~

~

"OBn

OBn

CO2Me ""'OBn

BnO~"" y

86%CombinedProductYield

Bno: II"'CO M, BnO"" ~ / ' ' " O B n OBn

Complimentary to the Wittig reaction is its Horner-Emmons modification. These reactions, unlike the phosphorus ylides utilized in Wittig reactions make use of phosphonate anions as the nucleophilic species. As shown in Scheme 2.8.7, this methodology is applicable to the formation of C-glycosides from sugars. The reactions shown, reported by Allevi, et al., 12s involve the coupling of triethylphosphonoacetate with 2,3,4,6-tetra-O-benzyl-D-mannopyranose and produce high yields of the desired B-C-glycosides bearing ester functionalities. It should be noted, however, that some epimerization of the stereocenter at C2 was observed. This can be explained by the relative acidiW of the proton at C2 considering the intermediate a,B-unsaturated ester. This is illustrated in the analogous mechanism for the reaction of lactols with phosphorus ylides shown

Chapter 2

E1ectrophilicSubstitutions

109

in Scheme 2.8.3. Preferential formation of the ct anomer is complimented by its total conversion to the 13anomer on treatment with base. Horner-Emmons Type Reactions with Lactols

Scheme 2.8.8

~,~O X

~OH

..~L (EtO)2OP SO2Ph

OH

X

O

> 60%

OAc

OH X = CN, CI X

NaH

SO2Ph

O

SO2Ph

> 72%

OAc Horner-Emmons Type Reactions with Lactols

Scheme 2.8.9

Na

1. H0""' ~

~""0 H

OH

O

()

(EtO)2OP'~SO2Ph

AcO AcO~,''

2. NaOMe/MeOH 3. Ac20/Py 50% from glucose

OAc

~OH

O ~ ~ . ~ (1

,,,,,,,....~ ~'"',,,OH

AcO ~

OH

SO2Ph

OH

O ' ~ OH

HO,,,"' T

,

r

OH HO~~

SO2Ph

~

80%

SO2Ph

,

AcO"" T OH

C-Glycosidic esters are not the only functional groups accessible by Wittig and related methodologies. As shown in Scheme 2.8.8, Barnes, et a/., 129 effected

Chapter 2

110

Electrophilic SubstitutJons

the formation of analogous compounds utilizing sulphone phosphonates. These reactions, like those with triethylphosphonoacetate formed anomeric mixtures which, on t r e a t m e n t with base, could effectively be converted fi anomeric products. Furthermore, subsequent work by Davidson, et aL, 13o shown in Scheme 2.8.9, demonstrated the applicability of this technology to free sugars as well as sugars protected with acetal groups.

Reactions with Sulfur Ylides

2.8.3

With the utility of phosphonate anions and phosphorus ylides in the preparation of C-glycosides, a discussion of the related chemistry surrounding sulfur ylides is warranted. Sulfur ylides, unlike phosphorus ylides, deliver methylene groups to carbonyls thus forming epoxides. As shown in Scheme 2.8.10, Fr6chou, et al., 131 exploited this chemistry in the formation of Cglycosides. As shown, the sulfur ylide was added to the benzyl protected glucose to give the olefinic epoxide shown. Cyclization could then be effected on treatment with base thus forming the C-glycoside with opening of the epoxide. Similar results were observed utilizing the sulfoxide ylide and the acetonide p r o t e c t e d furanose sugar shown. It should be noted that s p o n t a n e o u s cyclization occurred only when spontaneous elimination did not. Scheme 2.8.10

BnO~,,,

Reactions of Sulfur Ylides with Lactols

()

BnO,,,," ~

,.OH

II

OBn

88%

~OHI~o BnO" ~

BnO~'''" " " ~ ' ' ' O B n

OBn O

/~..,.-~ 45 55 9

O OH

II 0

0

O

OH

82%

O,~O~

all3 = 2.6/1

Chapter 2 2.9

Nucleophilic

Reductions

E1ectrophilic Substitutions

Additions

to Sugar Lactones

111

Followed by L a c t o l

Sugar lactones are useful substrates for the formation of C-glycosides and are readily available from the oxidation of lactols. As shown in Figure 2.9.1, the use of this a p p r o a c h involves the addition of a nucleophile to the lactone followed by subsequent reduction of the resulting lactol. The two step process provides C-glycosides in high yields and is useful with b o t h benzyl and silyl protected sugar lactones. Furthermore, as the hydride is generally delivered to the axial position, these reactions produce B-C-glycosides.

Figure 2.9.1

Example of C - G l y c o s i d e s from Sugar Lactones

__ t OH R

RM

=

hydride

axially delivered hydride

2.9.1

Lewis Acid-Trialkylsilane Reductions

Actual applications of this methodology have already been presented and are now reviewed. In Scheme 2.3.12, the addition of alkyllithium reagents to furanose-derived lactones was addressed. Although reduction of the resulting lactol was not discussed, this example illustrated a convenient conversion of the furanose lactol to a pyranose lactol. In Scheme 2.3.14, the use of allyl Grignard reagents was p r e s e n t e d followed by the Lewis acid-triethylsilane reduction of the lactol to the desired C-glycosides. In the following paragraphs, expansions u p o n these examples, along with the introduction of c o m p l i m e n t a r y methods for the formation of C-glycosides from sugar lactones, are discussed. As shown in Scheme 2.9.1, the versatility of products available from the addition of nucleophiles to sugar lactones was addressed by Horton, et al. 132 Following the illustrations in the scheme, gluconolactone was silylated and treated with a lithium reagent to give the observed lactol. This lactol was then a c e t y l a t e d a n d r e d u c e d , with r a n e y nickel, to the C - m e t h y l g l y c o s i d e . Alternately, the lactol was partially acetylated. S u b s e q u e n t r a n e y nickel reduction gave 1-methylglucose. In both cases, a b y p r o d u c t of the acetylations was the open chain glucose, A. Moving away from alkyllithium species, Scheme 2.9.2 illustrates the use of lithium acetylide derivatives as useful nucleophiles for the formation of Cglycosides. As described by Lancelin, et al., 133 lithium acetylides were a d d e d to

Chapter 2

112

Electrophilic Substitutions

sugar lactones giving lactols. The lactols were subsequently reduced to ~-Calkynylglycosides with complete stereospecificity. This reaction was subsequently shown to be a general method for a variety of sugars and alkynyllithium reagents.

C-Glycosides from Sugar Lactones

Scheme 2.9.1

-OT S

HO ~ O H

NO

cS>--Li

=TMSO~O 1. ~--S TMSO~ 2. MeOH,H20 TMSO 0 ~OAc

bH "O OH

Ac2O,Et3N,DMAP " A+ c

H..O

CsH5N,

"~Ac20

AO A~ ' c ~ O AcO I Sf OAc

Ac20,Et3J

1Ni(H2)

AcO~

AcO.~~,.~&~ AcO

~OAc ~co

+

~

H

~COlo~

s

~H2)

-..

OAc OAc

.A

Scheme 2.9.2

~.o~c

ACOoH

C-Glycosides from Sugar Lactones

~---OBn BnBO~

Li O

BF3"OEt2

Triethylsilane

~---OBn R = BnOBno,...,~,~,~~ ~ ~ O ~ R

~,

BnO~ BnO~

OBn O ~ R BnO

BnO OH 13-only

Chapter 2

E1ectrophilic Substitutions

113

C-Glycosides f r o m Sugar Lactones

Scheme 2.9.3

MgCI

OBn

OBn

~...,,~oOBn ( OBn

Bn '

Bn

OBn

OBn (~ Et3SiH/BF3"OEt2 88%

Bn OBn C-Glycosides f r o m Sugar Lactones

Scheme 2.9.4

OBn

OBn ( Bn

~.,.)

oOBn

0 Aryllithium

Et3SiH/BF3"OEt2

85%

80%

BnO*~" ) *" y

OBn OH

OBn ()

Ar

=

,

10% Pd/C

Bn

/''OBn

OBn

Ar

~

H

(

"""0 '' Bn OBn

, Ar

/'''OH OH

Utilizing aryl groups as nucleophiles, the related reactions, shown in Schemes 2.9.3 and 2.9.4, were carried out by Kraus, et a1.,134 and Czernecki, et al., 135 respectively. In both cases, the predominant product possessed the [~ configuration at the anomeric center. Furthermore, the reactions proceeded in greater than 80% yield. When viewed along with the methods discussed thus

Chapter 2

114

Electrophilic Substitutions

far, these reactions affirm the generality of o r g a n o l i t h i u m reagents and Grignard reagents for the preparation of C-glycosides from sugar lactones.

C-Glycosides from Sugar Lactones

Scheme 2.9.5

Li

OBn

Bn0~-"

OBn

OH

:~'~OBn .. OBn

Et3SiH/BF3*OEt 2

BnO"/ ""0Bn

o~N'N~

One final example of the use of aryllithium species as C-glycosidation agents when applied to sugar lactones is shown in Scheme 2.9.5. In this report, Krohn, et al., 136 applied the technology to furanose lactones. After the reductive deoxygenation, the illustrated product was isolated as a single isomer in 87% yield over the two steps. As with the examples described above where pyranose sugars were used, [~ selectivity is the general stereochemical outcome for these reactions.

2. 9.2

Other Reductions

Until now, all methods mentioned for the formation of C-glycosides from s u g a r l a c t o n e s involve the i n c o r p o r a t i o n of Lewis a c i d - t r i a l k y l s i l a n e methodology for the deoxygenation. There are, however, other methods for accomplishing this reaction. One particular example, shown in Scheme 2.9.6, was r e p o r t e d by Wilcox, et al., 137 and involves the use of s o d i u m c y a n o b o r o h y d r i d e in the presence of dichloroacetic acid. This r e a c t i o n proceeded in 68% yield. Furthermore, the use of p-toluenesulfonic acid instead of dichloroacetic acid totally blocked the desired transformation. Perhaps the most interesting aspect of this reaction is the fact that the a configuration is made accessible through sugar lactone transformations.

Chapter 2 Scheme 2.9.6

E1ectrophilicSubstitutions

115

Lactol R e d u c t i o n with Sodium Cyanoborohydride

TBDMSO

~

TBDMSOL~ )

O~

O~O

O

NaCNBH3 = HCCI2CO2H/CF3CH2OH 68%

~-

O

...... ,,,

" ~" O~O

Sugar-Sugar Couplings

2.9.3

Before closing this section, the application of nucleophilic additions to sugar lactones with respect to the joining of two sugar units deserves mention and will be further elaborated upon in Chapter 8. As shown in Scheme 2.9.7, Sinay, et al., 138 utilized the lithium anion of a C-acetylenic glycoside to effect formation of an acetylene bridged C-disaccharide. Furthermore, as shown in Scheme 2.9.8, Schmidt, et al., 139 utilized a similar a p p r o a c h involving a c a r b o h y d r a t e - d e r i v e d alkyllithium c o m p o u n d . These examples are not p r e s e n t e d to p r e e m p t the topics encompassed within Chapter 8, b u t to demonstrate that with the expansion of the chemistry surrounding C-glycosides, the preparation of increasingly more complicated structures becomes possible through substantially simpler processes.

Scheme 2.9.7

C-Glycosides from Sugar Lactones

~...-OBn BnO.-'-'~.X~O,

~-OBn

BnO-~~~~~~.

+ BnO BnO OMe

BnO

u

Li~ ~~~'~~0 ~~~-~'~nB n

OH

1

,......OBn BnO O ~' '~ O M e BnO--..-'~----...,~u ~~~,~-.,.~ i-..k--.~OBn gnO,~%~~~%.~-~''-~- "O,......i.~.~Ogn BnO

Chapter 2

116 Scheme 2.9.8

Electrophilic Substitutions

C-Glycosides from Sugar Lactones O

IOBn I

~OBn OBn

+

, 0 OBn

= BnBO

~..OBn

BnO _~__ OH

,I.OAc

co O,

! OBn

AcO

O-----)-'~OAc

zr

AcO--~-/ AcO

AcO

2.10 Nucleophilic Additions to Sugars Containing Enones Figure 2.10.1

Sugar-Derived Enones or 3-Ketoglycals

O Scheme 2.10.1

C-Glycosides from Sugar-Derived Enones

TBDMSO

TBDMSO ..,,,,~R

~ I H3C

R(PhS)CuLi H3CO~"

0

O R = n-Bu, t-Bu, Me, s-Bu

Chapter 2

Electrophilic Substitutions

117

C-Glycosides from Sugar-Derived Enones

Scheme 2.10.2

AcO

AcO

,,,,,,,[~ ..~

Ph2CuCNLi Ac20

AcO'~'"

AcO""" O

OAc

87%

Continuing from sugar lactones, a logical progression is the utilization of sugar-derived enones illustrated in Figure 2.10.1. These enones are readily available from the oxidation of glycals and the stereoselectiviW of addition reactions is dictated entirely by stereoelectronic effects. These reactions are particularly useful in that 2-deoxy C-glycosides are the products.

Figure 2.10.2

AcO o

Stereochemistry of C-Glycosidations Resulting from Cuprates and Sugar-Derived Enones

J

AcO-7~ , ~ O~~OcH2OAc

"~OcH2OAc

AcO--7

AcO~ "O"

O I

Ph

u-

\OAcPh

The formation of C-glycosides from enones has already been illustrated in Schemes 2.2.16 and 2.2.17. Recalling these schemes, cyanoglycosides were the p r o d u c t s o b t a i n e d on treating s u g a r - d e r i v e d e n o n e s with c y a n o h y d r i n s . However, the incorporation of enones as C-glycosidation substrates was known much earlier. For example, as early as 1983, Goodwin, et al., 14o utilized various o r g a n o c u p r a t e s to effect the formation of C-glycosides. As shown in Scheme 2.10.1, a variety of alkyl groups, including the bulky tert-butyl group, were efficiently i n c o r p o r a t e d to the glycosidic center. In this report, the products exhibited the ~ configuration at the anomeric center.

Chapter 2

118

Electrophilic Substitutions

C-Glycosides from Sugar-Derived Enones

Scheme 2.10.3

[~MS

AcO

AcO

O

O I

Ac

O ~

TiCI4,-78~

OAc

90%

O

OAc one diasteriomer

A f u r t h e r example of the use of organocuprates in the formation of Cglycosides from sugar-derived enones was reported by Bellosta, et aI.,141 and is illustrated in Scheme 2.10.2. In addition to the formation of the desired p r o d u c t in 87% yield, a high propensity for the formation of the ~ a n o m e r was observed. This observation was in good agreement with the previous example. Furthermore, as shown in Figure 2.10.2, this report attempted to rationalize the stereoselectivity t h r o u g h stereoelectronic considerations. T h r o u g h these considerations, a mechanism proceeding through a twist boat conformation is predicted. The cz selectivity, in this case, arises from the p s e u d o e q u a t o r i a l a p p r o a c h of the nucleophile to the enoneo One additional point with respect to the p r e s e n t l y discussed example is the ability to utilize acetate p r o t e c t i n g groups in the reaction complimentary to the example shown in Scheme 2.10.1 where silyl groups were used.

Scheme 2 . 1 0 . 4

C-Glycosides from Sugar-Derived Enones

AcO

AcO

,,,,,,~~~~] AcO

Pd(OAc)2 D. 110 C, benzene

AcO"'

"'"

"'"'~" +

AcO~''" O No Acetic Acid, 10% Yield In Acetic Acid, 70% Yield

AcO""" O 69 70

O : :

31 30

Complimentary to the use of organocuprates, silylenol ethers have been useful as agents capable of adding to sugar-derived enones. Already discussed

Chapter 2

Electrophilic Substitutions

119

in detail in section 2.5, silylenol ethers have been exploited in C-glycoside t e c h n o l o g y with respect to their c o m b i n a t i o n with a n o m e r i c a l l y activated sugars. As sugar-derived enones are highly activated sugars, the incorporation of silylenol ethers as reagents for effecting C-glycosidations is logical and c o m p l i m e n t a r y to methods previously addressed. As shown in Scheme 2.10.3, Kunz, et al., 142 effected the use of silylenol ethers in the formation of a 90% yield of the C-glycoside shown. Compared to the use of organocuprates, the use of silylenol ethers allows the formation of ~ anomers f u r t h e r d e m o n s t r a t i n g advantages to having a variety of available C-glycosidation methods. As a final example of the use of sugar-derived enones as substrates for the f o r m a t i o n of C-glycosides, the use of transition metal reagents will be addressed. As shown in Scheme 2.10.4, Benhaddou, et al., 143 effectecl the formation of ~-l-arylglycosides in addition to the substituted enones formed as the major products. As illustrated, the specific reaction proceeded in 70% yield only when acetic acid was used in the reaction. As shown in Figure, 2.10.3, this reaction proceeds t h r o u g h the intermediate 2-metallo c o m p o u n d capable of isomerizing b e t w e e n axial a n d e q u a t o r i a l orientations. Elimination thus liberates the enone while reduction affords the a-l-arylglycoside.

Figure 2.10.3

Palladium Mediated C-Glycosidations of Sugar-Derived Enones

~..~OAc AoO~ O

AcOPd

I

Ph

~

~

/OAc \ ,PdOAc AoO~ O"

I

Ph

Technically different from the chemistry discussed in this chapter, this final example was chosen to illustrate the versatility of sugar-derived enones. The use of transition metals as agents mediating the formation of C-glycosides will be addressed in detail in Chapter 4.

2.11 Transition Metal Mediated Carbon Monoxide Insertions As alluded to at the end of section 2.10 and to be discussed in Chapter 4, transition metals are capable of mediating reactions that produce C-glycosides. One such type of reaction is the transition metal mediated insertion of carbon monoxide generalized in Figure 2.11.1. As a means of preparing C-glycosides this technology has been, until recently, relatively unexplored. The examples that have b e e n r e p o r t e d d e m o n s t r a t e a p r o p e n s i t y for ~-selectivity. These reactions can be executed u n d e r catalytic conditions utilizing both benzylated

Chapter 2

120

Electrophilic Substitutions

and acylated sugars. Additionally, anomeric activation is not a prerequisite for reactions to proceed.

Figure 2.11.1

Example of T r a n s i t i o n Metal M e d i a t e d Carbon Monoxide Insertion Reactions

O M(CO)n

2.11.1 Scheme 2.11.1

M(CO)n.1

Manganese Glycosides C-Glycosides from Carbon Monoxide Insertions

~.OMe

.~OMe

M ~ O ~ Mn(CO)5 OMe

1. CO 2. XNa

1.6 kbar ~ C O 2 M e _ 2. hv, CH3CN

1. 6 kbar ~ C O 2 M e 2. H+

O

Me M O e ~ OMe X X = OMe,63% X = SPh,46% OMe M e M O e o ~

OMe 47% .~.-OMe MeO""'~ -~O`

_... ~

\

CO2Me

OMe ~"~\ 69% CO2Me

In one of the earliest examples of carbon monoxide insertion reactions for the f o r m a t i o n of C-glycosides, Deshong, et al., 144 utilized the m a n g a n e s e glycoside shown in Scheme 2.11.1. This c o m p o u n d was reacted with c a r b o n monoxide followed by the sodium salts of either methanol or thiophenol. The resulting p r o d u c t s were the corresponding ester and thioester. Additional

Chapter 2

E1ectrophilic Substitutions

121

examples demonstrated that vinylic and acetylenic esters were also substrates for these reactions yielding the corresponding Michael products. The manganese glycosides utilized in the above study are easily prepared. As shown in Scheme 2.11.2, Deshong, et al., 14s prepared these compounds from bromoglycosides. Interestingly, from pyranose sugars, the 13anomer could be obtained. However, when furano sugars were used, the a anomer was the predominant product. In all cases, the isolated yields ranged from 50% to 90%. Scheme 2.11.2

C-Glycosides from Carbon Monoxide Insertions

~...OBn

~.....OBn

Mn(CO)5 Br

Mn(CO)5

NaMn(CO)5, 75% Yield NaMn(CO)s, 3 eq. TBAB, 50% Yield NaMn(CO)s, 3 eq. KBr, 90% Yield OBn

BnO : : :

OBn

Ll~O~

o"

OBn

Br

""

+

Bn OBn BnO NaMn(CO)5, 75% Yield NaMn(CO)5, 3 eq. TBAB, 50% Yield NaMn(CO)5, 3 eq. KBr, 90% Yield

2.11.2

100 2 100

OBn 2 > 98

2

~ ~

d

BnO : : :

Mn(CO)5

:--...

OBn 1 2 1

Cobalt Mediated Glycosida tions

Manganese is not the only metal capable of effecting carbon monoxide insertion reactions. In 1988, Chatani, et aL, 146 d e m o n s t r a t e d the utility of cobalt in the generation of C-glycosides. Specific examples, shown in Scheme 2.11.3, involve the conversion of glucose and galactose pentaacetates to the trimethylsilyloxymethylglycosides with ~-selectivity. In the case of glucose pentaacetate, the use of trimethylsilylcobalt tetracarbonyl was illustrated. As a final example, in 1992, Luengo, et aL, 147 applied cobalt methodology to fucose tetraaectate. The results, shown in Scheme 2.11.4, are interesting in that formation of the methyldiethylsilyloxymethyl fucoside proceeded with near exclusive formation of the/]-isomer while employing allyltrimethylsilane

Chapter 2

122

Electrophilic Substitutions

in the r e a c t i o n yielded the ~-isomer in a 1 4 " 1 ratio. In a p p l y i n g this methodology to a practical synthesis, C-GDP-fucose, discussed in section 1.4 and shown in Figure 2.11.2, was prepared as a fucosyltransferase inhibitor.

Scheme 2.11.3

AcO'~..

(

C-Glycosides from Carbon Monoxide Insertions

T o,c

~.~ OSiMe3 Co2(CO)8/co AcO HSiMe~,Phil ,,. ""OAc 4~17675% v AcO"" ~ "'*OAc

AcO,,," ~ /

OAc

OAc

AcOv

AcO

T

~/

63%

""'OAc

"

AcO"

OSiMe3 \

OAc

OAc AcO~~ AcO""" ~ / " " " O A c

Me3SiCo(CO)4 "

C-Glycosides from Carbon Monoxide Insertions

.O.

.,OAc Co2(CO)8, CO

,,,,,

''"OAc

/

1. CO insertion 2. reduction ira, 3. catalystregeneration

OAc

Scheme 2 . 1 1 . 4

AcO"""-~

( ~ ~ . . CO(CO)4

AcO'"' ~

OAc

*,,,,,

""OAc

/

O

Ac

HSiEt2Me 85%

OAc .O, .,,OAc

*",,,..~O"~~ OSiEt2Me AcO""'" .''r "/ "~OAc OAc

20"1

allyltrimethylsilane AcO~''

.{ OAc

OAc

TMSOTf/CH3NO2

-10~ 91%

AcO,,,,..~ OAc

14

19

Chapter 2 Figure 2.11.2

,,,,..

Electrophilic Substitutions

123

C-GDP Fucose and Analogs 0

o-

o-

II

o\ OH

HO""'

0

II

HO""

OH

0

OH X = C H 2, C2H 4

N..

/

H2N

2.12 Reactions Involving Anomeric Carbenes The incorporation of anomeric carbenes in C-glycoside technology has not received much attention. However, anomeric carbenes, as shown in Figure 2.12.1, provide, to date, the only known method for the direct cyclopropanation of anomeric centers. Advantages to this method include general synthetic accessibiliW of the carbenes when benzylated sugars are utilized.

Figure 2.12.1

Example of Glycosidic Cyclopropanations

cyclopropanation

Two examples of the applicability of anomeric carbenes were reported by Vasella, et/t1.148,149 The first demonstrated the utility of olefinic substrates such as N - p h e n y l m a l e i m i d e , acrylonitrile, and d i m e t h y l m a l e a t e for the formation of glycosidic cyclopropanes. The carbene precursor, in this example, was the glucose-derived diazirine. As shown in Scheme 2.12.1, the use of dimethylmaleate produced a mixture of diastereomers with a combined yield of 72%. As s h o w n in Scheme 2.12.2, the m o r e d r a m a t i c e x a m p l e of cyclopropanations involving fullerenes is illustrated. The reaction proceeded with both benzyl and pivalyl protecting groups illustrating the versatility of this reaction under a variety of electronic conditions. The yields in both cases were approximately 55%. A particularly important aspect of this chemistry centers around the desired ability to functionalize the fullerenes and, especially,

Chapter 2

124

E1ectrophilicSubstitutions

C6o or buckminsterfullerene. Through the use of glycosidic carbenes, this technology has been demonstrated to be both efficient and capable of producing a variety of products not readily available through other methods.

Scheme 2.12.1

Glycosidic Cyclopropanations

~..-OBn BnO~ 0 BnO""--~..~~,T~" ,,~C02Me BnO y .....

~10Bn

Me02C

dioxane, r.t. dimethylmaleate

~...OBn

BnO----X----.~O\ BnOB n ~ O Me02C

Scheme 2.12.2

Glycosidic Cyclopropanations

+

ROo .'o

R = Bn, Piv

43%

+

C02Me 29%

Chapter 2

Electrophilic Substitu~'ons

12 5

2.13 Reactions Involving Exoanomeric Methylenes In the final section of this chapter, the elaboration of exoanomeric methylenes to more complex C-glycosides is addressed. These reactions, generalized in Figure 2.13.1, involve the addition of electrophiles to the anomeric olefin. Utilizing this technology makes double C-glycosidations possible. These reactions prefer benzyl protecting groups on the sugars. However, the olefins are easily g e n e r a t e d in situ and reactions at the intermediate tertiary carbocation may be induced.

Figure 2.13.1

Example of Electrophilic Additions to Exoanomeric Methylene Groups

E§

Scheme 2.13.1

~

E

Formation of Exoanomeric Methylene Groups

~----OBn Tebbe's Reagent B n O - ~ ' ~ . . ~ Ok BnO-~'~~.~ OBn ~J

~--- OBn 0

OBn "

Technically C-glycosides, themselves, sugars bearing e x o a n o m e r i c methylene groups are easily prepared by reacting sugar lactones with Tebbe's reagent. As shown in Scheme 2.13.1, RajanBabu, et al., 15o utilized this technology as applied to pyranose sugars. The resulting products, as shown in Scheme 2.13.2, were reacted under a variety of conditions yielding a broad spectrum of products. As demonstrated, alcohols may be introduced in high yields and high stereoselectivity. Interestingly, when less bulky agents such as borane-THF c o m p l e x were used, no s t e r e o s e l e c t i v i t y was o b s e r v e d . Furthermore, 1,3-dipolar cycloaddition reactions and arylations utilizing heavy metal reagents were demonstrated. In the later, non-specific delivery of the phenyl group resulted in the formation of a mixture of products. However, the ring-opened compound will cyclize under reductive oxymercuration conditions. Utilizing similar methodology, Wilcox, et a1.,54 derivitized furanose sugars. One specific example is shown in Scheme 2.13.3 and demonstrates the ability to form hemiketal analogs from these sugar derivatives. The advantage of this

Chapter 2

126

Electrophilic Substitutions

transformation is apparent considering the ability to further derivatize these compounds as previously illustrated in Scheme 2.3.23, Reactions with Exoanomeric Methylene Groups

Scheme 2.13.2

~.OBn BnO.~~.IO BnO-~~~ OBn ~" ehHgOAc, ~ ' O PdCI2

~10Bn 9-BBN

1"t202

BnO-~~~-~ OBn OH OTBDMS 94%, Only Isomer

+ .,....

OBn

BnBOno___~O\

O h1p 3%~ 0

"~ §

OTBDMS

~....OBn

BnO'~ ~ OBn

BnO.--~OHPh B n O ~ OBn "

IHgOAc2,

49% 0~0

78%

NaBH4

~...OBn BnO-~--~-O\ B n O - - ~ - ~ ~ Ph BnO I Scheme 2.13.3

Reactions with Exoanomeric Methylene Groups

o.yo

OTBDMS

~176

OTBDMS ^. / U/~C

OTBDMS Tebbe's Reagent 85%

Acetic Acid

~176

~176

Chapter 2

Electrophilic Substitutions

127

As a final example closing this chapter, the formation of difluoro olefins is discussed. As shown in Scheme 2.13.4, Motherwell, et al.,lSl, ls2 utilized p h o s p h o r u s chemistry to effect the formation of these species in yields ranging from S S% to 65%. Furthermore, reduction stereospecifically converted these difluoro olefins to difluoromethylglycosides. In the last example, reduction was effected with thiophenol and allyltin induced the chain elongation to form a difluorobutenyl glycoside.

Reactions with Exoanomeric Methylene Groups

Scheme 2.13.4

OR2

O.R2

~176 "~

~-

.F

~176

56%

O,~ .....mCF2H

r

"~

OR1

F

OR1 O

Br2F2C P(NMe2)3 Zn, THF ".,,,OR1reflux, 66% R 1

R 10 ~'". . . y. .

OR2 ~

OR1

OR1 (

()

F R1

)T j

CF2H '",,/OR 1

OR1

OR1 PhSH

AIBN

SPh

OR1

R1 = TMS R2 = TBDMS

OR 1 (

(

)

R1 OR1

F

Allyltin= AIBN 60% R 1

/

"'%OR1

OR1

This section has attempted to introduce the use of exoanomeric methylene groups as a means for the formation of more complex C-glycosides. Such species are also a p p a r e n t as intermediates in the formation of C-disaccharides and will be a d d r e s s e d in Chapter 8. For now, let it suffice that exoanomeric methylene groups, considered within other means of C-glycoside syntheses are quite c o m p l i m e n t a r y a n d beneficial to the general chemical knowledge surrounding C-glycosides.

Chapter 2

128

Elec trophilic Substitutions

2.14 References 0

0

0

4. 0

0

7. 0

o

10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.

Lopez, M. T. G.; Heras, F. G. D.; Felix, A. S. J. Carbohydrate Chem. 1987, 6, 273. Kini, G. D.; Petrie, C. R.; Hennen, W. J.; Dalley, N. K.; Wilson, B. E.; Robbins, R. K. Carbohydrate Res. 1987, 159, 81. Hoffman, M. G.; Schmidt, R. R. Liebigs Ann. Chem. 1985, 2403. Nicolaou, K. C.; Dolle, R. E.; Chucholowski, A.; Randall, J. L. J. Chem. Soc. Chem. Comm. 1984, 1153. Araki, Y.; Kobayashi, N.; Watanabe, K.; Ishido, Y. J. Carbohydrate Chem. 1985, 4, 565. Grynkiewicz, G.; Bemiller, J. N. Carbohydrate Res. 1982, 108, 229. Nicolaou, K. C.; Hwang, C. K.; Duggan, M. E. J. Chem. Soc. Chem. Comm. 1986, 925. Smolyadove, I. P.; Smit, W. A.; Zal'chenko, E. A.; Chizhov, O. S.1 Shashakov, A. S. Tetrahedron Lett. 1993, 34, 3047. Mukaiyama, T.; Kobayashi, S.; Shoda, S. I. Chemistry Lett. 1984, 1529. Grierson, D. S.; Bonin, M.; Husson, H. P. Terrahedron Lett. 1984, 25, 4645. Drew, K. N.; Gross, P. H. J. Org. Chem. 1991, 56, 509. Grynkiewicz, G.; BeMiller, J. N. Carbohydr. Res. 1983, 112, 324. Tatsuta, K.; Hayakawa, J.; Tatsuzawa, Y. Bull. Chem. Soc. Jpn. 1989, 62, 490. BeMiller, J. N.; Yadav, M. P.; Kalabokis, V. N.; Myers, R. M. Carbohydr. Res. 1990, 200, 111. Myers, R. W.; Lee, Y. C. Carbohydr. Res. 1986, 152, 143. Pochet, S.; Allard, P.; Tam, H. D.; Igolen, J. J. Carbohydrate Chem. 198283, 1,277. Albrecht, H. P.; Repke, D. B.; Moffat, J. G. J. Org. Chem. 1973, 38, 1836. Trummlitz, G.; Moffat, J. G. J. Org. Chem. 1973, 38, 1841. Ugi, I. Angew. Chem. 1962, 74, 9. Poonian, M. S.; Nowoswiat, E. F. J. Org. Chem. 1980, 45, 203. E1 Khadem, H. S.; Kewai, J. Carbohydr. Res. 1986, 153, 271. Hanessian, S.; Pernet, A. G. Can. J. Chem. 1974, 52, 1268. Cristol, S. J.; Firth, W. C. J. Org. Chem. 1960, 26, 280. Bihovsky, R.; Selick, C.; Giusti, I. J. Org. Chem. 1988, 53, 4026. Bellosta, V.; Czernecki, S. Carbohydrate Res. 1993, 244, 275. Bellosta, V.; Czernecki, S. J. Chem. Soc. Chem. Comm. 1989, 199. Shulman, M. L.; Shiyan, S. D.; Khorlin, A.Y. Carbohydrate Res. 1974, 33, 229. Hanessian, S.; Liak, T. J.; Dixit, D. M. Carbohydrate Res. 1981, 88, C14. Bolitt, V.; Mioskowski, C.; Falck, J. R. Tetrahedron Lett. 1989, 30, 6027. Brown, D.; Ley, S.V. Tetrahedron Lett. 1988, 29, 4869. Ley, S. V.; Lygo, B.; Wonnacott, A. Tetrahedron Lett. 1985, 29, 535. Ley, S. V.; Lygo, B.; Sternfeld, F.; Wonnacott, A. Tetrahedron Lett. 1986, 42, 4333.

Chapter 2

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.

E1ectrophilic Substitutions

129

Beau, J.-M.; Sinay, P. Tetrahedron Lett. 1985, 26, 6185. Cassidy, J. F.; Williams, J. M. Tetrahedron Lett. 1986, 27, 4355. Orsini, F.; Pelizzoni, F. Carbohydrate Res. 1993, 243, 183. Kozikowski, A. P.; Konoike, T.; Ritter, A. Carbohydrate Res. 1987, 1 71, 109. Bols, M.; Szarek, W. A. J. Chem. Soc. Chem. Commun. 1992, 445. Koll, P.; Oelting, M. Tetrahedron Lett. 1986, 27, 2837. Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976. Cupps, T. L.; Wise, D. S.; Townsend, L. B. Carbohydrate Res. 1983, 115, 59. Herscovici, J.; Muleka, K.; Antonakis, K. Tetrahedron Lett. 1984, 25, 5653. Herscovici, J.; Muleka, K.; Boumaiza, L.; Antonakis, K. J. Chem. Soc. Perkin Trans. 1 1990, 1995. Levy, D. E.; Dasgupta, F.; Tang, P. C. Tetrahedron A s y m m e t r y 1994, in press. Adams, D. R.; Bhatnagar, S. P. Synthesis 1977, 10, 661. Cooper, A. J.; Salomon, R. G. Tetrahedron Lett. 1990, 31, 3813. Newcombe, N. J.; Mahon, M. F.; Molloy, K. C.; Alker, D.; Gallagher, T. J. Am. Chem. Soc. 1993, 115, 6430. Terahara, A.; Haneishi, T.; Arai, M.; Hata, T. J. Antibiot. 1982, 35, 1711. Yoshikawa, H.; Takiguchi, Y.; Terao, M. J. Antibiot. 1983, 36, 30. Kozaki, S.; Sakanaka, O.; Yasuda, T.; Shimizu, T.; Ogawa, S.; Suami, T. J. Org. Chem. 1988, 53, 281. Cabaret, D.; Wakselman, M. Carbohydr. Res. 1989, 189, 341. De Mesmaeker, A.; Waldner, A.; Hoffman, P.; Hug, P.; Winkler, T. Synlett 1992, 285. Giannis, A.; Sandhoff, K. Tetrahedron Lett. 1985, 26, 1479. Allevi, P.; Anastasia, M.; Ciuffreda, P.; Fiecchi, A.; Scala, A. J. Chem. Soc. Chem. Comm. 1987, 1245. Wilcox, C. S.; Long, G. W.; Suh, H.S. Tetrahedron Lett. 1984, 25, 395. Acton, E. M.; Ryan, K. J.; Tracy, M. Tetrahedron Lett. 1984, 25, 5743. Martin, M. G. G.; Horton, D. Carbohydrate Res. 1989, 19, 223. Panek, J. S.; Sparks, M. A. J. Org. Chem. 1989, 54, 2034. Babirad, S. A.; Wang, Y.; Kishi, Y. J. Org. Chem. 1987, 52, 1370. Nicotra, F.; Panza, L.; Russo, G. J. Org. Chem. 1987, 52, 5627. Martin, O. R.; Rao, S. P.; Kurz, K. G.; E1-Shenawy, H. A. J. Am. Chem. Soc. 1988, 110, 8698. Bennek, J.; Gray, G. R. J. Org. Chem. 1987, 52, 892. Hosomi, A.; Sakata, Y.; Sakurai, H. Carbohydrate Res. 1987, 171,223. Araki, Y.; Kobayashi, N.; Ishido, Y. Carbohydrate Res. 1987, 171,125. Bertozzi, C. R.; Bednarski, M.D. Tetrahedron Lett. 1992, 33, 3109. Ichikawa, Y.; Isobe, M.; Konobe, M.; Goto, T. Carbohydrate Res. 1987, 171, 193.

130 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.

