Alkaloids: Chemical and Biological Perspectives

Alkaloids: Chemical and Biological Perspectives

Related Titles of Interest Books CLARIDGE: High-Resolution NMR Techniques in Organic Chemistry GAWLEY & AUBE: Principles of Asymmetric Synthesis GRIBBLE & GILCHRIST: Progress in Heterocyclic Chemistry LEVY & TANG: The Chemistry of C-Glycosides PALYI: Advances in Biochirality RAHMAN: Studies in Natural Products Chemistry RAHMAN: Handbook of Natural Product Data ROMEO: Recent Advances in Phytochemistry SESSLER & WEGHORN: Expanded, Contracted and Isomeric Porphyrins WONG & WHITESIDES: Enzymes in Synthetic Organic Chemistry Major Reference Works BARTON, NAKANISHI, METH-COHN: Comprehensive Natural Products Chemisti BARTON & OLLIS: Comprehensive Organic Chemistry KATRITZKY & REES: Comprehensive Heterocyclic Chemistry I CD-Rom KATRITZKY. REES & SCRIVEN: Comprehensive Heterocyclic Chemistry II KATRITZKY, METH-COHN & REES: Comprehensive Organic Functional Group Transformations LEHN, ATWOOD, DAVIES. MACNICOL, VOGTLE: Comprehensive Supramolecular Chemistry SAINSBURY: Rodd's Chemistry of Carbon Compounds TROST & FLEMING: Comprehensive Organic Synthesis Journals BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS CARBOHYDRATE RESEARCH HETEROCYCLES (distributed by Elsevier) JOURNAL OF SUPRAMOLECULAR CHEMISTRY PHYTOCHEMISTRY TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS Full details of all Elsevier Science publications, and a free specimen copy of any Elsevier Science journal, are available on request from your nearest Elsevier Science office.

Alkaloids: Chemical and Biological Perspectives Volume Fifteen

Edited by

S. William Pelletier Institute for Natural Products Research and Department of Chemistry The University of Georgia, Athens

2001

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Dedicated to Tuticorin Raghavachari Govindachari (1915.) T. R. Govindachari's contributions have been largely in the field of alkaloid chemistry. He was bom on July 30, 1915 in Madras (Chennai) India and obtained his B.Sc. (1934), M.Sc. (1936) and Ph.D. (1946) degreesfix)mthe University of Madras. He carried out post-doctoral work (1949) at the University of Illinois. He was mainly responsible for the structure elucidation of tylophorine and its congeners, tiliacorine, ancistrocladine, atalaphilline, and many other alkaloids. He isolated venenatine, isovenenatine and the papaya alkaloids carpaine, pseudocarpaine and assigned their structures. Diuing his stay at Illinois, he was associated with Professor Roger Adams and contributed to the structures of many pyrrolizidine alkaloids such as riddelliine, seneciophylline, arid senecionine from Senecia species. He was Professor of chemistry and Principal at Presidency College, Madras (1952-1962) and was director of the CIBA research Centre, Bombay (1963-1975). After retirement he directed work at the Amrutanjan Research Institute and the SPIC Science Foundation. Dr. Govindachari has an indefatigable interest in the study of Natural Products and has elucidated the structures of many novel oxygen heterocyclics and terpenoids like polyalthic acid and azadirachtins from the neem kernel extracts.

B. S. Joshi

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vii

Preface Volume 15 of this series features four important reviews of research on alkaloids. Chapter I by B. S. Joshi, S. W. Pelletier and S. K. Srivastava is the first comprehensive review of the catbon-13 and proton NMR shift assignments and physical constants of diterpene alkaloids and their derivatives. In addition to the catalogue of spectral and physical data, the chapter includes a table of the occurrences of these alkaloids in various plant species, tables containing molecular formulas versus calculated high-resolution mass values, and calculated high-resolution mass values versus the molecular formulas of diterpenoid alkaloids, as well as seven tables summarizing the carbon-13 chemical shifts of various functional groups in diterpenoid alkaloids. Chapter 2 by J. Kim, Y.H. Choi and K.-P. Yoo is a fascinating review of the supercritical fluid extraction of alkaloids. This technique using basic modifiers, provides an alternative method for the extraction of alkaloids. Chapter 3 by S. Prabhakar and M.R. Tavares summarizes recent advances in the synthesis of Amaryllidaceae alkaloids, an important class of naturally-occurring bases and neutral compounds. The increased activity in the synthesis of these alkaloids over the last decade is undoubtedly due to the fact that certain members of this family possess interesting and useful biological properties. Many elegant syntheses, chiral and otherwise, of structures incorporating many asymmetric centres are reviewed. Chapter 4 by J.J. Li reviews radical cyclization reactions in the total synthesis of indole alkaloids. The use of free radical chemistry in the synthesis of alkaloids has grown markedly because of the mild reaction conditions, tolerance of a wide variety of functional groups, and the good stereoselectivities. Each chapter in this volume has been reviewed by at least one specialist in the field. The editor thanks these reviewers for their important contributions to this volume. Indexes for both subjects and organisms are provided. S. William Pelletier Athens, Georgia May 28,2001

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ix

Contents ofPrevious Volumes Volume 1 1. The Nature and Definition of an Alkaloid S. William Pelletier 2. Arthropod Alkaloids: Distribution, Functions, and Chemistry Tappey H. Jones and Murray S. Blum

33

3. Biosynthesis and Metabolism of the Tobacco Alkaloids Edward Leete

85

4. The Toxicology and Pharmacology of Diterpenoid Alkaloids M H. Benn and John M. Jacyno 5. A Chemotaxonomic Investigation of the Plant Families of Apocynaceae, Loganiaceae, and Rubiaceae by Their Indole Alkaloid Content M Volkan Kisabiirek, Anthony J.M, Leeuwenberg, and Manfred Hesse

153

211

Volume 2 1. Some Uses of X-ray Diffraction in Alkaloid Chemistry Janet Finer-Moore, Edward Arnold, and Jon Clardy 2. The Imidazole Alkaloids RicharkK,Hill 3. Quinolizidine Alkaloids of the Leguminosae: Structural Types, Analyses, Chemotaxonomy, and Biological Properties A. Douglas Kinghom and Manuel F, Balandrin 4. Chemistry and Pharmacology of Maytansinoid Alkaloids Cecil R, Smith, Jr. and Richard G, Powell

49

105

149

X

Contents of Previous Volumes

5. ^^C and Proton NMR Shift Assignments and Physical Constants of Ci9-Diterpenoid Alkaloids S. William Pelletier, Naresh V. Mody, Balawant S. Joshi, and Lee C. Schramm

205

Volume 3 1. The Pyridine and Piperidine Alkaloids: Chemistry and Pharmacology Gahor B. Fodor and Brenda Colasanti 2. The Indolosesquiterpene Alkaloids of the Annonaceae Peter G. Waterman

I

91

3. Cyclopeptide Alkaloids Madeleine M, Joullie and Ruth F. Nutt

113

4. Cannabis Alkaloids Mahmoud A. ElSohly

169

5. Synthesis of Lycopodium Alkaloids Todd A. Blumenkopf and Clayton H. Heathcock

185

6. The Synthesis of Indolizidine and Quinolizidine Alkaloids of Tylophora, Cryptocarya, Ipomoea, Elaeocarptis, and Related Species R. B. Herbert 7. Recent Advances in the Total Synthesis of Pentacyclic Aspidosperma Alkaloids Larry E, Overman and Michael Sworin

Volume 4 1. Amphibian Alkaloids: Chemistry, Pharmacology and Biology John W. Daly and Thomas F. Spande

241

275

Contents of Previous Volumes 2. Marine Alkaloids and Related Compounds William Fenical 3. The Dimeric Alkaloids of the Rutaceae Derived by Diels-Alder Addition Peter G. Watermann 4. Teratology of Steroidal Alkaloids Richard F. Keeler

x\ 275

331

389

Volume 5 1. The Chemistry and Biochemistry of Simple Indolizidine and Related Polyhydroxy Alkaloids Alan D. Elhein andRussellJ. Molyneux 2. Structure and Synthesis of Phenanthroindiolizidine Alkaloids and Some Related Compounds Emery Gellert

55

3. The Aporphinoid Alkaloids of the Annonaceae Andre Cave, Michel Lehoeuf, Peter G. Waterman

133

4. The Thalictrum Alkaloids: Chemistry and Pharmacology Paul L Schiff. Jr.

271

5. Synthesis of Chephalotaxine Alkaloids Tomas Hudlicky, Lawrence D. Kwart, and Josephine W. Reed

639

Volume 6 1. Chemistry, Biology and Therapeutics of the Mitomycins William A. Remers and Robert T. Dorr 2. Alkaloids of Tabernaemontana Species Teris A. van Seek and Marian A.J. T. van Gessel

75

xii

Contents of Previous Volumes

3. Advances in Alkaloid Total Synthesis via Iminium Ions, a-Aminocarbanions and a-Aminoradicals David J. Hart

4. The Biosynthesis of Protoberberine Alkaloids Christopher W, W. Beecher and William J. Kelleher

5. Quinoline, Acridone and Quinazoline Alkaloids: Chemistry, Biosynthesis and Biological Properties Michael F. Grundon

227

297

339

Volume 7 1. Homoerythrina and Related Alkaloids /. Ralph C. Bick and Sirichai Panichanum 2. Carbon-13 NMR Spectroscopy of Steroidal Alkaloids Pawan K, Agrawal Santosh K. Srivastava, and William Gqffield 3. Carbon-13 and Proton NMR Shift Assignments and Physical Constants of Norditerpenoid Alkaloids S. William Pelletier and Balawant S. Joshi

43

297

Volume 8 1. Curare Norman G. Bisset

2. Alkaloid Chemistry and Feeding Specificity of Insect Herbivores James A. Saunders, Nichole R. O'Neill, and John T. Romeo

151

3. Recent Advances in the Synthesis of Yohimbine Alkaloids Ellen W. Baxter and Patrick S. Mariano

197

4. The Loline Group of Pyrrolizidine Alkaloids Richard G, Powell and Richard J, Petroski

320

Contents of Previous Volumes

xiii

Volume 9 1. Taxol M £ . Wall and M. a Want 2. The Synthesis ofMacroline Related Sarpagine Alkaloids Linda K. Hamaker and James M, Cook

23

3. Erythrina Alkaloids Amrik Singh Chawla and Vijay K. Kapoor

85

4. Chemistry, Biology and Chemoecology of the Pyrrolizidine Alkaloids Thomas Hartmann andLudger Witte

155

5. AlkaloidsfromCell Cultures of Aspidosperma Quebracho-Bianco P. Obitz, J. Stdckigt, L A. Mendonza, N, Aimi andS.-i. Sakai

235

6. Fumonisins Richard G. Powell and Ronald D. Planner

247

Volume 10 1. AlkaloidsfromAustralian Flora /. R. C. Bick 2. Pyridine and Piperidine Alkaloids: An Update Marilyn J, Schneider

155

3. 3-Alkylpiperidine Alkaloids IsolatedfromMarine Sponges in the Order Haplosclerida Raymond J. Andersen, Rob W. M Van Soest and Fangming Kong

301

4. P-Carboline and Isoquinoline AlkaloidsfromMarine Organisms Billl Baker

357

Contents of Previous Volumes Volume 11 1.

The Tlialictnm Alkaloids: Chemistry and Pharmacology (1985 - 1995) Paul L Schiff. Jr.

1

2.

Taxine Gioxwtni Appendino

237

3.

The Alkaloids of South American Menispermaceae Maiy D. Menachen^

269

4.

The Chemistry and Biological Activity of Calystegines and Related A'brtropane Alkaloids Russell J. MolyneiLX, Robert J. Nash, and Naoki Asano

303

5.

Polyhydroxylated Alkaloids that Inhibit Glycosidases Robert J. Nash, Naoki Asano, and Alison A. Watson

345

Volume 12 1.

Acronycine-type Alkaloids: Chemistry and Biology Frangois Tillequin, Sylvie Michel, and Alexios-Leandros Skaltsounis

1

2.

Solanum Steroid Alkaloids — an Update Helmut Ripperger

103

3.

Synthesis and Structure-Activity Studies of Lissoclinum Peptide Alkaloids Peter Wipf

187

4.

Pyroglutamate as a Chiral Template for the Synthesis of Alkaloids Michael B. Smith

229

5.

Analysis of Alkaloids by Capillary Electrophoresis and Capillary Electrophoresis — Electrospray Mass Spectrometry Joachim Stockigt, Matthias linger, Detlef Stockigt, and Detlev Belder

289

Contents of Previous Volumes 6.

Oxidation of Anthelmentic Marcofortine A, an Indole Alkaloid Byung H. Lee, Michael F. Clothier, and Gate I. Kornis

xv 343

Volume 13 1.

Alkaloids from Amphibian Skins John W. Daly, H. Martin Garraffo and Thomas F. Spande

1

2.

Naturally Occurring Cyclotryptophans and Cyclotryptamines Uffe Anthoni, Carsten Christophersen and Per Halfdan Nielson

163

3.

Recent Research on Pyrrole Alkaloids Philip W, LeQiiesne, Ying Dong and Todd A. Blythe

237

4.

Recent Developments in the Chemistry of Norditeipenoid and Diterpenoid Alkaloids Balawant S. Joshi and S. William Pelletier

289

5.

New Approaches to the Syntheses of Piperidine, Izidine, and Quinazoline Alkaloids by Means of Transition Metal Catalyzed Carbonylations Iwao Ojima and Donna M. Ma

371

Volume 14 1.

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Paul L Schiff, Jn

2.

Alkaloids from Malaysian Flora

285

3.

Applications of Palladium Chemistry to the Total Synthesis of Naturally Occurring Indole Alkaloids Jie Jack Li

437

TohSeokKam

1

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xvii

Contributors Young Hae Choi, College of Phannacy, Seoul National University, Seoul 151-742, KOREA. Balawant S. Joshi, Institute for Natural Products Research, University of Georgia, Athens, GA 30602, U.S.A. Jinwoong Kim, College of Pharmacy, Seoul National University, Seoul 151-742, KOREA. Jie Jack Lie, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI 48105, U.S.A. S. William Pelletier, Institute for Natural Products Research and The Department of Chemistry, University of Georgia, Athens, GA 30602, U.S.A. Sundaresan Prabhakar, Department of Chemistry, Faculty of Science and Technology, New University of Lisbon, 2825-114 Monte de Caparica, PORTUGAL. Santosh K. Srivastava, Central Institute of Medicinal and Aromatic Plants, Council of Scientific & Industrial Research, PO CIMAP, Lucknow-226015, INDIA. M. Regina Tavares, Department of Technology of Chemical Industries, INETI, 1649-038 Lisbon, PORTUGAL. Ki-Pung Yoo, Department of Chemical Engineering, Sogang University, Seoul 121-742, KOREA.

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xix

Contents 1.

2. 3.

4.

Carbon-13 and Proton NMR Shift Assignments and Physical Constants of Diterpenoid Alkaloids Balawant S. Joshi, S. William Pelletier, and Santosh K, Srivastava

1

Supercritical Fluid Extraction of Alkaloids Jinwoong Kim, Young Hae Choi, and Ki-Pung Yoo

415

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids Sundaresan Prabhakar and M. Regina Tavares

433

Applications of Radical Cyclization Reactions in Total Syntheses of Naturally Occurring Indole Alkaloids Jie Jack Li

573

Subject Index

623

Organism Index

633

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Chapter One

Carbon-13 and Proton NMR Shift Assignments and Pliysical Constants of Diterpenoid Alkaloids Balawant S. Joshi and S. Wtlliam Pelletier Institute for Natural Products Research and the Department of Chemistry The University of Georgia Athens, Georgia 30602-2556 U.S.A. Santosh K. Srivastava Central Institute ofMedicinal and Aromatic Plants Council ofScientific & Industrial Research PO'CIMAP, Lucknow'226015 India

CONTENTS 1. 2. 3. 4.

Introduction '^C-Chemical Shifts of Various Functional Groups of C2o-Diterpenoid Alkaloids Index of Naturally Occurring Diterpenoid Alkaloids and their Derivatives Calculated High Resolution Mass Values and Molecular Formulas of Diterpenoid Alkaloids 5. Occurrence ofDiterpenoid Alkaloids in Plant Species 6. Catalogue of Spectral Data and Physical Constants of Naturally Occurring Diterpenoid Alkaloids and their Derivatives

2 5 13 22 37 48

2

1.

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

Introduction

Diterpenoid alkaloids have been isolated from the genera of the families Ranunculaceae (Aconitum, Comolida, Delphinium^ Thalictrum), Garryaceae (Garraya), Rosaceae (Spiraea), and Compositae (Inula). These alkaloids can be divided into two broad categories: norditerpenoid alkaloids (based on a Ci9-skeleton) and the diterpenoid alkaloids (based on a C2o-skeleton)J The chemistry of the diterpenoid alkaloids has been reviewed in earlier literature. ^*^*^*^ Structural elucidation of norditerpenoid alkaloids is mostly straightforward since almost all the alkaloids fall in one major skeleton-type and have well defmed substitution and configurational pattern. In addition ^^C NMR data for norditerpenoid alkaloids is readily available to compare chemical shift data of alkaloids having closely related structures.^'^ Structure determination of the diterpenoid alkaloids (C20) has been a challenging task because of the diverse skeleta of these alkaloids. During the period (-1962-1972), many of the structures were determined by X-ray crystal structure determination. The development of high resolution NMR and Mass spectral instruments has facilitated the structure elucidation and determination of the stereochemistry of the diterpenoid alkaloids. The structures of more than 240 naturally occurring diterpenoid alkaloids have been determined in the past twenty five years making use of '^C NMR studies. The diterpenoid alkaloids are derived from tetra- or pentacyclic diterpenes in which C(19) and C(20) are linked with the nitrogen of |3-aminoethanol, methyl or ethylamine to form a heterocyclic ring. These alkaloids can be divided in two broad types namely, atisanes and the kauranes. The atisane skeleton contains the [2,2,2]-bicyclic ring system with the C(15)-C(16) bridge attached at C(12). This ring system incorporates an ent-aiisane skeleton, but does not obey the isoprene rule. The atisane group has been subdivided into four subtypes Al, A2, A3, and A4 as shown in Figure 1. The kaurane skeleton possesses a [3,2,l]-bicyclic ring system with C(15)- C(16) bridge connected to C(13), forming thefive-memberring D. These alkaloids are modeled on an e/7/-kaurane nucleus and obey the isoprene rule. The kaurane-type alkaloids have been divided into three subtypes Bl, B2, and B3. In contrast to the norditerpenoid alkaloids, the diterpenoid alkaloids are less oxygenated compounds. The diterpenoid alkaloids are found to be oxygenated at the C(l), C(2), C(3), C(6), C(7), C(9), C(ll), C(13), C(14), C(15), C(17), or C(19) positions. A large majority of alkaloids are oxygenated on three or four of the carbon atoms. Some unusual diterpenoid alkaloids. Acofine is the only example of the B3type having a chlorine atom at C(l) and cardionine is the sole alkaloid with a hydroxy 1 group attached at C(12). Methoxyl groups are commonly substituted on many of the carbon atoms in norditerpenoid alkaloids. Among the diterpenoid alkaloids, only two alkaloids of the B3-type, lingshanine and lingshanone, have a methoxyl group at C(l). Septatisine and septedine are the only examples of atisane-type (Al) diterpenoid alkaloids in which C(20) of the oxazolidine ring is bridged with C(14). In barbeline, barbisine, delgrandine, vakognavine and 15- deacetylvakognavine, all belonging to the A2type, the N-C(19) bond is broken and carbon-19 bears an aldehydic group.

Carbon-13 and Proton NMR Shift Assignments 13

i>3 i^'u

21--

A1

13

M

1 2 ( ^ 21-

-f-N 3U / ^

19

v

20

|10H

Is

.H

17

17 11

lie

]16

1

Jl5

|8

21-

^ 7

(J

a ^

it >

19

Me

J15

Is ^yi

^H

6

Me

18

18

A4

A3

Figure 1 The naturally occurring diterpenoid alkaloid miyaconitinone (Al-type) contains a diketone at the C(6), C(7) positions and caidionidine (Al-type) possesses an anhydride group in the B-ring between C(6), C(7). In albovionitme (Al-type), the C(18) methyl

4

BS. JoshU S.W. Pelletier and S.K. Srivastava

group is oxidized to a hydoxymethyl and the N-C(20) bond is cleaved, with the formation of a ketone at C(20). In delnudine, (A2-type) the C(12)-C(16) bond is broken and a new bond is established between C(l 1) and C(16). Eight dimeric diteipenoid alkaloids, all constituting an Al-type dimerized to an A3-type have been isolated from the mother liquors of Delphinium staphisagria L. All of these alkaloids are dimerized at C(17), C(17') and form a pyran ring at the C(16), (C15') position. These alkaloids are staphidine, staphigine, staphimine, staphinine, staphirine, staphisagnine, staphisagrine and staphisine. Coryphidine and coryphine are alkaloids of the A3 and Al-type, in which the C(17) carbon is attached to hexahydro-7Vmethylindoline. In tangirine, an Al-type diterpenoid alkaloid, C(17) carbon is attached at the C(8) position to the naturally occurring norditerpenoid alkaloid 6-benzoyl heteratisine. Zeraconine and zeraconine-iV-oxide are A2 type alkaloids in which the C (17) carbon is linked to the phenolic oxygen of/7-(Ar,Af-dimethylaminoethyl) phenol to form an ether. In pukeensine, the C(17) carbon atom of one of the A4 -type diterpenoid alkaloid forms an ether linkage with the ethanolamino group of a second diterpenoid alkaloid of the A4-type. The present catalogue provides proton and/or carbon-13 NMR chemical shift assignments and physical constants for many of the naturally occurring diterpenoid alkaloids and their derivatives. The literature search is not intended to be exhaustive. It is hoped that the '^C NMR data bank will serve as a useful guide for determining the structures of newly isolated alkaloids.

References: 1. TK Devon and AI Scott, "Handbook of Naturally Occurring Compounds" Vol. 2, pp. 188,241-248, Academic Press, N.Y. 1972. 2. SW Pelletier and LH Kieth, in "The Alkaloids" (RHF Manske ed.), vol. 12, Chapter 2, pp. 136-202, Academic Press, N. Y. 1970. 3. SW Pelletier and NV Mody, in "The Alkaloids" (RGH Rodrigo, ed.). Vol. 18, Chapter, 2, pp. 99-211, Academic Press, N. Y. 1981. 4. MS Yunusov, Diterpenoid Alkaloids in '*Natural Product Reports", Vol. 3, p. 451 1986; Vol. 8, p. 499,1992, The British Chemical Society, London. 5. BS Joshi and SW Pelletier, Recent Developments in the Chemistry of Norditerpenoid and Diterpenoid Alkaloids in "Alkaloids: Chemical and Biological Perspectives", (SW Pelletier, ed.). Vol 13, Chapter 4, pp. 292-2362, Pcrgamon Press, Amsterdam, 1999. 6. SW Pelletier, NV Mody, BS Joshi and LC Schramm, in "Alkaloids: Chemical and Biological Perspectives", (SW Pelletier, ed.),.Vol. 2, Chapter 5, pp. 205-462, John Wiley and Sons, N.Y. 1984. 7. SW Pelletier and BS Joshi, in "Alkaloids: Chemical and Biological Perspectives", (SW Pelletier, ed.),.vol. 7, Chapter 3, pp. 297-564, Springer Verlag, N. Y. 1991.

Carbon-13 and Proton NMR Shift Assignments

5

2. '^C-Chemical Shifts of Varioiis Functional Groups of Cio-Diterpenoid Allcaloids Table 1 TypeAl Vi2

17.

zr 21---I"

19

Functional Group C(l)-H2 C(l)-H2 If

ft

C(2)-H2 C (2)-0R C(3)-H2 tf

C (3)-OR C(4) rt

C(5)-H C (6)-ketone C(7)-H2 tf

C(8) C (9)-H C(9)-OH C(10) ft

C(ll)-H2 If

C(12)-H ft

C (13)-H2 ft

C(13)-ketone C (14).H ft

C(15)-H2 ft ft

C(16)

M«

Chemical Shift Range ppm 30-32 34-36 37-40 41-48 18-21 67-69 30-33 44-45 76-78 35-37 37-42 55-62 200-212 50-52 48-52 42-44 48-51 78-80 43-45 47-49 22-24 36-38 53-54 38-40 28-29 35-36 210-212 43-45 58-59 28-29 34-35 41-43 141-143

Remarks General range C(2)-OR,C(3)-OR C(2)-OH/C(3)-OH A^.CH2-CH2-0-C(19) General range C{3)-0R General range C(2)-0R General range General range C(3)-0R C (6)-ketone No subst. on C (7), C (9) C (6)-ketone; no subst. on C(9) C (6)-ketone; C (9)-0H C (6)-ketone Nosubst.onC(ll),C(15) General range Nosubst.onC(l),C(9), C(ll) C{9)-0H C(13)-ketone C(9)-OH;noC(13)-ketone C(13)-ketone No C (13)-ketone C(16)-0H General range General range NoC(13)-ketone C(13)-ketone C {9)-0H General range C (9)-0H, C (16)-0H C(13)-ketone

B.S. Joshi, S.W. Pelletier and S.K. Srivastava Functional QrQup tf

C(17)-H2 II

C(18)-H3 C(19)-H2 II

C (20)-H

Chgmiwl ghjft l^ngg ppm

Remarks

151-152 102-103 110-112 24-29 53-60 93-98 71-72

NoC(13)-ketone NoC(13)-ketone C(13)-ketone General range General range C (19)-0-CH2CHr General range

Table 2 TypeA2 13

^^ ^U

Functional Group

Chemical Shift Range ppm

Rem^rkg

C(l)-H2 C(l)-H2

33-35 30-36 44-46 68-79 19-21 26-28 68-71 75-76 210-211 33-35 37-41 50-51 71-72 36-38 42-44 60-62 50-55 63-65 98-100 32-37 27-30 43-45 44-46 49-50 53-55 65-66

General range C (2)-OH, -OCOR C (2)-ketone General range General range C(1)-0H General range C (3)-0H General range General range C (2)-a-0H, -OCOR C (2)-ketone General range General range C (2)-ketone General range C(9).p-0H General range General range General range C(9)-P-0H,C(15)-P-0H General range C(15)-0H Nosubst.onC(ll),C(15) C(11)-0H C(ll)-ketone

It

C(1)-P-0R C(2)-H2 C(2)-H2 C (2)-a-0R II

C (2)-ketone C(3)-H2 C (3)-0H C(4) II

C (5)-H II

C (6)-H C (6)-0H C(7)-H2 II

C(8) C (9)-H

Carbon-13 and Proton NMR Shift Assignments Functional Group

Chemical Shift Range ppm

Remark?

C (9)-P-0H C (lO)-H C(ll)-H2

79-81 50-55 22-23 37-40 210-212 72-76 33-36 52-53 27-33 68-72 75-80 67-68 211-213 42-45 51-52 61-62 78-80 27-30 72-76 142-147 154-156 107-110 28-30 25-27 60-64 58-60 90-92 68-75

General range General range General range C (9)-p.0H General range General range General range C(ll)orC(13)-OHorketone General range General range C(11)-0H C(13)-ketone General range General range C(13)-OH C(13)-ketone General range General range General range General range C(15)-p-OH General range General range C (3)-a-0H General range C (3)-a-0R General range General range

n

C(ll)-ketone C(11)-0H C (12)-H C(13)-H2 C(13)-0H C(13)-0H C(13)-0H C(13)-ketone C (14)-H C(14)-p-0H C(15>H2 C(15)-p-0H C(16) It

C(17)-H2 C(18)-H3 11

C(19)-H2 It

C(19)-OH C (20)-H Table 3 Type A3

rvi2 ^

/

»

^

JN^^ '^*-L F^

^.

'

/ ^

19

Functional Group

^ Chemical Shift Ranee ppm

Remarks

C(l)-H2 C(l)-H2 C(2)-H2 C(2)-H2 C(3)-H2 C(4) C (5)-H

40-43 35-37 22-24 19-20 39-41 33-34 48-52

General range N=C (20) General range N = C(20) General range General range General range

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

Fwgtipn»l Qrow

Chgmjggl Shif it Rangg ppm

Remarks

C(6)-H2

17-18 35-37 20-25 31-36 72-77 212-216 36-38 44-48 51-53 39-42 37-38 40-41 28-29 35-37 26-28 25-26 215-220 72-77 202-204 152-158 109-110 26-27 56-60 97-99 52-54 93-94 164-166

General range C (7)-ketone C(7)-0H General range General range General range C(14)orC(15)-P-OH C(15)-ketone C(7)-ketone,C(15)-p.OH General range General range C(20)-O.CH2CH2General range General range General range General range General range General range General range General range General range General range General range General range General range General range -N=CH(20)

H It

C(7)-H2 C (7)-a-0H C (7)-kctone C(8) If II

C (9)-H C{10) II

C(ll)-Hz C (12)-H C(13)-H2 C(14)-H2 C (14)-ketone C(15)-0H,0Ac C(15)-ketone C(16) C(17)-H2 C(18)-H3 C(19)-H2 C (19)-OCH2 C (20)-H2 C (20)-OCH2 C (20)-H2 Table 4 Type A4

1

Tio *% Te 1 ^1

/ ^ ^JH 6

ia

1^®

Functional Group

Chemical Shift Range ppm

Rem^k?

C(l)-H2 C (l)-a-OH C(2)-H2

40-41 70-72 21-23 30-32 69-70 27-30 68-69

General range General range General range C (l)-OH present General range General range General range

II

C (2)-a-0H C(3)-H2 C(3)-a-0H

Carbon-13 and Proton NMR Shift Assignments Functional Group ft

C(4) C (5)-H H

C(6)-H2 II

C(7)-H C(7>O-C(20) C(8) C(9) II

C(10) II

C(ll)-H2 II

C (12)-H II

C (13)-H2 C (13)-0R C(14)-H2 C(15)-H2 C(15)-0R C(16) C(16)-0H C(17) C(17) C(17) C(18)-H3 C(19)-H2 C(19)-H2 C (19)-OR C (20)-H C(20)-H C (20)-H C (21)-H3 C (21)-CH2CH2-0

Chemical Shift Rangeppm

Rfemarks

36-38 34-36 50-52 41-45 23-26 70-72 41-44 72-76 41-44 43-46 50-54 34-35 48-51 23-25 72-73 42-46 30-36 22-25 70-72 22-28 20-22 77-86 150-156 79-81 109-112 68-72 45-46 25-27 57-59 52-54 93-95 67-69 86-88 68-70 42-45 52-58

C (20)-O-C (7) present General range C(l)-a-OH present General range General range C(7)-p-0R present General range General range General range General range C(1)-0H present General range C(1)-0H present General range C (7)-0H p present General range C (7)-0-C (20) present General range General range General range General range General range General range CH20HatC(17) General range CH20HatC(17) Epoxide on C(16)-C (17) General range General range C (20)-O-(7) present General range General range C (20)-O-C (7) present C(1)-0H present General range General range

Table 5 Type Bl 12

Sj3

1

>S. i^rC^ C

20

17

' KS:s»CH2

2 / S < X ^ ^^Pj^ IS

18

10

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

Functional Group

Chemical Shift Range ppm

41-42 46-47 82-84 C(l)-OH C(2Hl2 22-23 71-72 C (2).a-0H M 76-77 36-37 C(3)-H2 " 42-43 36-37 C(4) M 40-41 45-46 C (5)-H 78-79 C (5)-P-0H 24-25 C(6)-H2 66-68 C (6)-a-0M 34-35 C(7).U2 It 39-40 52-53 C{S) 56-59 C (9)-H 51-52 C(10) C(ll)-a-OH,-OCOR 71-73 70-76 C(12)-a-0C0R 54-55 C(13)-H 52-54 C(14)-H 36-37 C(I5)-H2 148-150 C(16) 107-108 C(17).H2 23-25 C(18)-H3 61-62 C(19)-H2 168-169 C(19)=N63-65 C (20)-H

Remarks General range C(2)-a-0H General range General range General range C(l)-a-OH General range C (2)-a.0H C(5)-P-0H C(19) = NGcneral range General range General range C (5)-p-0H General range C(6)-a-0H General range C(11)--0H,0C0R General range General range C(ll)-a-OH,-a-COR General range General range General range General range General range General range General range General range General range

C(I)-H2 •1

Table 6 Type B2

12 1

20

^ S ^ .7

<\ssCH,

Functional Group

Chemical Shift Range ppm

RgmarHs

C(l)-H2

40-43

C(2)-H2 C(3)-H2 C(4)

18-20 38-41 33-35

General range. Normal: NCH2CH2-O-C (20); lso:NCH2CH2-0-C(19) General range General range General range

Carbon-13 and Proton NMR Shift Assignments

11

40-41 50-51 52-54 18-19 32-37 45-47 52-54 43-45 47-49 49-52 36-37 40-42 22-24 32-34 38-41 34-38 82-84 224-226 155-160 48-49 104-106 107-109 10-12 16-17 24-27 60-61 56-57 98-99 56-57 92-94 48-51

General range, Iso Iso Normal General range General range C(15)-0H C(15)-ketone C(15)-p-0H,p-0Ac C(15)-ketone C(15)-a-OH,a-OAc Iso Normal General range General range General range General range General range General range C(15).0H General range C(15)-P-0H,-0R C(15)-a-OH,-OR P-(CH3) a-(CH3) General range N-CH2CH2OH Normal Iso N-CH2CH2OH Normal Iso

Functional Group

Chemical Shift Range ppm

Esma^LS

C(1).0H C(l)-OAc C(l)-0... C(2)-H2

70-71 74-75 67-68 30-32

General range General range General range C(1)-0H,C(1)—O—C(19)

C(4) C(5)-H II

C(6)-H2 C(7)-H2 C(8) II

C (9)-H tl II

C(10) II

CdD-Hi C(12)-H2 C(13)-H C(14)-H2 C(15)-OH,OR C(15)-ketone C(16) C(16)-H C(17)-H2 II

C(17)-H3 II

C(18)-H3 C(19)-H2 II

C(19).H C (20)-H2 C (20).H II

Table 7 Type B3

12

B.S. Joshi, S.W. Pelletier and S.K. Srivastava It

C(3)-H2 tl

C(4) C(5)-H II

C(6)-H2 C (6)-0H C (7)-H C(8) C (9)-H II

C(10) C(ll)-H2 II

C(12)-H2 C(12)-0H C(12)-ketone C(13).H C(13)-H II

C(14)-H2 •t

C(15)-0H,-0Ac C(16) II

II

C(17)-H2 C(18)-H3 II

C(19)-H2 C(19)-0C (20)-H II

27-28 30-32 24-25 34-35 37-38 48-50 34-35 23-24 70-72 44-45 49-50 37-38 45-46 50-54 28-29 37-38 20-22 75-76 209-210 43-45 48-50 53-54 36-38 48-49 77-78 160-162 150-153 150-151 107-111 26-27 19-20 57-58 88-93 65-66 57-58

C(l)-OAc C(l).OH,.OAc C(1).0—C(19) C(l)-OH,-OAc C(l).-.0-.C(19) General range C(l)~.0.-C(19) General range General range General range General range C(l)-H,-OAc C(l)-..0—C(19) General range C(12)-0H C(12)-ketone General range General range General range General range C(12)-OH C (12)-ketone C(15)-P-0R C(15)-a-OH General range C(15)-p-0H C(15)-aorP-OAc C (12)-ketone General range General range C(l)—O—C(19) General range General range General range; N-Et No N-Et

Carbon-13 and Proton NMR Shift Assignments 3.

INDEX OF NATURALLY OCCURING DITERt»ENOID ALKALOIDS AND THEIR DERIVATIVES

Diterpcnoid Alkaloid

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

13

Natural Occurrence (N) Derivative (D)

1 -O-Aceiylacofine 15-O-AcetyIatisine-M20-azomethinc 7-O-Acetylbarbaline 11-O-Acetylbarbisine 11-O-Acetylcardionine 15-0>Acetylcardiopetamine 3-O-Acetylcardiopine 3-O-Acetylcardiopinine 13-0-Acetyl-15-dchydrocardiopetainine 15-0-Acetyl-13-dehydrocardiopetaminc 11 -0-Acetyl-1,19-dehydrodenudatine 3-O-Acelyl-2,20-dehydro-16,17-dihydro(14,20-5cco)hetidine 2-0-Acetyl-l 3-dehydro-11 -e/i/-hetisine 12-0-Acetyl-1,19-dehydrolucidusculine 12-e/;i-0-Acety 1-1,19-dehydronapelline 7-0-Acetyldelgrandine 13-0-Acetyl-9-deoxyglanduline 14-O-Acety 1-9-deoxyglanduline 1 l-0-Acetyl-2J 3-didehydrohetisine 13-O-Accty 1-2,11-didehydrohetisine 13-O-Acetylfissumine 13-0-Acetylglanduline 13-O-Acetylgoinandonine 2-0-Acetylhetisine 13-O-Acetylhetisine 13-0-Acetylhetisine-2-one 2-Acctyl-3-hexahydrobenzoyl-16,17dihydrohetidine 15-0-Acetyl-9-hydroxynominine 11-O-Acetylisohypognavine 11 -0-Acctyl!epenine 1 -O-Acetylluciculine 12-0-Acety llucidusculine 12-0-Acety Inapelline 12-O-Acetylnapelline-N-oxide 15-0-Acetylryosenamine

Structure Type

X-Ra)f

D D D D N N D D D N N D

B3 A3 A2 A2 A2 A2 A2 A2 A2 A2 B3 A3

__ -

D N N N N N D D D N N D N/D N/D D D N N N N N N D

'H

"c

~ ~ —

X X X X X X X X X X

_, X X X X X X X X X X X

A2 A4 B3 A2 A2 A2 A2 A2 A2 A2 A4 A2 A2 A2 Al

— — — — X .. ~

X X X X X X X X X X X X X X X

— X X X X X X X X X X X X X X

A2 A2 A4 83 83 83 83 A2

~ ~ ~ ~ -

X X X X X X X X

~ X X ~ — ~ ~

14 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76

B.S. Joshi, S.W. Pelletier and S.K. Srivastava 15-O-Acetylsczukinine 2-0-Acctylscplcnlriosine 15-O-Aceiylsongoraniine A^-Acelylspiradinc A 6-()-Acctylspiradine A Acofinc Acoridine Acorienlinc Acozcrinc Acsinatidine Acsinaline Ajaconinc Ajaconium chloride Albovionitinc Andersobine Andersobine-19-/7-Af,N-dimcthy laminobenzoate Anoptcrimine Anoplcriminc-//-oxidc Anoptcrinc (anopteryl-U,12-ditigtate) Anoplcry I-11 a-4'-hydroxybenzoalc-12atiglate Anoptcryl I2a-tiglate (I la-dcstigloyianopterine Apomiyaconine Atidine Atisine Atisinc-15-one Atisine-N,20-azomethine Atisinium chloride (Guan Fu Base G) Azitine Barbaline Barbisine 1 la-Benzoyl-7p-hydroxy-l la-destig loylanopterine(7p-Hydroxyanopteryil la-benzoate-l2a-tiglate) U-Benzoylkobusinc 15-Benzoylkobusine 6-Benzoylpseudokobusine 11 -Benzoylpseudokobusine 15-Bcnzoylpseudokobusine Brunonine Cardiodine Cardionidine Cardionine Cardiopetamine

D N D D D N N N N D N N D N N D

A2 A2 B3 Al A2 B3 A2 A2 Al A2 A2 A4 A3 Al A2 A2

-. -. X —

N N N N

— ~ — -. — — —

X X — X X X X X X — X X X X X

X X — ~ — X X X — X X X X X X

Bl Bl Bl Bl

~ ~ X —

X X X X

X X X ~

N

Bl

~

X

..

D N N D D N/D N N N N

Al A3 A3 A3 A3 A3 A3 A2 A2 Bl

X — — ~ X .X X

X X X X ~ ~ X X X X

X X X X X X X X X

D D D D N N N N N N

A2 A2 A2 A2 A2 A3 A2 Al A2 A2

« — X — X

X X X X X X X X X X

X X X X X

-

.

•

Carbon-13 and Proton NMR Shift Assignments 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114

Cardiopidine N Cardiopimine N Cardiopine N Cardiopinine N Chcllespontinc N Chiianfunine N Contorine (2-OAcctyl-3-anisoylhetidine) N Conlorsine (2-0-AcetyI-3-isobiUyr>'l N hetidinc) Contortinc (2-Acelyl-3(25)-mcthylbulyryl N hetidine) Coryphidine N Coryphine N Cossonidine N Cossoninc N Crassicaulinc B N Cuauchichicine N 16-c/;/-Cuauchichicine N Cuauchichicine-M20-azometliinc N 11,12,16-Cyclopropyl-16,17-dihydro D hetisane 2-Deacelylheterophynoidine N/D 15-DeacetylspiramineF D 15-Deacetylvakognavine N Ar-Deethyl-iV-acetyl-l,12,15-0-triacclyl D napelline N JV-Dcethyl-1,19-dchydrolucidusculine D 13 -Dehydrocardiopelamine D l5-Dehydrocardiopetaniine 2-Dehydrocardiopimine D 15-Dchydrocossonidine D D 3 -Dehydro-1 -desacetoxy-1,2-dehydro cardiopine D 3-Dehydro-1 -desacetoxy-1,2-dehydro cardiopinine D 2-Dehydro-l 1,13-O-diacetylhetisine D 13-Dehydro-2,11 -O-diacetylhetisine 2,20-Dehydro 16,17-dihydro-(14,20-5cco) D hetidine D 15,16-Dehydro-16,17-dihydrotatsirine ~ 11 -Dehydrohetisine N/D 1,19-Dchydrolucidusculine N 1 l-epi-1,19-dehydrolucidusculine N 12-C/7M ,19-dchydronapelline 1,19-Dehydronapelline (1,19-Dehydroluc N/D iculine)

15

A2 A2 A2 A2 Al B3 Al Al

.— .~ — — X X

X X X X X X X X

X X X X X X X X

Al

X

X

X

A3 Al A2 A2 A2 B2 B2 B2 A2

.. X ~ — «X .— X

X X X X X X X X X

X X X X — X X X ~

Al A4 A2 B3

_ ~ — -

X X X X

X X X X

B3 A2 A2 A2 A2 A2

.. — — — — -

X — X X X X

X X X ~ X X

A2

-

X

X

A2 A2 A3

.. — -

X X X

X X X

A2 A2 B3 B3 B3 B3

.. — —

X X X X X X

X X X — X X

~

~ ~

•

16 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158

B^. Joshi, S.W. Pelletier and S.K. Srivastava 13-Dehydropaniculatine 15-Dehydroryoscnamine Delatisine Dclbidine Delftssinol Delgrandine Delnudine Delnuttaline Delnuttidine Delnutline Dcnudatine 11'Desbenzoylcardiopetamine Ar-Desethylsongoraminc(norsongoraminc) 2-Desmethylbutyfylcardiopine N-Dcsmethyl'Nfi'SecO'S'hydroxycpiscop alidine-6-cathylate 1 la-Destigloylanopterinc (Anopteryl-l2a tiglate) 9,19-C7-Diacctylacsinatine 15-0,22-MDiaccty latidine 6,1 l-O-Diacetylcardionine (Basic) N,\ l-<9-Diacctylcardionine (Neutral) 13,15-O-Diacetylcardiopetamine 1,15-0-Diacetylcossonidine l,7-0-Diacetyicrassicauline B 11,15-0-Diacetyldenudatine 11,13-C7-Diacetyl-9-deoxyglanduIine 15-0,22-A^-Diacetyldihydroatisine 1,15-<9-Diacety I-16,17Hdihydrosongoriiie 15-0,22-/V-Diacetyldihydrovcatchine 6,13-O-Diacctylgcycrinc 2,11-0-Diacetylhetisinc 11,13-O-Diacetylhetisme 11,13-0-Diacctylhetisine-2-one 11,15-O-Diacctylisohypognavinc 1, 15-0-Diacety lluciculine 7,1 l-O-Diacctyloricntininc 2,15-0-Diacety Iryosenaminol 6,11-0-Diacetylvenulol 13,15-0-Diacetylvenuluson 11,15-0-Dibenzoylkobusine 6,11-0-Dibenzoylpseudokobusine 6,15-O-Dibenzoylpseudokobusine Dictyzinc (Dictysine) Dictysineacetonide 1,15-Didehydrocossonidine

D D N N N N N N N N N D N D D

A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A4 A2 83 A2 A2

-. X — — — X — ~ — X ~ —

X X X X X X X X X X .X X X X

X — X X X X .. X X X X X X X

N

Bl

—

X

—

N D D D D D D D N D D D D D D D N D D D D D D D D N N D

A2 A3 A2 Al A2 A2 A2 A4 A2 A3 B3 B2 A2 A2 A2 A2 A2 B3 A2 A2 A2 A2 A2 A2 A2 A4 A4 A2

X ~ ~ X -

X '" X X X X X X X X ~ X X X X X X X X X X X X X X X X

~ X X X X X X X X ~ X X X X X X X X X ~ X -. X

Carbon-ia and Proton NMR Shift Assignments 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198

2,11-Didehydrohetisine Dihydroajaconine Dihydroatisine N,20-Dihydroatisineazomethine Dihydrocuauchichicinc 16,17-Dihydro-15,16-dehydroepiscop alidine 16,17-DihdryO'2,20-dehydro (14.20 secoy hetidine 16,17-Dihydroepiscopalidinc Dihydrogarryfoline 16,17-Dihydrohetidine DihydFOOvatine Dihydrosongorine Dihydroveatchine M20-Dihydroveatchinc azomethine 4',7p-Dihydroxyanopterinc(7P-Hydroxy anopteryl-l 1 a-(£)-4'-hydroxy-2'-methyl but-2'-cnoate-12a-tiglate) Episcopalidine Finetianine Fissumine Flavidine Flavamine Garryfoline (Laurifoline) Garryfoline-M20-azomethine Ganyine Gcyeridinc Geyerine Geycrinine Glanduline Gomandonine Guan Fu Base A Guan Fu Base F Guan Fu Base G Guan Fu Base Y (Acorine) Guan Fu Base Z Hanamisine Heterophylloidine (Panicutine) Hetidine Hetisine Hetisine-2-one 7P-Hydroxyanopterine(7p-hydroxyanop teryl-lla,12a-ditiglate) 7P-Hydroxyanopteryl 11 a, 12a-ditiglate

17 D N/D N/D D D D

A2 A3 A3 A3 B2 Al

.X — —

— X — ~ ~ X

X X X X X X

D

A3

*-

X

X

D D D D N/D D D N

Al B2 Al B2 B3 B2 B2 Bl

~ — — —

X X X — X

X X X X X X X

N N N N N N D N N N N N N N N N N N N N N/D N N/D N

Al B3 A2 B3 B3 B2 B2 B2 A2 A2 A2 A2 A4 A2 A2 A2 A2 A2 A2 Al Al A2 A2 Bl

X — .. .. -. — — — — X X — X ~ — X X X X — —

X X X X X X X — X X X X X -. X X X X X X X X X X

X X X X X X X X X X X X X .— .. X X X X X X X X

N

Bl

-

X

X

IS 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239

B.S. Joshi, S.W. Pelletier and S.K. Srivastava 7P-Hydroxyanoptery I-11 a (4'-hydroxy) N benzoate-12a-tiglate 7P-Uydroxyanoptciyl 1 la-(E)-4'-Hydroxy N -2'-melhylbut-2'-cnoate 12a-liglate iV,6-l lydroxycpiscopalidinc-6-catliylatcD chloride A', 6-Hydroxyepiscopalidine chloride D 7a-Hydroxyisoatisine D 9-Hydroxynominine N Hypogiiaviiie N Hypognavinol D Ignavinc N Ignavinol (Anhydroigiiavinol) D N 3-«?p/-lgnavinol 6-0-Imidazoyllhiocarbonylpscudokobusinc D N Isoatisine D Isoatisinone N/D Isocuauchichicine D 16-£/7/-lsocuauchichicine N/D Isoganyfoline N Isohypognavine D Isopropylidine chuanfunine N Jynosine (15-0-Acetyl denudatine) N KirinineB N Kirinine C N Kobusine N Lassiocarpine N Lepedine N Lepenine N Liangshanine N Liangshanone N Lindheimerine N Luciculine (Napelline) N 12-e/ii-Lucidusculine N Lucidusculine (l5-0-AcetylnapeIIine) N Macrocentrine D A^-Methy l-A^,6-A'if co-6-dehy dropseudo kobusine D A^-Methyl-A^,20-dihydroalisineazometh ine D A^-Methyldihydroveatchineazomethine D A^-Methyl-6-oxospiradine A D 16-a-Methyltetrahydroatisine D 16-P-Methyltetrahydroatisine D 16-P-Meihyltetrahydrogarryfoline 16-a-Melhyltelrahydroveatchine D

Bl

-

X

-

Bl

-

X

X

A2

-

-

X

A2 A3 A2 A2 A2 A2 A2 A2 A2 A3 A3 B2 B2 B2 A2 B3 A3 A4 A4 A2 A4 A4 A4 B3 B3 B2 B3 B3 B3 A4 Al

— X X X X X — — — — ~ ~ — — — — — X ~ ~ ~ ~ ~ ~ — — X X ~

.. X ~ — X — X X X ~ — X X X X X X X X X X X X X X X X X X X

X X X X X X X X X X X X X X X X — X X X X — X X X X X — X X -

A3

-

~

X

B2 Al A3 A3 B2 B2

.. — X —

.. -, ~ — X

X X X X X X

€arbon-13 and Proton NMR Shift Assignments 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284

D 16-P-MclhyltelrahydroveatcIiine D Miyaconine N Miyaconiline N Miyaconitinone l-(?/?/-Napellinc N 12-t7?/-Napellinc N Napelline-A'-oxidc N 12-c/?/-Napellinc-A^-oxide N Nomininc (11-Dcoxykobusinc, Nomibase-l)N/D N Norsongoraniine N Norsongorine N Orientinine N Ovaline Palmadine N N Palmasine N Pantcudine N Paniculamine N Paniculatine N Pseudokobusine N Pukcensine N Ryosenamine N Ryosenaminol N Sadosine N Sanyonamine N Sczuktdine N Sczukinine N Sczukitine N Septatisine (Septedinine) N Septedine D Septenidine N Septenine N Septentriosine N Songoratnine Songorine (Napellonine, Shimoburo Base 1 N Bullatine G) Songorinc-A^oxide N Spiradine A N Spiradine B N N Spiradine C Spiradine D N N Spiradine F Spiradine G N N Spiramine A N Spiramine B N Spiramine C N Spiramine D

19 B2 Al Al AI B3 B3 B3 B3 A2 B3 B3 A2 B2 A2 A2 A2 A3 A2 A2 A4 A2 A2 A2 A2 Al Al Al Al Al A2 A2 A2 B3 B3

~ X ~ ~ ~ -_ ~ — ~ ~ — X .X — ~ X X X ~ — ~ ~ X — ~

X X X X X X X X X X ~ X X X X X X X X X X X X X X X X X X X X —

X X -, ~ X X ~ X X -. X X X X X ~ X X X X X X X X X X X ~ X X X X

B3 A2 A2 A2 Al A4 A4 A4 A4 A4 A4

~ X ~ ~ X -

X X .X " X X X X X

~ X ~ X X X X

20 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330

B.S. Joshi, S.W. Pelletier and S.K. Srivastava Spiramine E Spiramine F Spiramine G Spiramine H Spiramine I Spiramine J Spiramine K Spiramine L Spiramine M Spiramine P Spiramine Q Spiramine R Spirasine 1 Spirasine II Spirasine III Spirasine IV Spirasine V Spirasine VI Spirasine VII Spirasine VIII Spirasine IX Spirasine X Spirasine XI Spirasine XII Spirasine XIII Spirasine XIV Spirasine XV Spiredine Staphidine Staphigine Staphimine Staphinine Staphirine Staphisagnine Staphisagrine Staphisine Stenocarpine Subdesculine Tadzhaconine Talassamtne Talassimidine Talassimine Talatisine Tangirine Tangutisine Tatsirine

N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N

A4 A4 A3 A3 A3 A3 A3 A3 A3 A4 A4 A4 A2 Al Al A2 Al Al Al Al A2 A2 A2 A2 A2 A2 A2 A2 Al Al

A1/A3 A1/A3 A1/A3 A1/A3 A1/A3 A1/A3

A4 B3 A2 Al Al Al A2 Al A2 A2

^ — X — — -. — —'

— — — — — — — — — X — — .— — ~ — — — — — — -. — — — — X — — X — — X X — ~ —

X X X X — X X X X X X X X X X X — — — — X X X X X X X X X X X X X X X X X X X X X X — X X X

X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X — — X X X X ~ — — — X X —

Carboii-13 and Proton NMR Shift Assignments 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360

2,11,13,14-0-Tetraacety llangutisinc 2,11,13,19-O-Tetraacetyivakhmatine Tetrahydrouncinatine Thalicsessine Tlialicsiline Torokonine (Gomando Base I) 1,12,15-O-Triaccty luciculinc 2,1 l,l3-Tri-0-acelylhctisine 1,2,19-Trl-O-acety Iscplentriosiiie 2,3,13-0-Triacctylvakhmadine 2,11,13-O-Triacelylvakhmatinc TurpelHnc Uncinatinc Vakhmadinc Vakhmatine Vakognavine Veatchine Veatchine-M20-azomethinc Venudclphine Venulol Venuluson 15-Veratroylpseudokobusine Vilmorrianone Ycsodinc Yesoline Yesonine Yesoxine Zeraconine 2^raconinc-^-oxide Zeravshanisine

21 D D D N N N D D D N D N N N N N N D N N N N N N N N N N N N

A2 A2 A3 Al A4 A2 B3 A2 A2 Al A2 03 A3 A2 A2 A2 02 02 A2 A2 A2 A2 Al A2 Al Al A4 A2 A2 A2

~ ~ X X ~ ~ ~ — — — X X — .~ ~ ,. X « — — X — ~ X

X X X X X X X X X X X X X X X X X ~ X X X X X X X X X X X X

— X X X X X X X X X X X X X X X X X X X X X X X X X X — —

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

22

4.

Calculated High-Resolution Mass Values and Molecular Formulas of Diterpenoid Alkaloids

MW

295.1936 Spirasine IV Spirasine IX

C20H25NO

MW

297.2093 11,12,16-Cyclopropyl-16,17-dihydrohetisanc Nominine (11-Deoxykobusine, Nomibase-l) Spirasine XI

C20H27NO

MW

299.2249 Atisine-iV,20-azomethine Azitine Cuauchichicine-A^,20-azomethine Garryfolinc-M20-azomethine Veatchine-'iV,20-azomethine

C20H29NO

MW

301.2406 M20-Dihydroatisineazomethine M20-Dihydroveatchineazomethine

C20H31NO

MW

309.1729 1,15-Didehydrocossonidine

C20H23NO2

MW

311.1885 15-Dehydrocossonidine Spiradine A Spirasine X

C20H25NO2

MW

313.2042 Cossonidine 9-Hydroxynominine Kobusine Sanyonamine Spiradine B Spirasine XIV Spirasine XV Talassamine Venulol

C20H27NO2

MW

315.2198 15-0-Acetyl-9-hydroxynominine

C20H29NO2

MW

315.2562 /V-Methyl-/V,20-dihydroatisineazon[iethine A/-Methyldihydroveatchineazomethine

CziHjjNO

Carbon-13 and Proton NMR Shift Assignments

23

MW

325.1678 2,11 -Didehydrohetisine

C20H23NO3

MW

325.2042 N-Methyl-6-oxospiradine A

C21H27NO2

MW

327.1834 Il-Dehydrohetisine Delatisine Delnudine Delnuttidine yV-Desethylsongoramine(Norsongoramine) Hetisine-2-one Norsongoramine Panicudine Spirasine XII Spirasine XIII Venuluson

C20H25NO3

MW

327.2562 Denudatine

C22H33NO

MW

329.1991 Acorientine Acsinatidine 15,16-E)ehydro-16,17-dihydrotatsirine Delfissinol Hetisine (Delatine) Norsongorine Pseudokobusine Ryosenaminol Talatisine Tatsirine

C20H27NO3

MW

333.3032 16-a-Methy Itetrahydroveatchine

C22H39NO

MW

339.2198 Spiradine D

C22H29NO2

MW

341.1991 2-I>eactylheterophylloidine

C21H27NO3

MW

341.2355 15-0-Acety latisine-iV,20-azoniethine Atisine-15-one Lindheitnerine

C22H31NO2

24

BS. Joshi, S.W. Pelletier and S.K. Srivastava

MW

343.1784 Apomiyaconine Delbidine 11-Desbenzoylcardiopetamine

C20H25NO4

MW

343.2147 Finetianine N-Methyl-M6-5ec<7-6-dehydropseudokobusine Yesonine

C21H29NO3

MW

343.2511 Atisine Chellespontine Cuauchichicine 16-£rp/-Cuauchichicine Garryfoline (Laurifoline) Garryine Isoatisine Isoatisinone Isocuauchichicine 16-^p/-Isocuauchichicine Isogarryfoline Laurifoline Veatchine

C22H33NO2

MW

345.1940 Hypognavinol Ignavinol (Anhydroignavinol) 3-^pi-Ignavinol Septenidine Septentriosine Tangutisine Vakhmatine

C20H27NO4

MW

345.2304 Stenocarpine

C21H31NO3

MW

347.2460 Dictyzine (Dictysine)

C21H33NO3

MW

347.2824 16a-Methy Itetrahydroatisine 16P-Methy Itetrahydroatisine 16a-Methy Itetrahydrogarryfoline 16P-Methy Itetrahydroveatchine

C22H37NO2

MW

353.1991 6-O-AcetyIspiradine A N-Acetylspiradine A Spiredine

C22H27NO3

Carbon-13 and Proton NMR Shift Assignments

25

MW

354.2668 Dihydroatisine Dihydrocuauchichicine Dihydrogarryfoline Dihydroveatchine

C22H35NO2

MW

355.2147 Songoramine Spiradine C Spirasine I Spirasine II Talassimidine Talassimine

C22H29NO3

MW

357.1576 Orientinine

C20H23NO5

MW

357.1940 Hetidine Sczukidine

C2,H27N04

MW

357.2304 1,19-Dehydronapelline (1,19-Dehydroluciculine) 1 l-epi-1,19-Dehydronapelline Kirinine B Septatisine (Septedinine) Septedine Songorine (Bullatine-G, Shimoburo Base 1, Napellonine) Spiradine G Spiramine C Spiramine D Spiramine G Spiramine H Spirasine V Spirasine VI

C22H31NO3

MW

359.2097 2,20-Dehydro-16,17-dihy dro-( 14,20-5^co)hetidine 16,17-Dihdro-2,20-dehydro (14,20 seco)httidine 16,17-Dihydrohetidine

C21H29NO4

MW

359,2460 Ajaconine Atidine Brunonine 15-E)eacety Ispiramine Dihydrosongorine 7P-Hydroxyisoatisine Lepenine

C22H33NO3

26

B.S. Joshi, S.W. Pelletier and S.K. Srivastava Luciculine (Napelline) l-^p/-Napelline 12-e/7i-Nape1linc Uncinatine

MW

360.2175 Vakhmadine

MW

361.2253 Gomandonine

C2.H3,N04

MW

361.2617 Dihydroajaconine

C22H3JN03

MW

363.2773 Tetrahydrouncinatine

C22H37N03

MW

365.1627 Turpelline

C22H23N04

MW

367.1784 1 l-O-Acetyl-2,13-didehydrohetisine 13-G-Acetyl-2,11-didehydrohetisinc

C22H25N04

MW

369.1940 2-Acetyl-13-dehydro-11 -cpi-helisinc 13-0-Acety lhetisine-2-one Fissumine Spirasine III Thalicsessine

C22H27N04

MW

371.1733 Cardionidine Miyaconine

C2,H25NOj

MW

371.2097 2-0-Acetylhetisine 13-0-Acetyhetisine Acsinatine Andersobine iV-Deethy 1-1,19-dehydrolucidusculine Delnuttine Kirinine C

C22H29N04

MW

371.2460 Liangshanone Spiramine J Spiramtne K

C23H33N03

H30NO4

Carbon-13 and Proton NMR Shift Assignments

27

MW

373.2253 Songorinc ^-oxidc Spirasine VII Spirasine VIII

C22H3,N04

MW

373.2617 Lepedine Liangshanine

C23H35NO3

MW

375.2410 Flavamine Napelline-N-oxide 12-epi-Napelline-Moxide Spiramine P Spiramine Q

C22H33NO4

MW

379.2278 Atisinium chloride (Guan Fu Base G) Guan Fu Base G

C22H34CINO2

MW

383.2097 Heterophylloidine (Panicutine) Panicutine

C23H29NO4

MW

385.1889 E>elnuttaline Geyeridine

C22H27NO5

MW

385.2617 Jynosine (15-O-Acetyldenudatine) Ovatine

C24H35NO3

MW

387.2046 2-Acetylseptentriosinc Acorine Guan Fu Base Y (Acorine) Septenine

C22H29NO5

MW

387.2773 Dictysineacetonide Dihydroovatine

C24H37NO3

MW

389,2566 Albovionitine

C23H35NO4

MW

393.2515 Chuanfunine Macrocentrine Paniculamine

C22H35NO5

28

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

MW

395.2227 Ajaconium chloride

C22H34CINO3

MW

395.2460 Anopterimine

C25H33NO3

MW

397.1889 Vilmorrianone

C23H27NO5

MW

397.2253 15-0-Acetylsongorainine 1,15-0-Diacetylcossonidinc 6,11-0-DiacetylvenuIol

C24H31NO4

MW 399.2410 11-0-Acetyl-l 1,19-dehydrodenudatine 1 l-epi'O'ActiyX' 1,19-dehydronapellinc 1,19-I>ehydroIucidusculine 1 l-epi' 1,19-Dehydrolucidusculine Spiradine F Spiramine A Spiraminc B Subdesculine

C24H33NO4

MW

401.2202 3-(9-Acetyl-2,2-dehydro-16,17-dihydro-(14,20 seco hetidine) Acoridine

C23H31NO5

MW

401.2566 11-0-AcetylIepenine 1 -OAcetylluciculinc 12-0-Acetylnapelline Lucidusculine (15-0-Acety Inapelline) 12-epi-Lucidusculine Spiramine F Spiramine I

C24H35NO4

MW

403.2359 13-0-Acety Igomandonine

C23H33NO5

MW

409.1889 7,1 l-O-Diacetylorientinine

C24H27NO5

MW

411.2046 13-0-Acetylfissumine 2-Dehydro-11.13-0-diacety Ihetisine 13-E>ehydro-1,11 -0-diacetylhetisine 1 l,13-(9-Diacetylhetisine-2-one 13,15-Di-O-acetyl venuluson

C24H29NO5

Carbon-13 and Proton NMR Shift Assignments

29

MW

411.2410 Anopterimine-iV-oxide

C25H33NO4

MW

411.2773 1,15-0-Diacetyl-16,17-dihydrosongorine

C26H37NO3

MW

413.1838 Miyaconitinone

C23H27NO6

MW

413.2202 2,11-0-Diacetylhetisine 11,13-(7-Diacetyhetisine 2,15-0-Diacetylryosenaminol

C24H3,N05

MW

413.2566 Spiramine L Spiramine M Yesodine

C25H35NO4

MW

415.1995 Miyaconitine

C23H29NO5

MW

415.2359 Cardionine Spiramine R

C24H33NO5

MW

417.2304 11-Benzoylkobusine 15-Benzoylkobusine

C27H31NO3

MW

417.2515 12-0-Acetylnapelline-Moxide Flavidine Guan Fu Base Z Thalicsiline

C24H35NO5

MW

427.2359 Geyerine

C25H33NO5

MW

427.2723 11,15-0-Diactyldenudatine

C26H37NO4

MW

429.2151 Guan Fu Base A

C24H3,N06

MW

429.2879 15-0,22-iV-Diacetyldihydroatisine 15,-0,22-A^Diacetyldihydix)veatchine

C26H39NO4

30

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

MW

431.2097 15-Dehydroryosenamine

C27H29NO4

MW

433.2253 6-BenzoyIpseudokobusine 11-Benzoylpseudokobusine 15~Benzoy Ipseudokobusine Crassicauline B Isohypognavine Ryosenamine

C27H3,N04

MW

433.2828 Isopropylidinechuanfunine

C25H39NO3

MW

435.2540 Acofme

C25H38CINO3

MW

439.1930 6-ImidazoylthiocarbonyIpseudokobusine

^24^29 3 3

MW

441.2151 15-0-Acetyl Sczukinine

C25H31NO6

MW

441.2515 12-0-Acetyl-1,19-dehydrolucidusculine

C26H35NO5

MW

443.2672 12-0-Acetyllucidusculine 12-0,22-A^-Diacetylatidinc 1,15-O-Diacetylluciculine Spiramine E

C26H37NO5

MW

444.3141 2^raconine

C30H40N2O

MW

445.1889 13-Dehydrocardiopetainine 15-Dehydrocardiopetaiiiine

C„H„NO,

MW

445.2464 Yesoxine

C25H35NO6

MW

447.2046 Cardiopetamine

C27H29NOJ

MW

449.2202 Hypognavine Ignavine Torokonine (Gomando Base I)

C27H31NO5

Carbon-13 and Proton NMR Shift Assignments

31

MW

455.2308 9,19-O-Diacetylacsinatine 2,11,13-Tri-O-acetyJhetisine Venudelphine

C26H33NO5

MW

457.2464 1 l-6>-Acetylcardionine Guan Fu Base F

C26H35NO6

MW

459.2410 Palmasine

C29H33NO4

MW

459.2621 Anopteryl-12a-tilgate (1 la-E)estigloylanopterine) 1 la-Destigloylanopterine (Anopteryl-12a-tilgate)

C26H37NO6

MW

460.3090 Zeraconine-iV-oxide

C30H40N2O2

MW

465.2151 Sadosine

C27H3,N06

MW

469.2464 Contorsine(2-C7-Acetyl-3-isobutyrylhetidine)

C27H35NO6

MW

471.2257 Guan Fu Base G 2,11,13-0-Triacetylvakhmatine 1,2,19-Triacety Iseptcntriosine

C26H33NO7

MW

474.3246 Coryphine

C3,H42N202

MW

475.2359 I l-Acetylisohypognavine 15-C>-Acetylryosenamine Hanamisine

C29H33NO5

MW

477.2645 1 -C7-Acetylacofine

Cj^H^oClNO^

MW

483.2621 Contortine(2-AcetyI-3(25)-methyIbutyrylhetidine) Sczukitine

C28H37NO6

MW

485.2414 3,2,13-0-Triacetylvakhmadine

C27H35NO7

32

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

MW

485.2777 1,12,15-0-Triacetylluciculine

CjgHapNO^

MW

487.1995 15-0-Acetyl-13-dehydrocardiopetamine 13-0-Acetyl-15-dehydrocardiopetamine

C29H29NO6

MW

489.2151 15-(9-Acetylcardiopetaniine

C29H3JNO6

MW

490.3195 Acozerine

C3,H42N203

MW

491.2308 Zeravshanisine

C29H33NO6

MW

492.3352 Coryphidine

C3,H44N203

MW

493.2464 15-Veratroylpseudokobusine

C29H35NO6

MW

497.2777 Lassiocarpine

C29H39NO6

MW

499.2570 AT-Deethyl-N-acetyl-1,12,15-0-triacety Inapelline 6,11-O-Diacetylcardionine (basic) N, 11-0-Diacetylcardioninc (neutral)

C28H37NO7

MW

501.2515 Palmadine

C3,H35N05

MW

503.2308 16,17-Dihydro-15,16-dehydroepiscopal idine Episcopalidine

C30H33NO6

MW

503.2519 Glanduline

C27H37NO8

MW

505.2464 16,17-Dihydroepiscopalidine

C30H35NO6

MW

507.2621 Yesoline

C30H37NO6

MW

511.2570 6,13-0-Diacetylgeyerinc

C29H37NO7

Carbon-13 and Proton NMR Shift Assignments

33

MW

511.2934 2-0-Acetyl-3-hexahy drobenzoy 1-16,17dihydrohetidine

C3oH4,N06

MW

513.2363 2,11,13,19-0-Tetracetylvakhmatine 2,11,13,14-c^-Tetraacetyltangutisine

CjgHjjNOg

MW

517.2464 1,7.-0-Diacetylcrassicauline B 11,15,-0-Diacetylisohypognavine

C31H35NO5

MW

519.2859 Andersobine- 19-p-^,MDimethylaminobenzoate

C3,H39N205

MW

521.2566 11,15-0-Dibenzoylkobusinc

C34H35NO4

MW

529.2676 13-Acetyl-9-deoxyglanduline 14-Acety1-9-deoxyglanduline

C29H39NO8

MW

531.2257 13-£)ehydropanlculatine 13,15-6-Diacetylcardiopetamine

C31H33NO7

MW

533.2413 Contorine(2-0-Acetyl-3-anisoylhetidine) Cossonine Paniculatine Tadzhaconine

C3,H35N07

MW

536.1840 N, 6-hydroxyepiscopalidine chloride

C3oH3,ClN06

MW

537.2515 6,11-O-Dibenzoylpseudokobusine 6,15-Dibenzoylpseudokobusine

C34H35NO5

MW

541.3040 Anopterine (Anopteryl-11,12-ditiglatc)

C31H43NO7

MW

545.2625 13-0-Acetylglanduline

C29H39NO9

MW

549.2361 2-Desmethylbutyrylcardiopine

C3JH35NO8

34

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

MW

557.2413 3-E)ehydro-1 -desacetoxy-1,2-dehydrocardiopinine

C33H35NO,

MW

557.2989 7P-Hydroxyanoptcrine(7P-Hydroxyanopterylll(x,12a-ditiglate)

C3,H43N08

7-P-Hydroxyanopteryl-l l a , 12a-ditilgate MW

561.2363 C32H35NO8 AMDesmethyl N, 6-j^co-6-hydroxyepiscopalidine-6cathylate

MW

571.2781 11,13-0-diacctyl-9-deoxyglandulinc

C3,H4,N09

MW

573.2938 4', 7p-Dihydroxyanopterine (7P-Hydroxyanopteryl-11 a-(E)-4'-hydroxy-2'methylbut-2'-enoate 12a-tiglate) 7P-Hydroxyanopteryl-11 a(E)-4'-hydroxy-2'methylbut-2'-enoate 12a-tilgate

C3,H43N09

MW

577.2312 Barbisine 15-Deacty 1 vakognavine

C32H35NO9

MW

579.2832 Anopetryl-11 a-4*-hydroxybenzoate-12a-tilgate lla-Benzoyl-7p-hydroxy 11adestigloylanopterine(7P-Hydroxyanoptcryl1 la-benzoate-12a-tiglate)

C33H41NO8

MW

577.3978 3-E>ehy dro-1 -desacetoxy-1,2-dehy drocardiopine

C33H55NO7

MW

590.4236 Staphimine

C4,H54N20

MW

595.2781 C33H4JNO9 7P-Hydroxy anoptery 1-11 a-(4' -hydroxy )-benzoate12a-tilgate

MW

606.4549 Staphidine

C42H58N2O

Carbon-13 and Proton NMR Shift Assignments

35

MW

619.2417 Vaicognavine 11-O-Acetylbarbisine

C34H37NO10

MW

620.4342 Staphinine Staphirine

C42H56N2O2

MW

621.2938 2-Dehydrocardiopimine

C35H43NO9

MW

623.3094 Cardiopimine Cardiopinine

C35H45NO9

MW

633.2938 Cardiopidine Cardiopine

C36H43NO9

MW

635.2367 Barbaline

C34H37NO11

MW

636.4655 Staphisagrine Staphisine

C43H60N2O2

MW

650.4447 Staphigine

C43H58N2O3

MW

650.4811 Staphisagnine

C44H62N2O2

MW

667.3356 3 -O-Acety Icardiopinine

C37H49NO10

MW

668.4917 Pukeensine

C44H64N2O3

MW

675.3043 3-0-Acetylcardiopine

C38H45NO10

MW

676.2394 7-O-Acetylbarbaline

C36H38NO|2

B^. Joshi, S.W. Pelletier and S.K. Srivastava

36 MW

691.2993 Caidiodine

C38H45NOn

MW

741.2785 Delgtandine

C41H43NO12

MW

768.3020 7-0-Acetyldelgrandine

C43H45NO13

MW

790.4556 Tangirine

C49H62N2O7

Carbon-13 and Proton NMR Shift Assignments

5.

Occurrence of Diterpenoid Alkaloids in Plant Species

Aconitella stenocarpa (Hossain and P. H. Davis) Sojak. Syn. Consolida Stenocarpa Hossain and PH Davis Stenocarpine Aconitum alboviolaceum Kom. Albovionitine Aconitum anglicum Stapf. 15-0-Acetylcardiopetamine 15-0-Acetyl-13-dehydrocardiopetamine Cardiopetamine Aconitum baicalense Turcz. ex Rapaics {Aconitum czekanovaskyi Steinb) 12-cp/-NapeIline 12-e/7/-Napelline-^-oxide Aconitum barbatum Pers. 11 -O-Acetyl-1,19-dehydrodenudatine Songoramine Songorine (Napellonine, Shimoburo Base I, BuUetine G) Songorine-^-oxide Aconitum bullatifolium var. homotorichum Guan Fu Base A Guan Fu Base G Guan Fu Base Y (Acorine) Aconitum carmichaeli Debeaux Chuaniimine Ignavine Songorine (Napellonine, Shimoburo Base I, Bulletme G) Aconitum contortum Finet et Gagnep Contorine(2-0-Acetyl-3-anisoyIhetidine) Contorsine(2-0-Acetyl-3-isobutyrylhetidine) Contortine(2-Acetyl-3-(2S)-methylbutyrylhetidine) Episcopalidine Aconitum crassicaule Crassicauline B Aconitum czekanovskyi Steinb. Luciculine (Napelline) 12-epi-Napelline 12-epi-Napelline-iV^oxide Aconitum delphinifolium DC 13-0-Acety Igomandonine Dictyzine (Dictysine) Gomandonine Yesoxine Aconitum episcopate Levi. 2-Deacetylheterophylloidine

37

^^

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

Episcopalidine Aconitumfinetianum Hand-Mazz Finetianine Nominine (11-Deoxykobusine, Nomibase-1) Aconitum flavum Hand-Mazz 12-0-Acetyllucidusculine 1,19-Dehydronapelline (1,19-Dehydroluciculine) Flavadine Flavamine Luciculine (Napelline) Lucidusculine (15-0-Acetylnapelline) l-e/7/-Napelline 12-e/7i-Napelline Aconitum gigas Lev et Van. {Lycoctonum gigas Nakai) Atisine Aconitum heterophylloides Stapf. Atisine Heterophylloidine (Panicutine) Aconitum heterophyllum Wall. Atidine Atisine Dihydroatisine Hetidine Hetisine Hetisine-2-one Isoatisine Aconitum ibukiense Nakai 9-Hydroxynominine Ignavine Ryosenamine Ryosenaminol Aconitum japonicum Thunb. 11-O-Acetylisohypognavine 11,15-0-Diacetylisohypognavine Ignavine Isohypognavine Kobusine Sadosine Songorine (Napellonine, Shimoburo Base 1, Bulletine G) Subdesculine Aconitum Japonicum var. montanum Nakai 3-e/7/-Ignavinol Kobusine Aconitum Jinyangense W. T. Wang Denudatine Jyosine (l5-0-Acetyldenudatine)

Carbon-13 and Proton NMR Shift Assignments Aconitum karakolicum Rapaics 12-0-Acety Inapeliine 12-O-Acety lnapelline-A/-oxide Acofine Dihydrosongorine Luciculine (Napalline) 12-e/7i-Napelline Nappelline A^-oxide Songoramine Songorine (Napellonine, Shimoburo Base I, Bulletine G) Aconitum kihneme Nakai Kirinine B Kirinine C Aconitum kojimae Ohwi var. lassiocarpum Tamura Lassiocarpine Aconitum komarovii Steinb. Guan Fu Base Y Guan Fu Base Z Aconitum koreanum (Levi.) Rapaics {A. coreanum) (Syn. A. komarovii Steinb.) Acoridine Coryphidine Coryphine Guan Fu Base A Guan Fu Base F Guan Fu Base G Guan Fu Base Y (Acorine) Guan Fu Base Z Isoatisine Aconitum kusnezoffii Reichb. Denudatine Lepenine Aconitum leucostomum Vorosch. 11-O-Acetyllepenine Acsinatine 9,19-O-Diacetylacsinatine Lepenine Songorine (Napellonine, Shimoburo Base I, Bulletine G) Aconitum liangshanium W. Z. Wang 12-6/7/-1,19 Dehydrolucidusculine 1 l-epi' 1,19-Dehy dronapelline Liangshanine Liangshanone 12-ep/-Lucidusculine 12-€fp/-Napelline Aconitum lucidusculum Nakai Lucidusculine (15-O-Acetylnapelline)

39

40

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

Aconitum majimaii Nakai Isohypognavine Aconitum miyabei Nakai Miyaconitine Miyaconitinone Aconitum monticola Steinb. A^Desethylsongoramine (Norsongoramine) Norsongoramine Norsongorine Songoiamine Songorine (Napellonine, Shimoburo Base I, Bulletine G) Songorine-Moxide Aconitum nagarum var. lasiandrum W. T. Wang Songoramine Songorine (Napellonine, Shimoburo Base I, Bulletine G) Aconitum napellus (fed on Aphids Brachycaudus aconitici) 12-epi' 1,19-DehydronapeIline 12-e/?/-Napelline Aconitum napellus L. S. Str. (Syn. A. anglicum Stapf.) 15-0-Acety Icardiopetamine 15-0-Acetyl-13-dehydrocardiopetamine Cardiopetamine Luciculine (Napelline) Songoramine Aconitum napellus L. ssp. castellanum J. Molero et C. Blanche 12-c'p/-0-Acetyl-1,19-dehydronapelline 12-6/7/-1,19Dehydronapelline Songoramine Aconitum nasatum Fisch. Ex Reichb. Pseudokobusine Aconitum orientale Mill Acorientine Orientinine Aconitum palmatum Don Atisine 15-Deacety Ivakognavine Hetidine Hetisine Isoatisine Palmadine Paimasine 2,3,13-(9-Triacetylvakhmadine Vakhmadine Vakhmatine Vakognavine Aconitum paniculatum Lam.

Carboii-13 and Proton NMR Shift Assignments Heterophylloidine (Panicutine) Panicudine Paniculamine Paniculatine Aconitumpseudohuiliense, Cheng et Wang Lepedine Lepenine Aconitum pukeense W. T. Wang Pukeensine Aconitum sanyoense Nakai Hanamisine Hypognavine Ignavine Nominine (11-Deoxykobusine, Nomibase-1) Sanyonamine Aconitum sanyoense var. tonense Nakai Hanamisine Sanyonamine Aconitum sczukinii Turez Sczukidine Sczukinine Sczukitine Aconitum septentrionale Koelle (Syn. Aconitum lycoctonum) 2-0-Acetylseptentriosinc Septatisine (Septedinine) Septedine Septenine Septentriosine Aconitum soongaricum stapf. Songorine (Napellonine, Shimoburo Base I, Bulletine G) Aconitum species Ignavine Sadosine Aconitum subcuneatum Nakai Gomandonine Torokonine (Gomando Base I) Aconitum talassicum M. Pop Kobusine Talassamine Talassimidine Talassimine Talatisine Aconitum tanguticum Tangirine Tangutisine Aconitum turczaninowii

41

42

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

Tupelline Aconitum vilmorrianum Kom Vilmonianone Aconitum yesoense Nakai I -O-Acety llucicuUne Luciculine (Napelline) Aconitum yesoeme var. macroyesoense (Nakai) Tamura 12-0-Acetyl-1,19-dehy drolucidusculine 1 -O-Acetylluciculine 12-0-Acety llucidusculine 15-Benzoy Ipseudokobusine iV-Deethy 1-1,19-dehy drolucidusculine 1,19-Dehydrolucidusculine 1,19-Dehydronapelline (1,19-DehydrolucicuUne) Flavadine Kobusine Lucidusculine (15-0-Acetylnapelline) Pseudokobusine 15-Veratroylpseudokobusine Ycsodine Yesoline Yesonine Yesoxine Aconitum zeravschanicum Steinb. Acozerine Atisine Isoatisine Luciculine (Napelline) Nominine (11-Deoxykobusine, Nomibase-1) Tadzhaconine Zeraconine Zeraconine-iV-oxide Zeravshanisine Anopterus glandulosus Labill. Anopterine (Anopteryl-11,12-ditiglate) Anopteryl I2a-tiglate (lla-Destigloylanopterine) 1 la-Benzoyl-7a-hydroxy-l la-destigloylanopterine (7PHydroxy anopteryl-11 a-benzoate-12a-tiglate) ll-a-Destigloylanopterine (Anopteryl I2a-tiglate) 4',7P-Dihdryoxyanopterine (7p-Hydroxyanoptery 1-11 a-(£)-4'-hydroxy-2*niethylbut-2'-enoate 12a-tiglate) 7P-Hydroxyanopterine (7P-Hydroxyanopteryl-l la,12a-ditiglate) 7-P-Hydroxy anopteryl 1 la,12a-ditiglate Anopterus macleayanus F. Muell. Anopterimine

Carbon-13 and Proton NMR Shift Assignments Anopterimine A^oxide Anopterine (Anopteryl-11,12-ditiglate) Anopteryl lla-4'-hydroxybenzoate 12a-tiglate Anopteryl 12a-tiglate (lla-Destigloylanopterine) 1 la-Benzoyl-7a-hydroxy-l la-destigloylanopterine (7PHydroxyanoptery I-11 a-benzoate-12a-tiglate) 11-a-DestigloyIanopterine (Anopteryl 12a-tiglate) 4',7p-Dihdryoxyanopterine (7P-Hydroxyanopteryl-11 a-(E)-4'-hydroxy-2'methylbut-2*-enoate 12a-tiglate) 7p-Hydroxyanopterine (7p-Hydroxyanopteryl-l la,12a-ditiglate) 7-P-Hydroxy anopteryl-11 a, 12a-ditiglate 7P-Hydroxyanopteryl-lla (4'-hydroxy) benzoate-12a-tiglate 7-p-Hydroxyanoptery 1-11 a-(E)-4'-hydroxy-2'-methylbut-2'-enoate 12atiglate Cocculus laurifolius DC Garryfoline (Laurifoline) Comolida ambigua L. Syn. D, ajacis Ajaconine Dihydroajaconine Consolida axilliflora (DC) Schr6d. (Syn. Delphinium axilliflorum DC.) Ajaconine Hetisine Consolida glandulosa (Boiss. et Huet.) Bomm. (Syn. Delphinium glandularum Boiss et Huett) 13-0-Acetyl-9-deoxyglanduline 14-0-Acetyl-9-deoxy glanduline 13-O-AcetylglanduIine 11,13-O-Diacety 1-9-deoxy glanduline Glanduline Consolida hellespontica (Boiss). Chellespontine Consolida stenocarpa Hussain and P.H. Davis Stenocarpine Delphinium ajacis Ajaconine Dihydroajaconine Delphinium alhiflorum DC 2-Deacetylheterophylloidine Delphinium andersonii Gray Andersobine Delphinium axilliflorum DC Ajaconine Hetisine Delphinium barbeyi (Huth) Huth Barbaline

43

44

BS. Joshi, S.W. Pelletier and S.K. Srivastava

Barbisine Delbidine Geyeridine Delphinium hrunonianum Royle Ajaconine Brunonine Dictyzine (Dictysine) Delphinium cardiopetalum DC (Syn. D, verdunense Balbis) 11-0-Acetylcardionine 15-0-Acety Icardiopetamine 13-C>-Acetylhetisine-2-one Cardiodine Cardionidine Cardionine Cardiopetamine Cardiopidine Cardiopimine Cardiopine Cardiopinine Cossonidine Hetisine-2-one Delphinium carolinianum Walt Ajaconine Delphinium corumbosum Regel Dictyzine (Dictysine) Delphinium cossnianum Batt. Cossonidine Cossonine Delphinium delavayi Franch var. pogonanthum (Hand-Mazz.) Wang Ajaconine Hetisine Hetisine-2-one Delphinium denudatum Wall Delnudine Denudatine Hetisine-2-one Vilmorrianone Delphinium dictyocarpum DC Dictyzine (Dictysine) Dictyzineacetonide Delphinium elatum Ajaconine Delphinium elatum L. cv. pacific giant Delatisine Delphinium fissum Waldst. and Kit ssp. anatolicum Chaudhuri and Davis Delfissinol

Carbon-ia and Proton NMR Shift Assignments Fissiunine Delphinium geyeri Greene Geyeridine Geyerine Geyerinine Delphinium glandulosum Boiss et Huet. 13-0-Acetyl-9-deoxyglanduline 14-0-Acety I-9-deoxyglanduline 13-0-Acetylglanduline 11,13-0-Diacetyl-9-deoxyglanduline Glanduline Delphinium gracile DC 1 l-O-Acetylcardionine 13-0-Acetylhetisine-2-one Cardionine Cardiopetamine Hetisine-2-one Delphinium grandiflorum L 7-0-Acetylgrandine Delgrandine Delphinium macrocentrum Oliv. 13-0-Acetylhetisine Macrocentrine Delphinium nudicaule Torr and Grey Hetisine-2-one Delphinium nudicaule Torr and Grey Hetisine Delphinium nuttalianum Pritz. 13-O-Acetylhetisine Delnuttaline Delnuttidine Delnuttine Hetisine Delphinium occidentale (S. Wats) S. Wats Deibidine Hetisine Hetisine-2-one Delphinium peregrinum var. elongatum Boiss 13-0-Acetylhetisine-2-one Delphinium staphisagria Staphidine Staphigine Staphimine Staphinine Staphirine Staphisagnine

45

^^

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

Staphisagrine Staphisine Delphinium tamarae Kem. Nath. A^-Desethylsongoramine (Norsongoramine) Norsongoramine Delphinium tatsienense Franch Ajaconine Dictyzine (Dictysine) Hetisine Hetisine-2-one Tatsirine Delphinium uncinatum Hook f. and Thomas Uncinatine Delphinium venulosum Boiss. Hetisine Venudelphine Venulol Venuluson Delphinium verdunense Balbis. 13-0-Acetylhetisine-2-one Delphinium virescens Nutt. Ajaconine Ganya laurifolia Hartw. Cuachichicine Garryfoline (Laurifoline) Isocuauchichicine Isogarryfoline Garrya ovata var. Lindheimeri Torr Cuauchichicine Garryfoline (Laurifoline) Lindheimerine Ovatine Garrya veatchii Kellog Garryine Veatchine Lycotonum gigas Nakai Atisine Spiraea japonica L. fil Spiradine A Spiradine B Spiradine C Spiradine D Spiradine F Spiradine G Spiraea japonica L. fil var. acuminata Spiramine A

Carbon-13 and Proton NMR Shift Assignments Spiramine B Spiramine C Spiramine D Spiramine E Spiramine F Spiramine G Spiramine H Spiramine I Spiramine J Spiramine K Spiramine L Spiramine M Spiraea Japonica L. fil varfortunei (Planchon) Rehd Spiradine A Spiramine B Spiramine C Spiramine D Spirasine I Spirasine II Spirasine III Spirasine IV Spirasine V Spirasine VI Spirasine VII Spirasine VIII Spirasine IX Spirasine X Spirasine XI Spirasine XII Spirasine XIII Spirasine XIV Spirasine XV Spiredine Spiraea Japonica var. incisa Yu Spiramine P Spiramine Q Spiramine R Thalictrum sessile Hayata Spiradine A Spirasine I Spirasine II Spirasine III Spiredine Thalicsessine Thalicsiline

47

48

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

6. Catalogue of Spectral Data and Physical Constants of Naturally Occurring Diterpenoid Alkaloids and their Derivatives

l-O-ACETYLACOFINE CI

C27H40CINO4

Prepared from acofine 'H N M R : 5 0.64 (3H, 5, H-IS), 1.00 (3H, /, J=7 Hz, H-22), 1.35, 1.40, 1.44 (each 3H, s, Me), 2.00 (3H, s, OAc), 3.26 (IH, bw), 3.85 (IH, bw), 5.05 (IH, ^.Ji=10Hz,J2=7Hz,H.lp).

B Tashkhodzhaev, MN Sultankhodzhaev and IM Yusupova, Khim, Prir, Soedin., 267 (1993).

Carbon-13 and Proton NMR Shift Assignments

49

15.O-ACETYLATISINE-Ar,20-AZOMETHINE C22H3iN02;mp 144-148° [a]D-60° *" OAc

1,2

Prepared from atisine

^^C Chemical Shift Assignments^

1. 2. 3.

C-1

42.4

C-12

35.9

C-2

20.0

C-13

25.8

€-3

34.1

C-14

25.0

C-4

32.9

C-15

76.2

C-5

47.0

C-16

151.1

C-6

19.4

C-17

110.1

C-7

31.2

C-18

25.8

C-8

36.7

C-19

60.7

C-9

39.2

C-20

165.1

C-10

42.5

COCH3

170.8

C-11

28.0

COCH3

21.2

SW Pelletier and PC Parthasarathy, J, Am. Chem, Soc, 87,777 (1965). D Dvomik and OE Edwards, Can. J. Chem., 35,860 (1957). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

50 7-0-ACETYLBARBALINE

C36H3»NOi2; MW: [M-Hf 676.2368; mp237° Preparedfrombarbaline 'H NMR (CDCI3): 8 1.12 (3H. s, H-18), 1.96 (3H, s, OAc-3), 2.05 (3H, s, OAc1), 2.12 (3H, s, OAc-11), 2.18 (3H, s, OAc-7), 2.29 (IH, brd, J=18 Hz, H-15), 2.35 (IH, s, H-5), 2.47 (3H, s, N-Me), 2.64 (IH, dl, J=18, 1.5 Hz, H-15), 2.83 (IH, d, J=2 Hz, H-12), 2.88 (IH. hid, J=4 Hz, H-14). 2.89 (IH, dd, J=4,9.5 Hz, H-9), 3.06 (IH, brJ, J=4 Hz, H-6), 3.81 (IH, s, H-20), 4.95 (IH, bw, H-17), 5.05 (IH, brt, J=1.5 Hz, H-17), 5.12 (IH, d, J=4 Hz, H-7e,), 5.23 (IH, d, J=3.9 Hz, H-3„), 5.46 (IH, hidd, J=9.5, 2 Hz, H-11„), 5.57 (IH, d J=4.2 Hz, H-U,), 6.09 (IH, t. J=4.2, 3.9 Hz, H-2), 7.55,7.62,7.88 (5H, each m, Ar-H), 9.81 (IH, bw, H-19). C-1

72.3

'^C Chemical Shift Assignments 70.7 C-1' C-U

C-2

66.6

C-12

59.8

C-2', 6'

129.8

C-3

71.8

C-13

205.3

C-3', 5'

128.8

C-4

49.8

C-14

54.1

C-4'

133.7

C-5

58.4

C-15

29.8

N-CH3

33.6

C-6

60.1

C-16

136.0

ArCO

164.9

C-7

69.1

C-17

114.3

COCH3-I

169.1\20.9''

C-8

48.4

C-18

23.5

COCH3-3

170.2,20.6

C-9

49.2

C-19

195.0

COCH3-7

169.6,20.3

C-10

56.6

C-20

66.0

COCH3-II

170.6\21.0''

129.1

****Assignments may be interchanged.

GD Manners, RY Wang, M Benson, MH Ralphs and JA Pfister, Phytochemistry, 42, 875 (1996).

Carbon-13 and Proton NMR Shift Assignments

51

11 -O-ACETYLB ARBISINE C34H37NO10; MW: [M+Hf 620; mp SlOBlS^Cdec.)

.t^t

[a]D~57.1°(CHCl3) Prepared from barbisine *H NMR (CDCh): 6 1.10 (5, H-18), 2.00, 2.01,2.11 (each 3H, s, OAc), 2.48 (3H, 5, A^Me), 3.43 (in, d, J=4.5 Hz; H-9p), 3.70 (IH, 5, H-20), 4.78 (IH, d, J=4.5 Hz, H-ll^), 4.86-5.04 (3H, m, H-7p, H-17,), 5.11 (IH, d, J=3.1 Hz, H-l„), 5.38 (IH, q, J=3.1 Hz, H2p). ^^C Chemical Shift Assignments

C-1

68.5

C-ll

65.6

C-20

67.6

56.5 .

N-Me

35.0

C-2

67.8

C-12

C.3

29.5

C-13

206.9

COCH3

169.0,168.6,165.1

C-4

43.6

C-14

50.8

COCH3

20.9,20.8,20.5

C-5

57.5

C-15

28.8

ArCO

165.1

C-6

61.2

C-16

135.0

c-r

129.5

C-7

73.9

C-17

115.4

C-2', 6'

129.5

C.3', 5'

128.6

C.4'

133.3

C-8

47.0

C-18

26.0

C-9

56.4

C-19

193.1

C-10

53.5

P Kulanthaivel, E Holt, J Olsen and SW Pelletier, Phytochemistry, 29,293 (1990).

52

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

11-0-ACETYLCARDIONINE CzfiHjjNOe; MW: 457.2463

21 22 OCOCH

\

23 /^^

24

[ a b - S J l " (CHCb) Delphinium cardiopetalum, DC; D. gracile, DC.

'H NMR (CDClj): 8 1.20 (6H, d, J=7 Hz, H-23, H-24), 1.33 (3H, s, H-18), 1.56 (IH, s, H-5), 1.65 (IH, d, J=2 Hz, H-9), 2.04 (3H, s, OAc), 2.32 (IH, brd, J=10.8 Hz, W|/2=7.5 Hz, H-14), 2.37 (IH, d, J=12.2 Hz, H-19J, 2.59 (IH, s, H-20), 2.63 (IH, sept, J=7 Hz, H-22), 3.08 (IH, d, J=12.2 Hz, H-19B), 4.99 (IH, s. H-UJ, 5.01, 5.34 (each IH, d, J=2.5 Hz, H-17). 5.68 (IH, t. J=2.2 Hz, H-15B). Me OH

"C Chemical Shift Assignments (CDClj) C-1

35.6

C-14

40.9

C-2

19.4

C-15

71.1

C-3

27.7

C-16

148.0

C-4

38.2

C-17

109.4

C-5

61.3

C-18

30.6

C-6

99.0

C-19

60.3

C-7

39.6

C-20

73.4

C-8

45.8

C-21

177.1

C-9

56.3

C-22

34.3

C-10

50.4

C-23

19.2

C-11

76.3

C-24

19.3

C-12

73.1

COCH3

172.2

C-13

36.2

COCH3

21.4

G de la Fuente, JA Gavin, M Reina and RD Acosta, J. Org. Chem., 55,342 (1990).

Carbon-13 and Proton NMR Shift Assignments

53

15-O-ACETYLCARDIOPETAMINE H0\

./i-lo.J

C29H3,N06^MW: 489'-';mp236-237°'' [a]D+16°', [a]D+ 12° (EtOH)^ Aconitum napellus L. S. Str. (syn. A. anglicum Stapf.) ; Delphinium cardiopetalum DCl 'H N M R (CDCI3)': 5 1.10 (3H, s, H-18), 1.82 (2H, m, H-7), 2.02 (IH, ;r, H-5), 2.10 (3H, s, OAc), 2.22 (IH, d, J=12 Hz, H-19B),

2.28 (IH, d, J=13.3 Hz, H-U), 2.29 (IH, rf. J=10 Hz, H-14), 2.58 (IH, d, J=2.5 Hz, H-12), 3.37 (IH, bra, Wi/2=6 Hz, H-6), 3.48 (IH, d, J=13.2 Hz, H-IJ, 4.18 (IH, brrf, J=9.7 Hz, W,/2=6 Hz, H-13), 5.15 (IH, s. H-15), 5.26, 5.34 (each IH, s, H-17), 5.57 (IH, d. 3=9 Hz, H-11), 7.42,8.08 (5H, each m, Ar-H). C-1

'^C Chemical Shift Assignment^ C-15 44.1

72.0

C-2

212.0

C-16

144.7

C-3

50.0

C-17

116.5

C-4

42.6

C-18

28.6

C-5

60.2

C-19

64.6

C-6

65.2

C-20

70.1

C-7

32.9

ArCO

166.6

C-8

48.1

c-r

129.8

C-9

49.4*

C.2',6'

129.8

C-10

55.0

C-3', 5'

129.7

C-11

75.1

C-4'

133.3

C-12

47.8

COCH3

171.0

C-13

69.6

COCH3

21.3

C-14

49.6*

"Assignments may be interchanged. 1. 2. 3.

G de la Fuente, M Reina and E Valencia, Heterocycles, 29,1577, (1989). AG Gonzdlez, G de la Fuente, M Reina, PG Jones and PR Raithby, Tetrahedron le//., 24,3765 (1983). AG Gonzdlez, G de la Fuente, M Reina, R Diaz and I Timdn, Phytochemistry, 25, 1971 (1986).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

54 3-(?-ACETYL CARDIOPINE

C38H45NO10; amorphous; MW 675 Prepared from cardiopine ^H NMR (CDCI3): 8 0.57 (H, u J=7.4 Hz, H-4'), 0.88 (H, d, J=7.0 Hz, H.5'), 1.04 (3H, s, H-18), 1.73 (IH, dd, J=13.6, 2.6 Me Hz, H-7p), 2.04 (3H, 5, OAc), 1.89, 1.96 5' AcO (6H, 5, OAc, 2.31 (IH, 5, H-5), 2.22 (IH, brd]^n Hz H.15„), 2.53 (IH, d, J=12.8 Hz, H-19p), 2.37 (IH, d, J=9.9 Hz, H-12), 2.37 (lH,/w, H-15p), 2.63 (IH, dd, J=10.1 Hz, H-14), 3.29 (IH, d, J=12.8 Hz, H-19J, 3.46 (IH, bw, 3.46 W,/2=6.2Hz, H-6), 3.85 (IH, 5, H-20), 5.11 (IH, d, J=4.8 Hz, H-3p), 4.86 (IH, br^, H-17e), 4.99 (IH, bw, H-17z), 5.43 (IH, d, J=9.4 Hz, H-llp), 5.52 (IH, dt, J=9.9, 2.6 Hz, H-13p), 5.69 (IH, dd, J=3.2, 4.3 Hz, H-2p), 6.09 (IH, d, J=3.0 Hz, H-1 J, 7.46 (2H, r, J=7.8 Hz, Ar-H), 7.57 (2H, r, J=7.1 Hz, Ar-H), 8.11 (IH, ^, J=7.2 Hz, Ar-H).

4* 3* 2* r MeCHaCHCCXD*

'^C Chemical Shift Assignments

c-r

174.4

C-2'

39.5

73.3

C-3'

25.0

C-14

49.1

C.4'

10.7

58.9

C-15

33.6

C-5'

15.7

C-6

63.5

C-16

141.5

COCH3 170.0(1), 169.9(3), 171.0(11)

C-7

35.2

C-17

110.6

COCH3

C-8

44.1

C-18

25.1

ArCO

165.9

C-9

51.5

C-19

58.8

C-l"

129.8

C-1

72.3

C-ll

75.0

C-2

65.7

C-12

46.4

C-3

70.8

C-13

C-4

41.3

C-5

C-10 54.1

C-20 . 65.7

21.2(1), 20.6 (3), 21.4 (11)

C.2",6" 129.6 C-3", 5" 128.8 C-4''

133.1

M Reina, A Madinaveitia, JA Gavfn, and G de la Fuente, Phytochemistry, 41,1235 (1996).

Carbon-13 and Proton NMR Shift Assignments

55

3-aACETYL CARDIOPININE 3" 2"

4 . . / " y : QOCK ^

\ y

C37H43NO,o; amorphous; MW 661

^ A r> J^*^ ^CHa

^^l

^..JLi

J

Prepared from cardiopininc

'H NMR (CDCh): 5 0.10 (IH, d, J=3Hz, H-

2' C H C O O ^ . . . ^ A < L X * X y ^ I Me I N—]--. 4' ^.-U ^ ^ J ^ : ^ AcO' .'T^ ^ ^ ' ' ^Me

12), 5.71 (Ih, dd, J-5,3 Hz, HzP), 5.10 (IH, d. J-Sllz, H-3P), 2.30 (IH, 5, H-5), 3.61 (IH, brs, wl/2 6.2 Hz, H-6), 1.74 (IH, dd, J=14, 2.3 Hz, H-7),2.42(IH.m,H.9),5.45(lH,J,J=9.6Hz, "-^ ^p)' -•'•2 (HI,
72.0

C-11

74.9

c-r

174.8

C-2

65.5

C-12

46.2

C-2'

33.2

C-3

70.6

C-13

73.2

C-3'

18.1

C-4

41.0

C-14

48.8

C-4'

19.5

C-5

58.4

C-15

33.5

C-6

63.4

C-16

141.8

ArCO

165.8

C-7

34.7

C-17

110.9

C-l"

129.7

C-8

44.0

C-18

25.1

C-2", 6"

129.6

C-9

51.4

C-19

58.4

C-3", 5"

128.8

C-10

54.2

C-20

65.7

C-4"

133.6

COCH3

169.9(1), 170.0(3). 171.0(11)

C-5'

COCH3

21.2(1), 20.5 (3), 21.4 (11)

M Reina, A Madinaveitia, JA Gavfn and G de la Fuente, Phytochemistry, 41,1235 (1996).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

56

13.0-ACETYL-15-DEHYDRO CARDIOPETAMINE C29H29NO6

Prepared from 15-dehydo cardiopetamine

^^C Chemical Shift Assignments (CDCI3/ C-l

43.9

C-14

49.0

C-2

211.1

C-15

199.3

C-3

50.2

C-l 6

141.4

C-4

43.0

C-17

120.6

C-5

60.5

C-18

28.6

C-6

64.9

C-l 9

64.5

C-7

28.8

C-20

70.9

C-8

56.1

ArCO

166.4

C-9

52.9

C-l*

129.7

C-10

55.7

C-2',6'

129.7

C-11

75.7

C-3',5'

128.9

C-12

44.3

C-4'

133.8

C-13

70.9

COCH3

170.4

C0CH3

21.1

AG Gonzalez, G de la Fuente, M Reing, R Diaz and I Tim6n, Phytochemistry, 25, 1971 (1986).

Carbon-13 and Proton NMR Shift Assignments

57

15-0-ACETYL-13-DEH YDROCARDIOPETAMINE C29H29NO6; MW: 487.2007; mp 253-255° [a]D-46'' Aconitum napellus L. S. Str. (syn. A. anglicum Stapf.)' 'H NMR (CDCI3)': 8 1.12 (3H, s, H-18), 1.87, 1.93 (each IH, dd, Ji=10 Hz, J2=2.2 Hz, H-7), 2.08 (IH, s, H-5). 2.17 (3H, s, OAc), 2.21 (IH, d, J=13.7 Hz, H-19B), 2.41 (IH, d J=14 Hz, H-1B), 2.56 (IH, d.

J=1.8

Hz, H-14), 2.71 (IH, d J=13.2 Hz, H-19J, 2.75 (IH, rf. J=14 Hz, H - U , 2.80 (IH, s, H-12), 2.91 (IH, dd, Ji=8.5 Hz, J2=2.1 Hz, H-9), 3.16 (IH, s, H-20), 3.37 (brs, Wi/2=6 Hz, H-6), 5.47 (bra, W|/2=5 Hz, H15), 5.65 id, J=8 Hz, H-11), 7.48-7.95 (5H, m, Ar-H). " C Chemical Shift Assignments^

1. 2.

C-1

45.7

C-14

58.8

C-2

209.6

C-15

71.7

C-3

49.7

C-16

138.7

C-4

42.6

C-17

121.3

C-5

60.0

C-18

28.7

C-6

65.5

C-19

64.2

C-7

31.6

C-20

71.9

C-8

48.2

ArCO

166.2

C-9

49.8

C-1'

128.9

C-10

54.5

C-2', 6'

128.9

C-11

71.9

C-3', 5'

128.9

C-12

57.7

C-4'

133.9

C-13

204.9

COCH3

170.8

COCH3

21.3

G de la Fuente, M Reina and E Valencia, Heterocycles, 29,1577 (1989). AG Gonzalez, G de la Fuente, M Reina, R Diaz and I Tim6n, Phytochemistry, 25, 1971 (1986).

58

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

11-0-ACETYL-l, 19-DEHYDRODENUDATINE C24H33NO4; MW: 399.5; mp 202-203** [a]D-»-99.7(CHCl3) Aconitum barbatum Pers. *H NMR (CDCI3): 6 0.81 (3H, s, H-18), 1.01 (3H, /, J=7.2 Hz, H-22), 1.20 (IH, ddd, J=8.4,3.0,1.3 Hz, H-5), 1.24 (IH, w, H-3a), 1.28 (IH, w, H.14a), 1.46 (IH, w, H-2a), 1.50 (IH, w, H.13a), 1.52 (IH, m, HOb), 1.67 (IH, ddd, J=12.5,5.1, 3 Hz, H-6b), 1.72 (IH, d, J=10.5 Hz, H-9), 1.78 (IH, /w, J=5.3 Hz, H-2b), 1.87 (IH, w, H-13b), 1.88 (IH, dd, J=5.1, 1.6 Hz, H.7), 2.00 (3H, 5, CH3COO), 2.07 (IH, ddd, 13.9, 11.6, 6.9 Hz, H-14b), 2.33 (IH, m, J=0.9 Hz, H-12), 2.34 (IH, d, J=6.9 Hz, OH), 2.45 (IH, ddd, 12.5, 8.4, 1.5 Hz, H-21), 2.68 (IH, AB^, d, J=l 1.8, 7.2 Hz, H-21), 3.08 (IH, ddd, J=1.6, 1.5, 1.3 Hz, H.20), 3.69 (IH, s, H-19), 4.00 (IH, d, J=5.3 Hz, H-U), 4.31 (IH, ddd, J=6.9, 2.4, 2.1 Hz, H-15J, 4.84 (IH, dd, J=10.5, 0.9 Hz, H-11„), 5.00 (IH, dd, J=2.4, 1.1 Hz, H-17b), 5.24 (IH, dd, J=2.1,1.1 Hz, H-17a). '^C Chemical Shift Assignments (CDCI3) C-l

68.3

C-13

24.3

C-2

24.1

C-14

26.9

C-3

29.7

C-15

77.1

C-4

37.5

C-16

153.7

C-5

49.6

C-17

110.7

C-6

24.4

C-18

18.7

C-7

47.4

C-19

93.0

C-8

45.5

C-20

69.8

C-9

46.5

C-21

48.4

C-10

49.4

C-22

14.1

C-11

74.2

COCH3

170.4

C-12

43.3

COCHj

21.1

B Proksa, D Uhrin, D Batsuren, N Batbaiar and D Selenge, Planta Medica, 56,461 (1990

Carbon-13 and Proton NMR Shift Assignments

59

3-0-ACETYL-2,20-DEHYDRO-16.17-DIHYDRO-(14,20 SECO) HETIDINE C23H31NO5; MW: 401.2196; amorphous Prepared from episcopalidine ' H NMR: 8 0.94 (3H, d, J=7 Hz, H-17), 1.28 (3H, s, H-18), 2.12 (3H, s, OAc), 2.32 (3H, s, H-21), 2.80 (2H, his, H-19), 3.97 (IH, d, J=5 Hz, H-2), 4.28 (IH, s, H-20), 4.50(lH,s,H-3).

AcO-' MeO

'^C Chemical Shift Assignments (CDCI3) C-1

40.9

C-13

214.8

C-2

74.5

C-14

53.6

C-3

80.4

C-15

30.2

C-4

39.4

C-16

30.8

C-5

57.4

C-17

21.6

C-6

203.9

C-18

23.1

C-7

52.7

C-19

45.4

C-8

40.0

C-20

93.9

C-9

44.9

N-CH3

42.4

C-10

43.7

COCH3

171.3

C-ll

27.1

COCH3

21.6

C-12

50.3

FP Wang and XT Liang, Tetrahedron, 42,265 (1986).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

60

2-O-ACETYL-l 3-DEHYDRO-l 1 -£iV-HETISINE C22H27NO4; MW: 369 Prepared from 13-dehydro-2,ll-0-diacetylhetisine AcO-..

'H NMR (CDCI3): 8 1.04 (3H. s. H-18), 2.07 (3H, s, OAc), 3.11 (IH, d, J=5.1 Hz, H-9J, 4.14 (IH, d. J=5.1 Hz, H-11 J, 5.08 (2H brs, H-17), 5.21 (IH, brm, W,/2=10.3 Hz, H-2B).

QP Jiang, JA Glinski, BS Joshi, JA Maddry, MG Newton and SW Pelletier, Helerotycfej, 27,925 (1988).

Carbon-13 and Pivton NMR Shift Assignments

61

12-O-ACETYL-l, 19-DEHYDROLtJCiDUSCULINE

9Ac

C26H35NO5; MW: 441.2532; amorphous [a]D + 9.3°(EtOH) Aconitum yesoense var. macroyesoense (Nakai) Tamura 'H NMR (CDCb): 8 0.81 (3H, s, H-18), 1.01 (3H, /, J=7 Hz, H-21), 2.06,2.14 (each 3H, s, OAc), 3.68 (IH, s, H-19), 4.20 (IH, d, J=5 Hz, H-1), 4.59 (IH, m, H-12B), 4.98,

5.29

(each IH, s, H-17), 5.48 (IH, s, H-15). "C Chemical Shift Assignments (CDCI3) C-1

67.6

C-13

43.3

C-2

29.8

C-14

28.6

C-3

24.5

CAS

77.9

C-4

37.8

C-16

150.7

C-5

45.9

C-17

111.8

C-6

23.9

C-18

19.0

C-7

48.3

C-19

92.8

C-8

49.3

C-20

65.6

C-9

33.6

C-21

48.3

C-10

57.8

C-22

14.2

C-11

26.3

COCH3

170.8,170.4

C-12

77.4

COCH3

21.5,21.3

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocycles, 26, 2623 (1987).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

62

12.^/7/-0-ACETYL-l, 19-DEHYDRONAPELLINE OAc

C24H33NO4; MW: 399.2402 [a]D + 25*'(EtOH) Aconitum napellus L. ssp. castellanum J. Molero et C. Blanche. ^H NMR (CDCI3): 5 0.82 (3H, s. H-18), 1.01 (3H, /, J=7 Hz, H-22), 1.99 (3H, s, OAc), 2.62, 2.68 (each IH, dq, 1--12 Hz, H-21), 2.73 (IH, bw, H.20), 3.02 (IH, dd, Ji=8.6 Hz, J2=5.5 Hz, H-13), 3.68 (IH, s, H.19), 4.01 (IH, d, J=4.9 Hz, H-U), 4.24 (IH, bw, H-ISJ, 4.95, 5.22 (each IH, hxs, H-17), 5.11 (IH, dd, J|=8.5 Hz, J2=6.1 Hz, H.12J.