Chapter 2

Elec trophilic Substitutions

de Raddt, A.; Stutz, A. E. Carbohydrate Res. 1991,220, 101. Ferrier, R. J.; Petersen, P. M. J. Chem. Soc. Perkin Trans. 1 1992, 2023. Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1992, 33, 7911. Keck, G. E.; Enholm, E. J.; Kachensky, D. F. Tetrahedron Lett. 1984, 25, 1867. Nagy, J. O.; Bednarski, M.D. Tetrahedron Lett. 1991, 32, 3953. Waglund, T.; Cleasson, A. Acta Chemica Scandinavica 1992, 46, 73. Zhai, D.; Zhai, W.; Williams, R. M. J. Am. Chem. Soc. 1988, 110, 2501. Tolstikov, G. A.; Prokhorova, N. A.; Spivak, A. Y.; Khalilov, L. M.; Sultanmuratova, V. R. Zh. Org. Khim. 1991, 2 7, 2101. Posner, G. H.; Haines, S.R. Tetrahedron Lett. 1985, 26, 1823. Bellosta, V.; Chassagnard, C.; Czernecki, S. Carbohydrate Res. 1991,219, 1. Macdonald, S. J. F.; Huizinga, W. B.; McKenzie, T. C. J. Org. Chem. 1988, 53, 3371. Outten, R. A.; Daves, D. G. Jr. J. Org. Chem. 1987, 52, 5064. Outten, R. A.; Daves, D. G. Jr. J. Org. Chem. 1989, 54, 29. Hamamichi, N.; Miyasaka, T. J. Org. Chem. 1991, 56, 3731. Kwok, D. I.; Outten, R. A.; Huhn, R.; Daves, G. D. Jr. J. Org. Chem. 1988, 53, 5359. Farr, R. N.; Kwok, D. I.; Daves, G. D. Jr. J. Org. Chem. 1992, 57, 2093. Cai, M. S.; Qju, D.X. Carbohydrate Res. 1989, 191,125. Cai, M. S.; Oju, D.X. Syn. Comm. 1989, 19, 851. Frick, W.; Schmidt, R.R. Carbohydrate Res. 1991,209, 101. Schmidt, R. R.; Hoffman, M. Tetrahedron Lett. 1982, 23, 409. Schmidt, R. R.; Effenberger, G. Liebigs Ann. Chem. 1987, 825. E1-Desoky, E. I.; Abdel-Rahman, H. A. R.; Schmidt, R. R. Liebigs Ann. Chem. 1990, 877. Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1989, 30, 833. Allevi, P.; Anastasia, M.; Ciuffreda, P.; Fiecchi, A.; Scala, A. J. Chem. Soc. Chem. Comm. 1987, 101. Casiraghi, G.; Cornia M.; Colombo, L.; Rassu, G.; Fava, G. G.; Belicchi, M. F.; Zetta, L. Tetrahedron Lett. 1988, 29, 5549. Araki, Y.; Mokubo, E.; Kobayashi, N.; Nagasawa, J. Tetrahedron Lett. 1989, 30, 1115. Martin, O. R.; Hendricks, C. A.; Desphpande, P. P.; Cutler, A. B.; Kane, S. A.; Rao, S. P. Carbohydrate Res. 1990, 198, 41. Martin, O. R.; Mahnken, R. E. J. Chem. Soc. Chem. Comm. 1986, 497. Anastasia, M.; Allevi, P.; Ciuffreda, P.; Fiecchi, A.; Scala, A. Carbohydrate Res. 1990, 208, 264. Ramesh, N. G.; Balasubramanian, K.K. Tetrahedron Lett. 1992, 33, 3061. Casiraghi, G.; Cornia, M.; Rassu, G.; Zetta, L.; Fava, G. G.; Belicchi, M. F. Tetrahedron Lett. 1988, 29, 3323.

Chapter 2

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.

Electrophilic Substitutions

131

Casiraghi, G.; Cornia, M.; Rassu, G.; Zetta, L.; Fava, G.; Belicchi, F. Carbohydrate Res. 1989, 191,243. Matsumoto, T.; Hosoya, T.; Suzuki, K. Tetrahedron Lett. 1990, 32, 4629. Toshima, K.; Matsuo, G.; Ishizuka, T.; Nakata, M.; Kninoshita, M. J. Chem. Soc. Chem. Comm. 1992, 1641. Toshima, K.; Matsuo, G.; Tatsuta, K. Tetrahedron Lett. 1992, 33, 2175. Matsumoto, T.; Hosoya, T.; Suzuki, K. J. Am. Chem. Soc. 1992, 114, 3568. Matsumoto, T.; Katsuki, M.; Jona, H.; Suzuki, K. Tetrahedron Lett. 1989, 30, 6185. Gonzales, M. A.; Requejo, J.; Albarran, P.; Perez, J. A. G. Carbohydrate Res. 1986, 158, 53. Yamaguchi, M.; Horiguchi, A.; Ikegura, C.; Minami, T. J. Chem. Soc. Chem. Comm. 1992, 434. Narasaka, K.; Ichikawa, Y. I.; Kubota, H. Chemistry Lett. 1987, 2139. Ichikawa, Y.; Kubota, H.; Fujita, K.; Okauchi, T.; Narasaka, K. Bull Chem. Soc. Jpn. 1989, 62, 845. Araki, Y.; Watanabe, K.; Kuan, F. H.; Itoh, K.; Kobayashi, N.; Ishido, Y. Carbohydrate Res. 1984, C5, 127. Allevi, P.; Anastasia, M.; Ciuffreda, P.; Fiecchi, A.; Scala, A. J. Chem. Soc. Perkin Trans. I 19 89, 1275. Craig, D.; Munasinghem, V. R. N. J. Chem. Soc. Chem. Comm. 1993, 901. Dawe, R. D.; Fraser-Reid, B. J. Chem. Soc. Chem. Comm. 1981, 1180. Kunz, H.; Muller, B.; Weissmuller, J. Carbohydrate Res. 1987, 1 71, 25. Allevi, P.; Anastasia, M.; Ciuffreda, P.; Eicchim, A.; Scala, A. J. Chem. Soc. Chem. Comm. 1988, 57. Drew, K. N.; Gross, P. H. Tetrahedron 1991, 47, 6113. Koll, P.; Kopf, J.; Wess, D.; Brandenburg, H. Liebigs Ann. Chem. 1988, 685. Aebischer, B.; Vasella, A. Helv. Chim. Acta 1983, 66, 789. Baumberger, F.; Vasella, A. Helv. Chim. Acta 1983, 66, 2210. Aebischer, B.; Meuwly, R.; Vasella, A. HeW. Chim. Acta 1984, 67, 2236. Herscovici, J.; Delatre, S.; Antonakis, K. J. Org. Chem. 1987, 52, 5691. Herscovici, J.; Delatre, S.; Antonakis, K. Tetrahedron Lett. 1991, 32, 1183. Herscovici, J.; Boumaiza, L.; Antonakis, K. J. Org. Chem. 1992, 57, 2476. Acton, E. M.; Ryan, K. J.; Smith, T. H. Carbohydrate Res. 1981, 97, 235. Nicotra, F.; Russo, G.; Ronchetti, F.; Toma, L. Carbohydrate Res. 1983, 124,

CS.

123. Giannis, A.; Sandhoff, K. Carbohydrate Res. 1987, 171,201. 124. Dheilly, L.; Frechou, C.; Beaupere, D.; Uzan, R.; Demailly, G. Carbohydrate

Res. 1992, 224, 301.

125. 126. 127. 128.

Shen, Y.; Xin, Y.; Zhao, J. Tetrahedron Lett. 1988, 29, 6119. Sun, K. M.; Dawe, R. D.; Fraser-Reid, B. Carbohydrate Res. 1987, 171, 36. Bandzouzi, A.; Chapleur, Y. Carbohydrate Res. 1987, 171, 13. Allevi, P.; Ciuffreda, P.; Colombo, D.; Monti, D.; Speranza, G.; Manitto, P. J. Chem. Soc. Perka'n Trans. I 1989, 1281.

132

Chapter 2

E1ectrophilic Substitutions

129. Barnes, J. J.; Davidson, A. H.; Hughes, L. R.; Procter, G. J. Chem. Soc. Chem. Comm. 1985, 1292. 130. Davidson, A. H.; Hughes, L. R.; Qureshi, S. S.; Wright, B. Tetrahedron Left. 1988, 29, 693. 131. Fr6chou, C.; Dheilly, L.; Beaupere, D.; Demailly, R.U. Tetrahedron Lett. 1992, 33, 5067. 132. Horton, D.; Priebe, W. Carbohydrate Res. 1981, 94, 27. 133. Lancelin, J. M.; Zollo, P. H. A.; Sinay, P. Tetrahedron Lett. 1983, 24, 4833. 134. Kraus, G. A.; Molina, M. T. J. Org. Chem. 1988, 53, 752. 135. Czemecki, S.; Ville, G. J. Org. Chem. 1989, 54, 610. 136. Krohn, K.; Heins, H.; Wielckens, K. J. Med. Chem. 1992, 35, 511. 137. Wilcox, C. S.; Cowart, M. D. Carbohydrate Res. 1987, 171, 141. 138. Rouzaud, D.; Sinay, P. J. Chem. Soc. Chem. Comm. 1983, 1353. 139. Preuss, R.; Schmidt, R. R. J. Carbohydrate Chem. 1991, 10, 887. 140. Goodwin, T. E.; Crowder, C. M.; White, R. B.; Swanson, J. S.; Evans, F. E.; Meyer, W. L. J. Org. Chem. 1983, 48, 376. 141. Bellosta, V.; Czernecki, S. Carbohydrate Res. 1987, 171,279. 142. Kunz, H.; Weibuller, J.; Muller, B. Tetrahedron Lett. 1984, 25, 3571. 143. Benhaddou, R.; Czernecki, S.; Ville, G. J. Org. Chem. 1992, 57, 4612. 144. Deshong, P.; Slough, G. A.; Elango, V. J. Am. Chem. Soc. 1985, 107, 7788. 145. Deshong, P.; Slough, G. A.; Elango, V. Carbohydrate Res. 1987, 171,342. 146. Chatani, N.; Ikeda, T.; Sano, T.; Sonoda, N.; Kurosawa, H.; Kawasaki, Y.; Murai, S. J. Org. Chem. 1988, 53, 3387. 147. Luengo, J. I.; Gleason, J. G. Tetrahedron Lett. 1992, 33, 6911. 148. Vasella, A.; Waldraff, C. A. A. Helv. Chim. Acta. 1991, 74, 585. 149. Vasella, A.; Uhlmann, P.; Waldraff, C. A. A.; Diederich, F. Angew. Chem. Int. Ed. Eng. 1992, 31, 1388. 150. RajanBabu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51, 5458. 151. Motherwell, W. B.; Tozer, M. J.; Ross, B. C. J. Chem. Soc. Chem. Comm. 1989, 1437. 152. Motherwell, W. B.; Ross, B. C.; Tozer, M.J. Synlett 1989, 68.

C h a p t e r Three

3

Nucleophilic Sugar Substitutions

Introduction

As thoroughly covered in Chapter 2, the use of electrophilic substitutions at the anomeric center have provided a substantially diverse variety of methods for the preparation of C-glycosides. However, a complimentary approach to the preparation of these compounds, for which there is no counterpart in O-glycoside chemistry, is found through the use of sugar-derived nucleophiles. The formation of C i lithiated sugar derivatives can be accomplished through a variety of methods including direct hydrogen-metal exchange, metal-metal exchange, and sulfone reductions. Scheme 3.0.1

~ ~~176L

C-Glycosides from

Anomeric Nucleophiles

OMe ~~OMe

O

i

,,,,,,,....,.,,,.0...,.,.,.....,~~

+

TBDMS OTBDMS

~

TBDMSO

MeO OMe

OMe

OTBDMS BH3~ 2. Oxidation

60%

/ 1. DIBAL 12" POCI3

94%

OMe

OMe ". . . . . . . . .

TBDMSO"

OMe

=-,7i.

TBDMS

OTBDMS

. OTBDMS

133

Chapter 3

134

Nucleophilic Sugar Substitutions

As shown in Scheme 3.0.1, C1 lithiated carbohydrate analogs can act as nucleophiles in the formation of C-glycosides. This particular example, reported by Parker, et al., 1 p r o d u c e d an i n t e r m e d i a t e c o m p o u n d capable of being converted to either a substituted glycal or a C-aryl glycoside. In this c h a p t e r the formation of C1 lithiated sugar derivatives and their incorporation into the p r e p a r a t i o n of C-glycosides are addressed. Additionally, the use of electron withdrawing stabilizing groups are discussed.

3.1

C1 Lithiated Anomeric Carbanions by Direct Metal Exchange

The direct metallation of sugar derivatives, shown in Figure 3.1.1, is a useful m e t h o d for the preparation of anomeric nucleophiles. Anomeric halides and glycals are excellent substrates for this reaction. Additionally, selective generation of a and B anomers is possible.

Figure 3.1.1

General Metallation Examples

metal-exchange X = n-Bu3Sn .~X

metal-exchange

~ ~

Li

Li

X = H, n-Bu3Sn, I

3.1.1

Hydrogen-Metal Exchanges

Scheme 3.1.1

Glycal Lithiations

OTBDMS

OTBDMS X

Li R = H, OTBDMS X = H, SnBu 3

t-BuLi, 1.5 e q . TBD M SO~,,"' T

TBD M SO""" R

Chapter 3

Nucleophilic Sugar Substitutions

135

Direct applications of this methodology to the preparation of C-glycosides was demonstrated as early as 1986 when Sinay, et al., 2 converted glycals and 1-stannyl glycals to 1-1ithioglycals on treatment with tert-butyllithium. These results, shown in Scheme 3.1.1, were complemented by Nicolau's subsequent application to the generation of C-glycosides on treatment with allyl bromide, shown in Scheme 3.1.2.3 As illustrated, the product of this addition was the 1allylglycal shown. Utilizing a variety of methods described in Chapter 2, these compounds are easily transformed to a variety of true C-glycosides.

Scheme 3.1.2

C-Glycosides f r o m Glycals OR

OR

t-BuLi (2 equiv.) Cul, allylbromide 75%

RO~,,,''

r

RO ~,' OR

OR R = t-BuMe2Si, t-BuPh2Si

Scheme 3.1.3

Glycal S t a n n y l a t i o n s OR

OR

SnBu 3 t-BuOK/BuLi -78~ Bu3SnCI

RO""

RO,,,,"'" T OR R = t-BuMe2Si

OR

Scheme 3.1.4

Glycal Lithiations OBn

Bn

OBn

O

I

OBn

1. PhSCI/DBU 2. m-CPBA

3. LDA

Bn

"

(

OBn

SOPh

Chapter 3

136

Nucleophilic Sugar Substitutions

Later work elaborating on the chemistry of glycals demonstrated the ease of formation of 1-stannyl glycals. These compounds, introduced in Scheme 3.1.1, are useful substrates for the direct formation of C-glycosides as well as for metal-metal exchanges with lithium to be discussed later in this chapter. As shown in Scheme 3.1.3, Hanessian, et a1.,4 utilized potassium tert-butoxide and butyllithium to effect the formation of 1-stannyl glycals. Continuing with the direct metallation of glycals, 2-phenylsulfinyl derivatives have found utility. Their formation and subsequent lithiation, shown in Scheme 3.1.4, is accomplished on reaction of glycals with phenylsulfenyl chloride under basic conditions. Subsequent oxidation with mCPBA yields the sulfinyl compound ready for lithiation on treatment with lithium diisopropylamide. Advantageous to the formation of this species is the stabilization of the anion by chelation of the sulfoxide to the metal. This procedure reported by Schmidt, et al., 5 was utilized in the preparation of Cdisaccharides, discussed in Chapter 8. Similar reactions involving the lithiation of 2-phenylsulfinyl glycals, again reported by Schmidt, et al.,6 are shown in Scheme 3.1.5. The actual couplings involved the addition of benzaldehyde to the lithiated species. The coupling proceeded in approximately 86%. An important observation is the induction of stereochemistry at the newly formed center with a diastereomeric ratio of approximately 4 : 1. Utilizing this methodology, the compounds shown in Figure 1.4.1 were prepared as potential ~-glucosidase inhibitors. S c h e m e 3.1.5

Glycal Lithiations

OBn

OBn (

Bn

)" I s//O 1. LDA,-100 ~C --- Bn ~/~L,. 2. Benzaldehyde 86% OBn(

OH OBn OH ( () L'~p h "~Ph "~"" S~O ,~S ~~ + Bn OBn( OBn 4

:

1

Before moving to other means used in the preparation of C 1 lithioglycals, mention of a final example utilizing a hydrogen-metal exchange is warranted. The example of interest, shown in Scheme 3.1.6, was reported by Friesen, et ai.,7 and involves the formation of C1 iodinated glycals. As shown, direct lithiation was accompanied by treatment with tri-n-butyl stannylchloride. Subsequent treatment of the stannylated glycal with iodine gave the iodinated compound in 85% overall yield. These compounds have subsequently found use

Chapter 3

Nucleophilic Sugar Substitutions

13 7

in coupling reactions with arylzinc, vinyltin, and arylboron compounds. Thus, a compliment of unique C-glycosides are available through this methodology. Scheme 3.1.6

C-Glycosides from C1 Iodo Glycals

OTIPS

OTIPS

OTIPS I

1. t-BuLi/n-Bu3SnCI

R R-M

2. 12, 85% Overall

TIPSO""" TIPSO

TIPSO~,''

TIPSO

TIPSO"" ~ TIPSO

M

Yield (%)

ZnCI

74

B(OH)2

75

Sn~7"~- )3

67

I

3.1.2

Me tal-Me tal Exchanges

Although the hydrogen-metal exchange has found utility in the formation of C1 lithiated glycals, sometimes, the best method for the formation of these c o m p o u n d s rests in the ability to trans-metallate from a different metallo glycal. These metal-metal exchanges have been extensively exploited in the derivitization of glycals as well as providing an efficient means of forming true anomeric anions from stannyl glycosides. As already discussed in Scheme 3.1.3, Hanessian, et al., 8 prepared the C1 stannyl glycal shown. Further work by this group demonstrated the ability to transform this glycal analog to a lithiated species in preparation for coupling with an aldehyde. The reaction, shown in Scheme 3.1.7, produced a 68% yield of the C-glycoside as a mixture of isomers at the newly formed stereogenic center. Electrophiles other than aldehydes have been demonstrated to effect the formation of C-glycosides under conditions involving metal-metal exchanges. As shown in Scheme 3.1.8, such reactions have been accomplished utilizing allyl

Chapter 3

138

Nucleophilic Sugar Substitutions

halides. The reaction shown, reported by Grondin, et al., 9 involves the formation of the lithioglycal on reaction with butyllithium. The resulting anionic glycal was coupled with allyl halides utilizing copper bromide-dimethyl sulfide complex to assist the progression of the reaction via a tandem cuprate formation. Glycal Trans-Metallations

Scheme 3.1.7

OR OR SnBu3

Bn Bn

n-BuLi

R J

BnOoMe

RO""'

"'"

BnO

--

OR R = TBDMS

Glycal Trans-Metallations

Scheme 3.1.8 OTIPS

L

BnO / 0Me

68%

OTIPS

O

SnBu 3 i

TI PS

1. n-BuLi lid 2. Allyl halide, CuBr-Me2S TI PS

TIPSO

TIPSO

Applying this methodology to stannyl glycosides, the preparation of which was discussed in Chapter 2, Michael acceptors have found utility in the direct formation of C-glycosides. As shown in Scheme 3.1.9, Hutchinson, et al., lo t r e a t e d the p r o t e c t e d 2-deoxyglucose-derived ~-stannyl glycoside with butyllithium followed by copper bromide-dimethyl sulfide complex. Once formed, the cuprate was exposed to methyl vinyl ketone producing a 55% yield of the B-C-glycoside. Furthermore, utilizing the a-stannyl glycoside and comparable reaction conditions, a 75% yield of the desired a-C-glycoside was formed. One may infer, from these results, that the stereochemistry of anomeric anions is stable and remains intact through the duration of these reactions. Corroboration of the above described results was accomplished numerous times. However, one particular example deserved mention simply to illustrate the versatility available not only in the electrophile used but also in the nature

Chapter 3

Nucleophilic Sugar Substitutions

139

of the cuprate formed. As shown in Scheme 3.1.10, Prandi, et al., 11 utilized the same stannyl glycoside and formed the mixed cuprate from the lithioglycoside. The cuprate was formed utilizing lithium thienyl copper cyanide. Subsequent condensation with the epoxide, shown, produced the desired C-glycosides in 50% to 67% yields with retention of the anomeric stereochemistry. Glycosidic Trans-Metallations

Scheme 3.1.9

O

~....-OBn

1. n-BuLi

BnO~O,

~OBn -

2. CuBr-Me2S

BnO~SnBu3

B

O

~...-OBn

BnO--'x-~O~

1. n-BuLi

BnO--&~

J1.

~'~

n

O ~ 55% ~.i OBn BnO.-'-"~.~0 0

-

2. CuBr-Me2S

SnBu3 Scheme 3.1.10

75"/0

Glycosidic Trans-Metallations

~....OBn

1. n-BuLi

SnO~O~

BnO~SnBu3

2. Li(thienyl)CuCN

50% ~...OBn

~.....OBn

BnO---V..~O

1. n-BuLi

B n O ~

/OBn BnO \ .. OBn = BnO ~ ~ ~ ~

2. Li(thienyl)CuCN

OBn B n O L ~ o ~ ~

OBn OH

OBn

SnBu3 67% OH 3.1.3

Halogen-Me tM Exchanges

Complimentary to hydrogen-metal exchanges and metal-metal exchanges are halogen-metal exchanges. This method has particularly been useful in conversions involving glycosyl chlorides. As shown in Scheme 3.1.11, Lesimple,

Chapter 3

140

Nucleophilic Sugar Substitutions

et al., 12 treated 2-deoxy-3,4,6-tri-O-benzyl-D-glucopyranosyl chloride with trin-butyl stannyllithium. The result was the formation of the desired stannyl glycoside in 85% yield with inversion of the stereochemistry at the anomeric center. Thus, the a-pyranosyl chloride yielded the ~-stannyl glycoside. Scheme 3.1.11

Glycosidic Halogen-Metal Exchanges

~...OBn BnO.--.-.~0

~10Bn

n-Bu3SnLi

=

B n O ~

B n O ~ O BnO . . . ~ . ~ ~ ~ -

85% SnBu3

CI

3.2

Cl Lithiated Anomeric Carbanions by Reduction

Scheme 3.2.1

Glycosidic Halogen-Metal Exchanges

~...OBn BnO.-....~O B n O ~

~..OBn Lithium Naphthalide -" BuaSnCI

BnO-"k"- q SnBu3

CI

Figure 3.2.1

70%

B n O ~

Stable Lithioglycosides

~...OBn

~...OBn U

RBO

Configurationally Stable at-78~

I ~ . i

Complementary to the reaction shown in Scheme 3.1.11 is a method reported by the same group demonstrating the formation of the corresponding stannyl glycoside. 12 As shown in Scheme 3.2.1, this reaction provided a 70% yield of the desired product utilizing lithium naphthalide to form the intermediate C1 lithiated sugar. Furthermore, the intermediate lithioglycosides relevant to Schemes 3.1.11 and 3.2.1, shown in Figure 3.2.1, were demonstrated to be configurationally stable a t - 7 8 ~ C. These observations are in complete agreement with the observed stereochemical stabiliW of anomeric cuprates

Chapter 3

Nucleophilic Sugar Substitutions

141

r e p o r t e d by Hutchinson, et al., 10 and illustrated in Scheme 3.1.9 as reagents effecting the formation of C-glycosides on reaction with Michael acceptors.

Reductive Halogen=Metal Exchanges

Figure 3.2.2

reduction

~

Li

C-Glycosidations Following Reductive Halogen-Metal Exchanges

Scheme 3.2.2

~....OBn

IB 1. n-BuLi, THF,-100~ 2. Li-naphthalide (2.2 eq.)

~...OBn 7

nBOn I ,,or d

HOWl

~..-OBn electrophile

HOI

R

Electrophile

Electrophiles, Products, and Yields from Scheme 3 2.2 R

% Yield

MeOD MeOH MeCHO PhCHO iPrCHO HCHO MeI/CuI

D H CH(OH)Me CH(OH)Ph CH(OH)iPr CH2(~ Me

75 82 62 70 59 17 72

T a b l e 3.2.1

The t r a n s i e n t anomeric lithiation shown in Scheme 3.2.1 differs from s t a n d a r d halogen-metal exchanges in that a reductive m e c h a n i s m is involved. The use of reductive methods, illustrated in Figure 3.2.2, is c o m p l i m e n t a r y to the exploitation of metal exchange reactions for the formation of glycosidic n u c l e o p h i l e s in t h a t s t r a t e g i e s t o w a r d s s e l e c t i v i t y in the a n o m e r i c stereochemistry become available.

Chapter 3

142

Nudeophilic Sugar Substitutions

As shown in Scheme 3.2.2, Wittman, eta/., 13 utilized reductive anomeric lithiations in the preparation of a variety of glucose analogs. The specific p r o c e d u r e involved the use of 3,4,6-tri-O-benzyl-~-D-pyranosyl chloride. Initial t r e a t m e n t with b u t y l l i t h i u m d e p r o t o n a t e d the 2-hydroxyl group. Subsequent t r e a t m e n t with lithium naphthalide effected formation of the dianionic i n t e r m e d i a t e shown. Notably, this species possessed the configuration at the anomeric center. Treatment of this species with a variety of electrophiles provided a variety of compounds predominantly formed in greater than 60% yield. Additionally, reflecting the stereochemistry of the glycosidic anion, the products reported possessed the ~ configuration. The actual yields of the isolated ~ anomers obtained from various electrophiles are shown in Table 3.2.1. As a final point, formation of side products resulting from ~-elimination is unfavorable due to 02- being the leaving group. Similar reductive lithiations are available from 2-deoxy sugars. As shown in Scheme 3.2.3, tri-O-benzyl glucal was converted to the desired 2-deoxy glucopyranosyl chloride on t r e a t m e n t with hydrochloric acid. Following formation of the chloride, Lancelin, et al., 14 effected formation of the ~ lithiated sugar, via initial conversion to the axially oriented anionic radical, on treatment with lithium naphthalide.

Scheme 3.2.3

Reductive Halogen-Metal Exchanges

OBn

~10Bn

~-OBn

Hc'_ %Oo-'" Bn

LithiumNaphthalide

BnO

O,

BnO-~~~.~Li CI

OBn

Scheme 3.2.4

Reductive Metallations from Sulfones

OR RO~ R O ~ s o 2 P

h

0

1. Li-Naphthalide 2. Benzaldehyde -78"C,66%

C o m p l i m e n t a r y to the use of pyranosyl chlorides as substrates for reductive lithiations is the use of pyranosyl phenylsulfones. These species are

Chapter 3

Nudeophilic Sugar Substitutions

143

easily reduced to the corresponding lithioglycosides with equal propensities for the selective formation of ~ anomers. As shown in Scheme 3.2.4, Beau, et al., is utilized this methodology in the formation of C-glycosides resulting from the t r e a t m e n t of the formed lithioglycosides with various aldehydes. As shown, the use of b e n z a l d e h y d e effectecl the formation of the desired C-glycoside in 66% yield with exclusive formation of the a anomer. One additional example of reductive glycosidic lithiations is w a r r a n t e d in t h a t the specific example, shown in Scheme 3.2.5, results in a carboxyl stabilized glycosidic anion. As illustrated, Crich, et al., 16 treated the 2-deoxy-Dglucose derivative, shown, with l i t h i u m n a p h t h a l i d e to effect r e d u c t i v e lithiation. The resulting stabilized anion was treated with allyl b r o m i d e thus effecting allylation in 44% yield. Hydrolysis and recluctive decarboxylation u n d e r Barton conditions17,18 gave the ~ C-glycoside in 50% yield. Notably, the resulting C-glycoside exhibits the opposite stereochemistry usually observed u n d e r reductive conditions. This is due to the preference of the intermediate radical anion for the a configuration. Furthermore, the stabilized nature of the intermediate anionic species facilitates retention of the observed stereochemical outcome. These observations will be addressed in detail in Section 3.3.

Scheme 3.2.5

Reductive Halogen-Metal Exchanges

OBn

OBn 2Ph

e

CO2Me 1. Lithium Naphthalide 2. Allyl bromide 44%

Bn

Bn

OBn

OBn

OBn 1. KOH 2. Barton

BnO""" OBn

3.3

C1 Carbanions Stabilized by Sulfones, Carboxyl and Nitro G r o u p s

Sulfides,

Sulfoxides,

The use of c a r b a n i o n s in the p r e p a r a t i o n of C-glycosides is often d e p e n d e n t on the ability to generate stable lithiated species. Consequently, the use of electron withdrawing groups as a means for anion stabilization is often

Chapter 3

144

Nucleophilic Sugar Substitutions

employed. Shown in Figure 3.3.1 are several representations of sugar derivatives containing electron withdrawing groups in order to facilitate their C1 deprotonation and subsequent utility in the formation of C-glycosides.

Figure 3.3.1

Electron Deficient Sugar Derivatives

.~

_(/sR

"tSO2Ph. ~ SOPh

. ~ ~ CO2R. ~ ~ NO2

3.3.1

Sulfone Stabilized Anions

Scheme 3.3.1

Lithiation of Glycosyl Phenylsulfones OR

LDAorn-BuLi SO2Ph

Li

SO2Ph

o~:~l = 1:6(10) OR D20

_

OR

R

SO2Ph +

1

D

:

D

4

SO2Ph

R = Me, Bn, TBDMS

Of the examples shown in Figure 3.3.1, glycosyl phenylsulfones are extremely useful, particularly in conjunction with reductive methods discussed in Section 3.2. For example, Scheme 3.3.1 illustrates work reported by Beau, et al.,ls in which the illustrated phenylsulfone was utilized as follows. Deprotonation with either LDA or n-butyllithium effected the direct formation of the desired ~-lithiated species. Subsequent deuterium oxide quench provided a 4 : 1 mixture of anomeric favoring that bearing the deuterium in the position. As reported, This methodology is useful with a variety of protecting groups including methyl, benzyl, and tert-butyl dimethylsilyl ethers.

Chapter 3

NucleophilicSugar Substitutions

145

Lithiation of Glycosyl Phenylsulfones

Scheme 3.3.2

OTBDMS

~...-OTBDMS TBDMSO~

O

TBDMSO~so2P

1. LDA = TBDMSO~I~ O CO20H3 2. (CH30)20=O I "/ ~ " ~ ~ S O 2 P h h OTBDMS ~..OTBDMS

D M S O " 'L~\ ~ . ~I O\ x 1. Lithium Naphthalide~T BTBDMSO q 2. MeOH

72% overall, o~: [3 = 10:1

CO2CH 3

Scheme 3.3.3

Mechanism for C-Glycosidation of Sulfones

OR ,

OR (

O/sO2Ph~'~' I. LDA = 2. R'COX

R

Xv•,

OLi

OR L

x /O,

R' ~~-OLi

R OR R = TBDMS

OR

OR

OR

O\

,

OR

~'

2Ph LN =

LN = Lithium Naphthalide

OLi

TON

yOR ON

1

O R

RO~,,,," OR

!

Chapter 3

146

Nucleophilic Sugar Substitutions

In the application of this methodology to the preparation of C-glycosides, Beau, et al., 19 utilized dimethyl carbonate as an electrophile. As shown in Scheme 3.3.2, the resulting product mixture favored the 13oriented ester group in a ratio of 20 : 1. Subsequent reductive cleavage of the phenylsulfone was accomplished on t r e a t m e n t with lithium naphthalide giving the ~-C-glycoside, shown, in 72% overall yield. Similar results were o b s e r v e d w h e n p h e n y l benzoate was used as an electrophile. At first glance, and in a g r e e m e n t with the observations p r e s e n t e d in Scheme 3.2.5, the results shown in Scheme 3.3.2 seem c o n t r a r y to the stereochemical consequences of the reactions discussed thus far. For example, a l t h o u g h the d e p r o t o n a t i o n step proceeds as inferred in Scheme 3.3.1 with ~lithiation a n d f o r m a t i o n of p r o d u c t s possessing the 13 c o n f i g u r a t i o n at the a n o m e r i c center, the s t e r e o c h e m i s t r y converts to the ~ c o n f i g u r a t i o n on reductive cleavage of the phenylsulfone. This may not seem consistent with the preferential f o r m a t i o n of ~ lithioglycosides u n d e r reductive conditions. As shown in Scheme 3.3.3, this a p p a r e n t inconsistency is explained. Once the Cglycosidation has been accomplished, lithium naphthalide effects the formation of the ~ lithioglycoside which conjugates into the carbonyl of the a d d e d group. Upon quenching, the preferred ~ configuration is adopted. Additional work reported by Beau, et al.,20 extended the use of stabilized anions and reductive cleavages to the preparation of C-disaccharides. As shown in Scheme 3.3.4, the phenylsulfone was deprotonated and treated with a sugarderived aldehyde. The phenylsulfone was then cleaved from the resulting p r o d u c t utilizing lithium naphthalide. Unlike the example shown in Scheme 3.3.2, conjugation of the intermediate lithioglycoside resulting from cleavage of the phenylsulfone is not possible. Therefore, isomerization does not occur and the p r e d o m i n a n t product bears the B anomeric configuration.

Scheme 3 . 3 . 4

L i t h i a t i o n of Glycosyl Phenylsulfones

F. RO~IOR----~-..~O ,DA

RO"-'~"'"'~~"SO2Ph

Lithium Naphthalide

O H z(,~ / ao~/~...O~OMe "I/ PhO",[ ? / ~ ~,, OBn

OHC BnO-.~~_~ 2. BnOoMe L_ BnO~O

-

OH O

;

i1,~11 i

Bn

m

51%, R = TBDMS BnO OBn

Bn

Chapter 3

Nudeophilic Sugar Substitutions

147

Sulfide and Sulfoxide Stabilized Anions

3.3.2

Glycal M e t a l l a t i o n s

Scheme 3.3.5 .OBn

Bn0 " ' q ' ~ \ / O \

Bnb--~ "" ~ H

\

.OBn

n-BuLi, t-BuOK THF, -100"C Electrophile

BnO"~'x.~/O\ BnO-~ " ~ E

\

OBn E = D, Me, SMe, CO2Me

OBn

C2 Activated Glycals in C - G l y c o s i d a t i o n s

Scheme 3.3.6

.OBn

_OBn

BnO~Ox PhSCI DBU = BnO...3 - ~

Bno~O\ BnO...3 -

O•O

\ SPh

LDA/t-BuLi

.OBn H

\ SPh

1~176

EtCHO

I PhCHO

BnO-...~ - ~

OHC~~---~

\ Ph

••OBn %

BnO BnO...J - ~

\

u ~X

_OBn

\

Et

N I X = H, Y = OH, R = SPh Raney-Ni X = OH, Y = H, R = SPh - - ' X = R = H, Y = OH X=OH, Y = R = H -~

BnO"~O\ BnO-..3

\

" ....

IRaney-Ni

SPh

O•O \

\ OH

Until now, only glycosidic phenylsulfones have b e e n discussed as substrates for the formation of glycosidic anions. However, as illustrated in Figure 3.3.1, other sugar derivatives are useful. Among these are glycal analogs. Early examples of the utilization of glycal analogs were reported by Schmidt, et a1.,21 and are shown in Scheme 3.3.5. In this report, the ability to directly lithiate protected glycals and introduce new glycosidic moieties was

Chapter 3

148

NucleophilicSugar Substitutions

documented. As shown, metallations were accomplished utilizing butyllithium and potassium tert-butoxide at low temperatures. The observations illustrated in Scheme 3.3.5 were complimented, in the same report, by the demonstration of the utility of 2-phenylsulfide activated glycals as C-glycosidation substrates. As shown in Scheme 3.3.6, 2phenylsulfide substituted glycals were easily prepared on treatment with DBU and chlorophenylsulfide. Subsequent metallations were then accomplished utilizing tert-butyllithium and LDA. Treatment of the anionic species with a variety of aldehydes effected the formation of various C-glycosides.

Phenyl Sulfoxides in C - G l y c o s i d a t i o n s

S c h e m e 3.3.7

OBn

OBn

Bn()~.~( )~~~.s~O OBn~

1. LDA,-100~ 2. Benzaldahyde 86%

OH

OBn o

Ph+ O Bn

i,.

BnO*""

OH -

Ph O

OBn

OB 4"I

Scheme 3.3.8

Phenyl Sulfides in C - G l y c o s i d a t i o n s O~ , 3--~ sPh n-BuLi

MeO.

T P S O ''" v

"OMe

H+

OMe

O O SPh

OMe

As a logical extension to the use of 2-phenylsulfide substituted glycals as substrates for the formation of C-glycosides is the use of 2-phenylsulfoxide

Chapter 3

Nucleophilic Sugar Substitutions

149

substituted glycals. A particular advantage over the use of phenylsulfides is that incorporation of chirality to the phenylsulfoxide allows for stereospecificity in the addition of aldehydes to subsequently metallated species. As shown in Scheme 3.3.7, Schmidt, et al., 6 incorporated the above described technology in the ultimate preparation of the potential ~-glycosidase inhibitors illustrated in Figure 1.4.1. The key reaction, illustrated, involves LDA m e d i a t e d deprotonation of the substituted glycal followed by addition of benzaldehyde to the resulting lithiated species. This particular example proceeded in 86% yield with the formation of a 4 : 1 ratio of diastereomers. Concurrent with the development of phenylsulfoxide chemistry and complimentary to the use of 2-phenylsulfide substituted glycals came reports demonstrating the utility of glycosidic phenylsulfides of 2,3-di-deoxy sugars in the preparation of C-glycosides. As shown in Scheme 3.3.8, Gomez, et al., 22 applied this chemistry to coupling reactions with cyclic sulfates. The immediate product of the reaction was a 3-phenylsulfide-l-substituted glycal. Further elaborations converted this product to an unsaturated spiroketal via hydrolysis of the sulfate and eventual cyclization.

Carboxy Stabilized Anions

3.3.3 Scheme 3.3.9

C a r b o x y g l y c o s i d e s in C - G l y c o s i d a t i o n s HO

HO

HO~ CO2H

HO-~~-~CO2H OH

o

3

O

002R

1. LDA 2. Electrophile

.~.,,,,~CO2R

4_0 As already alluded to in Schemes 3.2.5 and 3.3.2, the carboxyl group is an excellent stabilizing group for anomeric anions. C1 carboxyl glycosides are easily p r e p a r e d from a n u m b e r of m e t h o d s discussed in C h a p t e r 2. Additionally, many naturally occurring C1 carboxyl glycosides are known.

Chapter 3

150

Nudeophilic Sugar Substitutions

Among these is 3-deoxy-D-manno-2-octulosonic acid. This sugar has been identified as a component of the lipopolysaccharides released by Gram-negative bacteria.Z3, 24 As shown in Scheme 3.3.9, Luthman, et at., 2s demonstrated ability to derivatize this sugar through C1 metallation and subsequent alkylation. The results, obtained from both the methyl and ethyl ester derivatives of this sugar d e m o n s t r a t e m o d e r a t e yields and high stereoselectivities. For example, utilizing tert-butyl bromoacetate, the yield of the desired alkylated sugar was only 30% with a ratio of 95 : 5 favoring the ~ anomer. However, utilizing f o r m a l d e h y d e afforded a 62% yield of the desired h y d r o x y m e t h y l analog exhibiting a ratio of 90 : 10 favoring the 13anomer. These results, accompanied by additional observations are shown in Table 3.3.1. In all cases, metallation was accomplished utilizing LDA. Table 3.3.1

CH2OH ~3 CH3 CH2C-=(}I CH2CO2tBu CH2Ph CH2CH2CO2CH3

C a r b o x y g l y c o s i d e s in C - G l y c o s i d a t i o n s R' 96 a 96 ~ Total > 95 <5 CH3 CH2C~3 10 90 CH2CH3 10 90 CH2CH3 5 95 CH2CH3 <5 > 95 CH2CM3 10 90 CH2C~3 <5 > 95 CH3 5 95 CH2CH3 25 75

Scheme 3.3.10

Yield (96) 47 55 47 62 50 50 30 67 27

Sialic Acid D e r i v a t i z a t i o n

OBnOBn H BnO~co2tBu BnO QBnoBn BnO

1. LDA 2. HCHO

OBn " OBn

co2tBu

BnO~

CH20H BnO

co2tBu OBn B n O ~ c H 2 O H

co2tBu

BnO

3"1

OH,..,,,

OBn

BnO

CH2OH

HO

CO2H CH2NH2

HO

Chapter 3

Nucleophilic Sugar Substitutions

151

Among the most studied of the naturally occurring C 1 carboxyglycosides is N-acetyl neuraminic acid or sialic acid. The importance of this molecule centers around it being a component of sialyl Lewisx, the natural ligand for the selectins and a key player in cell adhesion and leukocyte trafficking. 26 As shown in Scheme 3.3.10, Vasella, et ai.,27 prepared C-glycosidic sialic acid derivatives beginning with the 1-deoxy sialic acid analog shown. Deprotonation with LDA followed by t r e a t m e n t with formaldehyde p r o d u c e d a 3 : 1 ratio of the h y d r o x y m e t h y l a t e d products favoring the ~ anomeric configuration for the added group. Following deprotection, these compounds were found to be weak inhibitors of Vibro cholerae sialidase. In the same report, the ~-hydroxymethyl analog was converted to the corresponding aminomethyl derivative via the azide. As compared to the hydroxymethyl analogs, the aminomethyl analog was shown to stimulate Vibro cholerae sialiclase.

3.3.4

Nitro Stabilized Anions

Scheme 3.3.11

C-Glycosides f r o m Nitroglycosides

O,.-4 CHO

~......OBn BnO~ OH B

n

O

~10Bn BnO O, BnO-~~~

~ NOH OBn \

NOe

ozone

~......OBn .c.o BnO O K2C03= BnO.-..X~'~~ OBn NO2 ~.~OBn

~......OBn 56%(85"15) BnO

i~lO20Ac

nB ' 8u73%SnHB =nBOn~

BnO

OAc

Of the anionic activating groups shown in Figure 3.3.1, the nitro group has yet to be discussed. This group was among the first to be utilized in the preparation of C-glycosides with its usage appearing as early as 1983. At that time, Vasella, et ai.,28, 29 demonstrated the preparation of these compounds as shown in Scheme 3.3.11. Beginning with the oxime derived from 2,3,4,6-tetra-

Chapter 3

152

Nucleophilic Sugar Subsu'tutions

O-benzyl-D-glucopyranose, condensation with p-nitrobenzaldehyde afforded the imine shown. Subsequent ozonolysis afforded a 73% overall yield of the nitroglycoside as a mixture of anomers. Further exploration of the utility of these compounds as applied to the preparation of C-glycosides showed their ease in d e p r o t o n a t i o n utilizing bases as mild as potassium carbonate. Furthermore, deprotonation in the presence of formaldehyde followed by acetylation gave the acetoxymethyl derivative shown. Final cleavage of the nitro substituent was easily accomplished in 87% utilizing radical conditions and providing the desired C-glycoside exclusively as the B anomer. As a final note, it is important to mention that utilizing nitro stabilized anomeric anions, ~elimination of the substituent at C2 is rarely observed. 3.4 .

2. 0

1

.

6. 7. 8. .

10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

References

Parker, K. A.; Coburn, C. A. J. Am. Chem. Soc. 1991, 113, 8516. Lesimple, P.; Beau, J. M.; Jaurand, G.; Sinay, P. Tetrahedron Lett. 1986, 27, 6201. Nicolau, K. C.; Hwang, C. K.; Duggan, M. E. J. Chem. Soc. Chem. Comm. 1986, 925. Hanessian, S.; Martin, M.; Desai, R. C. d. Chem. Soc. Chem. Comm. 1986, 926. Schmidt, R.; Preuss, R. Tetrahedron Lett. 1989, 30, 3409. Schmidt, R. R.; Dietrich, H. Angew. Chem. Int. Ed. Engl. 1991, 30, 1328. Friesen, R. W.; Loo, R . W . J . Org. Chem. 1991, 56, 4821. Hanessian, S.; Martin, M.; Desai, R. C. J. Chem. Soc. Chem. Comm. 1986, 926. Grondin, R.; Leblanc, Y.; Hoogsteen, K. Tetrahedron Lett. 1991, 32, 5021. Hutchinson, D. K.; Fuchs, P. L. J. Am. Chem. Soc. 1987, 109, 4930. Prandi, J.; Audin, C.; Beau, J.-M. Tetrahedron Lett. 1991, 32, 769. Lesimple, P.; Brau, J. M.; Sinay, P. Carbohydrate Res. 1987, 171,289. Wittman, V.; Kessler, H. Angew. Chem. Int. Ed. Eng. 1993, 32, 1091. Lancelin, J. M.; Morin-Allory, L.; Sinay, P. J. Chem. Soc. Chem. Comm. 1984, 355. Beau, J. M.; Sinay, P. Tetrahedron Lett. 1985, 26, 6185. Crich, D.; Lim, L. B.L. Tetrahedron Lett. 1990, 31, 1897. Barton, D. H. R.; Crich, D.; Motherwell, W.B. Tetrahedron 1985, 41, 3901. Crich, D.; O_uintero, L. Chem. Rev. 1989, 89, 1413. Beau, J. M.; Sinay, P. Tetrahedron Lett. 1985, 26, 6193. Beau, J. M.; Sinay, P. Tetrahedron Lett. 1985, 26, 6189. Schmidt, R. R.; Preuss, R.; Betz, R. Tetrahedron Lett. 1987, 28, 6591. Gomez, A. M.; Valverde, S.; Fraser-Reid, B. J. Chem. Soc. Chem. Comm. 1991, 1207. Allen, N. E. Annu. Rep. IVied. Chem. 1985, 20, 155.

Chapter 3

24. 25. 26. 27. 28. 29.

Nudeophilic Sugar Substitutions

153

Ray, P. H.; Kelsey, J. E.; Bigham, E. C.; Benedict, C. D.; Miller, T.A. "Bacterial Lipopolysaccharides", ACS Symposium Series 231, 1983, 141. Luthman, K.; Orbe, M.; Waglund, T.; Clesson, A. J. Org. Chem. 1987, 52, 3777. Levy, D. E.; Tang, P. C.; Musser, J. H. Annu. Rep. Med. Chem. 1994, 29, 215. Wallimann, K.; Vasella, A. Helv. Chim. Acta 1991, 74, 1520. Acbischer, B.; Vasella, A. Helv. Chim. Acta 1983, 66, 789. Baumberger, F.; Vasella, A. Helv. Chim. Acta 1983, 66, 2210.

C h a p t e r Four

4

Transition Metal Mediated C-Glycosidations

Introduction

Whereas the c o m b i n a t i o n of electrophiles with sugar nucleophiles provides routes to C-glycosides, these conditions are not applicable when the electrophiles bear centers prone to epimerization. However, where acid/base chemistry is not applicable due to reactive stereogenic centers, the use of transition metal mediated cross coupling reactions may often be utilized. Substantial research in this area has been applied to the couplings between glycals with aryl and other n-conjugated aglycones. Some sugar-derived substrates for this type of reaction are shown in Figure 4.0.1 and include glycals, metallated glycals, halogenated glycals, and sugar derivatives bearing allylic anomeric leaving groups. In this chapter the C-glycosidations introduced in Schemes 2.4.2, 2.13.2 and Figure 2.10.3 are elaborated upon. Additionally, mechanistic and stereochemical aspects of these reactions are addressed.

Figure 4.0.1

General Substrates for Transition Metal M e d i a t e d C - G l y c o s i d a t i o n s X X = Sn, Zn

OR

OR X X = l , Br

X = leaving group

OR

4.1

Direct

Coupling of Glycals with Aryl Groups

The utility of glycals as substrates for C-glycosidations is emphasized by their availability from commercial sources as well as the examples presented 155

Chapter 4

156

Transition Metal Mediated C-GlycosidatJons

thus far. Consequently, the actual coupling of these compounds with both activated and unactivated aryl groups is complimentary to the general chemistry surrounding C-glycosides. In this section, coupling reactions with unactivated, metallated, and halogenated aromatic rings are discussed.

Arylation Reactions with [Inactivated Aromatic Rings

4.1.1

Palladium Catalyzed Coupling of Glycals with Benzene

Scheme 4.1.1

OAc O I Ac

OAc LTo~

Palladium Catalyzed CouPling of Glycals with Benzene Analogues

~}

OAc O

OAc L~O,.~.. ....., , , ~

~

Pd(OAc)20.2eq-" AcO"""

...,,,U .

AcOf~,~,~ , 40%to 90%

OAc

Scheme 4.1.2

OAc

Palladtu~m 9acetate...

+ Ac

OAc

10%

AcO"""~ OAc

OAc MeO~ OAc

54%

~OMe

MeO-/l~OMe L ~ O,,~...,,,,,,y + O,,,,,,1...,,,,,, Y (~dulOAi!~/o 0"2e~" AoO,~,,..L,~ OMe AoO~,,,,..L.~ OMe OAc

OAc Ac

O I

O

0 IP

Pd(OAc)21.0eq. 51%Yield .,o

Pd(OAc)20.3 eq. Cu(OAc)21.6eq. 30 %Yield

Ac

OAc

OAc

OAc

OAc

Chapter 4

Transition Metal Mediated C-Glycosidations

157

Beginning with the simplest of cases, the direct coupling of glycals with b e n z e n e is discussed. As shown in Scheme 4.1.1, this r e a c t i o n was accomplished by Czernecki, et al., 1 utilizing palladium acetate as a catalyst. The yields for this reaction were generally in the range of 40% to 90% and resulted in the selective formation of the a configuration at the anomeric center. Subsequent examples, reported by Czernecki, et al., 2 elaborate upon this chemistry. As shown in Scheme 4.1.2, various acetate protected glycals were reacted with benzene and 1,3-dimethoxybenzene. In all cases, palladium acetate was used as the catalyst. However, varying equivalents were used. Consequently, the variances observed in the composition of the product mixture reflected the specific conditions used to induce reaction and the highest observed yields were approximately 50%.

4.1.2

Arylation Reactions with Metallated Aromatic Rings

In light of the relatively low yields for transition metal mediated Cglycosidations with unactivated aromatic aglycones, the use of substituted aryl groups was explored. Two particular examples, already presented in Schemes 2.4.2 and 2.4.3 involved the palladium mediated the couplings of glycals and a r y l t r i b u t y l t i n compounds.3,4 While ~ anomeric selectivity was generally observed, the yields, some as high as 70%, were sensitive to the protecting groups used on the glycal substrates. The example shown in Scheme 2.4.2 is particularly important in that, as illustrated in Scheme 4.1.3, aryl mercury reagents were shown to produce comparable results. Consequently, research into the nature of the aryl groups useful in these reactions have provided interesting results. Specifically, in a d d i t i o n to u n a c t i v a t e d aryl groups, aryltin, a r y l m e r c u r y , and halogen substituted aryl compounds may be used. In the remainder of this section, examples utilizing these groups will be presented. S c h e m e 4.1.3

C-Glycosidation with Aryl M e r c u r y Reagents

OMe

CH3OCH20, O (iPr)3

+

CH3OCH20~O\~ O M e Pd(OAc)2 70Vo (ipr)3SiO/ IgOAc

15 8

Chapter 4

Transition Me tal Media ted C-Glycosida tions

As illustrated in Scheme 4.1.2, salt additives have been used as a potential means of enhancing arylation reactions while decreasing the a m o u n t of palladium catalyst required. In Scheme 4.1.2, only copper acetate was considered. However, as shown in Schemes 4.1.4, 4.1.5, 4.1.6, and 4.1.7, the uses of lithium chloride, lithium acetate, and sodium bicarbonate were explored. Specifically, these salts were examined in conjunction with coupling reactions between glycals and pyrimidinyl mercuric acetates. The examples shown in the cited schemes were r e p o r t e d by Cheng, et al.,5 and Arai, et al.,6 and are segregated by glycal type. In Scheme 4.1.4, the reaction of tri-O-acetyl-D-glucal with a pyrimidinyl mercuric acetate is shown utilizing lithium chloride and palladium acetate as the catalytic mixture. Additionally, the complex product mixture and respective yields are shown. Scheme 4.1.5 elaborates upon these results utilizing a variety of reaction conditions in transformations involving tri-O-aceW1-D-glucal and other glycals. As illustrated, the products of these reactions are variations or subsets of the mixture presented in Scheme 4.1.4.

Scheme 4.1.4

C-Glycosidation with

Aryl Mercury Reagents gOAc

OAc

MeN" O

O ' ~ N-~O Me _

MeN~

o/J/,,,. N.,~O

I

1 equiv. Pd(OAc)2 1 equiv. LiCI 2 equiv. OAc H2S workup

Ac

= Py

Me

OAc OAc O. '",,,,,,py Ac OAc A: Not Determined

OAc O

.,,,,,,Py

Ac

T

~Py

OH

.,,,*~PY "]""

AcO~~OAc B: 10% Yield

OAc

C: 10% Yield

OAc OAc D: 73% Yield

In Scheme 4.1.6, variations from the acetate protecting groups used in Schemes 4.1.4 and 4.1.5 are illustrated. As shown, utilizing phenyl acetals, the isolated yields drop substantially. However, one consistency lies in the o b s e r v a t i o n t h a t the s t e r e o c h e m i s t r y at C3 a d v e r s e l y affects the stereochemistry of the product. This is interesting in light of the fact that u n d e r most circumstances, the stereochemistry at this center is either entirely lost due to conversion to a planar center or, alternately, the acetate group

Chapter 4

Transition Metal Mediated C-Glycosidations

15 9

eliminates u n d e r the specified reaction conditions. These observations are f u rth er c o r r o b o r a t e d in Scheme 4.1.7 where the use of pentose-derived glycals are illustrated. As a final note, C3 keto derivatives become available when silyl groups are used to protect the alcohol at this center. C-Glycosidation with Aryl M e r c u r y R e a g e n t s

S c h e m e 4.1.5

Workup IgOAc MeN- ~

OAc

Na2S

O/J~N'~'O H2S Me = 1 equiv.

AcO**"

H2s

OAc

Catalyst/ Additive Product(s), % Yield(s) Pd(OAc)2 (1 equiv.) A (5%), B (26%), LiCI (2 equiv.) C (54%) Pd(OAc)2 (1 equiv.) LiOAc (2 equiv.)

B (40%) C (40%) '

PdCI2 (1 equiv.) LiOAc (2 equiv.)

D (40%)

Pd(OAc)2 (1 equiv.)

A (15%), B (31%), C (31%)

OAc

OAc O

O Pd(OAc)2 (1 equiv.) NaHCO 3 (4 equiv.)

I Ac

Ac OAc

OAc 40%

OAc AcO""'

,,,,,Py "

C (10%), OAc ~_

OAc

=

Pd(OAc)2 (1 equiv.)

~.....~py

AcO""

220/0

Pyranose-derived glycals are also useful as substrates in C-glycosidations with pyrimidinyl mercuric acetates. As shown in Scheme 4.1.8, Farr, et al., 7 carried out such reactions utilizing 3-O-silyl p r o t e c t e d glycals. Palladium acetate was used as the catalyst and no salt additives were used. Compared to the results p r e s e n t e d in the previous four schemes, the illustrated coupling proceeded cleanly with the formation of an 84% yield of a ~-C-glycoside.

Chapter 4

160

Transition Me tal Media ted C-Glycosida tions

Scheme 4.1.6

C-Glycosidation with Aryl Mercury Reagents Catalyst/ Additive Me N

Ac

o#-.~--o Me 1 equiv.

Ph"'"

Product(s), % Yield(s)

0

""' PY

Pd(OAc)2 (1 equiv.) LO~,,,,...Y NaHCO3 (4 equiv.) phi,,,''

OAc

p h,,e""LO,,,''."

25% O

Pd(OAc)2 (1 equiv.) NaHCO3 (4 equiv.)

.

OAc OyPy

phi,,,,,'

=

OAc

20%

ph,,,,,..l--..o,,,,., y p h,,,,""L O,,,''`

Pd(OAc)2 (1 equiv.) NaHCO3 (4 equiv.)

.

8%

0

0

O.

5

TIPSO 22% Scheme 4.1.7

C-Glycosidation with Aryl Mercury Reagents Catalyst/ Additive

.HgOAc

o %o Aco,,,,,..~,~ ~I Me 1 equiv.

Pd(OAc)2 (1 equiv.) =-LiCI (2 equiv.)

Product(s), % Yield(s)

0

.. =

OAc

.,,,,,,,Py

AcOe,,,.-

OAc

AcO~''

OTIPS

""' PY AcO"'

10% Q Pd(OAc)2 (1 equiv.) L y "LiCI (2 equiv.) AcO""

Py P,y

20%

.... OAc 8% O_Ac OH

AcO

32%

Chapter 4

Scheme 4.1.8

Transition Metal Mediated C-Glycosidations

161

C-Glycosidation with Aryl Mercury Reagents

.,gOAc MeN- -.~

OH

o;-.N~-.o

OH

Me 1 equiv. Pd(OAc)2 1 equiv.

TBDPSO~'

4.1.3

,~ /

TBDPSO

Me

84%

Arylation Reactions with Halogenated Aromatic Rings

C-Glycosidation with Aryl Mercury/Iodide Reagents

Scheme 4.1.9

O MeN-,-JL'NMe Ph~~oO

Ph/~o~O

Hg(OAc)2

O

Sy

1 equiv. Pd(OAc)2

~

MeN.,.,~/NMe 64% (o~'~ = 8"1) Ph~O~o

O 0 0

,

0.1 equiv. Pd(OAc)2

61% ((z" 13= 9" 1)

Oipr

Where mercury substituted aryl groups have proven useful in palladium mediated C-glycosidations with glycals, aryl iodides have been shown to be complimentary alternatives in these reactions. As shown in Scheme 4.1.9,

Chapter 4

162

Transition Metal Mediated C-Glycosidatl"ons

Kwok, et al.,8 effected couplings with both mercury and iodo compounds. In both cases, the yields were comparable and the reactions showed a consistent preference for a anomers.

Scheme 4.1.10

C-Glycosidation with

Aryl Iodide Reagents ocotBu ocOtBu

OAc

I

O 1. Pd(OAc)2 2. TBAF

0

TBDPSO"r

0 AcO

56%

The above described comparison between aryl mercuric acetates and aryl iodides is applied specifically to pyranose-derived glycals. When applied to f u r a n o s e - d e r i v e d glycals, the aryl iodides react similarly with respect to reaction yields. However, unlike the pyranose glycals, reactions with furanose glycals a p p e a r to yield products bearing ~ anomeric configurations. These observations were reported by Farr, et al., 9 and are illustrated in Scheme 4.1.10. As mentioned in the cited report, the products were utilized in the total synthesis of the antibiotics gilvocarcin, ravidomycin, and c h r y s o m y c i n illustrated in Figure 2.4.3. As illustrated in Schemes 4.1.4 through 4.1.9, the use of pyrimidinyl mercuric acetates have been instrumental in the development of C-nucleosides. Although the comparison in Scheme 4.1.9 illustrates the utiliW of aryl iodides in addition to aryl mercury compounds, the nature of the specific reagents were quite different. As shown in Scheme 4.1.11, Zhang, et a/.,10 utilized pyrimidinyl iodides in the p r e p a r a t i o n of C-nucleosides from furanose glycals. As illustrated, the product mixture composition was highly susceptible to the specific reaction conditions used. Thus, of the two products shown, either is available in comparable yields. A final example illustrating the utility of pyrimidinyl iodides in the preparation of C-nucleosides is shown in Scheme 4.1.12. As shown, Zhang, e t al., 11 utilized glycals similar to those incorporated in Scheme 4.1.8. The actual coupling was accomplished utilizing palladium acetate with triphenyl arsine as

Chapter 4

Transition Metal Mediated C-Glycosidations

163

an additive. Following removal of the silyl group and reduction of the resulting ketone, the product, 2'-deoxypseudouridine, was isolated in 63% overall yield. C-Glycosidation with A w l Iodide Reagents

Scheme 4.1.11

MeO N

OTr O~

MeO

'

MeO" ~ ~ O M e

~ = MeO

~

0.1 equiv. Pd(OAc)2 1.0 equiv. NaOAc

",,,,,,,~OTr

0.5 equiv, n-Bu4NCI 2.0 equiv. Et3N DMF, RT, 20 h 0.1 equiv. Pd(OAc)2 0.2 equiv. AsPh3 2.0 equiv. Et3N CH3CN, 75~ 10 h 0.1 equiv. Pd(OAc)2 0.2 equiv. PPh3 2.0 equiv. Ag2CO3 2.0 equiv. Et3N CH3CN, 75~ 10 h Scheme 4.1.12

OTr

53%

30%

20%

58%

40%

0%

C-Glycosidation with Aryl Iodide Reagents

OTr

0

HN~'

+ O/~

OTr

N . ~ O Pd(OAc)2/AsPh3

H

TBDPSJ""

o

/

F

H % 1 N\ ~.~0 NH

TBDPSO OH

1. TBAF 2. NaHB(OAc)3 63%overall

+ MeO

Chapter 4

164

4.2

Transition Metal Mediated C-Glycosidations

Coupling of S u b s t i t u t e d Glycals with Aryl Groups

Although the direct use of glycals as C-glycosidation substrates has been fruitful, the results can often be improved upon utilizing C1 activated glycals. Such activating groups include metals as well as halogens. Successful catalysts used to effect the coupling of these compounds with metal or halo substituted aryl compounds include nickel and palladium complexes. In this section, the formation of C-glycosides utilizing transition metal catalysts will be explored in the context of C1 activated glycals as reaction substrates. Beginning with a discussion of the utility of tin substituted glycals, Dubois, et al., 12 utilized 2,3,6-tri-O-benzyl-l-tri-n-butylstannyl glucal in coupling reactions with various aromatic substrates. As shown in Scheme 4.2.1, tetrakis t r i p h e n y l p h o s p h i n e p a l l a d i u m catalyzed the reaction with b r o m o b e n z e n e providing an 88% yield of the desired product. Additionally, when pn i t r o b e n z o y l chloride was used, dichloro d i c y a n o p a l l a d i u m effected the formation of the illustrated ketone in 71% yield. Unlike the reactions discussed in section 4.1, the products observed were C1 substituted glycals. Further elaborations of this chemistry d e m o n s t r a t e d its compatibility with b o t h u n p r o t e c t e d hydroxyl groups as well as very bulky aromatic bromides. 13 Additional reactions with dibromobenzene are addressed in Chapter 8.

Scheme 4.2.1

C-Glycosidation with S t a n n y l Glycals

OBn

OBn SnBu 3 cat. Pd(PPh3)4

BnO""'

BnO,,,'< OBn

OBn OBn

88% O

PdCI2(CN)2

O

c,J-1CL

BnO"""

NO 2

OBn

71%

NO2

At approximately the same time, Friesen, et al., 14 r e p o r t e d results in a g r e e m e n t with the work presented in Scheme 4.2.1. As shown in Scheme 4.2.2, the analogous silyl protected glycal was coupled to b r o m o b e n z e n e utilizing t e t r a k i s t r i p h e n y l p h o s p h i n e p a l l a d i u m as a catalyst. With

Chapter 4

Transition Metal Mediated C-Glycosidations

165

t e t r a h y d r o f u r a n as the solvent, a 70% yield of the expected p r o d u c t was isolated. Complimentary to the examples cited in Scheme 4.2.1, the results presented in Scheme 4.2.2 illustrate the compatibility of silyl protecting groups applied to this type of reaction.

Scheme 4.2.2

C-Glycosidation with S t a n n y l Glycals

OTBDMS

OTBDMS SnBu 3 cat. Pd(PPh3)4 . . B r

I

TBDMSO~'' TBDMSO

Scheme 4.2.3

TBDMSO~,''' TBDMSO

70%

C-Glycosidation w i t h C1 Zinc a n d Iodo Glycals OMOM

X Y +

TBDMSO~" OTBDMS OMOM

X = I, Y = ZnCI Ni(dppp)CI2 32% Pd(dppp)CI 2, DIBAL 0%

TBDMSO,

X = ZnCI, Y = I Ni(dpPp)CI2 Pd(dpPp)CI2

TBDMSO'

(~,.~ "

0

OMOM

24% 78.5% OMOM

Where C1 stannylated glycals have been useful in the formation of Cglycosides, zinc and iodo substituted glycals have provided complimentary avenues to these compounds. Utilizing either of these classes of glycals, the results of the coupling reactions were shown to be highly susceptible to the transition metal catalyst used. As shown in Scheme 4.2.3, Tius, et al., is compared the results of cross coupling reactions between iodo glycals and aryl zinc reagents to the

166

Chapter 4

Transition Metal Mediated C-Glycosidations

corresponding coupling reactions between stannyl glycals and aryl iodides. As illustrated, substituted glycals were reacted with substituted aryl compounds to give C1 aryl substituted glycals. When the starting glycal was substituted with iodine and an aryl zinc reagent was used, a 32% yield of the coupled product was obtained utilizing a nickel catalyst. Use of a palladium catalyst failed to promote this reaction. However, when the glycal was substituted with zinc and an aryl iodide was used, nickel catalysis produced a 24% yield while palladium effected yields greater than 78%. This technology was ultimately used in the preparation of the vineomycinone B2 methyl ester illustrated in Figure 4.2.1.

Vineomycinone B2 Methyl Ester

Figure 4.2.1

OH HO. ~ . . ~ 0

,,

0

"........L V ~ " ' '

~ ~ OH ~~v-V~CO2Me 0

Scheme 4.2.4

OH

Preparation of C1 Iodo Glycals

OTIPS

OTIPS I 1. tBuLi/Bu3SnCI =. 2.

TIPSO*'" TIPSO

12

TIPSO*"" TIPSO 85%

Centering specifically on C1 iodo glycals, prepared as shown in Scheme 4.2.4, Friesen, et al., 16 initiated coupling reactions with both arylzinc and a r y l b o r o n compounds. The results, shown in Scheme 4.2.5, illustrate approximately 75% yields for both cases. Thus, the formation of C1 substituted glycals en route to the preparation of C-glycosides is possible through a variety of methods utilizing C1 metallated and halogenated glycals with a variety of catalysts.

Transition Metal Mediated C-Glycosida tions

Chapter 4 Scheme 4.2.5

167

C-Glycosidation with C1 Iodo Glycals

OTIPS

,.•OTSnBu( 3

OTIPS

Pd(PPh3)2CI2 ZnC,

TiPSO@" y TIPSO

TIPSO@"

TIPSO OTIPS

74% ~'~

Pd(PPh3)2CI2

B(OH)2

4.3

TIPSO

75%

Coupling of ~-Allyl Complexes of Glycals

Until this point, all couplings have involved glycals/glycal derivatives and aryl compounds. However, the generality of this chemistry also applies to the use of 1,3-dicarbonyl compounds and other molecules with suitably electron deficient centers. These reactions proceed with both the neutral and anionic forms of these compounds and generally exhibit moderate to high yields. Unlike the examples shown in section 4.2, these reactions produce C-glycosides bearing unsaturation between carbons 2 and 3. Furthermore, the variety of compatible hydroxyl protecting groups include acetate, ketal, and benzyl groups. Scheme 4.3.1

C-Glycosides from Glycals and 1,3-Diketones

OAc

OAc

O

)

OAc

13-diketone catalyst

Ac '

O/

Chapter 4

168

Figure 4.3.1

Transition Metal Mediated C-Glycosidations

C-Glycosides from Glycals and 1,3-Diketones

13-Dicarbonyl

O-Acetylated

Glycal

Catalyst

% Yield

Acetylacetone Acetylacetone Acetylacetone Acetylacetone Acetylacetone Acetylacetone Methyl Acetoacetate Methyl Acetoacetate Ethyl Benzoylacetate Ethyl Benzoylacetate Ethyl 2-Oxocyclohexane carboxylate Ethyl 2-Oxocyclohexane carboxylate

Glycal Galactal Galactal Allal Allal Glucal Xylal Galactal Galactal

Pd(PhCN)2C12 BF3 Pd(PhCN)2C12 BF3 Pd(PhCN)2C12 BF3 Pd(PhCN)2C12 Pd(PhCN)2C12 Pd(PhCN)2C12 BF3

83 73 59 72 62 81 85 65 65 81

Glucal

Pd(PhCN)2C12

82

Glucal

BF3

82

Compound

Glycal

6:1 5:1 a only (z o n l y

5"1 5"1 4"1 1"4 only only

An early example of the utility of this approach to the formation of Cglycosides was presented by Yougai, et al., 17 and compares the use of different Lewis acids and transition metal catalysts. The general reaction reported is shown in Scheme 4.3.1 and utilizes tri-O-acetyl-D-glucal as a substrate for coupling with a variety of dicarbonyl compounds. The results of the cited study are summarized in Table 4.3.1. As the technology developed in this area, the advantages of utilizing glycal activating groups became apparent. Two reports by Brakta, et aL,18,19 involved the initial formation of phenolic glycosides on treatment of glycals with phenol. These species were then coupled, utilizing transition metal catalysts, to a variety of 1,3-dicarbonyl compounds. The general reaction and some results are presented in Scheme 4.3.2 and show that anomeric ratios as high as 100% can be obtained for either anomer and in respectable yields. A notable observation is the retention of the anomeric configuration on conversion from the phenolic glycoside to the corresponding C-glycoside. While the use of phenolic glycosides as activated glycals for use in the preparation of C-glycosides was shown to be successful in couplings with 1,3dicarbonyl compounds, deprotonated 1,3-dicarbonyl compounds showed some utility in comparable reactions with unactivated glycals. As shown in Scheme 4.3.3, RajanBabu, et al.,20 utilized such anionic species in conjunction with transition metal catalysts to effect successful C-glycosidations. These reactions proceeded in good yields and were dependent on the nature of the group at C3. Specifically, electron deficient groups such as trifluoroacetoxy groups proved to be the most successful while no reactions were observed utilizing acetates.

Chapter 4

Scheme 4.3.2

Transition Metal Mediated C-Glycosidations C-Glycosides f r o m P h e n o l i c Glycosides and 1 , 3 - D i k e t o n e s

OAc

OAc

PhOH AcO*""

OAc O.

)"

Ac

OAc

,,,Oeh

O.yOeh

+

Ac 85:15 OAc

OAc

OAc

, 0.~..,,,,,,R + Ac

AcO""

OAc O. y

169

Ac

Pd(OAc)2/dppb R = CH2(CO2Et)2 CH3CN, 70~

60%

75:5

Pd(OAc)2/dppe R = NO2CH2CO2Et THF, 60*C

80%

100:0

C)Ph Pd(OAc)2/dppb R = CH2(CO2Et)2 CH3CN, 70~

R

82%

0 : 100

Ac A s u b s e q u e n t study, r e p o r t e d by Dunkerton, et al., 21 showed that the a b o v e d e s c r i b e d c h e m i s t r y was also a p p l i c a b l e to 1 - O - a c e t y l - 2 , 3 anhydrosugars. The results, directly analogous to the use of phenolic glycosides shown in Scheme 4.3.2, are illustrated in Scheme 4.3.4. As shown, excellent yields and high anomeric selectivity was observed with a net retention of the anomeric configuration. Although c o m p l e m e n t a r y to similar C-glycosidations discussed thus far, it should be noted that the applications of this specific reaction type is limited with low yields observed when substituents are present at C4 of the substrate. F u r t h e r r e s e a r c h into the types of substrates available for t r a n s i t i o n m e t a l m e d i a t e d C - g l y c o s i d a t i o n s d e m o n s t r a t e d the u t i l i t y of glycosyl carbonates. As shown in Scheme 4.3.5, Engelbrecht, et al., 22 effected the formation of glycosyl carbonates on reaction of a n h y d r o s u g a r s with isobutyl chloroformate and pyridine. Under these conditions, the a glycosyl carbonate was isolated in 75% yield. Subsequent t r e a t m e n t with diethyl malonate in the

Chapter 4

170

Transition Metal Mediated C-Glycosidations

presence of a p a l l a d i u m catalyst afforded an 81% yield of the C-glycoside exhibiting a net retention of stereochemistry at the anomeric center. Similar results were observed with corresponding 13glycosyl carbonates.

Scheme 4.3.3

C-Glycosides f r o m A c t i v a t e d Glycals and A n i o n i c 1 , 3 - D i k e t o n e s

CO2Me

~ ,,, ~ OR

KCH(CO2Me)2 ~. 2-5%bis(dibenzylideneacetone) Pd(O),DIPHOS THF, r.t.

CO2Me

,~ 0 ~'''"

R = OCOCF3 R = OAc or OPO(OEt)2

OR 56% no reaction O

Aco O

0

//JL~o,,,,,"

AcO""

OR 63%

OAc

no reaction Scheme 4.3.4

C-Glycosides from Anhydrosugars and Anionic Nucloephiles

/O~ ,,~OAc

AcO" V L . ~ ~ '"

Pd(PPh3)4= DMF

~

~,,R

AcO

'"

NaC(NHAc)(CO2Me)2 90%

PhZnCI vinylZnCI A c OeO~, ~ . ,,,M . O~/~..,,,,,,OAc

94% 97%

Low Yields

Chapter 4 Scheme 4.3.5

AcOA

Transition Metal Mediated C-Glycosidations

171

C-Glycosides f r o m Glycosyl C a r b o n a t e s

~ O

O9H

/•O.,•CI O

= AcO~ ~

,iBu

",,,0002

75%

AcO"" CO2Et

co O) ,oco Pd(PPh3)4

AcO~"" --,,~

4.4

81O/o

" 9AcO

.....

CO2Et

AcOe,,....,,~

Mechanistic Considerations

As extensive research has been carried out in the field of palladium mediated C-glycosidations, a brief explanation of the mechanistic aspects of these reactions is w a r r a n t e d . Considering the coupling of glycals with p y r i m i d i n y l mercuric acetates, the first step in the r e a c t i o n involves t r a n s m e t a l l a t i o n to a p y r i m i d i n y l p a l l a d i u m complex. S u b s e q u e n t ~complexation to the glycal is followed by formation of a o-bond adduct between the palladium and one of the pyrimidinyl carbonyls. This process, explained in a review article by Daves23 and shown in Scheme 4.4.1, proceeds, under specific conditions, to the products observed. Specifically, acidic conditions promote ring opening, heat effects migration of the double b o n d without acetate elimination, formic acid promotes double b o n d m i g r a t i o n with acetate elimination, and hydrogenation yields saturated C-glycosides. An alternative mechanism applies to the chemistry s u r r o u n d i n g the pyranose analogs utilized in Schemes 4.3.2, 4.3.4, and 4.3.5. Addition of palladium to these species forms a ~-allylpalladium complex. As shown in Scheme 4.4.2, approach of the palladium is from the side of the sugar opposite that of the glycosidic substituent. This allows the nucleophilic species to approach from the opposite side of the palladium giving the product with a net retention of stereochemistry. Further insight into the mechanistic aspects of this chemistry is available from any of the references cited within this chapter.

Transi U'on Me ml Media ted C-Glycosida tions

Chapter 4

172

Mechanisms of Palladium Mediated Couplings

Scheme 4.4.1

O

O

MeN' ~ N M e Pd(OAc)2,PPh3 MeN/~NMe 0

"~

PyPdL3

0

Ac

Pd(OAc)2PPh3

OAc

Me

OAc /

OAc

PyPdL3

...... ~

Aco"'~

AcO'~"'y OAc

OAc

=

~ ~

_N~ ..~O ,r;/ //" O-~... ~ NMe

AoO,,,,....L,,/-..,,,p,0..~ I i

~

,/\, OAc u U ~2

OAc

OAc O......i...,,,,,, ,Py

Ac

~ OAc

OAc OH

Ac

1HCO3"

OAc

O ' " ~ '"I'"PY

AcO~""% ~ OAc Py OAc

O ..,,,,,,Py Ac

Mechanisms of Palladium Mediated Couplings

Scheme 4.4.2

~..OAc AcO'~~

~...OAc Pd(0) AcO"-"N Ird

R-M = A c O ' ~ _ ~

- A c O ~

OAc

M

Chapter 4 4.5 o

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

Transin'on Metal Mediated C-Glycosidations

173

References

Czernecki, S.; Gruy, E. Tetrahedron Lett. 1981, 22, 437. Czernecki, S.; Dechavanne, V. Can. J. Chem. 1983, 61,533. Outten, R. A.; Daves, D. G. Jr. J. Org. Chem. 1987, 52, 5064. Outten, R. A.; Daves, D. G. Jr. J. Org. Chem. 1989, 54, 29. Cheng, J. C.-Y.; Daves, G. D. Jr. d. Org. Chem. 1987, 52, 3083. Ari, I.; Lee, T. D.; Hanna, R.; Daves, G. D. Jr. Organometallics 1982, 1,742. Farr, R. N.; Daves, G. D. Jr. J. Carbohydrate Chem. 1990, 9, 653. Kwok, D. I.; Farr, R. N.; Daves, G. D. Jr. J. Org. Chem. 1991, 56, 3711. Farr, R. N.; Kwok, D. I.; Daves, G. D. Jr. J. Org. Chem. 1992, 57, 2093. Zhang, H. C.; Daves, G. D. Jr. J. Org. Chem. 1993, 58, 2557. Zhang, H. C.; Daves, G. D. Jr. J. Org. Chem. 1992, 57, 4690. Dubois, E.; Beau, J.-M. J. Chem. Soc. Chem. Comm. 1990, 1191. Dubois, E.; Beau, J.-M. Carbohydrate Res. 1992, 228, 103. Friesen, R. W.; Sturino, F. C. J. Org. Chem. 1990, 55, 2572. Tius, M. A.; Gomez, Galeno, J.; Gu, X. Q.; Zaidi, J. H. J. Am. Chem. Soc. 1991, 113, 5775. Friesen, R. W.; Loo, R . W . J . Org. Chem. 1991, 56, 4821. Yougai, S.; Miwa, T. J. Chem. Soc. Chem. Comm. 1982, 68. Brakta, M.; Le Borgne, F.; Sinou, D. J. Carbohydrate Chem. 1987, 6, 307. Brakta, M.; Lhoste, P.; Sinou, D. J. Org. Chem. 1989, 54, 1890. RajanBabu, T. V. J. Org. Chem. 1985, 50, 3642. Dunkerton, L. V.; Euske, J. M.; Serino, A.J. Carbohydrate Res. 1987, 1 71, 89. Engelbrecht, G. J.; Holzapfel, C.W. Heterocycles 1991, 32, 1267. Daves, D. G. Jr. Acc. Chem. Res. 1990, 23, 201.