'^C Chemical Shift Assignments (CDCI3) C-1

67.9

C-13

40.2

C.2

29.8

C.14

31.6

C.3

24.5

C-15

77.2

C-4

38.0

C-16

153.9

C-5

49.0

C-17

111.8

C-6

24.2

C-18

19.1

C-7

46.9

C-19

93.2

€-8

50.9

C-20

66.0

C-9

33.8

C-21

48.5

C-IO

52.1

C-22

14.4

C-11

27.1

COCH3

170.8

C-12

72.3

COCH3

21.5

G de la Fuente, M Reina, E Valencia and A Rodriguez-Ojeda, Heterocycles, 27, 1109 (1988).

^arbon-13 and Proton NMR Shift Assignments

63

7-O-ACETYLDELGRANDINE C43H«NO|3;inp 274-275° [ab-lUoCCHClj) Delphinium grandiflorum L. j/yi-c-o. 5 G

'H NMR (CjDsN): 8 1.12 (3H, s, H-18), 1.88, 2.04, 2.13, 2.15 (each 3H, s, OAc), 2.15 (IH, s, H-5), 2.20, 2.43 (each IH, dd, J=20 Hz, H-15), 2.47 (IH, d, J=9.6 Hz, H-9), 2.51 (3H, s, H-21), 2.58 (IH, d, J=3 Hz, H-12), 3.10 (IH, bw, H-6), 3.24 (IH, d, J=9 Hz, H-14), 3.90 (IH, s, H-20), 4.90 (IH, bcsr, H-7), 4.90, 5.07 (each IH, brs, H-17), 5.18 (IH, d, J=3.6 Hz, H-3), 5.30 (IH, d, J=9 Hz, H-13), 5.49 (IH, d, J=9.6 Hz, H-11), 6.00 (IH, d, J=3.9 Hz, H-1), 6.08 (IH, /, J=3.9, 3.6 Hz, H-2), 7.06,7.32,7.52,7.71 (5H, m, Ar-H), 9.48 (IH, brs, H-19). Me-

"C Chemical Shift Assignments (C5D5N) M

71.7

C-11

74.1

C-20

63.9

>2

65.9

C-12

45.3

N-CH3

34.2

:-3

71.7

C-13

73.8

COCH3

:-4

48.4

C-14

39.2

:-5

59.5

C-15

29.0

COCH3 ArCO

165.5, 163.9

:-6

60.1

C-16

140.6

c-r

129.3

:-7

73.1

C-17

111.6

C-2', 6'

128.8

:-8

48.9

C-18

22.8

C-3', 5'

128.1

:-9

52.3

C-19

191.7

C.4'

133.0

:-io

55.5

170.5,169.9,169.5,169.3 21.3,20.9,20.3,20.3

P Deng, DH Chen and WL Song, Acta Chimica Sinica, 50,822 (1992).

64

B^. Joshi, S.W. Pelletier and S.K. Srivastava 13-O-ACETYL-9.DEOXYGLANDULINE C29H39NO8; MW: 529.2706; mp 154156'*

AcO.,

[a]D+46.6*»(MeOH) Consoilda glandulosa (Boiss. et Huet) Bornm. syn. Delphinium glandulosum Boiss. et Huet. 'H NMR(CDCI3): 5 3.07 {dd. J-^ll.l, 22 Hz, H-1 J , 2.07 (dd, J=16.2, 4.4 Hz, HIp), 5.50 (w, W,/2=14 Hz, H-2p), 4.98 (d, J=4.4 Hz, H-3p), 1.79 (5, H.5), 3.13 (bw, W|/2=6.4 Hz, H-6), 1.89 (dd, J=14,3.4 Hz, H.7J. 1.41 (dd, J=14,2.5 Hz, H-7p), 2.04 (d, J-8.9 Hz, H-9), 4.28 (d, J-8.9 Hz, H1 Ip), 2.64 (d, J=2.5 Hz, H-12), 5.06 (/. J=2.2 Hz. H-13p), 2.17 (d, J=17.9 Hz, H.15J, 2.02 (m, H-15p), 4.77 (5, H-17e), 4.97 (s, H-17z), 1.02 (5, H-18), 3.35 W J=12.5 Hz, H-19J, 2.50 (d, J=12.5 Hz, H.19p), 3.54 (5, J=14,7,7 Hz, H-20), 2.35 (sext, J=7 Hz, H-20, 1.69 (ddq, J=14, 7, 7 Hz, H-3'A), 1.48 (ddq, J=14, 7, 7 Hz, H-3'B), 0.89 (z, J-7.4 Hz, H-40,1.25 (d, J=7 Hz, H-5'), 2.01 (s, 3-OAc), 1.99 (5,13-OAc). '^C Chemical Shift Assignments (CDCI3)

C-1

29.71

C-10

45.9 s

C-19

C-2

68.0 d

C-3

74.1 d

C-4 C-5

59.61

C-11

74.7 d

C-20

C-12

49.7 d

COCH3

42.2 s

C-13

81.1 d

COCH3

61.6 d

C.14

78.8 s

C-1'

175.7 s

C-6

62.6 d

C-15

30.71

C-2'

41.4 d

C-7

31.6t

C-16

143.3 s

C-3'

26.lt

C-8

44.7 s

C-17

109.51

C-4'

11.6q

C-9

53.2 d

C-18

25.4 q

C-5'

17.2 q

69.5 d 170.3 (3), 169.6(13)8 20.7 (3), 21.4 (13) q

G Almanza, J Bastida, C Codina and G de la Fuente, Phytochemistry, 44,739 (1997).

^arbon-lS and Proton NMR Shift Assignments

65

14-0-ACETYL-9-DEOXYGLANDULINE C29H39NO»; MW: 529.2692; mp 145148° [a]D + 20»(MeOH) Consolida glandulosa (Boiss. et Huet) Bonun., syn. Delphinium glandulostm Boiss. et Huet. 'H NMR (CDCb): 8 0.94 (f, J=7.4 Hz, H-4'), 1.12 (s, H-18), 1.21 («/, J=7 Hz, H-SO, 1.49 (OT, J=14,7,7 Hz, H-3'B), 1.50 (brrf, J=14 Hz, H-7p), 1.70 {ddq, J=14,7,7 Hz, H-3'A), 1.98 (s, H-5), 1.99 {s, H-14„, OAc), 2.00 {s, H-3„, OAc), 2.04 (
31.lt

C-IO

46.1s

C.19

58.61

:-2

67.2 d

C-ll

75.6 d

C-20

69.2 d

:-3

73.1 d

C-12

51.6 d

COCH3

170.0(3), 177.6 (14) i

:-4

41.1s

C-13

80.8 d

COCH3

20.7 (3), 20.6 (14) q

:-5

60.4 d

C-14

80.2 s

c-r

175.6 s

:-6

63.2 d

C-15

30.51

C-2'

41.5 d

:-7

31.31

C-16

143.0 s

C-3'

26.61

:-8

44.0 s

C-17

108.71

C.4'

11.5 q

:-9

53.3 d

C.18

22.5 q

C-5'

17.0 q

Almanza, J Bastida, C Codina and G de la Fuente, Phytochemistry, 44,739 (1997).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

66

ll-O-ACETYL-2,13-DlDEHYDROHETISINE C22H25N04;mp 285-287' Prepared from 11 -0-acetylhetisine 'H NMR (CDClj): 81.16 (3H, s. H-18), 2.08 (3H, s, OAc). 3.00 (IH. s. H-6B), 3.36

(IH,

hrs, H-20), 4.98, 5.10 (each IH, hts, H-17), 5.25(1H,
"C Chemical Shift Assignments (CDCI3) C-1

44.5

C-12

60.1

C-2

210.1

C-13

206.5

C-3

49.7

C-14

58.9

C-4

42.4

C-15

33.1

C-5

60.8

C-16

138.4

C-6

65.6

C-17

113.5

C-7

34.5

C-18

28.6

C-8

45.2

C-19

64.2

C-9

54.8

C-20

71.7

C-10

52.6

COCH3

170.2

C-U

72.3

COCH3

21.2

JA Glinski, BS Joshi, QP Jiang and SW Pelletier, Heterocycles, 11 y 185 (1988).

Carbon-13 and Proton NMR Shift Assignments

67

13-0-ACETYL-2,11-DIDEHYDROHETISINE C22H25NO4; MW: 367; amorphous

AcOv.

Prepared from 13-
"C Chemical Shift Assignments (CDCI3) C-1

43.5

€-12

58.5

C-2

210.1

C-13

69.6

C-3

50.7

C-14

49.6

C-4

42.9

C-15

33.1

C-5

59.3

C-16

138.1

C-6

65.5

C-17

114.3

C-7

34.5

C-18

28.3

C-8

45.0

C-19

65.0

C-9

64.8

C-20

70.6

C-10

50.5

COCH3

169.6

C-11

207.8

COCH3

20.7

JA Glinski, BS Joshi, QP Jiang and SW Pelletier, Heterocycles, 27,185 (1988).

B JS. Joshi, S.W. Pelletier and S.K. Srivastava

68 13-O-ACETYLFISSUMINE

C24H29NO5

Preparedfromfissumine *H NMR: 8 1.96, 2.08 (each 3H, s, C-9, C13, OAc), 5.17 (IH, brrf, J=9 Hz, H-13).

^^C Chemical Shift Assignments (CDCI3) C-l

44.0

C-12

50.5

C-2

210.4

C-13

70.4

C-3

48.8

C-14

55.2

C-4

41.2

C-15

34.5

C-5

57.8

C-16

145.6

C-6

65.0

C-17

108.5

C-7

28.3

C-l 8

29.6

C-8

43.7

C-19

61.4

C-9

75.0

C-20

70.0

C-10

54.4

COCH3

176.6,177.0

c-n

28.4

COCH3

22.4.22.8

A Ulubelen, AH Meri^li, F Meri9li, R Ilarsan and W Voelter, Phytochemistry, 34, 1165, (1993).

Carboii-13 and Proton NMR Shift Assignments

69

13-O-ACETYLGLANDULINE AcO-.. CHa

C29H39NO9; MW: 545.2625, mp 110115° [olD+15.2''(MeOH) ConsoUda glanduhsa {Boiss. et Huet) Bomm., syn. Delphinium glandulosum Boiss. syn. et Huet.

'H NMR (CDCI3): 8 0.89 (/, J=7.4 Hz, H-4'), 1.03 (5, H-18), 1.23 (rf, J=7 Hz, H-5'), 1.48 {ddq, J=14.6,7.3,7.3 Hz, H3'B), 1.68 (ddq, J=14.6, 7.3, 7.3 Hz, H-3'A), 1.70 {dd, J= 13.4, 3 Hz, H-7J, 1.75 {dd, J=13.8, 2.2 Hz, H-7B), 1.99 {d, J=18 Hz, H-15p), 1.99 (5, H-13„-0Ac), 2.02 is, H-3„-OAc), 2.04 (d, J=18 Hz, H-15„), 2.09 {dd, J=16.6, 4.7 Hz, H-l«), 2.36 {sext, J=7 Hz, H-2'), 2.54 {d, J=12.5 Hz, H-19B), 2.59 (s, H-5), 2.65 (
28.81

C-15

27.91

C-2

68.1 d

C-16

143.1 s

C-3

74.2 d

C-17

109.5 t

C-4

41.8 s

C-18

25.7 q

C-5

55.7 d

C-19

59.91

C-6

61.8 d

C-20

68.0 d

C-7

26.41

c-r

175.9 s

C-8

50.6 s

C-2'

41.3 d

C-9

80.9 s

C-3'

26.lt

C-10

47.3 s

C-4'

11.5q

C-11

84.0 d

C-5'

17.1 q

C-12

48.4 d

COCH3

170.6(3), 169.8 (13) s

C-13

80.4 d

COCH3

20.7 (3), 21.4 (13) q

C-14

77.3 s

G Almanza, J Bastida, C Codina and G de la Fuente, Phytochemistry, 44, 739 (1997).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

70

13-O-ACETYLGOMANDONINE C23H33N05;MW: 403

ACQ

Aconitum delphinifolium DC. *H NMR (CDCI3): 5 0.70 (3H, 5, H-18), 2.06 (3H, 5, OAc), 2.27 (3H, 5, H.21), 2.48 (IH, d, J=4.5 Hz, H.17J, 3.12 (IH, d, J=4.5 Hz, H-17p), 3.51 (IH, bw, H-20), 3.84 (IH, dd, J=9.5, 6.5 Hz, H-l), 4.18 (IH, bw, H15), 4.91 (IH, dd, J=8.8,4 Hz, H-U).

'^C Chemical Shift Assignments (CDCI3) C-1

70.6 d

C-12

40.7 d'

C-2

31.4t

C-13

71.5 d

C-3

36.11*

€-14

38.21"

C-4

33.7 s

C.15

76.6 d

C-5

51.8 d

C-16

64.2 s

C-6

23.5 t**

C-17

45.5 t

C-7

38.8 d'

C-18

25.8 q

C-8

43.6 s

C.19

59.lt

C-9

43.9 d'

C-20

68.5 d

C-10

50.9 s

C-21

41.7 d

C-11

23.91**

COCH3

21.4 q

COCH3

170.7 s

«bcAssignments

may be interchanged.

P Kulanthaivel and MH Benn, Phytochemistry, 11,3998 (1988).

Carboii-13 and Proton NMR Shift Assignments

71

2-O.ACETYLHETISINE C22H29NO4; MW: 371; mp 245-247^ Prepared from hetisine *H NMR (CDCI3): 5 0.98 (3H, s, H-18), 2.03 (3H, 5, OAc), 3.68 (IH, 5, H.20), 4.17

AcO».

(2H, dd, J=8 Hz, H-11B, H - H J , 4,64,

4.80

(each IH, br5, H-17), 5.11 (IH, br5, H-2B).

"C Chemical Shift Assignments (CDCI3) C-l

30.8

C-12

51.5

C-2

70.0

C-13

72.2

C-3

36.3

C-14

52.2

C-4

36.7

C-l 5

34.2

C-5

61.2

C-16

145.7

C-6

64.1

C-17

107.8

C-7

36.6

C-l 8

29.6

C-8

43.5

C-19

63.4

C-9

55.2

C-20

67.9

C-10

50.7

COCH3

170.5

C-11

76.2

COCH3

21.8

JA Glinski, BS Joshi, QP Jiang and SW Pelletier, Heterocycles, 27,185 (1988).

72

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

13-O.ACETYLHETISINE AcO-v

C22H29NO4; MW: 371; mp 241-243*'*; 243250** (perchlorate)^ Delphinium nuttalianum^ macrocentrum div/

Ha.

Pritz.; D,

Prepared from hetisine* 'H NMR (CDCU)*'^: 8 0.97 (3H, s, H-18), 2.17 (3H, s, OAc), 3.23 (IH, bw, H-6fl), 3.49 (IH, s, H-20), 4.19 (IH, bw, Wi/2=10 Hz, H-2fl), 4.24 (IH, brrf, J=8.5 Hz, H -1 1B), 4.72, 4.88 (each IH, bw, H-17), 5.13 (IH, hrd, J=9 Hz, H-13). X-ray structure^ '^C Chemical Shift Assignments (CDCb)'*^

i

T

C-l

33.8

34.01

C-12

48.5

50.4 d

C-2

66.7

68.8 d

C-l 3

74.5

75.8 d

C-3

40.3

40.51

C-14

50.4

48.6 d

C-4

36.6

36.7 s

C-15

33.5

33.71

C-5

61.5

61.6 d

C-16

144.8

144.9 s

C-6

64.3

64.4 d

C-17

108.7

108.71

C-7

36.0

36.21

C-l 8

29.7

29.8 q

C-8

43.6

43.7 s

C-19

63.2

63.71

C-9

55.2

55.4 d

C-20

68.6

67.0 d

C-10

50.6

50.7 s

COCH3

170.3

170.1 s

C-11

75.6

74.5 d

COCH3

21.2

21.3 q

1

2'

"Assignments have not been made. 1. 2. 3.

JA Glinski, BS Joshi, QP Jiang and SW Pelletier, Heterocycles, 27,185 (1988). MH Benn, JF Richardson and W Majak, Heterocycles, 24,1605 (1986). MH Benn, FI Okanga and RM Manavu, Phytochemistry, 28,919 (1989).

Carbon-13 and Proton NMR Shift Assignments

73

13.0-ACETYLHETISINE.2-ONE C22H27NO4; MW: 369; mp 219-220°' [a]D+17°(EtOH) Delphinium cardiopetalum DC syn. D. verduneme Balbis'; D, gracile DC}; D. peregrinum var. elongatum Boiss.^ Prepared from hetisine-2-one* 'HNMRCCDCby: 5 1.14 (3H, 5, H-18), 2.22 (3H, 5, OAc), 4.28 (IH, c/. J=9 Hz, H-11), 4.79, 4.95 (each IH, 5, Wi/2=7 Hz, H.17), 5.12 (IH, d, t, J=10 Hz, H-13). '^C Chemical Shift Assignments^

1. 2. 3. 4.

C-l

45.2

C-12

48.4

C-2

213.0

C-13

73.6

C-3

50.2

C-14

49.9

C-4

42.8

C-15

33.7

C-5

60.9

€-16

144.5

C-6

65.3

C-17

109.9

C-7

36.0

C-18

28.7

C-8

44.7

C-19

64.7

C-9

54.7

C-20

70.7

C-10

55.5

COCH3

170.3

C-11

74.4

COCH3

21.1

AG GonzMez, G de la Fuente and M Reina, An, Quim., 77C, 171 (1981). AG Gonzdlez, G de la Fuente, M Reina and T Tim6n, Heterocycles, 22, 667 (1984). AG Gonzdlez, G de la Fuente, M Reina, R Dfaz and I Tim6n, Phytochemistry, 25, 1971 (1986). G de la Fuente, JA Gavin, RD Acosta and JA Morales, Heterocycles^ 11, 1 (1988).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

74

2-O.ACETYL-3-HEXAHYDROBENZOYL.16, IT-DIHYDROHETIDINE C30H41NO6; MW: 511.2883;mp229-23^ ' Me Prepared from episcopalidine'

MeO

*H NMR: 8 0.96 (3H, d, J=7 Hz, H-17), 1.50 (3H, 5, H.18), 2.10 (3H, j , OAc), 2.50 (3H, 5, N-CH3), 2.82 (IH, ^, H.20), 2.56, 3.22 (each 2H, AB^, J=12 Hz, H-19), 4.62 (IH, t/, J=4.3 Hz, H-3) 5.42 (IH, dt, J=4.3, 2Hz,H-2).^

^C Chemical Shift Assignments^ C-l

35.2

C-15

34.5

C-2

67.4

C-16

32.4

C-3

75.4

C-17

22.2

C-4

41.7"

C-l 8

25.4

C-S

64.2

C-l 9

56.1

C-6

202.6

C-20

70.2

C-7

51.2

N-CHj

43.1

C-8

41.4'

ArCO

174.5

C-9

47.7

C-l'

41.7

C-10

44.3

C-2'. 6'

28.9

C-11

23.3

C-3', 5'

25.4

C-12

48.9

C-4'

25.8

C-13

215.7

COCH3

169.2

C-l 4

57.9

COCH3

21.2

'Assignments may be interchanged.

1. 2.

FP Wang and XT Liang, Tetrahedron, 42,265 (1986). FP Wang and XT Liang, Youji Huaxue, 1,19 (1986).

Carbon-13 and Proton NMR Shift Assignments

75

15-0-ACETYL-9-HYDROXYNOMININE C22H29NO3; MW: 355.2123; amorphous Prepared from 9-hydroxynominine

OAc

^H NMR (CDCI3): 8 1.01 (3H, s, H-18), 5.00, 5.01 (each IH, s, H-17), 5.51 (IH, s, H-15J.

S Sakai, I Yamamoto, K Hotoda, K Yamaguchi, N Aimi, E Yamanaka, J Haginiwa and T Okamoto, Yakugaku Zasshi, 104,222 (1984).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

76 11-O-ACETYLISOHYPOGNAVINE

C29H33NO5; MW: 475; mp 187.5-188.5'' AcO. BzOv.

[a]D + 74.r(CHCl3) Aconitumjaponicum Thunb. 'H N M R (CDCIS): 5 1.02 (3H, s. H-18),

1.98 (3H, s. OAc), 3.94 (IH, d, J=8 Hz, H-15), 5.06 (IH, d. J=5 Hz, H-11), 5.005.19 (each IH, s. H-17), 5.50 (IH, m. H-2), 7.40-7.58 (each 3H, Ar-H), 7.98 (2H, dd, J=6,2Hz,Ar-H).

S Sakai, H Takayama and T Okamoto, Yakugaku Zasshi, 99,647 (1979).

Carbon-13 and Proton NMR Shift Assignments

77

1 l-O-ACETYLLEPENINE pH2

ACQ

C24H35N04» MW 401; mp 130-131^ Aconitum leucostomum Vorosch. *HNMR (CDCI3): 8 0.70 (3H, s, H-18), 1.05 (3H, r, J=7.5 Hz, H-22), 2.08 (3H, s, OAc), 3.85 (IH, dd, J=5 Hz, H-lp), 4.32 (IH, rf, J=2.2Hz, H-15J, 4.97, s-23, (each IH, rf, J=2.2Hz, H-17), 5.52 (IH,rf,H-11 J.

'^C Chemical Shift Assignments (CDCI3) C-l

70.2

C-11

76.2

C-2

31.0

C-12

42.0

C-3

38.5

C-13

24.0

C-4

33.7

C.14

37.2

C-5

49.0

C-15

77.6

C-6

23.5

C-16

153.8

C-7

43.3

C-17

109.6

C-8

43.5

C-18

25.9

C-9

52.0

C-19

56.6

C-10

51.0

C-20

67.6

C-21

50.7

C-22

13.5

COCH3

171.1

COCH3

21.5

J Yue, J Xu, Q Zhao and H Sun, J. Nat Prod, 59,277 (1996).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

78 1-O-ACETYLLUCICULINE OH

C24H35NO4; MW: 401; amorphous [a]D+3.6^(MeOH) Aconitum yesoeme NakaiJ; A. yesoense var. macroyesoense (Nakai) Tamara^.

22

Me

*H NMR (CDCI3): 8 0.75 (3H, s, H-18), 1.07 (3H, /, J=7 Hz, H.22), 2.04 (3H, s, OAc), 3.42 (IH, w, H-12fl), 4.16 (IH, bw, W,/2=9 Hz, H-15), 5.03 (IH, dd, J=l 1, 7 Hz, H-1B),5.12(2H,^,H.17).

^^C Chemical Shift Assignments (CDClj)*'^^ C-l

74.5

C-13

47.8,47.9"

C-2

27.0

C-14

37.9,28.6

C-3

30.1,37.9

C-l 5

77.5

C-4

34.4

C-16

159.2

C-5

47.8,50.1''

C-l 7

108.6

C-6

23.2

C-18

26.0

C-l

44.7

C-19

57.4

C-8

50.1*, 50.0''

C-20

65.2

C-9

36.9

C-21

50.8,51.0*

C-10

50.4*. 50.5"

C-22

13.4

C-11

28.6,30.1

COCHj

171.2

C-12

75.7

COCH3

22.1

'Assignments may be interchanged. **Previous assignments were revised by private communication from Prof. S Sakai.

1. 2. 3.

H Takayama, A Tokita, M Ito, S Sakai, F Kurosaki and T Okamoto, Yakugaku Zasshi, 102,245 (\9n), K Wada, H Bando, T Amiya and N Kawahara, Heterocycles, 29,2141 (1989). H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Meterocycles, 26,2623 (\9S7).

Carbon-13 and Proton NMR Shift Assignments

79

12-0-ACETYLLUCIDUSCULINE QAc

C26H37NO5; MW: 443.2637*; 443.2659^ mp 132-134''*; 144-147^ [a]D- 94.1° (CHCI3)*; -19.2° (EtOH)^ AconitumflavumHand-Mazz.*; A. yesoeme var. macroyesoeme (Nakai) Tamura^ *H NMR (CDCI3)*: 8 0.74 (3H, s, H-18), 1.04 (3H, U J=6.8 Hz, H-21), 1.17 (IH, dd, J=12.4, 3.8 Hz, Heq-14), 1.98 (IH, d, J=12.8 Hz, H,x-14), 2.01, 2.09 (each 3H, ^, 2 x OAc), 2.20, 2.43 (each IH, g, J=11.3 Hz, H-19), 2.47 (IH,
1. 2.

ZG Chen, AN Lao, HC Wang and SH Hong, Heterocycles, 26,1455 (1987). H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocj/cfej, 26,2623 (1987).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

80 2-O-ACETYLNAPELLINE

C24H3JNO4; MW: 401; mp 205-206"^

QAc 1 1

OH

f

22

Aconitum karakolicum Rapaics'"^ 1 1 1

'H NMR (CDCh)'-^: 5 0.70 (3H, s, H-18), 1.05 (3H, t, H-22). 1.91 (3H, s. OAc), 4.93,5.10 (each IH, d, J=1.5 Hz, H-17).

Me

v.. 21

1. 2.

p

H

OH

MN Sultankhodzhaev, LV Beshitaishvili, MS Yunusov and SY Yunusov, Khim. Prir. Soedin., 14,479 (1978). MN Sultankhodzhaev, LV Beshitaishvili, MS Yunusov and SY Yunusov, Khim Prir. Soedin., 12, 681 (1976).

Carboii-13 and Proton NMR Shift Assignments

81

12-0-ACETYLNAPELLINE-Ar-OXIDE C24H33N05;MW: 4l7;mp235'' Aconitum karakolicum Rapaics

OH

'H NMR: 8 0.80 (3H, s, H-18), 1.37 (3H, /, H-22), 1.91 (3H, j.OAc), 4.86, 5.11 (each lH,bK,H-17).

..'

21

U /•

H

OH

MN Sultankhodzhaev, MS Yimusov and SY Yunusov, Khim. Prir. Soedin., 18, 265 (1982).

82

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

15-O-ACETYLRYOSENAMINE C29H33NO5; MW: 475; mp 184.5-185«^'^ Prepared from ryosenamine BzQ*.^ .x^^d^-'^iNLv.x-^

^H NMR (CDCI3): 5 1.02 (3H, s, HAS), 2.09 (3H, s, OAc), 3.23 (IH, br^, H-6), 4.94, 4.98 (each IH, s, H-IT), 5.50 (2H, s. H-15a, 2B), 7.28-8.10 (each 5H, Ar- H).

1. 2.

S Sakai, I Yamamoto, K Hotoda, K Yamaguchi, N Aimi, E Yamanaka, J Haginiwa and T Okamoto, Yakugaku ZasshU 104,222 (1984). S Sakai, K Yamaguchi, I Yamamoto, K Hotoda, T Okazaki, N Aimi, J Haginiwa and T Okamoto, Chem. Pharm. Bull, 31,3338 (1983).

Carbon-13 and Proton NMR Shift Assignments

83

15-O-ACETYLSCZUKININE C25H3iN06;mp: 251-253° Prepared from sczukinine 'H NMR (CD3OD): 8 1.46 (IH, dd, J=15,5 Hz, H-3a), 1.49 (IH, dd, J=15, 4.6 Hz, Hla), 1.59 (IH, s, H-18), 1.70 (IH, d, H-3b), 1.75 (IH, s, H-5), 1.78 (IH, d, J=10 Hz, H1 la), 1.99 (IH, s, OAc), 2.00 (IH, d, J=15 ^Me O Hz, H-lb), 2.03 (IH, s, OAc), 2.05 (IH, m, H-1 lb), 2.19 (IH, dd, J=10,2 Hz, H-9), 2.39 (IH, s, N-CH2), 2.54 (IH, d, J=18 Hz, H-7a), 2.56 (IH, d, J=l 1 Hz, H-19a), 2.66 (IH, d, J=l 1 Hz, H-19b), 2.87 (IH, s, H-20), 3.06 (IH, d, J=18 Hz, H-7b), 3.09 (IH, d, J=2 Hz, H-14), 3.14 (!H, d, J=3 Hz, H-12), 5.17 (IH d, 3=2 Hz, H-17a), 5.21 (IH, d, J=2 Hz, H17b), 5.21 (IH, m, H-2), 5.99 (IH, s, H-15).

"C Chemical Shift Assignments (CDCb)" 35.8

C-12

59.0

C-2

68.3

€-13

209.8

C-3

43.7

C-14

52.1

C-4

36.7

C-15

72.1

C-5

59.0

C-16

143.0

C-6

202.6

C-17

114.5

C-7

48.5

C-18

31.1

C-8

44.2

C-19

60.3

C-9

45.2

C-20

70.5

C-10

46.8

C-21

43.2

C-U

22.0

COCH3

169.6

COCH3

21.5

C-1

DH Chen, Q Chang, I Kitakawa, M Yoshikawa and M Kobayashi, Chinese Chem. Letters (Natural Products study and Development), X 1 (1991).

84

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

2-O-ACETYLSEPTENTRIOSINE C22H29NO5; MW: 387; mp 182-184"' [a]D" + 6.4<'(EtOH) Aconitum septentrionale Koelle

AcO*

HO-

'H N M R (CDCI3): 5 1.08 (3H, s, H-18), 2.07 (3H, s, OAc), 2.76 (IH, bw, H-20), 3.60 (IH, br*. H-6). 4.18 (IH, 5, H-19) 4.52 (IH, s, H-1), 4.59, 4.74 (each IH, d, J=1.5 Hz, H-17), 5.00 (IH, /, J=1.5 Hz, H-2).

MeH

"C Chemical Shift Assignments C-1

67.9 d

C-12

36.1 d

C-2

73.2 d

C-13

32.91

C-3

39.21

C-14

43.7 d

C.4

42.1s

C-15

30.71

C-5

50.7 d

C-16

150.4 s

C-6

60.5 d

C-17

104.71

C-7

30.91

C-18

21.5 q

C.8

42.1s

C-19

91.7 d

C-9

79.6 s

C-20

67.9 d

C-10

53.7 s

COCH3

169.9 s

C-11

33.81

COCH3

22.5 q

SA Ross, BS Joshi, SW Pelletier, MG Newton and AJ Aasen, J. Nat. Prod, 56, 424 (1993).

Carbon-13 and Proton NMR Shift Assignments

85

15-0-ACETYLSONGORAMINE O

C24H31NO4; MW: 397; mp 110-115° Prepared from songoratnine

MS Yunusov, YV Rashkes, SY Yunusov and AS Samatov, Khim. Prir. Soedin., 6, 101, (1970).

B.S. Joshi, S.W. Pellctier and S.K. Srivastava

86 A^-ACETYLSPIRADINE A

li.

C22H27N03;mp 173-175° Prepared from spiradine A

Ac-- •"

^H NMR (CDCI3): 8 1.16, 2.07 (each 3H, s), 4.70,4.89 (each IH, 5).

G Goto, K Sasaki, N Sakabe and Y Hirata, Tetrahedron Lett, 1369 (1968).

Carbon-13 and Proton NMR Shift Assignments

87

6-0-ACETYLSPIRADINE A

h

C22H27N03;mp 215-216** Prepared from spiradine A *H NMR (CDCI3): 8 1.04, 2.00 (each 3H, 4 4.68,4.84 (each lH,j).

G Goto, K Sasaki, N Sakabe and Y Hirata, Tetrahedron Lett., 1369 (1968).

88

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

ACOFINE C25H38CINO3; MW: 435.2550; mp 159160° Aconitum karakolicum Rapaics *H NMR: 5 0.66 (3H, s, H-18), 0.99 (3H, U J=7 Hz, H-22), 1.35, 1.39, 1.44 (each 3H, 5, Me), 3.23 (IH, hxs\ 4.17 (IH, q, Ji-10 Hz, J2=7 Hz, H-lp). X-ray structure

B Tashkhodzhaev, MN Sultankhodzhaev and IM Yusupova, Khim. Prir, Soedin,, 267 (1993).

Carbon-13 and Proton NMR Shift Assignments

89

ACORIDINE C2jH3iN03; MW: 401; mp 204- 206° CHz

3" 2

[a]D+16°(MeOH) Aconitum Koreanum (Levi.) Rapaics.

MeCH2CCK,

'H NMR: 8 (ppm): 0.86 (3H, s, H-18), 1.07 (3H, /, J=7.5 Hz, H-3'), 1.33 (1H, J=14, 3 Hz, H-7), 1.48 (1H, s, H-5), 1.64 (1H, dd, J=15.5, 4 Hz, H-3„), 1.90-1.70 (each 3H, m, H-ln, H-30, H-7), 2.00-1.90 (each 3H, s, H-9„, H-15„iP), 2.28 (2H, q, 3=1.5 Hz, H-2'), 2.42 (1H, bw, H-12), 2.84 (1H, d, J=16 Hz, H-l„), 2.91, 2.48 (each 1H, d, J=12 Hz, H-19oP), 3.05 (1H, brs, H-6), 3.46 (1H, s, H-20), 3.98 (1H, brs, H-13), 4.15 (1H, d, J=9 Hz, H-ll), 4.99, 4.60 (each 1H, brs, H-17), 5.08 (1H, brs, H-2). 13,

C Chemical Shift Assignments

C-1

31.21

C-13

79.9 d

C-2

69.9 d

C-14

80.4 s

C-3

36.81

C-15

31.2t

C-4

37.7 s

C-16

144.9 s

C-5

60.1 d

C-17

108.21

C-6

63.1 d

C-18

29.7 q

C-7

32.lt

C-19

63.lt

C-8

44.4 s

C-20

69.2 d

C-9

53.6 d

174.0 s

C-10

46.5 s

c-r c-r

C-ll

76.0 d

C-3'

9.2 q

C-12

52.7 d

28.31

IA Bessonova, LN Samusenko, MS Yunusov, MR Yagudaev and VO Kondrat'ev, Khim. Prir. Soedin., 91 (1991).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

90 ACORIENTINE HO*'

C20H27NO3; MW: 329 1984 [a]D+13.5''(CHCl3) Aconitum orientate Mill

'H NMR (CD3OD): 8 1.35,1.92 (2H, m, H1), 1.10,1.55 (IH, m, H-2), 1.58 (2H, m, H'^Me OH 3), 1.83 (IH. H-5), 2.12, 2.35 (2H, H-7), 2.10 (IH, H-9), 1.95,2.35 (2H, H-11), 2.65 (IH, H-12), 3.98 (IH, d, J=5 Hz, H-13), 2.45 (IH, hrs, H-14), 4.02 (IH, s, H-15„), 5.16, 5.27 (2H, brs, H-17), 1.42 (3H, s, H-18), 2.37,2.67 (2H, H-19), 3.86 (IH, s, H-20).

'^C Chemical Shift Assignments (CDCI3)'* C-1

39.3

C-11

37.6

C.2

18.9

C-12

39.5

C-3

35.1

C-13

72.0

C-4

35.9

C-14

40.7

C-5

59.3

€-15

73.6

C-6

100.9

C-16

150.3

C.7

46.7

C-l?

116.1

C-8

40.9

C-IS

29.9

C-9

54.1

C-19

57.3

C-10

49.6

C.20

67.2

A Ulubelen, AH Meri9li, F Meri9li and F Yilmaz, Phytochemistry, 41,957 (1996).

Carbon-13 and Proton NMR Shift Assignments

91

ACOZERINE C31H42N2O3; MW: 490

Aconitum zeravshanicum Steinb'*^ -Me

^H NMR (CDCI3): 8 0.96, 1.98, 2.29 (each 3H, s, H-18, H-22), 5.59 (IH, bw,H-15).

'^C Chemical Shift Assignments (CDCb)^

1. 2. 3.

C-l

37.2

C-17

34.1

C-2

21.7

C-18

27.3

C-3

39.9

C.19

43.7

C-4

36.8

C-20

228.5

C-5

54.5

€-21

170.2

C-6

19.4

C-22

23.6

C-7

35.6

N-CH3

40.1

C>8

42.6

C-2'

54.6

C-9

51.8

C.3'

36.2

C-10

53.9

C-4'

155.6

C-11

28.2

C-5'

126.3

C«12

35.7

C-6'

197.1

C-13

30.9

C-7'

38.0

C-14

54.3

C.3a

47.1

C-15

131.2

C-7a

70.0

C-16

145.7

ZM Vaisov, BT Salimov and MC Yunusov, Khim. Prir. Soedin., 800 (1984). IM Yunusova, IA Bessonova, B Tashkhodzhaev, MS Yunusov, MR Yagudaev and ZM Vaisov, Khim, Prir. Soedin,, 396 (1991). Z Vaisov, L Spirikhin, L Khalilov, AS Narzullaev and MS Yunusov, Mendeleev Commi/w., 237 (1993).

92

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

ACSINATIDINE iX

. CH2

C20H27NO3; MW 329; mp 224-226** Prepared from acsinatine

HO

OH

VA Tel'nov, SK Usmanova and ND Abdullaev, Khim. Prir. Svedin., 409 (1993).

Carbon-13 and Proton NMR Shift Assignments

93

ACSINATINE C22H29NO4; MW: 371; mp 251-253*^ Aconiium leucostomum Vorosch.

AcO.

'H NMR: 8 1.01 (3H, 5, H-18), 1.98 (3H, s, OAc), 3.45 (IH, br5), 4.51 (2H, bw, H-17, H.19), 4.67 (IH, bw, H-H), 5.17 (IH, bw, H-2p).

^^C Chemical Shift Assignments C-l

31.8

C-12

36.9

C-2

70.7

C-13

34.3

C-3

37.8

C-14

43.9

C-4

42.2

C-15

31.7

C-5

55.1

C-16

152.1

C-6

60.8

C-l 7

104.3

C-7

29.6

C-18

23.0

C-8

42.1

C-19

92.0

C-9

78.8

C-20

70.1

C-10

50.4

COCH3

169.6

C-11

39.0

COCH3

21.7

VA Ternov, SK Usmanova and ND AbduUaev, Khim, Prir Soedin., 409 (1993).

B^. Joshi, S.\V. Pelleticr and S.K. Srivastava

94 AJACONINE

C22H33NO3; MW: 359; mp 170-172^ [a]D-135''(EtOH) Delphinium brunonianum Royle\ D. delavayi Franch var. pogonanthum (Hand-Mazz.) Wang^, D. carolinianum Walt^, D. tastsienense Franch^, Consolida ambigua L. Syn. D. ajacis^'^, D. virescens Nutt^.» D. elaium^, C. axillijlorum (DC) SchrSd. syn., D. axelliflorum (DC)'. *H NMR (CDCI3-CD3OD)*': 8 0.76 (3H, s, H-18), 2.93 (IH, dt, J=14.2, 5 Hz, H6p). 3.46 (IH, /w, H-21A), 3.64 (IH, J, J=4.2 Hz, H.7), 3.65 (IH, w, H-21B), 4.16

(IH, bw, H-15J, 4.63 (IH, s, H-20), 5.01,5.16 (each IH, his. H-17).

C-l

'^C Chemical Shift Assignments (CDCI3, CD30D)^ (CD3OD) (CDCI3) 42.4 C-12 C-1 26.8 C-12 41.3

C-2

21.1

C.13

27.0

C.2

22.0

C-13

27.9

C.3

40.3

C-14

26.6

C-3

41.1

C-14

26.4

C-4

33.6

C-15

72.2

C-4

34.5

C-15

73.5

C-5

44.4

C.16

157.3

C-5

45.4

C-16

157.2

C-6

25.1

C-17

108.0

C-6

27.4

C-17

108.0

C-7

75.5

C-18

25.3

C-7

76.3

C-18

25.5

C-8

41.6

C-19

51.7

C.8

42.9

C-19

54.0

C-9

37.0

C-20

87.8

C.9

38.3

C-20

89.7

C-10

35.4

C.21

57.3

C-10

36.5

C.21

58.3

C-ll

30.1

C-22

58.0

C-ll

31.2

C-22

60.0

1. 2. 3. 4. 5.

7. 8. 9.

27.9

W Deng and WI Sung, Heterocycles, 24, 869 (1986). SW Pelletier, FM Harraz, MM Badawi, S Tantiraksachai, FP Wang and SY Chen, Heterocycles. 24,1853 (1986). SW Pelletier, JA Glinski, BS Joshi and SY Chen, Heterocycles, 20,1347 (1983). SW Pelletier, NV Mody and HK Desai, Heterocycles, 16,747 (1981). SW Pelletier, RS Sawhney, HK Desai and NV Mody, J. Nat. Prod, 43, 395 (1980); JA Goodson, J. Chem. Soc, 245 (1945). SW Pelletier, NV Mody, AP Venkov and SB Jones, Jr., Heterocycles, 12, 779 (1979). SW Pelletier and NV Mody, J. Amer. Chem. Soc, 101,492 (1979). SW Pelletier, SA Ross and HK Desai, Phytochemistry, 29,2381 (1990). G de la Fuente, L Ruiz-Mesa, J Molero and C Blanche, Fitotherapia, 67,87 (1996).

Carbon-ia and Proton NMR Shift Assignments

95

AJACONIUM CHLORIDE K

C22H34CINO3 2

Prepared from ajaconine

'^C Chemical Shift Assignments (D2O) C-l

42.6

C-12

36.4

C-2

21.1

C-13

29.6

C-3

37.3

C-14

26.8

C-4

35.2

C-l 5

72.2

C-5

44.8

C-16

156.5

C-6

20.6

C-17

112.9

C-7

70.7

C-l 8

26.2

C-8

44.3

C-19

66.2

C-9

41.3

C-20

184.7

C-10

48.1

C-21

61.5

C-11

29.6

C-22

59.8

SW Pelletier and NV Mody, J. Amer. Chem. Soc, 101,492 (1979).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

96 ALBOVIONITINE

C23H3JNO4; MW: 389; mp 150-152° Aconitum alboviolaceum Kotn. 'H N M R (CDCI3): 8 1.03 (IH, m, W,/2=13 Hz, H-2^, 1.11 (IH, dd, H-U), 1.26 (IH, dt, H-6J,

1.53 (IH, dd, H-7B), 1.67 (IH, m, W,a=5 Hz, H-2»), 1.70 (IH, m, H-llJ, 1.71 (IH, m, H-13„), 1.75 (IH, dd, H-3i,),

23

Me-N-CHa' 21 CHj

1.28 (IH, dd, H-5B),

HO'

1.79 (IH, m. H.6B). 1.85 (IH, bid,

H-

11»), 1.90 (IH, brd, H-9B), 2.00 (IH, brrf,

22CH2OH

H-13B), 2.04 (IH. d. H-14B), 2.08 (IH, t.

H-1 J, 2.16 (IH, m. H-7a), 2.29 (IH, bw, H-^B), 2.53 (IH, d. H-19B), 2.37 (3H, s, H-23), 2.40 (IH, /, H-3J, 2.67 (2H, dm, H-21), 3.12 (birf, H-19J, 3.23 (IH, hrd, H-18B), 3.70 (2H, dm, H-22), 4.00 (IH, d H-18„), 4.12 (IH, brs, H-15B), 4.95 (IH, brs, H-17e), 5.04 (IH, brs, H-17z). "C Chemical Shift Assignments (CDCb) C-1

29.61

C-12

34.6 d

C-2

18.31

C-13

32.61

C-3

30.21

C-14

51.4 d

C-4

41.2 s

C-15

71.3 d

C-5

50.6 d

C-16

156.0 s

C-6

21.61

C-17

106.91

C-7

31.61

C-18

73.91

C-8

43.4 s

C-19

57.41

C-9

47.2 d

C-20

227.4 s

C-10

53.4 s

C-21

62.61

C-11

28.21

C-22

59.91

C-23

45.2 q

ZG Hao, JH Liu, SX Zhao and ZC Miao, Phytochemistry, 30,3494 (1991).

Carbon-13 and Proton NMR Shift Assignments

97

ANDERSOBINE Ha

C22H29NO4; MW: 371; mp 310° Hb

OAc HO'

Delphinium andersonii Gray 'H NMR (CD3)2SO: 8 0.95 (3H, s, H-18), 1.31 (IH, dd, Ji^i„=13 Hz, Ji„.ip=13 Hz, H-U), 1.83 (IH, m, Ji„.ip=13 Hz, H-l„). 1.42 (IH, m, H-2^, 1.68 (IH, m, H-2B), 3.30 (IH, m, H-3B), 1.38 (IH, s, H-5), 3.34 (IH, bra,

H-6), 1.62 (IH, dd, h^7f=l3 Hz, J7a.6=2.5 Hz, H-7B), 1.40 (IH, m, H-TJ, 1.68 (IH, m,

H-9), 1.47 (IH, td, Jiip.n.=13 Hz, Jiip.i2=2 Hz, J„„.,=2 Hz, H-IU), 1.87 (IH, dd, Jii„iirl3 Hz, J„„.i2=4 Hz, H-ll„), 2.17 (IH, m, H-12), 1.15 (IH, td, J,J„,,3B=13 Hz, Ji3a.i2=2 Hz, Ji3..u=2 Hz, H-13„), 1.68 (IH, m, H-13B), 1.80 (IH, d, Ji4.i3p=11.6 Hz, H-14), 5.29 (IH, brs, J=<1 Hz, H-15a), 4.92 (IH, t. J=1.6, 1.6 Hz, H-17a), 4.83 (IH, t, J=1.6, 1.6 Hz, H-17b), 4.07 (IH, s, H-19), 2.52 (IH, brs, H-20), 2.02 (3H, s, OAc), 4.40 (IH, d, J=4.6 Hz, 3-OH), 5.12 (IH, s, 19-OH). 'H NMR (C5D3N): 8 1.42 (IH, m, H-U). 1.82 (IH, m, H-1 J, 1.84 (IH, m, H-2J, 2.08 (IH, w, H-2B), 3.83 (IH, dd, Ji^=UA Hz. J3B^B=5.5 Hz, H-3), 1.50 (IH, s, H-5), 3.86 (IH, s, H-6), 1.78 (IH, m, H-7B), 1.82 (IH, m, H-9), 1.68 (IH, m, H-1U), 1.91 (IH, m, H - l l J , 2.14 (IH, m, H-12), 1.08 (IH, rrf, JI3„.I3B=13 HZ, JI3„.12=3 HZ, J,3„.I4=3 HZ, H-13„), 1.71 (IH, m, H-13B), 2.08 (IH, td, J|4.I3B=10.3 HZ, JM. I3„=2 HZ, H-14), 5.67 (IH,

t, J=<1 Hz. H-15J, 5.18 (IH, /, J=1.6,1.6 Hz, H-17a), 5.00 (IH, /, J=1.6,1.6 Hz, H-17b), 1.64 (3H, s, H-18), 4.89 (IH, s, H-19), 2.72 (IH, s, H-20), 2.16 (3H, s, OAc), 6.08 (IH, d, J=4.5 Hz, 3-OH), 4.94 (IH, s, 19-OH). "C Chemical Shift Assignments (€03)280 C-1

25.61

C-12

33.0 d

C-2

31.81

C-13

32.51

C-3

73.0 d

C-14

42.9 d

C-4

48.5 s

C-15

71.8 d

C-5

61.7 d

C-16

151.7 s

98

B.S. Joshi, S.W. Pelletier and S.K. Srivastava C-6

60.6 d

C-17

C-7

28.01

C-18

19.1 q

C-8

44.0 s

C-19

87.6 d

C-9

43.5 d

C-20

69.9 d

C-10

48.5 s

C-21

170.5 s

C-11

26.21

C-22

20.8 q

109.91

'^C Chemical Shift Assignments (C5D5N) C-l

26.71

C.12

34.3 d

C.2

29.41

C-13

33.71

C-3

74.5 d

C-14

44.1 d

C-4

49.4 s

C-l 5

73.0 d

C-5

63.0 d

C-17

110.51

C-7

33.01

C-18

20.4 q

C-8

44.7 s

C.19

89.3 d

C-9

45.1 d

C-20

71.4 d

C-10

50.1s

C-21

171.2 s

C-11

27.01

C-22

21.2q

BS Joshi, MS Puar, Y Bai, AM Panu and SW Pelletier, Tetrahedron, 50,12283 (1994).

Carbon-13 and Proton NMR Shift Assignments

99

ANDERS0BINE-19-p-Ar,iV-DIMETHYLAMIN0BENZ0ATE C31H39N2O5; MW: 518; mp 204-207° Prepared from andersobine OAc HO'

' H NMR (CDCI3): 8 3.50 (IH,TO,H-3), 4.93, 4.99 (each IH, hts, H-17), 5.44 (IH, bts, H-15), 5.60 (IH, s. H-19), 6.64 (2H, d, J=8.6 Hz, 3', 5' Ar-H), 7.92 (2H, d. J=8.6 Hz,2',6'Ar-H).

" C Chemical Shift Assignments (CDCI3) C-1

26.6

C-15

72.7

C-2

29.8

C-16

151.4

C-3

75.7

C-17

110.6

C-4

44.7

C-18

18.4

C-5

63.4

C-19

91.1

C-6

60.9

171.1

C-7

26.7

COCH3 COCH3

C-8

44.9

ArCO

165.4

C-9

44.5

C-1'

C-10

49.3

C-2', 6'

131.9

C-11

24.8

C-3', 5'

110.9

C-12

33.7

C-4'

148.4

C-13

32.3

N(CH,)2

C-14

42.7

21.3 93.6

40.0

BS Joshi, MS Puar, Y Bai, AM Panu and SW Pelletier, Tetrahedron, 50,12283 (1994).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

100 ANOPTERIMINE

C25H33N03;MW: 395; mp 235-238'' O - C - C = C H - Me

[a]D +106" (CHCI3) Anopterus macleayanus F. Muell. 'H NMR (CDCI3): 5 1.03 (3H, s, H-18), 1.74 (3H, brd, J=7 Hz, H-4'), 1.82 {3H, bw, H-2'), 3.17 (IH, m, Ji3.i2=3 Hz, H-13), 4.37 (IH, dd, J=4, 6 Hz, H-11), 4.61 (IH, bra, H-20), 4.77, 5.02 (each IH, brs, H-17), 5.11 (IH, dd, J=3, 6 Hz, H-12), 6.87 (IH, brg, H-3'),7.42(lH,bK,H-19).

"C Chemical Shift Assignments (CDCI3) C-1

40.51

C-U

71.0 d

C-2

21.6t

C-12

76.2 d

C-3

36.51

C-13

54.6''d

C-4

40.5 s

C-14

53.2" d

C-5

45.6 d

C-15

36.51

C-6

24.41

C-16

149.7 s

C-7

34.lt

C-17

107.71

C-8

53.2's

C-18

23.8 q

C-9

58.7" d

C-19

168.5 d

C-10

51.4's

C-20

63.2 d

•'^^Assignments may be interchanged.

NK Hart, SR Johns, JA Lamberton, H Suares and RI Willing, AusU J. Chem., 29, 1319 (1976).

Carbon-13 and Proton NMR Shift Assignments

101

ANOPTERIMINE-iV-OXIDE C25H33NO4; MW: 411; mp 233-235° ta]D + 95{CHCl3) Anoplerus macleayanus F. Muell. 'HNMR(C6D6): 8 6.80(lH,br5, H-19), 7.01 (IH, m, H-3'), (CDCI3): 8 7.01 (IH, m, HOO. 1.08 (3H, s, H-18), 1.80 (3H, brrf, J=7 Hz, H.4'), 1.85 (3H, bw, H-2'), 3.17 (IH, m, H-B), 4.38 (IH, dd, J=4, 6 Hz, H-U), 4.79, 4.94 (each IH, bts, H-20, H-17), 5.03 (IH, brs, H-17), 5.13 (IH, dd, J=3, 6 Hz, H-12), 6.89 (2H. m, H-19,3'). "C Chemical Shifi Assignments (CDCI3) C-1

40.lt

C-11

70.4 d

C-2

21.31

C-12

75.6 d

C-3

37.81

C-13

53.4" d

C-4

41.5 s

C-14

51.8" d

C-5

45.6 s

C-15

36.01

C-6

23.71

C-I6

148.4 s

C-7

33.61

C-17

108.41

C-8

50.7" s

C-18

24.3 q

C-9

57.9''d

C-19

143.8 d

C-10

50.3" s

C-20

70.4 d

•,b

Assignments may be interchanged.

NK Hart, SR Johns, JA Lamberton, H Suares and RI Willing, ^w^/. /. Chem,, 29,1319 (1976).

102

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

ANOPTERINE (ANOPTERYL-11,12-DITIGLATE) 2-

2'

Me

Me I OCOC=CH-Me

Me-HC=COCO 4*

3'

C31H43NO7; MW: 541.3036; mp 2222230I-3

Anopterus glandulosus LabillJ'', y4 . macleayanus F. Muell.^'^'^

1'

'H NMR (CDCbf ^ 8 1.21 (3H, H-18), 1.46 (IH, Hcq-3J, 1.74 (3H, H-20, 1.76 (3H, H-40, 1.84 (3H, H-4'0, 1.88 (IH, Me OH Hcq-7J, 1.90 (3H, H-2'0,1.92 (IH, H^3B), 2.04 (IH, Hax-U), 2.17 (IH, H-15J, 2.33 (IH, H-9fl), 2.34 (3H, H-21), 2.35 (IH, Heq14«), 2.47 (IH, H«.70), 2.49 (IH, Heq-1 J, 2.72 (IH, Heq-19B), 2.75 (IH, H.15B), 2.96 (IH, Hcq-13„), 3.57 (IH, H.60), 3.71 (IH, 19J, 4.04 (IH, H-20J, 4.14 (IH, Heq-2), 4.90, 5.06 (each IH, H-17), 5.16 (IH, Heq-12fl), 5.52 (IH, H^-lU), 6.75 (IH, H-3'), 7.08 (IH, H-3"). X-ray structure^

1. 2. 3. 4. 5.

'^C Chemical Shift Assignments (CDCI3/

C-1

36.8

C-11

70.3

C-2

66.5

C-12

73.1

C-3

42.7

C-13

53.3

C-4

36.4

C-14

57.0

C-5

78.8

C-15

39.8

C-6

71.9

C-16

148.7

C-7

46.2

C-17

108.5

C-8

50.9

C-18

24.2

C-9

54.4

C-19

61.9

C-10

51.5

C-20

65.8

C-21

43.1

ME Wall, MC Wani, BN Meyer and H Taylor, J. Nat, Prod. (Lloydia), 50, 1152 (1987). NK Hart, SR Johns, JA Lamberton, H Suares and RI Willing, Aust. J. Chem., 29, 1295(1976). WA Denne, SR Johns, JA Lamberton, AM Mathieson and H Suares, Tetrahedron Lett., nil (1972). SR Johns, JA Lamberton, H Suares and Rl Willing, Aust. J. Chem., 38, 1091 (1985). YC Wu, TS Wu, M Niwa, ST Lu, Y Hirata, DR McPhail, AT McPhail and KH Lee, Heterocycles, 27,1813 (1988).