This Page Intentionally Left Blank

C h a p t e r Five

S

Anomeric Radicals

Introduction

Thus far, the C-glycosidations discussed involve ionic mechanisms. However, neutral free radicals are also useful in the formation of C-glycosides. Specifically, the ability to form free radicals at anomeric centers, illustrated in Figure 5.0.1, provides an additional dimension to the developing C-glycosidation technologies. Interesting features of free radical chemistry applied to Cglycosidations include the ability to couple these species with numerous readily available radical acceptors. The stereochemical course of these reactions generally provides ~ selectivity. This chemistry is nicely applied to acylated sugars and tolerates many substrate functional groups. Finally, intramolecular radical r e a c t i o n s p r o v i d e a v e n u e s into c o m p o u n d s b e a r i n g difficult stereochemical relationships as well as fused ring systems.

Figure 5.0.1

Anomeric Radicals

. ~ X Initiator

X = Br, I, NO2, etc.

5.1

Axialanomericradical

Sources of Anomeric Radicals and Stereochemical Consequences

Anomeric free radicals can be generated from sugar substrates bearing a variety of activating groups. Additionally, the conditions required for the generation of these reactive species include both chemical and photolytic methods. Through combining specific reaction conditions and appropriate activating groups, both a and ~ oriented C-glycosides are available. In this section, the generation of anomeric radicals is discussed with respect to the utility of various activating groups. F u r t h e r m o r e , the s t e r e o c h e m i c a l consequences of reaction conditions, as applied to different activating groups, are explored. 175

Chapter 5

176

Anomeric Radicals

Nitroalkyl C-Glycosides as Radical Sources

5.1.1

One source of anomeric radicals and evidence for the preference of axial radical orientations has already been introduced in work r e p o r t e d by Vasella, et al.,1, 2 a n d illustrated in Scheme 3.3.11. The specific reaction, reviewed in Scheme 5.1.1, involves the cleavage of a nitro group u n d e r radical forming conditions. The starting nitroglycoside existed as a mixture of anomers and the p r o d u c t was composed of the ~ a n o m e r exclusively. This observation suggests the formation of an a oriented radical which accepts a h y d r o g e n radical from tributyltin hydride. Specific delivery of the h y d r o g e n radical to the stable anomeric radical thus explains the exclusive formation of the observed f)-Cglycoside.

Scheme 5.1.1

Axially Oriented Anomeric Radicals

~..-OBn

~.OBn n-Bu3SnH. 87%

BnBOnO~~

BnO i~102 OAc

BnO

OAc

O.~ ~ J

-CO2Et

(x : 13=85 : 15 Scheme 5.1.2

Stereochemical Preference of Anomeric Radicals

OBn

OBn

NO2 O.

Bu3SnH(30equiv.) CO2Et AIBN,110~ "

Bn

Bn

OBn

NO2 O"

,,"'L ......

OBn Bu3SnH

CO Et

.CO2Et O-

Bn

4 5 30

CO2Et

,,,,','1

A BN

Bn Bu3SnH (equiv.)

OBn

Temp. (~

80 110 110

Bn (x (%)

54 37 70

~

13(%) 46 63 30

Chapter 5

Anomeri c Radicals

177

An excellent exploration into the actual stability of anomeric radicals was r e p o r t e d by Brakta, et al., 3 and involves the migration of a free radical to the anomeric center of pre-formed C-glycosides. As shown in Scheme 5.1.2, the Cglycosidic nitroacetates were subjected to various radical mediated denitration conditions. Utilizing the ~-C-glycoside, t r e a t m e n t with 30 e q u i v a l e n t s of tributyltin hydride effected denitration with exclusive isolation of the modified ~-C-glycoside. However, w h e n the a-C-glycoside was used, s u b s t a n t i a l scrambling of the stereochemistry at the anomeric center was observed. The mechanism, shown in Scheme 5.1.3, involves a 1,2-shift of a h y d r o g e n atom thus forming the more stable anomeric radical. Subsequent isomerization from the ~ to the a anomeric radical thus explains the loss of stereochemical integrity. S c h e m e 5.1.3

Stereochemical Preference of A n o m e r i c Radicals

OBn

OBn

NO 2

o

,,,,L .....

C O 2 Et

BnO"'

O,

"

~l ..... C02Et

Bn 1,2-Hydride shift

OBn

OBn Q

O~C02Et Bn 5.1.2

~~,' .~

C02Et

Bn Radicals from Activated Sugars

As alluded to in the introduction of this chapter, glycosidic radicals prefer to a d o p t an a a n o m e r i c configuration. However, this p r e f e r e n c e can be m a n i p u l a t e d t h r o u g h the use of a variety of anomeric activating groups and radical initiating conditions. Some glycosidic substrates used in the generation of anomeric free radicals are shown in Figure 5.1.1 and include oxygen-derived glycosides, 4 thioglycosides,S, 6 and selenoglycosides.7 From these compounds, as well as utilizing either chemical or photolytic radical formations, both a and ~ Cglycosides have been shown to be accessible. Specific examples utilizing these substrates will be presented later in this chapter. In addition to the use of substrates similar to those shown in Figure 5.1.1, glycosyl halides have found much utility in the chemistry of glycosidic radicals.

Chapter 5

178

Anomeric Radicals

As will be elaborated upon later in this chapter, glycosyl fluorides and bromides tend to produce a anomeric radicals while chlorides and iodides show substantially less selectivity. One particular study, involving the reduction of glycosyl bromides under various conditions, was reported by Somsak, et al.,8 and is shown in Scheme 5.1.4. As shown, this study compared a variety of reducing conditions on two 1-bromo-l-cyano glycosides. In both cases, utilizing tributyltin hydride and a radical initiator, the major products observed resulted from delivery of a hydride with retention of the anomeric configurations. These observations support the preferential formation of a anomeric radicals. Figure

Substrates

5.1.1

for A n o m e r i c Radical F o r m a t i o n

~

OBz

~0"~ 0

0

,SPh

O~ocSSMe

TBDMSO_ ~ 0

n

DSPh

OAc SePh

.... ,.O02M e

AcO"'

OAc

Although the anomeric configuration of glycosidic radicals is relatively stable, groups migrating from C2 to C 1 of a given sugar migrate in a cis fashion. This can, in m a n y cases, yield products contrary to the already stated observations of the stereochemical preference for glycosidic free radicals. As shown in Schemes 5.1.5 and 5.1.6, Giese, et al.,9,10 treated 2,3,4,6-tetra-Oacetyl-a-D-glucopyranosyl bromide with tributyltin hydride as the limiting reagent and a radical initiator. Through the mechanism shown, the C2 acetate migrated to the anomeric position yielding the observed a anomer in 92% yield. Similarly, utilizing 2,3,4,6-tetra-O-acetyl-a-D-mannopyranosyl bromide the corresponding B anomer is obtained in 65% yield thus confirming the nature of the migration. Similar observations for the cis migration of C2 acetoxy groups to the anomeric position of sugars were observed for both pyranosyl iodides and furanosyl selenides.

Chapter 5

Anomeric Radicals

179

Reduction of Glycosyl Bromides

Scheme 5.1.4 AcO ~.OAc

AcO~OAc

AcO ...OAc

= AoO'~A

On + A o O ~ . ~ ~ CN AcO CN AcO Time (min) ~/13 Yield (%) Conditions Zn/AcOH, reflux 15 7/3 64 Zn/iprOH, reflux 20 6/4 78 15 4/6 77 Bu3SnH/C6H6,AIBN, reflux 10 6/4 64 NaBH4/DMF, room temp. CN Br

A C O ~ A c O ~CN Br

OoCc.oc

O O A c ~ OAc + AcO OAc AcO AcO Yield (%) Time (min) od13 Conditions Zn/AcOH, reflux 64 15 6/4 Zn/iprOH, reflux 66 20 6/4 67 Bu3SnH/C6H6,AIBN, reflux 15 2/8 (37 NaBH4/DMF, room temp. 10 6/4 1,2-Migrations of Anomeric Radicals

Scheme 5.1.5

AcO '

~_ ,,~Br AcO j.~ " Bu3SnH/AIBN= 92% AcO,,,,,'" ~ ""'OAc AcO" OAc

,/ AcO'~ AcO~,,,'" ~

:OAc

cO

(

OAc

....~ 9

AcO,,,,,, ~

k

/

~"

,,~OAc "'"

OAc

=~cO,,,,,,~.AcO~, O" ..,,,,,OAc

"~

OAc

OAc

Chanter 5

180

Anomeric Radicals

1,2-Migrations of Anomeric Radicals

Scheme 5.1.6

OAc

OAc ()

,,~Br

Ao Bu3SnH/AIBN 65%

Ac

AcO~,,,''

~OAc OAc

OAc

I

().

,,,,OAc

,,,~1 Bu3SnH/AIBN 72%

Ac

""OAc

AcO"" OAc

OAc OBz [ ~ O . , ~ ....,~SePh

OBz Bu3SnH/AIBN 75%

BzO,~""

~..OBz

.... ,~OBz

Bzd

Having i n t r o d u c e d the stereochemical course followed by reactions involving glycosidic free radicals, the remainder of this chapter will present examples of the utility of these species in b o t h i n t e r m o l e c u l a r a n d intramolecular reactions.

5.2

Anomeric Couplings with Radical Acceptors

The intermolecular reactions between glycosidic free radicals and radical acceptors have provided a variety of novel structures inaccessible from other glycosidation pathways. Although the Wpes of radical acceptors useful are quite varied, the different anomeric activating groups used in the generation of free radicals substantially influence the yields and stereochemical outcome of the reactions. The two divisions within this section address the use of glycosyl halides and non-halogenated sugar derivatives in the exploitation of free radical C-glycosidations.

Chapter 5

Anomeric Radicals

181

Non-Halogena ted Radical Sources

5.2.1

Radical C-Glycosidations with Nitroglycosides

Scheme 5.2.1

O

~

NO2

#~CN

0-.~]

....... '~". ~ c .

CN ~ C N _- ' o Bu3SnH

O.~O ~tOBn

55%

~.OBn

o0~O~ BoO~ O ~ C N BBnO....&~.~.~t,,,~ BnO'"~'~~'~t~~'BnOIOAc gu3SnH BnO~ OAc NO2 45% ~CN Radical C-Glycosidations with Glycosidic Methylthiothiocarbonates

Scheme 5.2.2

OBz

CO2Me OBz

~O'~o',,,,~SMe( CO2Me= ~D.~ ~" O.~O

S

Bu3SnH AIBN

~(" CO2Me

O,~O

O OBz === L ~ . - O ~ ~ U ~ HO~,.. ~,,,OH

NH Showdomycin O

CO2Me 63%

Chapter S

182

Anorneric Radicals

Understanding the chemistry surrounding the formation and subsequent stereochemical preference of anomeric radicals, the various reactions utilizing these species in the preparation of C-glycosides can be discussed. Beginning with nitroglycosides, Depuis, et al., 11 effected reactions with acrylonitrile. As shown in Scheme 5.2.1, the radicals were formed utilizing tributyltin hydride. The observed products were isolated in approximately 50% yields and, in the case of the hexose, exhibited no stereochemical preference. Scheme 5.2.3

Radical C-Glycosidations with P h e n y l t h i o g l y c o s i d e s

0

,.SPh

CSn u,

TBDMSO~V~..~,O

" TBDMS

Conditions

Yield (%)

Photochemical Cat. Bu3SnOTf

87

13 92:8 1:99 r

95

OR

OR

~

O,,,~.....,,~SPh

""~SnBu3

R

Conditions

CH2OCH2Ph

Photochemical Cat. Bu3SnOTf Photochemical Cat. Bu3SnOTf

TBDMS ~.....OBn

"•SnBu3

BnO--'V O,

Yield (%)

Complex Mixture 80 1:99 79 40:60 91 59:41 ~....OBn ~:13=1:1

BnO-~~~

BnO

SPh

~:13

BnO -~"

An example exhibiting a higher yield and substantially b e t t e r stereoselectivity involves a radical coupling with dimethylmalonate. As shown

Chapter 5

A n o m e r i c Radicals

183

in Scheme 5.2.2, Araki, et al.,4 generated anomeric radicals from the illustrated glycosidic methylthiothiocarbonate on treatment with tributyltin hydride and a radical initiator. The resulting product, formed in 63% yield, was subsequently utilized in the preparation of showdomycin. Additional work demonstrating the utility of anomeric radicals in the p r e p a r a t i o n of C-glycosides was r e p o r t e d by Keck, et al., s and involved transformations utilizing phenylthioglycosides. As shown in Scheme 5.2.3, Cmethallylglycosides were prepared from both pyranose and furanose sugars in yields ranging from 79% to 95%. Interestingly, the stereochemical course of the reactions shown were d e p e n d e n t upon the method used for generation of the anomeric radicals. Specifically, with respect to pyranose sugars, photochemical conditions induced predominant formation of ~ anomers while ~ anomers were formed utilizing chemical methods. Furthermore, in the case of furanose sugars, these observations were dependent upon the protecting groups used. Finally, the complete lack of stereochemistry observed u n d e r all conditions in the reaction involving 2,3,4,6-tetra-O-benzyl phenylthioglucopyranose deserves mention. S c h e m e 5.2.4

Radical C - G l y c o s i d a t i o n s with Phenylthioglycosides

AcO

AcO

k

A .., cO~~Oo c

~

Aco ; _y SPh

SnBu3= A..c(~.~,,,,~OAc uv Light

AcO

CO2Me ~O 0

CO2Me

S. Ph ..,,,'C02Me

~O

O

30%, (z : 13= 1 : 1 CO2Me ....,,,,,'",,,,,,,..~"

~,,"'~ SnBu3 UVLight .~O

30%, (z'13= 90" 10

An additional example illustrating the utility of thiophenyl glycosides in free radical mediated C-glycosidations was reported by Waglund, et al.6 As shown in Scheme 5.2.4, 1-methylcarboxy-l-phenylthioglycosides were treated with allyltributyltin and irradiated with ultraviolet light. The resulting C-allyl derivatives were formed in approximately 30% yields with the stereochemical

Chapter 5

184

Anomeric Radicals

course of the reactions highly dependent upon the nature of the protecting groups used, For example, the peracetylated sugar was transformed to a 1 : 1 anomeric mixture of C-glycosides while the acetonide protected sugar exhibited predominant formation of the ~ oriented C-allylglycoside. 5.2.2

G l y c o s y l H a f i d e s as R a d i c a l S o u r c e s

With all the anomeric activating groups useful in the generation of sugarderived free radicals, glycosyl halides have been most exploited. In the remainder of this section, various reactions involving glycosyl halides will be discussed. Additionally, the stereochemical consequences of these reactions will be analyzed.

Scheme 5.2.5

Radical C - G l y c o s i d a t i o n s w i t h Glycosylfluorides

~iOBn

~...OBn

BnO~

~CN

0

BnO-~~~~

BnO

F

Bu3SnH AIBN

61%, o~: ~ = >10 : 1 BnO [

Glycosyl fluorides, already addressed as substrates for cyanations and allylations, are excellent substrates for radical mediated C-glycosidations. As shown in Scheme 5.2.5, Nicolau, e t al.,12 demonstrated such reactions in the coupling of 2,3,4,6-tetra-O-benzyl glucopyranosyl fluoride with acrylonitrile. The reaction proceeded in 61% yield with an anomeric ratio of greater than 10 : 1 favoring the a isomer.

Scheme 5.2.6

Radical C-Glycosidations with Glycosylchlorides

AcO

1

1 AcO

CI Allyltributyltin bis(tributyltin)" A Photolysis

AcO OAc C

O

~

c AcO

3 o

2

60~176~ : ~ = 1 : 1

E

t

Chapter 5

A n o m e r i c Radicals

185

Complimentary to the use of glycosylfluorides is the ability to convert glycosylchlorides to C-glycosides under radical conditions. As shown in Scheme 5.2.6, Bednarski, et al., 13 effected such reactions utilizing allyltribuWltin and photolytic conditions. Although the modified sialic acid was isolated in 60% yield, no stereochemical induction was observed. Additional work involving glycosylchlorides as substrates for radical mediated C-glycosidations have shown interesting stereochemical consequences. As shown in Scheme 5.2.7, Paulsen, et al., 14 effected the conversion of 1methylcarboxy-l-chloroglycosides to the corresponding 1-methylcarboxy-1allylglycosides in excellent yield. Unfortunately, the stereochemical course of the reaction involving 2-deoxy sialic acid favored the a-allyl isomer in a ratio of 1.8 : 1. However, utilizing similar conditions, the analogous sialic acid glycosylbromide provided similar 2-hyclroxy compounds favoring the ~-allyl isomer in a ratio of 3 : 1. Although the yield was lower than that observed for the 2-deoxy sialic acid derivative, these results demonstrate the versatility available from the use of a variety of sugar derivatives in the formation of Cglycosides. S c h e m e 5.2.7

Radical C-G1ycosidations w i t h Glycosylchlorides/bromides

AcO A

CI

OAc O ~

c

Allyltributyltin AIBN/60~ 93%

CO2Me

AcO Ac_O ,.,_

CO2Me

U/.~C

AcO OAc

AcO +

AcO AcO

I OAc

AcO

I

CO2M

_u_Ac

e

....

~

c

o

2

M

e

AcO

Allyltributyltin AIBN/60~ 69%

CO2Me I

=

AcO OAc

-

. . . TIw"""'~'~ L ~ u ~ : ~"'''&'~Un AcO~ O .~Jn AcO

O

Br

AcO !

c

1 "1.8

-

AcO_ ,,_

A

+ A O O ~ oAoH . ~ LN"~.~'~-J.~ ~CO2Me OH-" 3"1

AcO

Chapter 5

186

Anomeric Radicals

Acrylonitrile has already been established as an excellent radical acceptor for the formation of C-glycosides and further examples utilizing this reagent will be presented shortly. However, before continuing with the chemistry s u r r o u n d i n g this reagent, the applicability of the electronically similar a,~unsaturated carbonyl compounds deserves mention. As shown in Scheme 5.2.8, Giese, et al., is utilized the lactone, shown, as an acceptor for radicals derived from 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl bromide. The anomeric radicals were generated utilizing tributyltin hydride and a radical initiator. Following treatment of the radicals with the acceptor, the product was isolated in 22% yield with an anomeric ratio of 10 : 1 favoring the a anomer. Unfortunately, the final h y d r o g e n t r a n s f e r adjacent to the c a r b o n y l p r o c e e d s with little stereoselectivity exhibiting an isomeric ratio of approximately 60 : 40. In spite of the low yield for the illustrated reaction, the utility of carbonyl-derived radical acceptors has been d e m o n s t r a t e d and additional examples will be examined later in this section.

Scheme 5.2.8

Radical C - G l y c o s i d a t i o n s with Glycosylbromides

~1OAc

OH ~.OAc

Aco

AcO

HO",,,,.~ ' - x

O,

1. Bu3SnH/AIBN 2. Acetylation 22%

AcO~ & ~ ~ - ~ AcOI Br

"

O

Scheme 5.2.9

O

A c O ~ AcOI

0-"

HO ~

,~.

,,,\U I-I

-(3-

Radical C - G l y c o s i d a t i o n s with Glycosylbromides

A c O ~ O AcO----~--.-._.~O ~CN A c O ~ = A c O ~ AcO I n-Bu3SnH AcO Br OAc OAc / " " CN AcO-~"~

klCN

OAc +

68%

Br

OAc

33% + double addition

AoO-"k" I "~

AcO--~~~~~. CN

Reactions involving the coupling of acrylonitrile with anomeric radicals derived from glycosyl bromides have been useful for the preparation of C-

Chapter 5

A n o m e r i c Radicals

187

cyanoalkyl glycosides. As shown in Scheme 5.2.9, Giese, et al., 16 g e n e r a t e d glycosidic radicals utilizing chemical methods. S u b s e q u e n t t r e a t m e n t with acrylonitrile effected the formation of the desired products. In the case of 2 , 3 , 4 - t r i - O - a c e t y l - D - x y l o p y r a n o s y l b r o m i d e , the r e a c t i o n p r o d u c e d the a n o m e r in 33% yield with substantial double addition observed. However, w h e n 2 , 3 , 4 - t r i - O - a c e t y l - D - l y x o p y r a n o s y l b r o m i d e was used, a 68% yield comprising a mixture of anomers was obtained. The relatively low yields and poor anomeric selectivity observed in the reactions with pentose-derived glycosyl bromides does not translate to higher sugars. As shown in Scheme 5.2.10, Giese, et al., 16 d e m o n s t r a t e d reactions with acrylonitrile and other radical acceptors. The results observed with 2,3,4,6tetra-O-acetyl-D-glucopyranosyl bromide include isolation of a 75% yield of the expected C-glycoside comprising a mixture of a n o m e r s in a ratio of 93 : 7 favoring the a isomer. Additionally, utilizing f u m a r o n i t r i l e as the radical acceptor, high stereoselectivity was observed in light of the substantially lower isolated yield. Finally, utilizing 2 , 3 , 4 , 6 - t e t r a - O - a c e t y l - D - m a n n o p y r a n o s y l bromide, a 68% yield was obtained with p r e d o m i n a n t a p p r o a c h of the radical acceptor to the a position.

Scheme 5.2.10

Radical C - G l y c o s i d a t i o n s w i t h Glycosylbromides

~...-OAc

c-~

ACOc ~ C N . AcO I Br

ACOc

~.....-OAc

4

+ AC~ AcO L "-1 J4,5 = 5.2 Hz / CN 93:7

n-Bu3SnH 75%

_ AcO " ' " CN J4,5 = 9.6 Hz

r--OAo

NC~cN

470/o

I OAc/~CN

~ ~"~ /

OAc

/OAc OAc

ACOco-Br

r.--oAc ~CN.68%

I OAc.

~~t.,

CN

OAc /'~~ CN

OAc

In a novel example of the conversion of xylose derivatives to more complex sugars, Blattner, et al., 17 treated 1,2,3,4-tetra-O-acetyl-5-bromo-[~-D-

Chapter 5

188

Anomeric Radicals

xylopyranose with tributyltin hydride followed by acrylonitrile. As shown in Scheme 5.2.11, the resulting product was converted to the glycosylbromide u n d e r s t a n d a r d conditions. This product was then subjected to radical Cglycosidation conditions similar to those previously described thus providing a 60% overall yield of the C1, C5 modified xylopyranose.

Scheme 5.2.11

Radical C - G l y c o s i d a t i o n s with Glycosylbromides

NC \ ACO~oAc ~CN= A c O ~ O AcO Br "OAc n-Bu3SnH A c O ~ O A c OAc NC NC \ \ ~CN= A c O ~ q n-Bu3SnH AcO.~&~~ AcO.~k.~~ AcO'Br AcO[ ~ C N

HBr

Aco O

Figure 5.2.1

60%OverallYield

Stereoview of Vitamin B12

o

r

o

o

Chemical methods for the generation of glycosidic free radicals are not limited to tin hydrides or irradiation. Catalysts such as vitamin B12, shown in Figure 5.2.1, have also been used. As shown in Scheme 5.2.12, Abrect, et al., is

Chapter 5

Anomeric Radicals

189

utilized vitamin B12 in the generation of free radicals from 2,3,4,6-tetra-Oacetyl-a-D-glucopyranosyl bromide. Subsequent treatment with acrylonitrile or methyl vinyl ketone provided the desired cz anomeric C-glycosides in yields greater than 50%. Scheme 5.2.12

Radical C-Glycosidations with Glycosylbromides

~..-OAc

~IOAc

AoO----X-~o, A c O ~

~R Vitamin B 12

AcO Br

Scheme 5.2.13

"

AoO--X-41o

R = CN, C O C H 3

A c O ~ AcO [

~R

Radical C-Glycosidations with Glycosylbromides

x..-OAc AoO--X--.~ Ox AcO~ AcO Br O

nBu3SnH/AIBN

68%(5.5-1)

~

AoQ

~

-oo AcO

O

O

OAc 73% (5.5" 1)

Ac~i

0 "".Will

O OAc

O

~...OAc SePh

PhSe~

,

O

_

"r

O

C1,-\I x~.--.-- O

47%

- A c O ~...,,,,,,,~~

AcO

'~

O

Chapter 5

190

Anomeric Radicals

The use of methyl vinyl ketone in Scheme 5.2.12 and the previously described conjugated lactone used in Scheme 5.2.8 illustrate the utility of various radical acceptors complimentary to the commonly used acrylonitrile. In the next several examples, the use of conjugated carbonyl compounds will be addressed in the general technology surrounding the chemistry of anomeric free radicals. Extensive exploration into the applicability of conjugated c a r b o n y l compounds for the preparation of C-glycosides was carried out by Bimwala, et ai.,19, 20 and involves both conjugated ketones and lactones. As shown in Scheme 5.2.13, the anomeric radicals were generated utilizing tin hydride reagents a n d the couplings, all exhibiting a preference for a a n o m e r i c selectivity, proceeded in moderate to good yields. Further elaboration of the products shown provided strategies to novel C-linked clisaccharides and will be further discussed in Chapter 8. Figure 5.2.2

Radical Acceptor a n d Final C - D i s a c c h a r i d e

OBn

AcO~

OBn (

Bn

(

Scheme 5.2.14

"",,,,,,,,,,,"'V " " , ,

/

Bn OBn

OBn

0 Ac

OAc

Radical C - G l y c o s i d a t i o n s with G l y c o s y l b r o m i d e s

OAc

o,c (

)_ ..,,,,,Br

'"/OAc

Ac OAc

( Me3SnO OSnMe 3 Ph2C_CPh2 Ac

....... ~

OAc

80%

Earlier work in the area of anomeric radicals demonstrated the feasibility of directly joining two sugar units to form C-disaccharides. The work, described by Giese, eta/., 21 involved use of the modified sugar shown in Figure 5.2.2. The reported coupling, to be elaborated upon in Chapter 8, proceeded in 70% yield

Chapter 5

A n o m e r i c Radicals

191

with high selectivity for the ~ anomer. Through these observations, the ability to prepare higher C-glycosides has been demonstrated and applied to a variety of interesting and useful targets. While tin reagents have provided ample methods for the generation of anomeric radicals, the variety of structures useful as radical acceptors is extremely diverse. In addition to the conjugated nitriles and conjugated carbonyl compounds, oximes have also been used. As shown in Scheme 5.2.14, Hart, e t al., 22 effected a C-glycosidation utilizing an O-benzyl oxime and a tin reagent. The reaction proceeded in 80% yield with ~ anomeric selectivity. Scheme 5.2.15

Radical C-Glycosidations with G lyc o sy Ib ro m i d e s / i o d i d e s

OAc

CO2Me (

)- .,,,ii~Br

)

OAc

(C02Me

(

Bu3SnH/AIBN

"""OAc

Ac

Ac

,,,,~ CO2Me

""~ .....

CO2Me

~ """OAc

OAc

OAc

21%

OAc ~CO2Me Ac ' Bu3SnH/AIBN

()" .~''', c O~ 2 M e ' * * - - ...."OAc OAc

40%

OAc NEt

OAc

O = Bu3SnH/AIBN Ac '

(

( OAc

,9s S

Ac

"~OAc OAc

55%

In closing this section, the use of iodides in radical m e d i a t e d Cglycosidations is addressed. As illustrated throughout this section, radicals g e n e r a t e d from b r o m i d e s generally provide p r o d u c t s b e a r i n g the configuration in wide margins with respect to their yields. As shown in Scheme 5.2.15, these observations were confirmed by Araki, e t al. 23 The radicals were generated utilizing chemical methods and the radical acceptors were conjugated

Chapter 5

192

A n o m e r i c Radicals

ketones. However, w h e n the c o r r e s p o n d i n g glycosyliodide was used in conjunction with a photochemical radical generation, the observed yield was significantly higher with no stereochemical preference at the anomeric center. The use of free radicals in the formation of C-glycosides has been fruitful a n d a wide variety of novel and versatile structures are now available. This section has served to introduce this technology with respect to intermolecular chemical reactions. Further examples illustrating the utility of this chemistry will be touched upon in later discussions surrounding the syntheses of C-di and trisaccharides.

5.3

Intramolecular

Radical R e a c t i o n s

T h r o u g h the use of free radicals, C-glycosidic s t r u c t u r e s o t h e r w i s e inaccessible are easily formed. However, the variability in yields a n d the f r e q u e n t l y o b s e r v e d i n c o n s i s t e n c i e s with r e s p e c t to t h e d e g r e e of s t e r e o c h e m i c a l i n d u c t i o n r e g a r d i n g i n t e r m o l e c u l a r radical reactions have revealed limitations in the general applicability of this technology. In order to alleviate some of these problems, the use of the intramolecular delivery of free radical acceptors was developed. An early example of intramolecular radical r e a c t i o n is s h o w n in Scheme 5.3.1. As i l l u s t r a t e d , Giese, et a1.,24 stereospecifically formed bicyclic dideoxy sugars. The isolated yield was 53% and the stereochemical approach of the allyl group was entirely dictated by the stereochemistry at C3. Although, as shown in Figure 5.3.1, several intermediate c o n f o r m a t i o n s r e g a r d i n g the r a d i c a l species are possible, the a c t u a l i n t e r m e d i a t e radical species is p o s t u l a t e d to be t h a t b e a r i n g the b o a t c o n f o r m a t i o n . The two o t h e r illustrated c o n f o r m a t i o n s are r u l e d out, as i l l u s t r a t e d in Scheme 5.3.2, due to the inability of the 6-deoxy-6-allyl compound to cyclize under the same conditions used in Scheme 5.3.1.

S c h e m e 5.3.1

I n t r a m o l e c u l a r Radical C - G l y c o s i d a t i o n s AcO

~......OAc Aco~O\ I

n-Bu3SnH AIBN 53%

AcO

.......

,,~

+

OAc

OAc 90:10

OAc

OAc

Complimentary to the direct modification of the sugar ring as a means of a t t a c h i n g radical receptors is the selective blocking of the sugar h y d r o x y l groups. As shown in Scheme 5.3.3, Mesmaekerm, et al., 2s substituted the 2hydroxyl group of glucose derivatives with allyl and trimethylsilyl p r o p a r g y l groups. Subsequent t r e a t m e n t with tributyltin hydride and a radical initiator

Chapter 5

Anomeric Radicals

193

effected yields in excess on 90% in both cases. The stereochemistry of the cyclizations proceeded as expected with approach of the radical acceptors forming cis-fused ring systems. Finally, unlike the previous examples p r e s e n t e d in this section, the radicals g e n e r a t e d in Scheme 5.3.3 were generated from phenylselenoglycosides.

Proposed Conformations of Anomeric Radicals

Figure 5.3.1

II AcO

OAc

OAc

Scheme 5.3.2

9

OAc

-

OAc

OAc

OAc

A t t e m p t e d Radical Cyclization of 6-Deoxy-6-Allyl Sugars

AcO AcO.~.k..~~ AcO tI

A AcO

A further extension of the modification of sugar hydroxy groups is the actual tethering of free radical acceptors to these groups via cleavable linkers. Convenient groups used to make these tethers are silyl groups. As shown in Scheme 5.3.4, Stork, et ai.,26 successfully i n t r o d u c e d styrene units to the anomeric position of various sugars. This chemistry was applicable to both pyranose and furanose sugars. As with the examples presented in Scheme 5.3.3, the free radicals were g e n e r a t e d from p h e n y l s e l e n o g l y c o s i d e s . Additionally, as expected, the stereochemical a p p r o a c h e s of the radical acceptors were dictated by the stereochemistry of the hydroxyl group bearing the tethered substituent. Following cyclization, the bicyclic system was cleaved on removal of the silicon via treatment with potassium fluoride. In general, the products were formed in high yields with high stereoselectivity at the anomeric positions. Furthermore, the products contained one u n p r o t e c t e d hydroxyl group making accessible further functional changes on the sugar ring.

Chapter s

194

Anomeric R.aaic~s

Attempted Radical Cyclization of 6-Deoxy-6-Allyl Sugars

Scheme 5.3.3

OBn L O

OBn (

) T SePh

Bu3SnH/AIBN 90%

...., , 0 . / ' ~

Bn

OBn

OBn (

OBn

OBn ()-~

) T sePh

Bu3SnH/AIBN 95% =Bn

~"'"O~

Bn

,,,,,~'~

OBn

,,,,~FTMS

.~ii:ii,~? OBn

TMS Intramolecular C-Glycosidations with Tethered Radical Acceptors

Scheme 5.3.4

OBn

OBn ( ).....~SePh / o/Si ~

/~...,,,~\

Bn

!" n-Bu3SnH 2. F

OBn ~Ph OMe , ()~.... SePh Me

~''OMe

Ph

Si

Bn

~~.~

...,,,,,~~ Ph

"""OH OBn 83% OMe

Me

/"""OMe OH

/\ OBn

L~O'~

(

,,,..-

v'SePh\/

Ph

73%

OBn L ~ ' O ~

Ph

BnO""" %H

75%

Chapter 5

Anomeric Radicals

195

As a natural extension to the utility of silicon tethered radical acceptors for the p r e p a r a t i o n of C-glycosides, Xin, et al., 27 applied this technology to the p r e p a r a t i o n of a C-maltose derivative. This example, centering a r o u n d the preparation of a C-disaccharide, will be discussed in detail in Chapter 8. In one final example of the utility of i n t r a m o l e c u l a r delivery of free radical acceptors to the preparation of C-glycosides, Lee, et al., 28 utilized radical chemistry to actually form the sugar ring from a p p r o p r i a t e enol ethers. As shown in Scheme 5.3.5, the enol ethers were p r e p a r e d on coupling ethyl p r o p a r g y l a c e t a t e with various alcohols. In all cases, the radicals were g e n e r a t e d from tin r e a g e n t s and radical initiators. The yields o b s e r v e d exceeded 96% and the chemistry was a d a p t e d to reactions in which radicals were g e n e r a t e d from acetylenes. This, and other applications are contained within the cited report. F o r m a t i o n of C-Glycosides via Radical C y c l i z a t i o n s of Acyclic Precursors

S c h e m e 5.3.5

OH

Ra~.fO~ -----CO2E t

R~0n \

O

Br

"

(N)

(~

CO2Et Br

Me Ra~.,/O~'~~'~.

Br

R O CO2Et Bu3SnH AIBN ~ - ~,,,C O 2, E t " ( _~'--' "'"

R H H

Me

Me

Yield(%) 95 96 1 98 2 96

n 1 2

This chapter has endeavored to present approaches to the preparation of C-glycosides utilizing the chemistry of free radicals. T h r o u g h the use of intermolecular and intramolecular reactions, a variety of novel structures are available. Further insight into the variations available within this technology, reviewed by Descotes, 29 include discussions of the kinetics of radical systems and topics complimenting the specific realm of C-glycosides. 5.4 .

2. 3.

References Acbischer, B.; Vasella, A. Helv. Chim. Acta 1983, 66, 2210. Baumberger, F.; Vasella, A. Helv. Chirn. Acta 1983, 66, 2210. Brakta, M.; Lhoste, P.; Sinou, D.; Banoub, J. Carbohydrate Res. 1990, 203, 148.

196

0

Q

o

7. o

9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.

Chapter 5

Anomeric Radicals

Araki, Y.; Endo, T.; Tanji, M.; Nagasawa, J. Tetrahedron Lett. 1988, 29, 351. Keck, G. E.; Enholm, E. J.; Kachensky, D. F. Tetrahedron Lett. 1984, 25, 1867. Waglund, T.; Claesson, A. Acta Chem. Scand. 1992, 46, 73. Giese, B.; Ruckert, B.; Groninger, K. S.; Muhn, R.; Lindner, H.J. Liebig's Ann. Chem. 1988, 997. Somsak, L.; Batta, G.; Farkas, I. Tetrahedron Lett. 1986, 27, 5877. Giese, B.; Gilges, S.; Groninger, K. S.; Lamberth, C.; Witzel, T. Liebig's Ann. Chem. 1988, 615. Giese, B.; Groninger, K. S. Org. Syn. 1990, 69, 66. Dupuis, J.; Giese, B.; Hartung, J.; Leising, M.; Korth, H.-G.; Sustmann, R. J. Am. Chem. Soc. 1985, 107, 4332. Nicolau, K. C.; Dolle, R. E.; Chucholowski, A.; Randall, J. L. J. Chem. Soc. Chem. Comm. 1984, 1153. Nagy, J. O.; Bednarski, M.D. Tetrahedron Lett. 1991, 32, 3953. Paulsen, H.; Matschulat, P. Liebig's Ann. Chem. 1991, 487. Giese, B.; Witzel, T. Angew. Chem. Int. Ed. Engl. 1986, 25, 450. Giese, B.; Dupuis, J.; Leising, M.; Nix. M.; Lindner, H.J. Carbohydrate Res. 1987, 171,329. Blattner, R.; Ferrier, R. J.; Rennet, R. J. Chem. Soc. Chem. Comm. 1987, 1007. Abrecht, S.; Scheffold, R. Chimia 1985, 39, 211. Bimwala, R. M.; Vogel, P. Terrahedron Lett. 1991, 32, 1429. Bimwala, R. M.; Vogel, P. J. Org. Chem. 1992, 57, 2076. Giese, B.; Hoch, M.; Lamberth, C.; Schmidt, R.R. Tetrahedron Lett. 1988, 29, 1375. Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988, 110, 1631. Araki, Y.; Endo, T.; Tanji, M.; Nagasawa, J. Tetrahedron Lett. 1987, 28, 5853. Groninger, K. S.; Jager, K. F.; Giese, B. Liebigs Ann. Chem. 1987, 731. Mesmaekerm, A. D.; Hoffmann, P.; Ernst, B.; Hug, P.; Winkler, T. Tetrahedron Lett. 1989, 30, 6307. Stork, G.; Suh, H. S.; Kim, G. J. Am. Chem. Soc. 1991, 113, 7054. Xin, Y. C.; Mallet, J. M.; Sinay, P. J. Chem. Soc. Chem. Comm. 1993, 864. Lee, E.; Tae, J. S.; Lee, C.; Park, C. M. Tetrahedron Lett. 1993, 30, 4831. Descotes, G. J. Carbohydrate Chem. 1988, 7, 1.

C h a p t e r Six

6

Rearrangements and Cycloadditions

Introduction

As alluded to in section 5.3, the ability to direct reactions to the anomeric centers of modified sugars provides novel routes to C-glycosides. In Chapter 5, these reactions involved the intramolecular delivery of radical acceptors to anomeric free radicals. However, as the chemistry of C-glycosides developed, the use of a variety of cycloadditions and structural rearrangements became useful. Some s u b s t r a t e s for these reactions, b o t h i n t e r m o l e c u l a r and intramolecular, are shown in Figure 6.0.1. By examining these structures, a variety of specific reaction types can be envisioned and recognized as applicable to the p r e p a r a t i o n of C-glycosides. Among these are Claisen rearrangements, Wittig rearrangements, and carbenoid displacements. In this chapter, these and other reactions will discussed through examples of their use in the formation of novel C-glycosidic structures.

Rearrangement and

Figure 6.0.1

Cycloaddition Substrates

~

O,,,.j_.R

~.0

OR

.••

~ L ~

R1

OR2 R1 = SPh, OMe R 2 = Benzyl, Silyl Enol Ether

X

X = CN, CHO, Nitrile Oxide, etc.

197

Chapter 6

198

6.1

Rearrangements and Cycloaddin'ons

Rearrangements by Substituent Cleavage and Recombination

Many rearrangements involve the cleavage of substituents from a given substrate followed by recombination of the cleaved group to yield a new product. A classical example of this type of reaction is the Wittig rearrangement. In the following paragraphs, this reaction will be presented in the context of its applicability to the preparation of C-glycosides. Furthermore, it will be compared to mechanistically similar rearrangements associated with carbenoids.

6.1.1

Wi ttig Rearrangements

Scheme 6.1.1

Wittig Rearrangements

OH

OH

O'O

j ~ 0~...,,,,,,,

_0~ ..,,,,0 O#'y

O~y'""

"'''OH ' ' ~

'''OH n-BuLi LDA

11 4

" "

8 23

D o

= ~ ~ 0. 0 ~ ~

0

(

( ,~,~' OH 1.~oO~~,~/ ""'OH

~(~..~oOH HO

n-BuLi

/ ''"OH OH 16

9

OH 9

The Wittig rearrangement, 1 useful in the transformation of ethers to alcohols, has found utility in the formation of a variety of C-hydroxyalkyl glycosides. The actual mechanism of this reaction is believed to involve a radical cleavage followed by recombination to the final product.2, 3 As shown in Scheme 6.1.1, Grindley, et M., 4 applied this methodology to the preparation of Cglycosides from their corresponding O-benzyl glycosides. Although the

Chapter 6

Rearrangements and Cycloadditions

199

reactions proceeded with retention of stereochemistry at the anomeric center and inversion of the chair conformation, the configuration at the newly formed stereogenic center could not be u n a m b i g u o u s l y assigned. Regardless of this complication, the product ratio was found to be highly d e p e n d e n t upon the base used to initiate the reaction. For example, when n-butyllithium was used, the O-benzyl arabinoside was transformed to the corresponding C-glycosides with a ratio of 11 : 8. However, when LDA was used, the ratio c h a n g e d to 4 : 23 favoring the other isomer.

Carbenoid Rearrangements

6,1,2 Scheme 6.1.2

Carbenoid Rearrangements N2

~,,,,.OAc SPh AcO. ~ , ~ ~ ~ OAc

E-~E

Ac E~,,,, SPh

E = CO2Me

E

No Reaction

B n O ~ ~ . . . , ~ . ~ SPh OBn

SPh

AC~

Rh(ll) 84%

~.OBn BnO~ O

AcO

~,-OAc

74%

AcO

Ac~

OAc

~ Ac~OAc

~r~'SPh OAc

E"/

SPh

E E E " ~ SPh 57%

OAcI AcO O

Ac

Where the Wittig r e a r r a n g e m e n t provides products formed with retention of the c o n f i g u r a t i o n at the anomeric center, the use of c a r b e n o i d s in the formation of C-glycosides provides a c o m p l i m e n t a r y a p p r o a c h allowing the

200

Chapter 6

Rearrangementsand Cycloadditions

p r e p a r a t i o n of products with inverted anomeric configurations. As shown in Scheme 6.1.2, Kametani, et al.,5 observed the formation of a variety of Cglycosides in yields as high as 84%. Interestingly, these reactions p r o c e e d e d well utilizing peracetylated sugars while no reaction was observed with the corresponding perbenzylated sugars. This particular observation is rationalized t h r o u g h the p r o p o s e d reaction m e c h a n i s m shown in Scheme 6.1.3. As illustrated, the carbene adds to the thiophenyl group forming an ylide-type species. Addition of the resulting stabilized anion to the neighboring acetate group is followed by cleavage of the thiophenyl group thus forming an oxonium ion. As the acetate group is regenerated, the carbene-derived s u b s t i t u e n t is stereospecifically transferred to the oxonium ion. Considering this mechanism, it can be inferred that if a thiophenyl glycoside is utilized with the thiophenyl g r o u p on the same face as the 2-acetoxy group r e t e n t i o n of the a n o m e r i c configuration will be observed. T h o u g h n o t Wittig r e a r r a n g e m e n t s , the i l l u s t r a t e d c a r b e n o i d r e a r r a n g e m e n t s are mechanistically similar by virtue of the cleavage a n d recombination of the reactive structural components. One distinct difference b e t w e e n these reactions is the i n t r a m o l e c u l a r n a t u r e of the c a r b e n o i d r e a r r a n g e m e n t s as compared to the corresponding intermolecular m e c h a n i s m o b s e r v e d in Wittig r e a r r a n g e m e n t s . However, the similarities a n d the c o m p l i m e n t a r i t y a p p a r e n t in carbenoid reactions warrants their inclusion in this section. As a final note, the utility of carbenoid reactions was subsequently illustrated in the synthesis of showdomycin5 complimentary to the preparation illustrated in Scheme 5.2.2.6

Scheme 6.1.3

Mechanism of Carbenoid Rearrangements

~0~ ~h E O"

E

1 ~~~.~' SPh El/ E

SPh

Chapter 6

6.2

Rearrangements and Cycloadditions

201

Electrocyclic Rearrangements Involving Glycals

The r e a r r a n g e m e n t of modified glycals provides novel strategies to the p r e p a r a t i o n of C-glycosides. Such reactions involve the sigmatropic mechanisms associated with both Cope and Claisen reactions. In this section, these and related reactions are presented.

Sigma tropic Rearrangements

6.2.1

Sigmatropic rearrangements of glycal derivatives are recognized as useful strategies for the preparation of C-glycosides. In fact, this methodology was used as early as 1984 when Tulshian, et al., 7 observed the formation of h y d r o x y m e t h y l g l y c o s i d e s on t r e a t m e n t of g a l a c t a l a n a l o g s w i t h i o d o m e t h y l t r i b u t y l t i n . As shown in Scheme 6.2.1, the s t r u c t u r e of the hydroxymethyl compound was confirmed via an alternate synthesis beginning with a glucal analog.

Scheme 6.2.1

ph ~ ~ O ~ ~ _ . ~ O OH

1,4-Sigmatropic Rearrangements

2.1"n-Bu3Sn80% CH21B .tuLN i aH, 78"Ctor.t.

~,,.OAc

Et2AICN A c O ~ AcO""~--'~~O C6"6 AcO~-~.._.~ reflux,90%

OR R = CH2SnBu3 R = CH3

CH20H ILiAIH4

~,,,,.OAc

1."TsOH/MeOH~ l -=C~ 2. PhCHO

"

CN

x = CHO

X

In the same report, the utility of sigmatropic r e a r r a n g e m e n t s was expanded to include orthoester Claisen rearrangements and the related Cope rearrangements. The results, shown in Scheme 6.2.2, illustrate the ease of formation of C-glycosides bearing a variety of ester, aldehyde, and amide substituents. In all examples, the starting galactal was protected as the 4,6benzylidine acetal. The reagents utilized to effect various reactions include triethyl orthoacetate, ethyl vinyl ether, and 1,1-dimethoxy-1dimethylaminoethane. From triethyl orthoacetate, two esters were formed. Though not Cglycosides, the chemistry p r e s e n t e d in previous chapters provide ample

202

Chapter 6

Rearrangements and Cycloaddio'ons

strategies to the conversion of these compounds to other products. From ethyl vinyl ether, the actual isolated product was the C-glycosidic aldehyde formed in 75% yield. Finally, from 1 , 1 - d i m e t h o x y - l - d i m e t h y l a m i n o e t h a n e , the Cglycosidic amide was formed in 85% yield. As illustrated, these products were all easily interconverted as well as derivatized to a variety of other useful products.

3,3-Sigmatropic

S c h e m e 6.2.2

Rearrangements

Ph EtCO2H O t-m(I,}

r

+

OH ICH2=CHOEt

CO2E t

CO2Et

lM0~o4

x t~ (1) :s zCM O

:s O v ot ~ "T" O

l~'"~

PhCN reflux, 1 h ~

O~

75~ ~PhNO2 ",~eflux, 2 h

d,

~,,,"~

\80%

CHO

,,

NMe2

6.2.2

CHO

Claisen Rearrangements

Drawing specifically on Ireland's ester enolate Claisen rearrangements,8-10 Curran, et al., 11 d e m o n s t r a t e d the generality of this methodology in the c o n v e r s i o n of a v a r i e t y of acetoxyglycals to t h e i r c o r r e s p o n d i n g methylcarboxymethylglycosides. Not shown, the acetoxyglycals were treated with LDA followed by tert-butyldimethylchlorosilane thus producing near quantitative yields of the ketenesilyl acetals illustrated in Scheme 6.2.3. As shown, the ketenesilyl acetals were converted to the C-glycosides on heating. Notably, all reactions proceeded in yields exceeding 55% with less than 5% of the double Claisen products observed. The stereochemical outcome of these

Chapter 6

Rearrangements and Cycloadditions

203

reactions appeared to be influenced by the stereochemical configurations at C3 coupled with vinyligous anomeric effects. 12 Scheme 6.2.3

Claisen Rearrangements

O)

=

O ~ , ~ ~ / ~ . ~ CO2Me

60~

TBDMSO

..f ~'~OTBDMS

OTBDMS

60'/o(lessthan5%doubleclaisen) ',,,,,

55%

O"S

T=OM=O.~

0 I

/O.. ,,,~

-i

.....

CO =e

o~-<-...~ /~OTBDMS

OTBDMS

= TBDMSO~]]~...O~,,,, "" O ~

cO2Me

55% OTBDMS

~~"~OTBDMS

Vinylogousanomericeffect

A final example of the utility of sigmatropic rearrangements in the preparation of C-glycosides is shown in Scheme 6.2.4. As illustrated, Colombo, et al., 13 effected Claisen-type rearrangements utilizing heterocycles as the migrating groups. As with the previous examples mentioned in this chapter, this chemistry proceeded with the stereochemistry at the anomeric position dependent upon the stereochemistry at C3 of the glycal. The high anomeric stereospecificity of this chemistry coupled with the high yields demonstrates the tremendous versatility available within the application of sigmatropic rearrangements for the preparation of C-glycosides.

Chapter 6

204

Rearrangements and CycloadditJ'ons

Claisen-Type Rearrangements

Scheme 6.2.4

m

O /~0""

CCI4, PPh3 Et3N, CH3CN

/ ~ O ~'"

0 N

NHCOPh O

Ph m

Ph

=

0

O, 87%

6.3

Rearrangements from the 2-Hydroxyl Group

W h e r e Wittig r e a r r a n g e m e n t s have p r o v i d e d C-glycosides via rearrangements from anomeric hydroxyl groups and Claisen rearrangements have p r o v i d e d C-glycosides via migrations from 3-hydroxyl groups, the delivery of substituents from 2-hydroxyl groups have yielded novel Cglycosidic structures. Two examples will be illustrated in this section. The first example, shown in Scheme 6.3.1, was reported by Craig, et ai.,14 and previously illustrated in Chapter 2. The reiteration of this example is to show the types of strained fused-ring systems available from the delivery of nucleophilic species to adjacent centers. The second example, shown in Scheme 6.3.2, was reported by Martin, et a/.,ls and augments the discussions surrounding Schemes 2.4.16 through 2.4.19. The examples illustrated fit more within the profile of rearrangements than the example in Scheme 6.3.1 in that following delivery of the benzyl groups to the anomeric centers, cleavage of the benzyl ether can be accomplished utilizing hydrogenation techniques. The net result is a two step rearrangement of a 2benzylated sugar to a true C-glycoside. While direct rearrangements from 2hydroxyl groups to anomeric centers have not been well documented, the examples presented in this section provide strategies complimentary to the true rearrangements presented thus far.

Chapter 6

(~

O

..SPh

o

AgOTf/MoI.Sieves= t 50% 0 " ~ Bu BnO OBn OTBDMS

TBDMSO+~ u Scheme 6.3.2

OAc

.,OTBDMS \

tBu

Rearrangements from 2-Hydroxyl Groups

OR'

,=,o"

......

.~

R R'= = R' H "21% 46% 9

~

OR

~~/O'~

OMe

tBu

.... -,,/a-'-

H

SnCI4 = ~ , ~ . ~

RO.#"

/

......"" .....'"O

OBn

I H~ o-...j

OR' ~,~O"~

205

Rearrangements from 2-Hydroxyl Groups

Scheme 6.3.1

BnO

Rearrangements and Cycloadditions

\ OR

OR

SnC'4, ~ O ~ O M e +

49%

~_.~

....'i

30%

206 6.4

Chapter 6

Rearrangements and Cycloadditions

Bimolecular Cycloadditions

Complimentary to the intramolecular rearrangements discussed thus far are the Lewis acid mediated intermolecular reactions of the types discussed in Chapter 2. As relevant examples are extensive in the literature and many have already been presented, the reader is referred to the following schemes: 2.3.16; 2.3.17; 2.3.18; 2.3.38; 2.3.39; 2.3.40; 2.3.41. Through the reexamination of these examples, the mechanistic course of these reactions are realized t h r o u g h comparisons with ene and Prins-type mechanisms. Furthermore, although the reactions differ from the examples in this chapter involving intramolecular mechanisms, high stereoselectivity is observed with a p r o p e n s i t y for the formation of a anomeric C-glycosides.

6.5

Manipulations of C-Glycosides

Thus far, this book has addressed a wide variety of methods useful for the formation of C-glycosides bearing different functional groups at the anomeric center. In context with the discussions set forth in this chapter, these f u n c t i o n a l groups are subject to f u r t h e r modification by a v a r i e t y of cycloaddition and rearrangement reactions. Though these reactions are being illustrated on pre-formed C-glycosides, it is suitable to close this chapter with examples illustrating the ease of several transformations available for the conversion of simple C-glycosides to more complex entities. The examples p r e s e n t e d in this section will include transformations involving glycosidic aldehydes and glycosidic nitrile oxides.

Scheme 6.5.1

~ CO2H

Nitrile Transformations

~ . ~ CONH2

_i.--7._.._.__ NI~

~CHO ~CH2NO2 1.11.~,.

Chapter 6

Rearrangements and Cycloadditions

207

Within this section, we can recognize C-glycosidic nitriles, available as set forth in Chapter 2, as i m p o r t a n t substrates for further modification. As shown in Scheme 6.5.1, these c o m p o u n d s are easily t r a n s f o r m e d to a va r ie ty of different groups including aldehydes 16 and nitrile oxides. 17 Additionally, nitrile oxides are also available from C-nitromethylglycosides 18 p r e p a r e d as discussed in Chapter 2. The discussions set forth in this c ha pte r 's final section center a r o u n d Knoevenagel condensations and 1,3-dipolar cycloadditions.

6.5.1

Knoevenagel Condensations

Knoevenagel Condensations

S c h e m e 6.5.2

O ) ....,,,~CHO

MeO2C~,~.,. o H,~~

o 0

H

0

~

89.3%,One Diasteriomer

Knoevenagel Mechanism

S c h e m e 6.5.3

MeO2Cx~

O ) .....,,CHO .

......,,,//

MeO2C\J /~ ~"~ CO2Me

.-o

Me02C~ ~ H. 71 \",~C02Me

MeO2C~,~

o%/ s

~

Chapter 6

208

Rearrangements and Cycloadditions

Beginning with C-glycosidic aldehydes, the Knoevenagel condensation has provided interesting double ring systems suitable for further elaboration. As shown in Scheme 6.5.2, Herrera, et al., 19 treated the arabinose derivative, shown, with m e t h y l a c e t o a c e t a t e to give the i l l u s t r a t e d p r o d u c t in approximately 90% yield as a single diasteriomer. The mechanism for this reaction is shown in Scheme 6.5.3 and involves the initial condensation of the aldehyde with methyl acetoacetate. Following the first condensation, a second molecule of methyl acetoacetate condenses with the ketone and cyclizes via a Michael-type addition. Spontaneous decarboxylation liberates the observed product.

6.5.2

1,3-Dipolar Cycloaddi tions

With respect to 1,3-dipolar cycloadditions, several approaches have been utilized in the p r e p a r a t i o n of C-glycosides. As shown in Scheme 6.5.4, Kozikowski, et ai.,18 effected the reaction of the ribose-derived nitrile oxide with the olefin, shown. The reaction provided a 70% yield of the isoxazoline glycoside with no deleterious effects on the configuration at the anomeric center.

Scheme 6.5.4

1,3-Dipolar Cycloadditions

oAc

oAc

L , ~ O ~ N1vO

Me

"

ox o

OMe

~176

,0%

In addition to aliphatic olefins, cyclic olefins have also been utilized in the preparation of C-glycosides via 1,3-dipolar cycloadditions. As shown in Scheme 6.5.5, Dawson, et aL,2O utilized a 2,3-anhydro glucose analog in the reaction with the sugar-derived nitrile oxide. Again, the observed product was an isoxazoline ring separating two additional ring systems. Unlike the previous example, the oxazoline was fused to the ring previously bearing the double bond. Consistent with the observations of the previous example, this reaction proceeded in approximately 66% yield. In a final example demonstrating the various types of olefins useful in 1,3-dipolar cycloadditions, RajanBabu, et al., 21 utilized sugar derivatives bearing exoanomeric methylenes. The specific reaction, previously shown in Scheme 2.13.2, is specifically illustrated in Scheme 6.5.6 in order to compare the nature

Chapter 6

Rearrangements and Cycloadditions

209

of the observed product with the products of the previous two examples. As shown, the reaction proceeded in 78% yield with the isoxazoline forming a spiro ring system with the methylene bearing glucose derivative. Thus, the incorporation of 1,3-dipolar cycloadditions into the chemistry surrounding the formation and modification of C-glycosides provides novel heterocyclic structures suitable for isolation or further elaboration.

Scheme 6.5.5

1,3-Dipolar Cycloadditions

jO )

N

OAc I~ O ,,,~OEt

....,.OEt

AcO~"

AcO~,,,,..~_~( OAc

3 AcO~,,'" OAc

Scheme 6 . 5 . 6

66%

1,3-Dipolar Cycloadditions

OBn OTBDMS

~-.OBn

L~O~N o

''re BnO--'k"-k~~ BnO OTBDMS

BnO ~"~O .O Bn

o

78% This chapter has not only centered around the formation of C-glycosides

via rearrangements and cycloadditions, it has also introduced methods used solely for the modification of previously formed C-glycosides. Furthermore, substantial reviews of examples from previous chapters have been presented. In light of this, it is important to note that as discussions surrounding the chemistry of C-glycosides advance, the interdependence of the various reactions

Chapter 6

210

Rearrangements and Cycloadditions

becomes more notable. This will become more prominent in the final two chapters where ring cyclizations and methods for the preparation of C-di and trisaccharides are discussed. 6.6 I"

2. 11

.

5. 6. .

8. 0

10. 11. 12. 13. 14. 15. 16.

17. 18. 19. 20. 21.

References Schollkof, U. Angew. Chem. Int. Ed. Eng. 1970, 9, 763. Lansbury, P.; Pattison, V. A.; Sidler, J. D.; Bieber, J. B. J. Am. Chem. Soc. 1966, 88, 78. Hebert, E.; Welvart, Z.; Ghelfenstein, M.; Swarc, H. Tetraheclron Lett. 1983, 24, 1381. Grindley, T. B.; Wickramage, C. J. Carbohydrate Chem., 1988, 7, 661. Kametani, T.; Kawamura, K.; Honda, T. J. Am. Chem. Soc., 1987, 109, 3010. Araki, Y.; Endo, T.; Tanji, M.; Nagasawa, J. Tetrahedron Lett. 1988, 29, 351. Tulshian, D. B.; Fraser-Reid, B. J. Org. Chem., 1984, 49, 518. Ireland, R. E.; Thaisrivongs, S.; Varner, N. R.; Wilcox, C. S. J. Org. Chem. 1980, 45, 48. Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868. Ireland, R. E.; Wilcox, C.S. Tetrahedron Lett. 1977, 2839. Curran, D. P.; Suh, Y. G. Carbohydrate Res., 1987, 171, 161. Denmark, S. E.; Dappen, M. S. J. Org. Chem. 1984, 49, 798. Colombo, L.; Casiraghi, G.; Pittalis, A. J. Org. Chem. 1991, 56, 3897. Craig, D.; Munasinghem, V. R. N. J. Chem. Soc. Chem. Comm. 1993, 901. Martin, O. R. Carbohydrate Res. 1987, 171, 211. Rabinovitz in Rappoport, Z. (ed), "The Chemistry of the Cyano Group," Wiley, New York, 1970, 307-340. Torssell, K. B. G. (ed), "Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis," VCH, New York, 1988. Kozikowski, A. P.; Cheng, X. M. J. Chem. Soc. Chem. Comm. 1987, 680. Herrera, F. J. L.; Fernandez, M. V.; Segura, R.G. Carbohydrate Res. 1984, 127, 217. Dawson, I. M.; Johnson, T.; Paton, R. M.; Rennie, R. A. C. J. Chem. Soc. Chem. Comm. 1988, 1339. RajanBabu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51, 5458.

C h a p t e r Seven

7

Sugar Ring Formations

Introduction

Each of the chapters thus far have dealt with m e t h o d s used in the conversion of natural sugars, and derivatives thereof, to C-glycosides. Deviating from this trend, this chapter addresses the formation of C-glycosides from noncarbohydrate substrates. Specifically, the formation of the sugar ring is the focus of the chemistry discussed herein. Several methods for the execution of this approach are presented in the following schemes and include cyclizations of alcohols to olefins, alcohols participating in SN2 d i s p l a c e m e n t s , a n d cycloaddition reactions. The first of these examples, illustrated in Scheme 7.0.1, involves olefination of the ring-opened sugar followed by cyclization to the previously formed double bond. This addition is usually facilitated by the use of halogens or by converting the double bond to an epoxide thus creating more electrophilic species. The second approach mentioned, shown in Scheme 7.0.2, compliments the first through the cyclization of hydroxy halides or hydroxy epoxides.

Scheme 7.0.1

Olefination of Ring-Opened Sugars

=

Scheme 7.0.2

H y d r o x y H a l i d e / E p o x i d e Cyclizations

X = Leaving group (halide or epoxide)

211

R

Chapter 7

212

Sugar IUn8 Formatdons

With respect to the final approach mentioned above, several types of cycloadditions are applicable to the preparation of C-glycosides. One particular example, the hetero Diels-Alder reaction, is illustrated in Scheme 7.0.3. Through this method, some versatility is added through the resulting site of unsaturation inadvertently formed. Through expansion of, and the introduction of c h e m i s t r y c o m p l i m e n t a r y to, the m e t h o d o l o g y p r e s e n t e d in these i n t r o d u c t o r y schemes, this chapter presents specific examples in which the formation of the sugar ring is the key step involved in the preparation of Cglycosides.

Scheme 7.0.3

Hetero Diels-Alder Reactions

yo %

7.1

II

--

ao-

Wittig Reactions of Lactols Followed by Ring Closures

The Wittig reaction is a valuable method for the formation of olefins from aldehydes and ketones. In the case of carbohydrates, the aldehyde is masked in the form of a hemiacetal at the reducing end of a sugar or polysaccharide. However, due to the equilibrium between the hemiacetal and ring opened form of sugars, the Wittig reaction can drive the equilibrium entirely to the ring o p e n e d form with the final p r o d u c t being a newly formed olefin. Once prepared, these hydroxyolefins can be cyclized under a variety of conditions allowing the formation of C-glycosides. 7.1.1

Base Media ted Cycliza tions

As Michael-type reactions are among the most useful of base-mediated cyclizations, the first examples presented in this chapter center a r o u n d this chemistry. Thus, utilizing Wittig methodology, Vyplel, et al., 1 p r e p a r e d the hydroxyolefin, shown in Scheme 7.1.1, from the starting protected glucosamine. treatment of this intermediate species with DBU effected cyclization of the 5hydroxy group to the unsaturated ester in a Michael fashion. The resulting product was ultimately used in the preparation of C-glycosidic analogs of lipid A and lipid X initially presented in the introductory chapter. Notably, the cyclization provided the a anomer in 43% yield with an additional 7% accounted for in the isolation of the ~ anomer.

Chapter 7 Scheme

7.1.1

Sugar Pang Formations

213

Wittig Reactions Followed by Base Cyclizations

H O ~ o

H Ph3P=CHCO2AIlyl

Ph~~OOH~cO2AIlyl NH

o-<

R

R

DBU

HOO~co2AIlyl R

7.1.2 Scheme 7.1.2

Halogen Mediated Cycliza tions Wittig Reactions Followed by Bromo Cyclizations

~.....-OTips ~...OTips NBS, Br2 O...---~~OH --~O'~ OTips 52% ~ ~ ~ ' ~ o z i p s Br

~OTips /// - ~

O~~BOr,N

OTiP

Unlike base mediated cyclizations, halocyclizations do not depend on the presence of Michael acceptors. As shown in Scheme 7.1.2, Armstrong, et al., 2 treated a hydroxyolefin (derived from a Wittig reaction applied to a protected arabinose) with N-bromosuccinimide and catalytic bromine to effect the illustrated cyclization. The reaction proceeded through an intermediate bromonium ion providing a 52% yield of the ~ anomer. This observation compliments the preference for ~ anomers observed in base mediated

Chapter 7

214

Susar Rin 8 Formations

cyclizations. Furthermore, the isolation of a bromine substituted C-glycoside provides opportunities for the preparation of new and novel structures.

Scheme 7.1.3

Wittig Reactions Followed by Iodocyclizations

HO

HO I via Debenzylation

ool

I

BnO

BnO

:.,OBn

BnO R=H, Bn

ool :"o o

nO"

,no O" BnO\~""V

"~OBn OBn

42%

Bno~/O~

'

BnO\~"" V

"~OBn OBn

o~:13=9:41

The use of bromine mediated cyclization reactions is nicely complimented by iodocyclizations. The mechanism of these reactions proceeds through a similar iodonium ion and the products all bear potential iodide leaving groups. However, as illustrated by the products shown in Scheme 7.1.3, the iodides are all primary and aliphatic suggesting a preference for approach of the hydroxy group from the opposite side as that observed in the case of bromocyclizations. The examples presented in Scheme 7.1.3 were reported by Nicotra, et al.,3 and demonstrate the utility of these reactions as emphasized by yields as high as 78%. Furthermore, where choices were available, the reactions proceeded with a preference for the formation of five membered rings.

7.1.3

Me tal Media ted Cycliza tions

Methodologies that compliment the halogen mediated cyclizations are found within the chemistry surrounding mercury and selenium. Beginning with mercury, oxymercurations provide access to cyclic ethers via the coordination of a mercury reagent to olefins. The resulting products, as those isolated from halogen mediated cyclizations, generally bear mercury substituents which are easily modified or replaced under a variety of conditions. As shown in Scheme

, Chapter 7,

Sugar,Ring Formation s

215

7.1.4, Pougny, et al., 4 utilized an oxymercuration in the cyclization of a hydroxyolefin resulting from a Wittig reaction applied to 2,3,4,6-tetra-Obenzyl-D-glucopyranose. Subsequent cleavage of the m e r c u r y was accomplished under reductive conditions yielding a C-methylglycoside. Furthermore, oxidative conditions yielded the corresponding hydroxymethyl derivative. Scheme

7.i.4 .

.

.

.

.

Wittig Reactions Followed by Oxymercurations .

.

.

.

~...~OBn = BnO~ OH

~.-.OBn

~,,-

~...OBn BnBO0.__\ ~---v-..~O. ~.~

B o O - ~ . ~ 'OBo ~~

--

---

B o\ 7O L

1

~10Bn

~..OBn

Bn On ROI Me Scheme

7.1.5

" HgCI

BnO L "OH

Wittig Reactions Followed by Oxymercurations

~...-OBn

~.....OBn H2C=PPh3 ,,

B n O ~ OBn OH ~..-OBn

BnO ~

B n O ~ OBn ~...-OBn

B n O B n o ~ ~NHCBZ 2~1"KclHg(OAc)2 ~ BnBOo~ BnO

3. O3/NaBH4

1. DCC

~ O H

2. NH2OH .~

3. LiAIH4

4. CBZ-CI

BZ BnO

L_OH

A reaction sequence similar to that just described was subsequently applied to the preparation of piperidinyl sugars. As shown in Scheme 7.1.5, Liu, e t al., s treated 2,3,4,B-tetra-O-benzyl-D-glucopyranose with

Chapter 7

216

SugarRin~ Formations

m e t h y l e n e t r i p h e n y l p h o s p h o r a n e and the resulting hydroxyolefin was converted to the N-CBZ amino derivative in four steps. Subsequent cyclization was accomplished on treatment with mercuric acetate followed by potassium chloride. Finally, ozonolysis liberated the final alcohol. This product was ultimately utilized in the preparation of a-glucosidase inhibitors. In a final example specifically devoted to the use of mercury reagents following Wittig olefinations, 0jao, et al.,6 utilized mercuric trifluoroacetate to effect ring closure. This example, shown in Scheme 7.1.6, was utilized in the synthesis of the C-phosphonate disaccharide, shown in Figure 7.1.1, as a potential inhibitor of peptidoglycan polymerization by transglycosylase.

Scheme 7.1.6

Wittig Reactions Followed by Oxymercurations

P" o o.

Ph3P=CH2 79%

BnO

1. Hg(CF2CO2)2~ 2. KCI/I2 80%

Figure 7.1.1

BnO--~ BnO

OH

B n O ~ BnO

L.

Potential P e p t i d o g l y c a n

Polymerization I n h i b i t o r NHAc

~.....OH o

HOt.; O co

H

O OH Mercury mediated cyclizations are not unique in the use of metals to initiate the formation of pyranose and furanose C-glycosides. As shown in Scheme 7.1.7, Lancelin, et al.,7 effected similar reactions utilizing selenium reagents. As illustrated, the starting hydroxyolefin, prepared utilizing Wittig methodology, was treated with N-phenylselenophthalimide and camphor sulfonic acid (CSA). The resulting product mixture exhibited a 60% yield of the pyranosyl phenylselenide and a 30% yield of the furanosyl C-glycoside. Further

Chapter 7

Sugar Ring Formations

217

reactions included the conversion of the pyranosyl phenylselenide to the olefin on t r e a t m e n t with sodium periodate and sodium bicarbonate. This final reaction proceeded in 90% yield and provided a product suitable for further manipulations as set forth in section 2.13. Selenium Mediated Cyclization of Wittig P r o d u c t s

S c h e m e 7.1.7

BnO..,.~

BnO'"~ __ BnO~-~.~.~OH B n O ~ BnO

~

SePh

O NSePh O

~z

Bn

'.-o.

OBn

+

BnO "'"~ Bno~O~ BnO--&~~

60%

BnO L ~SePh Nal04 NaHC03

BnO"~ 0 BnO-~-X--..~~ B n O - ~ BnO "~

7.1.4

90%

Comparison of Cyclization Methods

With the variety of methods used, in conjunction with Wittig chemistry, for the formation of C-glycosides, it is helpful to compare the results of one m e t h o d to another. Several reports have accomplished this. As shown in Scheme 7.1.8, Freeman, et al., 8 effected the cyclization of a Wittig-derived hydroxy olefin to the furanosyl C-glycoside shown. The reagents utilized in this report encompass both halogen and metal mediated cyclizations and provided the desired product in yields as high as 65%. A later c o m p a r i s o n of the methods available for the cyclization of hydroxyolefins was reported by the same group and includes a study of the stereochemical consequences of the reactions. 9 As illustrated in Scheme 7.1.9, the cyclization proceeded in yields as high as 87% and generally exhibited p r e f e r e n c e s for the ~ anomeric C-glycosides. However, w h e n p h e n y l

Chapter 7

218

SugarRJng Formations

s e l e n o c h l o r i d e was used as the cyclization reagent, the a a n o m e r was favored in a ratio of 60 40. 9 H y d r o x y o l e f i n C y c l i z a t i o n Methods

Scheme 7 . 1 . 8

OBn

OBn

Electrophile

X

oxo g

.

Electrophile

X

Yield (%)

12 Br2 Hg(OAc)2 then 12workup Hg(OCOCF3) 2 then 12workup (CF3SO3)2Hg,amine PhSeCI

I Br I I

65 34 54 54 0 46

SePh

H y d r o x y o l e f i n C y c l i z a t i o n Methods

Scheme 7 . 1 . 9 OBn

OBn

,ectroo,',i,e ,

~nO~

~O~n

,,--" % BnO

Electrophile

Yield (%)

12

79 75 87 63 46

Br2 Hg(OAc)2 Hg(OCOCF3)2 PhSeCI

X

Bn ~" 13

18:82 16 : 84 11:89 11 : 89 60:40

Additional reports examining the differences b e t w e e n the various m e t h o d s for h y d r o x y o l e f i n cyclizations are available a n d will n o t be d i s c u s s e d f u r t h e r . Instead, this c h a p t e r will c o n t i n u e with discussions c e n t e r e d a r o u n d a l t e r n a t e m e t h o d s u s e d in t h e f o r m a t i o n of h y d r o x y o l e f i n i c s p e c i e s as i n t e r m e d i a t e s to the f o r m a t i o n of C-glycosides.

Chapter 7 7.2

Sugar Ring Formations

219

A d d i t i o n of Grignard and Organozinc Reagents to Lactols

Wittig reactions are only one means of converting lactols to hydroxy olefins. C o m p l i m e n t a r y olefinations are available utilizing Grignard and organozinc reagents. Where Wittig reactions rely on the olefination of a reactive aldehyde, the use of vinylzinc and the corresponding magnesium reagents provide simple additions to carbonyl groups and effectively provide unprotected hydroxyl groups suitable for selective manipulations. Finally, the r e a g e n t s u l t i m a t e l y utilized to effect ring closure of the r e s u l t i n g hydroxyolefins lie within those described in the previous section. As shown in Scheme 7.2.1, Boschetti, et al., lo effected olefinations on a variety of furanoses utilizing divinyl zinc. In general, the initial additions proceeded in high yields and stereoselectivity with the vinyl group being delivered from the same face as the 2-benzyloxy groups. In this report, the final cyclizations were effected utilizing mercury reagents and provided yields ranging from 51% to 71%.

Scheme 7.2.1

Divinyl Zinc Additions and Mercury Cyclizations

OBn

OBn O

OH ~ Z n ~

OBn

,..

20 ~

,~ BnO

OBn

oBn

.....

ira,

95%

51%

BnO~"" T

""'OH

HgCI

/"""OH

Bn

OBn only isomer

OBn

o

OBn

O'~

"•

HgCl2

y

OBn

OH

HgCI 71%

BnO

"~. OBn

BnO"" .."r. ~ ~'OH OBn 95"5

Bn

-

OBn

A similar reaction sequence, reported by Lay, et al., 11 is shown in Scheme 7.2.2. In this study, Grignard reagents were used to convert furanose Nglycosides to 2-amino-2-deoxy pyranose C-glycosides. The reactions proceeded with a preference for the formation of a anomers. A particular advantage to this chemistry is that conventional C-glycosidations do not work well for glucosamine analogs. Similar results were independently reported by Carcano, et al., 12 thus confirming these observations.

220

Chapter 7

Susar Fang Forman'ons

Scheme 7.2.2

Addition-Oxymercuration w i t h Aminoglycosides

OBn

~.-OBn ~MgBr

BnO---'~.-.~t OH B

BnO~'"

n

O

Hg(OCOCF3)2

~

BnHN 77% yield + Manno isomer

"OBn

~-.OBn BnO~O\ / 24.42ppm,JHI',H2'= 4.5 Hz B n O ~ . ~ ~ . ~ ~" BnHN C HgCI

77%

~...OBn BnRO~O\

~__ 31.14ppm,JHI',H2' = 10 Hz

BnHN

7.3

HgCI

20%

C y c l i z a t i o n of Suitably S u b s t i t u t e d Polyols

The chemistry presented in the previous two sections centered a r o u n d the formation of hydroxyolefins followed by cyclization to the desired Cglycosides. The latter steps in the examples shown essentially rely upon the cyclization of protected polyols. In this section, cyclization methods including ether formations, ketal formations, and halide displacements are presented.

7.3.1

Cyclizations via Ether Formations

Among the simplest of the cyclizations utilized in the formation of Cglycosides involves the acid mediated formation of ethers. Such reactions can be viewed as a dehydration between two alcohol units with the driving force for the reaction being the elimination of water. The following paragraphs present this reaction in the context of the cyclization of polyol units as a means of preparing C-glycosidic products. As shown in Scheme 7.3.1, Frick, et ai.,13 formed the perbenzylated polyol on treatment of the lithiated flavonoid with the ring opened form of penta-Obenzylglucose. As illustrated, catalytic hydrogenation in acetic acid produced a C-furanoside after three hours and a C-pyranoside after two days. Additionally,

Chapter

7

Suf~arPa'n~Formations

221

the furanoside form was easily converted to the pyranoside on t r e a t m e n t with hydrochloric acid in dioxane. S c h e m e 7.3.1

Acid M e d i a t e d C y c l i z a t i o n s

BnOJ~ Li

OBn OBnO

9

!

MeO~O.....,,.~Ar

?

II

~

~

OBn

,-, ^,,,,,,..L..,...,,,,~OBn ~nu

"r"

,,.....[

-

OBn OBn OBn=

.OH

BnO'

MeO ! O

-O

MeO ~

/

./,-%./.OMe Ar =

II

MeO C)~/O

1

'-~~

Ar

~

H=, Pd/C

I H=, Pd/C

AoOH,2days

1AoOH' h~ 3

OH H

HO~T/"'~. , ~ O H ~

HCI,Dioxane Me

Ar

MeO

\

/

OH

HO~,,,..-.,.~0 Ar

eO

MeO

\

/

Similar acid m e d i a t e d cyclizations have been r e p o r t e d on a variety of substrates. For example, as shown in Scheme 7.3.2, Casiraghi, et al., 14 treated 2 , 3 , 4 , 6 - t e t r a - O - b e n z y l - D - g l u c o p y r a n o s e with a p y r r o l e - d e r i v e d G r i g n a r d reagent and a titanium based Lewis acid. As shown, the addition proceeded in 64% yield with the formation of a single diasteriomer. Subsequent exposure to an acidic DOWEX resin p r o v i d e d a 50% yield of the ~-C-glycoside and an additional 21% isolated as the corresponding a anomer.