Carbon-13 and Proton NMR Shift Assignments

103

ANOPTERYL lla-4'-HYDR0XYBENZ0ATE 12a-TIGLATE C33H4iNO«; MW: 579; mp 273-276° 26 CH,

[a]D-28<'(CHCiyMeOHl.l) Anopterus macleayanus F. Muell. 'H NMR (CDCh + CD3OD): 5 1.15 (3H, s, H-18), 1.42 (IH, H-3e,). 1.84 (3H, H-26), 1.85 (IH, H-7e,), 1.88 (3H, s, H-25), 1.92 (IH. H-3.x), 2.11 (IH, H-l.x), 2.18 (IH, H-15), 2.33 (IH, H-9), 2.34 (3H. H-21), 2.41 (IH, H-14c), 2.51 (IH, H-7.x), 2.61 (IH, H-U,), 2.64 (IH, H19e,), 2.80 (IH, H-15), 3.00 (IH, H-13e,), 3.59 (IH, H-6e,), 3.79 (IH, H-19„), 4.09 (IH. H-20). 4.10 (IH. H-2e,), 4.91 (IH. H-17). 5.09 (IH, H-17), 5.24 (IH, H12e,), 5.64 (IH, H-1 l,x), 7.18 (IH, H-24), 7.77 (2H, H-2', 6'), 6.79 (2H, H-3', 5').

SR Johns. JA Lamberton, H Suares and RI WilUng, Aust. J. Chem., 38,1091 (1985).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

104

ANOPTERYL 12a-TIGLATE (1 la-DESTIGLOYLANOPTERINE) CMHJTNOS; M W : 459.2621; mp 184-

0-C-?=dH-Me

187°(Me20H)'*'^

[aJo+lS-'CCHClj) + 28»(CHCl3 + MeOHl:l) Anopterus glandulosus Labill', A. macleayanus F. Muell.^ 'H NMR (CDCb + CDsOD)^ 5 1.17 (3H, s, H-IS), 1.44 (IH. H-3), 1.84 (3H, H-26), 2.20 (IH, H-7e,), 1.93 (3H, s, H-25), 1.93 (IH, H-3„). 2.24 (IH, H-l,x), 2.11 (IH, H-15), 2.26* (IH, H-9), 2.33 (3H, J, H-21), 2.19* (IH, H-M.,), 2.46 (IH, H.7.x), 2.41 (IH, H-1.,), 2.64 (IH, H-19e,), 2.58 (IH, H-15), 2.91 (IH, H13eq), 3.60 (IH, H-6e,), 3.81 (IH, H-19«), 3.99 (IH, H-20), 4.08 (IH, H-2eq), 4.83 (IH, H-17), 5.03 (IH, H-17), 5.07 (IH, H-12e,), 4.35 (IH, H-ll.x), 7.17 (IH, H24).

'Assignments may be interchanged. 1. 2.

ME Wall, MC Wani, BN Mayer and H Taylor, J. Nat. Prod, 50,1152 (1987). SR Johns, JA Lamberton, H Suares and Rl Willing, Aust. J. Chem., 38, 1( (1985).

Carbon-19 and Proton NMR Shift Assignments

105

APOMIYACONINE C20H25NO4; MW: 343.411; mp 259.5-260^ CHo

Prepared from miyaconitine ^H NMR (CDCI3): 8 1.22 (3H, s, H-18), 2.38 (3H, s, N-Me), 5.05 (2H, c/, J=10 Hz, H-17), 7.75 (IH, d, J=12 Hz, OH-14).

'^C Chemical Shift Assignments (CDCI3) C-l

33.71

C-l 2

46.6 d

C-2

64.9 d

C-13

208.3 s

C-3

47.51

C-14

55.0 d

C-4

34.8 s

C-15

22.81

C-5

55.0 d

C-16

140.6 s

C-6

211.5 s

C-l 7

113.31

C-7

—

C-l 8

25.4 q

C-8

61.5 s

C-19

56.lt

C-9

79.6 s

C-20

64.3 d

C-10

49.1s

N-CH3

41.4 q

C-11

33.31

Y Ichinohe, M Yamaguchi and K Matsushita, Chemistry Lett., 1349 (1974).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

106 ATIDINE

C22H33NO3; MW: 359; mp 182.5-183.5^ [a]D-47.0« (CDCb)''^ Aconitum heterophyllum Wall.**^*^ *H NMR (CDCb^ ^ 8 0.77 (3H, 5, H-18), 1.95-2.95 (4H, w, H.19, H.20), 2.46 (2H, U J=5.5 Hz, H-21), 3.67 {2H, /, J=5.5 Hz, H-22), 4.53 (IH, bK, H-15), 5.04,5.17 (each lH,/w,H.17). X-ray structure '^C Chemical Shift Assignments (CDCI3/

1. 2. 3. 4. 5. 6.

C-1

40.7

C-12

36.0

C.2

22.6

C.13

26.6

C-3

39.1

C-14

25.3

C-4

33.5

C-15

72.8

C-5

47.9

C-16

151.5

C-6

36.2

C-17

109.5

C-7

215.8

C-18

25.8

C-8

53.0

C-19

58.9

C-9

41.6

C-20

53.5

C-10

37.2

C-21

58.0

C-11

28.0

C-22

60.5

SW Pelletier, R Aneja and KW Gopinath, Phytochemistry, 7,625 (1968). SW Pelletier, Chem. & Ind., 1016 (1956). SW Pelletier, J. Amer. Chem. Soc, 87,799 (1965). SW Pelletier and TN Oeltmann, Tetrahedron, 24,2019 (1968). J Finer-Moore, NV Mody, RS Sawhney and SW Pelletier, Cryst. Struct. Commun. 8,649 (1979). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

Carbon-13 and Proton NMR Shift Assignments

107

ATISINE C22H33N02;mp 329-331°^ [a]D-30.7° (EtOH)^ Aconitum heterophylloides Stapf.\ A. phyllum

hetero-

WalP*^, A, palmatum Don^, A. gigas

Lev et Van. (Lycoctonum

gigas Nakai)^; A.

zerauschanicum Steinb.^ ^^'H NMR (CDCI3): 8 0.70, 0.75 (3H, each s, H-18), 4.28 (IH, J, H-20), 4.95 (2H, m, H-17). '^C Chemical Shift Assignments (CDCb)^'"

C-1

A 42.0**

B 42.0^

C-12

A 36.6

B 36.6

C-2

22.4

21.7

C.13

27.7

27.7

€-3

41.0**

40.9"

C-14

25.5

25.5

C-4

33.8

28.2

C-15

77.0

77.0

C-5

51.6

48.9

C-16

157.5

157.5

C-6

17.8

18.5

C-17

108.9

108.4

C-7

34.6

32.0

C-18

26.7

26.1

C-8

37.5

37.5

C-19

56.4

53.3

C-9

40.0

39.6

C-20

93.9

94.2

C-10

40.4

40.4

C-21

50.3

50.3

C-11

28.2

28.2

C-22

64.1

59.2

"The data reported are for atisine, which is a mixture of the two H-20 epimers. **Assignments may be interchanged. *^H-20 epimers A and B. 1.

SW Pelletier, NV Mody, J Finer-Moore, HK Desai and HS Puri, Tetrahedron le//., 22,313 (1981).

2.

SW Pelletier and NV Mody, J. Amer. Chem. Soc, 99.284 (1977).

3.

SW Pelletier, R Aneja and KW Gopinath, Phytochemistry, 7,625 (1968).

4.

QP Jiang and SW Pelletier, J. Nat. Prod.. 54,525 (1991).

5.

S Sakai, N Shinma and T Okamato, Heterocycles, 8,207 (1977).

6.

ZM Vaisov, BT Salimov, B Tashkhodzhaeu and MS Yunusou, Khim. Prir. Soedin., 653 {\9S6).

108

B^. Joshi, S.W. Pelletier and S.K. Srivastava

ATISINE-IS-ONE C22H31NO2; mp 100-102** 22 r'

[a]D-27^(CHCl3)

Prepared from atisine^

21

'H NMR (Mixture of H-20 epimers A and B)*: 8 0.73, 0.78 (each 3H, s, H-IS), 5.17, 5.90 (each 2H,H.17). '^C Chemical Shift Assignments^^ H-20 epimers

A

H-20 epimers

A

B

C.12

36.2

36.2

C-l

40.8''

Q 40.8''

C-2

22.4

21.5

C-13

27.7

27.7

C-3

40.5'*

40.5"

C-14

29.3

29.3

C-4

33.8

27.7

C-15

204.0

203.0

C-5

51.5

48.6

C-16

147.4

147.1

C-6

17.4

18.2

C-17

116.3

115.9

C-7

34.2

34.2

C-18

26.6

25.9

C-8

44.7

44.7

C-19

55.9

53.2

C-9

44.2

44.2

C-20

93.4

93.4

C-10

41.7

41.7

C-21

50.1

50.1

C-11

29.6

29.6

C-22

64.3

59.2

•H-20 epimers A and B. ''Assignments may be interchanged.

1. 2.

SW Pelletier and PC Parthasarathy, J. Amer. Chem. Soc, 87,777 (1965). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

Carbon-13 and Proton NMR Shift Assignments

109

SINE-Ar,20-AZOMETHINE

K

^^CHg "^OH

C20H29NO; mp 178-179^ [a]D-2P(CHCl3) Preparedfromatisine'

H

^^C Chemical Shift Assignments^

1. 2.

C-l

42.4

C-11

28.1

C-2

20.0

C-12

36.0

C-3

34.1

C-13

26.1

C-4

32.8

C-14

25.5

C-5

46.9

C-15

75.2

C-6

19.6

C-16

156.2

C-7

31.0

C-l 7

108.9

C-8

37.4

C-l 8

25.8

C-9

38.1

C-19

60.2

C-10

42.5

C-20

166.4

SW Pelletier WA Jacobs, J. Am. Chem. Soc. 78,4139 (1956). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

B.S. Joshi, S.W. Pelletier and S.K. Srivastavj

110

ATISINIUM CHLORIDE (GUAN FU BASE G)

[

CH2

CI HO-

^H

C22H34CINO2

Aconitum gymnandrum^, A. pseudohuilieni Chang et Wang^, Delphinium coreanum^, an ^- gracile^ Prepared from atisine^ X-ray structure^

'^C Chemical Shift Assignments

1. 2. 3. 4. 5. 6.

C-l

42.7

C.12

26.8

C-2

21.5

C.13

27.6

C-3

37.6

C-14

27.2

C-4

35.4

C-l 5

77.2

C-5

46.6

C-16

156.8

C-6

21.2

C-l?

112.5

C-7

32.5

C-18

26.3

C-8

39.4

C-19

66.1

C-9

41.8

C.20

185.5

C-10

48.6

C.21

61.7

C-11

29.9

C.22

59.8

SW Pelletier and NV Mody, J Am. Chem. Soc, 101,492 (1979). F Wu and Z Zhu, Lanzhou Daxue Xuebao, Ziran Kexuebam, 19,183 (1983). AG Gonzalez, G de la Fuentc, M Reina and I Timon, Heterocycles, 22,667 (1984). JH Liu and XF Chen, Nanjing Yaoxueyuan Xuebao, 16, 58 (1985), [Chem. Ab. 103, 193190(1985)]. W Song, H Li and D Chen, Proc. CAMS and PUMC, 2,48 (1987). SW Pelletier, WH DeCamp and NV Mody, J. Am. Chem. Soc. 100,7976 (1978).

Carbon-13 and Proton NMR Shift Assignments AZITINE

111

C20H29NO; MW: 299; mp 177-179** Consolida hellespontica (Boiss) Chater syn., Delphinium hellespontica (Boiss) and D, tomentosum (Boiss)'. Prepared from atisine^ ' H N M R ' : 6 3.41, 3.42 (each IH, 5, H-19), 3.69 (IH, 5, H-15), 5.10, 5.40 (each IH, br^, H-17),7.87(lH,j,H-20). C Chemical Shift Assignments (C5D5N)'

(CDC13)'

25.9

C-l

26.1

C-2

19.5

c-2

19.6'

C-3

34.2

C-3

34.1

C-4

32.9

C-4

32.8

C-5

46.9

C-5

46.9

C-6

20.1

C-6

20.0'

C-7

42.3

C-7

42.4'

C-8

37.3

C-8

37.4

C-9

38.1

C-9

38.1

C-10

42.5

C-10

42.5

C-11

30.9

C-11

31.0'

C-12

35.9

C-12

36.0

C-13

25.1

C-13

25.5'

C-14

28.1

C-14

28.1'

C-l 5

75.8

C-15

75.2

C-16

156.6

C-16

156.2

C-17

109.2

C-17

108.9

C-l 8

25.9

C-l 8

25.8

C-19

60.4

C-19

60.2

C-20

166.2

C-20

166.4

C-l

*These values have been revised from those given in earlier literature.^ 1. HK Desai, BS Joshi and SW Pelletier, Heterocycles, 36,1081 (1993). 2. NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978). 3. SW Pelletier and WA Jacobs, J. Am. Chem. Soc, 78,4139 (1956).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

112 BARBALINE

C34H37NO11; MW [M-Hf: 624.2269; mp 297°

^u,

[a]D-17.2''(CHCl3) Delphinium barbeyi (Huth) Hulh

'H NMR: 8 1.16 (3H, s, Me-18), 1.96 (3H, s, OAc-3), 2.03 (3H, s, OAc-1), 2.10 (3H, s, OAc-11), 2.77 (IH, d. J=18 Hz, H-15), 2.43 (3H, s, N-Me), 2.52 (IH, s, H-5), 2.80 (IH, btd, J=4 Hz, H-14), 2.84 (IH. d, J=2 Hz, H-12), 2.93 (IH, dz, J=18,1.5 Hz, H-15), 2.96 (IH, dd, J=4,9.5 Hz, H-9), 3.03 (IH, btd, J=4 Hz, H-6), 3.81 (IH, s. H20), 3.94 (IH, d, J=4 Hz, H-7e), 4.96 (IH, brt, J=1.5 Hz, H-17), 5.06 (IH, hts, J=1.5 Hz, H-17), 5.22 (IH, d, J=3.9 Hz, H-3.), 5.43 (IH, dd, J=2,9.5 Hz, H-11,), 5.55 (IH, d, J=4.2 Hz, H-le), 6.09 (IH, /, J=4.2 Hz, H-2e), 7.98, 7.48-7.66 (5H, each m, Ar-H), 9.69 (IH, bts, H-19). X-ray structure '^Chemical Shift Assignments C-1

72.4

C-11

71.0

NCH3

C-2

66.6

C-12

60.0

COCH3-I

169.2^ 20.9*

C-3

71,9

C-13

206.2

COCH3-3

170.2,20.6

C-4

49.2

C-14

53.8

C0CH3-n

170.6*, 21.5*

C-5

57.6

C-15

30.1

ArCO

164.9

C-6

62.7

C-16

136.8

C-1'

129.2

C-7

67.6

C-17

113.9

C-2', 6'

129.8

C-8

49.5

C-18

23.3

C-3', 5'

128.8

C-9

48.6

C-19

196.4

C-4'

133.7

C-10

56.5

C-20

66.0

33.6

"'^Assignments may be interchanged. GD Manners, RY Wang, M Benson, MH Ralphs and JA Pfister, Phytochemistry, 42,875 (1996).

Carboii-13 and Proton NMR Shift Assignments

113

BARBISINE C32H35NO9; MW [M+H]*: 578; mp 251254» [a]D-62.9(CHCl3) Delphinium barbeyi (Huth) Huth 'H NMR (CDCI3): 81.11 (3H, s, H-18), 2.10, 2.14 (each 3H, s, OAc), 2.45 (3H, s, N-Me), 3.10 (IH, d, J=4.5 Hz, H-9B), 3.62 (IH, s, H-20). 3.78 (IH, d, J=4.5 Hz, H-11 J, 4.95,5.03 (each IH, d, J=2.1 Hz, H-17a, 17b), 5.05 (IH, s, H-7B), 5.17 (IH, d, J=3.1 Hz, H-U, 5.30 (IH, q, J=3.1 Hz, H-2B), 7.43, 7.56, 7.85 (each 5H. w, Ar-H), 9.23(lH,s,H-19). X-ray structure "Chemical Shift Assignments (CDCI3) C-1

68.8

C-15

28.9

C-2

68.4

C-16

135.5

C-3

29.6

C-17

115.7

C-4

43.9

C-18

26.1

C-5

59.3

C-19

196.6

C-6

61.7

C-20

67.2

C-7

74.5

NCHj

34.9

C-8

46.9

COCH3

170.0,20.9

C-9

56.4

COCH3

170.0,20.6

C-10

54.1

AiCO

165.3

C-U

63.2

C-1'

129.6

C-12

61.0

C-2', 6'

129.6

C-13

208.8

C-3', 5'

128.6

C-14

50.6

C-4'

133.5

P Kulanthaivel, E Holt, J Oslen and SW Pelletier, Phytochemistry, 29,293 (1990).

114

B^. Joshi, S.W. Pelletier and S.K. Srivasta^

1 la.BENZ0YL-7B-HYDR0XY-l la-DESTIGLOYLANOPTERINE (7fl-HYDROXYANOPTERYL-lla-BENZOATE-12a-TlGLATE)

%-i

2" Me I

OCOC=CH-Me

C33H4iNOg; MW: 579; mp 268-269°' M D - 9.5 (MeOH)' Anopterus glandulosus Labilr and A . macleayanus F. Muell.^ 'H N M R (CDCI})^

8 1.21 (3H, H-18),

1.42 (IH, He,-3), 1.83 (3H, H-4"), 1.89 (3H, H-2"). 1.96 (IH, H,x-3), 2.22 (IH, H„-l), 2.30 (3H, H-21), 2.46 (IH, H.,-14), 2.60 (IH, He,-1), 2.64 (IH, He,19), 2.90 (IH, H-9), 3.03 (2H, H-15, H,,13), 3.60 (IH, He,-6). 3.75 (IH, H«,-19), 3.93 (IH, He,-7), 4.13 (IH, H-20), 4.17 (IH, He,-2), 4.95, 5.13 (each IH, H-17), 5.31 (IH, Heq-12), 5.67 (IH, H„-l 1), 7.11 (IH, H-3"), 7.41 (2H, H-3', 5'), 7.55 (IH, H-4'), 7.92 (2H, H-2', 6').

1. 2.

ME Wall, MC Wani, BN Meyer and H Taylor, J. Nat. Prod., 50,1152 (1987). SR Johns, JA Lamberton, H Snares and RI Willing, Aust J. Chem., 38, 1091 (1985).

Carbon-13 and Proton NMR Shift Assignments

115

11-BENZOYLKOBUSINE

b

C27H31NO3; MW: 417; mp 214-215° Prepared from kobusine *H NMR (CDCI3): 8 3.97 (IH, s, H-15), 5.36(lH,c/,J=5Hz,H-ll).

S Sakai, I Yamamoto, K Yamaguchi, H Talcayama, M Ito and T Okamoto, Chem. Pharm. 5w//, 30,4579 (1982).

B J5. Joshi, S.W. Pelletier and S.K. Srivastava

116 15-BENZOYLKOBUSINE

C27H3iNOj;MW: 417; mp 125-134° Preparedfromkobusine OBZ

'H NMR (CDClj); 8 4.07 (IH, d, J=5 Hz, H-11),5.70(1H,5,H-15).

S Sakai, K Yamaguchi, H Takayama, I Yamamoto and T Okamoto, Chem. Pharm. Bull., 30,4576(1982).

Carbon-13 and Proton NMR Shift Assignments

117

6-BENZOYLPSEUDOKOBUSINE

b

C27H31NO4; MW: 433.2254; mp 238-239° Prepared from pseudokobusine 'H NMR (CDCI3): 8 0.99 (3H, s), 3.96 (IH, s), 4.06 (IH, d, J=4.6 Hz), 5.12, 5.22 (each IH, s), 7.31-7.63 (3H, m), 7.94-8.12 (2H,w).

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocycles, 26, 2623 (1987).

118

B^. Joshi, S.W. Pelletier and S.K. Srivastava

11-BENZOYLPSEUDOKOBUSINE C27H31NO4; MW: 433.2234; amorphous Prepared from pseudokobusine *H NMR (CDCI3): 8 1.38 (3H, 5, H-18), 4.02 (IH, s), 5.15, 5.32 (each IH, 5), 5.37 (IH, d J=4.6 Hz), 7.31-7.61 (3H, w), 7.878.01 (2H,w).

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocycles, 26 2623 (1987).

Carbon-13 and Proton NMR Shift Assignments

119

15-BENZO YLPSEUDOKOBUSINE

t:

C27H31NO4; MW: 433.2244; amorphous [a]D-6.9°(EtOH) Aconitum yesoense var. macroyesoense (Nakai) Tamura

^MeOH

'H NMR (CDCI3): 8 1.33 (3H, s\ 4.07 (IH, d, J=4.6 Hz), 5.27, 5.48, 5.82 (each IH, s\ 7.34-7.63 (3H, m, Ar-H), 7.91-8.03 (2H, m, Ar-H).

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocycles, 26, 2623(1987).

120

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

BRUNONINE C22H33NO3; MW: 359.2443 ; mp 208-209^ [a]D+174*» (EtOH) Delphinium brunonianum Roylc 22

^H NMR (CDCI3): 8 0.97 (3H, s, H-18), 1.27 (3H, /, J=7.2 Hz, H-22), 3.67, 4.14 (each IH, dq, J=10.8, 7.2 Hz, H-21), 4.30 (IH, bw, H-19), 8.03 (IH, H-20).

21

Me-CH2-0'

13.C

Chemical Shift Assignments (CDCI3)

C-l

35.lt

C-12

35.9 d

C-2

19.51

C-13

28.01

C-3

34.01

C-14

25.5 t

C-4

36.2 s

C-15

70.6 d

C-S

48.5 d

C-16

155.7 s

C-6

19.51

C-17

109.11

C-7

69.5 d

C-l 8

24.9 q

C-8

42.9 s

C.19

94.7 d

C-9

38.2 d

C-20

165.51

C-10

42.6 s

C-21

64.61

C-U

28.21

€-22

15.2 q

W Deng and WL Sung, Heterocycles, 24,869 (1986).

Carbon-13 and Proton NMR Shift Assignments

121

CARDIODINE C3sH43NOii;MW: 691.2952; amorphous [a]D-26»(C,0.05) 4"/ Vcoa, Delphinium cardiopetalum DC. 5~6" 'H NMR (CDCb)': 8 0.57 (3H, /, J=7.4 Hz, H-4'), 0.88 (3H, d, J=7.4 Hz, H-5'), 1.05 (3H, 5, H-18), 1.20 (2H, m, H-3'), 1.30 (IH, m, H-2'), 1.49 (IH, dd, J=13.9, 2.2 Hz, H-7|,), 1.87 (3H, s, OAc), 1.90 (3H, s, OAc), 2.00 (IH, m, H-7„), 2.09 (3H, s, OAc), 2.18 (IH, dt, J=18, 2 Hz, H-15p), 2.23 (IH, s, H-5), 2.30 (IH, dt, J=18, 2 Hz, H-15„), 2.40 (IH, d, J=9.4 Hz, H-9), 2.41 (IH,rf,J=12.5 Hz, H-19p), 2.47 (IH, d, J=2.8 Hz, H-12), 3.21 (IH, bw, W|/2=6 Hz, H-6), 3.23 (IH, d, J=12.5 Hz, H-19J, 3.68 (IH, s, H-20), 4.87 (IH, bw, H-17e), 5.01 (IH, bw, H-17z), 5.12 (IH, rf, J=4.9 Hz, H-3p), 5.40 (IH, d, J=9.4 Hz, H-1 Ip), 5.55 (IH, r, J=2.4 Hz, H-13p), 5.70 (IH, dd, J=5, 3.1 Hz, H-13,0. 5.70 (IH, dd, J=5, 3.1 Hz, H-2p). 6.08 (IH,
"C Chemical Shift Assignments (CDCb)'-^ C-1

72.4

C-12

47.9

C-3'

24.9

C-2

65.8

C-13

80.4

C-4'

10.7

C-3

70.9

C-14

78.6

C-5'

15.8

C-4

42.5

C-15

30.7

COCHj

170.0 (1), 169.9 (3),171.0 (11

C-5

58.0

C-16

141.5

COCHj

21.2(1), 20.6 (3), 21.4 (11)

C-6

62.5

C-17

110.6

ArCO

165.6

C-7

31.3

C-18

25.3

C-1"

130.0

C-8

44.9

C-19

59.1

C-2", 6"

129.6

C-9

49.7

C-20

67.0

C-3", 5"

128.7

C-10

49.5

c-r

174.5

C-4"

133.5

C-U

74.9

C-2'

39.6

1. 2.

M Reina, A Madinaveitia, JA Gavin and G de la Fuente, Phytochemistry, 41,1235 (1996). G Almanza, J Bastida, C Codina and G de la Fuente, Phytochemistry, 44, 739 (1997).

122

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

CARDIONIDINE C21H25NO5; MW: 371.1737; mp 310-315° (dec.)

HO.

[a]D-50MEtOH) Delphinium cardiopetalum DC* *H NMR (CDCI3)*: 5 1.25 (3H, 5, H-18), 2.03 (3H, 5, N-Me), 2.07, 3.07 (each IH, d, J=14 Hz, H-lp, H-1 J, 2.10, 2.70 (each IH, c/, J=11.4 Hz, H-19„, H-19p), 2.37 (IH, dd, J=7, 2.4 Hz, H-9), 2.70, 2.85 (each IH, du J=17, 2 Hz, H-15p, H.15J, 3.00 (IH, dd, J=9.8, 2.4 Hz, H-13p), 4.76, 4.89 (each IH, bw,H-17e,H-17z). X-ray structureJ .2 '^C Chemical Shift Assignments [CDCI3: CD3OD (1:3)]* C-1

—

C-12

—

C-2

210.1

C.13

69.2

C-3

—

C-14

—

C-4

—

€-15

—

C-5

—

C.16

146.1

C-6

167.6

C-17

107.3

C-7

170.9

C-18

22.7

C-8

—

C-19

—

C-9

—

C-20

—

C-10

— —

C-21

41.8

C-11

*^C NMR [CDCI3: CD3OD (1:3)]^ 5 29.3,29.6,33.4,36.5,40.9,45.6,45.8,56.3, 57.6, 62.3, 64.2,67.9 1. M Reina, A Madinaveitia, G de la Fuente, ML Rodriguez and I Brito, Tetrahedron Z^/A, 33,1661(1992). 2. I Brito, ML Rodriguez, M Reina, G de la Fuente and A Madinaveitia, Bol. Soc. ChiLQuim,, 41,21(1996).

Carbon-13 and Proton NMR Shift Assignments

123

CARDIONINE C24H33NO5; MW: 415.2362; mp 235° [a]D4.68°(EtOH) 23

/Me OCOCK

21 22 \ M e 24

Delphinium cardiopetalum DC; D. gracile, DC.

*H NMR [CDCI3 -CD3OD (1:1)]: 8 1.22 (6H, rf, J=7 Hz, H-23, H-24), 1.39 (3H, s, H-IS), 1.62(lH,5,H-5), 1.66(lH,i/, J=1.7 Hz, H-9), 2.36 (IH, brJ, J=10.7 Hz, Wi/2=7.5 Hz, H-M), 2.51 (IH, d J=l 1.8 Hz, H-19J, 2.63 (IH, sept, J=7 Hz, H-22), 2.73 (IH, 5, H-20), 3.18 (IH, d. J=l 1.8 Hz, H.19B), 3.86 (IH, s, H-llJ, 5.07 (IH, d, J=2 Hz, H-17e), 5.36 (IH, d, J=2 Hz, Me OH

H-17z), 5.73 (IH, t. J=2 Hz, H-15B).

^^C Chemical Shift Assignments (CDCI3 - CD3OD) C-1

35.7

C-13

35.8

C.2

19.6

C-14

41.1

C-3

27.7

C-15

71.1

C.4

38.3

C-16

148.6

C-5

60.9

C-17

110.3

C-6

99.0

C-18

30.4

C-7

38.8

C-19

59.5

C-8

45.8

C-20

72.8

C.9

58.2

C-21

177.9

C-10

—

C-22

34.7

C-11

71.9

C-23

19.5

C-12

74.6

C.24

19.5

G de la Fuente, JA Gavin, M Reina and RD Acosta, J. Org. Chem., 55,342 (1990).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

124

CARDIOPETAMINE 3' 2' O

C27H29NO3; MW: 447; mp 302-305" (dec.)

HOv

,/-y«-o..>

[a]D+ 65<'(EtOH)^ + 45'''

Aconitum napellus L. s. str. (Syn. A. anglicum Stapf.)'; Delphinium cardiopetalian DC^^; D.gracile.^ 'H NMR (CDClj)': 8 1.13 (3H, s, H-18), 2.04 (IH, s, H-5), 2.31 (IH, d, J=13 Hz, H-lp), 2.62 (IH, d, J=2.5 Hz, H-12), 2.70 (IH, d. J=13 Hz. H-19p), 2.75 (IH. dd, Ji=8.3 Hz. J2=2 Hz, H-9), 3.07 (IH, s, H-20), 3.37 (IH, bra, Wi/2=7 Hz, H-6), 3.50 (IH, d, J=13 Hz, H-IJ, 3.94 (IH, s, H-15), 4.15 (IH, brrf, J=10.8 Hz, Wi/2=6.5 Hz, H-13), 5.18 (2H, s, H-17), 5.61 (IH, d, J=8.5 Hz, H-11), 7.42-8.08 (5H,m,Ar-H). X-ray structure^

5" 6"

"C Chemical Shift Assignments' C-1

44.0

C-10

54.5

C-18

28.3 65.0

C-2

212.1

C-11

75.1

C-19

C-3

49.6

C-12

47.7

C-20

69.8

C-4

42.1

C-13

69.0

ArCO

165.8

C-5

59.7

C-14

48.9

C-1'

130.1

C.6

64.9

C-15

69.8

C-2', 6'

129.6

C-7

33.1

C-16

150.5

C-3', 5'

128.9

C-8

49.3

C-17

112.1

C-4'

133.5

C-9

48.7

1. 2.

G de la Fuente, M Reina and E Valencia, Heterocycles, 29,1577 (1989). AG Gonzalez, G de la Fuente, M Reina, PG Jones and PR Raithby, Tetrahedron Ie/M4,3765 (1983). AG Gonzalez, G de la Fuente, M Reina, R Diaz and I Tim6n, Phytochemistry, 25, 1971 (1986). AG Gonzalez, G de la Fuente, M Reina and I Tim6n, Heterocycles, 22,667 (1984).

125

Carbon-13 and Proton NMR Shift Assignments CARDIOPIDINE

CJ6H4JNO9; MW: 633.2991; amorphous

3" 2"

[a]D-22.5''(EtOH) Delphinium cardiopetalum DC.

AcO HO.

'H NMR (CDCI3): 8 0.87 (3H, t, J=7.4 Hz, H-4'), 0.99 (3H, s, H-18), 1.12 (3H, 5' 3" 2- r d, J=6.9 Hz, H-5'), 1.25 (IH, m, H-3*), MeCHaCHCOO I 1.70 (IH, dd, J=3.6, 2.2 Hz, H-7p), 1.89 Me (IH, dd, J=13.6,3.1 Hz, H-7J, 1.97 (3H, 4' s, OAc), 2.02 (3H, s, OAc), 2.15 (IH, hrd, J=18 Hz, H-15J. 2.20 (IH, s, H-5), 2.30 (IH, dd, J=9.6,2.2 Hz, H-9), 2.40 (IH, htd, J=18 Hz, H-15p), 2.40 (IH, d, J=12.6 Hz, H-19|,), 2.50 (IH, dd, J=9, 2.1 Hz, H-14), 2.53 (IH, d, J=2.5 Hz, H-12), 2.65 (2H, m, H-2'), 3.27 (IH, bw, W,/2=6.5 Hz, H-6), 3.39 (IH, d, J=12.6 Hz, H-19J, 3.91 (IH, s, H-20), 4.28 (IH, dd, J=4.6, 3.4 Hz, H-2p), 4.85 (IH, bK, H-17e), 4.94 (IH. d, J=4.8 Hz, H-3p), 5.01 (IH, bw, H-17z), 5.36 (IH, dl, J=9.5,2 Hz, H-13p), 5.14 (IH, d, J=9.2 Hz, H-1 Ip), 6.05 (IH, rf, J=3.2 Hz, H-U, 7.50 (2H, /, J=7.5 Hz, Ar-H), 7.56 (2H, /, J=7.5 Hz, Ar-H), 8.23(lH,rf,J=8Hz,Ar-H). "C Chemical Shift Assignments (CDClj) C-1

74.1

C-12

46.0

C-3'

26.6

€-2

67.1

C-13

73.9

C-4*

11.6

C-3

73.3

C-14

50.2

C-5»

16.7

C^

41.8

C-15

33.7

COCH3

171.0,170.4

C-5

59.5

C-16

142.7

COCH3

21.3.21.4

C.6

63.6

C-17

110.4

ArCO

165.7

C?

35.7

C-18

25.6

r

130.1

C-8

43.6

C-19

60.0

T

130.0

C-9

51.5

C-20

66.1

y

128.5

C-IO

53.7

c-r

175.7

4'

133.2

C-ll

75.2

C-2'

41.2

M Reina, A Madinaveitia, JA Gavin and G de la Fuentc, Phytochemistry^ 41,1235 (1996).

126

BS. Joshi, S.W. Pelletier and S.K. Srivastava

CARDIOPIMINE C35H45NO9; MW: 619.2784

3" 2'

[a]D-81.3''(EtOH) AcO-.. AcO

^

Delphinium cardiopetalum DC.

HO.

'H NMR (CDCI3): 8 1.01 (3H, s, H-18), 1.12 (IH,
C-2

74.2 67.0

C-11 C-12

75.2 46.0

c-r

C-2'

176.3 34.1

C-3

73.3

0-13

73.7

C-3'

18.8

C-4

41.8

C-14

50.2

C-4'

19.2

C'5

59.6

C-15

33.7

COCH3

170.4,171.

C'6

63.7

C-16

147.7

COCH3

21.3,21.4

C-7

35.7

C-17

110.4

ArCO

165.8

C-8

43.6

C-18

25.5

C-1"

130.1

C-9

51.6

C-19

60.0

C-2", 6"

129.9

C-10

53.9

C-20

66.1

C-3", 5"

128.5

C-4"

133.2

C-1

M Reina, A Madinaveitia, JA Gavin and G de la Fuente, Phytochemistry, 41, 1235 (1996).

Carbon-13 and Proton NMR Shift Assignments

127

CARDIOPINE C36H43NO9; MW:

197°

633.2848; mp 194-

[a]D-26.3"'(EtOH) 4" 3'

Z V

Delphinium cardiopetalum DC.

MeCHjCHCOO

'H NMR (CDCI3): 8 0.57 (H, t, J=7.5 Hz, H-4'), 0.85 (H, d, J=6.5 Hz, H-5'), 1.08 (IH, m, H-3'), 1.10 (IH, m, H-2'), 1.14 (3H, s, H-18), 1.66 (IH, dd, J=13.6, 2.6 Hz, H-7p), 1.88 (IH, dd, J=13.6,3.6 Hz, H-7J, 2.00 (3H, s, OAc), 2.06 (3H, s,OAc), 2.15 (IH, s, H-5), 2.18 (IH, dl, J=17.8, 2.1 Hz, H-15), 2.33 (IH, dd, J=9.6, 2.1 Hz, H-9), 2.37 (IH, d, J=12.8 Hz, H-19p), 2.38 (IH, d, J=2.7 Hz, H-12), 2.39 (IH, dt, J=17.8, 2.1 Hz, H-15p), 2.53 (IH, dd, J=9.9, 1.9 Hz, H-14), 3.10 (IH, d, J=12.8 Hz, H-19J, 3.30 (IH, bis, W,/2=6 Hz, H-6), 3.67 (IH, s, H-20), 3.87 (IH, d, J=5 Hz, H-3,0. 4.87 (IH, hrs, H-17e), 4.97 (IH, bw, H-I7z), 5.42 (IH, d, J=9.5 Hz, H-1 Ip), 5.51 (IH, dt, 1=9.7, 2.6 Hz, H-13p), 5.60 (IH, dd, J=.2,2.9 Hz, H-2p), 6.09 (IH, d, J=2.9 Hz, H-1 J, 7.47 (2H, t, 3=7 Hz, Ar-H), 7.57 (2H, t, 3=7 Hz, Ar-H), 8.14 (IH, d, 3=7.2 Hz, Ar-H). "C Chemical Shift Assignments (CDClj) C-1

73.2 d

C-12

46.6 d

C-3'

25.01

C-2

68.9 d

C.13

73.8 d

C.4'

10.8 q

C-3

70.8 d

C-14

50.4 d

C-5'

15.7 q

C-4

42.7 s

C-15

33.91

COCH3

C-5

59.5 d

€-16

142.7 s

COCH3

C-6

63.9 d

C-17

110.3t

ArCO

165.9

C-7

35.71

C-18

25.7 q

C-1"

130.1

C-8

44.1s

C.19

59.3 t

C-2", 6"

129.8 d

C-9

51.7d

C.20

66.1 d

C-3", 5"

128.7 d

C-10

53.9 s

c-r

177.4 s

C-4"

133.4 d

C-11

75.4 d

C'T

39.6 d

170.2 s, 171.0 s 21.2 q, 21.5 q

M Reina, A Madinaveitia, JA Gavin and G de la Fuente, Phytochemistry, 41,1235 (1996).

B^. Joshi, S.W. Pelletler and S.K. Srivastava

128 CARDIOPININE 3"

CsjHtiNOi.; MW: 619.2776; mp 218-220'

2"

4"/y^coc>».

[a]D-26.6''(EtOH) Delphinium cardiopetalum DC.

'HNMR(CDCl3): 5 0.59 (IH,rf,J=7 Hz, H-3'), 0.90 (IH, d, J=7 Hz, H.4'), 1.14 {3H, s, H-18), 1.25 (IH, sept, J=6.6 Hz, H-2'), 1.69 (IH, dd, J=13.4,2.4 Hz, H-7p), 1.90 (IH, dd, J=13.4, 3.2 Hz, H-7J, 1.99 (3H, s, OAc), 2.05 (3H, s, OAc), 2.16 (IH, s, H-5), 2.19 (IH, hrd, J=17.5 Hz, H-15 J, 2.30 (IH, dd, J=9.6, 2 Hz, H-9), 2.35 (IH, d, J=12.8 Hz, H-19,), 2.39 (IH, hrd, J=17,5 Hz, U-150, 2.40 (IH, d, J=2.6 Hz, H-12), 2.54 (IH, dd, J=9.9, 2 Hz, H-14), 3.10 (IH, d, J=12.8 Hz, H-19J, 3.32 (IH, hrs, V/m=6A Hz, H-6), 3.67 (IH, s, H-20), 3.85 (IH, d, J=5.1 Hz, H-3p), 4.84 (IH, hrs, H-17c), 4.97 (IH, bw, H-17Z), 5.43 (IH, d, J=10.4 Hz, H-11^, 5.48 (IH, dt, J=10, 2 Hz, H-13p), 5.59 (IH, dtf, J=5.1,2.8 Hz, H-2p), 6.08 (IH, d, J=2.9 Hz, H-1 J, 7.47 (2H, /, J=7.6 Hz, Ar-H), 7,55 (2H, t, J=8 Hz, Ar-H), 8.15 (IH, dd, J=8 Hz, Ar-H). "C Chemical Shift Assigrments (CDCIj) Z'\

73.1 d

C-11

75.4 d

c-r

177.4 s

Z'l

68.9 d

C-12

46.6 d

C-2'

33.1 d

C.3'

17.9 q 19.3 q

3-3

70.6 d

C-13

73.8 d

3-4

42.7

C-14

50.4 d

C-4'

2-5

59.3 d

C.15

33.71

COCH3

170.2 s, 171.0 s

3-6

63.8 d

C-16

147.8 s

COCH3

21.2 q, 21.4 q

3-7

35.71

C-17

110.3t

ArCO

165.8

3-8

44.1

C-18

25.7 q

C-1"

130.1 s

3-9

51.7 d

C-19

59.3 t

C-2", 6"

129.8 d

3-10

53.9

€-20

66.1 d

C-3", 5"

128.7 d

C-4"

133.4 d

M Reina, A Madinaveitia, JA Gavin and G de la Fucnte, Phytochemistry, 41,1235 (1996).

Carbon-13 and Proton NMR Shift Assignments

129

CHELLESPONTINE C22H33NO2; MW: 343; mp 227-230° [a]D+14.6''(MeOH) Consolida helkspontica (Boiss). 'H NMR (C5D5N): 8 0.84 (3H, s, H-18), 3.93 (IH. hts, H-15p), 5.10, 5.37 (each IH, bw, H-17), 9.43 (IH, s, H-22).

"C Chemical Shift Assignments (CsDjN) C-1

25.9

C-12

36.3

C-2

19.8

C-13

25.9

C-3

41.0

C-14

28.1

C-4

33.4

C-15

75.0

C-5

44.9

C-16

156.4

C-6

19.4

C-17

109.5

C-7

35.0

C-18

24.7

C-8

38.1

C-19

59.5

C-9

40.1

C-20

58.3

C-10

46.4

C-21

64.5

c-n

31.0

C-22

183.5

HK Desai, BS Joshi and SW Pclletier, Heterocycles, 36,1081 (1993).

BS. Joshi, S.W. Pelletier and S.K. Srivastava

130

CHUANFUNINE C22H35NO5; MW: 393; amorphous ^-CHg-OH

Aconitum carmichaeli Debx.

*H NMR (C5D5N): 8 4.72 (IH, dd, J,=l 1 Hz, J2=7 Hz, H-lp), 2.15, 2.92 (each IH, m, H-2), 1.26, 1.48 (each IH, m, H-3), Me OH 2.69 (IH, J, J=9 Hz, H-5), 5.28 (IH, d, J=9 Hz, H-6p), 2.26 (IH, bw, H-7), 1.65 (IH, J, J=8 Hz, H.9), 1.61, 3.76 (each IH, m, H-11), 1.51, 2.41 (each IH, w, H12), 2.47 (IH, d, J=5 Hz, H-13), 1.30, 1.95 (each IH, w, H-14), 4.52 (IH, s, H15), 4.62,4.79 (each IH, d, J=12 Hz, H-H), 0.73 (3H, s, H-18), 2.80, 3.42 (each IH, d, J=13 Hz, H-19), 4.61 (IH, hxs. H-20), 3.16, 3.40 (each IH, w, H-21), 1.56 (3H, /, J=7 Hz, H-22). '^C Chemical Shift Assignments C-l

68.0

C-12

21.0

C-2

30.2

C-l 3

43.5

C.3

37.5

C-14

28.8

C-4

34.8

C-15

84.5

C-5

53.0

C-l 6

80.0

C-6

70.4

C-17

69.1

C-7

46.1

C-18

25.5

C-8

43.2

C-l 9

55.0

C-9

50.8

C-20

68.8

C-10

53.2

C-21

54.3

C-11

23.8

C-22

10.5

XY Wei, SY Chen and J Zhou, Chinese J. Bot., 2,57 (1990).

Carbon-13 and Proton NMR Shift Assignments

131

CONTORINE(2-0-ACETYL-3-ANISOYLHETIDINE) C31H35NO7; MW: 533.2392; mp 238° (dec.) [a]D-44.9°(EtOH) Aconitum contortum Finet et Gagnet ,^g O

'H NMR (CDClj): 8 1.57, 2.04, 2.44 (each 3H, s), 3.30 (IH, d, J=12.1 Hz), 3.86 (3H, s), 4.83 (IH, ddd, S'=2.2,2.2, 0.7 Hz), 4.85 (IH, d, J=4.5 Hz), 4.99 (IH, /, J=2.3 Hz), 5.51 (IH, ddd, J=4.5, 4.5, 2.3 Hz), 6.92 (2H, d, J=9 Hz), 7.93 (2H, d, J=9 Hz). X-ray structure

"C Chemical Shift Assignments (CDCI3) C-1

34.5

C-I6

141.9

C-2

67.6

C-17

110.9

C-3

75.8

C-18

25.7

C-4

41.8

C-19

56.3

C-5

58.2

C-20

70.6

C-6

—

C-21

43.3

C-7

50.3

COCH3

169.3

C-8

44.3

21.2

C-9

49.7

COCH3 ArCO

165.2

C-10

41.9

c-r

113.6

C-11

22.9

C-2". 6*

122.1

C-12

52.7

C-3', 5'

131.6

C-13

211.5

C-4'

163.7

C-14

63.1

C-7'

55.5

C-15

34.7

K Niitsu, Y Ikeya, T Katsuhara, H Mitsuhashi, H Liang and S Chen, Heterocycles, 34, 1231 (1992).

132

B^. Joshi, S.W. Pelletier and S.K. Srivastava

CONTORSINE (2.0-ACETYL-3-1SOBUTYRYLHETIDINE) C27HJ5NO6; MW: 469.2441; mp 203206° CHg

A*^*v'''/Sl^'TVy«^ Me—--N \ ^ \ ^^urrc^y^^^.A--^ M e / 2'V ly\,^ H 4' MeO

[a]D-88.r(EtOH) Aconitum contortum. Finet et Ganep 'H NMR (CDCI3): 5 1.15, 1.16 (each 3H, d, J=7 Hz), 1.50, 2.07, 2.42 (each 3H,*), 2.46 (1H,
"C Chemical Shift Assignments (CDCI3) C-1

34.4

C-15

34.6

C-2

67.2

C-16

141.8

C-3

75.3

C-17

111.0

C-4

41.5

C-18

25.4

C-5

58.1

C-19

56.5

C-6

—

C-20

70.6

C-7

49.7

C-21

43.1

C-8

44.3

COCH3

169.4

C-9

49.6

COCH3

21.3

C-10

41.9

C-r

175.9

C-11

22.8

C.2'

34.1

C-12

52.7

C-3'

18.9

C-13

211.2

C-4'

18.8

C-14

62.8

K Ntitsu, Y Ikeya, T Katsuhara, H Mitsuhashi, H Liang and S Chen Heterocycles, 34, 1231 (1992).

Carbon-13 and Proton NMR Shift Assignments

133

CONTORTINE(2-ACETYL-3-(2S)-METHYLBUTYRYLHETIDINE) C2«H37N06; MW: 483.2632; mp 230233"' CH,2 ^z^'^-f/^^lfK'''^'''^ Me- "N " MICH,CHCOO'-SO''W^ I / ' * > H II Me Me O

[a]D-82.1°(EtOH) Aconitum contortum Finet et Ganep

'HNMR(CDCl3): 80.89(3H,U=7.4

Hz), 1.13 (3H, d, i=l Hz), 1.52, 2.07, 2.75 (each 3H, s), 2.50 (IH, d, J=12 Hz), 3.21 (IH, d, J=12 Hz), 4.64 (IH, d, J=4.4 Hz), 4.83 (IH, t, J=2 Hz), 4.98 (IH, /, J=2.4 Hz), 5.41 (IH, ddd, j=4.4,4.4,2.3Hz). X-ray structure

'^C Chemical Shift Assignments (CDClj) C-1

34.3

C-15

34.5

C-2

67.3

C-16

141.6

C-3

75.2

C-17

111.1

C-4

41.5

C-18

25.4

C-5

58.2

C-19

56.9

C-6

—

C-20

70.8

C-7

49.3

C-21

42.9

C-8

44.9

COCH3

169.4

C-9

49.6

COCH3

21.3

C-10

41.9

C-22

175.4

C-11

22.8

C-23

41.2

C-12

52.6

C-24

26.5

C-13

211.0

C-25

11.5

C-14

62.5

C-26

16.4

K Niitsu, Y Ikeya, T Katsuhara, H Mitsuhashi, H Liang and S Chen, Heterocycles, 34, 1231 (1992).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

134

CORYPHIDINE C31H44N2O3; MW: 492.3341; mp 2472490 3a X' Aconitum Koreanum (Levi.) Rapaics. fsi-Me 2. ^ ^H NMR (C5D5N): 8 0.87 (3H, 5, H-18), 1.92 (3H, s, N-COCH3), 2.31 (3H, s, NCH3), 2.95 (IH, ddd, J=8.2, 7, 1.8 Hz, H-7a), 3.14, 3.45 (each IH, J, J=13.2 Hz, H-19„, H-19p), 4.17 (IH, tdd, J=10.8, 5.5, 1.8 Hz, H-60, 5.53-5.60 (each 3H, m, H-4', H-5', H.15). '^C Chemical Shift Assignments C-1

46.3 t

C-17

36.5" t

C-2

22.41

C-18

27.6 q

C-3

40.5 t

C-19

55.3** t

C-4

38.9 s

C-20

171.41*^8

C-5

55.3d

C-21

171.5^8

C-6

20.2 t

C-22

23.2 q

C-7

37.4' t

N-CH3

40.8 q

C-8

40.5 s

C-2'

54.8** t

C-9

52.8 d

C-3'

38.0" t

C-10

55.3 s

C-3a

43.1s

C-11

28.71

C-4'

131.2d

C-12

36.61

C-5'

130.7 d

C-13

32.91

C-6'

63.9 d

C-14

3I.5t

C-7'

35.0" t

C.15

135.7 d

C-7a

70.5 d

C-16

147.8 s

"•^'''^Assignments may be interchanged. lA Bessonova, MR Yagudaev and MS Yunusov, Khim. Prir, Soedin., 243 (1992).

Carboii-13 and Proton NMR Shift Assignments

135

CORYPHINE

22r

,.-^o.

21»

C31H42N2O2; MW: 474.3227; mp 199-200** [a]D+150°(MeOH) Aconitum Koreanum (Levi.) Rapaics.* *H NMR^ 8 1.00 (3H, s, H-18), 2.26 (3H, s, N-CH3), 2.42, 2.61 (each IH, d, J=11.4 Hz, H-19), 2.60 (2H, w, H-2'), 2.84 (IH, ddd, J=2, 7, 12.3 Hz, H.7), 3.02, 3.10 (each IH, du J=3.9 Hz, H-21), 3.55, 3.78 (each IH, m, H-22), 5.38 (IH, s, H-15), 5.87 (IH, d, J=10 Hz, H.50,6.60 (IH, dd, J=1.8,10 Hz, H.4'). X-ray structure (coryphine perchlorate)* '^C Chemical Shift Assignments (CDCbr^

C-l

44.41

C-16

C.2

23.lt

C-l 7

34.7** t

C.3

41.51

C-18

28.5 q

C-4

35.0 s

C-19

57.81

C-5

53.3" d

C-20

105.7 s

C-6

19.91

C-21

51.7t

C-7

34.4** t

C-22

61.41

C-8

43.8 s

N.CH3

40.0 q

C-9

48.3 d

C-2'

54.61

C-10

47.1 s

C-3'

36.01

C-11

27.91

C-3a

47.1s

C-12

35.7 d

C-4'

156.1 d

C-13

31.4t

C-5'

125.9 d

C.14

54.4" d

C-6'

197.6 s

c-r

37.3 t

C-7a

70.1 d

C.15

136.3 d

146.5 s

•'^Assignments may be interchanged, 1. 2. 3.

IM Yusupova, lA Bessonova, B Tashkhodzhaev, MS Yunusov, MR Yagudaev and ZM Vaisov, Khim. Prir Soedin,, 396 (1991). IA Bessonova, MR Yagudaev and MS Yunusov, Khim, Prir. Soedin., 243 (1991). ZM Vaisov, LV Spirikhim, LM Khalilov, AS NuxzuUaev and MS Yunusov, Mendeleev Commun,, 237 (1993).

BJS. Joshi, S.W. Pelletier and S.K. Srivastava

136 COSSONIDINE

C20H27NO2; MW: 313.2046; mp 243-245° (dec.) [a]D + 34.7«'(EtOH) Delphinium cardiopetalum DC; D. cossnianum Batt. 'H NMR: 8 4.19 (brs, Wi/2=6 Hz, H-1 J , 1.79 (m, H-2J, 1.77 (m, H-2p), 1.25 (m, H3J, 1.74 (m, H-3p), 1.89 (s, H-5), 3.40 (bw, W,/2=6 Hz, H-6), 1.68 {dd, J=13.2,3,1 Hz, H-7J, 2.02 (dd, J=13.2,2.4 Hz, H-7p), 2.01 (d, J=l 1,5 Hz, H-9), 1.92 ( dd, J=14.2,4,2 Hz, H-HJ, 1.76 (m, H-11,,), 2.21 (m. Wi/2=8 Hz, H-12). 1.07 (
66.3 d

C-11

26.81

C.2

27.21

C-12

33.7 d

C-3

27.91

C-13

33.lt

C-4

37.2 s

C-14

43.6 d

C-5

56.6 d

C-15

71.6 d

C-6

65.8 d

C-16

156.4 s

C-7

32.61

C-17

108.91

C-8

45.8 s

C-18

28.5 q

C-9

41.4 d

C-19

63.01

C-10

55.1s

C-20

75.8 d

M Reina, JA Gavin, A Madinaveitia, RD Acosta and G de la Fuente, J. Nat. Prod, 59, 145 (1996).

137

Carbon-13 and Proton NMR Shift Assignments COSSONINE

C31H35NO7; MW: 533.2443; amorphous [a]D + 45«(CHCl3) Delphinium cossonianum Batt. 'H N M R (CDCI3): 8 1.01 (3H, s, H-18), 1.57 (IH, dd, J=13.4, 2.4 Hz, H-7p), 1.77 (IH, dd, J=13.4,3.1 Hz, H-7„), 1.81 (IH, dd, J=14.6, 11.6 Hz, H-lp), 1.84 (IH, s, H-5), 1.86, 2.20 (each 3H, 5,2 x OAc), 1.96 (IH, dd, J=9.3, 2.1 Hz, H-9), 2.01 (IH, d, J=16 Hz, H-15J, 2.18 (IH, d, J=16 Hz, H-15p), 2.31 (IH, d, J=9.6,2 Hz, H-14), 2.39 (IH, d, J=2.3 Hz, H-12), 2.51 (IH, d, J=13.3 Hz, H-19p), 2.82 (IH, d, J=13.3 Hz, H-19J, 3.01 (IH, s, H-20), 3.14 (IH, brs, H-6). 3.24 (IH, dd, J=14.6, 5.1 Hz, H-IJ, 4.22 (IH, d, J=9.3 Hz, H-1 Ip), 4.68 (IH, hrs, H-17e), 4.86 (IH, hrs, H-17z), 5.10 (IH, m, H-13p), 5.21 (IH, d, J=10.1 Hz, H-3p), 7.41 (2H, m, Ar-H), 7.53 (2H, t, Ar-H), 7.96 (IH, d, Ar-H). Aca.

"C Chemical Shift Assignments (CDC13) C-1

31.9t

C-14

49.9 ds

C-2

72.3 d

C-15

33.61

C-3

73.6 d

C-16

144.2 s

C-4

77.2 d

C-17

109.31

C-5

43.6 s

C-18

24.9 q

C-6

62.2 d

C-19

61.21

C-7

64.1 d

C-20

69.2 d

C-8

35.81

CDCH3

170.8,170.8!

C-9

44.0 s

COCH3

20.8,21.1 q

C-10

54.3 d

ArCO

165.8 s

C-11

51.9 s

C-2', 6'

129.6 d

C-12

74.8 d

C-3'. 5'

128.4 d

C.13

48.3 d

C-4'

130.0 d

G de la Fuente, JA Gavin, RD Acosta and F Sanchez-Ferrando, Phytochemistry, 34, 553 (1993).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

138 CRASSICAULINE B BzQ

C27H31NO4; MW: 433;mp311-315'^ Aconitum crassicaule''^ 'H NMR (CDCb)'-^ 6 1.10 (3H, s, H-18), 3.58 (IH, d, J=3 Hz, CHOW), A.TI (IH, m, CHOH), 4.65,4.76 (each IH, s, H-17), 5.34 (IH, m, H-13), 7.55, 7.67-8.06 (5H, m, Ar-H).

1. 2.

FP Wang and QC Fang, Planta Med, 42,375 (1981). FP Wang and XT Liang, Planta Med. 51,443 (1985).

Carbon-13 and Proton NMR Shift Assignments

139

CUAUCHICHICINE C22H33N02;mpl52.154*» Me

[a]D-69°(CHCl3)^ Garrya laurifolia Hartw.^; G. ovata var. Lindheimeri Ton*/ ^H NMR (CDCh)'"^: 6 4.29 (IH, bw, H20), 2.65 (2H, bw, H-19), 1.11 (3H, c/, H17),0.81(3H,5,H-18). X-ray structure'^

^^C Chemical Shift Assignments*'^

1. 2. 3. 4. 5.

C-1

41.6

C-12

22.4

C-2

18.4

C-13

33.7

C-3

38.4

C-14

34.7

C-4

34.0

C-15

224.7

C-5

52.4

C-16

49.5

C-6

17.9

C-17

10.0

C-7

32.6

C-18

25.5

C-8

52.0

C-19

56.7

C-9

47.7

C-20

92.7

C-10

40.5

C-21

50.5

C-11

22.7

C-22

64.5

C Djerassi, CR Smith, AE Lippmann, SK Figdor and J Herran, J, Am. Chem. Soc, 77,4801,6633(1955). SW Pelletier, NV Mody and DS Seigler, Heterocycles, 9,1409 (1978). SW Pelletier, HK Desai, J Finer-Moore and NV Mody, J, Am, Chem. Soc., 101, 6741 (1979). SW Pelletier, NV Mody and HK Desai, J. Org. Chem., 46,1840 (1981). SW Pelletier, NV Mody, HK Desai, J Finer-Moore, J Nowacki and BS Joshi, J. Org. C/iem., 48,1787(1983).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

140

16-£P/-CUAUCHICHICINE ,H

C22H33NO2; mp 136-138°

"""Me [a]D-74<'

"••••">>

Prepared from cuauchichicine

2r

*H NMR (CDCI3): 5 0.74,0.91 (each 3H, 5, H-IS), 1.16 (3H, d, J=8.5 Hz, H-17), 4.38 (lH,br5,H-20).

^^C Chemical Shift Assignments (CDCI3) C-1

41.8,41.3

C-12

28.7,29.7

C-2

18.8,20.9

C-13

34.2

C-3

37.4

C-14

36.6

C-4

34.2

C-15

226.0

C-5

52.1

C-16

49.2

C-6

18.3,19.6

C.17

15.9

C-7

32.9,31.1

€-18

25.9,25.2

C-8

52.8

C-19

56.7, 55.9

C-9

46.8,47.5

C-20

92.9,93.8

C-10

41.0

C-21

50.6

C-11

22.7

C-22

64.7, 59.0

SW Pelletier, NV Mody, HK Desai, J Finer-Moore, J Nowacki and BS Joshi, J. Org. C/iem., 48,1787(1983).

141

Carbon-13 and Proton NMR Shift Assignments CUAUCHICHICINE-A/;20-AZOMETHINE C2oH29NO;mp 135-137" [a]D- 114.4°

Prepared from a mixture of lindheimerine, ovatine, garryfoline' and veatchine^ 'H NMR': 8 0.81 (3H, s, H-18), 1.12 (3H, d, H-17), 3.43,3.48 (each 2H, s, H-19), 7.93 (lH,br5,H-20). "C Chemical Shift Assignments^

1. 2.

C-1

42.4

C-11

20.4

C-2

20.4

C-12

25.1

C-3

35.8

C-13

35.2

C-4

33.1

C-14

34.2

C-5

46.9

C-15

224.1

C-6

18.5

C-16

48.1

C-7

32.0

C-17

9.8

C-8

52.0

C-18

26.2

C-9

47.6

G-19

59.8

C-10

45.6

C-20

166.3

SW Pelletier, NV Mody and HK Desai, J. Org. Chem,, 46,1840 (1981). H Varbruggen and C Djerassi, J. Am. Chem. Soc, 84,2990 (1962).

142

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

11,12,16-CYCLOPROPYL-16,17-DIHYDROHETISANE C20H27NO; MP 187-188"; MW: 297 [a]D + 53.4* Prepared from kobiisine 'H NMR: S 0.76 (IH, M, H-12), 0.94 (3H, S, H-18), 1.16 (IH, g, H-11), 1.20(3H, S, H17), 3.19(1H, br§, H-6), 3.77(1H, S, H-15) X-ray Structure

S Sakai, K Yamaguchi, H Takayatna, I Yamamoto and T Okamoto, Chem. Pharm Bull, 30,4579(1982).

Carbon-13 and Proton NMR Shift Assignments

143

2-DEACETYLHETEROPHYLLOIDINE C21H27NO3; MW: 341.1991^ 341.2042'; mp 160-162°*; 154-158«''-^ [a]D^°-60°(CHCl3) Prepared from heterophylioidine (panicutine) Aconitum episcopate Levi; Delphinium albiflorum DC* ' H N M R (CDCI3)*: 8 2.02 (IH, dd, Ji„.,p= 13.8 Hz, J,„jp=4.4 Hz, H-l„), 1.61 (IH, dd, J,p,,„=13.8 Hz, J,p,2p=5.5 Hz, H-lp), 3.92 (IH, br*. Wi/2=5 Hz, H-2p), 1.80 (IH, m, H3J, 1.72 (IH, m, H-3p), 1.85 (IH, s, H-5), 2.41 (2H, m, H-7„, H-?,,), 1.91 (IH, m, H-9), 2.07 (IH, m, H - l l J , 1.85 (IH, m, H-llp), 2.92 (IH, brd, W,/2=7.5 Hz, H12), 2.60 (IH, \xt, W,/2=6 Hz, H-14), 2.35,2.49 (each IH, AB, Jg.m=18.1 Hz, H15„, H-15p), 4.76,4.94 (each IH, hts, Wi/2=5 Hz, H-17a, H-17b), 1.08 (3H, s, H18), 2.10, 2.40 (each IH, AB, J=8 Hz, H-19„, H-19p), 3.21 (IH, s, H-20), 2.45 (3H, s, H-21), 6.62 (IH, his, OH-2). "C Chemical Shift Assignments (QDe)* C-1

40.61

C-8

40.6 s

C-15

35.91

C-2

64.8 d

C-9

46.9 d

C-16

144.0 s

C-3

48.51

C-10

45.9 s

C-17

108.91

C-4

36.9 s

C-11

23.41

C-18

28.4 q

C-5

59.7 d

C-12

53.5 d

C-19

58.01

C-6

206.6 s

C-13

209.4 s

C-20

68.2 d

C-7

51.9t

C-14

57.7 d

C-21

42.0 q

1. 2. 3. 4. 5.

SW Pelletier, NV Mody, J Finer-Moore, HK Desai and HS Puri, Tetrahedron Lett, 22,313(1981). SW Pelletier, BS Joshi, HK Desai, A Panu and A Katz, Heterocycles, 24, 1275 (1986). FP Wang and XT Liang, Acta Pharmaceutica Sinica, 20,436 (1985). A Ulubelen, HK Desai, BS Joshi, V Venkateswarlu, SW Pelletier, AH Meri9li, F Meri9li and H Oz9elik, J. Nat, Prod, 58,1555 (1995). A Katz and E Stehlin, Helv. Chim. Acta, 65,286 (1982).

144

B^. Joshi, S.W. Pelletier and S.K. Srivastava

15-DEACETYLSPIRAMINE F C22H33NO3; MW: 359.248; amorphous [ajD-HO'CCHCb) Prepared from spiramine A and spiramine F 'H N M R (CDCI3): 5 0.73 (3H, s, H-18), 3.30 (2H, m, H-21), 3.55 (2H, m, H.22), 3.75 (IH, d, J=5 Hz, H-7), 3.91 (IH, bw, H15), 4.55 (IH, bw, H-20), 4.99, 5.01 (each lH,brj,H-17). "C Chemical Shift Assignments (CDCI3) C-1

41.3

C-12

37.1

C-2

21.1

C-13

25.1

C-3

30.1

C-14

21.lt

C-4

34.6

C.15

70.2 d

C-5

44.6

C-16

155.6

C-6

25.2

C-17

112.4

C-7

74.6 d

C-18

26.5

C-8

40.3

C-19

51.6

C-9

44.6

C-20

87.6 d

C-10

34.6

C-21

57.5

C-11

23.7

C-22

58.0

XJ Hao, M Node, J Zhou, SY Chen, T Toga, Y Miwa and K Fuji, Heterocycles, 36, 825 (1993).

Carbon-13 and Proton NMR Shift Assignments

145

15-DEACETYLVAKOGNAVINE C32H35NO,; MW: (M*- 60) 549; mp 224226.5'' 2

[a]D-73.4°(CHCl3) Aconitum palmatum Don. 'H NMR: 8 1.07 (3H, s, H-18), 2.02 (6H, s, OAc), 2.28 (3H, s.A^-CHa), 3.16 (IH, bw, H-6), 3.85 (IH, s, H-20), 5.41 (IH, d, J=3.7 Hz, H-1 J, 5.65 (IH, dd, J=7.9, 1.3 Hz, Hllp), 5.72 (IH, brm, J=9 Hz, H-2p), 7.53 (3H. m, Ar-H), 7.93 (2H, m, Ar-H).

"C Chemical Shift Assignments (CDCI3) C-1

70.5

C-15

70.7

C-2

67.2

C-16

142.1

C-3

29.2

C-17

117.6

C-4

44.1

C-18

26.4

C-5

59.8

C-19

195.0

C-6

57.3

C-20

66.6

C-7

28.4

N-CH3

33.0

C-8

49.6

COCH3

170.7,169.4

C-9

49.6

COCH3

21.5,21.1

C-10

56.4

Ar-CO

165.4

C-11

70.5

c-r

129.6

C-12

58.8

C-2', 6'

129.6

C-13

207.0

C-3', 5'

128.6

C-14

51.6

C-4'

133.0

QP Jiang and SW Pelletier, Tetrahedron Lett, 29,1875 (1988).

B.S. Joshi, S.W. Pcllctier and S.K. Srivastava

146

A^-DEETHYL-AT-ACETYL-I, 12, 1 S-T^-TRI ACETYLNAPELLINE

OAc

C28H37NO7; MW: 499 Prepared from napelline 'H NMR (CDCI3): 8 0.84 (3H, .v, H-18), 2.01, 2.17, 2.17, 2.11 (each 3H, .y, OAc), 2.50 (IH, ^, J=3.9 Hz, H-13), 2.86, 3.65 (each IH, ABq, J=14.6 Hz, H-19), 4.32 (IH, .y, H-20), 4.51 (IH, dd, J=10.4, 6.8 Hz, H-12o), 5.02, 5.30 (each IH, w, H-17),

Ac--- "1

5.04 (IH, dd, J=9,6.1 Hz, H-1B), 5.50 (IH,

/w,H-l5J. '^C Chemical Shift Assignments (CD3OD) C-1

73.7

C-12

78.5

C-2

27.4

C-13

50.1

C-3

29.6

C-14

38.3

€-4

34.3

C-15

77.5

C-5

49.9

C-16

153.3

C-6

24.8

C-17

112.0

C-7

49.5

C.18

25.8

C-8

51.3

C-19

50.6

C-9

39.4

C-20

62.6

C-10

50.7

COCH3

C-11

26.4

coai3

171.6,171.9,172.1,172.3 21.1,21.5,21.6,22.3

ZG Chen, AN Lao, HC Wang and SH Hong, Planta Med, 54,318 (1988).

Carbon-13 and Proton NMR Shift Assignments

147

A^-DEETHYL.1,19-DEHYDR0LUCIDUSCULINE C22H29NO4; amorphous [a]D-9.6^(EtOH)* CH2

Aconitum yesoense (Nakai) Tamura**^

var. macroyesoense

*H NMR*: 8 0.86 (3H, s, H-18), 2.14 (3H, 5r, OAc), 3.87 (IH, s, H-19), 4.15 (IH, d, J=4.8 Hz. H-1B), 4.93, 5.16 (each 1H,5,H-17), 5.50(1H,5,H-15).

^--j-

"C Chemical Shift Assignments (CDCb)^

1. 2.

C-l

67.8

C-l 2

76.1

C-2

29.6

C-l 3

46.6

C-3

23.7

C-14

28.1

C-4

37.8

C-15

77.7

C-5

45.6

C-16

151.6

C-6

23.5

C-l 7

110.5

C-7

48.1

C-18

19.0

C-8

49.4

C-l 9

87.8

C-9

34.0

C-20

57.5

C-10

50.6

CX)CH3

170.6

C-11

30.2

COCHj

21.5

K Wada, H Bando and T Amiya, Heterocycles, 23,2473 (1985). H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocycles, 26,2623(1987).

148

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

13-DEHYDROCARDIOPETAMINE C27H27N05

3' 2

../->J.o. J

Prepared from cardiopetamine

'^C Chemical Shift Assignments^ C-l

45.8

C-10

54.4

C-18

28.6

C-2

209.9

C-U

71.9*

C-19

64.2

C-20

7i.r

ArCO

166.0

C-3

49.6

C-12

57.7

C-4

42.5

C-13

205.6

C-5

59.9

C-14

58.6

C-l'

129.1

C-6

65.7

C-15

71.3

C-2', 6'

129.9

C-7

31.6

C-16

143.4

C-3', 5'

128.8

C-8

49.5

C-l 7

117.9

C-4'

133.7

C-9

49.1

^Assignments may be interchanged

AG Gonzalez, G de La Fuente, M Reina, R Diaz and I Tim6n, Phytochemistry^ 25,1971 (1986).

Carbon-13 and Proton NMR Shift Assignments

149

15-DEHYDROCARDIOPETAMINE 3'

2'

C27H27NO5; MW: 445; mp 275-278°

HO.

4'f^coo, J;

Prepared from cardiopetamine* *H NMR*: 8 4.38 (IH, brc/, J=9 Hz, H-13), 5.37 (IH, c/, J=9 Hz, H-U), 5.31,6.07 (each IH, J, H-17).

'^C Chemical Shift Assignments^

1. 2.

C-l

43.8

C-14

51.1

C-2

211.4

C-15

199.3

C-3

49.9

C-16

142.5

C-4

42.6

C-17

119.1

C-S

60.3

C-l 8

28.6

C-6

64.9

C-19

64.4

C-7

29.0

C-20

70.4

C-8

55.8

Ar-CO

166.4

C-9

53.0

C-l'

129.4

C-10

55.7

C-2', 6'

129.9

C-11

75.8

C-3', 5'

128.7

C-12

47.5

C-4'

133.5

C-13

69.1

AG Gonz&lez, 0 de la Fuente, M Reina, PG Jones and PR Raithby, Tetrahedron Lett., 24,3765 (1983). AG Gonzilez, G de la Fuente, M Reina, R Diaz and Tim6n, Phytochemistry, 25, 1971 (1986).

150

BS. Joshi, S.W. Pelietier and S.K. Srivastava

2-DEHYDROCARDIOPIMINE C}5H43N09; MW: 617; amorphous Prepared from cardiopinine 'H NMR (CDClj): 8 5.99(1H,5, H-l„), 5.50 (m,s,

3'

Me

2'CHibo'' 4"i

Me

H-3B), 2.57

(IH, s,

H-5),

3.40 (IH, hts, Wm=6 Hz, H-6), 5.37 (IH, d, J=8.3 Hz, H-I1B), 2.63 (IH, d. J=3.2 Hz, H-12), 5.39 (IH, dt, J=10 Hz, H-13B), 1.69 (3H, s, OAc), 2.14 (3H,

s,

OAc), 2.30 (IH, hrd, J=17 Hz, H-15J, 5.07 (IH, hrs, H-17z), 4.89 (IH, br.y, H-17e), 1.17 (3H, s, H-18), 3.20 (IH, s, H-20), 1.20 (3H, d, J=4.5 Hz, H-3'), 1.22 (3H, d, J=4.5 Hz, H-4'), 7.59 (4H, t, J=7.4 Hz, Ar-H), 8.30 (IH, dd, J=7.2, 1.8Hz,Ar-H).

M Reina, A Madinaveitia, JA Gavfn and G de la Fuente, Phytochemistry, 41, 1235 (1996).

Carboii-13 and Proton NMR Shift Assignments

151

1S-DEHYDROCOSSONIDINE K

C20H25NO2; MW: 311.1881; amorphous [a]D + 26.0*'(EtOH) Prepared from cossonidine

^H NMR (CDCL3): 8 1.03 (3H, s, H-18), 1.89 (IH, s, H-5), 2.14 (IH, dd, J=14.2, 4 Hz, H-lla), 2.19 (IH,rf/,J=11.9, 1.6 Hz, H-14), 2.40 (IH, J, J=12.5 Hz, H-19J, 2.54 (IH, d, J=12.5 Hz, H-19p), 2.61 (IH, s, H-20), 2.64 (IH, /w, H-12), 3.39 (IH, br^, W,/2=7 Hz, H.6), 4.29 (IH, br^, Wi/2=6.4 Hz, H-1 J, 5.08 (IH, d, J=1.5 Hz, H.17e), 5.89 (IH, d, J=1.5 Hz, H-17z). '^C Chemical Shift Assignments (CDCI3) C-1

66.1

C-ll

27.6

C.2

27.4

C.12

33.7

C-3

27.8

C-13

32.4

C-4

37.5

C-14

45.6

C-5

56.6

C-15

201.8

C-6

65.2

C-16

147.6

C-7

28.3

C-17

115.2

C-8

52.7

C-18

28.4

C-9

47.6

C-19

62.6

C-10

55.7

C-20

76.0

M Reina, JA Gavin, A Madinaveitia, RD Acosta and G de la Fuente, J. Nat. Prod, 59, 145 (1996).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

152

3-DEHYDRO-l-DESACETOXY-l,2-DEHYDROCARDIOPINE

A

C34Hj7N07; MW: 571; amorphous

coo.

Prepared from cardiopine

'H NMR (CDCb): 8 7.75 (IH, s, H1„), 3.01 (IH, s, H-5), 3.45 (IH, br*. MeCHjCHCOa. W,/2=6.3 Hz, H-6), 2.37 (IH, brrf, J=9 5-Me Hz, H-9), 5.35 (IH, d, J=10 Hz, H11B), 2.80 (IH, d, J=4.8 Hz, H-14), 2.15 (IH, brrf, J=18 Hz, H-15„), 5.09 (IH, hrs, H-17z), 4.90 (IH, br^, H17e), 1.21 (3H, 5, H-18), 3.27 (IH, d, J=13.2 Hz, H-19J, 2.75 (IH, d, J=13.2 Hz, H-19B), 1.87 (3H, s, OAc), 3.61 (IH, s, H-20), 0.94 (3H, /, J=7.4 Hz, H-4'), 1.23 (3H, d, J=6.3 Hz, H-5'), 7.50 (2H, t, J=8.2 Hz, Ar-H), 7.56 (2H, t, J=8 Hz, ArH), 8.02 (IH, dd, J=8.4,1 Hz, Ar-H).

4- 3-

2- V

^^C Chemical Shift Assignments (CDCI3) C-1

138.4

C-12

44.6

C-3'

26.6

C-2

128.5

C-13

73.4

C-4'

11.6

C-3

193.4

C-14

51.3

C-5'

16.5

C-4

37.5

C-15

33.6

COCH3

170.0

C-5

67.6

C-16

142.0

COCH3

20.8

C-6

66.5

C-17

111.2

ArCO

165.9

C-7

35.2

C-18

21.0

C-1"

129.7

C-8

45.9

C-19

65.0

C-2", 6"

129.6

C-9

49.5

C-20

75.0

C-3", 5"

128.6

C-10

49.2

c-r

176.0

C-4"

133.1

C-11

75.0

C-2'

40.7

M Reina, A Madinaveitia, JA Gavin and G de la Fuente, Phytochemistry, 41, 1235 (1996).

Carbon-13 and Proton NMR Shift Assignments

153

3-DEHYDRO-l-DESACETOXY-l,2-DEHYDROCARDIOPININE C33H35NO7; MW: 551; amorphous Prepared from cardiopinine *H NMR (CDCI3): 8 7.73 (IH, s, H-1 J, 3.00 (IH, s, H-5), 3.46 (IH, hrs, Wi/2=6.8 3' Hz, H-6), 1.94 (IH, dd, J=13.4, 3.2 Hz, Me H-7J, 1.84 (IH, dd, J=13.4,2.4 Hz, H-7fl), 2' V CHCOQ 1.86 (3H, 5, OAc), 2.38 (IH, dd, J=10.4, 4|iMe 1.9 Hz, H-9), 5.35 (IH, hvd, J=10 Hz, H-13fl), 2.44 (IH, dd, J=9.4, 2.8 Hz, H-14), 2.2 (IH, brJ, J=17.8 Hz, H-15J, 2.43 (IH, hrd, J=17.8 Hz, H-15B), 5.10 (IH, br^, H-17z), 4.91 (IH, br^, H-17e), 1.21 (3H, 5, H-18), 3.28 (IH, d, J=13 Hz, H.19J, 2.75 (IH, d, J=13 Hz, H-19B), 3.62 (IH, s, H-20), 2.68 (3H, sept, J=7 Hz, H.2'), 1.23 (3H, d, J=7 Hz, H-3'), 1.26 (3H, d, J=7 Hz, H-4'), 7.45 (2H, r, J=8 Hz, Ar-H), 7.58 (2H, /, J=8 Hz, Ar-H), 8.04 (IH, dd, J=8,12 Hz, Ar-H). '^C Chemical Shift Assignments (CDCI3) C-l

138.2

C-17

111.2

C-2

128.5

C-18

20.9

C-3

193.9

C-19

64.9

C-4

38.1

C-20

75.0

C-5

67.7

C-V

175.0

C-6

66.6

C-2'

33.5

C-7

35.2

C-3'

18.7

C-8

45.9

C-4'

19.0

C-9

49.5

COCH3

C-10

49.1

COCH3

169.5 20.8

C-11

74.9

ArCO

166.0

C-12

44.5

C-l"

129.6

C-l 3

73.4

C-2", 6"

129.6

C-14

51.2

C-3", 5"

128.6

C-l 5

33.6

C-4"

133.1

C-16

142.0

M Reina, A Madinavcitia, JA Gavin and G de la Fuente, Phytochemistry, 41,1235 (1996).

B.S. Joshi, S.W. Pellctier and S.K. Srivastava

154

2-DEHYDRO-l 1,13-O-DIACETYLHETISINE C24H29NO5; MW: 411 CD (MeOH) Prepared from 11,13-0-diacetylhetisine *H NMR (CDCI3): 6 1.13 (3H, s, H-18), 2.06, 2.25 (each 3H, 5, OAc), 3.30 (IH, bw, H-6D), 4.82, 5.00 (each IH, brs, H-17), 5.10, 5.19 (each IH, bw, H-1 1B, H-13p). '^C Chemical Shift Assignments (CDCI3) C-l

43.8

C.12

44.8

C-2

211.7

C-13

72.4

€-3

50.2

C-I4

49.8

C-4

42.8

C-15

33.6

C-5

60.5

0-16

142.9

C-6

65.2

C.17

110.4

C-7

35.8

C-18

28.6

C-S

44.8

C-19

64.8

C-9

52.6

C-20

70.5

C-10

55.4

COCH3

170.6, 170.2

C-11

75.3

COCH3

21.4,21.1

JA Glinski, BS Joshi, QP Jiang and SW Pelletier, Heterocycles, 11,185 (1988).

Carbon-13 and Proton NMR Shift Assignments

155

13-DEHYDRO-2,11-O-DIACETYLHETISINE O

C24H29NO5; MW: 411; mp 222-223'^

AcO. J X ^ ^CHo

CD(MeOH)

M l ---U

AcOv

J

|Sj—|-.,H Y^^^/^^^ l y \ ^ ^®

Prepared from 2,11 -0-diacetylhetisine *HNMR(CDCl3): 8l.00(3H,br5, H-18), 2.04, 2.07 (each 3H, s, OAc), 3.22 (IH, brs, H-66), 4.81, 4.92 (each IH, bw, H-17), 5.15, 5.22 (each IH, 5, H.2B, H-1 1B).

'^C Chemical Shift Assignments (CDCI3) C-l

31.2

€-12

61.1

€-2

69.7

C-13

207.6

C.3

36.2

C-14

59.1

C-4

36.6

C-15

34.6

C-5

60.6

C-16

138.8

C-6

64.6

C-17

113.1

C-7

33.3

C-l 8

29.4

C-8

43.6

C-19

63.1

C-9

52.9

C-20

68.1

C-10

50.1

COCH3

170.3,170.1

C-11

72.6

COCH3

21.7,21.3

JA Glinski, BS Joshi, QP Jiang and SW Pelletier, Heterocycles, 27,185 (1988).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

156

2,20-DEHYDRO 16,17-DIHYDRO.(14, lO-SECO) HETIDINE C21H29NO4; MW: 359.2119; amorphous Prepared from episcopalidine ^H NMR (90 MHz): 5 0.94 (3H, d, J=7 Hz, H-17), 1.40 (3H, 5, H-19), 2.32 (3H, s, NCH3), 2.52, 2.80 (each IH, AB^, J=ll Hz, H-19), 3.20 (IH, s, H-3), 3.95 (IH, J, J=5.7 Hz,H.2),4.30(lH,^,H.20).

MeO

il C

Chemical Shift Assignments

C-l

44.9

C.12

49.9

C-2

76.5

C.13

214.7

C-3

78.8

C-14

53.2

C-4

38.9

C-15

29.7

C-5

57.4

C-16

30.4

C-6

204.5

C-17

22.6

C-7

52.4

C-l 8

22.9

C-8

40.7

C-19

48.9

C-9

44.7

C.20

93.7

C-10

43.5

N'CHi

42.0

C-11

26.6

FP Wang and XT Liang, Tetrahedron, 42,265 (1986).

Carbon-13 and Proton NMR Shift Assignments

157

15,16-DEHYDRO-16, 17-DIHYDROTATSIRINE C20H27NO3

Rearrangement product oftatsirine ' H NMRCCDSODS): 6 I.IO(IH. brt, J=l 1.6

HO.

^MeOH

Hz, H-11 p), 1.40 (3H, 5, H-18), 1.46 (IH, m, H9), 1.50(lH.m,H-14), 1.52(lH,m,H-lp), 1.56 (IH, m, H-3p). 1.66 (1H, s, H-5), 1.70 (1H. m, H-lla). 1.86(lH.m,H-3a), 1.83(1H,5,H-I7). 1.96 (IH, br^, J=14.2 Hz, H-Ia), 2.22 (IH.
" C Chemical Shift Assignments a (CD3OD) b (CDjClj), c (CD^CIj+l %CD30D) c b a (b) (a) (c) 25.4 26.31 25.5 34.4 C-U 34.7 35.01 C-1 €-12 42.7 44.0 d 42.9 65.2 66.3 66.9 d C-2 74.0 74.6 75.4 d C-13 41.7 41.6 42.41 C-3 C-14 59.1 d 58.3 57.8 36.7 36.7 37.6 s C^ 123.4 122.4 124.0 d C-15 59.2 59.6 61.0 d 0-5 143.8 143.2 144.1s C-16 101.4 98,0 100.7 s C-6 C-17 21.7 21.8 q 21.8 40.7 41.81 41.5 C-7 30.5 30.7 C-18 31.1 q 48.2 48.3 C-8 60.31 59.0 58.1 C-19 48.8 48.8 49.8 d C-9 69.7 69.2 70.8 d C-20 44,8 45.0 C-10 45.9

X Zhang, JK Synder, BS Joshi, JA Glinski and SW Pclleticr, Heterocycles, 31,1879 (1990)

B JS. Joshi, S.W. Pelletier and S.K. Srivastava

158 11-DEHYDROHETISINE

C2oH25N03;MW: 327; mp 292-298° Prepared from hetisine 'H N M R (CDCb): 8 1.01 (3H, s, H.18), 4.20 (2H, brm, H-IQ, H-13p), 4.98 (2H, br5, H-17).

HO.

'^C Chemical Shift Assignments (H2SO4 + D2O) C-l

32.4

C-11

215.4

C-2

67.8

C-12

62.8

C.3

38.7

C-13

67.2

C-4

36.4

C-14

50.6

C-5

61.8

C-15

33.2

C-6

66.5

C-16

140.1

C-7

32.4

C-17

115.1

C-8

44.6

C-l 8

29.2

C-9

56.9

C-19

64.8

C-10

49.0

C-20

69.0

JA Glinski, BS Joshi, Q? Jiang and SW Pelletier, Heterocycles, 27,185 (1988).

Carboii-13 and Proton NMR Shift Assignments

159

1,19-DEHYDROLUCIDUSCULINE C24H33NO4; MW: 399; mp 186-189*»*'^ [a]D+2.6^(EtOH)^ Aconitum yesoense var. macroyesoense (Nakai) Tamura**^ Prepared from lucidusculine^ 'H NMR^: 8 0.81 (3H, 5, H.18), 1.01 (3H, r, J=7 Hz, H-22), 2.13 (3H, 5, OAc), 3.69 (IH, 5, H-19), 4.06 (IH, £/, J=4.9 Hz, H-U), 4.92, 5.12 (each IH, 5, H-17), 5.49 (IH, br5,H-15). '^C Chemical Shift Assignments (CDCI3)*

1. 2.

C-l

67.6

C-13

46.8

C-2

29.7

C-14

28.1

C-3

24.5

C-l 5

77.7

C-4

37.7

C-16

151.7

C-5

45.8

C-17

110.4

C-6

23.8

C-18

18.9

C-7

48.3

C-19

92.8

as

49.4

C-20

65.6

C-9

33.7

C-21

48.3

C-10

51.7

C-22

14.1

C-11

30.2

COCH3

170.7

C-12

76.1

COCH3

21.5

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocvcfej, 26,2623 (1987). K Wada, H Bando and T Amiya, Heterocycles, 23,2473 (1985).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

160

12-EPI-l, 19 DEHYDROLUCIDUSCULINE OH

C24H33NO4; MW: 399.2412; amorphous [a]D-9.6°(CHCl3) Aconitum liangshanium W. Z. Wang 'H NMR: 8 0.81 (3H, s, H-18), 1.00 (3H, t, J=7.2 Hz, H-22), 2.74 (IH, s, H-20), 2.86 (IH, dd, J=8.5,4.7 Hz, H-13), 4.18 (IH, t, J=7 Hz, H-12), 5.19 (2H, hts, H-17), 5.56 (lH,/,J=2.2Hz,H-15).

H Takayama, E Wu, H Eda, K Oda, N Aimi and S Sakai, Chem. Pharm. Bull.. 39,1644 (1991).

Carbon-13 and Proton NMR Shift Assignments

161

12-£PM,19-DEHYDRONAPELLINE C22H31NO3; MW: 357.2291 [a]D + 45« (EtOH); + 56.8^ (CHCI3/ Aconitum napellus L. ssp. castellanum J. Molero et C. Blanch^*; A. nappellus fed on Aphids Brachycaudus aconit^; A. liangshainum W. Z. Wang^ *H NMR (CDCI3)* ^ 8 0.81 (3H, j , H18), 1.00 (3H, U J=7 Hz, H-22), 2.66, 2.67 (each IH, dq, J=7.1 Hz, H.21), 2.73 (IH, d, J=1.7 Hz, H-20), 2.80 (IH,rfrf,J=8.7,4.5 Hz, H-H), 3.67 (IH, bw, H.19), 4.01 (IH,rf,J=5 Hz, H-IB), 4.12 (IH, dd, J=8.5, 4 Hz, H-12J, 4.27 (IH, bw, H15J, 5.20,5.39 (each IH, bw, H-17). '^C Chemical Shift Assignments (CDCI3)*

1. 2. 3.

C-l

67.9

C-12

67.5

C-2

30.0

C-l 3

42.6

C-3

24.8

C-14

31.9

C-4

37.9

C.15

77.3

C-S

48.9

C.16

154.0

C-6

24.2

C-l 7

112.6

C-7

46.0

C-l 8

19.1

C-8

50.9

C-19

93.1

C-9

33.3

C-20

66.1

C-10

52.1

C.21

48.9

C-11

30.9

C-22

14.4

G de la Fuente, M Reina, E Valencia and A Rodriguez-Ojeda, Heterocycles, 27, 1109(1988). H Liu and A Katz, J. Nat. Prod, 59,135 (1996). H Takayama, E Wu, H Eda, K Oda, N Aimi and S Sakai Chem. Pharm. Bull., 39, 1644(1991).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

162

1,19-DEHYDR0NAPELLINE(1,19-DEHYDROLUCICULINE) C22H31NO3; MW: 357.2274; mp 103.5105**^ 98.5-101.5°^ 92-92.5**^ CH2

[a]D+78.3'»(EtOH)* AconitumflavumHand-Mazz; A. yesoeme var. macroyesoense (Nakai) Tamara^ Prepared from 1,19-dehydroluciduscuUne^

*H NMR (CDCb)^*^: 8 0.80 (3H, s, H-18), 1.00 (3H, /, J=6.8 Hz, H-22), 1.14 (IH, dd, J=l 1.9, 4.3 Hz, Hcq-14), 1.85 (IH, d, J=l 1.9 Hz, Hax-14), 2.45 (IH, d, J=4.5 Hz, H-13), 2.80 (IH,bw, H-20), 3.65 (IH, w, H-12), 3.68 (IH,5, H-19), 4.03 (IH, d, J=5.3 Hz, H-l), 4.21 (IH,dt, J=7.6,2.3 Hz, H-15), 5.16 (2H, brJ, J=1.5 Hz, H-H). '^C Chemical Shift Assignments (CDCI3) C-1

1 67.9

3 61.1

C-12

1 76.4

3 76.2

C-2

29.9

29.8

C-13

48.8

46.6

C-3

lAA

24.4

C-14

30.4

27.7

C-4

37.8

37.7

C-15

77.5

77.4

C-5

32.5

45.8

C-16

157.7

157.5

C-6

24.0

23.9

C-17

109.5

109.3

C-7

46.7

48.7

C-18

19,0

18.9

C.8

50.4

50.3

C-19

93.1

93.0

C-9

36.9

32.4

C-20

66.0

65.9

C-10

51.9

51.8

C-21

48.4

48.3

C-11

27.8

30.3

C-22

14.3

14.2

1.

ZG Chen, AN Lao, HC Wang and SH Hong, Heterocycles, 26,1455 (1987).

2.

K Wada, H Bando, T Amiya and N Kawahara, Heterocycles, 29,2141 (1989).

3.

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Meterocycto, 26,2623 (1987).

Carboii-13 and Proton NMR Shift Assignments

163

13.DEHYDROPANICULATINE C31H33NO7; MW: 531

Prepared from paniculatine ^HNMRCCDClj): 8 1.05 (3H, j , H-I8), 1.76-1.84,1.90-2.00 (each 4H, m, H-3, H7), 2.03, 2.04 (each 3H, ^, 2 x OAc), 2.14 (IH, 5, H-5), 2.47 (IH, dd, H-12), 2.58 (IH, H-14), 2.28, 2.58 (2H, AB, JAB=18 Hz, H-15), 2.53, 2.85 (2H, AB, JAB=12

Hz, H-19), 2.87 (IH, d, J=6 Hz, H-9), 3.38 (IH, m, W,/2=7 Hz, H.6), 3.94 (IH, 5, H20), 4.95, 5.06 (each IH, s, H-17), 5.42 (IH, s, H-1), 5.40 (IH, H-11), 5.49 (IH, /w, Wi/2=10 Hz, H-2), 7.54 (2H, /, Ar-H), 7.62 (IH, /, Ar-H), 8.08 (2H, d, Ar-H). '^C Chemical Shift Assignments (CDCI3)

C-l

72.1 d

C-15

34.61

C-2

71.6 d

C-16

138.3 s

C-3

33.51

C-17

113.lt

C-4

36.7 s

C-l 8

29.3 q

C-5

51.5 d

C-19

63.41

C-6

. 66.8 d

C-20

57.7 d

C-7

32.81

COCH3

169.6,170.9 s

C-8

43.6 s

COCH3

21.2,21.4 q

C-9

64.4 d

ArCO

165.4

C-10

54.4 s

c-r

129.9

C-11

68.3 d

C.2', 6'

129.3

C-12

60.6 d

C-3', 5'

128.8

C-l 3

206.7 s

C-4*

133.3

C-14

59.9 d

A Katz, J. Nat. Prod, 52,430 (1989).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

164 15-DEHYDRORYOSENAMINE

C27H29NO4; MW 413; mp 275-278" Prepared from ryosenamine ' H N M R (CDCI,): 5 1.07 (3H, s, H-18), 5.55

Bza.

(IH.m, H-2p).5.10.5.88 (each IH,5, H-17).

S Sakai, I Yamamoto, K Hotoda, K Yamaguchi, N Aimi, E Yamanaka, J Haginiwa, and T Okamoto, YakugakuZasshh 104,222 (1984).

Carbon-13 and Proton NMR Shift Assignments

165

DELATISINE Ha

C20H23NO3; MW: 327.1829; mp 274.5276.5° [a]D + 8.6*'(CHCl3)

Delphinium datum L. cv. pacific giant 'H NMR (CDCI3): 5 1.15 (3H, 5, H-18), 1.57 (IH, J, J3„3p=n.2 Hz, J3p,2
C-11

75.7 d

C-2

79.6 d

C-l 2

50.2 d

€-3

41.61

C-13

72.2 d

C-4

50.5 s

C-14

50.0 d

C-l

C-5

62.0 d

C-15

33.91

C-6

66.3 d

C-16

145.7 s

C-7

37.31

C-17

108.21

C-8

45.7 s

C-l 8

21.9 q

C-9

55.4 d

€-19

100.2 d

C-10

52.7 s

C-20

64.4 d

SA Ross, BS Joshi, HK Desai, SW Pelletier, MG Newton, X Zhang and JK Snyder, Tetrahedron, 47,9585 (1991).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

166 DELBIDINE HO,

C20H25NO4; MW: 343; mp > 360° ltt]D + 223'iMeOH) Delphinium barbeyi (Huth) Huth, D. occidentale (S. Wats) S. Wats. 'H N M R (DMSO-rfe): 8 1.36 {3H, s, H-18), 4.50.4.70 (each IH, br^, H-17).

'Me OH

"C Chemical Shift Assignments (CDCI3) C-l

44.21

C-11

69.9 d

C.2

212.9 s

C-12

53.7 d

C-3

51.5 t

C-13

73.3 d

C-4

42.3 s

C-14

51.1 d

C-5

60.9 d

C-15

44.01

C.6

97.9 s

C-16

148.1 s

C-7

33.3 t

C-17

106.11

C-S

45.2 s

C-18

30.2 q

C-9

51.3 d

C-19

62.71

C-10

55.6 s

C-20

68.9 d

BS Joshi, HK Desai, EA El-Kashoury, SW Pelletier and JD Olscn, Phytochemistry, 28, 1561 (1989).

Carbon-13 and Proton NMR Shift Assignments

167

DELFISSINOL C20H27NO3; MW: 329.195; amorphous [a]D-39.r(MeOH) Delphinium fissum Waldst and Kit ssp. anatolicum Chaudhurs and Davis ^H NMR (CDCI3): 8 2.72, 3.07 (each IH, d, J==12.5 Hz, H.19), 4.16 (IH, bre/, J=7 Hz, H11), 4.26 (IH, brrf, J=8.6 Hz, H-B), 4.48 (IH, /, J=5 Hz, H-7), 4.68, 4.86 (each IH, bw, H17).

'^C Chemical Shift Assignments (CDCI3) C-1

34.4

C-11

75.8

C-2

19.2

C-12

50.8

C-3

32.3

C-13

73.2

C-4

38.7

C-14

52.0

C-5

56.7

C-15

35.4

C.6

65.6

C-16

145.2

C-7

70.1

C-17

108.2

C-8

44.3

C-18

29.9

C-9

50.5

C-19

612.0

C-10

51.5

C-20

70.1

A Ulubelen, AH Meri^li, F MeriQli, R Ilarsan and W Voelter, Phytochemistry, 34,1165 (1993).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

168 DELGRANDINE

C4iH43NO,2: MW (M-l)*:740; mp 300302° [ab"-130.2" (CHClj) Delphinium grandiflorum L. 'H NMR: 81.11 (3H, s, H-18), 1.88,2.02, 2.11 (each 3H, s, OAc), 2.05 (IH, s, H-5), 2.20, 2.88 (each IH, d, J=19 Hz, H-15), 2.40 (IH, d, J=9.3 Hz, H-9), 2.58 (IH, bw, W,/2=10 Hz, H-12), 2.67 (3H, s, A^-CH,), 3.28 (IH, bK, H-6), 3.35 (IH, d, J=9.3 Hz, H-14), 3.50 (IH, brs, OH), 3.82 (IH, brj, W,/2=10 Hz, H-7), 3.92 (IH, s, H-20), 4.90, 5.05 (each IH, brj, H-17), 5.15 (IH, d, J= 3.5 Hz, H-3), 5.35 (IH, d, J=9.3 Hz, H-13), 5.52 (IH, d, J=9.3 Hz, H-11), 6.00 (IH, d, J=3.5 Hz, H-1), 6.05 (IH, dd, Ji=3.5 Hz, J2=3.5 Hz, H-2), 7.04 (2H, t, J=8 Hz, Ar-H), 7.33 (3H, m, Ar-H), 7.54 (3H, m, Ar-H), 7.69 (2H, d, J=8 Hz, Ar-H). "C Chemical Shift Assignments (C5D5N) C-1

72.0

C-15

29.4

C-2

66.2

C-16

141.5

C-3

71.8

C-17

111.3

C-4

48.9

C-18

22.9

C-5

59.4

C-19

190.5

C-6

62.7

C-20

64.6

C-7

72.9

AT-CHj

35.0

C-8

49.9

COCH3

C-9

52.4

COCH3

C-10

55.3

ArCO

165.5,164.0

C-11

74.6

c-r

129.4

C-12

45.9

C-2', 6-

129.0

C-13

73.7

C-3', 5'

128.3

C-14

39.3

C-4'

133.1

170.0,169.3 21.6,21.2,20.6

YP Deng, DH Chen and WL Sung, Acta Chimica Sinica, 50,822 (1992).

Carbon-13 and Proton NMR Shift Assignments

169

DELNUDINE C20H25NO3; MW: 327; mp 235-237^^ Delphinium denudatum Wak^ ^H NMR*: 5 1.63 (3H, s, H-IS), 4.72, 4.96 (eachlH,€/,H-17).

HO.

X-ray structure^'^ 'Me OH

1. 2. 3.

M G6tz and K Wiesner, Tetrahedron Lett, 5335 (1969). KB Bimbaum, Acta Crystallogr,, Sect, B, 27,1169 (1971). KB Bimbaum, Tetrahedron Lett., 5245 (1969).

170

BS. JoshI, S.W. Pelletier and S.K. Srivastava

DELNUTTALINE C22H27NO5; MW: 385.1877; mp 269-271°

AcO. Ql^

Delphinium nuttallianum Pritz

'H NMR (C5D5N): 8 1.68 (3H, s, H-18), 1.79 (IH, d, J=14.5 Hz, H-llp), 1.90 (IH, d, J=12.7 Hz, H-7p), 1.92 (IH, d, J=17.8 Hz, H-15B), 2.27 (3H. s, OAc). 2.34 (IH, d, J=13.9 Hz, H-3J, 2.38 (IH, d, J=12.2 Hz, H-19p), 2.41 (IH, br5, H-12), 2.49 (IH, d, J=13.9 Hz, Me OH H-3p), 2.55 (IH, s, H-20), 2.58 (IH, d. J=17.8 Hz, H-15A), 2.60 (IH, d, J= 14.2 Hz, H-11„), 2.62 (IH, d, J=9.6 Hz, H-14), 2.68 (IH, d, J=13 Hz, H-U), 2.77 (IH, d, J=12.7 Hz, H-7A), 2.87 (IH, d, J=13 Hz, H-l„), 3.08 (IH, s, H-5), 3.55 (IH, d, J=12.2 Hz, H-19A), 4.70 (IH, bw, H-17B), 4.91 (IH, bre, H-17A), 5.09 (IH, hrd J=9.6 Hz,H-13J. "C Chemical Shift Assignments (C5D5N) C-1

41.6

C-12

41.6

C-2

212.2

C-13

73.2

C-3

52.8

C-14

48.5

C-4

43.5

C-15

30.9

C-5

56.0

C-16

147.9

C-6

99.1

C-17

108.1

C-7

40.7

C-18

30.8

C-8

46.2

C-19

63.9

C-9

78.4

C-20

67.5

C-10

57.5

COCH3

170.2

C-ll

34.4

COCH3

20.9

Y Bai, F Sun, M Benn and W Majak, Phytochemistry, 37, 1717 (1994).

171

Carbon-13 and Proton NMR Shift Assignments DELNUTTIDINE Ha

C20H25NO3; MW: 327.1833 Delphinium nuttallianum Pritz

*H NMR {C5D5N): 8 1.49 (IH, dd, J=8.7, 14.5 Hz, H-1 Ip), 1.65 (3H, s, H-18), 1.91 (IH, rf, J=8.7 Hz, H-9), 1.95 (IH, rf, J=17.4 Hz, H-15B), 2.12 (lH,f/, J=14.5 Hz, H-llJ, 2.17 (IH, £/, J=17.4 Hz, H-15A), 2.25 (IH, 5, H-5), 2.27 (IH, rf, J=13.7 Hz, H-7B), 2.35 (IH, d, J=13.7 Hz, H-IB), 2.40, 2.52 (each IH, c/, J=14.5 Hz,'H-3A, H.3B), 2.74 (IH, d, J=13.7 Hz, H.7A), 2.83 (IH,rf,J=12.1 Hz, H-19B), 3.29 (IH, d, J==13.7 Hz, H-IA), 3.37 (IH,rf,J=9.3 Hz, H-H), 3.85 (IH, d, J=12.1 Hz, H.19A), 3.90 (IH,5, H-20), 4.24 (IH, J, J=9.3 Hz, H-13J, 4.61,4.80 (each IH, br5r, H-17). ^^C Chemical Shift Assignments (C5D5N) C-1

41.7

C-11

22.6

C-2

209.5

C-12

42.9

C-3

51.8

C-13

69.1

€-4

42.8

C-14

49.5

C-5

58.0

C-15

33.0

C-6

101.9

C-16

148.1

C-7

42.5

C-17

107.3

C-8

43.8

C-18

29.7

C-9

49.1

C.19

59.1

C-10

53.1

C-20

68.9

Y Bai, F Sun, M Benn and W Majak, Phytochemistry, 37,1717 (1994).

BS. Joshi, S.W. Pelletier and S.K. Srivastava

172

DELNUTTINE AcO.

C22H29NO4; MW: 371.2082 Delphinium nuttalianum Pritz.

'H NMR (CDCI3 + CDjOD): 8 0.93 (3H, j , H-18), 1.20 (IH, m, H-lp), 1.33-1.40 (4H, m, H-IA, H-2B, H-3B, H-13p), 1.50 (IH, s, H-5), 1.50-1.55 (IH, m, H-2A), 1.73 (IH, m, H13J, 1.99 (3H, s, OAc), 2.07 (IH, htd, J=10.5 Hz, H-14), 2.17-2.26 (3H, m, H-9, H-12, H3A), 2.39 (2H, s, H-19), 2.58 (IH, s, H-20), 3.20 (IH, hrs, H-6), 3.87 (IH, d, J=2.8 Hz, H-7p), 4.37 (IH, s, H-15J, 4.97, 5.02 (each IH, brs, H-17), 5.18 (IH, d, J=8.3 Hz, H-11 j). "C Chemical Shift Assignments (CDCI3 + CD3OD) C-1

27.9

C-12

40.0

C.2

19.6

C-13

28.9

C-3

33.0

C-14

37.6

C-4

37.5

C-15

65.4

C-5

59.0

€-16

152.0

C-6

70.3

C-17

111.3

C-7

66.8

C.18

28.7

C-8

50.8

C-19

61.9

C-9

46.4

C.20

73.4

C-10

53.0

COCH3

170.7

C-11

75.6

COCH3

21.2

Y Bai, F Sun, M Benn and W Majak, Phytochemistry, 37,1717 (1994).

Carbon-13 and Proton NMR Shift Assignments

173

C22H33NO2; MW: 343; mp 248-249° [a]D-»-0.15°(EtOH) Delphinium denudatum Wall*'^ Aconiturn kusnezqffii Reichb.^*', A, jinyangense W. T. Wang^ X-ray structure^'^

'^C Chemical Shift Assignments (CDaSOCDa/*^

1. 2. 3. 4. 5. 6. 7. 8.

C-l

26.1

C-12

41.8

C-2

20.3

C-13

24.0

C-3

39.8

C-14

27.7

C-4

33.5

C-l 5

76.7

C-5

51.7

C-16

154.2

C-6

22.5

C-17

108.5

C-7

46.6

C-l 8

26.5

C-8

43.1

C-19

57.1

C-9

52.2

C-20

71.0

C-10

45.0

C-21

50.1

C-11

71.6

C-22

13.5

N Singh, J, Sci. Ind Res., B20,39 (1961); N Singh, A Singh and MS Malik, Chem. andind,, 1909(1961). M G(5tz and K Wiesner, Tetrahedron Lett., 4369 (1969). LH Wright, MG Newton, SW Pelletier and N Singh, Chem. Comm., 359 (1970). D Uhrin, B Proksa and J Zhamiansan, Planta Med, 57,390 (1991). HK Desai, BS Joshi, SW Pelletier, B Sener, F BingOl and T Bayakal, Heterocycles, 36,1081 (1993). DH Chen and WL Sung, Acta Pharmacutica Sinica, 16,748 (1981). Atta-ur-Rahman, A Nasreen, F Akhtar, MS Shekhani, J Clardy, M Parvez and MI Chaudhuiy, J. Nat. Prod, 60,472 (1997). D. Batsuren, J Tunsag, N Batbayon, AM Meri^li, F Meripli, Q Teng, HK Desai, BS Joshi, SW Pelletier, Heterocycles, 49 327 (1998).

174

B^. Joshi, S.W. Pelletier and S.K. Srivastava

11-DESBENZOYLCARDIOPETAMINE C20H25NO4; MW: 343; mp 306-308° (dec.)

HO. \ HO,

N-

H

Prepared from cardiopetamine^

'OH

P

*HNMR(CDCl3 + CD30Dy: 8 3.79 (IH, bM, H-15), 4.02 (IH, brJ, J=9 Hz, H-13), 4.40 (IH, d, J=9 Hz, H-11), 5.09 (2H, bw. H-17).

^^C Chemical Shift Assignments^ C-1

44.9

C-11

72.2

C-2

213.1

C-12

50.4»

C-3

49.8

C-13

70.1

C-4

41.4

C-14

49.6

C-5

60.2

C-15

69.8

C-6

64.8

C.16

152.4

C-7

33.3

C-17

110.4

C-8

48.8

C-18

28.4

C-9

50.5*

C-19

65.0

C-10>

54.6

C-20

69.8

'Assignments may be interchanged.

1. 2.

AG Gonzdlez, G de la Fuente, M Reina, PG Jones and PR Raithby, Tetrahedron Lett., 24,3765 (1983). AG Gonzalez, G de la Fuente, M Reina, R Diaz and I Timon, Phytochemistryy 25, 1971 (1986).

Carbon-13 and Proton NMR Shift Assignments

175

A^-DESETHYLSONGORAMINE{NORSONGORAMINE) C20H25NO3; MW: 327; mp 286-288*' Delphinium tamarae Kem. Nath.\ A. monticola Steinb.^ *H NMR (CDCI3)*: 8 1.12 (3H, 5, H-18), 4.63,4.85 (each IH, bw, H-17).

1. 2.

LV Beshitaishvili, MN Sultankhodzhaev, KS Mudzhiri and MS Yunusov, Khim. PrirSoedin., 11,199 {\9%l). EF Ametova, MS Yunusov and VA Telnov, Khim. Prir. Soedin., 18,504 (1982).

B^. Joshi, S.W. Pelletler and S.K. Srivastava

176 2-DESMETHYLBUTYRYLCARDIOPINE

CjiHjsNOs; MW: 549; amorphous Preparedfromcardiopine 'H NMR (CDCI3): 8 6.03 (IH, d, J=3 Hz, H-IJ, 4.15 (IH, bTS. W,/2=7.5 Hz, H-2^, 3.52 (IH, d, J=5.2 Hz, H-3p), 2.08 (IH, s, H5), 3.26 (IH, bTS, W,a=5 Hz, H-6), 1.85 (IH, dd, J=13.6,3.2 Hz, H-7J, 1.65 (IH, dd, J=13.6, 2.3 Hz, H-7p), 2.00 (3H. s, OAc), 2.05 (3H, s, OAc), 2.27 (IH, dd, J=9.5, 2.1 Hz, H-9), 5.42 (IH, d, 3=9.5 Hz, H-llp), 2.53 (IH, d, J=2.7 Hz, H-12), 5.36 (IH, dt, J=9.6,2 Hz, H-15J, 2.49 (IH, dd, J=9.6,2 Hz, H-14), 2.17 (IH, dt, J=17.9,2.1 Hz, H-15p), 5.01 (IH, dt, J=17 Hz), 4.85 (IH, s, H-17e), 1.13 (3H, s, H-18), 3.09 (IH, d, J= 12.6 Hz, H-19J, 2.31 (IH, d, J=12.6 Hz, H-19^, 3.67 (IH, s, H-20), 7.53 (2H, t, J= 7.4 Hz, Ar-H), 7.60 (2H, t, J=7.2 Hz, Ar-H), 8.22 (IH, d, J=7 Hz, Ar-H). BzOv

"C Chemical Shift Assignments (CDCI3) C-1

73.9

C-15

33.9

C-2

68.4

C-16

142.8

C-3

70.4

C-17

110.4

C-4

43.3

C-18

25.9

C-5

59.2

C-19

59.5

C-6

63.8

C-20

66.3

C-7

35.9

COCHj

170.1.170.6

C-8

43.8

COCH3

21.3,21.5

C-9

51.5

ArCO

165.5

C-10

53.7

c-r

130.2

C-11

75.3

C-2*, 6'

129.9

C-12

46.0

C-3'. 5'

128.6

C-13

74.5

C-4'

133.4

C-14

50.2

M Reina, A Madinaveitia, JA Gavfn and G de la Fuente, Phytochemistry, 41, 1235 (1996).

Carbon-13 and Proton NMR Shift Assignments

177

A/^DESMETHYL-Wie-SECO-e-HYDROXYEPISCOPALIDINE-e-CATHYLATE C32H35NO»; MW: 561.2374' 2 Prepared from episcopalidine' AcO.