222

Chapter 7

Sugar Rin~ Formations

Scheme 7.3.2

Acid Mediated Cyclizations

MgBr ~-~/~

OBn (

~..,,) "oOBHnCITi(Oipr)3

HO BnO = '

HO

H N

Bn OBn HN

OBn

OBn

()

...H,,,"NL~

(

acidic DOWEX resin

+ / ''"0 Bn OBn 50%

Bn

~.~

"'*OBn OBn 21%

Bn

Cycliza tions via Ke tal Formations

Z3.2

Cyclizations via Ketal Formations

Scheme 7.3.3

O

OBn OBn

OMe O

OMe

MeoOan

OBn OBn

OBn OBn OBn "

~. ~ MeO

~

Bn OBn

MeO

OMe OAc 1. Swern 2. H2, Pd/C 3. Acetylation

Ac

)'..,,,,OAc OAc

Ketals are capable of being formed under acidic conditions. Consequently, this technology compliments the acid mediated cyclizations set forth in the

Chapter 7

Sugar Ring Formations

223

previous two examples. As applied to the preparation of C-glycosides, the general approach is similar to the previous examples in that a nucleophile is a d d e d to a sugar derivative. As shown in Scheme 7.3.3, Schmidt, et al., is utilized a perbenzylated open-chain glucose. The resulting alcohol was then oxidized to the corresponding ketone and the benzyl groups were removed u n d e r catalytic conditions. On acetylation, the resulting polyol cyclized with formation of a single diasteriomer of the papulacandin spiroketal. It should be n o t e d t h a t the ketals formed utilizing this technology are anomerically alkylated C-glycosides bearing resemblances in chemistry and appearance to both O and C-glycosides.

Cyclizations v i a Ketal Formations

Scheme 7.3.4

OMOM i

OyO

BnO"" " T " ""o Bn OBn

OBn

OTBDMS OH

OMO M

II

42%

MOMO/]~

Bn OBn

TBDMSO MOMO.

0

OMOM

OMOM OH 1. TBAF 2. H2, Pd/C ~,,,"

",a t

H

OH

The papulacandins are a class of antifungal antibiotics isolated from Papularia sphaerosperma. 16 As the antifungal properties of these compounds are interesting, substantial effort has been directed towards their preparation. Utilizing a similar a p p r o a c h of spiroketal formation, Rosenblum, et al., 17 achieved a somewhat shorter preparation of the above described product. As shown in Scheme 7.3.4, perbenzylated gluconolactone was treated with an aryllithium compound producing a 42% yield of the desired hydroxyketone. Subsequent removal of the silyl protecting group followed by hydrogenation and yielded a polyol which spontaneously cyclized to a spiroketal. This final ketal formation afforded the key intermediate in the illustrated papulacandin preparation.

Chapter 7

224

Sugar Ring Formations

Cycliza tions via Halide Displacements

7.3.3

T h o u g h technically ether formations, the d i s p l a c e m e n t of halides by hydroxyl groups differs from the examples presented earlier in this section in that these reactions are base mediated. As such, C-glycosidations u n d e r these conditions compliment the previously described cyclization strategies in that they allow reactions with acid sensitive substrates. As shown in Scheme 7.3.5, Schmid, et al., is utilized this a p p r o a c h in the p r e p a r a t i o n of C-furanosides. Specifically, the illustrated triol was protected with silyl groups. Subsequent t r e a t m e n t of the ketone with allylmagnesium chloride effected formation of a hydroxide which readily displaced the terminal chloride. The final C-glycoside was isolated as a 2.7 : 1 mixture of diastereomers.

Scheme 7.3.5

Cyclizations via Halide Displacements

IfOTBDMS

OH 1. TBDMS-CI HO

O

7.3.4

~.

CI 2. Allylmagnesium Chloride

OH

~

Ring Cyclizations: A Case Study

Perhaps the most extensive studies into the cyclizations of p r o t e c t e d polyols as methods for the preparation of C-glycosides was p r e s e n t e d by Kishi, et al. 19 This study involves the exploration of three routes to similar e n d products from similar starting materials. In the first of these strategies, shown in Scheme 7.3.6, a glucose derivative was converted to a hemiketal by Swern oxidation of the free alcohol followed by removal of the acetonide. Following spontaneous cyclization, the primary alcohol was protected. Utilizing reductive conditions to remove the anomeric hydroxyl group, the desired ~-C-glycoside was obtained. In the second a p p r o a c h , shown in Scheme 7.3.7, the same glucose derivative used in Scheme 7.3.6 was converted to the p - n i t r o b e n z o a t e in the following manner. The acetonide was removed under hydrolytic conditions and the resulting diol was cleaved oxidatively. Spontaneous cyclization afforded the h e m i a c e t a l which was s u b s e q u e n t l y p r o t e c t e d as the c o r r e s p o n d i n g pn i t r o b e n z y l ester. This O-PNB glycoside was t h e n c o n v e r t e d to a Callenylglycoside utilizing propargyltrimethylsilane and a Lewis acid. The allene was then cleaved on treatment with ozone. Reduction of the resulting aldehyde and protection of the resulting alcohol gave a product identical to that formed in Scheme 7.3.6 with the exception of the anomeric stereochemistry.

Chapter 7 Scheme

Sugar tong Formations

Kishi

7.3.6

225

Polyols -- Route A

PhCO0_ 0 +O

OBn OH

~/q

BnO ....

Bn OBn OMPM PhCO0.

PhCO0. 0

I

BnO ,..

BnO,,, r ~ o + "

BnO~~,

7.3.7

0

B n O ~ " OH

~

OMPM Scheme

,

"~" ""OBn OMPM OBn

BnO

OBn

0

Kishi Polyols

-

pOq ......."L"/l'Y """OBn OBn

-- R o u t e B

OPNB

O

OBn OH

O

~(

~) '"~'OBn OBn OMPM

OBn

OMPM

Bn o; = BnO~/J..,,,R OMPM

BnO~'...,,,,,,,,,,~,... ~ )~...,,,,OBn OBn

PhCOO, O

!

=

,,.

BnO ....

O

BnO@

j ....""*""".LT J. '"~ ,

OH

PO4

OBn

In the third approach, shown in Scheme 7.3.8, a glucose derivative was converted to an epoxide via hydrolysis of the acetonide followed by tosylation of the terminal hydroxyl group and treatment with sodium hydride. Subsequent removal of the PMB group with ceric ammonium nitrate and treatment with p-toluenesulfonic acid effected cyclization to the pyranoside.

Chapter 7

226

Sugar Rin8 Formations

Protection as previously described afforded a product identical to that obtained in Scheme 7.3.7 with the exception of an acetylated hydroxyl group. Kishi P o l y o l s -- R o u t e C

Scheme 7.3.8

"~'---0

-__BnO

OBn OMPM~'/0"~

' ~MPM~./0

B n O ~ ' ~ , , ,' T OBn OAc PhCO0. BnO ....

OBn 0

BnO~

I!

FOq L

'""'*""" T

OAc

OAc

",OBn OBn .

0

J

_

'""OBn

OBn

The work reported by Kishi, et al., provided landmark insight into the preparation of C-disaccharides. As the examples presented in this section are representative of C-disaccharides, they were intentionally vague and will be discussed in much greater detail in Chapter 8. 7.4

Rearrangements

Chapter 6 addressed the subject of the formation of C-glycosides via rearrangements. In the examples presented therein, the rearrangements were executed on substrates that already possessed suitable ring configurations for the desired C-glycosidic products. The rearrangements presented in this section differ from those in Chapter 6 in that the core ring required for the C-glycosides are either formed or substantially modified. The r e a r r a n g e m e n t types presented include electrocyclic reactions as well as ring contractions.

7.4.1

Electrocyclic Rearrangements

The preparation of C-glycosides, via formation of the sugar ring, can be achieved through the rearrangement of suitable substrates. For example, as shown in Scheme 7.4.1, Burke, et a1.,2o utilized the enolate Claisen rearrangement. In the cited study, a series of 6-alkenyl-l,4-dioxane-2-ones

Chapter 7

Sugar Rin~ Formations

227

was converted to dihydropyrans bearing C-methylcarboxyl glycosidic units. All reactions were stereospecific and the yields and s u b s t i t u t i o n p a t t e r n s are shown in Table 7.4.1.

Enolate Claisen Rearrangement

Scheme 7.4.1

2

3

R1~ O

R1

i-Pr

'xO

MSONa ~

R3

0

i-Prv CY "CO2Me

i.Pr, ] O y

R2~__~]3 R1~ s

R2

'Oy

i.prv! O y Table 7.4.1

o2_2

i.Pr~,- -()/

"",/C02M e

Enolate Claisen Rearrangement Results Dihyd ropyran Product Yield (96) Substrate R1 R2 R3 X X X X X X Y Y Y Y Y

Z4.2

0 i-vr OTMS

H H H H Me Me H H H H Me

H Me H H H Me H Me H H H

H H SiMe3 Me H H H H SiMe3 Me H

67 75 52 70 90 80 69 78 61 81 91

Ring Contractions

In addition to Claisen-type rearrangements, other methods are applicable to the formation of C-glycosides. As shown in Scheme 7.4.2, Fleet, et al., 21 utilized ring c o n t r a c t i o n t e c h n i q u e s in the t r a n s f o r m a t i o n of O - m e t h y l pyranosyl glycosides to C-furanosyl glycosides. The reactions proceeded in 51%

Chapter 7

228

SugarRing Formations

to 91% yields, depending upon the anomeric configuration of the starting galactosides, and produces approximately 2 : 1 ratios of diastereomeric products. A potential mechanism is also presented in Scheme 7.4.2 and involves the displacement of the triflate by the pyranose ring oxygen followed by opening of the three membered intermediate by an azide group. In this respect, the mechanism resembles that belonging to the classical Favorskii rearrangement. S c h e m e 7.4.2

Ring Contractions

TBDPSO~/'O~~IOMe .~_~_0 ~

''OTf

NAN3,40~ DMF TBDPS

-

TBDPSO

S c h e m e 7.4.3

OMe

~

N3

d

ira,

~

+ ,,,,OMe/

'"

Ring Contractions

BzO.~~ () ,.OH m-CPBA.

BzO"'" ~ ~~,,,,,,Seph OBz

1

B z O ~ ~ . . . (~

.OH

BzO""'"~ ~..,,,,,,SeO2Ph OBz

BzO'/~~ O) ......"%O /

BzO

\

OBz

BzO~... O~ OH+ BzO'" y OBz

Chapter 7

Sugar Ring Formations

229

Additional types of rearrangements have been used in the preparation of C-glycosides. One particular example, reported by Kaye, et al., 22 involves an oxidative pathway and was ultimately used in the preparation of showdomycin analogs. The reaction, shown in Scheme 7.4.3, proceeds in a similar fashion to that in the previous example with the ring oxygen displacing the selenium leaving group. However, a substantial difference is noted by the observation that once oxidation of the phenylselenide is complete, no additional reagents need be added in order to induce reaction.

Other Rearrangements

Z4.3

Benzylidine Acetal Rearrangements

Scheme 7.4.4 AcO.

~O

~O Ac20, H2SO4 =

AcO ~

Ar

AcO

§

Ar

AcO ~O

,7." AcO

Ar

AcO AcO.

"C

"cO'

OAc AcO / ~

AcO +

AcO.

AcO / ~

AcO

AcO

In a final example of the utility of rearrangements in the formation of Cglycosides, Kuszmann, et ai.,23 reported reactions involving benzylidine acetals. A specific reaction, illustrated in Scheme 7.4.4, yielded two diastereomeric Cglycosides in a combined yield of approximately 30%. The m e c h a n i s m associated with this reaction involves initial acetylation of one of the ring oxygens followed by cleavage of the ring with formation of a conjugated

Chapter 7

230

Sugar Rang Formations

carbocation. Migration of an acetate to the carbocation yields a species bearing an olefin on one side and an oxonium ion on the other. Ring closure followed by quenching of the resulting carbocation by an acetate group gives the observed products.

7.5

Cycloadditions

Perhaps the most useful m e t h o d for the formation of s u b s t i t u t e d ring systems from acyclic substrates is the Diels-Alder reaction. As will be explored in this section, the Diels-Alder reaction fits well within the t h e m e of this chapter t h r o u g h its use in the direct formation of ring systems capable of being converted to sugars. As shown in Scheme 7.5.1, Katagiri, et al., 24 i n c o r p o r a t e d this methodology in transformations involving furan derivatives. As illustrated, the Diels-Alder r e a c t i o n b e t w e e n 3 , 4 - d i b e n z y l o x y f u r a n a n d d i m e t h y l (acetoxymethylene)malonate afforded a 57% yield of the bicyclic adduct. This p r o d u c t was t h e n subjected to catalytic h y d r o g e n a t i o n followed by basic reductive conditions. The resulting cascade of reductions and r e a r r a n g e m e n t s produced the dimethylmalonyl-C-lyxoside in an 85% isolated yield.

Scheme 7.5.1

C-Glycosides via Diels-Alder Reactions

.OAc

Bno- OAc H2 I OAc O

MeO2CLCO2Me

BnO BnO

O

"VOO2Me P~

OBn

CO2Me

K2003 NaBH4

BnO~, .s R

I__.

".,~

=

OBn CHO

R = CH2OH

OH

CO2Me

m

HO

....(o9 ....

I CO2Me

......(OHFc(co .~

BnO~

...

~*C)Bn

e)

O

HO

R'

OH

OH R'= CH(CO2Me)2

Where, as illustrated in the above described example, the Diels-Alcler reaction provides avenues into the formation of C-glycosides from f u r a n derived dienes, the hetero Diels-Alder reaction allows for the direct formation of sugar rings from carbonyl groups. As shown in Scheme 7.5.2, Schmidt, et al., 2s effected reactions between conjugated carbonyl c o m p o u n d s a n d olefins. The illustrated reaction proceeded in 81% yield giving an a d d u c t which, after further manipulations, was converted to a C-aryl glycoside.

Chapter 7

Sugar Ring Formations

231

C-Glycosides via

S c h e m e 7.5.2

Hetero Diels-Alder Reactions

PhS

CH2OBn

AoOO

CH2OBn

>----(

~- PhS

OMe OMe

OMe AcO J.OAc

=,e,s ~cO~-~o, /~~O=e

- A c O ~

OMe C-Glycosides via Hetero Diels-Alder Reactions

S c h e m e 7.5.3

OTMS

CH2OBn MeO-~

OHC,,~

,.

H2OBn

~ " MgBr

BnO- !~ ~ O B n OAc 0

"•

CH2OBn

Steps

Bn~/O'~.~/~OBn

AcO

"cO O AcO"""" y

.... OAc OAc

Where the previous example utilized carbonyl compounds as Diels-Alder dienes, complimentary technology is available incorporating carbonyl compounds as dienophiles. As shown in Scheme 7.5.3, this approach was explored by Danishefsky, et ai.,26 in the preparation of a papulacandin precursor. Utilizing the diene, shown, and the substituted benzaldehyde, Diels-

Chapter 7

232

SugarRing Formations

Alder methodology effected ring formation in a 92% yield. Subsequent Michael addition with vinylmagnesiumbromide provided the C-glycosidic precursor in 70% yield. This compound, after several synthetic transformations, was converted to the required peracetylated intermediate. As illustrated in the previous two examples, the hetero Diels-Alder reaction provides a useful entry into the preparation of C-monosaccharides. However, as illustrated in Scheme 7.5.4, Danieshefsky, er al., 2728 utilized this methodology in the preparation of a C-linked disaccharide. As shown, the aldehyde produced from a galactose derivative was reacted with a diene under chelation control. The ultimate result was a single isomer of a C-glycoside containing extremely versatile functionalities. C-Disaccharides via Hetero Diels-Alder Reactions

S c h e m e 7.5.4

CHO

0HC~,]/O...,,,~0,

....

"~176d

OMe

"'ea~

O

X

O

O~~..., O OTMS

OBz MgBr2 Chelation control

H~I,'~~~ "OBz

BnO""'1~ O~..,iiiiO~ --T

79%, only

isomer

"" O

Diels-Alder m e t h o d o l o g y is well suited to the p r e p a r a t i o n of Cmonosaccharides and higher carbohydrate analogs. In general, these reactions provide products with high degrees of stereochemical induction as well as exhibiting synthetically useful yields. Further examples of Diels-Alder reactions applied to the preparation of C-disaccharides will be elaborated upon in Chapter 8.

Chapter 7 7.6

SugarRing Formations

233

O t h e r M e t h o d s for the F o r m a t i o n of Sugar Rings

The methods described thus far represent only a small subset of the available methodologies for the formation of C-furanosides and C-pyranosides. Other methods shown to be useful include cyclizations of halo olefins and eneynes. As shown in Scheme 7.6.1, Lee, et a1.,29 p r e p a r e d halo olefins from suitable alcohols and acetylenic esters. Subsequent application of free radical conditions thus effected cyclizations. All reactions p r o c e e d e d in yields exceeding 95%. Furthermore, where the formation of diastereomers was an issue, selective cis formation was observed. Thus the ease of preparation of the vinyl ether substrates required for these cyclization reactions makes this methodology an extremely useful addition to the technology surrounding the preparation of C-glycosides. S c h e m e 7.6.1

Radical Cyclizations

R

~CO2Et ~ ,~, Br

CO2Et

I~)n \Br

(~)

Me R~O\

~ ~-"-

~, (in \ 0

R

O

CO2Et Bu3SnH ~ ' / - ~ C O 2 E t AIBN (nL~

Br

-,,,,,~~CO2E t

(in

R

n

Yield(%)

H H Me Me

1 1 2

95 96 98 96

2

0

Bu3SnH .~, ~ AIBN " ( ~

Scheme 7.6.2

CO2Et

n

21

SnBu3

Yield(%)

9898

Pyran Modifications

Cp(CO)2M~i~O'~ MeLi.-78~

Cp(CO)2Mo~A

-.

+Mo(CO)2Cp

56%

LiCH2CO2Me=_92% ,,,,,,,

,, +Mo(CO)2CP ~/~O~/~

..........

1. Decomplexation 2. Hydrolysis ,,~C02Me3. Hydrogenation

,,,,,,,,,,...~...,,,,,,,~C02 H

Chapter 7

234

Suf~artO'n8 Formations

Where this chapter has examined the formation of C-glycosides via the formation of sugar rings, available methodologies allow the formation of Cglycosides by building off of pyran rings. As shown in Scheme 7.6.2, Hansson, et al., 30 demonstrated the utility of reacting alkyllithium compounds with complexes involving 2H-pyran and molybdenum. The initial addition of methyllithium provided a dihydropyran which, after oxidation back to a pyran, was ready for further elaboration. Following decomplexation, the illustrated disubstituted tetrahydropyran was isolated. The lessons apparent in this chapter demonstrate that although some Cglycosides can be synthetically challenging targets, their availability from a variety of acyclic substrates compliments the chemistry made use of in the first six chapters. Many more methods are available for the preparation of Cglycosides and many more will be discussed in the final chapter as they apply to the preparation of C-di and trisaccharides. 7.7 0

0

3. 0

So

6. 7. 8.

9. 10. 11. 12.

References

Vyplel, H.; Scholz, D.; Macher, I.; Schindlmaier, K.; Schutze, E. J. Med. Chem., 1991, 34, 2?59. Armstrong, R. W.; Teegarden, B. R. J. Org. Chem. 1992, 57, 915. Nicotra, F.; Panza, L.; Ronchetri, F.; Russo, G.; Toma, L. Carbohydrate Res. 1987, 1 71, 49. Pougny, J. R.; Nassr, M. A. M.; Sinay, P. J. Chem. Soc. Chem. Comm., 1981, 375. Liu, P. S. J. Org. Chem. 1987, 52, 4717. Qjao, L.; Vederas, J. C. J. Org. Chem., 1993, 58, 3480. Lancelin, J. M.; Pougny, J. R.; Sinay, P. Carbohydrate Res. 1985, 136, 369. Freeman, F.; Robarge, K. D. Carbohydrate Res. 1985, 137, 89. Freeman, F.; Robarge, K.D. Carbohydrate Res. 1987, 171, 1. Boschetti, A.; Nicotra, F.; Panza, L.; Russo, G. J. Org. Chem., 1989, 54, 1890. Lay, L.; Nicotra, F.; Panza, L.; Verani, A. Gazzetta Chimica ItMiana, 1992, 122, 345. Carcano, M.; Nicorra, F.; Panza, L.; Russo, G. J. Chem. Soc. Chem. Comm.

1989, 297.

13. 14. 15. 16. 17. 18. 19. 20.

Frick, W.; Schmidt, R. R. Liebig's Ann. Chem. 1989, 565. Casiraghi, G.; Cornia, M.; Rassu, G.; Sante, C. D.; Spanu, P. Tetrahedron 1992, 48, 5619. Schmidt, R. R.; Frick, W. Tetrahedron 1988, 44, 7163. Traxler, P.; Gruner, J.; Auden, J. A. L. J. Antibiotics 1977, 30, 289. Rosenblum, S. B.; Bihovsky, R. J. Am. Chem. Soc. 1990, 112, 2?46. Schmid, W.; Whitesides, G. J. Am. Chem. Soc. 1990, 112, 9670. Wang, Y.; Babirad, S. A.; Kishi, Y. J. Org. Chem., 1992, 57, 468. Burke, S. D.; Armistead, D. M.; Schoenen, F. J.; Fevig, J.M. Tetrahedron, 1986, 42, 2787.

Chapter 7 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

Sugar Ring Formations

235

Fleet, G. W.; Seymour, L.C. Tetrahedron Lett. 1987, 28, 3015. Kaye, A.; Neidle, S.; Rees, C. B. Tetrahedron Lett. 1988, 29, 2711. Kuszmann, J.; Podanyi, B.; Jerkovich, G. Carbohydrate Res. 1992, 232, 17. Katagiri, N.; Akatsuka, H.; Haneda, T.; Kaneko, C. J. Org. Chem. 1988, 53, 5464. Schmidt, R. R.; Frick, W.; Haag-Zeino, B.; Apparao, S. Tetrahedron Lett. 1987, 28, 4045. Danishefsky, S.; Philips, G.; Ciufolini, M. Carbohydrate Res. 1987, 1 71, 317. Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Charence, J. M.; Springer, J. P. J. Am. Chem. Soc., 1985, 107, 1256. Danishefsky, S. J.; DeNinno, M. P. Angew. Chem. Int. Ed. Eng., 1987, 26, 15. Lee, E.; Tae, J. S.; Lee, C.; Park, C.M. Tetrahedron Lett. 1993, 30, 4831. Hansson, S.; Miller, J. F.; Liebskind, L. S. J. Am. Chem. Soc. 1990, 112, 9660.

This Page Intentionally Left Blank

C h a p t e r Eight

8

Syntheses of C-Di and Trisaccharides

Introduction

In this book, Chapter 1 served to introduce C-glycosides with respect to their nomenclature, availability from natural sources, and their use as potential clinical agents. Chapters 2 through 7 presented different technologies used in the preparation of a wide variety of C-glycosides. However, those intermediate six chapters also concentrated primarily on the simpler C-monosaccharides. In this chapter, the methods used in Chapters 2 through 7 will be applied to the preparation of the more complex C-di and trisaccharides. These compounds are characterized by the direct anomeric linking atom being carbon instead of oxygen. The examples are presented chronologically beginning with the earliest reported synthesis of a C-disaccharide.

8.1

Syntheses Reported in 1983

Scheme 8.1.1

Sinay C-Disaccharide Synthesis Part I

OH

~.-CHO

BnO6Me

BnO~Me

Li

Br ~O

BnO6Me

Br

OMe

In 1983, the first synthesis of a C-disaccharide was reported by Sinay, et

~t]., and involved the addition of an acetylenic anion to a sugar lactone. The 237

Chapter 8

238

Syntheses of C-Di and Trisaccharides

synthesis, shown in Scheme 8.1.1, began by applying a Swern oxidation to the tri-O-benzyl methylglucoside shown. The resulting aldehyde was converted to an acetylene anion via the intermediate dibromo olefin. The synthesis was completed, as shown in Scheme 8.1.2, by addition of the anion to the illustrated glucose lactone. As shown, this addition yielded the acetylene bridged glycoside. Deoxygenation was s u b s e q u e n t l y achieved utilizing triethylsilane in the presence of a Lewis acid. Catalytic hydrogenation subsequently reduced the acetylene and removed the benzyl protecting groups thus liberating C-gentiobiose. S c h e m e 8.1.2

Sinay C-Disaccharide S y n t h e s i s Part II

~ ..-OBn O

~10Bn

BoO---v O,

BnO'~'~i'"-"~

BnO

BnO-~~~..

BnO

'o

OMe

OBn

BnO~H

u

..-OBn O

gnO---'~-~-~i u~ B o O ~ BnO HO" - ~ , I ~ . I " " ~

BnO '~' '''~

BnO ~' '~ O M e ~l-~--OBn ~b~OBn

HO OMe

"OH

8.2

Syntheses Reported in 1984

Shortly after the Sinay report, additional reports of C - d i s a c c h a r i d e syntheses became visible. In 1984, the reported technologies included the dimerization of nitroalkanes as well as the use of hetero Diels-Alder reactions. Beginning with nitroalkane dimerizations, Vasella, et al.,2 initially studied the cross coupling of nitroalkanes and furanoside nitroglycosides discussed in section 2.6 and reviewed in Scheme 8.2.1. As demonstrated in the same report, the d i m e r i z a t i o n of furanoside nitroglycosides effectively p r o d u c e d Cdifuranosides. The specific reaction, shown in Scheme 8.2.2, proceeded under basic conditions and the nitro group was removed on treatment with sodium sulfide.

Chapter 8

239

Cross Coupling of Nitroalkanes and Nitroglycosides

Scheme 8.2.1

__/.~ /-O"

Syntheses of C-Di and Trisaccharides

o~...~o~ H

- /o "-'~

'101 ~~2 ' ' 'DlM tBiSugOOhKt =,

O•O

O

NO2

O~"~'NO

85%

2

O,~O

l 7~. c~o~

1~6a~s

......,,,~ NO2

A ~

Scheme 8.2.2

~

Dimerization of Nitro Glycosides

"•0••__• "''~

"-~

0

,NO2

~176

,

o~o

NO2

sL_J

\

,,,,,o,,/__

0

b"'llll 0

2. Na2S

o~o

Chapter 8

240

Syntheses o f C-Di and Trisaccharides

The use of hetero Diels-Alder reactions in the preparation of C-glycosides was introduced in Chapter 7. This cycloaddition reaction has shown substantial promise as a means of directly forming sugar rings from acyclic substrates. As early as 1984, this technology was utilized in the preparation of C-disaccharides utilizing sugar-derived aldehydes. As shown in Scheme 8.2.3, Jurczak, et al.,3 i n c o r p o r a t e d this methodology in the p r e p a r a t i o n of a s u g a r - s u b s t i t u t e d d i h y d r o p y r a n ring system. The reaction proceeded with the formation of a single isomer via an e n d o approach of the dienophile. The stereochemical preferences for these reactions were predictable from Felkin's models.4, s

Scheme 8.2.3

Preparation of C-Disaccharides Utilizing Hetero Diels-Alder Reactions OMe

0

OMe ---=-

....

"'tll~~f~ ~ ~ .ol~ 9 0

53 ~

20 kbar

...."~O

o,"-// A similar approach to C-disaccharides was concurrently r e p o r t e d by Danishefsky, et aL,6 thus positioning hetero Diels-Alder technology as a key strategy in the p r e p a r a t i o n of these complex molecules. As this c h a p t e r progresses, Diels-Alder methodology will become a r e c u r r i n g t h e m e in increasingly more interesting synthetic strategies to biologically i m p o r t a n t targets.

8.3

Syntheses Reported in 1985

The examples presented in the previous two sections r e p r e s e n t early approaches to the preparation of C-disaccharides. Building upon these early studies, new techniques became apparent and interesting reports surfaced in 1985. Aside from additional studies involving Diels-Alder methodology, Beau, et aL, 7 reported the use of addition reactions between phenylsulfone anions and s u g a r - d e r i v e d a l d e h y d e s as a viable m e t h o d for the f o r m a t i o n of Cdisaccharides. As shown in Scheme 8.3.1, the sulfone associated with the addition p r o d u c t was cleaved on t r e a t m e n t with lithium n a p h t h a l i d e thus giving the final product.

Chapter 8

Syntheses of C-Di and Trisaccharides

241

Sulfone Glycosides and Sugar Aldehydes

Scheme 8.3.1

OR

SO2Ph

9B n O o ,"O- ~H C

"

RO0~ ~ ~ _ B

BnO~

R = TBDMS

BnO'Meu

OBnOM e nBx.

BnO O n

2. 3. Lithium Naphthalide

Returning to Diels-Alder methodology, Danishefsky, et al.,8 demonstrated its use in the preparation of interesting C-disaccharides. The key synthetic reaction, illustrated in Scheme 8.3.2, proceeded in a chelation controlled manner giving a 79% yield of a C-disaccharide precursor. The resulting dihydropyranone unit was recognized as suitable for subsequent conversion to various sugar derivatives. Scheme 8.3.2

Hetero Diels-Alder CHO

OHC.-

0

...., , ~ O ~ /

BnO ....,ql0

OMe

~,% OTMS OBz MgBr2

79%, only isomer

0

....,,~O

Chapter 8

242 8.4

Syntheses of C-Di and Trisaccharides

Syntheses Reported in 1986 Metallations

Scheme 8.4.1

OR

OR

SnBu3 tBuOK/BuLi -78"C, Bu3SnCI

RO*'"

RO""'

OR

OR R = TBDMS

55%

RO .,~

a

1. BuLi,-78"C

OH(]. BnO~ BnO BnOoMe

BnO~"~O/~OR BnO~~BnO

-

OMe 68%

Scheme

8.4.2

1,3-Dipolar Cycloadditions OBn BnO BnO

~OBn

BnOI

,N

78%

BnO

~0

" TBDMSO

In 1986, as the technology surrounding the preparation of C-disaccharides progressed, the use of metallated glycals, radical reactions, and dipolar cycloadditions began to be used. With respect to metallated glycals, extensively discussed in Chapter 3, Hanessian, et al.,9 stannylated the tri-O-silylated glucal

Chapter 8

Syntheses o f C-Di and Trisaccharides

243

shown in Scheme 8.4.1. The resulting product was then lithiated and added to a glucose aldehyde thus giving a mixture of diastereomeric alcohols at the newly formed C-glycosidic linkage. Radicals

S c h e m e 8.4.3

~....OAc HO ;)~____~..,,,,,,0H (

~.OAc 1. nBu3SnH AcO--~-~.~..~Ok AIBN + A c O ~ 2. acetylation AcOBr

Aco~O A c O ~

HO

AcO I,,,,.....

-

...,,,,OH

others . ~ _.,~ 0c:13=10:1 O-" -(3H transfer= 60 : 40

22% +

0

~IOBz I

H O , , , .....

~OBz

~

O

BzO.~

BZO~M e

35%

BZO6Me O HO

BzO~-O B z O ~ BzO(~Me

.....

BzO--V--~Io~ BzO~S~~--~ 54%

BZOoMe

The 1,3-dipolar cycloaddition of exocyclic methylenes with nitrile oxides has already been addressed in section 2.13.10 This work, shown in Scheme 8.4.2, is notable in that high stereoselectivity in the resulting isoxazoline can be obtained. This is presumably the consequence of the bulk of the nitrile oxide directing approach to the cz face of the sugar methylene. Through the use of these reactions, C-disaccharides, bridged by isoxazoline rings have been made accessible. Complementary to anion chemistry and 1,3-dipolar cycloadditions is the use of free radicals in the preparation of C-disaccharides. An early example of the use of this technology was reported by Giese, et al., 11 and demonstrates the

Chapter 8

244

Syntheses of C-Di and Trisaccharides

use of sugar halides as precursors t o sugar radicals. Their subsequent addition to exocyclic methylenes present on sugar lactones is illustrated in Scheme 8.4.3. In all cases, yields were low to moderate but produced anomeric ratios in the range of 10 to 1.

8.5

Syntheses Reported in 1987

Scheme 8.5.1

Wittig/Mercury

~......OBn BnBO n

0

~..- OBn Ph3P=CH2 =- B n O ~ O H 80%

1. DCC/DMSO D. 3. LiAIH4 4. CBZ-CI

2. NH2OH

BnO-~u BnO

F

49%

~10Bn ~....OBn NHCBZ 1. Hg(OAc)2 = IgngOo BnO %

B

n

O

~ BnO

2 KCI

L

]

cBZ /

L..H C

O3/NaBH4 71%

OAc ~/0..,,,~ Br ~.....OBn

BnOLO H

AcO~.~.,,,OAc

OAc OBn CBZ

AcO,,,,""r" A

BnO'''' t'''" "J'"O Bn

"h" ,,,OAc

OAc

OBn

In a notable synthesis, r e p o r t e d in 1987, Liu, et al., 12 illustrated the applicability of the Wittig reaction to sugars in the preparation of C-glycosides. The specific p r o d u c t of interest was a sugar derivative in which the ring oxygen was r e p l a c e d with nitrogen. As illustrated in Scheme 8.5.1, t r e a t m e n t of 2,3,4,6-tetra-O-benzyl-D-glucopyranose with m e t h y l e n e t r i p h e n y l p h o s p h o r a n e effected formation of an 80% yield of the desired hydroxy olefin. Conversion of the free alcohol to a protected amine was accomplished in four steps with an overall yield of 49%. Final cyclization to the d e s i r e d aza s u g a r was a c c o m p l i s h e d by first utilizing mercuric acetate a n d p o t a s s i u m chloride. Completion of the synthesis with ozone and sodium b o r o h y d r i d e provided a t h r e e step yield of 71%. As the ultimate goal of this synthesis was the p r e p a r a t i o n of C-disaccharide inhibitors of a-glucosidases, the C-glycosidic aza

Chapter 8

Syntheses of C-Di and Trisaccharides

245

sugar was coupled with 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl bromide in a 79% yield. Upon examining the structure of the final product, characteristics representative of both C and O-glycosides are apparent. This, however, does not weaken the importance of this report. The specific highlights utilizing Wittig and mercury methodology further demonstrates the utility of these reactions as general to the preparation of C-glycosides. C-Isomaltose and C-Gentiobiose Analogs

Figure 8.5.1

OH

.o OH

O. HO

OMe

C-Isomaltoside

OH HO

~""' O

HO

OMe

'oH C-Gentiobioside

Additional work in 1987 centered a r o u n d studies of the p r e f e r r e d conformations of various C-disaccharides. Preliminary work by Kishi, et al.,13 was subsequently confirmed by the same group in 1991.14 In these reports, utilizing C-glycosidic analogs of isomaltose and gentiobiose (Figure 8.5.1), it was determined that conformations of C-disaccharides can be predicted on the basis of steric interactions alone. This conclusion, based, in part, on similarities regarding the conformations and behaviors of conventional disaccharides in variable t e m p e r a t u r e p r o t o n NMR studies, was later e x t e n d e d to the conformations of C-trisaccharides introduced in Chapter 1. 8.6

S y n t h e s e s R e p o r t e d in 1988

In 1988, methodologies utilized in the preparation of C-disaccharides i n c l u d e d Michael additions, p h o t o c h e m i c a l reactions, a n d 1,3-dipolar cycloadditions. Three examples illustrating the utility of these methodologies are presented in this section. Beginning with conjugate additions, Giese, et a1.,15 utilized Michael-Wpe additions as a direct means of coupling two sugar units. As shown in Scheme 8.6.1, the Michael acceptor was p r e p a r e d from the phenylsulfoxide via t r e a t m e n t with base followed by f o r m a l d e h y d e and acid. The final Cglycosidation was accomplished by generating free radicals from 2,3,4,6-tetra-

Chapter 8 Synthesesof C-Diand Trisaccharides

246

O-acetyl-D-glucopyranosyl bromide. Subsequent 1,4-addition of this radical species y i e l d e d the desired m e t h y l e n e - b r i d g e d C-disaccharide with good stereoselectivity and a 45% yield for the overall sequence. Michael Additions

S c h e m e 8.6.1

OBn

OBn

OBn

SOPh

SOPh

(

1. LDA

H+ .~ v

2. HCHO 77%

BnO""

64%

BnO"'""

T

Bn

""'OTMS

OBn

OBn

OBn

OAc ~

.0 ..,,,Br

AcO~

OBn AcO*'~~",,OAc OAc

=.

( JD,

nBu3SnH/AIBN

4 5 % overall

70%

~ ''",,"~"~''"OAc

Bn

OBn

OAc

The use of free radicals is complimented by reactions catalyzed by light. Utilizing photochemical techniques, Giese, et al., 16 effected the dimerization of a selenoglycoside to yield a C-disaccharide. The reaction, shown in Scheme 8.6.2, proceeded in poor yield with no stereoselectivity. However, through the use of tethers as well as varying the steric bulk on the protecting groups, it is reasonable to believe that this chemistry will ultimately find utility in a variety of applications. S c h e m e 8.6.2

OAc

Photochemistry

oy

OAc

Ac

OAc

SePh (Me3Sn)2/hv

I

D,

'

O

32%

Ac OAc

OAc

Ac OAc

Chapter 8

Syntheses o f C-Di and Trisaccharides

247

As an extension to the 1,3-dipolar cycloadditions presented in Scheme 8.4.2, Dawson, et at., 17 demonstrated the formation and conversion of bridging isoxazolines to ~-hydroxy ketones. A particular example, shown in Scheme 8.6.3, proceeded with good stereochemical control. However, although the chemical yield was 66%, the ratio of regioisomers formed in the reaction was 1" 1. Subsequent reductive hydrolysis afforded the illustrated carbonyl bridged C-disaccharide.