O

i' n n ' * < . , ^ t " v L ^

~r "• "' O

p '

'H NMR:' 81.18 (3H, s, C(4)-C/fj), 1.20 (3H, /, J=7.2 Hz, 0-CHJCH}), 1.98 (3H, s, OAc), 3.40 (IH, d, J=6 Hz, C(20)-ff, 3.02,

\ H 1 3.52 (each 2H, h&q, J=12 Hz, C(19)-W), \ | e OCOOCHaMe 4.12 (2H, q, J=7.2 Hz, O-CHT-CHJ), 4.78, 4.92 (each IH, brs, C(16)-W), 5.04 (IH, d, J=5.4 Hz, C(3)-W). 5.52 (IH, m, C(2)-H), 7.58-8.04 (each 5H, m, aromatic). "C Chemical Shift Assignments^

1. 2.

C-1

37.8

C-16

141.6

C-2

68.2

C-17

113.3

C-3

74.4

C-18

25.2

C-4

40.9

C-19

60.9

C-5

63.9

C-20

73.7

C-6

103.1

COCU3

169.4

C-7

58.3

COCH3

21.1

C-8

40.9

ArCO

165.6

C-9

47.9

c-r

128.5

C-IO

43.5

C-2', 6"

128.8

C-11

23.5

C-3', 5'

129.4

C-12

52.4

C-4'

133.2

C-13

209.5

CO-0

152.8

C-14

59.9

Oil

63.9

C-15

32.8

CHj

14.2

FP Wang and XT Liang, Tetrahedron, 42,265 (1986), FP Wang and XT Liang, Youji Huaxue, 1,19 (1986).

178

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

1 la-DESTIGLOYLANOPTERINE (ANOPTERYL 12a-TIGLATE) 2"

Me I OCOC=CH-Me ; 1' 34'

C26H37NO6; MW: 459; mp 184-187°'-^ t«li> + ^^° (CHCI3); + 28» (CHCI3 + MeOHl:l) Anopterus glandulosus Labill.', A. macleayanus F. Muell.^

'H N M R (CDCI3 + CD30D)^ 8 1.17 (3H, H-18), 1.44 (IH, H-S,,), 1.84, 1.93 (each 3H, H-2', H-4'), 1.93 (IH, H-3,x), 2.11 (IH, H-15), 2.19" (IH, H-14e,), 2.20 (IH, H-7eq), 2.24 (IH, H-l„), 2.26* (IH, H-9), 2.33 (3H, H-21), 2.41 (IH, H-l«,), 2.46 (IH, H-7.x), 2.58 (IH. H-15). 2.64 (IH, H-19.,), 2.91 (IH, H-B.,), 3.60 (IH, H-6«,), 3.75 (IH, H-19,x), 3.99 (IH, H-20), 4.08 (IH, H-2e,). 4.35 (IH, H-11.,). 4.83,5.03 (each IH, H-17), 5.07 (IH, H-12eq). 7.17 (IH. H-3'). 'Assignments may be interchanged.

1. 2.

ME Wall. MC Wani, BN Meyer and H Taylor, J. Nat. Prod.. 50.1152 (1987). SR Johns, JA Lamberton, H Snares and RI Willing, Aust. J. Chem., 38,1091 (1985).

Carbon-13 and Proton NMR Shift Assignments

179

9,19-O-DIACETYLACSINATINE

I AcO.

C26H33NO6; MW: 455; mp 195-198*' CH,

Aconitum leucostomum Vorosch. ' H NMR: 8 0.90 (3H, 5, H-IS), 1.88 (3H, 5, OAc), 2.06 (6H, 5,2 X OAc), 5.69 (IH, s, H19J.

VA Tei'nov, SK Usmanova and ND Abdullaev, Khim, Prir. Soedin,, 409 (1993).

BJS. Joshi, S.W. Pelletier and S.K. Srivastava

180 15-0,22.Ar-DIACETYLATIDINE

t

C26H37NO5; MW: 443; mp 182-190** Preparedfromatidine'

'^C Chemical Shift Assignments^

1. 2.

C-l

41.0

C-13

26.8

C-2

23.3

C-14

25.6

C.3

39.3

C-l 5

73.6

C-4

33.5

C-16

149.2

C-5

47.4

C-17

110.8

C-6

36.2

C-l 8

25.6

C-7

211.5

C-19

59.1

C-8

50.8

C-20

52.9

C-9

42.3

C-21

57.0

C-IO

37.3

C-22

61.1

C-11

27.8

COCH3

170.3,169.9

C-12

36.1

COCH3

21.9,21.0

SW Pelletier, J. Amer Chem, Soc, 87,799 (1965). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

Carbon-13 and Proton NMR Shift Assignments

181

6,11-0-DIACETYLCARDIONINE (BASIC) C28H37NO7; MW: 499.2550 Prepared from cardionine 22 / ^OCOCH

23

' H N M R (CDCI3): 5 1.03 (3H,5, H-18), 1.17 (6H, d, J=7 Hz, H-23, H.24), 2.01, 2.04 (each

24

3H, s,2x

OAc), 2.32 (IH, brd, J=ll Hz,

W,/2=7.5 Hz, H-14), 2.34 (IH, s, H-5), 2.43

Me OAc

(IH, d, J=12.6 Hz, H-7J, 2.43 (IH, c/, J=12.5 Hz, H'\%\ 2.54 (IH, 5, H.20), 2.57 (IH, sept,

J=7 Hz, H-22), 2.96 (IH, d, J=12.5 Hz, H-19p), 4.95 (IH, s, H-11«), 4.99, 5.31 (each IH, d, J=2.5 Hz, H-17e, H-17z), 5.65 (IH, /, J=2 Hz, H-15p). '^C Chemical Shift Assignments (CDCI3) C-1

35.5

C-14

C-2

19.6

C-15

71.2

C-3

27.6

C-16

148.2

C-4

37.4

C-17

109.7

C-5

60.4

C-18

29.9

C-6

103.1

C-19

61.7

C-7

34.5

C-20

72.2

C-S

45.5

C-21

176.9

C-9

55.6

C-22

34.4

C-10

50.8

C-23

19.1

C-11

76.5

C-24

19.2

C.12

73.3

COCH3

169.7, 172.4

C-13

36.1

COCH3

21,4,22.5

40.8

G de la Fuente, JA Gavin, M Reina and RD Acosta, J. Org, Chem., 55,342 (1990).

182

B.S. Joshl, S.W. Pcllcticr and S.K. Srivastava

A^, 11-O-DIACETYLCARDIONINE (NEUTRAL) C28H37NO7; MW: 499.2554 Prepared from cardionine 22 / M e ^OCOCH 23 \ i Me

A c — -H

24

Me O

^H NMR (CDCI3): 6 1.08 (3H, .v, H-18), 1.14 (6H, ^, J=7 Hz, H-23, H-24), 1.67 (IH, d, J=3 Hz, H-9), 2.04 (3H, s,OAc), 2.14 (3H, s, N-Ac), 2.52 (IH, sept, H22), 2.99,3.31 (each 1H, d, J=12.4 Hz,

H-19„, H-19p), 3.97 (IH, s, H.20), 5.16 (IH, 5, H-l 1 J , 5.22, 5.33 (each IH, s, H-17C, H-17Z), 5.65 (1H,5, H-15p). '^C Chemical Shift Assignments (CDCI3) C-l

41.9

C-15

74.5

C-2

21.4

C-16

146.0

C.3

40.5

C-l 7

111.6

C-4

35.5

C-l 8

27.5

C-5

60.4

C-19

52.4

C-6

209.7

C-20

67.9

C-7

50.8

C-21

177.0

C-8

42.5

C-22

34.3

C-9

54.0

C.23

19.0

C-10

43.9

C-24

19.1

C-11

73.3

N-CO-CH3

170.9

C-12

72.5

N.CO-CH3

22.9

C-l 3

35.1

O.CO-CH3

171.3

C-14

51.3

O-CO-CH3

21.3

G de la Fuente, J A Gavin, M Reina and RD Acosta, J. Org. Chem., 55,342 (1990).

Carbon-13 and Proton NMR Shift Assignments

183

13, 15-O-DIACETYLCARDlOPETAMlNE OAc

C5iH33N07;M\V:531

Prepared from cardiopetamine

OAc

*HNMR (CDCI3): 8 2.13,2.30 (each 3H, A-, 2 X Oac), 5.12 (IH, brc/, J=9 Hz, H-13), 5.27 (IH, brs, H-15J, 5.37 (2H, hrs, H-17), 5.60 (lH,
'^C Chemical Shift Assignments^ C-1

44.1

C-10

55.1

C-19

64.7

C-2

211.3

C-ll

74.7

C-20

70.1

C-3

50.2

C-12

44.2

ArCO

166.4

C-4

43.0

C-13

71.7

c-r

129.7

C-5

60.3

C-14

47.3

C.2', 6'

129.6

C-6

65.0

C-15

71.8

C-3', 5'

128.8

C-7

32.6

C-16

143.2

C-4'

133.5

C-8

48.0

c-n

118.0

COCH3

170.1.170.8

C-9

49.4

C-18

28.6

COCH3

21.1,21.2

"Assignments may be interchanged

AG Gonzalez, G de La Fuente, M Reina, R DIazand and I Tim6n, Phytochemistry, 25, 1971 (1986).

BS. Joshi, S.W. Pclletier and S.K. Srivastava

184 1,15-O-DIACETYLCOSSONIDINE

C24H31NO4; MW: 397.2257

K

[o]D + 5.2''(EtOH) Prepared from cossonidine 'H N M R (CDCI3): 8 1.02 (3H, s, H-18), 1.10 (IH, dt, J=13.5,2.8 Hz, H-13J, 1.29 (IH, hrd, J=13.2 Hz. H-3J, 1.53 (IH, dd, J=13, 9.2 Hz, H-11^, 1.86 (IH, s, H-5), 2.09,2.11 (each 3H, s, 2 X OAc), 2.17 (IH ', J=3.2 Hz, H.12), 2.38 (IH, d, J=12.6 Hz, H-19J, 2.56 (IH, s, H-20), 2.57 (IH, d, J=12.6 Hz, H-19p), 3.37 (IH, brs, Wi/2=7 Hz, H-6), 4.92 (IH, d, J=1.4 Hz, H-17e). 4.95 (IH, t, J=1.3 Hz, H-17Z), 5.23 (IH, bis, V/m=6A Hz, H-la), 5.43 (IH, s, H-15J. "C Chemical Shift Assignments (CDCI3) C-1

69.7

C-11

26.3

C-2

23.9

C-12

33.4

C-3

28.2

C-13

33.1

C-4

37.4

C-14

43.3

C-5

57.3

C-15

72.4

C-6

65.4

C-16

150.9

C-7

32.3

C-17

110.9

C-8

44.1

C-18

28.3

C-9

42.6

C-19

62.5

C-10

53.3

C-20

75.5

M Reina, JA Gavin, A Madinaveitia, RD Acosta and G de la Fuente, J. Nat. Prod., 59, 145 (1996).

Carbon-13 and Proton NMR Shift Assignments

185

1,7-O-DIACETYLCRASSICAULINE B C31H35NO6; MW: 517.2463; mp 119-121° Prepared from crassicauline B *H NMR (CDCI3): 8 1.03 (3H, s, H-18), 2.11, 2.15 (each 3H, 5, 2 x OAc), 4.57, 4.73 (each IH, 5, H-H), 4.89 (IH, d, J=3 Hz, H7), 5.28 (IH, m, H-1), 5.30 (IH, m, H-13), 7.48,7.60,8.00 (5H, m, Ar-H).

FP Wang and XT Liang, Planta Medica, 49,443 (1985).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

186

11,15-0-DIACETYLDENUDATINE C26H37NO4; MW: 427; mp 134-135^ Prepared from denudatine' and 15-0acetyl denudatine^

Me

^HNMR(CDCI3+ CDsOD)^ 80.71 (3H, 5, H-18), 1.05 (3H, /, J=7 Hz, H-22), 2.05, 2.17 (each 3H, ^, 2 x OAc), 3.44 (IH, br^, H-20), 4.84 (IH, d, J=IO Hz, H-1IJ, 4.94 (2H, br5, H-17), 5.41 (IH, /, J=2 Hz, H15„). '^C Chemical Shift Assignments (CDCI3 + CD3OD)*

1. 2.

C-l

39.7

C-13

23.6

C-2

20.2

C-14

22.2

C-3

27.3

C-l 5

77.7

C-4

33.9

C-16

147.2

C-5

50.2

C-17

110.2

C-6

25.6

C-l 8

26.4

C-7

43.2

C-19

56.9

C-8

42.9

C-20

70.9

C-9

51.7

€-21

51.0

C-10

45.2

C-22

12.9

C-11

73.9

COCH3

170.5,21.3

C-12

41.9

COCH3

170.8,21.4

FP Wang, JZ Wang and R Zhang, Heterocycles, 45,659 (1997). DH Chen and WL Sung, Acta Pharmaceutica Simica, 16,748 (1981).

Carbon-13 and Proton NMR Shift Assignments

187

11,13-O-DIACETYL-9-DEOXYGLANDULINI1 . ^ ^*r ^^^*-.J^^^''\. II J

4* ^^®

/<4>^0-^.,^x^;)sJ/t^^ ^^ |l N—1-,[^ Aca

-' \ . x ^ i ^ 4 / ^ />CH

^Me

CilhiNOy; MW: 57\.2191; mp 195-198° lajD + 36° (MeOH) Comolhia f^landulosa (Bo'iss. er Huct) Bornin., Syn. Delphinium ghmdulosum i„ i^f^,^ (CDCb): 5 0.92 (3H, .v, J=7.9 Hz, H-4'),1.02(3H,.v, IM8), 1.24(3H,c/,

•^"'^ "^- ^*"'^'^' '•^'* <-**'''''' J=I4, 2 Hz, H-7p), 1.50 (HI,
H-3'B), 1.70 (HI, ddq, J-14.8, 7.4, 7.4 Hz, H-3'A), 1.80 (IH, .V, H-5), 1.83 (IH, dd, J=15.3, 4.5, 5 Hz, H-l„), 1.91 (IH, dd, J=14,3.3 Hz, H-7J, 1.99,2.00, 2.02 (each 3H, 5, OAc + 3„, 11„, 3„ resp.), 2.12 (IH, J, J=14 Hz, lM5p), 2.20 (IH, d, J=14 Hz, H-15J, 2.23 (IH,
29.91

C-14

78.6 s

C-2

67.9 d

C-15

30.6 s

C-3

73.9 d

C-16

141.8s

C-4

42.2 s

C-17

110.6t

C-5

61.1 d

C-18

25.4 q

C-6

62.5 d

C-19

59.61

C-7

31.3 t

C-20

69.3 d

C-8

44.9 s

c-r

175.7 s

C-9

51.3d

C-2'

41.4d

C-10

45.6 s

C-3'

26.2 t

C-11

75.1 d

C-4'

11.6q

C-12

46.1 d

C-5'

17.1 q

C-13

80.5 d

COCH3

170.2 (3),170.4(11),169J (13)1

COCH3

20.7 (3), 21.2 (11), 21.4 (13) q

G Almanza, J Bastida, C Codina and G de la Fuente, Phytochemistry, 44,739 (1997).

188

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

15-a 22-^-DIACETYLDIHYDROATISINE C26H39NO4

CHg

AcO—.

I i.;

T

H

T

Prepared from atisine^

OAc

'^C Chemical Shift Assignments (CDCla)^

1. 2.

C-l

40.5

C-13

27.4

C-2

23.2

C-14

26.3

C-3

41.8

C-l 5

77.2

C-4

33.6

C-16

151.3

C-5

49.9

C-17

110.7

C-6

17.3

C-l 8

26.3

C-7

31.9

C-19

60.4

C-8

36.8

C-20

53.9

C-9

40.5

C-21

57.2

C-10

38.2

C-22

61.6

C-11

28.0

COCH3

170.9,170.2

C-12

36.4

COCH3

21.3,20.9

SW Pelletier and PC Parthasarathy, J. Am, Chem. Soc, 87,777 (1965). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

Carbon-13 and Proton NMR Shift Assignments

189

1,15-0-DIACETYL-16,17-DIHYDROSONGORINE C2«H37N05;MW: 443; mp 128-130° l^g

Prepared from songorine' and dihydrosongorine^ ' H NMR (CDCia)^: 6 0.63 (3H, d, J=7 Hz, H-17), 0.68 (3H, s, H-18), I.OO (3H, t, J= 7 Hz, H-22), 1.97,2.02 (each 3H. s, 2 X OAc), 4.97 (IH, q, H-1 J , 5.12 (IH, d, J=8Hz,H-15J.

1. 2.

MS Yunusov, YV Rashkes, SY Yimusov and AS Samatov, Khim. Prir. Soedin., 101 (1970). MN Sultankhodzhev and MS Yunusov, Khim. Prir. Soedin., 917 (1970).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

190

15-0, 22-iV-DIACETYLDIHYDROVEATCHINE C26H39NO4

Prepared from veatchine' AcO---^^

'^C Chemical Shift Assignments^ C-l

41.6"

C-13

41.9

C-2

18.3

C-14

37.6

C-3

40.9*

C-15

82.7

C.4

33.6

C-16

154.8

C-5

49.9

C-17

109.9

C-6

18.3

C-18

26.3

C.7

32.7

C.19

60.3

C-8

47.0

C-20

55.8

C-9

49.9

C-21

57.2

C-10

40.2

C.22

61.4

C-11

22.4

COCH3

170.2,170.2

C-12

32.4

COCH3

21.0,21.0

"Assignments may be interchanged.

1. 2.

SW Pelletier and DM Locke, J. Am. Chem. Soc, 87,761 (1965). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

Carbon*13 and Proton NMR Shift Assignments

191

6,13-aDIACETYLGEYERINE Aca MeCHrCH-CCX>^

C29H37NO7; MW: 511

Prepared from geyerine 'H NMR (CDCI3): 8 0.97 (3H, /). 119 (3H, s), 1.24 {3H, d, J=7 Hz), 1.55 (IH, m), 1.77 (2H, m), 2.02 (3H, 5), 2.07 (3H, s), 2.10-2.48 (7H, m), 2.64-2.50 (6H, m), 2.69 (IH, s), 2.84 (IH, s), 3.15 (IH, d, J=12.6 Hz), 3.35 (IH, J, J=13.3 Hz), 4.83 (IH, 5), 5.00 (IH, s), 5.15 (2H, d, J=9.4 Hz).

JA Grina, DR Schroeder, ET Wydallis, FR Stermitz, J Melman and JL Capinera, J. Org. C/iem.,51,390(1986).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

192 2. ll-O-DIACETYLHETISINE

C24H31NO5; MW: 413; mp 270-272" Prepared from hetisine 'H N M R (CDCI3): 8 1.01 (3H, s, H-18), 2.12 (6H, s. OAc), 3.80 (IH, s, H-20), 4.20 (IH, brd, J=8 Hz, H-13J, 4.80, 4.91 (each IH, bis, H-17), 5.15, 5.25 (each IH, brs, H2p,H-llp).

AcC

"C Chemical Shift Assignments (CDCI3) C-1

29.6

C-12

49.1

C-2

69.8

C-13

70.8

C-3

36.2

C-14

51.9

C-4

36.7

C-15

34.0

C-5

60.9

C-16

145.4

C-6

64.2

C-17

108.4

C-7

36.7

C-18

29.6

C-8

43.9

C-19

63.5

C-9

53.1

C-20

67.6

C-10

50.5

COCH,

170.9,170.4

C-11

76.4

COCHj

21.7,21.5

JA Glinski, BS Joshi, QP Jiang and SW Pelletier, Heterocycles, 27,185 (1988).

Carbon-13 and Proton NMR Shift Assignments

193

11, n-O-DIACETYLHETISINE C24H31NO5; MW: 413; mp 225-227*** [a]D + 26.P(CHCl3) Prepared from hetisine*

HO^.

*H NMR (CDCI3)*: 8 1.00 (3H, 5, H-18), 2.12, 2.23 (each 3H, s. OAc), 3.62 (IH, s, H-20), 4.20 (IH, bw, H-.2p), 4.82, 5.00 (eachlH,bw,H-17). ^^C Chemical Shift Assignments {CDCI3) 1

2

1

2

C-1

32.0

32.0

C-12

45.1

45.2

C.2

66.5

67.4

C-13

73.0

73.2

C-3

40.6

40.6

C-14

50.2

50.4

C-4

36.8

36.8

C-15

34.0

34.1

C-5

61.4

61.4

C-16

144.0

143.9

C-6

64.3

64.5

C-17

109.6

109.8

C-7

36.1

36.2

C-18

29.8

29.8

C-8

43.9

44.0

C-19

63.6

63.9

68.5

68.7

C.9

53.1

53.3

C-20

C-10

50.6

50.6

COCH3

179.8, 170.5

170.4,170.8

C-11

75.9

76.1

COCH3

21.5, 21.2

21.3,21.6

1. 2.

JA Glinski, BS Joshi, QP Jiang and SW Pelletier, Heterocycles, 27,185 (1988). AG Gonzalez, G de la Fuente, M Reina, R Dfaz and I Tim6n, Phytochemistry, 25, 1971 (1986).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

194 11,13.0-DIACETYLHETISINE-2-ONE

C24H29NO5; MW: 411 Prepared from 13-0-acetylhetisine-2-one^ *H NMR (CDCb)^ 5 1.17 (3H, s, H-18), 2.05, 2.20 (each 3H, s, OAc), 4.80, 5.00 (each IH, 5, H-17), 5.12 (2H, m, H-11, H13).

'•^C Chemical Shift Assignments^

1. 2.

C-l

43.9

C-12

44.8

C-2

211.8

C-13

72.5

C-3

50.3

C-14

49.9

C-4

42.9

C-l 5

33.7

C-5

60.5

C-l 6

142.9

C-6

65.3

C-17

110.5

C-7

35.9

C-18

28.7

C-8

44.9

C-l 9

64.8

C-9

52.7

C-20

70.5

C-10

55.4

COCH3

170.3,170.7

C-11

75.4

COCH3

21.1,21.5

AG Gonzalez, G de la Fuente and M Reina, Ann. Quim., 77C, 171 (1981). AG Gonzdlcz, G de la Fuente, M Reina, R Diaz and I Timon, Phytochemistry, 25, 1971 (1986).

Carbon-13 and Proton NMR Shift Assignments

195

11,15-O-DIACETYLISOHYPOGNAVINE C31H35NO6; MW: 517; mp 181-183° [a]D + 55.3°(CHa3) BzQ.

Aconitumjaponicum Thunb.* ^H NMR (CDCla)*'^: 81.98,2.06 (each 3H, s, OAc), 5.00, 5.17 (each IH, s, H-17), 5.03 (IH, d, J=5 Hz, H-11), 5.45 (IH, 5, H-15), 5.54(lH,m,H-2).

1. 2.

S Sakai, H Takayama and T Okamoto, Yakugaku Zasshi, 99,647 (1979). FP Wang and XT Liang, Planta Medica, 49,443 (1985).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

196 1,15-O-DIACETYLLUCICULINE

C26H37NO5; MW: 443; amorphous^

QH

Preparedfromlucidusculine*

ACQ

*HNMR: 8 2.07,2.09 (each 3H,jp,0Ac), 3.56 (IH, /w, H-12), 4.94 (IH, s, H-17), 5.10 (2H, H-lp, H-17), 5.48 (IH, s, H.15).

'^C Chemical Shift Assignments^

1. 2.

C-l

74.2

C-l 3

48.3

C-2

26.8

C-14

29.0

C-3

37.8

C-l 5

77.3

C-4

34.3

C-16

153.2

C-5

50.3

C-l 7

109.6

C-6

23.4

C-18

25.9

C-7

44.3

C-l 9

57.2

C-8

49.2

C-20

65.0

C-9

38.1

C-21

50.6

C-10

50.0

C-22

13.4

C-11

29.8

COCH3

170.7,170.9

C-12

75.0

COCH3

21.6,22.0

H Takayama, A Tokita, M Ito, S Sakai, F Kurosaki and T Okamoto, Yakugaku 2a^5/iU02,245 (1982). K Wada, H Bando, T Amiya and N Kawahara, Heterocycles, 29,2141 (1989).

Carbon-13 and Proton NMR Shift Assignments

197

7, ll-O-DIACETYLORIENTININE C24H27NO7

Prepared from orientinine ^H NMR (CDCI3): 8 1.04 (3H, 5, H-IS), 2.06, 2.10 (each 3H, s, OAc), 4.86, 4.96 (each IH, br5, H-17), 4.76 (IH, hvd, J=8.5 Hz, H-1 Ip), 5.15 (IH, /, J=2.5 Hz, H-7p).

'^C Chemical Shift Assignments C-l

45.7

C-11

69.8

C-2

213.8

C-12

49.4

C-3

51.5

C-l 3

211.0

C-4

40.2

C-14

79.0

C-5

58.9

C-15

37.1

C-6

65.5

C-16

146.2

C-7

68.6

C-l 7

107.9

C-8

44.2

C-18

23.9

C-9

53.8

C-19

63.0

48.2

C-20

68.5

C-10

A Ulubelen, AH Meri9li, F Meri9H and F Yilmaz, Phytochemistry, 41,957 (1996).

198

B.S. Joshi, S.W. Pellet ler and S.K. Srivastava

2,15-O-DIACETYLRYOSENAMINOL

b AcO^

C24H31NO5; MW: 413; mp 195-198° Prepared from ryosenaminol ^H NMR (CDCI3): 8 1.01 (3H, 5, H-18), 2.06, 2.11 (each 3H, s, OAc), 5.00, 5.01 (each IH, 5, H-17), 5.26 (IH, m, H.2p), 5.53 (1H,J,H-15J.

'^C Chemical Shift Assignments (CDCI3) C-1

28.9"

C-12

35.3

C-2

70.0

C.13

33.1

€-3

39.5

C-H

42.7

C-4

35.9

C-15

73.6

C.5

54.3

C-16

150.2

C-6

63.8

C-17

111.9

C-7

28.7*

C-18

29.5

C-8

43.8

C-19

63.6

C-9

79.1

C-20

74.0

C-10

50.7

COCH3

170.1,170.2

C-11

36.9

COCH3

21.7,21.3

"Assignments may be interchanged.

S Sakai, I Yamamoto, K Hatoda, K Yamaguchi, N Aimi, E Yamanaka, J Haginiwa and T Okamoto, Yakugaku Zasshi, 104, 222 (1984).

Carbon-13 and Proton NMR Shift Assignments

199

6,11-0-DIACETYLVENULOL

AcO,

C24H31NO4

b

Prepared from venulot 'H NMR: 8 2.03 (3H, s), 2.07 (3H, s), 5.13 (lH,d,H-ll). Me OAc

" C Chemical Shift Assignments C-1

30.3

C-12

44.0

C-2

19.7

C-13

27.2

C-3

38.8

C-14

47.9

C-4

43.0

C-15

36.0

C-5

60.4

C-16

146.2

C-6

101.4

C-17

109.6

C-7

36.0

C-IS

29.2

C-8

43.4

C-19

60.4

C-9

43.0

C-20

68.0

C-10

56.0

COCH3

169.6,170.1

C-11

73.2

coah

21.2,21.0

A Ulubelen, AH Meri^li, F Meri9li, R Ilarsan and SA Matlin, Phytochemistry, 31, 3239 (1992).

B^. Joshi, S.W. Pdletier and S.K. Srivastava

200 13, IS-O-DIACETYLVENULUSON AcQ

C24H29NO5

"J.

Prepared from venuluson *CH2

'H NMR: 8 2.00, 2.03 (each 3H, s. OAc), 4.46 (IH, s, H-15), 5.26 (IH, s, H-13).

OAc

Shift Assignments C-1

31.5

C-12

42.2

C-2

212.3

C-13

72.0

C-3

41.0

C-14

49.6

C-4

42.7

C-15

76.0

C-5

59.7

C-16

155.0

C-6

62.9

C-17

110.0

C-7

35.7

C-18

28.7

C-8

44.0

C-19

60.7

C-9

45.1

C-20

69.8

C-10

60.6

COCH3

170.1,170.4

C-11

27.8

COCH3

21.3,21.0

A Ulubelen, AH Meri9li, F Meri9li, R Ilarsan and SA Matlin, Phytochemistry, 31, 3239 (1992).

Carbon-13 and Proton NMR Shift Assignments

201

11,15-0-DIBENZOYLKOBUSINE C34H35NO4; MW: 521; amorphous Preparedfromkobusine 'H NMR (CDCI3): 8 5.44 (IH, d, J=5 Hz, H-ll),5.77(lH,s,H-15).

S Sakai, I Yamamoto, H Takayama, K Yamaguchi, M Ito and T Okamoto, Chem. Pharm. B«//., 30,4579 (1982).

BS. Joshi, S.W. Pellctier and S.K. Srivastava

202

6,11-DIBENZOYLPSEUDOKOBUSINE C34H35NO3; MW: 537.2510; mp 211-213° Prepared from pseudokobusine

•^Me O B z

'H NMR (CDCI3): 8 1.00 (3H, s, H-18). 4.04 (IH, d, J=8.5 Hz, OH-15), 5.11, 5.29 (each IH, s, H-17), 5.40 (IH, d, J=4.6 Hz), 7.597.32 (6H, m, Ar-H), 7.19-8.10 (4H, m, Ar-H).

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocycles, 26, 2623 (1987).

Carbon-13 and Proton NMR Shift Assignments

203

6,15-0-DIBENZOYLPSEUDOKOBUSINE C34H35NO5; MW: 537.2497; mp 249-251 ° Prepared from pseudokobusine

'^Me OBz

^H NMR (CDCI3): 8 0.99 (3H, j , H-18), 4.07 (IH, d, J=4.6 Hz) 5.26,5.45, 5.75 (each IH, s\ 7.29-7.66 (6H, m, Ar-H), 7.90-8.12 (4H, m, Ar-H).

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocycles, 26, 2623 (1987).

204

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

DICTYZINE (DICTYSINE) C21H3JNO3; MW: HjOH

347.2404; mp 181-

182°'-^-* [a]D-120''(CHCl3)' Delphinium tatsieneme Franch', D. dict-

Mer--

yocarpum DC.'"^, D. brunonianum Royle', D. corumbosum Regel*, Aconitum delphinifolium' DC. 'H N M R (CD3OD)*: 8 0.70 (IH, s, H-18), 1.10 (IH, brrf, J5.6p=7.8 Hz, H-5),

1.13 (IH, m, H-14p), 1.18 (IH, m, H-6J, 1.20 (IH, m, J30A.=7.5 HZ, H-3p), 1.23 (IH, m, H - l l J , 1.27 (IH, m, H-13p), 1.40 (IH, m, ;i„.i,=14.4 Hz, J,^2„=8.8 Hz, H-lp), 1.43 (IH, m, J2p.2„=12.7, J2„,ir8.8 Hz, H-2J, 1.54 (IH, m, J3«.3rl2 Hz, J3„A.=4.1 HZ, J3„.2p=2.2 Hz, H-3„), 1.60 (IH, m, H-Up), 1.61 (IH, m, H-12), 1.82 (IH, m, H-9), 1.88 (IH, m, Jip.i„=12.5 H A H - U , 1.96 (IH, m, H-13J, 1.96 (IH, m, H-14J, 2.10 (IH, brrf, J7.6„=5.4 Hz, H-7), 2.23 (IH, m, J2„.2p=12.7 Hz, H-2p), 2.26 (IH, s, H-21 (iV-CH3), 2.29 (IH, AB, Jge™=11.2 Hz, H-19p), 2.42 (IH, AB, Jgem=11.2 Hz, H-19J, 2.68 (IH, dd, J6p,6„=13.2 Hz, J6p.5=7.8 Hz, H-6p). 3.30 (IH. s, H-20), 3.58 (IH, d, J»en.=11.7 Hz, H-17-pro. S), 3.88 (IH, s, H-15), 3.98 (IH, d, Jgem=l 1 7 Hz, H-17-pro. R). ;-ray structure '^C Chemical Shift Assignments (CD3OD)* "CChemit

C-1

27.6

c-11

24.7

C-2

21,8

C-12

36.5

C-3

41.2

C-13

23.0

C-4

35.3

C-14

29.0

C-5

54.0

C-15

87.1

C-6

24.0

C-16

81.1

C-7

44.0

C-17

67.9

C-8

43.0

C-18

27.0

C-9

42.5

C-19

60.8

C-10

46.9

C-20

74.7

Ar-CH3

44.5

Carbon-13 and Proton NMR Shift Assignments 1. 2. 3. 4. 5. 6. 7. 8.

205

BS Joshi, JK Wunderiich and SW Pelletier, Can. J, Chem., 65,99 (1987). BT Salimov, ND Abdullev, MS Yunusov and SY Yunusov, Khim. Prir. Soedin., 235 (1978). W Deng and WL Sung, Heterocycles, 24,869 (1986). BT Salimov, MS Yunusov, ND AbduUaev and ZM Vaisov, Khim. Prir Soedin, 95 (1985). BT Salimov, MS Yunusov, YV Rashkes and SY Yunusov, Khim. Prir. Soedin., 812 (1979). B Tashkhodzhaev, Khim. Prir. Soediru, 230 (1982). BT Salimov, B Tashkhodzhaev and MS Yunusov, Khim. Prir. Soedin., 86 (1981). BS Joshi, SW Pelletier, X Zhang and JK Snyder, Tetrahedron, 47,4299 (1991).

206

B^. Joshi, S.W. Pelletier and S.K. Srivastava

DICTYSINEACETONIDE C24H37NO3; MW: 387; mp 151-153° [a]D-102''(CHClj) Delphinium dictyocarpum DC. 21

Me-

'H NMR (CDCI3): 8 0.63, 1.28, 1.38 (each 3H, s, H-18, H-23, H-24), 2,19 (3H, H-21), 3.24 (IH, s), 3.67 (IH, d, J=10 Hz), 3.92 (IH, s), 4.37 (IH, d, J=10 Hz).

BT Salimov, B Tashkhodzhaev and MS Yunusov, Khim. Prir. Soediit, 86 (1982).

Carbon-13 and Proton NMR Shift Assignments

207

1,15-DIDEHYDROCOSSONlDINE C20H23NO2; MW: 309.1733 [a]D-13°(EtOH) Prepared from cossonidine 'H NMR (CDCI3): 8 1.05 (3H, s, H-18), 1.34 (IH, dt, J=13.6, 2.8 Hz, H-13J, 2.12 (IH, s, H-5), 2.47 (IH, dd, J=14.2, 5.2 Hz, H-llJ, 2.54 (IH, bK, W,/2=10 Hz, H-12), 2.70 (IH, d J=12.7 Hz, H-19J, 2.77 (IH, d, J=12.7 Hz, H-19p), 3.36 (IH, s, H-20), 3.48 (IH, bK, Wi/2=7 Hz, H-6), 5.08 (IH, d, J=1.5 Hz, H-17e), 5.89 (IH, d, J=1.5 Hz, H-17Z). "C Chemical Shift Assignments (CDCI3) C-1

214.9

C-11

30.4

C-2

38.1

C-12

33.8

C-3

38.6

C-13

32.9

C-4

38.4

C-14

45.9

C.5

68.5

C-15

201.3 s

C-6

66.6

C-16

147.3 s

C-7

28.0

C-17

115.6t

c-s

51.7

C.18

27.3

C-9

45.5

C-19

64.4

C-10

66.1

C-20

79.6

M Reina, JA Gavin, A Madinaveitia, RD Acosta and G de la Fuente, J. Nat. Prod, 59, 145 (1996).

208

B^. Joshi, S.W. Pelletier and S.K. Srivastava

2,11-DIDEHYDROHETISINE HO..

C20H23NO3; MW: 325.17; mp 237-240^ Prepared from 13-0-acetyl 2, 11-didehydrohetisine

'^C Chemical Shift Assignments (CDCI3)

1. 2.

1

2

1

2

C-1

43.1

43.3

C-11

209.7

209.3

C-2

210.8

210.7

C.12

62.6

62.8

C-3

50.4

50.5

C-13

67.4

68.0

C-4

42.6

42.7

C-H

51.8

51.9

C-5

59.1

59.4

C-15

33.2

33.3

C-6

65.6

65.7

C-16

139.9

139.7

C-7

34.8

35.0

C-17

112.7

113.0

C-8

45.0

45.1

C-18

28.4

28.5

C-9

64.8

65.0

C-19

64.8

65.1

C-10

52.4

52.5

C-20

69.8

69.9

JA Glinski, BS Joshi, QP Jiang and SW Pelletier, Heterocycles, 27,185 (1988). AG Gonzdlez, G de la Fuente, M Reina, R Diaz and I Tim6n, Phytochemistry, 25, 1971 (1986).

Carboii-13 and Proton NMR Shift Assignments

209

DIHYDROAJACONINE C22H35NO3; MW: 361; mp 99-100^ [a]D-35MEtOH) Consolida ambigua (Delphinium ajacisy

HO"

Prepared from 7a-hydroxyisoatisine^ ^HNMR(CDCl3): 8 0.80(3H,5,H-18), 5.12(2H,m,H.17).

'^C Chemical Shift Assignments (CDCI3)

1. 2.

C-l

39.8

C-12

36.1

C-2

23.1

C-13

26.4

C-3

41.1

C-14

25.4

C-4

33.5

C-15

71.9

C-5

47.9

C-16

156.0

C-6

20.6

C-17

110.1

C-7

70.4

C-18

26.5

C-8

42.6

C-19

60.2

C-9

39.5

€-20

53.9

C-10

38.0

€-21

58.0

C-11

28.1

C-22

60.7

SW Pelletier, RS Sawhney and NV Mody, Heterocycles, 9,1241 (1978). SW Pelletier and NV Mody, J. Am. Chem. Soc. 101,492 (1979).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

210 DIHYDROATISINE

J'^X^CH^

C22H35N02mp 159-161° (a]D-44.5^(ElOH) Aconilum heterophyllum^

HO-.-^l

Prepared from atisine^; prepared from chellespontine^ X-ray structure^ '^C Chemical Shift Assignments^ 3 C-1

SCCjDsN) 5 (CDCb)

40.2

28.4

3

5 (C5D3N) 5 (CDCl

26.4

C-12

36.4

37.1

36.4

C-2

23.2

23.1

23.2

C-13

27.7

26.9

26.4

C-3

41.4

40.8

40.2

C-14

26.4

28.4

27.7

C-4

33.6

33.7

33.6

C-15

76.8

77.0

76.8

C-S

49.6

50.1

49.6

C.16

156.3

157.5

156.3

C-6

17.4

17.9

17.4

C-17

109.6

109.4

109.6

C.7

31.5

42.0

41.4

C-18

26.4

26.7

26.4

C-8

37.4

38.0

37.4

C-19

60.2

59.8

60.2

C-9

39.5

39.9

39.5

C-20

54.0

61.0

58.0

C-10

38.0

38.3

38.0

€-21

58.0

54.7

54.0

C-U

28.0

32.1

31.5

C-22

60.7

62.4

60.7

1. 2. 3. 4. 5.

SW Pelletier, R Aneja and KW Gopinath, Phytochemistry, 7,625 (1968). SW Pelletier, WH De Camp and NV Mody, J. Am. Chem. Soc, 100,7976 (1978). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978). OE Edwards and T Singh, Can. J. Chem., 32,465 (1954). HK Dcsai, BS Joshi, SW Pelletier, B Sener, F Bing5l and T Baykal, Heterocycles, 36,(1993).

Carboii-13 and Proton NMR Shift Assignments

211

AT, 20-DIHYDROATISINEAZOMETHINE K

C20H31NO

Preparedfromatisine

'^C Chemical Shift Assignments^

1. 2.

C-l

40.6

C-11

28.0

C-2

23.3

C-l 2

35.5

C-3

31.5

C-l 3

27.7

C-4

32.4

C-14

26.4

C-5

49.7

C-l 5

76.7

C-6

17.6

C-l 6

156.4

C-7

31.6

C-l 7

109.5

C-8

37.5

C-l 8

26.4

C-9

39.7

C-19

51.8

C-10

36.5

C-20

45.6

SW Pelletier and PC Parthasarathy, J, Am, Chem. Soc, 87,777 (1965). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

B JS. Joshi, S.W. Pelletier and S.K. Srivastava

212 DIHYDROCUAUCHICHICINE

C22H35NO2 Prepared from dihydrolaurifoline' and ganyfoline^

'^C Chemical Shift Assignments^

1. 2.

C-l

41.3

C-12

24.8

C-2

18.0

€-13

38.4

C-3

39.9

C-14

34.5

C-4

33.7

CAS

224.7

C-5

49.4

€-16

47.8

C-6

18.0

C-17

10.2

C-7

32.4

€-18

26.4

C-8

52.3

C-19

60.5

C-9

48.6

C-20

55.7

C-10

40.6

€-21

58.1

C-ll

23.3

C-22

60.9

C Djerassi, CR Smith, AE Lippman, SK Figdor and J Herran, J, Am. Chem. Soc, 77,4805(1955). SW Pelletier, NV Mody, HK Desai, J Finer-Moore, J Nowachki and BS Joshi, J. Org. CAew., 48,1787 (1983).

Carbon-13 and Proton NMR Shift Assignments

213

16,17-DIHYDRO-15,16-DEHYDROEPISCOPALIDINE C30H33NO6; MW: 503.2308'

•^® Prepared from episcopalidine^ ^'^•Y'<>
3- z Me--j|--^N I " J 4/~\t_co-0'' p ^ j j N ^ Vff ^ e O

'H NMR^: 8 1.61 (3H, s, H-18), 1.82 (3H,

d, J=1.2 Hz, H-16), 2.05 (3H, s, OAc), 2.75 (3H, s, H-21), 3.18 (IH, s, H-20), 3.32, 3.72 (each 2H, ABq. J=12 Hz, H-19), 4.93 (IH, d, J=4.5 Hz, H-3), 5.55 (IH, dt, J=4.5,2 Hz, H-2), 5.38 (IH, s, H-15), 7.50, 7.55, 7.97 (each 5H, m, Ar-H).

"C Chemical Shift Assignments'

1. 2.

C-1

35.6

C.15

—

C-2

67.6

C-16

139.9

C-3

75.9

C-17

19.6

C-4

41.4

C-18

25.4

C-5

59.8

C-19

57.5

C-6

—

C.20

70.1

C-7

47.4

C-21

42.7

C-8

45.2*

ArCO

165.4

C-9

50.6

c-r

129.5

C-10

45.9*

C-2', 6'

128.5

C-11

22.7

C-3', 5'

129.7

C-12

52.8

C-4'

133.2

C-13

211.0

COCH3

169.1

C-14

58.1

COCH3

21.2

FP Wang and XT Liang, Youji Huaxue, 1,19 (1986). FP Wang and XT Liang, Tetrahedron, 42,265 (1986).

214

B.S. Joshi, S.W. Pclletier and S.K. Stivastava

16,17-DIHYDRO-2,20-DEHYDRO (14,20 5£CO)-HETIDINE C21H29NO4; MW: 359.2119; amoiphous Prepared from episcopalidine 'H NMR (CDCI3): 8 0.94 (3H, d, J=7 Hz, H-16), 1.40 (3H, 5, H-IS), 2.32 (3H, s.NCH3), 2.52, 2.80 (each 2H, AB^, J=ll Hz, H-19), 3.20 (IH, 5, H-3), 3.95 (IH, d, J=5.7 Hz,H-2),4.30(lH,5,H-20).

^^C Chemical Shift Assignment (CDCI3) C-1

44.9

C-12

49.9

C.2

76.5

C-13

214.7

C.3

78.8

C-14

53.2

C-4

38.9

C-15

29.7

C-5

57.4

C-16

30.4

C-6

204.5

C-17

22.6

€-7

52.4

C-18

22.9

C-8

40.7

C-19

48.9

C-9

44.7

C-20

93.7

C-10

43.5

C-21

42.0

C-11

26.6

FP Wang and XT Liang, Tetrahedron, 42,265 (1986).

Carbon-13 and Proton NMR Shift Assignments

215

16,17-DIHYDROEPISCOPALIDINE C30H35NO6; MW: 505.2477 Prepared from episcopalidine^

AcO BzO''

^^C Chemical Shift Assignments'

1. 2.

C-1

32.8

C-15

27.9

C.2

66.2

C-16

30.9

C-3

74.5

C-17

21.2

C.4

39.9

C-18

24.6

C-5

58.7

C.19

58.2

C-6

—

C-20

70.4

C-7

46.6

C-21

40.3

C-g

41.2

ArCO

164.3

C-.9

45.6

c-r

128.5

C-10

43.9

C-2', 6'

127.5

C-11

22.2

C.3', 5'

128.5

C-12

47.7

C-4'

132.3

C-13

213.4

COCH3

169.0

C-14

57.0

COCH3

20.8

FP Wang and XT Liang, Youji Huaxue, 1,19 (1986). FP Wang and XT Liang, Tetrahedron, 42,265 (1988).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

216 DIHYDROGARRYFOLINE

C22H35NO2

.OH 22<

^^/<

JL

J

/™CH2

Prepared from ovatine

'^C Chemical Shift Assignments C-l

41.4

C-12

32.9

C-2

18.1

C-13

39.8

C-3

40.7

C-14

36.9

C-4

33.8

C-l 5

82.4

C-5

49.7

C-l 6

158.1

C-6

19.1

C-17

105.1

C-7

37.1

C-l 8

26.6

C-8

45.4

C-19

60.4

C-9

42.6

C-20

56.2

C-10

39.8

C-21

58.0

C-11

23.5

C-22

60.8

SW Pelletier, NV Mody and HK Desai, J. Org. Chem,. 46,1840 (1981).

Carbon-13 and Proton NMR Shift Assignments

217

16,17-DIHYDROHETIDINE C21H29NO4; MW: 359

Me

Prepared from hetidine

'^C Chemical Shift Assignments C-l

38.7

C-12

53.1

C-2

63.8

C-13

214.1

C-3

76.8

C-14

57.8

C-4

41.3'

C-15

36.7

C-5

58.3

C-16

33.6

C-l 7

21.7

C-6

199.2 (207.9)

C-7

52.2

C-l 8

23.1

C-8

41.8*

C-19

53.1

C-9

48.2

C-20

66.9

C-10

45.1

N-CU3

45.6

C-11

24.1

'Assignments may be interchanged.

FP Wang and XT Liang, Youji Huaxue, 1,19 (1986).

218

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

C24H37NO3; MW: 387; amorphous C24H37N03-HCI; mp 190-194° Prepared from ovatine 'H NMR: 8 0.76 (3H, 5, H-18), 2.15 (3H, 5, OAc), 3.66 (2H, /, H.22), 4.90, 5.18 (each IH, H-17).

'^C Chemical Shift Assignments (CDCI3) C-1

41.5

C-13

40.4

C-2

18.0

C-14

37.4

C.3

41.1

C-15

81.8

C-4

33.9

C-16

153.7

C-5

49.9

C-17

106.7

C-6

19.2

C-18

26.7

C-7

37.1

C-19

60.6

C-8

45.8

C-20

56.5

C-9

44.3

C-21

58.2

C-10

40.1

C-22

61.4

C-11

23.7

COCH3

171.8

C-12

33.3

COCH3

21.4

SW Pelletier, NV Mody and HK Desai, J. Org. Chem., 46,1840 (1981).

Carbon-ia and Proton NMR Shift Assignments

219

DIHYDROSONGORINE C22H33NO3; MW: 359; mp 202-204^ Aconitum karakolicum Rapaics^ Prepared from songorine^ Mes.

22 21

1. 2.

r *HNMR(CDCl3): 8 0.68 (3H, 5, H-18), 0.74 (3H, d, J=7 Hz, H-17), 1.00 (3H, /, J=7 Hz, H-22).

MN Sultankhodzhev and MS Yunusov, Khim. Phr. Soedin,, 23,917 (1987). MS Yunusov, YV Rashkes, SY Yunusov and AS Samatov, Khim. Phr. Soedin., 6, 101 (1970).

220

BS. Joshi, S.W. Pelletier and S.K. Srivastava

DIHYDROVEATCHINE C22H3SNO2; MW: 345.2668; mp 142-143° ^^

[ab-SlJ-CCHCla) Prepared from veatchine'

'H N M R (CDCI3): 8 0.77 (3H, s, H-18), 0.99, 2.14 (each IH, m, H-1), 1.00 (IH, hrs, H-5), 1.05 (IH, m, H-9), 1.35, 1.71 (each IH, m, H-7), 1.36,1.67 (each IH, w, H-3), 1.40 (2H,OT,H-12), 1.41,1.87 (each IH, 5, H-14), 2.11,2.42 (each IH, d, AB, J=l 1.3 Hz, H-19), 2.40 (2H. /, J=5.4 Hz, H-21), 2.55,2.73 (each IH. d, J=4.9 Hz, H-20), 2.71 (IH, m, H-13), 3.60 (2H, t, J=5.5 Hz, H-22), 3.77 (IH, hrs. H-15), 5.06,5.20 (each IH. s, H-17). '^C Chemical Shift Assignments (CDCI3) 1

2

1

2.

C-l

40.71

41.2*

C-12

32.31

32.3

C-2

18.41

18.5

C-13

41.7 d

41.7

C.3

41.21

40.7*

C-14

36.71

36.8

€-4

33.7 s

33.6

C-l 5

82.6 d

82.3

C.5

50.1 d

50.4

C-16

159.7 s

159.1

C-6

18.21

18.2

C-17

108.51

108.2

C-7

33.lt

33.2

C-l 8

26.4 q

26.4

C.8

47.2 s

47.2

C-19

60.21

60.2

C.9

50.4 d

50.0

C-20

55.91

55.9

C-IO

40.2 s

40.2

C-21

60.61

57.8

Cll

23.41

23.4

C-22

57.81

60.6

^Assignments may be interchanged.

1. 2.

HK Desai, Y Bai and SW Pelletier, J. Nat, Prod. 60,684 (1997). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

Carbon-13 and Proton NMR Shift Assignments

221

M 20-DIHYDROVEATCHINE AZOMETHINE C20H31NO; mp 166-169° [a]D-98.6°(CHCl3)' Prepared from veatchine-^, 20-azomethine*

'^C Chemical Shift Assignments^ C-l

40.8*

C-11

23.7

C-2

18.3

C-12

32.3

C-3

40.3*

C-l 3

41.9

C-4

32.7

C-14

36.5

C-5

51.0

C-l 5

82.7

C-6

18.3

C-16

160.0

C-7 •

33.6

C-17

108.3

C-8

47.5

C-18

26.6

C-9

50.7

C-19

52.8

C-10

39.2

C-20

48.0

"Assignments may be interchanged.

1. 2.

SW Pelletier and DM Locke, J, Am, Chem. Soc, 87,761 (1965). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

222

B.S. Joshi, S.W. Pelietier and S.K. Srivastava

4 , 7P-DIHYDR0XYAN0PTERINE (TP-HYDROXYANOPTERYL-l la-(£).4'-HYDROXY.2'-METHYLBUT-2'.ENOATE 12a-TIGLATE) C31H43NO9; MW: 573; mp 246-248^*-^

2'

Me

I

2"

OCOC=CH—Me !

Me ^4-

V

3- r

^MeOH

3'

4*

Anopterus glandulosus Labill.^'^, A. macleayanus F. Muell.^'^*^ *H NMR (CDjOD)^: 8 1.19 (3H, H-18), 1.76 (IH, H-Bcq), 1.85,1.92 (each 3H, H2\ H-4'), 1.96 (IH, H-3ax), 2.15 (IH, H1.x), 2.32 (3H, H-21), 2.39 (IH, H-Meq), 2.42 (IH, H-lcq), 2.66 (IH, H.19eq), 2.98 (IH, H-13cq), 3.02 (IH, H-15), 3.54 (IH, H^6cq), 3.75 (IH, H-7eq), 4.10 (2H, H-20, H.2cq), 4.26 (2H, H-4"), 4.93, 5.10 (each 1H,H-17),5.50(1H, H-12ax), 6.70,7.16 (eachlH,H-3',3").

'^C Chemical Shift Assignments (CDCb/CDaOD)^

1. 2. 3. 4.

C-l

37.4

C-12

73.3

C-2

65.4

C-l 3

53.5

C-3

41.7

C-14

55.8

C-4

36.6

C-l 5

38.9

C-5

78.2

C-16

148.5

C-6

82.7

C-l 7

108.9

C-7

75.7

C-18

24.4

C-8

52.6

C-19

61.5

C-9

54.3

C-20

65.4

C-10

47.2

C.21

42.8

C-U

70.8

ME Wall, MC Wani, BN Meyer and H Taylor,./. Nat. Prod., 50,1152 (1987). SR Johns, JA Lamberton, H Suares and RI Willing, Aust. J. Chem., 38, 1091 (1985). NK Hart, SR Johns, J A Lamberton, H Suares and RI Willing, Aust. J. Chem., 29, 1319(1976). YC Wu, TS Wu, M Niwa, ST Lu, Y Hinata, DR McPhail, AT McPhail and KH Lee, Heterocycles, 27,1813 (1988).

223

Carbon-13 and Proton NMR Shift Assignments EPISCOPALIDINE

C30H33NO6; MW: 503.2269; mp 210-220°'; 213-214°* [a]D - 80° (CHCI3); -73.2° (CHCb/ Aconitum episcopate Levi.', A. conlortum Finetc/Gagnep'*-"'* 'HNMR(CDCI3)'*: 8 1.58 (3H.s, H-18), 1.78 (IH, ABx, JAB=16 HZ. JAX=4.5 HZ, H1), 2.02 (IH, ABx, JAB=16 HZ, JBX=2.2 HZ,

H-1), 2.04 (3H, s, OAc), 2.25, 2.76 (each lH,
1. 2. 3. 4.

C-l

34.7

C-ll

22.9

C-20

70.7

C-2

67.5

C-12

52.8

C-21

43.4

C-3

76.2

C-13

210.8

COCH3

169.4

C-4

41.8

C-14

58.2

COCH3

21.6

ArCO

165.6

C-5

63.1

€-15

34.5

C.6

200.2

C.16

141.9

c-r

129.9

C-7

50.3

C-17

110.0

C-2', 6'

129.7

C-8

41.8

C-18

25.8

C-3', 5'

128.6

C-9

49.7

C-19

56.4

C-4*

134.3

C-10

44.3

FP Wang and QC Fang, Acta Pharmaceutica Sinica, 18,514 (1983). FP Wang and XT Liang, Youji Huaxue, 1,19 (1986). a) BT Salimov, B Tashkhodzhaev and MS Yunusov, Khim. Prir Soedin., ,86 (1982), b) B Tashkhodzhaev, ibid, 230 (1982). K Niitsu, Y Ikaya and H Mitsuhashi, Heterocycles, 31,1517 (1990).

224

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

FINEHANINE C2iH29N03;MW: 343; mp 236-238^ Aconitumfinetianum Hand-Mazz '^

Me-

[a]D^^-143.7^ *HNMR(CDCl3 + CD30D): 8 0.76(3H, s, 4'CHi), 2.34 (3H, s, N-CHi), 3.88 (IH, m, H-1), 4.34 (IH, bw, H-15), 5.22 (2H, bw, C=CH2), ppm 8 C (CD3OD), 44.32 {N-CH^\ ppm, m/z 343 (NT, 100%).*'^ X-ray structure^; absolute stereochemistry^

^^C Chemical Shift Assignments ^

1. 2.

C-1

71.6

C-11

39.4

C-2

32.5*

C-12

213.2

C-3

32.5'

C-13

55.1

C-4

35.3

C-14

39.2

C-5

50.6

C-15

77.9

C-6

23.6**

C-16

151.7

C.7

44.2^

C-17

111.7

C-8

53.3

C-18

26.4

€-9

36.9^

C-19

60.6

C-10

50.4

€-20

68.2

PJ Zheng and M Wang, Acta Chimica Sinica, 45,776 (1987). PJ Zheng, M Wang and BY Wang, Acta Chimica Sinica, 45,328 (1987).

Carboii-13 and Proton NMR Shift Assignments

225

C22H27NO4; MW: 369.189; amorphous [a]D-33.8MCHCl3) DelphiniumfissumWaldst. and Kit subsp. anatolicum Chaudhuri and Davis *H NMR (CHCI3): 8 2.05 (3H, 5, OAc), 2.52 (IH, d, J=9 Hz, H-14), 2.75, 3.04 (each IH, d, J=13 Hz, H.19), 4.24 (IH, brJ, J=9 Hz, H-13), 4.69,4.88 (each IH, bw, H-17).

^^C Chemical Shift Assignments (CDCI3) C-l

44.4

C-12

50.3

C-2

210.6

C-l 3

70.8

C-3

48.9

C-14

55.1

C-4

41.2

C-l 5

34.5

C-5

58.3

C-16

143.8

C-6

64.7

C-17

108.5

C-7

28.3

C-l 8

29.4

C-8

43.7

C-19

61.6

C-9

75.1

C-20

69.3

C-10

54.4

COCH3

176.9

C-11

28.3

COCH3

22.6

A Ulubelen, AH Meri9li, F Merifli, R Uarsan and W Voelter, Phytochemistry, 34,1165 (1993).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

226 FLAVADINE OH

C24H35NO5; MW: 401.2583 [M*-16];mp 198200° H2

Aconitum flavum \\Qx\d'M2a£^ A. yesoense var. macroyesoense^ (Nakai) I'aniura

*H NMR (C5D5N)': 5 0.71 (3H, .v, H-18), 1.21 (IH, dd, J=l 1.8, 4.1 Hz, H-14cq), 1.25 (IH, m, H3), 1.40 (3H, /, J=7 Hz, H-22), 1.43 (IH, dd, J=14.1, 5.1 Hz, H-6J, 1.53 (IH, d, J=7.6 Hz, H5), 1.92 (IH, dd, J= 14.1,6.9 Hz, H-6p), 2.04 (IH, J, J=5.1 Hz, H-7), 2.05 (IH, m, H-3), 2.06 (IH, w, H-9), 2.06,2.85 (2H, m, H-2), 2.20 (IH, i/, J=l 1.9 Hz, H-14«), 2.24 (3H, 5, C-l5.0Ac), 2.41,2.55 (each IH, m, H-l 1), 2.85 (IH, d, J=4 Hz, H-13), 3.12, 3.31 (each IH, /w, H-21), 3.22, 3.38 (each IH, q, J=13.6 Hz, H-19), 4.02 (IH, dd, J=9.6, 6.9 Hz, H-12), 4.05 (IH. 5, H-20), 4.07 (IH, /, J=6.8 Hz, H-l), 5.15 (2H, w, H-l 7), 5.82 (IH, /, J=2.2 Hz, H-l 5). '^C Chemical Shift Assignments

C-1

1*, (CD3OD)

2 (CDCI3)

68.0

66.6

1*, (CD3OD)

2 (CDCI3)

C-13

47.2

46.3

29.9

29.2

C-2

29.9

30.2

C-14

€-3

35.2

34.6

C-15

77.8

76.7

C-4

36.4

35.4

C-16

154.3

151.9

C-5

48.4

47.3

C-17

110.8

110.8

C-6

23.5

23.0

C-18

26.3

26.4

C-7

47.2

45.8

C-19

74.8

74.3

C-8

49.6

48.3

C-20

81.1

80.3

C-9

40.7

39.3

C-21

68.0

67.1

C-10

55.2

54.1

C-22

7.9

7.6

C-ll

31.1

29.4

COCH3

172.3

170.7

C-12

76.4

75.3

COCH3

21.3

21.6

•Previous assignments' of C-3, C-5, C-11, C-13 and C-14 are revised^. 1. 2.

ZG Chen, AN Lao, HC Wang and SH Hong, Planta Medica, 54, 318 (1988). K Wada, H Bando, T Amiya and N Kawahara, Heterocycles, 29,2141 (1989).

227

Carbon-ia and Proton NMR Shift Assignments FLAVAMINE C22H33NO4; MW: 375; mp 224-226° [a]D-30.5°(CH3OH) Aconhum flavum Hand-Mazz.^

'H NMR (C5H5N)': 6 0.69 (3H, 5. H-18), 1.19 (IH, cW, J=12, 4.5 Hz, H-14eq), 1.23 (IH, w, H-3), 1.40 (3H, r, J=7 Hz, H-22), 1.43 (IH, dd, J=13.6, 4.9 Hz. H-6J. 1.63 (IH, ^, J=7.5 Hz, H-5), 1.99 (IH, m, H-2), 2.12 (IH, c/, J-5 Hz, H-7). 2.18 (IH, d, J-11.9 Hz, H-I4«). 2.25 (2H, w, H-9, HO), 2.47,2.57 (each IH, m, H-11), 2.74 (IH, w. H-2), 2.91 (IH, d, J=3.9 Hz, H-13), 3.11, 3.24 (each IH, m, H-21), 3.20,3.29 (each IH, q, J-13,2 Hz, H-19), 3.40 (IH, dd, J=13.6, 8 Hz, H-6p), 4.07 (IH, dd, J«10.2, 6.6 Hz, H-12), 4.11 (IH, 5, H.20), 4.15 (IH, U J=6.4 Hz, H-1), 4.55 (IH, hxd, J=7.9 Hz, H-15), 5.27. 5.51 (each IH, m, H.17), 6.61 (IH,d, J=7.9Hz. H-15). '^C Chemical Shift Assignments l',(CD30D)

2(CDCl3)

1*,(CD30D)

2 (CDCI3)

C-1

68.1

66.7

€-12

76.7

75.6

C-2

30.1

30.3

C-13

48.5

46.2

C-3

35.3

34.6

C-M

29.6

28.7

C.4

36.2

35.3

€-15

77.6

76.9

C-5

48.5

46.9

C-16

158.9

158.1

C-6

22.9

22.5

C-17

109.3

109.5

C-7

47.3

46.1

C-18

26.5

26.4

C-8

49.8

49.0

C-19

75.3

74.3

C-9

39.1

38.0

C-20

81.5

80.4

C-10

55.5

54.3

C-21

67.9

67.0

C-11

31.3

29.5

C-22

7.8

7.8

•Previous assignments' of C-3, C-5, C-11, C-13 and C-14 are revised^

1. 2.

ZG Chen, AN Lao, HC Wang and SH Hong, Planta Medica, 54,318 (1988). K Wada, H Bando, T Amiya and N Kawahara, Heterocycles, 29,2141 (1989).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

228 GARRYFOLINE (LAURIFOLINE)

C22H33NO2; MW: 343; mp 133-136*»*'^ [a]D-48.8^(CHCl3)^ Garrya ovata var lindheimeri Torr'*^, G. laurifolia Hartw''*, Cocculus laurifolius DC^ ^H NMR (CDCb)^: 8 0.76, 0.81 (each 3H, s, H-18), 2.60 (2H, bw, H-21), 3.82 (2H, m, H.22), 4.43 (IH, 5, H-20), 5.00,5.10 (each IH,rf,H-17). '^C Chemical Shift Assignments (Mixture H-20 cpuners A and B) (CDCI3)* A

B

C-12

32.0

30.9

20.0

C-13

40.4

40.4

37.6

37.6

C-14

37.4

37.4

C-4

34.2

34.1

C-15

83.1

83.1

C.5

52.3

53.1

C-16

159.3

159.8

C.6

18.9

17.5

C.17

104.4

106.0

C-7

35.1

35.1

C-18

26.0

26.5

€-8

45.4

45.7

C-19

56.6

56.1

€-9

43.9

43.2

C-20

93.2

94.5

C-IO

40.2

40.1

C-21

50.5

49.4

C-11

28.8

21.9

C.22

64.6

59.0

A

B

C-1

41.9

41.6

C-2

19.3

C-3

1. 2. 3. 4.

SWPelletier,NVModyandHKDesai,y. Org Chem.,46,1840(1981). SW Pelletier, NV Mody and DS Seigler, Heterocycies, 9,1409 (1978). H Vorbruggen and C Djerassi, J. Am. Chem, Soc, 84,2990 (1962). C Djerassi, CR Smith, AE Lippman, SK Figdor and J Herran, J. Am. Chem. Soc, 77,4801,6633(1955).

Carboii-13 and Proton NMR Shift Assignments

229

GARRYFOLINE-JV, 20-AZOMETHINE C2oH29NO;mp 176-178° [a]D-79.8°(EtOH) Prepared from a mixture of lindheimerine, ovatine and garryfoline 'H NMR (CDCI3): 8 0.81 (3H, s, H-18), 3.38 (2H, s, H-19), 3.81 (IH, 5, H-15), 4.96, 5.06(eachlH,5,H-17). "C Chemical Shift Assignments (CD3OD) C-1

43.2

C-11

22.5

C-2

18.7

C-12

35.2

C-3

37.4

C.13

41.5

C-4

33.8

C-14

36.0

C-5

47.4

C-15

82.6

C-6

21.4

C-16

158.7

C-7

35.7

C-17

105.5

C-8

46.5

C-18

26.4

C-9

43.4

C-19

59.8

C-10

46.3

C-20

170.4

SW Pelletier, NV Mody and HK Desai, J. Org, Chem., 46,1840 (1981).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

230

GARRYINE C22H33NO2; mp 74-82° (hydrate) H2 [a]D-84«(CHCl3) Garrya veatchii Kellog''^

^^C Chemical Shift Assignments^

1. 2. 3.

C-1

40.6

C-12

32.4

C-2

20.6

C-13

41.7

C-3

40.6

C-14

36.8

C-4

40.3

C.15

82.7

C-5

50.6

C-16

159.6

C-6

18.2

C.17

108.5

C-7

33.8

C-18

24.4

C-S

47.4

C-19

98.2

C-9

49.1

C-20

51.1

C-10

35.9

C-21

54.8

C-ll

22.3

C-22

58.7

JF Oneto, J. Am. Pharm. Assoc, 35,204 (1946). K Wiesner and Z Valenta, Prog. Chem. Org Nat. Prod., 16,26 (1958). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

Carbon-13 and Proton NMR Shift Assignments

231

GEYERIDINE C22H27NO5; MW: 385.1889

AcOs,

Delphinium geyeri Greene\ D, barbeyi^ *H NMR (CDCI3): 8 1.48 (3H, s, H-18), 1.79 (IH, J, J=13 Hz), 2.00 (IH, s\ 2.04 (3H, s, OAc), 2.09 (IH, bw), 2.17-2.28 (6H, m), 2.35-2.43 (5H, m), 2.98 (IH, s, H-20), 3.20 (IH, J=12 Hz, H-3J, 3.34 (IH, dd, J= 13,2 Hz, H-1 J , 4.17 (IH, ddd, J=9,3,1 Hz, H-11). 4.79, 4.94 (each IH, bw, H-17), 5.14 (lH,br^,J-9, l,
'Me OH

'^C Chemical Shift Assignments (CDCh)**^ C-l

43.2

0-12

48.6

C-2

210.0

C-13

75.3

C.3

51.4

C-14

49.7

C-4

42.8*

C-l 5

42.9

C-5

59.2

C-16

143.2

C-6

100.2

C-17

109.9

C.7

32.9

C-18

30.2

C-8

45.9^

C-19

59.9

C-9

52.2

C-20

68.4

C-10

55.7

COCH3

170.6

C-11

69.8

COCH3

21.3

"These values have been reversed.^

1. 2.

JA Grina, DR Schroeder, ET Wydallis, FR Stermitz, J Melman and JL Capinera, J. Or^.C/rem., 51, 390 (1986). BS Joshi, HK Desai, El-Sayeda, A El-Kashousy, SW Pelletier and JD Olsen, Phytochemistry, 28,1561 (1989).

232

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

GEYERINE HO. MeO I II MeHoC-HC-C-O-, 24

23

C25HJ3NO5; MW: 427.2341 CHa

[a]D" + 9.6''(EtOH)

22 21

Delphinium geyeri Greene 'H N M R (CDCI3): 8 5.14 (IH, ddd, J=10, 3, 1 Hz, H-11), 4.80, 4.98 (each IH, bre, H-17), 4.36 (IH, ddd, J=l, 9, 1 Hz, H-13), 3.54 (IH, dd, J=15, 2 Hz, Me OH H-1,), 3.36 (IH, btd, J=12 Hz, H-3J, 2.88 (IH, s. H-20), 2.65 (IH, d, J=14 Hz, H-lp), 2.58 (IH, m. J=7 Hz, H-22), 2.50 (IH, dd. J=3.1 Hz, H-12). 2.43-2.48 (2H, m), 2.23-2.34 (4H, m), 1.96-2.14 (6H, m), 1.78-1.70 (IH, m, J=7 Hz, H-23), 1.55 (3H, s, H-18), 1.49-1.53 (IH, m, J=7 Hz, H-23), 1.20 (3H, d, J=7 Hz, H-25), 0.96 (3H,«W,Ji=J2=7Hz,H-24). "C Chemical Shift Assignments C-1

44.41

C-14

48.4 d

C-2

211.2 s

C-15

43.81

C-3

51.6t

C-16

143.6 s

C-4

45.8 s

C-17

109.81

C-5

60.3 d

C.18

30.3 q

C-6

99.2 s

C-19

61.21

C-7

33.lt

C-20

69.2 d

C-8

42.9 s

C-21

176.0 s

C-9

53.7 d

C-22

40.9 d

C-10

56.1s

C-23

26.51

C-11

74.0 d

C-24

11.7q

C-12

48.1 d

C-25

16.8 q

C-13

72.1 d

JA Grina, DR Schroeder, ET Wydallis, FR Stermitz, J Melman and JL Capinera, J. Org. C/jem., 51,390(1986).

Carbon-13 and Proton NMR Shift Assignments

233

GEYERININE Me

C27H38NO7; MW: MH* 488.2648

Delphinium geyeri Greene 25

II O

'H NMR (CDCI3): 8 0.95 (3H, 0, 1.21 (3H, d, J=7 Hz,), 1.32 (IH, s), 1.40 (3H, 5, H-18), 1.48-1.60 (2H, m), 1.73 (IH, m), 1,82-2.10 (6H, m), 2.15 (3H, s), 2.20-2.50 (4H, m), 2.64 (IH, m), 3.02, 3.48 (each IH, d, J=12 Hz. H-19), 3.12 (IH, dd, J=15, 2 Hz, H-IHJ, 3.76 (IH, s, H-20), 4.13 (IH, m, Wi/2=12 Hz, H-2p), 4.32 (IH, brrf, J=9,1, <1 Hz, H-13), 4.78,4.94 (each IH, brs, H-17), 4.86 (IH, «/, J=4 Hz, H-3), 5.13 (IH, dd, J=9, 3, 1 Hz, H11).

Me OH

"C Chemical Shift Assignments C-1

31.6

C-15

44.7

C-2

67.4

C-16

144.3

C-3

77.4

C-17

109.2

C-4

51.5

C-18

26.8

C-5

63.4

C-19

77.4

C-6

96.9

C-20

67.7

C-7

33.6

C-21

175.9

C-8

44.9

C-22

41.4

C-9

54.3

C-23

26.5

C-10

57.8

C-24

11.6

C-U

75.1

C-25

16.8

C-12

48.7

CO

170.2

C-13

73.6

CHj

21.1

C-14

49.4

JA Grina, DR Schroeder, ET Wydallis, FR Stermitz, J Melman and JL C^inera, J. Org. Chem.,51,390(1986).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

234 GLANDULINE

C27H37NO8; MW: 137°

503.2517; mp 134-

[a]D + 24°(MeOH) Comolida glandulosa (Boiss. et Huet) Bornm. Syn., Delphinium glandulosum (Boiss. et Huet) 'H N M R (CDCia): 8 0.92 (3H, /, J=7.4 Hz, H-4'), 1.10 (3H, s, H-18), 1.18 (3H, d, J=17 Hz, H.5'), 1.49 (IH, ddq, J=14,7, 7 Hz, H-3'B), 1.70 (IH, ddq, J=14, 7, 7 Hz, H.3'A), 1.80 (IH, d, J=18 Hz, H-7J, 1.85 (IH, d, J=18 Hz, H-7p), 2.00 (IH, d, J=16 Hz, H-15p), 2.01 (3H, s, OAc), 2.10 (IH, d, J=16 Hz, H.15„), 2.15 (IH, dd, J=16, 3.7 Hz, H-lp), 2.45 (IH, sext, J=7 Hz, H-2'), 2.51 (IH, rf, J=1.8 Hz, H-12), 2.70 (IH, t/, J=12.5 Hz, H-19p), 2.72 (IH, br^, H-5), 3.04 (IH, brJ, J=16 Hz, H-IJ, 3.34 (IH, bw, W„2=6.4 Hz, H-6), 3.59 (IH, rf, J=12.5 Hz, H-19J, 4.06 (IH, s, H-20), 4.09 (IH, bw, H-13p), 4.12 (IH, 5, H-llp), 4.74 (IH, 5, H-17e), 4.90 (IH, d, J=4.7 Hz, H.3p), 4.91 (IH, 5, H-17z), 5.45 (IH, m, W,/2=14 Hz, H-2p). '^C Chemical Shift Assignments (CDCI3)

C-1

29.71

C-15

28.01

C-2

67.9 d

C-16

143.6 s

C-3

73.5 d

C-17

108.8 t

C-4

41.2 s

C-18

25.8 q

C.5

55.0 d

C-19

59.41

C-6

62.61

C-20

67.7 d

C-7

26.lt

c-r

175.9 s

C-8

50.7 s

C-2'

41.6 d

C-9

81.0 s

C-3*

26.61

C-10

46.7 s

C-4'

11.6q

C-11

85.3 s

C-5*

17.0 q

C-12

51.0d

COCH3

170.2 s

C-13

79.7 d

COCH3

20.7 q

C-14

78.5 s

G Almanza, J Bastida, C Codina and G de la Fuente, Phytochemistry, 44,739 (1997).

Carboii-13 and Proton NMR Shift Assignments

235

GOMANDONINE

Ha

KT:.

C21H31NO4; MW: 361;mp248-249'^ [a]D-42.5° (MeOH)* Aconitum subcuneatum Nakai*, A. delphinifolium^ DC. ' H NMR (C5D5N + D2O)*: 5 0.71 (3H, s, H-18), 2.25 (3H, s, H-21), 2.66 (IH, d, J=6.3 Hz, H-17b), 3.47 (IH, hxdd, J=13.8, 8.2 Hz,

H-6p), 3.63 (IH, d, J=6.3 Hz, H-17a), 3.89 (IH, bw, H-20), 4.13 (IH, dd, J=10.9, 6.3 Hz, H-1), 4.37 (IH, dd, J=8.4,4.4 Hz, H-13), 5.00 ( I H , s , WAS). ;-ray structure '^C Chemical Shift Assignments (C^Dst^)^^

C-1

70.6

C-11

25.6'

C-2

32.1

C-12

41.6"

C-3

40.1**

C-13

69.1

C-4

33.8

C-14

39.2*^

C-5

52.7

C-15

76.5

C-6

24.1'

C-16

65.5

C-7

42.6'

C-17

45.0

C-8

44.6"

C-18

26.3

C-9

43.9'

C-19

59.6

C-10

51.4

C-20

68.9

C.21

43.9'

•*''*'Assignments may be interchanged.

1.

S Sakai, T Okazaki, K Yamaguchi, H Takayama and N Aimi, Chem. Pharm. Bull, 35,2615 (1987).

2.

P Kulanthaivel and MH Benn, Phytochemistry, 27, 3998 (1988).

236

B^. Joshi, S.W. Pelletier and S.K. Srivastava

GUANFUBASEA

AcC

C24H3iN06^ ^mp 198^^ [a]D + 49^(CHCl3)^

Aca.

Aconitum bullatifolium var. homotorichum, A. koreanum (Levi.) Rapaics**^'^*^ X-ray structure^

1. 2. 3. 4. 5.

YL Zhu and RH Zhu, Heterocycles, 17,607 (1982). JH Chu and SD Fang, Acta Chimica Sinica, 31,222 (1965). HG Gao, FH Ye and JH Chu, Acta Pharmaceutica Sinica, 13,186 (1966). M Reinecke, DE Minter, DC Chen and WM Yan, Tetrahedron, 42,6621 (1986). J Lin, Y Han, Z Hao, W Sun, S Zhao, L Win, and A Zheng, Zhonggu Yaoke Daxue Xuebao,22,104 (1991).

Carbon-13 and Proton NMR Shift Assignments

237

GUAN FU BASE F C26H35NO6; MW: 457; mp 181-182° [a]D + 58''(CHCl3) Aconitum koreaman (Levi.) Rapaics 'H NMR: 8 0.96 (3H, s, H-18), 1.09, 1.13 (each 3H, d, J=6.5 H2, H-3', 4'), 1.33 (IH, dd, J=14,2H2, H-7p), 1.49 (IH, s, H-5), 1.56 (IH, dd, J=15.5, 4Hz, H-3p), 1.97 (3H, s, OAc), 1.64-2.06 (6H, m, H-lp, H-3„ H-7„, H-9, H-15), 2.40 (IH, m, H-2'), 2.55 (IH, d, J=4Hz, H-12), 2.47, 2.83 (each IH, d, J=12Hz, H-19), 2.88 (IH,rf,J=16Hz, H-1 J, 3.07 (IH, bw, H-6), 3.32 (IH, s, H-20), 4.19 (IH, d, J=9Hz, H-11), 4.68, 4.89 (each IH. brs, H-17), 4.99 (IH, hxs, H-13), 5.12 (IH, bK,H-2)

lA Bessanova, LN Samusenko and MS Yunusov, Khim. Priv. Soedin., 561 (1989).

238

B JS. Joshi, S.W. Pelletier and S.K. Srivastava

GUANFUBASEG AcO.

C26H33NO7; MW: 471; mp 178° Aconitum bullatifolium var. homotorichum» A. koreanum' Rapaics

Aca

*H NMR (CCI4): 8 0.96 (3H, 5, H-18), 1.96 (6H, 5, OAc), 2.02 (3H, 5, OAc), 3.30 (IH, s, H-20), 3.65 (IH, OH), 4.80,5.04 (IH, 2H, H.2, H-11, H.12), 4.88, 4.94 (each IH, H17). X-ray structure**^

1. 2.

YL Zhu and RH Zhu, Heterocycles, 17,607 (1982). JH Liu, HC Wang, YL Gao and JH Chu, Chinese Traditional Medicine and Herbs, 12,27(1981).

Carbon-13 and Proton NMR Shift Assignments

239

GUAN FU BASE Y (ACORINE) C22H29NO5; MW: 387'; MW: 387.2083^ mp 218-219°; mp 214-215°' Aconitum. bullatifoUum var. AcCX homotrichum?, A. Koreanum (Levi.) Raipaics fSyn A. kdmarovii Steinb.)'"^ 'H NMR (CDCb)'-^: 5 1.02 (IH. s, H-18), 1.39 (IH, dd, J=13.9, 2.4 Hz, H-7p), 1.55 ^Me" (IH, s, H-5), 1.59 (IH, dd, J=15.5,4.9 Hz, H-3,0.1-82 (IH, dd, J=13.9,3.3 Hz, H-7J, 1.86 (IH, dd, J=15.8,4.6 Hz, H-V, 1.86 (IH, m, H-3J, 1.99 (IH, d, J=8.9 Hz, H-9), 1.99 (IH, ddd, J=17.9, 2.5, 2.5 Hz, H-15p), 2.08 (IH, ddd, J=?, 2, 2 Hz, H.15J, 2.51 (IH, brrf, J=3 Hz, H-12), 2.57 (IH, d, J=12 Hz, H-19|^, 2.91 (IH, ddd, J=15.9, 2,2 Hz, H-1 J, 2.98 (IH. d, J=12 Hz, H-19J, 3.13 (IH, htm, H-6), 3.55 (IH, d, J=1.2 Hz, H-20), 4.07 (IH, dd, J|=J2=2.4 Hz, H-13), 4.23 (IH, btd, J=9 Hz, H-11), 4.70 (IH, dd, J=l, 3 Hz, H-17e), 4.89 (IH, dd, J=l, 3 Hz, H-17z), 5.14 (IH, dddd, W,/2=9.5 Hz, H-2). HQ

'^C Chemical Shift Assignments (CDCI3) 1 2 52.5 d 31.2 C-12

2 52.7

C-1

1 31.lt

C.2

70.0 d

70.1

C-13

79.9 d

80.0

C-3

36.61

36.6

C-14

80.3 s

80.3

C-4

37.6 s

37.5

C-15

31.0t

31.2

C-5

60.0 d

60.1

C-16

144.6 s

144.8

C-6

63.1 d

63.1

C-17

108.21

108.2

C-7

32.01

32.0

C-18

29.7 q

29.7

C-8

44.3 s

44.2

C-19

63.01

63.1

C-9

53.5 d

53.6

C-20

69.2 d

69.2

C-10

46.4 s

46.4

COCH3

170.6 s

171.2

C-11

76.0 d

76.2

COCH3

21.8 q

21.6

1. 2.

MG Reinecke, DE Minter, DC Chen and WM Yan, Tetrahedron, 42,6621 (1986). lA Bessonova, MS Yunusov, VG Kondrat'ev and AS Shreter, Khim, Prir, Soedin., 690(1987).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

240 GUANFUBASEZ

C24H33NO5; MW: 415'; MW: 415.2358^ mp 230-231**'*^ Aconitum koreanum Levi. Raipaics'*^; >4. Koreanum (Levi.) Rapaics (A. komarovH Steinb.)'

H-c-a

*H NMR (CDCb)"^: 8 1.01 (3H, s, H-18), 1.16 (6H, d, J=6.8 Hz, H-3', H.4'), 1.37 (IH, dd, J=13.9, 2.2 Hz, H-7p), 1.52 (IH, s. H.5). 1.59 (IH, dd, J=15.4,4.1 Hz, H3p), 1.77 (IH, m, H-3J, 1.80 (IH, m, H-7„), 1.86 (IH, m, H-lp), 1.98 (IH, w, H9), 2.00 (2H, w, H-15), 2.47 (IH, m, H-I2), 2.50 (IH, sepU J-6.8 Hz, H.2'), 2.52 (IH, d, J=12.2 Hz, H-19^, 2.85 (IH, c/, J=15.7 Hz, H-IJ, 2.95 (IH, J, J=12.2 Hz, H-19J, 3.11 (IH. bw, H-6), 3.53 (IH, 5, H.20), 4.04 (IH, bey, H-13), 4.22 (IH, d, J=8.7 Hz, H-11), 4.68 (IH, bw, H-17c), 4.86 (IH,bw, H-17z), 5.13 (IH, /w, H-2). '^C Chemical Shift Assignments (CDCb)^*^ C-1

31.41

C-13

80.0 d

C.2

69,6 d

C.14

80.2 s

C.3

36.71

C-15

31.lt

C-4

37.6 s

C-16

144.7 s

C-5

59.9 d

CAl

108.2 t

€-6

63.0 d

C-18

29.7 q

C-7

32.01

€-19

63.0 t

C-8

44.3 s

C-20

69.1 d

C-9

53.5 d

c-r

176.5 s

C-10

46.3 s

C-2'

34.4 d

Cll

76.0 d

C-3'

19.1 q

52.7 d

C.4'

19.1 q

C.12

1. 2. 3.

MG Rcinccke, WH Watson, DC Chen and WM Yan, Heterocycles, 24,49 (1986). MG Reinecke, DE Minter, DC Chen and WM Yan, Tetrahedron, 42,6621 (1986). lA Bessonova, MS Yunusov, VG Kondrat'cv and AL Shrctcr, Khim, Prir, Soedin., 690(1987).

Carbon-13 and Proton NMR Shift Assignments

241

HANAMISINE C29H33NO5; MW: 475; mp 124-127*'' [a)D + 122.6*'(MeOH)'

COO,

Aconitum sanyoense Nakai, A. sanyoense var. /onenseNakai' 'H NMR {CD3OD)': 6 1.08 (3H. 5, H-18), 2.10 (3H, s, OAc), 3.98 (IH. brs, H-IS), 4.96 (2H, w. H-17), 5.30 (2H, w. H-2, H-1). X-ray structure* '^C Chemical Shift Assignments' (CDCI3) C-1

69.9

C-14

42.5

€-2

71.4

C.15

73.8

C-3

33.8

C.16

156.2

C-4

36.5

C-17

108.8

C.5

57.0

C-18

29.1

C-6

65.2

€-19

63.5

C-7

27.0

C-20

C-8

44.7

COCH3

169.8

C-9

44.0

COCH3

21.0

C-10

52.2

ArCO

165.1

C-11

33.3

c-r

129.9

C-12

33.5

C.2',6»

129.6

32.7

C-3\ 5'

128.2

C-4*

133.3

€-13

1. 2.

70.0

T Okamoto, H Sanjoh, K Yamaguchi, Y litaka and S Sakai, Chem, Pharm, Bull. Japan, 31,1431 (1983). S Sakai, Personal Communicatioa July 4,1986.

242

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

HETEROPHYLLOIDINE (PANICUTINE) C23H29NO4; MW: 383; mp 160-165^'-^ [a]D-82.0^(CHCl3)''' Aconitum paniculatum Lam.'*^, A. helero-phylloides Stapf.'-^ 'HNMR(CDCl3)^: 6 1.48(3H.5, H-18), 1.45-1.55, 1.70-1.80 (2H. H-3), 1.55-1.60, 2.00-2.05 (2H, w, H-1), 1.60 (IH, J, H-9), 1.80-1.90, 2.00-2.10 (2H, /w, H-11). 2.05 (3H, 5, OAc), 1.99-2.07 (2H, m, H14), 2.26, 2.69 (each IH, JAB=18 HZ, H-7), 2.35 (3H. 5, H-21), 2.35. 2.49 (IH, JAB=16 HZ, H.15), 2.50 (IH, d, ^m^S Hz, H-20), 2.54, 2.68 (each IH, JAB=10 Hz, H.19), 2.60 (IH, 5, H-5), 2.92 (IH, m, W,/2=7 Hz, H-12), 4.82, 4.98 (IH, W|/2=4 Hz, H-17), 5.14 (IH, w. W,/2=10 Hz, H-2). X-ray structure^^ .2.-« '^C Chemical Shift Assignments (CDCby

C-1

35.9

C-9

50.0

C-17

110.5t

C-2

68.5

C-10

44.5

C-18

31.2q

C-3

43.9

C-U

22.7

C-19

60.4

C-4

36.8

C-12

52.8

C-20

70.9

C-5

63.2

C-13

211.5

C-21

43.3

C.6

203.8

C-14

59.2

COCH3

169.8

C-7

50.4

C-15

34.8*

COCH3

21.6

C-8

41.8

C-16

142.3 s

•Assignments may be interchanged. 1.

SW Pelletier, BS Joshi, HK Desai, Al Panu and A Katz, Heterocycles, 24, 1275 (1986).

2. 3.

A Katz and E Staehelin, Helv. Chim. Acta, 65,286 (1982). SW Pelletier, NV Mody, J Finer-Moore, HK Desai and HS Puri, Tetrahedron Lett., 22,313(1981). FP Wang and XT Liang, Youji Huaxue, 1.19 (1986). A Haur Rahman, A. Nasveen, F Aklitar, MS Shekhoni, J Clardy, M Purvez and MI Choudhary, J. Nat. Prod, 60,472 (1997).

4. 5.

243

Carbon-13 and Proton NMR Shift Assignments HETIDINE C21H27NO4; MW: 357.1975^ mp 218-221*'* AconUum heterophyllum Wall', A. palmatum Don^ Prepared from episcopalidine^ 'H NMR (CDCb)^: 6 1.17 (3H, 5, H-18), 2.46 (3H, 5, H-21), 4.80, 4.98 (each I H , H.17). X-ray structure '^C Chemical Shift Assignments*

C-1

38.8

C-12

53.1

€-2

67.5'

C-13

209.6

C-3

76.6

C-H

56.7

C-4

41.0*'

C-15

35.9

C-5

58.0

C.16

142.1

€-6

202.2

C-17

109.3

C-7

52.0

C-18

23.1

C-8

41.6**

C-19

51.8

C-9

46.3

C-20

67.9'

C-10

44.3

C-21

41.4

C-Il

22.7

•.bAssignments may be interchanged.

1.

SW Pelletier, R Aneja and KW Gopinath, Phytochemistry, 7,625 (1968).

2.

QP Jiang and SW Pelletier, Tetrahedron Lett., 29,1875 (1988).

3.

SW Pelletier, KN Iyer, VK Bhalla, MG Newton and R Aneja, J. Chem. Soc, Comm., 393 (1970).

4.

FP Wang and XT Liang, Youji Huaxue, 1,19 (1986).

5.

FP Wang and XT Liang, Acta Pharmaceutica Sinica. 20,436 (1985).

Chem.

B^. Joshi, S.W. Pelletier and S.K. Srivastava

244

HETISINE C20H27NO3; MW: 329; mp 256-259** [a]D+10.9°(CHCl3)' Aconitum heterophyllum Wall*, A. palmaturn Don^ Delphinium occidentale S. Wats^, D, delavayi Franch var. pogonanthurn (H.-M. Wang/, D. tatisenense Franch^, D. nudicaule Torr and Grey^, D. nuttalanum Pritz^, D. venulosum Boiss*, Consolida axilliflora (DC) Schr5d. syn., Z). axilliflorum (DC)^ *H NMR (CDCI3 + CDaOD)^ 8 0.99 (3H, 5, H-18), 3.80(IH, bw, H-20), 4.004.15 (3H, m, H.2B, H-1 U, H - U J , 4.65,4.90 (each IH, bw,H-17). X-ray structure'®*" '^C Chemical Shift Assignments 12 C-l

34.3

2 13 (CD3OD) (CDCI3)

12

2 13 (CD3OD) (CDCI3)

35.1

34.5

C-11

76.5

77.0

76.7

C-12

50.9

52.3

50.8

C-2

66,9

67.8

67.0

C-3

38.8

39.9

39.4

C-13

72.4

73.2

72.4

C-4

36.8

37.7

36.7

C-14

52.2

53.4

52.9

C-5

61.4

62.6

61.7

C-15

34.1

34.6

34.5

C-l 6

146.1

148.3

146.4

C-6

64.3

65.5

64.5

C-7

36.4

37.3

36.6

C-17

107.7

107.6

107.7

C-8

43.5

44.6

43.6

C-l 8

29.9

30.2

30.3

C-9

55.5

56.7

55.8

C-19

63.3

64.1

63.7

C-10

50.7

52.0

51.2

C-20

68.1

69.1

68.4

1. 2. 3.

SW Pelletier, R Aneja and KW Gopinath, Phytochemistry, 7,625 (1968). QP Jiang and SW Pelletier, J. Nat Prod, 54,525 (1991). P Kulanthaivel, SW Pelletier and JD Olsen, Heterocycles, 27,399 (1988).

Carbon-13 and Proton NMR Shift Assignments 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

245

SW Pelletier, FM Harraz, MM Badawi, S Tantiraksachai, FP Wang and SY Chen, Heterocycles, 24,1853 (1986). SW Pelletier, JA Glinski, BS Joshi, and SY Chen, Heterocycles, 20, 1347 (1983). P Kulanthaivel and MH Benn, Heterocycles, 23,2515 (1985). Y Bai, M Benn and W Majak, Heterocycles, 31,1233 (1990). A Ulubelen, AH Meri9li, F Meri9li, R Ilarslan and SA Matlin, Phytochemistry, 31,3239(1992). G de la Fuente, L Ruiz-Mesa, J Molero and C Blanche, Fitotherapia, 67, 87 (1996). M Przybylska, Can, J. Chem,, 40, 566 (1962); Acta Crystallogr,, 16, 871 (1962). KI Varughese and SW Pelletier, J, Nat Prod., 47,470 (1984). JA Glinski, BS Joshi, QP Jiang and SW Pelletier, Heterocycles, 27, 185 (1988). AG Gonzdlez, G de la Fuente, M Reina, R Diaz and I Timdn, Phytochemistry, 25,1971 (1986).

246

B^. Joshi, S.W. Pelletier and S.K. Srlvastava

HETISINE-2-0NE C20H25NO3; MW: 327; mp 268-270*'^'^-^'' [a]D+40°(CHCl3)^ Delphinium occidentale S. Wats^ D, delavayi Franch y2x,pogonanthum (H. M. Wang)^, D. nudicaule Torr and Grey"^, D. gracile DC",£). cardinale Hook^',D. tatisenense Franch^, D. denudatum Waif, D. cardiopetalum DC^, Aconitum heterophyllum Wall^ Prepared from hetisine^ ^H NMR (CDCbf: 5 1.17 (3H, s, H-IS), 3.29 (2H, bw, OH), 4.21 (2H,rf,J-8.6 Hz, H-1 Ip. H.13J, 4.70,4.88 (each IH, bw, H-17). '^C Chemical Shift Assignments 9

10

9

10

C-1

45.21

45.3

C-U

71.5 d

75.8

C.2

214.3 s

213.0

C-12

52.0 d

50.7

C.3

49.91

49.7

C-13

75.6 d

71.6

C.4

42.4 s

42.3

C-14

50.8 d

52.4

C-5

60.4 d

60.4

C-15

33.91

33.8

C-6

65.2 d

65.2

C-16

145.4 s

145.2

C-7

36.lt

36.1

C-17

108.21

108.2

C-8

44.4 s

44.3

C.18

28.7 q

28.8

C-9

55.0 d

54.9

C-19

64.41

64.3

C-10

55.7 s

55.4

C-20

70.3 d

70.4

1. 2. 3.

P Kulanthaivel, SW Pelleti SW Pelletier, FMl ^arraz Chen, Heterocycles, 24,1853 (1986). P Kulanthaivel and MH Benn, Heterocycles, 23,2515 (1985).

Carbon-13 and Proton NMR Shift Assignments 4. 5. 6. 7. 8. 9. 10. 11.

247

AG Gonzdlez, G de la Fuente and M Reina, An. Quim,, Sec. C, 11 (2), 171 (1981). SW Pelletier, JA Glinski, BS Joshi and SY Chen, Heterocycles, 20, 1347 (1983). SW Pelletier, R Aneja and KW Gopinath, Phytochemistry, 7,625 (1968). RT Aplin, MH Benn, SW Pelletier, J Solo, SA Telang and H Wright, Can. J. C/iem., 46,2635(1968). MH Benn, Can. J. Chem., 44,1 (1966). JA Glinski, BS Joshi, QP Jiang and SW Pelletier, Heterocycles, 27,185 (1988). AG Gonzdlez, G de la Fuente, M Reina, R Diaz and I Tim6n, Phytochemistry, 25,1971 (1986). AG Gonzdlez, G de la Fuente, R Reina and I Tim6n, Heterocycles, 11, 667 (1984).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

248

7B-HYDR0XYAN0PTERINE (7p-HYDR0XYAN0PTERYL-l la,12a-DITIGLATE) C31H43NO,; MW: 557;mp246-248°'-' [a]D-12° (CHCI3/MCOH 1:1)^-^ Anopterus glandulosus Labill''^ A. macleay9COC==CH—Me , 1" 3" 4" anus F. MuelF 'H NMR (CDCI3 + CDjOD)^': 6 1.17 (3H, H-18), 1.40 (IH, He,-3), 1.75 (3H, H.2'), 1.77 (3H, H-4'). 1.84 (3H, H-4"), 1.91 (3H, H-2"), 1.95 (IH, H,x-3), 2.11 (IH, H.x-1), 2.29 (IH, H-15), 2.33 (3H, H-21), 2.39 (IH, H«,-14), 2.47 (IH, Heq-l), 2.60 (IH. H„-19), 2.80 (IH, H-9), 3.00 (IH, Heq-13), 3.01 (IH, Me OH H-15), 3.56 (IH, H.,-6), 3.75 (IH, U^-T), 3.85 (IH, H,x-19), 4.10 (IH, He,-2), 4.92, 5.10 (each IH, H-17), 5.20 (IH, H«,12), 5.48 (IH, H„-l 1), 6.78 (IH, H-3'), 7.20 (IH, H-3"); (CDClj): 8 1.21 (3H, H18), 1.42 (IH, He,-3), 1.75 (3H, H-2'), 1.76 (3H, H-4'), 1.84 (3H, H-4"), 1.92 (3H, H-2"), 1.97 (IH, H,x-3), 2.13 (IH, H„-l), 2.29 (IH, H-15), 2.31 (3H, H-21), 2.43 (IH, H«,-14), 2.47 (IH, He,-1), 2.66 (IH, He,-19), 2.78 (IH, H-9), 2.98 (IH, H.,13), 3.03 (IH, H-15), 3.62 (IH, H«,-6), 3.75 (IH, H„-19), 3.92 (IH, He,-7), 4.11 (IH, H-20), 4.15 (IH, He,-2), 4.91,5.09 (each IH, H-17), 5.20 (IH, He,-12), 5.49 (IH, H„-l 1), 6.76 (IH, H-3'), 7.09 (IH, H-3"). "C Chemical Shift Assignments (CDCI3)''' C-2

36.2 66.5

C-11 C-12

76.3 73.4

C-3

41.8

C-13

53.2

C-4

36.2

C-14

56.1

C-5

77.9

C-15

38.8

C-6

82.6

C-16

148.2

C-7

76.0

C-17

108.7

C-8

52.3

C-18

24.5

C-9

54.2

C-19

61.6

C-10

47.0

C-20

64.9

C-21

42.8

C-1

1. 2. 3.

ME Wall, MC Wani, BN Meyer and H Taylor, J. Nat. Prod, 50,1152 (1987). SR Johns, JA Lamberton, H Suares, and RI Willing, Aust J. Chem., 38, 1091 (1985). NK Hart, SR Johns, JA Lamberton, H Suares and RI Willing, Aust J. Chem., 29, 1319(1976).

Carbon-13 and Proton NMR Shift Assignments

249

7-B-HYDROXYANOPTERYL lla,12a-DITIGLATE 2"

Me I OCOC=CH—Me I r 34-

C31H43NO8; MW: 557; mp 247-249^ [a]D-14° (MeOH) Anopterus macleayanus F. MuelP, A . glandulosus Labill^

*H NMR (CDCb)^: 8 1.21 (3H, 5, H-18), 1.42 (IH, Heq-3), 1.75 (3H, H.2% 1.76 (3H, H-4% 1.84 (3H, H-4"), 3.92 (IH, Heq'Me6H 7), 1.92 (3H, H-2"), 1.97 (IH, Hax-3), 2.13 (IH, Hax-1), 2.29 (IH, H-15), 2.78 (IH, H9), 2.31 (3H, H-21), 2.43 (IH, Hcq-14), 2.47 (IH, Heq-1), 2.66 (IH, Heq-19), 3.03 (IH, H-15), 2.98 (IH, Heq-13), 3.62 (IH, Heq-6), 3.75 (IH, Hax-19), 4.11 (IH, H20), 4.15 (IH, Heq-2), 4.91 (IH, H-17), 5.09 (IH, H-H), 5.20 (IH, Heq-12), 5.49 (IH, Hax-11), 6.76 (IH, H-3'), 7.09 (IH, H-3"). '^C Chemical Shift Assignments (CDCb)^

1. 2.

C-l

36.2

C-11

70.3

C-2

66.5

C-12

73.4

C-3

41.8

C-13

53.2

C-4

36.2

C-14

56.1

C-5

77.9

C-15

38.8

C-6

82.6

C-16

148.2

C-7

76.0

C-17

108.7

C-8

52.3

C-18

24.5

C-9

54.2

C-19

61.6

C-10

47.0

C-20

64.9

C-21

42.8

NK Hart, SR Johns, JA Lamberton, H Suares and RI Willing, Aust 1 Chem., 29, 1319(1976). SR Johns, JA Lamberton, H Suares and RI Willing, Aust J, Chem., 38,1091 (1985).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

250

7P-HYDR0XYAN0PTERYL-1 l a (4'.HYDR0XY) BENZ0ATE-12a-TIGLATE 2-

Me o. 0

OCOC—CH—Me

C33H41NO9; MW: 595

Anopterus macleayanus F. Muell

*H NMR (CDCI3+ CD3OD): 5 1.18 (3H, H-18), 1.42 (IH, Heq-3), 1.85 (3H, H-4"), 1.89 (3H, H-2"), 1.96 (IH, Hax-3), 2.21 HO (IH, Hax-1), 2.31 (IH, H-15), 2.36 (3H, Me H-21), 2.42 (IH. Heq-14), 2.62 (IH, Heq21 1), 2.63 (IH, Hcq-19), 2.90 (IH, H.9), 3.03 (IH, Hcq-13), 3.06 (IH, H-15), 3.56 Me OH (IH, Heq-6), 3.78 (IH, Hcq-7), 3.88 (IH, Hax-19), 4.10 (IH, Heq-2), 4.19 (IH, H20), 4.96 (IH, H.17), 5.13 (IH, H-17), 5.29 (IH, Hcq-12), 5.62 (IH, Hax-11), 6.80 (2H, H-5', H-3"), 7.21 (IH, H-3"), 7.80 (2H, H-6', H-2'); (CDCI3): 5 1.22 (3H, H18), 1.43 (IH, Heq-3), 1.84 (3H, H.4"), 1.89 (3H, H-2"), 1.95 (IH, Hax-3), 2.20 (IH, Hax-11), 2.33 (IH, H-15), 2.45 (IH, Hcq-14), 2.58 (IH, Heq-1), 2.63 (IH, Heq19), 2.87 (IH, H.9), 3.02 (IH, Heq-13), 3.07 (IH, H-15), 3.58 (IH, Hcq-6), 3.73 (IH, Hax-19), 3.94 (IH, Heq-7), 4.11 (IH, H-20), 4.16 (IH, Hcq-2), 4.95 (IH, H17), 5.13 (IH, H-17), 5.28 (IH, Heq-12), 5.63 (IH, H-11), 6.81 (2H, H-5\ H-3'), 7.11 (IH, H-3"), 7.82 (2H, H-6', H-2'). &

SR Johns, JA Lamberton, H Suares and RI Willing, Aust. J. Chem., 38,1091 (1985).

Carboii-13 and Proton NMR Shift Assignments

251

7-B-HYDROXYANOPTERYL 1 la-(E)-4'-HYDROXY-2'-METHYLBUT-2'-ENOATE I20-TIGLATE C31H43NO9; MW: 573; mp 242-244°

*' f f

[ah-9°

'*>c=9-c-o.

(MeOH)

Anopterus macleayanus F. Muell'"^

'H NMR (CDCI3 + CDjOD)^: 8 1.19 (3H, H-18), 1.42 (IH, He,-3), 1.76 (3H, H-2'), 4.26 (2H, H-4'), 1.85 (3H, H-4"), 3.75 (IH. H.,-7), 1.92 (3H, H-2", 1.96 (IH, H«-3), 2.15 (IH, H„-l), 2.28 (IH, H-15), 2.78 (IH, H-9), 2.32 (3H, H-21), 2.39 (IH, H«,-14), 2.42 (IH, He,-1), 2.56 (IH, He,-19), 3.02 (IH, H-15), 2.98 (IH, He,-13), 3.54 (IH, He,-6), 3.81 (IH, H.x19), 4.10 (IH, H-20), 4.10 (IH, He,-2), 4.93 (IH, H-17), 5.10 (IH, H-17), 5.20 (IH, H„-12), 5.50 (IH, H„-l 1), 6.70 (IH, H-3'), 7.16 (IH, H-3"). "C Chemical Shift Assignments

1. 2.

C-1

37.4

C-11

70.8

€-2

65.4

C-12

73.3

C-3

41.7

€-13

53.5

C-4

36.6

€-14

55.8

C-5

78.2

C-15

38.9

C-6

82.7

C-16

148.5

C-7

75.7

C-17

108.9

C-8

52.6

C-18

24.4

C-9

54.3

C-19

61.5

C-10

47.2

C-20

65.4

C-21

42.8

NK Hart, SR Johns, JA Lamberton, H Suares and RI Willing, Aust. J. Chem., 29, 1319(1976). SR Johns, JA Lamberton, H Suares and RI Willing, Aust. J. Chem., 38,1091 (1985).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

252

M6-HYDROXYEPISCOPALIDINE-6-CATHYLATE-CHLORIDE C33H28CINO8 Prepared from episcopaldine AcO a'

5*

g Me

6'

O

MeO-COOCHaMe

^^C Chemical Shift Assignments C-l

33.6

C-18

24.5

C-2

72.5

C-l 9

65.4

C-3

77.1

C-20

75.6

C-4

39.5

C-21

40.8

C-S

57.7

C-22

169.7

C-6

103.9

C-23

69.1

C-7

46.9

C-24

13.9

C-8

43.4

ArCO

165.1

C-9

48.3

c-r

128.4

C-10

46.9

C-2', 6'

128.6

C-11

22.9

C-3', 5'

129.4

C-12

51.9

C-4'

133.6

C-13

205.5

COCH3

169.7

C-14

55.0

COCH3

21.5

C-15

30.6

CO

C-16

139.4

0CH2

69.1

C-17

112.5

CHi

13.9

FP Wang and XT Liang, Youji Huaxue. 1,19 (1986).

150.7

Carbon-13 and Proton NMR Shift Assignments

253

//,(5-HYDR0XY EPISCOPALIDINE CHLORIDE C30H31CINO6

P^z

a: ^

Preparedfromepiscopaldine

J

"C Chemical Shift Assignments C-1

31.5

C-15

30.4

C-2

68.2

C-16

141.8

C-3

75.2

C-17

113.7

C-4

40.7

C-18

25.4

C-5

56.9

C-19

58.2

C-6

104.6

C.20

74.6

C-7

47.0

C-21

37.8

C-8

43.5

ArCO

167.2

C-9

47.9

C-r

129.8

C-10

46.3

C-2'. 6"

130.0

C-11

22.9

C-3', 5'

130.4

C-12

52.2

C-4'

135.4

C-13

211.5

COCH3

171.5

C-14

54.1

COCH3

21.3

FP Wang and XT Liang, Yotiji Huaxue, 1,19 (1986).

254

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

7a-HYDR0XYIS0ATISINE CzaHijNOj; MW: 359.5; mp 118-120» [aJo-ieJocCHCb) Prepared from ajaconine

"C Chemical Shift Assignments (CDCI3) C-1

40.3

C-12

36.2

C-2

22.0

C.13

28,3

C-3

39.6

C.14

25.5

C-4

38.1

C-15

71.9

C-5

46.4

CA6

155.8

C-6

20.7

C-17

110.1

C-7

70.6

C-18

24.3

C-8

42.6

C.19

98.3

C-9

39.6

C-20

49.5

C-10

35.7

C-21

54.9

C-11

28.4

C-22

58.8

SW Pelletier and NV Mody, J. Am. Chem. Soc. 101,492 (1979).

Carboii-13 and Proton NMR Shift Assignments

255

9.HYDROXYNOMININE

h

C20H27NO2; MW: 313.2044; mp 287-291° (dec.) [ajD + eg.SoCMeOH) Aconitum ibukiense Nakai ' H NMR (CD3OD + CDCI3): 8 1.02 (3H, s, H-18), 2.22, 2.44 (each IH, d, J=17 Hz, H19), 4.02 (IH, s, H-15„), 5.00, 5.01 (each 1H,J,H-17). "C Chemical Shift Assignments (CD3OD + CDCI3)

C-1

28.9

C-11

38.5

C-2

19.6

C-12

35.1

C-3

33.4

C-13

33.4

C-4

37.3

C-14

41.5

C-5

54.6

C-15

73.2

C-6

64.8

C-16

154.6

C-7

24.5

C-17

109.9

C-8

45.1

C-18

29.0

C-9

79.2

C-19

62.4

C-10

52.8

C-20

72.3

S Sakai, I Yamamoto, K Hotoda, K Yamaguchi, N Aimi, E Yamanaka, J Haginiwa and T Okamoto, Yakugaku Zasshi, 104,222 (1984).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

256 HYPOGNAVINE

C27H3iN03;mp 239-24 r* [a]D+127.r (MeOH)* 4/^-coo,^ 6'

Aconitum sanyoense Nakai

6*

X-ray structure^

'^C Chemical Shift Assignment^

1. 2. 3.

C-1

68.1

C-13

33.5

C-2

73.2

C-14

42.4

C-3

33.0

C-15

72.4

C-4

35.8

C-16

154.6

C-5

50.6

C.17

110.0

C-6

64.1

C-18

29.3

C-7

29.0

C-19

63.5

C-8

44.3

C-20

71.8

C-9

80.3

ArCO

165.5

C-10

54.9

c-r

129.9

C-11

39.2

C-2',6'

129.5

C-12

34.8

C-3', 5'

128.7

C-4'

133.3

E Ochiai, T Okamoto, T Sugasawa, H Tani and S Sakai, Chem. Pharm. Bull. Japan, 1,152(1953). S Sakai, K Yamaguchi, I Yamamoto and T Okamoto, Chem. Pharm. Bull. Japan, 30,4573 (1982) and papers cited therein. S Sakai, K Yamaguchi, I Yamamoto, K Hotoda, T Okazaki, N Aimi, J Haginiwa and T Okamoto, Chem. Pharm. Bull. Japan, 31,3338 (1983).

Carbon-13 and Proton NMR Shift Assignments

257

HYPOGNAVINOL C2oH27N04;mp 307-308°' [a]D + 67.7^ (MeOH)'

HO,

Prepared from hypognavine'*^'^ X-ray structure^

^^C Chemical Shift Assignments^

1. 2. 3. 4.

C-l

79.3

C-11

39.6

C-2

71.2

C-12

35.7

C-3

36.4

C-13

33.6

C-4

36.4

C-14

42.9

C-5

51.7

C-15

72.3

C-6

64.7

C-16

156.0

C-7

29.8

C-17

109.1

C-8

44.7

C-l 8

29.8

C-9

80.7

C-19

63.9

C-10

55.5

C-20

71.3

E Ochiai, T Okamoto, T Sugasawa, H Tani and S Sakai, Chem. Pharm. Bull Japan, 1,152(1953). SW Pelletier, SW Page and MG Newton, Tetrahedron Lett, 795 (1971). S Sakai, K Yamaguchi, I Yamamoto and T Okamoto, Chem. Pharm, Bull Japan, 30,4573(1982). S Sakai, Private Conununication, July 14,1986.

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

258 IGNAVINE

C27H31NO5; MW: 449; mp 216.5-218*'\ 172-173^^228-230^^ [a]D + 47.0^(MeOH)^

BzO.