Scheme 8.6.3

Dipolar C y c l o a d d i t i o n s

)

zO N"

OAc O. ,,,OEt

AcO,,,,,..~( OAc OAc L O ..,,,,,OEt Ac

Ac OH

( H '

1. NaOH

O

"~-N

,q..,,.,,,OEt ~'%OH

2. Pd/H2 97%

HO,r AcO

OAc + regioisomer(1 1)9

8.7

66%

~,,~,/..,,,,/OHO OH

S y n t h e s e s R e p o r t e d in 1989

In 1989, refinements and complementary additions to C-disaccharide technology surrounding acetylene anions were made. Additionally, technology relating to couplings with glycals bearing sulfoxides at C2 was explored. Furthermore, examples of dimerization reactions, additions to difluoro olefins, and polyol cyclizations were reported. These technologies will be discussed in conjunction with furanose and pyranose sugars. Most notably, a synthesis of Csucrose, bearing a furanose and a pyranose unit, will be examined. Beginning with the use of acetylene anions, Armstrong, et ai.,18 prepared linear a c e t y l e n e - b r i d g e d C-disaccharides. An example of the synthetic

Chapter 8

248

Syntheses of C-Di and Trisaccharides

strategies is illustrated in Scheme 8.7.1 and begins with the ketone, shown. Stereoselective formation of the acetylene equivalent was achieved via formation of a primary alcohol followed by a Swern oxidation and a Wittig reaction with carbon tetrabromide. Although the intermediate aldehyde formed as a mixture of isomers, conversion to the desired stereoisomer was achieved on treatment with excess triethylamine.

Scheme 8.7.1

OBn

~

Acetylene Anions

OBn

(L

,,,,0Me '"

( 1. C H 2 = P P h 3

2. Thexylborane

"''OBn

OH

45%

).

.,,,0Me

~

''

1. Swern 2. PPh3, CBr4

80%

"""OBn

OBn

OBn OBn

OBn

OBn

)-;iiiiio~

nBuLi

n

CBr20Bn

Bn 1.

OBn OBn

~0_

..,.ii,0Me

OBn

"OBn

)

2. Et3SiH, BF3-0Et 2 80%

S. Bn "

OBn

( / """OBn OBn

Regarding the final coupling to the C-disaccharide, the dibromo olefin was converted, in situ, to an acetylenic anion utilizing butyllithium. Addition of this species to tetra-O-benzyl gluconolactone followed by reduction of the hemiketal afforded the final product in approximately 80% yield for the two steps. The use of 2-sulfoxide substituted glycals in the p r e p a r a t i o n of Cglycosides was extensively discussed in chapter 3. As shown in Scheme 8.7.2, Schmidt, et a1.,19 utilized this chemistry in the preparation of C-disaccharides. The key step involved deprotonation of the glycal followed by addition of the resulting anion to a sugar aldehyde. Final reductive cleavage of the sulfoxide provided a true C-disaccharide in good chemical yield and stereochemical purity. As already alluded to, the dimerization of sugar units has provided some conceptually useful methods for generating C-disaccharides. As shown in Scheme 8.7.3, Boschetti, et al.,20 effected the dimerization of two furanose units thus providing a one-step synthesis of a C-disaccharide. The reaction was

Chapter 8

Syntheses of C-Di and Trisaccharides

249

initiated utilizing a Lewis acid and proceeded in 93% yield. Furthermore, the only site of m u l t i p l e s t e r e o i s o m e r s was the h e m i k e t a l . However, as d e m o n s t r a t e d t h r o u g h o u t this book, these species are easily r e d u c e d with substantial control over the stereochemistry of the relevant center. Thus, this i m p o r t a n t reaction sets substantial precedence in the applicability of this chemistry to the generation of increasingly more complex C-disaccharides and higher sugar analogs. G lyc al- 2-S u l f o x i d e s

S c h e m e 8.7.2

OBn

OBn ( 1. LDA,-100~

1. PhSCI/DBU 2. MCPBA

BnO*""

OBn Lo

SOPh

Bn

.,,,,,OBn

OBn

OBn

OHG*~~'~OBn OBn

OH

OBn =_ t

O - ~ . ~ ~OH BnO

nO.

~

v

( -)~'''O

Bn

~ OBn

"OBn 1. H

SOPh

Raney Ni (74%)

HoHO~~J~~OH

2. BH3, Me2S, NaOH, H202 74%

O HO"*"' y

"'OH """OH

OH

The use of free radicals in the generation of C-glycosides was extensively a d d r e s s e d in Chapter 5. Furthermore, Scheme 8.4.2 illustrates the use of free radicals in the p r e p a r a t i o n of C-disaccharides via Michael acceptors. An extremely c o m p l i m e n t a r y addition to this technology is the use of difluoro olefins as free radical acceptors. As shown in Scheme 2.13.4, Motherwell, e t al., 21 u t i l i z e d these species as s u b s t r a t e s for C - g l y c o s i d a t i o n s thus d e m o n s t r a t i n g their importance to free radical chemistry. In this same report, a difluoro olefin-derived from a furanose sugar was utilized in the formation of a C-disaccharide. The actual coupling, shown in Scheme 8.7.4, was initiated with tributyltin hydride and AIBN thus providing a 25% yield of the illustrated C-disaccharide as a single stereoisomer.

Chapter 8

250

Syntheses of C-Di and Trisaccharides

Sugar Dimerizations

S c h e m e 8.7.3

Bn0,,,, OH O'~cH3

~

OBn

0 BF3-OEt2 BnO

93%

BnO

OBn BnO

OBn

OBn

BnO

OBn

OBn

T

BnO

S c h e m e 8.7.4

OBn

D i f l u o r o Olefins OMe

Br

o4o 0

\

F

,,,,......~ 0

Bz F

0

""OBz OBz

.

o)

-

Bz

....,,,,,~~ OBz

0 0

0 X

25%

Among the most important C-disaccharide syntheses reported in 1989 is the p r e p a r a t i o n of C-sucrose. This analog of table sugar is interesting in that unlike natural sucrose, it cannot be metabolized to lower sugars. An actual synthesis of C-sucrose was reported by Nicotra, et ai.,22,23 and is illustrated in Scheme 8.7.5. As shown, the C-glucoside, p r e p a r e d as discussed in Chapter 2, was converted to a metallated alcohol in 97% yield. Subsequent oxidation of the metal with iodine followed by oxidation of the alcohol to a ketone and

Chapter 8

Syntheses of C-Di and Trisaccharides

251

t r e a t m e n t of the iodide with t r i p h e n y l p h o s p h i n e provided a 40% yield of the illustrated Wittig reagent. Condensation of the t r i p h e n y l p h o s p h o r a n e with a protected glyceraldehyde gave the conjugated ketone, shown, in an 88% yield. The final conversion of this species to C-sucrose was achieved in six steps beginning with an osmylation of the olefin to a diol and ending with removal of the benzyl groups utilizing catalytic hydrogenation. Upon examination, the importance of this synthesis becomes apparent through recognition of a variety of chemical technologies described t h r o u g h o u t this book. Furthermore, with respect to the food industry, sugar derivatives that possess the sweetness of natural sugars b u t lack susceptibility to metabolic processes are of substantial commercial value.

Scheme 8.7.5

C-Sucrose from a Polyol Glycoside

OBn

OBn

HgCI

( HgCI2 =

(

1. 12

97%

Bn

2. PDC 3. PPh3 40%

Bn OBn

OBn

OBn ( Bn

PPh30HC...~,,,O~.. L-.O "

):ii i ioBn

Bn

OH H O ~ 1. 0504, NMO

1. Florisil

2. Ac20/Py 3. FeCI3/SiO2

2. K2CO 3 3. H2, Pd/C

Ii,

L HO ~

~,~..,,ii,OH

~

~iiiii,OBn OBn

~O

,,,i -~

OH

O

0'"

(

88%

OBn

)

OBn

C-Sucrose

'

Chapter 8

252 8.8

Syntheses of C-Di and Trisaccharides

S y n t h e s e s R e p o r t e d in 1990

In 1990, additional research into the conformational features of Cdisaccharides was reported. 24 In addition to the insights provided by this study, significant developments in the synthetic methodology s u r r o u n d i n g these c o m p o u n d s became apparent. Of notable interest are the use of Cnitroalkyl glycosides and palladium mediated coupling reactions.

Scheme 8.8.1

OBn .j~T Bn()*"" y

Palladium Mediated Couplings

OBn SnBu3

cat. Pd(PPh3)4 gr

O"

BnO"'" OBn OBn

OBn

88% O

PdCI2(CN)2 O

BnO*""

NO2

OBn NO2

B r , ~ ~ Br

OBn

O ~ . . . O'[ SnBu3 " BnO"~" T

(~,,,,,. L~O~,,~,~OSiMe2(tBu)

OSiMe2(tBu) o..,Tj-.,,,,, o

t, o)

The use of palladium catalyzed couplings of 1-stannyl glycals with aryl halides was used by Dubois, et al., z5 in the preparation of aryl-bridged Cdisaccharides. As shown in Scheme 8.8.1, the high yielding reactions with arylhalides and acid chlorides were c o m p l i m e n t e d by the use of 1,3dibromobenzene. As illustrated, unlike the earlier examples, this c o m p o u n d acted as a linker thus joining two sugar units together. The resulting novel

Chapter 8

Syntheses of C-Di and Trisaccharides

253

a r y l - b r i d g e d C-disaccharide can be envisioned as capable of mimicking a trisaccharide. Furthermore, t h r o u g h the use of a variety of different sugar analogs, the ability to explore alternatives to a variety of naturally occurring trisaccharides becomes viable.

Nitroalkyl Couplings

Scheme 8.8.2

O"CyO. ....."Ox

~.OAc

KF, 18-crown-6 52%

"etl#]0

OAc

NO 2

.OAc Ac

A

]D,

~....OAc

AoO---X-.-Xq O2N~]

HO

AcO

OAc

O

.....,~O.

Ac20, Py 90%

I

OAc I ~ / O ~

,,,,~O

""~

1. NaBH4

2. Bu3SnH 3. HO

HO HO~oHO H

Chemistry involving the use of C-nitroalkyl glycosides has already been d i s c u s s e d in C h a p t e r 2 a n d p r e s e n t e d in Schemes 8.2.1 a n d 8.2.2. C o m p l i m e n t a r y to the dimerization reaction presented in Scheme 8.2.2 is the ability to a p p l y similar c h e m i s t r y to the u n s y m m e t r i c a l coupling of two different sugar units. Unlike the dimerization, the u n s y m m e t r i c a l couplings center a r o u n d the addition of stabilized anions to aldehydes. As shown in Scheme 8.8.2, Martin, et al., z6 reported the incorporation of this chemistry into the p r e p a r a t i o n of C-disaccharides. As illustrated, the actual c o u p l i n g proceeded in a 52% yield with the subsequent elimination giving the olefin in a

Chapter 8

254

Syntheses of C-Di and Trisaccharides

90% yield. Final reduction of the double bond and removal of all protecting groups liberated the ethylene-bridged C-disaccharide. As shown in Scheme 8.8.3, the same report demonstrated the application of similar methodology to the preparation of methylene-bridged C-disaccharides via coupling with openchain sugar analogs.

Scheme 8.8.3

Nitroalkyl Couplings

CHO ---O

/OAc ~ 0 AcO'~'~

NO2

I

0

-o X

OAc

KF

AcO~

.o

.NO20~

,. O ( ~

AcO

o:c

18-crown-6 52%

-oox

OPiv

OPiv ~......OAc -

8.9

AcO~

OAc O AoO~OAc

AcO~~-~...~~_~u~ OAc

OAc

Syntheses Reported in 1991

In 1991, new syntheses of C-disaccharides i n c o r p o r a t e d Lewis acid m e d i a t e d couplings with allylsilanes. Additionally, alkyllithium sugar derivatives were coupled to sugar lactones and electron deficient anions were added to sugar carbonates. Finally, complimentary to the anion chemistry used, sugar cuprates were utilized. The use of allylsilanes in the formation of C-glycosides was extensively covered in chapter 2. This technology was adapted to the preparation of Cdisaccharides by Stutz, et al.27 As shown in Scheme 8.9.1, the illustrated glucose derivative was converted, in two steps, to the methyl ester. Treatment of the m e t h y l ester with trimethylsilylmethyl Grignard followed by ptoluenesulfonic acid gave the allylsilane derivative shown. Combining this c o m p o u n d with tri-O-acetyl glucal in the presence of a Lewis acid gave the desired product in moderate yields. Thus, by combining well established Lewis acid mediated C-glycosidations, the preparation of a variety of C-disaccharides has been made available from relatively inexpensive and easily accessible starting materials.

Chapter 8

Syntheses of C-Di and Trisaccharides

Sugar Allylsilanes

Scheme 8.9.1 OH

CO2Me ~_

).

,,,OMe

'

(

'"OBn

~,,,,OM e 1. TMSCH2MgBr

r Bn

255

,,

(

l "~

""OBn

Bn

2. TsOH 45%

OBn

OBn

Acol_Oi OAc

( )_

TMS

,,,,OM e

OAc

""'OBn

BnO,,,," ~ OBn

BF3.OEt2 35 to 45% yield

B n 0 *"" ~ ' ' ' 0

Bn

OBn

Where the use of Lewis acid chemistry demonstrates the utility of electrophilic substitutions in the preparation of C-disaccharides, methodologies involving nucleophiles are extremely complimentary. Already discussed in Chapter three and presented in numerous schemes throughout this chapter, sugar-derived nucleophiles provide excellent sources of C - g l y c o s i d a t i o n substrates. These observations were further exemplified by Schmidt, et M., 28 in a study illustrating the generality of anionic additions to various sugar-derived lactones. As shown in Scheme 8.9.2, lithiated sugars were added to both glucose and galactose-derived lactones giving moderate yields of the coupled compounds. These products were subsequently deoxygenated under standard reductive conditions to give diastereomerically pure C-disaccharides. Although the yields of the additions were approximately 50%, the utility of these sequences is supported by the apparent control in the selective generation of ~C-glycosides. Continuing with various anionic species utilized in the preparation of Cdisaccharides, the importance of sugar-derived cuprates deserves discussion. As shown in Scheme 8.9.3, Prandi, et al., 29 generated cuprates from stannyl glycosides via transmetallation and subsequent treatment with copper salts. On exposing these species to various epoxides in the presence of Lewis acids, Cglycosides were formed. An interesting observation is the stability of the stereochemistry of the formed cuprate thus allowing the formation of optically pure products. As shown, this chemistry was easily applied to the formation of glycal-derived cuprates. Interestingly, when glycals were used, the yields of

Chapter 8

256

Syntheses of C-Di and Trisaccharides

the reactions with epoxides appeared to increase as demonstrated by the isolation of an 80% yield of the illustrated C-disaccharide. Furthermore, in retaining the glycal skeleton, in conjunction with the methoxy glycoside of the added unit, further selective chemical manipulations may possibly generate substantially more complex structures.

Lithiated Sugars

Scheme 8.9.2

IOBn OH

IOB

5 steps

Li~

OBn

OBn

B~noO~_~// BnO ~ / ~

BnO - - O B n

Bno_

O

n

O BnO

~

~

B

9

AcO

O ~

AcO // L.

o

~

0

OAc

/_/,/OAc

n

O

~

i

BnO ~_ OH

OBn 4 steps

OA~.- OAc

0

OBn

i

OH

BnO

j.OBn

OBn

B

on

BoO

4a~/o

~

O

1

,..-OAc ACAOO

OBn

AcO

O AcO

O ~

OAc OAc

AcO

Although anionic species have proven useful in the preparation of Cglycosides and C-disaccharides, substantial versatility is available from the use of neutral palladium mediated couplings discussed in Chapter four and presented in Scheme 8.8.1. Such reactions, applied to non-aromatic systems, were demonstrated by Engelbrecht, et aL,3O in the reaction of electron deficient species with glycosidic carbonates. The reactions, shown in Scheme 8.9.4, incorporate diethyl malonate as the nucleophilic species. Palladium was used to effect the coupling of this compound to unsaturated sugars. When the more

Chapter 8

Syntheses of C-Di and Trisaccharides

257

electron deficient cyano ester was used, a double coupling was observed thus forming a symmetrical C-disaccharide. Of notable interest is the apparent control over the stereochemistry of the addition by varying the steric bulk surrounding the glycosidic carbonate. Furthermore, areas where further derivitization may be useful can be envisioned following decarboxylation of the methylene-bridge of the C-disaccharide. Sugar Cuprates

Scheme 8.9.3

OBn

OBn ..,,,,,SnBu 3

1. BuLi,-78~ 2. Li(thienyl)CuCN

...." " " ~ ~ 0

3. BF3-OEt2

BnO"" OBn

O[~..~OBn

OH

BnO*""

OBn

Bn

OBn

67%

OBn

SnBu3

T~'O'~.~ BnO"""~

BnO""

OBn

OBn

OBn

~OBn OH

50% OTBDMS Me

OTBDMS SnBu3

OMe

-...,,,,,,,~..0 H

+

BnO*".

. . OBn

.

. TBDMSO

~"l',~ [~0

TBDMSO 0 . ~ . ] BnO'-~~OB

n

OBn 80%

As a final example to close this section, further advances in free radical chemistry will be explored. Unlike the examples presented earlier in this chapter, the radical acceptors used by Bimwala, et M.,31 were derived from sugar synthons. Specifically, as shown in Scheme 8.9.5, treatment of the bicyclic ketone, shown, with tert-butyl-dimethylsilyltriflate followed by the Eschenmoser salt provided the desired conjugated ketone. 32-34 The nature of the actual coupling reaction, which proceeded in a 48% yield, will be further elaborated upon in the next section.

Chapter 8

258

Glycosidic Carbonates

Scheme 8.9.4

AcO~.. AcO~,,,'' AcO ~

Syntheses of C-Di and Trisaccharides

AcO~.,

O/"OH

O" .."'OCO2R

~cO,~

O O _(3 ..,,,~,,OCO2iBuEtO~..,~OE t

A~O~

Pd(0)

R=iBu, tBu C02Et /~

,,,,,L

/o_

,,. AcO- -.-T.- -.,}...... CO2Et ..,..L /J

AcO,,," -..~

Aco.).oco2tBuEtO OEt,0.o. O

O

CO2Et

" AcO~,.... O"

AcO,,,,,' -,.,.,~

CO2Et

AcO~,,""-,,,,~ NO

co2tBu

O AcO'''' '''~

Scheme 8.9.5

Pd(0)

"

AcO,,,,,..'-,,,~, ~'

O

~'~o~c

Glycosidic Radicals Added to Michael Acceptors

O

O 1. TBDMSOTf o 2. H2C=NMe21

,h

PhSe~

6t-,/

OAc [~.ffOy Br

AcO""" ~ "'OAc OAc

O PhSe.,~-~--OAc CI "(

nBu3SnH/AIBN

OAc

O

''"OAc

O

Chapter 8

Syntheses of C-Di and Trisaccharides

259

8. 10 Syntheses Reported in 1992 Scheme 8.10.1

Glycosidic Radicals Added to Michael Acceptors

OAc ~iw~O

.Br

O/j~~

AcO,~~.,,OAc o o

OAc nBu3SnH/AIBN

O

% .~..OAc

. : ~~'"~OAc

~

i~o

Z--;oo o AcO---a OAc 68 Yo(5.5" 1) ~

..o c

O AcO-~a

OAc 73% (5.5 1) 9

O

O PhSe

O

O

-

~Ac

7

/~OAc

PhSe

AcO

/

~. OAc 47%

In 1992, the reported preparations of C-disaccharides included the utilization of free radical reactions. Additionally, the use of various polyol cyclizations were discussed. In the application of radical chemistry to the synthesis of C-disaccharides, Bimwala, et al., 3s expanded upon his earlier work illustrated in Scheme 8.9.5. As shown in Scheme 8.10.1, glycosidic radicals were added ~,~-unsaturated carbonyl compounds producing yields ranging from 47% to 73%. Furthermore, the illustrated C-disaccharide precursors exhibited diastereomeric ratios of approximately 5.5 : 1.

Chapter 8

260

Syntheses of C-Di and Trisaccharides

Scheme 8.10.2

Bromocyclizations

~...-.OTPS -----\ -OH

~OBn NBS/CH3CN cat. Br2 32%

~.,,-OTPS --~ \ -0 O0

=~

~OBn 0

n o , B OMe .o__ Oo -OH -~ H

O

Me

~ HOlM e Route A Starting Material

Scheme 8.10.3

0

~

"""~OTs

3. OsO4/NMO 4. Nal04

3. Nal/NaHC03 4. PPh3

OH

~-~0

O

~

1. Na-Hg 1. NaBH4 2. Nail, BnBr, BU4N+r .. 2. MsCI

~""'" j

' 9 O

0

IPh3P"~

OBn

~ C H O OBn BuLi

i~". . . .

""OBn OBn

'0 0 '~0 O

OBn

~

""OBn

i~''''"

1. OsO 4 2.

NaH/MPM-Br

OBn ._._-

OBn

0•0_

OBn OH

OBn

OMPM

0

F ( ~~) "'"0Bn OBn

The cyclization of polyols to t e t r a h y d r o p y r a n rings was discussed, in context with the formation of C-glycosides, in Chapter seven. T h r o u g h

Chapter 8

Syntheses o f C-Di and Trisaccharides

261

extensions of this chemistry, such cyclizations have been adapted to the preparation of higher C-polysaccharides. As an introductory example, a report by Armstrong, et al., 36 is presented in Scheme 8.10.2. As illustrated, the use of bromine as an agent capable of effecting ring closure of certain hydroxyolefins provides a means of forming C-disaccharides from suitably derivitized sugars. Although the yield is relatively low, the illustrated reaction provides a novel and stereoselective strategy for ring closures. The above mentioned bromocyclization is an excellent example of the formation of C-disaccharides through the cyclization of appropriately protected polyols. Utilizing different methodologies, Kishi, et M., 37 effected similar reactions on sugar-derived polyols. The general strategies were illustrated in Schemes ?.3.6, 7.3.7, and ?.3.8 and are discussed, in derail, in the following paragraphs.

Route A Completion

Scheme 8.10.4

_OCOPh N'~O_ O

OBn 7.---

OBn

O_H -

~/~O~

1-%

1. Swern _ 2. HCI 3. PhCOCI

OMPM

OBn

..OCOPh

0

".,,,,,

~" OMPM

/ ~ _ Pr3SiH, BF3-OEt2

~

"OBn

OBn / MeSH BF3-OEt2 ~ '

~OCOPh

O BnO,,,,,,..

O

O

O

Bu3SnH/AIBN BnO,,,,,...

"OBn

BnO OH

OBn

O

.,.."

BnO

~ /

O

f"~

t~nu,,,,,,..

O

O

"OBn

BnO OH

OBn

The strategy eluded to in Scheme ?.3.6 is elaborated upon in Scheme 8.10.3 and involves the allyl sugar derivative shown. Conversion of the allyl group to the phosphonium salt is accomplished in eight steps. Wittig olefination with the illustrated protected aldehyde provides the cis olefin which is dihydroxylated under asymmetric conditions and selectively protected as the PMB ether. In Scheme 8.10.4, the above described protected polyol is converted to the illustrated hemiacetal via a Swern oxidation followed by spontaneous cyclization. The hemiacetal is converted to the final product through two

Chapter 8

262

Syntheses of C-Di and Trisaccharides

routes. The first, being a direct strategy involves the Lewis acid mediated deoxygenation. The second route provides the same compound through the two step process involving formation of a thiomethylglycoside followed by removal of the thiomethyl group under radical conditions. The strategy eluded to in Scheme 7.3.7 is elaborated upon in Scheme 8.10.5 and involved the starting material p r e p a r e d in Scheme 8.10.3. Cyclization of the polyol is effected on removal of the acetonide u n d e r acidic conditions followed by the oxidative cleavage of the resulting diol. Spontaneous formation of the hemiacetal is followed by protection as the p - n i t r o b e n z y l ether. Although two diastereomers are formed in this sequence, the minor product is easily converted to the major under mild basic hydrolysis of the pnitrobenzyl ether followed by reprotection of the isomerized hemiacetal. This c o m p o u n d is t h e n converted to the allene, shown, on t r e a t m e n t with propargyltrimethylsilane in the presence of trimethylsilyl triflate.

Scheme 8.10.5

Route B Starting Material OPNB

OBn_ OH_ F O i

OBn OMPM BnO ,..

y

"O n OH

~,,O-..~O

1. AcOH/H20 2. Pb(OAc)4 3. PNB-CI, Py

"BnO~~"] "'" y"OBn

propargyI-TM~

OH

OBn

majo-,~-1. K2003,MeOH 2. PNB-CI, Py minor;

g n O ~ "'j''''''*" y "Ogn OH OBn In Scheme 8.10.6, the above formed allene disaccharide is selectively converted to two diastereomeric disaccharides. This is accomplished through the inversion of the unprotected alcohol via Swern oxidation followed by borane reduction. The beauty of this demonstration is apparent through the remarkable stereochemical versatility achieved through the choice of the method used to effect polyol cyclization. The final strategy, eluded to in Scheme 7.3.8, further exemplifies the range of C-disaccharides available from a single polyol when utilizing different methods of cyclizations. As shown in Scheme 8.10.7, the easily p r e p a r e d aldehyde is coupled to the phosphonium salt described in Scheme 8.10.3. The resulting cis olefin was asymmetrically dihydroxylated and the resulting diol

Chapter 8

Syntheses of C-Di and Trisaccharides

263

was protected as the p-methoxybenzylidine ketal. Ring opening of the ketal gave the PMB ether and the resulting free hydroxyl group was protected as the corresponding acetate. Cleavage of the acetonide followed by tosylation of the p r i m a r y alcohol and t r e a t m e n t with sodium h y d r i d e gave the epoxide. Cyclization with ring opening of the epoxide was effected on removal of the PMB group followed by treatment with acid. The resulting C-disaccharide was then functionalized to represent the products described in the previous two approaches.

Route B Completion

Scheme 8.10.6

BnO ,...

[,,0...~~

BnO~

"j ...... "''" y " " O B n OBn OH

1. 0 3, Me2S / 2. NaBH4 ~ .~. Swern 3. PhCOCI/ -" BH3"THF

1. 0 3, Me2S 2. NaBH4 3. H2, Pd(OH)2/C" ~

OH

_OCOPh BnO ,...

~'~(

O

0

HO ,...

BnO~ V J " =_., , , , , , ,,,~,"~ )~I..,,,,,OBn

OH

OH

OBn

1!~. NaOMe/MeOH H2, Pd(OH)2/C MeOH/HCI

"''" ~'''" ~ OH

OH MeOH/HCI

--OHOH

~

O . ~ ~ ( ).

H0 ~

FoqO

.o.LT.! ,,,,,,,,,,Jy,,,o. I.

--OHoH HO ,...

O

OH

. ~

...9

,,~OMe H0

...~~. ()....,,,,,0Me O j ",,,,," ~ ,.~..,,,,,OH

''"OH OH

OH

Chapter 8

264

Syntheses o f C-Di and Trisaccharides Route C

Scheme 8.10.7

O 0

~/"--O

OBn

.

,

~

_.

+

=

/"~"" O

OBn /..L.. ~ v

-

OBn

iPh3PO

~/L__ s

~-

'""OBn

/P

OBn

O\ ./~..

I""

BuLi

OsO4 MeOPhCH(OMe)2,PPTS 5. HCI 6. p-TsCI,Py 3. NaBHaCN,CF3CO2H 7. Nail 4. Ac20,Py I.

""'~OBn 2.

OBn

v =

OBn

OH 0

OBnOH ~

0,,,,

/

. . . . .

OBn

/

.y. '. . . . . .

OMPM

1. CAN ""OBn

BnO ,,..

0-ZsOH

O

'''" "'" ~

BnO

OBn .O00Ph

OAc

""O Bn OBn

0 ~,,,,.Oq !

1. K2COa

BnO ,,..

2. PhO001,PY

0

~ 1

I...,,,,,,,,,,,,,,,,,..

L

" T

BnO OH

J

~OBn"~

OBn

All the work described in Schemes 8.10.3 through 8.10.7 are nicely complimentary to an earlier preparation of C-disaccharides by Kishi, et al.3s This report, published in 1991, differs from that just described in that the products are ethylene-linked C-disaccharides instead of being methylenelinked. The synthesis began, as shown in Scheme 8.10.8, with the illustrated hydroxymethyl C-glucoside. Swern oxidation followed by a Wittig reaction and subsequent treatment with base gave the acetylenic glycoside. Elaboration to the vinyl iodide was accomplished on treatment with iodine followed by potassium azodicarboxylate. Coupling to the aldehyde, shown, was then effected utilizing NiC12/CrC12 in DMSO.

Chapter 8

Syntheses of C-Di and Trisaccharides

Scheme 8.10.8

BnO~.~.

(

Ethylene-Bridged C - D i s a c c h a r i d e s - - Part 1

"~ ....~ ~ )

OH

BnO~.~

1. Swern

BnO,,,,," ~

2. CBr4/PPh3 3. BuLi

''"OBn

(

OBn ....

OBn :

1. 12

2. KO2CN=NCO2K

OBn

I TBDPSO OBn OBn

''"OBn

BnO,,,," ~

(

BnO,,,,,," ~

OBn BnO~

265

NiCI2(0.1%)-CrCl2

OBn

OBn OBn OH BnO,,,,,...[~..,,,,,OBn

TBDPSO

;

.,,,,,,... ~ O B n

OBn OBn Ethylene-Bridged C - D i s a c c h a r i d e s - - Part 2

Scheme 8.10.9

OBn Bn0,,,, F~..,,,,,OBn

OBn OH TBDPSO

-

........

OBn

"""" L' O

OBn OBn

OH HO,,,,,..F. .'.~. .' ' ' O H

5. p-TSA 7. NaH/Mel H2, Pd(OH)2/C 6.

,,.

MeO~~.O~,~, , ,. HO"

~

"OH =

OH

1. H2, Pt/AI203 2. DHP/PPTS 3. TBAF 4. Swern

266

Chapter 8

Syntheses of C-Di and Trisaccharides

Completion of the synthesis was accomplished, as shown in Scheme 8.10.9, beginning with the selective catalytic hydrogenation of the olefin followed by protection of the secondary alcohol and removal of the silyl protecting group. Cyclization of the protected polyol was subsequently effected by oxidation of the alcohol under Swern conditions followed by removal of the THP protecting group. After spontaneous formation of the hemiacetal, conversion to the Omethylglycoside resulted from treatment with sodium hydride and methyl iodide. Finally, all protecting groups were removed under catalytic conditions to give the O-methylglycoside-ethylene-bridged-C-disaccharide. 8.11 Syntheses Reported in 1993

Scheme 8.11.1

Tethered Radicals

~.OBn BBnnO ~O O~SePh OH

~ O + gnO BnO~Me

~..-OBn

~..OBn

BnBO~?

SePh ~(~Bn nBuaSnH 40'/0 single isomer"

HO-~

BnO~

HOBnO ~

~....-OH 0 BnO~)Me

O\\".~_._O~/i e

-

Me2SiCI2 BuLi 95%

c.~OH HO lJ-~-..~_10 HO ~ Me

Trends in the state of C-disaccharide chemistry continued to change, and, in 1993, acetylene anions were revisited. Additionally, the use of tethers directing the approach of radical species to olefins gained much notoriety. An application of this technology, reported by Sinay, et ai.,39,40 is shown in Scheme 8.11.1 and begins with the selenoglucoside, shown. Coupling of this species to the olefinic sugar derivative was effected using a dimethyldichlorosilane linker.

Chapter 8

Syntheses of C-Di and Trisaccharides

267

Treatment of the resulting coupled compound with tributyltin hydride effected the formation of a 40% yield of the C-disaccharide as a single isomer. Removal of the protecting groups yielded the ~-C-maltoside shown.

Scheme 8.11.2

Acetylene-Bridged C-Disaccharides

O ~ , , . ( )- .,,II~OCH3 OHC. ~ ( )/,~..,,,~OCH3 (ipc)2B"-~/''OTHP 1. DIBAL ""OBn BF3,OEt2 MeOPh*""LO".... ~ ,~'~,OBn 2. Swern PMBO ~''" ~ OBn OBn OH OBn = _ ~176 ~ O ] 1. PTSA ""~OCH3 1. ozone THPO ....t, ) . . , 2.3.Nail,CAN BnBr Bn6HO~''-''l'Y '--Bn'*O 2. Swern PMBO~" y "OBn OBn OBn OBn OBn - H .--= H BnO,, ~ -.O ..,,~OCH3 BnO~O. IIOCH3 1. TMS-~-~ , BuLi_- ~ > ~ Z 'H~" 2. Et3SiH,BF3"OEt2 O ~'OBn O ~ O ~ " , , , O ~, Bn 3. TBAF OBn OBn BnO "

BnO,,,

H

BuLi- 1.

300

-9

""

0

0

T .:"~'~OBn H OBn ..

~OP

"-2. Et3SiH,BF3,OEt2

-

OH H

HO~O" OH | H HO,,, ~t. I O

]

..,,"OCH3

.....L.~ 0 ~ 11,. 11~ ""'~OH ,,,,,~-'~ H ~H .,~},""

H3 C O ~ " " C O ~ O H H OH Utilizing the addition of acetylene anions to sugars, Armstrong, et al., 4i prepared novel acetylene-bridged C-disaccharides. His synthesis, shown in Scheme 8.11.2, begins with the p-methoxybenzylidine protected sugar shown. Treatment of this compound with DIBAL followed by the application of the Swern oxidation to the resulting alcohol gave the aldehyde. Allylboration gave the extended side chain which was adjusted through protecting group manipulations giving the alcohol. Ozonolysis of the olefin followed by Swern oxidation of the spontaneously formed hemiacetal gave the sugar-fused sugar

Chapter 8

268

Syntheses of C-Di and Trisaccharides

lactone. Addition of the propargyltrimethylsilane anion followed by deoxygenation and removal of the silyl group gave the acetylene glycoside. Repeating this process with the sugar lactone gave the novel acetylene linked dipyranyl C-disaccharide after removal of the protecting groups. A novel extension of this technology resulted in the acetylene-bridged glucose oligomer shown in Figure 8.11.1.

Acetylene Bridged C-Disaccharides

Figure 8.11.1

HO-'-~

O

HO'--~ O

C_ HO

HO--~ O

(_ ?-=,,,,,,,.C_ OH

HO

Scheme 8.11.3

OH

HO

OH

C-Sucrose

BnO_

BnO_ BnO,,,,...r~ 0 ;

(~Bn

OBn

~ "

~

i

Os04 o

BnO,,,,1

"-r"

tsnu

OH 0--~

~OH

-0 OBn

= "

OBn

~ OH

~

O

O"~

1. TsCI/Py 2. Nail

BnO..

AcO..i AcO,,, ~ ""

;~ 0

AcO~-..,,,,,,,,,,,... AcO AcO

0

"

.

1. PPTS/MeOH

BnO,,,,..~O

~'O OBn

2 " H2, 10% ed(OH)2/C

OAc 3.

Ac20/Py/DMAP

OBn

OH %

Additional work, originally reported in 1988 and elaborated upon in 1993, presents a synthesis of epi-C-sucrose and C-sucrose complimentary to that presented in Scheme 8.7.5. This chemistry, reported by Kishi, et a1.,42,43 involves the cyclization of a polyol. However, unlike the previously described

Chapter 8 Synthesesof C-Diand Trisaccharides

269

p r e p a r a t i o n (Scheme 8.7.5), the key cyclization involves the t a n d e m ring opening of an epoxide. As shown in Scheme 8.11.3, C-sucrose was prepared from the illustrated olefin. Osmylation of the olefin followed by tosylation of the primary alcohol and treatment with base gave the epoxide. The acetonide was then hydrolyzed and the benzyl groups were removed. Spontaneous cyclization of the furanose ring was effected on removal of the acetonide. In all, an efficient synthesis of C-sucrose was accomplished in five steps from the starting olefin. Figure

8.11.2

Blood Group D e t e r m i n a n t s

OH ( )~.,. O-Ceramide

HO.

--

OH

i

"''"OH

_= n

OH RO"

v..

13-lactose

-O""

1

,,,,,,.....~0,~0 HO'' _

HO.

H

Ac

-7

I

Group A: R = o~-D-N-acetylaminogalactosyl Group B: R = o~-D-galactosyl GroupO: R=H

O

ROv

v

,,,,,~Seo,. ,,..~_~O

HO"

I

Type II blood group determinant

OH HO.

--

_

OH

"OH

OH

. OH

,,0..~ v

-'OVl

OH OH

Type l blood group determinant

So far, this c h a p t e r has primarily focused on the synthesis of Cdisaccharides. However, notable preparations of C-trisaccharides have been reported. In one particular example, Kishi, et a1.,44, 45 targeted the synthesis of

Chapter 8

270

Syntheses of C-Di and Trisaccharides

the blood group determinants illustrated in Figure 8.11.2. In this rather extensive synthesis, the initial starting material, prepared as shown in Scheme 8.11.4, was derived from the illustrated sugar analog. Conversion to the methyl ketone was accomplished via Swern oxidation to the aldehyde followed by addition of methyl Grignard and an additional Swern oxidation. The coupled product was prepared via aldol condensation with the aldehyde. This compound was then cyclized on removal of the silyl protecting group. The resulting hemiacetal was deoxygenated under previously described conditions and the alcohol was oxidized to a ketone rendering the diastereomeric mixture irrelevant.

Starting Material A

Scheme 8.11.4

OBn

OBn

O , . . . ~ ~ ,,,,OCH3 1. Swern ~

O

" ""

""OBn 2.3. MeMgBr Swern

HO

1. LiN(TMS)2

O ~

""O Bn

OBn

OBn

OBn

2. TBDMSO ~ ' ' x / O B n

OBn TBDMSO

HO

ii'''OCH 3 1. TBAF

O *'......

OBn OBn

BnO_ BnO ,..

""OBn OBn

BnO,.

OBn

O L..~ O . ~ ..,II~OMe 1. Bu3SnH/AIBN BnO

~ , , , , ,

HO

2. MESH, BF3-OEt2

OBn O ~ ~ . O_ .,,,,,0Me

2. Swern

" "'I / ""O Bn SMe I OBn

OBn

Starting Material B

Scheme 8.11.5

,,,,,,.....~,,OyO H BnO*"" ..""F/ =

OBn

~OBn

1. PropargyI-TMS,TMSOTf ID 2. 03, Me2S 3. NaBH4

BnO*~''" Y

=

OBn

~OBn

Syntheses of C-Di and Trisaccharides

Chapter 8

271

A+B

Scheme 8.11.6 ,,,...

Swern

= BnO""~OBn OBn

BnO"" "Y/. . "~OBn OBn

"',...CO ~ BnO.

OBn

......

Bn0o, I

L .0~

~~,,,..vL~

,~OMe 1. LiN(TMS)2 2" MgBr2

"",oOBn OBn

O R .... ,

+

Bn

BnO,,". . [ " ~ 0 Bn OBn

R

= Bn~I,,.O.~OB=~H

BnO.

Scheme 8.11.7

BnO_ BnO~ I

R=

O~,,,~~..,OOBn I

OBn

Conclusion of Synthesis

OBn L .0...,,,,OMe

,,,,,,....F.,.O.~oH

BnO.

OBn

HO

HO

OH

= =

,,,,,,,..

HO -

L .().- ,,,OMe

BnO~,,,.l"-.v~OBn OBn

=

%.. HO " 0 HO". C , / ~ " ~

OBn

BnO~, t

1. MsCI 2. NH3 3. Bu3SnH

BnO,,,,"Lv~OBn OBn

1. NaBH4 2. H2, Pd(OH)2/C

OBn

BnO~~,.~O~O....,,~OMe

OBn

OBn

0

OH L

0 ~i~"... /k~ ) ... ,OMe HO

OH

OBn

Chapter 8

272

Syntheses of C-Di and Trisaccharides

The next starting material, p r e p a r e d as shown in Scheme 8.11.5, is the r e s u l t of Lewis acid m e d i a t e d C-glycosidation of the i l l u s t r a t e d fucose derivative. Ozonolysis of the resulting allene followed by reduction gave the desired alcohol. Starting materials A a n d B were s u b s e q u e n t l y c o u p l e d as shown in Scheme 8.11.6 via oxidation of the alcohol to an aldehyde followed by an aldol condensation. The resulting products were separated and the diastereomeric mixture of alcohols were carried on as shown in Scheme 8.11.7. The conclusion Kishi's synthesis of C-glycosidic analogs of the blood group d e t e r m i n a n t s stems from the diastereomeric mixture of alcohols described in Scheme 8.11.6. As shown in Scheme 8.11.7, the alcohol groups were mesylated a n d s u b s e q u e n t l y t r e a t e d with a m m o n i a in t e t r a h y d r o f u r a n . The resulting enones were r e d u c e d on t r e a t m e n t with tributyltin hydride thus yielding the illustrated C2,-equatorial ketone as a single isomer. Completion of the synthesis was accomplished on reduction of the ketone with sodium borohydride followed by removal of the benzyl groups under catalytic conditions. 8 . 1 2 Syntheses Reported in 1 9 9 4

Scheme 8.12.1

Hydroxyethylene-Bridged C-Dipyranosides

••..

''tllO ,~~ C~NjO # ",,,,,.,~" () )'~...,,. BnO u 93%, 78:22 AcO"" J''OAc AcO,,,,..~ / ""'OAc

OAc

O

1. KCN,MeOH ~. 2. H2, RaneyNi, H3BO4

55%

~

OH

0~ ......' L 'J''

OH

%0~ BnUHO

OH 9-. ~ -,F'..,,,,,OH 9H 1. NaBH4,79%,65:35 2. CF3CO2H,92%

(

[/'"

I

I

HO"" ~ "J'""O H OH

,oX

BnO

OAc

()

HO""

/ 0 ~ .....,.O

~

-~ OH

OBn

+ 18% Hydroxyamino

Chapter 8

Syntheses of C-Di and Trisaccharides

273

Although no preparations of C-trisaccharides were reported in 1994, advances in the technologies applied to the synthesis of C-disaccharides yielded several interesting papers. Among the chemistry reported is an extension of the isoxazoline chemistry discussed in Schemes 8.4.2 and 8.6.3. As shown in Scheme 8.12.1, Paton, et al., 46 effected isoxazoline formation utilizing pyranosederived nitrile oxides and furanose sugars bearing vinyl substituents. As expected, the 1,3-dipolar cycloadditions provided isoxazoline-bridged Cdisaccharides. The illustrated reaction favored the product shown and exhibited a 93% yield with a 78 : 22 ratio of isomers at the newly formed stereogenic center. However, where hydrolysis of the isoxazolines prepared in Scheme 8.6.3 yielded carbonyl-bridged C-disaccharides, hydrogenation of Paton's isoxazolines afforded hydroxyketones. The illustrated example proceeded in 55% yield with an additional 18% accounted for as the corresponding hydroxyamino analog. As shown, reduction of the isolated hydroxyketone produced a 65 : 35 mixture of diols in 79% combined yield favoring the R configuration. Exposure of the major isomer to trifluoroacetic acid effected rearrangement of the furanose component thus providing a novel method to the preparation of hydroxyethylene-bridged C-dipyranosides. T e t h e r e d Radicals

Scheme 8.12.2

).

HO

,,,,0Me BnO"

''"OBn OBn

BnO~...

+ ()~..... S02Ph

/ ""'OH OBn

Me2SiCI2=

~

~( )~ .,bSO2Ph T \/

BnO,,,....~ ,~...,,,,,o / S i l o ~ ( ) )

82%

OBn

BnO"" ~

OMe

_=

0~-,~..,,, ,'OBn

i =

n ,, HE, H20

~"0 ~

BnO BnO""' ~ / ' ' O H

OBn

''"OBn

OBn ~Sml2 OMe ....,,o Bn

50%

NO~~,~OB

~

"(

~()\ ~ - = /

"T"

BnO,,,,.'L'-.,,,.,,--'J".,,,,oj OBn

..o,,,OMe

"OBn

274

Chapter 8

Syntheses of C-Di and Trisaccharides

As discussed in the previous section, the use of dimethylsilyl tethers as a means of directing the delivery of one sugar to a n o t h e r u n d e r free radical conditions has gained much notoriety. As illustrated in Scheme 8.11.1, the source of the radicals were selenoglycosides and the radicals were g e n e r a t e d utilizing tributyltin hydride. In 1994, Sinay, eta/., 47 extended this chemistry to include phenylsulfones as sources of glycosidic free radicals g e n e r a t e d on t r e a t m e n t with samarium diiodide. As shown in Scheme 8.12.2, the t e t h e r e d c o m p o u n d was obtained in 82% yield. Subsequent formation of the C-glycosidic linkage was achieved on treatment with samarium diiodide. Completion of the synthesis was accomplished on removal of the tether utilizing HF in water. The c o m b i n e d yield for the final two steps was 50% thus d e m o n s t r a t i n g a high yielding and potentially general method for the preparation of C-disaccharides.

8.13 Trends of the Future Figure 8.13.1

Oxabicyclo [4.1.0] heptenes X

X = H, CI, Br ~..

8 Scheme 8.13.1

Preparation of Oxabicyclo [4.1.0] heptenes X

X

(

OH

Microbial Dioxygenase r

H

X

X

OH 0

"

O

I~

H

Chapter 8

Syntheses of C-Di and Trisaccharides

275

T h r o u g h o u t this book, the evolution of the chemistry s u r r o u n d i n g the p r e p a r a t i o n of C-glycosides was presented. Examples were shown which not only p r e s e n t e d the actual C-glycosidations b u t also utilized t h e m is the p r e p a r a t i o n of increasingly more complex target molecules. As it would be p r e s u m p t u o u s to assume that we now know all we need in o r d e r to p r e p a r e any C-glycoside of choice, one final example is presented. In mid 1994, Hudlicky, et al., 48 p u b l i s h e d a r e p o r t d e s c r i b i n g the p r e p a r a t i o n of new synthons for C-disaccharides. The actual c o m p o u n d s of interest are the oxabicyclo[4.1.0]heptenes illustrated in Figure 8.13.1. Unlike the chemistry presented thus far, the compounds r e p r e s e n t e d in Figure 8.13.1 were p r e p a r e d utilizing the biocatalytic oxidation of haloarenes illustrated in Scheme 8.13.1.49,so

Scheme 8.13.2

A d d i t i o n of Carbon Nucleophiles to Oxabicyclo [4.1.0] h e p t e n e s

~

+

~MgBr

,#< X

Product

Yield(%)

CI

OH

83

OH

With the p r e p a r a t i o n of the oxabicyclo[4.1.0]heptenes established, their use as synthons for C-disaccharides was explored. As shown in Scheme 8.13.2,

Chapter 8

276

Syntheses o f C-Di and Trisaccharides

addition of carbon nucleophiles such as cyclohexylmethylmagnesiumbromide provided good yields of various addition products. In contrast to the good results obtained with Grignard reagents, the use of organocuprates provided substantially lower yields with measurable quantities of side products. However, as can be deduced from the illustrated results, use of Grignard reagents derived from protected sugars may potentially lead to new C-glycoside analogs capable of exhibiting interesting and useful pharmacological properties. The ability to prepare C-glycosides has benefited numerous areas of carbohydrate research from the study of conformational stabilities to the potential development of stable carbohydrate analogs suitable for clinical use. As this field continues to mature, we can look back upon the chemistry developed thus far and truly appreciate the excitement associated with the discovery of future technologies and potential applications. 8.14 References .

2. 3. 4. S. 6. "

8. Q

10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Rouzaud, D.; Sinay, P. J. Chem. Soc. Chem. Comm. 1983, 1353. Aebischer, B.; Meuwly, R.; Vasella, A. Helv. Chim. Acta 1984, 67, 2236. Jurczak, J.; Bauer, T.; Jarosz, S. Tetrahedron Lett. 1984, 25, 4809. Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2201. Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205. Danishefsky, S.J. Maring, C. J.; Barbachyn, M. R.; Segmuller, B. E. J. Org. Chem. 1984, 49, 4564. Beau, J. M.; Sinay, P. Tetrahedron Lett. 1985, 26, 6189. Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Charence, J. M.; Springer, J. P. J. Am. Chem. Soc. 1985, 107, 1256. Hanessian, S.; Martin, M.; Desai, R. C. J. Chem. Soc. Chem. Comm. 1986, 926. RajanBabu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51, 5458. Giese, B.; Witzel, T. Angew. Chem. Int. Ed. Eng. 1986, 25, 450. Liu, P. S. J. Org. Chem. 1987, 52, 4717. Goekjian, P. G.; Wu, T.-C.; Kang, H.-Y.; Kishi, Y. J. Org. Chem. 1987, 52, 4823. Goekjian, P. G.; Wu, T.-C.; Kang, H.-Y.; Kishi, Y. J. Org. Chem. 1991, 56, 6422. Giese, B.; Hoch, M.; Lamberth, C.; Schmidt, R. R. Tetrahedron Lett. 1988, 29, 1375. Giese, B.; Ruckert, B.; Groninger, K. S.; Muhn, R.; Lindner, H.J. Liebigs Ann. Chem. 1988, 997. Dawson, I. M.; Johnson, T.; Paton, R. M.; Rennie, R. A. C. J. Chem. Soc. Chem. Comm. 1988, 1339. Daly, S. M.; Armstrong, R.W. Tetrahedron Lett. 1989, 30, 5713. Schmidt, R.; Preuss, R. Tetrahedron Lett. 1989, 30, 3409.

Chapter 8 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.

Syntheses of C-Di and Trisaccharides

277

Boschetti, D.; Nicotra, F.; Panza, L.; Russo, G.; Zucchelli, L. J. Chem. Soc. Chem. Comm. 1989, 1085. Motherwell, W. B.; Ross, R. C.; Tozer, M.J. Synlett 1989, 68. Carcano, M.; Nicotra, F.; Panza, L.; Russo, G. J. Chem. Soc. Chem. Comm. 1989, 642. Lay, L.; Nicotra, F.; Pangrazio, C.; Panza, L.; Russo, G. J. Chem. Soc. Perkin Trans. 1 1994, 3, 333. Neuman, A.; Longchambon, F.; Abbes, 0.; Pandraud, H. G.; Perez, S.; Rouzaud, D.; Sinay, P. Carbohydrate Res. 1990, 195, 187. Dubois, E.; Beau, J. M. J. Chem. Soc. Chem. Comm. 1990, 1191. Martin, O. R.; Lai, W. J. Org. Chem. 1990, 55, 5188. de Raddt, A.; Stulz, A. E. Carbohydrate Res. 1991,220, 101. Preuss, R.; Schmidt, R. R. J. Carbohydrate Chem. 1991, 10, 887. Prandi, J.; Audin, C.; Beau, J. M. Tetrahedron Lett. 1991, 32, 769. Engelbrecht, G. J.; Holzaphel, C.W. Heterocycles 1991, 32, 1267. Bimwala, R. M.; Vogel, P. Tetrahedron Lett. 1991, 32, 1429. Black, K. A.; Vogel, P. J. Org. Chem. 1986, 51, 5341. Fattori, D.; de Guchteneere, E.; Vogel, P. Tetrahedron Lett. 1989, 30, 7415. Roberts, J. L.; Borromeo, C. D.; Poulter, C. D. Tetrahedron Lett. 1977, 1621. Bimwala, R. M.; Vogel, P. J. Org. Chem. 1992, 57, 2076. Armstrong, R. W.; Teegarden, B. R. J. Org. Chem. 1992, 57, 915. Wang, Y.; Babirad, S. A.; Kishi, Y. J. Org. Chem. 1992, 57, 468. Goekjian, P.; Wu, T.-C.; Kang, H. Y.; Kishi, Y. J. Org. Chem. 1991, 56, 6423. Xin, Y. C.; Mallet, J. M.; Sinay, P. J. Chem. Soc. Chem. Comm. 1993, 864. Vauzeilles, B.; Cravo, D.; Mallet, J. M.; Sinay, P. Synlett 1993, 522. Sutherlin, D. P.; Armstrong, R.W. Tetrahedron Lett. 1993, 34, 4897. O'Leary, D. J.; Kishi, Y. J. Org. Chem. 1993, 58, 304. Dyer, U. C.; Kishi, Y. J. Org. Chem. 1988, 53, 3383. Haneda, T.; Goekjian, P. G.; Kim. S. H.; Kishi, Y. J. Org. Chem. 1992, 57, 490. Kishi, Y. Pure & Appl. Chem. 1993, 65, 771. Paton, R. M.; Penman, K.J. Tetrahedron Lett. 1994, 35, 3163. Chenede, A.; Perrin, E.; Rekai, E. D.; Sinay, P. Synlett 1994, 6, 420. Hudlicky, T.; Tian, X.; Konigsberger, K.; Rouden, J. J. Org. Chem. 1994, 59, 4037. Hudlicky, T.; Fan, R.; Tsunoda, T.; Luna, H.; Andersen, C.; Price, J. D. Isr. J. Chem. 1991, 31,229. Carless, H.A. Tetrahedron Lett. 1992, 33, 6379.

This Page Intentionally Left Blank

Index

A

aliphatic olefin 208 alkylation 42, 150 alkyllithium reagents 113,254 alkynation 42 alkynyllithium reagents 114 allene 61,224, 262,272 allenylation 42 allyl 193 ~-allyl complexes 167 allylation 42, 55, 90, 184 allylboration 267 allylic alcohol 103 allylic alcohols, O-silyl protected 103 allylic ethers 103, 104, 105,106 ~-allylpalladium complex 171 allyltin reagents 68 aloe 8 aloin A 7, 8 aloin B 7, 8 aluminum 68 aryl 74 nucleophiles 71 olefins 51 reagents 35, 37 amide 201,202 amino acids 40, 41 unnatural 40 C-glycosyl 40, 41 amino sugar 59 anhydroglucose 208 anhydrosugar 169 anion 200 carboxy stabilized 149 chemistry 42 stabilization 143 nitromethyl 100

acetate 158, 167, 168 acetone cyanohydrin 38 acetoxy 64, 75 acetylation 229 aceWlene anion 247, 266, 267 aceWlene-bridged 247, 267 acetylenes 196 aceWlenic anion 237, 248 acetylenic esters 233 aceWlenic tin reagents 70, 71 N-acetyl neuraminic acid 151 acid 221 acid sensitive 224 acidic 171 acrylamide polymers 19 acrylonitrile 182, 184, 186, 187, 188, 189 addition reaction 240 1,4-addition 246 axial addition 48 conjugate 245 double 187 affinity labeling 12 affiniW labels 13 agglutination 20 aglycones 157 aromatic 157 AIBN 249 alcohols 198 aldehyde 146, 201,208 aldehydes 105,106, 148, 206, 207, 208 aldol condensation 270 279

280 phosphonate 11 O, 112 stabilized 146 sulfoxide 147 sulfide 147 sulfone 144 anionic 42, 49, 50, 51, 90, 255 addiUon 255 nucleophiles 42, 49, 50, 51, 90 anomeric 4, 29, 30, 106, 125, 127, 133, 134, 137, 138, 140, 149, 175, 177, 182,203 activating groups 29 anions 137, 138, 149 carbanions 134, 140 carbenes 125 effect 4 vinyligous 203 esters 106 halides 134 isocyanides 30 nitriles 30 nucleophiles 133, 134 olefin 127 radical 175, 177, 182 anthracene 90 anthracycline 58 anthraquinone 9 anthrone 9 antibacterial 10 anUbioUcs 223 anUfungal 223 anUperiplanar 4, 6 anUtumor 10 antiviral 10 arabinose 208 arabinoside 199 benzyl 199 Artemia salina bioassay 9 aryl iodides 161,162, 166 aryl mercuric acetates 162 aryl mercury 157, 162 aryl tin 157 aryl-bridged 252 arylation reactions 72, 90 C-arylation 79

Index

arylboron 166 Arylsulfides 68 arylsulfonium 34, 67 aryltin reagents 74 aryltributyltin compounds 157 arylzinc 166 Asphodelus ramosus 9

axially 30 aza sugar 244 azide 228 azidosugar 64

B Barbados aloe 8 barbaloin 8 barbiturates 90 Barton 143 base 224 benzaldehyde 149 benzenesulphonyl 47 benzyl 167 benzylidine acetals 229 bergenin 79 biocatalyUc oxidaUon 275 biosynthesis 14 blood glucose levels 12 blood group 7 blood group determinants 6, 269, 272 boat 193 bond 4 lengths 4 rotational barriers 4 a-bond 171 borane 262 bromide 192 bromine 213, 214, 261 bromonium ion 213 N-bromosuccinimide 213 BSA 62 buckminsterfullerene 126

Index

C C60 126 camphor sulfonic acid 216 carbanions 143 carbene 200 carbenoid 198, 199, 200 displacement 197 rearrangement 199, 200 carbohydrate binding proteins 13 carbohydrates, modified 50 carbon monoxide 121, 122, 123 carbon tetrabromide 248 carbonyl 230 carbonyl-bridged 273 carboxyl group 149 carboxyl stabilized 143 Carthamus tinctorius 8, 9 catalytic hydrogenation 266 CBZ 216 cell adhesion 15, 151 cellobiase 11 ceric ammonium nitrate 225 chair 199 chelation 232 chelation control 241 chemical reactivities 4 chirality 149 chlorophenylsulfide 148 chrysomycin 77, 162 Chrysopogon acicula tis 9 cis-fused bicyclic 85 Claisen rearrangement 197, 201, 202, 204 Claisen-Wpe rearrangement 203, 227 cleavage 198 cobalt 123 ~-complexation 171 conformation 4 conformational behavior 6 ~-conjugated aglycones 155 conjugated carbonyl compound 190, 191

2 81

conjugated ketone 190, 192 conjugated nitrile 191 Cope rearrangement 201 copper acetate 158 coupling constants 4, 6 cross coupling 155 cuprate 43, 138, 140, 139, 255 additions 45 chemistry 44 glycal-derived 255 mixed 45 nucleophiles 44, 45 cyanation Reactions 30, 184 cyclic ethers 214 cyclic olefin 208 cyclization 149, 260 base mediated 213 bromo 214, 261 halo 213 iodo 214 polyol 247, 259 cycloaddition 206, 209, 211,212 cyclopropanation 125

D DAHP 22 DBU 148, 212 decarboxylation 143,208 2-deoxy sugar 59, 88, 91 deoxynojirimycin 11 deprotonation 146, 149 DHQsynthase 22 diamond lattice 6, 7 diazirine 125 diazoketone 12, 40 diazomethane 40 DIBAL 267 dicarbonyl compounds 168 dichloro dicyanopalladium 164 1-deoxy-l-nitrosugar 102 2'-deoxypseudouridine 163 dideoxy sugar 193

282 Diels-Alder 58, 60, 230, 231,240, 241 hetero 212, 230, 232,238, 240, 241 dienes 231 dienophile 231,240 diethyl malonate 169, 256 diethylaluminum cyanide 37 C-difuranoside 238 dihydropyran 227, 234, 240 dihydropyranone 241 1,3-diketones 169 dimerization 248 1,1-dimethoxy- 1-dimethylaminoethane 201,202 dimethyl(acetoxymethylene)malonate 230 dimethyl carbonate 146 dimethylaluminum cyanide 35 dimethylmalonate 182 2,3-diphenylindole 80 dipolar cycloaddition 127, 207, 208, 243,242,245,247 dipole moments 4 disaccharide 190, 191, 196 C-linked 65, 232 C-disaccharides 61, 66, 102, 117, 29, 136, 146, 226, 232,237 aceWlene-bridged 117 divinyl zinc 219 double bond migration 171 double Claisen 202 double ring 208 DOWEX 221

E e-coli 16 electonegativities 4 electrocyclic 226 electron deficient 59, 144, 167, 168 electron withdrawing groups 143 electronegativity 4

Index

electrophile 137, 138, 155 electrophilic aromatic substitution 75, 78, 79, 81, 88 electrophilic substitution 29, 255 enamines 90, 98, 99, 100 endothelium 15 endotoxins 15 ene 206 ene-ynes 233 enol ether 90, 196 enolate Claisen rearrangement 202, 226 enolate equivalents 105 enolates 90, 91 enones 67, 118, 119, 120, 121 enzyme inhibitors 10 epi-C-sucrose 268 epimerization 96, 110, 155 epoxide 44, 211, 225 equatorial 30 erythrocytes 18 Eschenmoser salt 257 Escherichia coli 16 ester 106, 11 O, 201 acetylenic 123 vinylic 123 ethers 198, 220, 224 ethyl propargylacetate 196 ethyl vinyl ether 201,202 ethylene-bridged 254 ethylene-linked 264 exoanomeric effect 4 exoanomeric methylene 127, 129, 208 exocyclic methylene 243, 244

F Favorskii rearrangement 228 Felkin 240 five membered ring 214 flavone 9 flavonoid 220

Index fluoroglucoside 63 foodstuffs 10 formic acid 171 formycin 10 formycin B 10 free radical 177, 233, 243, 245, 246, 249, 257, 259, 274 free radicals 175 glycosidic 274 Friedel-Crafts 73, 81, 82 fucose 14 a- 1,3-fucosyltransferase 14, 15 fucosyltransferase inhibitor 14, 124 fullerenes 125 fumaronitrile 187 furan 80, 83 3,4-dibenzyloxy 230 furanose 216, 247 furanoside 221 cyano 40 fluoro 72, 84 C-furanosides 233 furanosyl selenide 179 fused ring 175 C-glycoside 54 system 204

G galactal 201 ~-galactosidase 13 B-D-galactosidase 11, 12 galactoside, C-cyano 40 [~-1,4-galactosyltransferase 14 GDP-L-fucose 15 C-GDP-fucose 124, 125 geminal diacetates 105 gentiobiose 245 C-gentiobiose 238 gilvocarcin 77, 162 gilvocarcin M 89 glucal, tri-O-aceW1-D- 158 gluconolactone 223

283 glucopyranose, phenylthio 183 glucopyranosyl bromide 178, 186, 187, 189 fluoride 184 glucosamine 90, 212, 219 glucose 193 ~-glucosidase 11 ~-glucosidase inhibitors 136 glucosidase inhibitors 46, 216 a-glucosidases 244 glucoside 11,266 O-nitrophenyl-~-D- 11 seleno 266 C-glucosides 73 aryl 73 glycals 65, 82, 83, 88, 98, 103, 104, 134, 135,147 acetoxy 202 activated 164 allyl 135 anionic 138 furanose 162 furanose-derived 162 iodinated 136 iodo substituted 137, 165, 166 keto 118 1-substituted 67 2-substituted 67 lithio 135, 136, 138 metallated 242 metallo 137 pentose-derived 159 pyranose-derived 159, 162 stannyl 135, 136, 137, 164, 166, 252 stannylated 136, 165 tin substituted 164 unactivated 168 glycoconjugates 10 glycogen 13 glycogen phosphorylase 12 glycosidase inhibitors 11 glycosidases 11 glycosidation 90 aryl 90

284 glycoside 18, 35, 37-39, 42, 48, 56, 58, 62-64, 71, 81, 84, 94-96, 100, 113, 119, 121-123, 129, 137, 138, 140, 143, 146, 149, 150-152, 168-169, 176-177, 182-183, 185, 187, 193-194, 198, 201-202, 207, 215, 220, 224, 227, 238, 246, 255, 262, 274 acetoxy 94 ~-C-alkynyl 113 allenyl 224 allyl 185 amino 220 aminomethyl 39 aryl 121 benzyl 198 bromo 37 carboxy 149, 150 chloro 63, 96, 185 cyano 37, 38, 42, 119 cyanoalkyl 187 2-deoxy cyano 38 difluorobutenyl 129 difluoromethyl 129 fluoro 35, 37, 95, 96 halo 63, 71, 81, 94 hydroxyalkyl 198 hydroxymethyl 201 isocyano 37 lithio 140, 143, 146 manganese 122, 123 methallyl 183 methyl 215 O-methyl 62, 63, 84 methyl carboxymethyl 202 nitro 64, 151, 152, 176, 182, 238 nitroalkyl 100 p-nitrobenzoyloxy 58 nitromethyl 207 phenolic 168, 169 phenylseleno 193, 194 phenylthio 183 pyranosyl 227

Index

seleno 177, 246, 274 sialic acid 18 stannyl 137, 138, 140, 255 thio 48, 177 thiomethyl 262 trifluoroaceoxy 56, 94 C-glycosidation 82, 85-86, 127 aryl 82 double 85,127 intramolecular 86 N-glycosidation 80 C-glycoside 1, 71, 73, 74, 81, 82, 83, 87, 88, 89, 117, 134, 230 acetylenic 71, 117 allyl 82 aryl 73-74, 81-83, 88-89, 134, 230 cyano 31, 67 definition and nomenclature of 1 2-deoxy 119 furano 83 furanosyl 227 furanyl 74 naphthyl 88 nitroalkyl 252,253 O-glycoside 87 glycosidic 47, 126, 142-143, 147, 177, 256, 259, 274 anion 142, 143, 147 carbenes 126 carbonate 256 esters 47 free radical 274 radical 177, 259 sulphones 47 [I-glycosidase inhibitors 149 [~-C-glycosylbarbiturates 90 glycosyl 139, 169, 170, 177, 178, 180, 184, 185, 186, 187, 188, 192 bromide 178, 185, 186, 187, 188 carbonates 169, 170 chlorides 139, 185

Index fluoride 178, 184, 185 halide 177, 180, 184 iodide 192 glycosyltransferases 13 Gram-negative bacteria 15, 150 Grignard 219, 276 allyl 113 reagents 45, 46, 47, 48, 115 allylmagnesium chloride 224 guinea pig ileum 20

285 atom 177 bonds 4 radical 176 hydrogen-metal exchange 133, 134, 136, 137, 139 hydrogenation 171 hydrolysis 4 hydroxyethylene-bridged 273 hydroxyketone 273 2-hydroxyl groups 204 3-hydroxyl groups 204 hydroxymethyl 215

H H-bonding 4 hafnocene dichloride-silver perchlorate complex 89, 90 halichrondrins 55 halides 224, 243 haloarene 275 halogen-metal exchange 139, 140, 141,142 halogenated 166 halogens 211 heat 171 heavy metal reagents 30 hemagglutination inhibitors 18 hemiacetal 224, 261 hemiketal 224, 248 herbicides 22 herbicidins 55 heterocycles 42, 203 C-glycosidic 41 heterocyclic 209 aromatic species 74 aryl species 83 substrates 80 B-D-hexosaminase A inhibitor 108 homoenolates 105 Horner-Emmons 110 Hundsdiecker reaction 42 hydride reduction 39 hydrogen

immunostimulants 15 immunostimulatory effects 16 influenza 20 influenza hemagglutinin 18 influenza virus 17, 18 insertion reactions 121, 122, 123 intermolecular 180, 192, 196, 200 intermolecular reaction 83,206 intramolecular 175, 193, 196, 200, 206 delivery 62, 84, 96 electrophilic aromatic substitutions 83, 85 enol ether 96 rearrangement 206 inverted 200 iodide 192, 214 iodine 250 iodomethyl tributyltin 201 iodonium ion 214 ionic 175 irradiation 189 isobutyl chloroformate 169 isomaltose 245 isomerization 146 isoxazoline 208, 209, 243,247, 273 isoxazoline-bridged 273

286

Index

K

M

ketal 167, 222 ketenesilyl acetals 202 keto 159 ketone 105, 106, 164, 208, 223 Knoevenagel condensation 207, 208

maltose 196 mannopyranosyl bromide 178, 187 mannosides, C-awl 73 Meerwein reagent 42 mercuric 37, 216, 244 acetate 216, 244 cyanide 37 trifluoroacetate 216 mercury 214, 216 metal-metal exchange 133, 136, 137, 139 metallated 166 metallations 134, 142, 147, 148, 150 methoxy 64 methyl acetoacetate 208 methyl vinyl ketone 189, 190 methylene-bridged 254 methylenetriphenylphosphorane 215,244 methylthiothiocarbonate 183 Michael 212 acceptors 138, 1 4 1 , 2 1 3 , 2 4 9 addition 232, 245 products 123 Michael-type 208, 212,245 addition 208, 245 reaction 212 migration 177, 178 N-C migration 80 O-C migrations 86, 87, 88, 89, 90 milk 15 molybdenum 234 C-monosaccharides 232

L lactols 219 reduction of 112 lactone 190 LDA 148, 149 lectins 16, 18 leukocyte trafficking 151 leukocytes 15 leukotriene antagonists 20 leukotriene D4 20 Lewis acid 168, 206, 254, 262 Lewis acid-triethylsilane reduction 113 light 246 lignan 9 linker 194 lipid A 15, 212 lipid X 15,212 lipopolysaccharides 15, 150 lithiation 134, 135, 136, 141,142, 143, 144, 145, 146 lithium 113, 142, 146, 158, 240 acetate 158 acetylides 113 chloride 158 naphthalide 142, 146, 240 LTD4 19 LTD4 antagonists 19 lysozyme 11, 12 lyxopyranosyl bromide 187 lyxoside 230

N 2-naphthol 88

Index naphthopyran 104 neuraminidase 18 neutrophils 15 nickel 164, 166 nitrile 206, 207 nitrile oxide 206, 207, 208, 243 nitro 64, 151,176-177, 238 acetates 177 alkane 238 alkyl 176 group 64, 151,176 stabilized anions 151 nitroalkylation reactions 100-103, 108 p-nitrobenzaldehyde 152 p-nitrobenzoate 224 p-nitrobenzoyloxy 58 nitrobenzyl ester 224 nitromethane 101,102 nitronates 100 2-nitropropane 102 nOe 7 nucleic acids 10 nucleophiles 155, 255 nucleophilic 171 nucleophilic additions 112, 118 C-nucleosides 10, 162

0 octosyl acid 55 octulosonic acid 150 olefin 51 dibromo 248 clifluoro 129, 247, 249 halo 233 hydroxy 2 1 2 , 2 1 3 , 2 1 5 stannyl 51 unactivated 51, 53 unfunctionalized 54 organoaluminum reagents 71, 72 organocuprate 119, 12 O, 276 organolithium reagents 49, 50, 115

287 organotin reagents 68 organozinc reagents 47, 48, 49, 219 orthoester Claisen rearrangement 201 osmylation 251,269 oxabicyclo [4.1.0] heptene 275 oxazinomycin 10 oxidative 215 oximes 102, 191 oxonium ion 54-55,230 oxymercuration 127, 214 ozone 244 ozonolysis 216, 267, 272

P palladium 164, 166, 170-171,252, 256 acetate 157-159, 162 tetrakis triphenylphosphine 164 papulacandin 223, 231 Papularia sphaerosperma 223 pathogenic organisms 16 penicillin 22 peptidoglycan 22 peptidoglycan polymerization 216 pharmacophores 10 phenyl acetals 158 phenyl benzoate 146 phenyl selenochloride 217 phenylselenide 229 N-phenylselenophthalimide 216 phenylsulfenyl chloride 136 phenylsulfide 68, 148, 149 phenylsulfides 149 phenylsulfinyl 136 phenylsulfinyl glycals 136 phenylsulfone 146, 240, 274 phenylsulfones 142, 144, 145, 146, 147 phenylsulfoxide 148, 149, 245 phosphonates, sulphone 111

288 phosphonium salt 261 photochemical 68, 183, 192,245, 246 photochemistry 246 photolytic 70, 175, 177, 185 pinacole 104 planar center 158 PMB 225 PNB 62, 75 O-PNB 224 polyvalent 18 potassium 216, 264 azodicarboxylate 264 chloride 216 Prins 54, 206 propargyl groups 61 pyran 234 pyranose 216, 247 pyranoside 221 C-pyranosides 233 pyranosyl 142, 179, 216 chlorides 142 iodide 179 phenylselenide 216 pyrazofurin 10 pyrimidinyl 158, 159, 162, 171 carbonyls 171 iodides 162 mercuric acetate 158, 159, 162, 171 palladium complex 171 pyrrole 74, 221

R radical acceptors 175, 180, 257 radical reaction 242 ravidomycin 77, 162 rearrangements 206, 209, 229 recombination 198 reduction 140 reductive 215 reductive cleavage 146

Index

retention 199, 200 ribose 208 ring 171,210, 226, 227, 261 closure 261 contraction 226, 227 cyclization 210 opening 171 ring system, spiro 209

S saliva 15 salt additives 158, 159 samarium diiodide 274 selectins 15 selenium 214, 216, 229 shikimate pathway 20 showdomycin 10, 183,200, 229 sialic acid 14, 150, 151,185 sialyl Lewis x 14, 15, 151 ~-2,3-sialyltransferase 14 sigmatropic 2 0 1 , 2 0 2 , 2 0 3 silanes SS, 60, 61, 64, 90, 95, 224, 254, 262,266, 268 acetylenic 5 S allyl 55, 60, 90, 254 acetate substituted 60 allyltrimethyl 55, 95 dimethyldichloro 266 propargyl 60 propargyl trimethyl 61, 64, 224, 262,268 silver triflate 82, 96, 99 silyl 51, 55, 67, 90, 92-96, 98, 99, 104, 120, 159, 165, 194 acetylenes 67 compounds 55 enol ethers 90, 92-96, 98, 99, 120 enol ethers, steroidal 96 ethers 104 groups 159, 194 olefins 51

Index protecting groups 165 SN2 211 sodium 116, 158, 217 bicarbonate 158, 217 cyanoborohydride 116 periodate 217 stability 4 stabilizing group 149 stannylations 135 stereochemistry 158 stereoelectronic effects 30, 120 stereoselectivity 29 steric 4, 245 styrene 194 sucrose 250 C-sucrose 247, 250, 268, 269 sugar 49, 102, 109, 112, 113,215, 237, 240, 254 carbonate 254 cuprate 254 lactones 109, 112, 113, 237, 254 modified 49 nitro 102 nitroalkyl 102 piperidinyl 215 ring 240 sugar-derived 133, 240, 255, 261 aldehyde 240 cuprate 255 nucleophiles 133 polyol 261 suicide substrates 12 sulfate 149 sulfides 148 sulfone 240 sulfones 142, 145 reductions of 133 sulfoxide 148, 247, 248 sweet almonds 11 Swern oxidation 224, 238, 248, 261, 262,264, 267, 270

289

T table sugar 250 Tebbe's reagent 127 tert-butyl-dimethylsilyltriflate 257 tert-butyllithium 148 tether 246, 266 dimethylsilyl 274 silicon 195 tethered radical 266 tethering 194 tetrahydropyran 234, 260 thiophenyl 183 tin 52, 68, 71,189 hydride 189 nucleophiles 71 tetrachloride 52 titanium tetrachloride 40 p-toluenesulfonic acid 225 tosylation 225, 269 Trachelospermum asiaticum 8, 9 trans-metallate 137, 138, 139 transglycosylase 22, 216 transition metal 121, 155, 164, 165, 168 transmetallation 171,255 trichloroacetimidates 31, 61, 79, 94 trichloroacetonitrile 62 trichothecene 67 triethyl orthoacetate 201 triflate 228 trifluoroacetoxy 75, 168 trimethylsilyl propargyl 193 triflate 262 cobalt tetracarbonyl 123 triphenyl 162, 251 arsine 162 phosphine 251 phosphorane 251 trisaccharide 192,253

290 C-trisaccharide 7, 245,269 trityl perchlorate 34, 57, 93 tubers 9 type I pili 16

U Ugi condensation 40 unsaturated carbonyl compounds 186 a,~-unsaturated ester 110

V Van der Waal 4 Van der Waal radii 4 Vibro cholerae sialidase 151 vineomycinone B2 methyl ester 166 vineomycins 90 vinyl ether 233 vinylmagnesiumbromide 232 vinylzinc 219 Vitamin B12 188, 189

W Wittig 16, 106-108, 110, 197-200, 204, 212, 215, 244, 248, 261, 264

Index

reaction 16, 106, 107, 108, 110, 212, 215, 244, 248, 261,264 reagents 107, 108 rearrangement 197, 198, 199, 200, 204 Wittig-type reactions 109

X xylopyranose 188 xylopyranosylbromide 187 xylose 188

Y ylide 110, 112,200 phosphorus 110, 112 sulfoxide 112 sulfur 112

Z zinc 165 zinc bromide 57 zirconicene dichloride-silver perchlorate complex 81

Authors' Biographies

Daniel E. Levy received his Bachelor of Science from the University of California at Berkeley where he pursued research programs under the direction of Professor Henry Rapoport. While pursuing his Ph.D. at the Massachusetts Institute of Technology, under the direction of Professor Satoru Masamune, Dr. Levy studied and compiled his thesis on the total synthesis of calyculin A. Since completing his Ph.D., Dr. Levy has been studying the chemistry surrounding C-glycosides at Glycomed, Inc.

Cho Tang received his Bachelor of Science from the Chinese University of Hong Kong after which, he pursued his Ph.D. at the University of Chicago under the direction of Professor William Wulff. In this capacity, Dr. Tang studied and compiled his thesis on the subject of chromium carbene complexes. After completing a postdoctoral a p p o i n t m e n t at Columbia University, u n d e r the direction of Professor Gilbert Stork, Dr. Tang became involved in drug design and drug discovery at Hoffman-La Roche. Upon moving to Glycomed, Inc., Dr. Tang became involved in numerous programs centering around the chemistry of C-glycosides. Dr. Tang is currently studying tyrosine kinase inhibitors at Sugen, Inc.

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