Aconitum ibukiense Nakai',y4. carmichaeli Debeaux^, A. japonicum Thunb.^'^, A. sanyoeme Nakai^, A, species^ *H NMR (CD3OD): 8 1.17 {3H, s, H.18), 4.99 (2H, bw, H-17), 5.39 (IH, bw, H.2), 7.54 (3H, m), 7.99 (2H, dd, J=8,2 Hz).^ X-ray structure.3.5 '^C Chemical Shift Assignments (CDaOD)^ 25.7 (q\ 25.7 (/), 30.0 (/), 34.3 {s\ 36.3 (^, 39.7 (/), 42.2 {s\ 43.2 (J), 45.4 (^, 51.5 (5), 52.1 (0, 62.4 (/), 65.7 (^, 71.3 (^, 73.0 {d), lAJ (J), 75.8 ((/), 80.1 {s\ 110.2 (0,129.8 (J, 2C), 130.2 (J, 2C), 130.4 (5), 134.4 (t/), 155.6 (5), 166.8 (5).

1.

S Sakai, I Yamamoto, K Hotoda, K Yamaguchi, N Aimi, E Yamanaka, J Haginiwa and T Okamoto, Yakugaku Zasshi, 104,222 (1984).

2.

H Hikino, Y Kuroiwa and C Konno, J. Nat. Prod, 46,178 (1983).

3.

T Okamoto, H Sanjoh, K Yamaguchi, A Yoshino, T Kaneko, Y litaka and S Sakai, Chem. Pharm. Bull, 30,4600 (1982).

4.

E Ochiai, T Okamoto, T Sugasawa, H Tani and HS Hai, Yakugaku Zasshi, 72 , 816 (1952).

5.

SW Pelletier, SW Page and MG Newton, Tetrahedron Lett., 4825 (1970).

6.

H Takayama, S Hasegawa, S Sakai, J Haginiwa and T Okamoto, Chem. Pharm. 5M//., 29,3078 (1981).

7.

H Takayama, S Hasegawa, S Sakai, J Haginiwa and T Okamoto, Yakugaku Zasshi, 102,525(1982).

Carbon-13 and Proton NMR Shift Assignments

259

IGNAVINOL (ANHYDROIGNAVINOL^) K

C20H27NO4; MW: 345; mp 302-304° Prepared from ignivine ^ X-ray structure^'^

" C Chemical Shift Assignments (C5D5N)

1. 2. 3.

C-l

28.5

C-11

39.6

C-2

73.0

C-12

36.0

C-3

74.3

C-13

33.9

C-4

42.3

C-14

42.6

C-S

52.0

C-l 5

74.0

C-6

65.3

C-16

156.6

C-7

30.2

C-l 7

109.6

C-8

44.7

C-18

26.6

C-9

80.1

C-19

62.4

C-10

52.0

C-20

73.0

H Takayama, T Okazaki, K Yamaguchi, N Aimi, J Haginiwa and S Sakai, Chem. P;iarm.Sii//., 36,3210 (1988). T Okomato, H Sanjoh, K Yamaguchi, A Yoshino, T Kaneko, Y litika and S Sakai, Chem. Pharm. Bull, 30,4600 (1982). SW Pelletier, SW Page and MG Newton, Tetrahedron Lett,, 4825 (1970).

B^. Joshi, S.W. Peiletier and S.K. Srivastava

260 3-£:/'MGNAVIN0L

C20H27NO4; MW: 324.1935; mp 292-293" (dec.) [a]D + 49.1''(McOH) Aconitumjaponicum var. montanum Nakai 'H NMR (CD3OD): 8 1.14 (3H, s, H-18), 4.99 (2H, d, J=1.7 Hz, H-17), 3.98 (IH, t, H15), 4.08 (IH, m, H-2), 3.37 (IH, d, J=4.6 Hz, H-3). X-ray structure '^C Chemical Shift Assignments C-1

31.6

C-ll

39.9

C.2

70.5

€-12

36.6

C.3

75.3

€-13

34.1

C-4

43.0

C-H

43.2

C-5

56.7

C-15

73.8

C-6

64.9

C.16

156.1

30.1

C-17

110.1

45.1

C-18

26.8

C-9

80.5

C.19

60.7

C-10

51.9

C.20

73.2

C-7 C-8

H Takayama, T Okazaki, K Yamaguchi, N Aimi, S Sakai and J Haginiwa, Chem. Pharm. 5w//., 36, 3210 (1988).

Carboii-13 and Proton NMR Shift Assignments

261

6-0-IMIDAZOYLTfflOCARBONYLPSEUDOKOBUSINE C24H29N3O3S; MW: 439.1956; amorphous Preparedfrompseudokobusine *H NMR (CD3OD -f CDCI3): 5 1.01 (3H, s, H-18), 3.96 (IH, 5, H-15), 4.06 (IH, d, J=4.9 Hz, H-U), 5.12, 5.23 (each IH, s, H-l?), 7.07,7.64, 8.36 (each IH, s, imidazoyl-H).

'^C Chemical Shift Assignments (CD3OD + CDCI3) 180.4 (J, C-21), 149.7 (s, €-16), 136.8 (d), 130.7 (J), 117.9 (d), 115.2 (/, C-17), 110.7 {s, C-6), 72.3 (J), 70.2, 67.6 (d), 61.7 (0, 59.8 (d), 53.7 (d), 50.8 (5), 47.4 (5), 41.3 (^0,40.7 id), 37.2 (si 35.4 (0,29.6 (q), 29.2 (0,27.5 (/), 19.4 (r).

K Wada, H Bando and N Kawahara, Heterocycles, 32,1297 (1991).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

262 ISOATISINE

C22H33N02;MW: 343; mp 148-152°^-^'' [a]D-22.4°(95%EtOH)^ Aconitum palmatum Doa',y4. heterophyHum Wall.^, A. koreanum (Levi.) Rapaics\ A. zeravschanicwn Steinb'*' 'H N M R (CDCb)^^ 6 0.93, 1.07 (each 3H, s. H-18), 2.79 (2H, dd, H.20), 3.78, 3.96 (each IH, 5, H-19), 5.02, 5.08 (each 1H,5,H-17).

Minor qiiiner

Major epiincr

'^C Chemical Shift Assignments (CDCb)^'^ A^

B^

5

A^

B^

5

C-1 C-2

40.6' 22.1

40.9 22.2

40.6 22.1

C-12 C-13

36.4 27.6

36.3 27.2

36.4 27.6

C-3

40.0*

34.5

40.0

C-14

26.4

26.3

26.4

C-4

38.1

38.5

38.1

C-15

76.9

76.8

76.8

C.5

48.6

50.9

48.6

C-16

156.5

156.6

156.2

C-6

19.2

17.4

19.2

C-17

109.8

109.7

109.8

C'l

31.9

32.0

31.9

C.18

24.3

24.2

24.3

C-8

37.4

37.5

37.5

C-19

98.5

96.3

98.4

49.8

51.4

49.8

C-9

39.7

39.0

39.6

C-20

C-IO

35.9

35.2

35.9

C-21

54.9

52.2

54.9

C-U

28.2

28.5

28.1

C-22

58.6

64.6

58.6

* Assignments may be interchanged 1. 2. 3. 4. 5.

QP Jiang and SW Pelletier, Tetrahedron Lett., 29,1875 (1988). SW Pelletier, R Aneja and KW Gopinath, Phytochemistry, 7,625 (1968). MG Reinecke, WH Watson, DC Chen and WM Yan, J. Org. Chem., 52, 5051 (1987). SW Pelletier and PC Parthasarathy, J, Am. Chem. Soc., 87, 777 (1965). NV Mody and SW Pelletier, Tetrahedron. 34,2421 (1978).

Carboii-13 and Proton NMR Shift Assignments 6. 7. 8. 9.

263

SW Pelletier and TN Oeltmann, Tetrahedron, 24,2019 (1968). BT Salimov, B Tashkhodzhaev, IM Yusupova, SV Lindeman and YT Strutchkov, Chem. Nat. Compd, 28, 329 (1992). ZM Vaisov, BT Salimov and MS Yunusov, Khim. Prir. Soedin, 800 (1984). ZM Vaisov, BT Salimov, B Tashkhodzhaev and MS Yunusov, Khim. Prir. Soedin, 653 (1986).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

264 ISOATISINONE

C22H33NO2; mp 161-162»' (285-2950 dec.) [a]D-93''(CHCl3)' Prepared from isoatisine'

1^O' j-\" "C Chemical Shift Assignments^ C-1

40.3'

C-12

35.8

C-2

22.0

C-13

27.7

C-3

39.7'

C-H

24.9

C-4

39.3

C-15

202.3

C-5

48.3

C.16

146.3

C-6

18.9

C-17

116.7

C-7

29.3

C-18

24.1

C-8

44.4

C-19

97.4

C-9

43.8

C-20

49.2

C-10

35.8

C-21

54.6

C-11

26.2

C-22

58.6

'Assignments may be interchanged.

1. 2.

SW Pelletier and PC Parthasarathy, J. Am. Chem. Soc., 87,777 (1965). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

Carbon-13 and Proton NMR Shift Assignments

265

ISOCUAUCHICHICINE C22H33N02;mp 134-136^ [a]D-84.0°(CHCl3) Garrya laurifolia' Prepared from cuauchichicine^

'^C Chemical Shift Assignments^ C-I

40.6

C-12

24.9

C-2

20.1

C-13

38.5

C-3

39.7

C-14

34.6,34.2

C-4

40.6

C-15

224.7

C-5

50.6

C-16

48.8

C-6

18.0

C-17

10.1

C-7

33.0

C-18

24.3

C-8

54.4

€-19

98.4,96.8

C-9

47.9

C-20

48.4

C-10

35.9

C-21

54.9, 56.5

22.3

C-22

58.8,64.9

C-ll

1. 2. 3.

H Vorbruggen and C Djerassi, J. Am. Chem. Soc, 84,2990 (1962). SW Pelletier, HK Desai, J Finer-Moore and NV Mody, J. Am. Chem. Soc, 101, 6741 (1979). SW Pelletier, NV Mody and HK Desai, J. Org. Chem., 46,1840 (1981).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

266 16-£/'/-IS0CUAUCHICHICINE

C22H33N02;mp 141-143^ ,Me

(aJo-SS.O^'CCHCb) Prepared from isocuauchichicine 'H NMR (CDCI3): 5 0.92, 1.07 (each 3H, 5, H-18), 1.08 (3H, li, J=4.2 Hz, H-16),3.91(1H,.T,H-19).

'^C Chemical Shift Assignments (CDCI3) C-1

40.8

€-12

22.3

C-2

20.2

c-n

37.0

C-3

39.9

C-14

36.5

C^

40.6

€-15

225.3

C-5

50.7

C-16

46.3

€-6

18.3

C-17

15.9

C-7

32.9

C-18

24.3

C-8

52.8

C-19

98.4

C-9

47.8

C-20

48.4

C-10

36.0

C-21

54.8

C-11

30.1

C-22

58.8

SW Pelletier, NV Mody and HK Desai, J. Org. Chem., 46, 1840 (1981).

Carbon-13 and Proton NMR Shift Assignments

267

ISOGARRYFOLINE C22H33N02;mp 140-144°* ^CHp 21

[a]D-57°(CHCl3)* Garrya launjblia Hartw. Prepared from ovatine^ *H NMR (CDCh)^: 6 1.05 (3H, s, H18). 2.66 (2H, bw, H-20), 3.78 (2H, w, H22), 3.98 (IH, bw. H-19), 5.00. 5.18 (eachlH,br5,H-17).

'^C Chemical Shift Assignment^ C-1

40.7

C.12

33.0

C.2

21.3

C-13

39.7

C-3

40.5

C-H

37.6

C^

39.9

C-15

82.6

C-5

48.7

C-16

158.1

C-6

18,2

C.17

105.2

C-7

37.2

C-18

24.5

45.5

C.19

98,6

C-9

42.8

C-20

51.3

C-10

36.1

C-21

54.9

C-ll

22.4

C.22

58.7

C-8

1. 2.

C Djerassi, CR Smith. AE Lippman, SK Figdor and J Herran, J. Amer. Chem. Soc, 77,4801,6633(1955). SW Pelletier, NV Mody and HK Desai, J. Org. Chem,, 46,1840 (1981).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

268 ISOHYPOGNAVINE

C27H3,N04; mp (HCl) 190-192** (dec.)**^

•o3'

2'

Aconiium JaponicumThunb, A. majimai

ca. *H NMR (CDCla)^ 8 1.04 (3H. s, H-l 8), 3.30, 3.46 (each IH, OH), 3.89 (IH, 5, H15), 4.00 (IH,
31.4

C-13

32.5

C-2

70.1

C.14

42.0

C-3

37.3

C.15

IS.l

C-4

36.5

€-16

150.4

C-5

60.3

C.17

114.2

C-6

64.6

€-18

29.2

C.7

30.4

C-19

63.3

C-8

45.3

C.20

70.8

C-9

55.4

ArCO

165.8

C-10

46.7

c-r

130.1

C-11

67.4

C-2', G

129.3

C-12

41.5

c-y, 5'

128.5

C.4'

133.0

1.

T Okamoto, M Natsume and S Kamata, Chem. Pharm. Bull Japan, 12,1124 (1964).

2.

E Ochiai, T Okamoto, S Sakai and S Inoue, Yakugaku Zasshi, 75,638 (1955).

3.

E Ochiai. T Okamoto, S Sakai, M Kaneko, K Fugisawa, Y Nagai and H Tani, Ya-. kugaku Zasshi, 76, 550 (1956).

4.

S Sakai, H Takayama and T Okamoto, Yakugaku Zasshi, 99,647 (1979).

5.

S Sakai, Personal Communication, July 14,1986.

269

Carbon-13 and Proton NMR Shift Assignments ISOPROPYLIDINE CHUANFUNINE 17

'CH2-OH

C25H39NO5; amorphous Prepared from chuanfunine ' H NMR (CDCI3): 8 0.71 (3H, 5, H-18), 1.04 (3H. /, J==7 Hz, N-CH2C//3), 1,33,1.45 (each3H,5,2',3-Me),2.22,2.49(each IH, d, J=12 Hz, H-19), 3.61 (IH, brs, H-20), 3.88 (IH, 5, H-15J, 3.96,4.43 (each IH, d, J=12 Hz, H-17), 4,14 (IH, dd, J=10, 6 Hz, H-l), 4.46 (IH, d, J=10 Hz, H-6),

^^C Chemical Shift Assignments C-1

71.2'd

C-13

42.4 d

C.2

31.41

C-14

27.61

C-3

38.71

C-15

84.6 d

C-4

33.7 s

C.16

88,3 s

C-S

52.7 d

C-17

68,41

C-6

71.5* d

C-18

25,8 q

C-7

46.9 d

C-19

57.21

C-8

43.0 s

C-20

67.0 d

C-9

51.5 d

C.21

50.8 t

C-IO

51.1s

C-22

13.6 q

C-ll

23.51

c-r

106,6 s

C-12

21.41

C-2'

27.6** q

C-3'

26.0** q

••**Assigmnents may be interchanged.

XY Wei, SY Chen and J Zhou, Chinese J. Bot, 2,57 (1990).

270

BS. Joshi, S.W. Pelletier and S.K. Srivastava

JYNOSINE (15-O-ACETYL DENUDATINE) C24H35NO3; MW: 385; mp 254-256° :H2

[a]D-37.4''(CHCl3) Aconitumjinyangeme W. T. Wang 'H N M R (CDCI3): 8 0.76 (3H, s, H-18), 1.02 (3H, r, J=7 Hz, H-22), 2.25 (3H, s, COCH3), 3.38 (IH, J, H-20), 3.74 (IH, m, H-11„), 4.95 {2H, d, i^'l Hz, H-17), 5.37 (IH,/, J=2Hz,H-15J.

DH Chen and WL Sung, Acta Pharmaceutica Sinica, 16,748 (1981).

Carbon-13 and Proton NMR Shift Assignments KIRININEB

271

C22H31NO3; MW: 357; mp 157-158° Aconitum kirinense Nakai 'H NMR: 4.19 (IH, d, J=5.3Hz, H-l,), 1.24 (IH, m, H-2,), 1.83 (IH, m, H-2b), 1.56 (IH, m, H-3a), 1.63 (IH, m, H-3b), 1.61 (IH, m, H-5), 1.67 (IH, m, H-6,), 2.35 (IH, dddd, J=12.6, 8.5, 2.0 Hz), 1.84 (IH, /», H-7), 1.28 (IH, d, J=9.6, 6.8Hz, H-9), 3.74 (IH, dd, J=9.6, 6.8Hz, H-11), 2.21 (IH, dd, J=5.3, 5.2Hz, H-13.), 1.47 (IH, m, H-13b), 1.97 (IH, ddd, J=14.0, 11.7, 7.0Hz. H-14a), 1.21 (IH, m, H-14b), 4.28 (IH, dt, J=6.8,2.0, 2.0 Hz, H-15„), 5.04, 5.23 (each 111, f, J=2.0, 2.0Hz, H-17), 0.78 (IH, s, H-18), 3.68 (IH, s, H-19), 3.04 (IH, dd, J=4.1, 2.4 Hz, H-20), 2.63, 2.69 (2H, m, H-21), 0.99 (3H, t, J=7.3 Hz, H-22), 1.76 (IH, rf, J=6.8Hz, OH), 1.40 (IH,
"C Chemical Shift Assignments (CDCI3) C-l C-2 C.3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

68.7 d 24.61 30.01 37.6 s 50.2 d 24.61 47.5 d 45.9 s 51.5 d 49.8 s

C-11 C-12 €-13 C-14 C-l 5 C-16 C-17 C-18 C-19 C.20 €-21 C-22

F Feng, JH Liu and SX Zhao, Phytochemistry, 49,2557 (1998)

72.7 d 47.2 d 24.71 27.21 77.3 d 154.3 s 110.4t 18.7 g 93.1 d 70.1 d 48.51 14.1 g

272

B^. Joshi, S.W. Pelletier and S.K. Srivastava

KIRININEC

C22H29NO4; MW: 371; mp 218-220" Aconitum kirinense Nakai 'H NMR: 8 5.0 (IH, dd, J=10.8, 7.2Hz. HIp), 1.30 (IH, m, H-2a) 1.98 (IH, m, H-2b), 1.23 (IH, m, H-3a), 1.51 (IH, m, H-3b), 1.43 (IH, m, H-5), 1.30 (IH, m, H-6a), 2.91 (IH, ddd, J=14, 7.8, 1.3 Hz, H-6b). 2.17 (IH, m, H.7), 1.35 (IH, d, J=9.2Hz, H-9), 3.84 (IH, dd, J=9.2,1.4 Hz, H-11), 2.15 (IH, m, H-12), 1.48 (IH, m, H-13,), 1.69 (IH, m, H-13b), 1.96 (IH, m, H-14a), 1,25 (IH, m, H-14b), 4.28 (IH, brs, H-15J, 5.22 (2H, /, J=2Hz, H17), 0.98 (3H, s, H-18), 7.25 (IH, s, H-79), 4.67 (IH, brs, H-20), 1.86 (IH, brs, OH), 1.81 (IH, brs, OH), 2.05 (3H, s, OAc)

"C Chemical Shift Assignments (CDCI3) C-l C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

72.6d 27.lt 33.5t 44.6s 49.1d 24.5t 47.9d 47.9s 56.3d 48.1s

C-11 C-12 C-l 3 C-14 C-l 5 C-16 C-l 7 C-l 8 C-19 C-20 COCH3 COCH3

F Feng, JH Liu and SX Zhao, Phytochemistry, 49,2557 (1998)

73.8d 46.7d 25.lt 26.7t 77.3d 154.3s 109.7t 21.Og 169.3d 68.5d 21.6g 170.7s

Carbon-13 and Proton NMR Shift Assignments KOBUSINE

273

C20H27NO2; MW: 313; mp 262-263» [a]D+104.4<'(MeOH)''^ Aconitum yesoense var. macroyesoense (Nakai)^ Tamura, A. japonicum "niumb, A. talassicumM. Pop*, A. japonicum var. moManum Nakai^

' H NMR (CDClj)': 8 0.89 (m, H-13p), 0.94 (s, H-18), 1.25 (td, J=2.5,14 Hz, H-3p), 1.40 Ip), 1.47 (m, H-2^. 1.49 (J, H-5), 1.62 (M. H-2„). 1.63 (dd, J=13.6,2.6 Hz, H-7„), 1.67 (i, H-9), 1.76 (m, H-IJ, 1.77 (rf
1. 2.

7

8

C-11

67.7

67.5 d

19.51

C-12

41.4

41.4 d

33.8

33.81

C-13

30.1

30.3 t

C.4

37.9

37.8 s

C-14

41.7

41.6 d

C-5

61.0

61.0 d

C-15

71.7

70.9 d

C-6

65.2

65.1 d

C-16

150.6

150.7 s

C-7

32.4

32.41

C-17

114.6

114.3t

C-8

45.8

45.9 s

C-18

28.8

28.8 q

C.9

54.8

54.9 d

C-19

62.5

62.41

C-10

49.2

49.1s

C-20

75.0

75.0 d

7

8

C-1

26.9

26.91

C-2

19.5

C-3

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and S Sakurai, Heterocyc/«, 26,2623 (1987). H Takayama, A Tokita, M Ito, S Sakai, F Kurosaki and T Okamoto, Yakugaku Zasshi, 102,245 (1982).

274 3.

B JS. Joshi, S.W. Pelletier and S.K. Srivastava S Sakai, I Yamamoto, K Yamaguchi, H Takayama, M Ito and T Okamoto, Chem. Pharm, Bull, 30,4579 (1982).

4.

SW Pelletier, LH Wright, MG Newton and H Wright, J. Chem. Soc. Chem, Commw«.,98(1970).

5.

H Takayama, T Okasaki, K Yamaguchi, N Aimi, J Haginiwa and S Sakai, Chem. Pharm. Bull., 36,3210 (1988).

6.

AA Nishanov, MN Sultankhodzaev and MS Yunusov, Khim. Prir. Soedin, 857 (1989).

7.

M Reina, JA Gavfn, A Madinaveitia, RD Acosta and G de la Fuente, J. Nat. Prod., 59,145 (1996).

8.

A Ulubelen, HK Desai, SK Srivastava, BP Hart, JC Park, BS Joshi, SW Pelletier, AH Meri9li and F Meri9li, J. Nat. Prod, 59,360 (1996).

Carbon-13 and Proton NMR Shift Assignments

275

LASSIOCARPINE C29H39NO«; MW: 497.2784; mp 141143° [alo-n^'CMeOH) Me

Aconitum kojimae Ohwi var. lassiocarpttm Tamura 'H NMR (C5D5N): 8 4.83 (IH, dd, J=10.9, 5.7 Hz, H-1), 2.85 (IH, m, H-2), 2.00 (IH, m, H-2), 1.59 (IH, d, J=12.2 Hz, H.3), 1.38 (IH, m, H-3), 1.53 (IH, d, J=7.3 Hz, H-5), 3.61 (IH, dd, J=7.3, 13.6 Hz, H-6), 1.37 (IH, m, H-6), 2.28 (IH, s, H-7), 2.53 (IH, d, J=8.9 Hz, H-9), 5.53 (IH, d, J=8.9 Hz, H-11), 2.65 (IH, bw, H-12), 1.76 (IH, /, J=12.1 Hz, H-13), 2.62 (IH, m, H-13), 2.28 (IH, m, H-14), 1.37 (IH, m, H-14), 4.66 (IH, d, J=3.4 Hz, H-15), 5.77 (IH, d, J=l 1.4 Hz, H-17), 5.63 (IH, d, J=n.4 Hz, H-17), 0.72 (3H, s, H-18), 2.27 (IH, d, J=10.9 Hz, H-19), 2.56 (IH, H-19), 4.15 (IH, s, H-20), 2.39 (IH, m, H-21), 2.55 (IH, m, H-21), 1.05 (3H, t, J=7.3 Hz, H-22), 8.26 (2H, d, J=7.6 Hz, Ar-H), 7.25 (2H, dd, J=7.6 Hz, Ar-H), 7.42 (IH, dd, J=7.6 Hz, Ar-H). "C Chemical Shift Assignments (C3D5N) C-1

70.4 d

C-15

86.2 d

C-2

32.01

C-16

79.1s

C-3

39.41

C-17

72.3 t

C-4

33.9 s

C-18

26.5 q

C-5

53.6 d

C-19

57.51

C-6

24.lt

C-20

68.3 d

C-7

43.2 d

C-21

51.lt

C-8

44.1s

C-22

14.0 q

C-9

51.9 d

ArCO

167.3

C-10

51.9 s

c-r

132.1

C-11

71.6 d

C-2', 6'

130.0

C-12

45.5 d

C-3*, 5'

128.5

C-13

22.01

C-4'

132.6

C-14

28.71

H Takayama, JJ Sun, N Aitni and S Sakai, Tetrahedron Lett., 30,3441 (1989).

276

B^. Joshi, S.W. Pelletier and S.K. Srivastava

LEPEDINE C23H35NO3; mp 156-158° [alo-SpoCMeoH)

Me

Aconitum pseudohuiliense Cheng et Wang 'H NMR: 8 0.71 (3H, s, H-18), 1.07 (3H, d, H.22), 3.31 (3H, s, H-23), 3.60 (IH, H.20), 3.95 (IH, d, J=9 Hz. H-11), 4.11 (IH, H15), 4.88,5.13 (each 1H,H-17).

WL Song, HY Li and DH Chen, Proc. CAMS and PUMS, 2,48 (1987).

277

Carbon-13 and Proton NMR Shift Assignments LEPENINE k

C22H33NO3; MW: 359; mp 191-193°^ 203205<'^ 120-122<^ [a]D-8.5»(MeOH)' Aconitum kusnezoffli Reichb\ A. pseuolohuiliense, Cheng et Wang'; A. leucostomum Vorosch*. 'H NMR (CDCI3)': 8 0.69 (IH, s, H-18), 1.04 (IH, /, J=7.1 Hz, H-22), 1.11 (IH, m, H-14a), 1.25 (IH, m, H-6a), 1.26 (IH, d, J=9 Hz, H-9), 1.28 (IH, d, J=13.4 Hz, H-3p), 1.46 (IH, OT, H-13a), 1.58 (IH, dd, J=2.8,4.3 Hz, H-3J, 1.72 (IH, m, H-13b), 1.79 (IH, m, H-2p), 1.93 (IH, m, H-14b), 2.17 (IH, d, J=7 Hz, H-7), 2.18 (IH, m, H-12), 2.23,2.49 (each IH. AB, Jgem=l 1 Hz, H-19), 2.32 (IH, m, H-2„), 2.33 (IH, d, J=6.2 Hz, OH-15), 2.40, 2.52 (each IH, /, J=7.1 Hz, Jgem=14 Hz, H-21), 2.73 (IH, s, OH-11), 2.73 (IH, dd, J=8.6,13.7 Hz, H-6b), 4.15 (IH, dd, J=6.7,10.2 Hz, H-lp), 4.27 (IH, dd, J=7.8,6.2 Hz, H-15), 5.02, 5.24 (each lH,s,H-17). "C Chemical Shift Assignments 2 (CD3)2SO

3 (CDCI3)

C-12

41.4

46.2

31.1

€-13

24.1

24.5

38.5

38.6

C-14

27.1

27.4

C-4

33.0

33.7

C-15

76.3

77.9

C-5

51.9

52.3

C-16

153.9

154.3

C-6

22.8

23.1

C-17

107.9

109.5

C-7

46.4

42.2

C-18

26.0

26.0

C-8

43.0

43.6

€-19

56.8

57.0

C-9

52.8

53.8

C-20

66.8

67.8

C-10

50.3

50.9

C-21

50.1

50.8

C-11

71.7

72.9

C-22

13.3

13.6

2 (CD3)2SO

3 (CDCI3)

C-1

68.7

70.7

C-2

30.6

C-3

1.

WL Song, HY Li and DH Chen, Proc. CAMS and PUMS, 2,48 (1987).

2.

D Batsuren, J Tunsag, N Batbayar, AH Meri9li, F Meri9li, Q Teng, HK Desai, BS Joshi and SW Pelletier, Heterocycles, 49,327 (1998).

3.

J Yue, J Xu, Q Zhao and H Sun, 7. Nat, Prod,, 59,277 (1996).

4.

J Yue, J Xu, Q Zhao and H Sun, J, Nat, Prod, 59,277 (1996).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

278 LIANGSHANINE

C23H35NO3; MW: 373.2615; amorphous [a]D-16.4°(CHCl3) Aconitum liangshanium ^H NMR (CDCI3): 8 0.73 (3H, 5, H-18), 1.04 (3H, U J=6.8 Hz, H-22), 3.31 (3H, 5, H-23), 4.16 (IH, dd, J=4.4, 9.1 Hz, H.12), 4.18 (IH, bw, H-15), 5.09, 5.31 (each IH, ^,J=0.8Hz,H-17). '^C Chemical Shift Assignments (CDCI3) C-l

80.7

C-12

67.4

C-2

25.8

C-13

44.4

C-3

38.1

C-14

32.6

C-4

34.5

C-15

77.0

C-5

50.7

C-16

155.4

C-6

23.3

C-17

111.1

C-7

44.6

C-18

26.0

C-8

51.4

C-19

57.0

C-9

38.2

C-20

66.3

C-10

51.4

C-21

51.2

C-11

28.8

C-22

13.5

C-23

55.6

H Takayama, FE Wu, H Eda, K Oda, N Aimi and S Sakai, Chem. Pharm. Bull, 39,1644 (1991).

Carbon-13 and Proton NMR Shift Assignments

279

LIANGSHANONE C23H33NO3; MW: 371.2458; amorphous [a]D-101°(CHCl3) Aconilum liangshanium ' H NMR (CDCI3): 8 0.75(3H,t/, H-18), 1.06 (3H, /, J=6.9 Hz, H-22), 3.28 (3H, s, H-23), 3.30 (IH, dd, J=10.5, 6.6 Hz. HIp), 4.34 (IH, brs, H-15J, 5.20, 5.29 (each lH,rfrf,J=1.2,2.6Hz,H-17). ^^C Chemical Shift Assignments (CDCI3) C-1

80.4

C-12

210.7

C-2

25.8

C-13

54.1

C-3

37.9

C-14

31.7

C-4

34.3

C-15

77.3

C-5

50.4

C-16

151.3

C-6

22.9

C-17

111.4

C-7

44.1

C-18

26.0

C-8

49.8

C-19

56.9

C-9

35.9

C-20

66.4

C-10

51.3

C-21

51.1

38.0

C-22

13.6

C-23

55.5

C-11

H Takayama, FE Wu, H Eda, K Oda, N Aim! and S Sakai, Chem. Pharm. Bull, 39, 1644 (1991).

280

BS. Joshi, S.W. Pelietier and S.K. Srivastava

LINDHEIMERINE C22H31NO2; MW: 341; amorphous CH2

[a]D-113.8«(CHCl3y'' Garrya ovata var. lindheimeri Torr.**^ *H NMR (CDCb)**^ 8 0.82 (3H, s, H-IS), 2.18 (3H, 5), 3.42 (2H, 5, H-19), 4.98, 5.28 (each IH, brrf, H-l?), 8.00 (IH, s, H-20).

'^C Chemical Shift Assignments (CDCb)^

1. 2.

C-l

42.4

C-12

34.0

C-2

18.0

C-13

40.7

C-3

36.5

C-14

34.8

C-4

33.0

C-l 5

81.6

C-5

47.0

C-16

153.8

C-6

20.5

C-l 7

106.8

C-7

35.2

C-l 8

26.2

C-8

45.6

C-19

59.7

C-9

43.6

C-20

167.7

C-10

45.2

COCH3

171.3

C-11

21.3

COCH3

21.2

SW Pelietier, NV Mody and HK Desai, J. Org, Chem., 46,1840 (1981). SW Pelietier, NV Mody and DS Seigler, Heterocycles, 9,1409 (1978).

Carbon-ia and Proton NMR Shift Assignments LUCICULINE (NAPELLINE) HO

281

C22H33NO3; MW: 359; mp 114-116°*'^-' [a]D - 93.9*^ (H2O) (HCl)^ - 13« (McOH) Aconitum yesoense NakaiJ, A, karakoiicum Rapaics^i4. napellus^^ A, czekanovskyi Steinb^, A. flavum^^ A, zeravschanicum Steinb^.

*H NMR (CDCI3)': 8 0.76 (3H, 5, H-18), 1.05 (3H, /, J=7 Hz, H.22). 3.55 (IH, m, H-12p), 3.92 (IH, /, J=7 Hz, H-lp), 4.18 (IH, bw, J=4 Hz, H-15), 5.12 (2H, H-17). '^C Chemical Shift Assignments (CsDsN)**' 1

7

C-1

70.5

70.5

C-12

1 76.2

76.2

C-2

31.9'

31.9

C.13

49.9**

49.4

C-3

32.4«

38.4

C.14

38.4

29.4

C-4

34.7

34.7

C-15

77.8

77.8

C-5

49.4**

49.8

C-16

160.8

160.8

C-6

23.6

23.6

C-17

107.4

107.4

€-7

45.0

45.0

C-18

26.4

26.4

C-8

50.3

50.3

C-19

57.7

57.7

C-9

38.2

38.2

C-20

66.2

66.2

C-10

53.5

53.5

C-21

57.6

51.6

C-11

29.4

32.4

C-22

13.3

13.3

7

••**Assignnients may be interchanged. 1. 2. 3. 4. 5. 6. 7.

H Takayama, A Tokita, M Ito, S Sakai, F Kurosaki and T Okamoto, Yakugaku Za55/i/, 102,245 (1982). MN Sultankhodzhaev, MS Yunusov and SY Yunusov, Khim. Prir. Soedin., 18,660 (1982). W Freudenberg and EF Rogers, J. Am. Chem. Soc, 59,2572 (1937). ZG Chen, AN Lao, HC Wang and SH Hong, Planta Med, 54,318 (1988). C Zhapova, LD Modonova and AA Semenov, Khim. Prir. Soedin., 717 (1985); 382 (1986). ZG Chen, HC Wang, AN Lao, HC Wang and SH Hong, Youji Huaxue, 9,490 (1989). K Wada, H Bando, T Amiya and N Kawahara, Heterocycles, 29,11 (1989).

282

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

12-£P/-LUCIDUSCULINE C24H35NO4; MW: 401.2566; mp 160-164*' [a]D-100^(CHCl3) Aconitum liangshanium W.Z. Wang 'H NMR: 8 0.69 (3H, s, H-IS), 0.98 (3H, /, J=7.2 Hz, H-22), 2.05 (3H, s, OAc), 3.24 (IH, s, H-20), 3.84 (IH, dd, J=6, 7.8 Hz, H1), 5.08, 5.15 (each IH. H-17), 5.50 (IH, rf, J=2.2Hz,H-15).

H Takayama, FE Wu, H Eda, K Oda, N Aimi and S Sakai, Chem. Pharm, Bull, 39,1644 (1991).

Carboii-13 and Proton NMR Shift Assignments

283

LUCIDUSCULINE(15-0-ACETYLNAPELLINE) C24H35NO4; MW: 401; mp 175.177*»*'^-^ [a]D-95.5'^(CHCl3) Aconitum yesoense var. macroyesoense (Nakai) Tamura, A. lucidusculum Nakai, A. flavum Hand-Mazz^ *H NMR (CDCla)^: 8 0.76 (3H, 5, H-18), 1.04 (3H, r, J=7 Hz, H-22), 2.08 (3H, s, OAc), 3.64 (IH, m, H-12B), 3.92 (IH, r, J=7 Hz, H-1B), 4.91, 5.10 (each IH, s, H-17),

5.28(lH,5,W,/2=4Hz,H.15). X-ray structure^ ^^C Chemical Shift Assignments (CDCI3)

1. 2. 3. 4. 5. 6.

2

6

C-1

69.9

69.9

C-2

31.6

C-3

2

6

€-13

48.8

47.7

31.6

C-14

36.5

29.1

30.5

36.5

C-15

77.5

77.5

C-4

34.0

34.0

C-16

153.1

153.1

C-5

47.7

48.8

C-17

109.5

109.5

C-6

23.7

23.7

C-18

26.4

26.4

C-7

43.7

43.7

C-19

57.9

57.9

C-8

49.6

49.6

C-20

65.7

65.7

C-9

37.7

37.7

C-21

50.8

50.9

C-10

52.5

52.5

C-22

13.4

13.4

C-11

29.1

30.5

COCH3

170.6

170.6

C-12

75.5

75.5

COCH3

21.6

21.6

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocyc/e5,26,2623 (1987). H Takayama, A Tokita, M Ito, S Sakai, F Kurosaki and T Okamoto, Yakugaku Zajj/i/, 102,245 (1982). R Majima and S Mono, Chem. Ber„ 65, 599 (1932). T Okamoto, M Natsume, Y litaka, A Yoshino and T Amiya, Chem. Pharm. Bull, 13,1270(1965). ZG Chen, AN Lao, HC Wang and SH Hong, Hetewcycles, 26,1455 (1987). K Wada, H Bando, T Amiya and N Kawahara, Heterocycles, 29,2141 (1989).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

284 MACROCENTRINE

ix p"

C22H35NOJ; MW: 393.2511; mp 207209» Delphinium macrocentrum Oliv.'"^ 'HNMR(CD30D): 80.80(3H,J,H-18),

1.11 (3H, /, J=7 Hz, H-21), 3.19 (IH, d, J= 4.5 Hz), 3.52,4.00 (each IH, d, J=l 1.5 Hz), 3.76 (IH, brm, J=10 Hz), 3.90 (IH, s). X-ray structure' "C Chemical Shift Assignments (CD3OD) (C5D5N)' CD3OD

C5D5N

CD3OD

C5D5N

C-1

31.91

33.01

C-12

42.7 d

43.6 d

C-2

69.0 d

70.1 d

C-13

23.31

24.41

C-3

67.5 d

68.5 d

C-14

22.21

22.6* t

C-4

38.7 s

39.3 s

C-15

86.0 d

86.4 d

C-5

39.6 d

41.0 d

C-16

79.2 s

80.4 s

C-6

27.51

28.71

C-17

67.31

67.31

C-7

35.7 d

36.1 d

C-18

21.7 q

22.8'q

C-8

41.9 s

42.4 s

C-19

48.71

50.lt

C-9

51.5 d

52.5 d

C-20

75.9 d

76.8 d

C-10

45.4 s

46.0 s

C-21

49.71

49.41

C-11

21.51

22.8* t

C-22

12.2 q

12.7 q

"Assignments may be interchanged.

1. 2.

MH Benn, F Okanga, JF Richardson and RM Manavu, Heterocycles^ 26, 2331 (1987). MH Benn, F Okanga, and RM Manavu, Phytochemistry, 28,919 (1989).

Carbon-13 and Proton NMR Shift Assignments

285

JV-METHYL-AT.e-SECO-e-DEHYDROPSEUDOKOBUSINE C21H29NO3; MW: 343.2152; amoiphous Prepared fh>m pseudokobusine methiodide 'H NMR (CDCI3): 8 1.45 (3H, s. H-18), 2.29 (3H, s. H-21), 3.84 (IH. s), 4.10 (IH. d, J=4.6 Hz), 5.10,5.24 (each IH, s, H-17).

Me-

^MeO

K Wada, H Bando and T Amiya, Heterocycles, 27,1249 (1988).

286

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

//-METHYL-M20-DIHYDROATISINEAZOMETHINE C21H33NO

Prepared from atisine Me-

'^C Chemical Shift Assignments (CDCI3)* C-l

41.9'

C-11

28.2

C-2

22.5

C-12

36.5

C-3

40.7'

C-l 3

27.7

C-4

33.7

C-14

26.5

C-5

49.5

C-l 5

77.0

C-6

17.4

C-16

156.8

C-7

31.7

C-l 7

109.5

C-8

37.6

C-18

26.4

C-9

39.6

C-19

62.7

C-10

38.2

C-20

56.2

C-21

46.9

'Assignments may be interchanged.

1. 2.

NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978). SW Pelletier and WA Jacobs, J. Am. Chem. Soc, 78,4139 (1956).

Carbon-13 and Proton NMR Shift Assignments

287

A/^METHYLDIHYDROVEATCHINEAZOMETHINE C21H33NO sCHg

Prepared from veatchine

Me----N

^^C Chemical Shift Assignments (CDCI3)* C-l

41.7"

c-u

22.7

C-2

18.2

C-12

32.4

C-3

41.2*

C-13

41.9

C-4

33.8

C-14

36.7

C-5

50.6

C-15

82.8

C-6

18.2

C-16

159.9

C-7

33.4

C-17

108.3

C-8

47.4

C-l 8

26.5

C-9

50.0

C-19

62.7

C-10

40.3

C-20

58.2

C-21

47.0

"Assignments may be interchanged.

1. 2.

NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978). SW Pelletier and DM Locke, J. Am. Chem. Soc, 87,761 (1965).

288

B^. Joshi, S.W. Pelletier and S.K. Srivastava

7/.METHYL-6-OXOSPIRADINE A C2iH27N02;mpl67°^ Prepared from spiradine A

Me— "I

^MeO '^C Chemical Shift Assignments (CDCb)^ C-l

40.6

C-11

211.1*

C-2

18.7

C-12

65.3

C-3

30.2

C-13

33.6

C-4

47.0

C-14

45.6

C-5

60.3

C-15

35.1

C-6

204.0"

C-l 6

143.5

C-7

50.7

C-17

110.2

C-8

43.0

C-l 8

30.7

C-9

78.2

€-19

61.01

C-10

38.1

C-20

53.4

C-21

43.1 q

"Assignments may be interchanged.

1. 2.

G Goto, K Sasaki, N Sakabe and Y Hirata, Tetrahedron Lett., 1369 (1968). YC Wu, TS Wu, M Niwa, ST Lu and Y Hirata, Heterocycles, 26,943 (1987).

Carbon-13 and Proton NMR Shift Assignments

289

16a~METHYLTETRAHYDROATISINE \\

.^Me

IIC

C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

40.3 23.3 41.4 33.7 49.8 17.3 31.8 36.3 38.9 38.1

C22H37NO2

Prepared from atisine X-ray structure

Chemical Shift Assignments C-11 C-12 C-13 €-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

27.5 42.5 28.5 28.5 83.0 31.8 19.6 26.6 60.2 54.1 58.0 60.7

SW Pelletier, NV Mody. HK Desai, J Finer-Moore, J Nowacki, and BS Joshi, J. Org. C/jcm. 48.1787(1983).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

290 16-p-METHYL TETRAHYDROATISINE

C22H37NO2

Prepared from atisine

13

C Chemical Shift Assignments

C-1 C-2 C-3 C-4 C-5 C'6 C'l C-8 C-9 C-IO

40.0 23.3 41.5 33.6 49.8 17.6 32.6 35.6 38.9 38.1

C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

27.5 35.3 27.5 27.5 76.1 32.4 13.4 26.4 60.3 54.0 58.0 60.8

SW Pelletier. NV Mody. HK Desai, J Finer-Moore, J Nowacki. and BS Joshi, J. Org. C/i6m. 48,1787(1983).

Carbon-13 and Proton NMR Shift Assignments

291

16-p-METHYLTETRAH YDROGARRYFOLINE C22H37NO2

Prepared from garryfoline

/•?-

C Chemical Shift Assignments

C-l

41.5

C-11

C-2

18.6" 40.9 33.7 49.8

C-12

26.1

C-13 C-14 C-15

43.3 38.7 80.7

C-16 C-17 C-18 C-19 C-20 C-21 C.22

38.4

C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

19.6' 37.9 46.3 43.3 39.8

23.6

9.7 26.6 60.5 56.2 58.0 60.8

SW Pelletier, NV Mody. HK Desai, J Finer-Moore, J Nowacki, and BS Joshi, J. Org, C/i^m. 48,1787(1983).

292

B JS. Joshi, S.W. Pelletier and S.K. Srivastava

16-a-METH YLTETRAH YDROVEATCHINE C22H37NOj;mp 119-120"

,-OH

Mo ' 75.r Prepared from veatchine *H NMR (CDCI3): 6 0.83 (3H. j , H-18), 0.99 (3H, d, 1=9 Hz, H.17), 3.67 (2H. /, H-22).

C Chemical Shift Assignments C-1

41.4

C-12

23.5

C-2

18.8'

C-13

42.7

C-3 C-4 C-5

40.9 33.9 50.7

C.14 C-15 C-16

40.1 82.6 40.9

C-6

19.2*

C-17

15.0

C-7 C-8 C-9 C-10 C-11

34.7 48.6 50.2 40.5 30.5

C-18 C-19 C-20 C-21 C-22

26.6 60.4 56.0 58.0 60.8

SW Pelletier, NV Mody. HK Desai, J Finer-Moore, J Nowacki, and BS Joshi, 7. Org, Chem. 48,1787 (1983).

Carbon-13 and Proton NMR Shift Assignments

293

16-p-METHyLTETRAHYDROVEATCHINE C22H37NO2; MW 347.28242; mp 165-166**

.,.-OH «.^

Prepared from veatchine 'H NMR: 5 0.80 (3H, .¥, H-18), 1.16 (3H, d. J=9 Hz,H-!7),3.67(2H,r.H-22).

' C Chemical Shift Assignments C-l

41.5

C-12

25.1

C-2

18.6*

C-13

38.7

03 C-4 05

41.9 33.8 51.8

C-14 C-15 C-16

38.7 88.5 47.8

C-6

19.0'

C-17

13.6

C-7 C-S C-9 C-10 C-11

34.0 47.3 50.4 40.4 23.5

C-18 C-I9 C-20 C-21 C-22

26.6 60.6 56.1 58.1 60.9

SW Pcllcticr. NV Mody, HK Dcsia, J Finer-Moore, J Nowacki and BS Joshi, J, Org. Chem, 48,1787(1983).

294

BJS. Joshi, S.W. Pelletier and S.K. Srivastava

MIYACONINE C21H25NO5; MW: 371.423; mp 278.5°^ 253°^ [a]D-8.6°(Me2CO)^ Prepared from miyaconitine*'^ *H NMR (CDCI3): 8 1.15 (3H, s, H-18), 2.45 (3H, s, H-21), 5.03 (2H, br^, H-17), 7.67(lH,c/,J=10Hz,OH-7).

'^C Chemical Shift Assignments (CDCI3)

1. 2.

C-l

35.81

C-11

26.3 t

C-2

64.4 d

C-12

43.8 d

C-3

50.41

C-13

208.2 s

C-4

36.2 s

C-14

53.6 d

C-5

47.9 d

C-15

26.3 t

C.6

85.6 s

€-16

138.3 s

C-7

178.8 s

C-17

113.4t

C-8

56.5 s

C-18

25.3 q

C-9

84.6 s

C-19

54.71

C-10

50.8 s

C-20

64.0 d

C-21

41.6 q

YIchinohe,M Yamaguchiand KMatsushita, Chem. Lett.,\349 (1974). H Suginome, S Furusawa, Y Chiba and S Kakimoto, J. Fac. Sci. Hokkaido Univ, Series III, Chem,, 4,1 (1950).

Carbon-13 and Proton NMR Shift Assignments

295

MIYACONITINE C23H29NO6; MW: 415.20; mp 218° (dec.)*'^ [a]D-87.8*^(CHCl3)^ Aconitum miyahei Nakai*'^ 'H NMR (CDCI3)': 8 1.55 (3H, s, H-18), 2.04 (3H, 5, OAc), 2.40 (3H, 5, H-21),4.95 (2H, br^, H-17), 4.97 (IH, s, OH-9), 5.19 (lH,br5,Wi/2=10Hz,H-2). X-ray structure (HBr. 2 liiOf

1. 2. 3.

Y Ichinohe, M Yamaguchi, N Katsui and S Kakimoto, Tetrahedron Lett,, 2323 (1970). H Shimanouchi, Y Sasada and T Takeda, Tetrahedron Lett., 2327 (1970). H Suginome, S Furusawa, Y Chiba and S Kakimoto, J. Fac. ScL Hokkaido Univ. Series III Chem., 4,1 (1950).

296

B^. Joshi, S.W. Pelletier and S.K. Srivastava

MIYACONITINONE C23H27NO6; MW: 413.19; mp 285° (dec.)' [a]D-27.6*»(AcOH)^ AcO

Aconitum miyabei Nakai'*^ *H NMR (CDCI3)*: 8 1.38 (3H, s, H-18), 2.28 (3H, 5, H-21), 4.97 (2H, brJ, H-17).

1. 2. 3.

Y Ichinohe, M Yamaguchi, N Katsui and S Kakimoto, Tetrahedron Lett., 2323 (1970). S Kakimoto, N Katsui and Y Ichinohe, Bull Chem, Soc, 32,1153 (1959). H Suginome, S Furusawa, Y Chiba and S Kakimoto, J. Fac, Sci. Hokkaido Univ. Series III Chem., 4,1 (1950).

Carbon-13 and Proton NMR Shift Assignments

297

1-EW-NAPELLINE C22H33NO3; MW: 359.2466; mp 87-89° [o]D-11.7°(MeOH) Aconitumflavum Hand-Mazz. 'H NMR (CD3OD): 8 0.80 (3H, s, H-18), 1.00 (IH, dd, J=12,4 Hz, He,-14), 1.13 (3H, t, J=7.1 Hz, H-22), 1.98 (IH, d, J=12 Hz, H„-14), 2.09,2.37 (each IH, g, J=l 1.2 Hz, H-19), 2.38 (IH, d, J=3.7 Hz, H-13), 3.45 (IH, hts, H-20), 3.52 (IH, dd, J=9.5, 7 Hz, H-12), 3.89 (IH, dd, J=9.9, 6.3 Hz, H-1), 4.15 (IH, bw, H-15), 5.12, 5.15 (eachlH,bw,H-17). "C Chemical Shift Assignments (CD3OD) C-1

77.0

C-12

76.7

C-2

31.2

C.13

50.6

C-3

32.4

C-14

38.5

C-4

35.3

C-15

78.4

C-S

49.1

C.16

160.0

C-6

24.1

C-17

108.4

C-7

45.8

C-18

26.8

C-8

51.0

C-19

59.0

C-9

38.1

C-20

67.0

C-10

54.0

C-21

52.1

C-11

29.7

C-22

13.7

ZG Chen, AN Lao, HC Wang and SH Hong, Heterocycles, 26,1455 (1987).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

298 12.£P/-NAPELLINE

C22H33NO3; MW: 359.2470; mp 72-73.5^^ 163-164°\ 118-121°^ [a]D-40.2^(CHCl3)* Aconitum flavum Hand. Mazz.^ A. Hangshanium, W. Z. Wang^, A, baicalense Turcz. ex Rapaics (A. czekanovskyi Steinb)^, A, napellns fed on aphids Brachycaudus aconitii^, A. karakolicum Rapaics^. 'H NMR (CDCI3)': 8 0.79 (3H, s, H.18), 1.09 (IH, dd, J=12.1, 4 Hz, H«,-14), 1.18 (3H, U J=7.1 Hz, H.22), 1.76 (IH, d, J=12.2 Hz, Hax-14), 2.30, 2.71 (each IH, AB^, J=11.8 Hz, H-19), 2.80 (IH, dd, J=8.8, 3.7 Hz, H-13), 3.52 (IH, br5, H-20), 3.87 (IH, dd, J=8.6,6.7 Hz, H-1), 4.18 (IH, dd, J=8.8,4.8 Hz, H-12), 4.21 (IH, bw, H-15), 5.12, 5.32 (each IH, bw, H-17). (See also ref. 4 for other *H NMR data). 2,4 '^C Chemical Shift Assignments (CD3OD)*, (CDCI3)'

1

2

4

C-12

71.8

70.0

67.2

31.8

C.13

45.7

44.0

44.0

31.7

36.3

C-14

38.8

36.3

32.8

35.2

33.8

33.8

C-15

78.1

77.0

77.1

C-5

51.6

48.8

48.8

C-16

154.8

155.0

154.7

C-6

24.3

23.6

23.7

C-17

112.2

111.4

111.8

C-7

45.1

44.0

44.0

C-18

26.7

26.3

26.5

C-8

51.6

51.1

51.0

C-19

58.9

58.3

58.4

C-9

39.6

37.2

37.1

C-20

67.3

66.2

66.3

C-10

53.8

52.6

52.6

C-21

52.1

50.9

51.2

C-ll

33.6

32.7

29.7

C-22

13.7

13.3

13.5

1

2

4

C-1

69.5

67.2

70.0

C.2

31.5

29.7

C-3

32.4

C-4

1. 2. 3. 4. 5. 6.

ZG Chen, AN Lao, HC Wang and SH Hong, Heterocycles, 26,1455 (1987). G de la Fuente, M Reina, E Valencia and A Rodriguez-Ojeda, Heterocycles, 27, 1109(1988). H Takayama, FE Wu, H Eda, K Oda, N Aimi and S Sakai, Chem. Pharm. Bull, 39, 1644(1991). J Zhapova and AA Semenov, Khim. Prir. Soedin., 888 (1993). H Liu and A Katz, J. Nat. Prod, 59,135 (1996). MN Sultankhodzhaev and MS Yunusov, Khim. Prir. Soedin., 386 (1987).

Carbon-13 and Proton NMR Shift Assignments

299

NAPPELLINE A^-OXIDE HO

C22H33NO4; MW: 375; mp 197-199° Aconitum karakolicum Rapaics C^t

»H NMR (CD3OD): 8 0.80 (3H, s, H-18), 1.32 (3H, /, H-22), 5.09, 5.25 (each IH, d, J=1.5Hz,H-17).

MN Sultankhodzhaev, LV Beshitaishvili, MS Yunusov and SY Yunusov, Khim. Prir. 5oef/i>i., 826(1979).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

300

12-£'P/-NAPELLINE-JV-0XIDE C22H33NO4; MW: 375; mp 224-225" (perchlorate) Aconitum bacailense Turcz. ex Rapaics (A. czekanovskyi Steinb.) 'H N M R (CDCI3): 5 3.86 (IH, d, J=7.1 Hz, H-1), 2.45 (IH, m, H-2e), 1.95 (IH, m, H2,), 1.95 (IH, m, H-3e), 1.30 (IH, m, H-3.), 1.50 (IH, hrd, J=~7.9 Hz, H-5), 2.71 (IH, dd, J=7.9,14 Hz, H-6e), 1.30 (IH, m, H-6,), 2.02 (IH, d, J=5.3 Hz, H-7), 2.08 (IH, dd, J=6.5, -13 Hz, H-9), 2.25 (IH, ddd, J=15, 12.9, 6 Hz, H-IU), 1.70 (IH, dd, J=15, 6.5 Hz, H-11,), 4.18 (IH, dd, J=8.7, ~6 Hz, H-12), 2.80 (IH, dd, i=%n, 4.1 Hz, H-13), 1.72 (IH, d, J=~12 Hz, H-14e), 1.13 (IH, dd, J= -12, 4.1 Hz, H-14,), 4.20 (IH, \>td, J=2.4 Hz, H-15), 5.33 (IH, brs, H-17A), 5.15 (IH, \>xd, J=2.4 Hz, H-17B), 0.82 (3H, s, H-18), 3.28, 3.10 (each IH, d, J=13.8 Hz, H-19A, H-19B), 3.75 (IH, bra, H-20), 3.24 (IH, m, H-21A), 3.10 (IH, m, H-21B), 1.39 (3H, /, J=7.1 Hz, H-22). "C Chemical Shift Assignments (CDClj) C-1

67.2

C-12

66.6

C-2

30.5

C-13

43.8

C-3

32.6

C-14

34.9

C-4

35.2

C-15

76.4

C-5

46.6

C-16

153.6

C-6

22.8

C-17

112.7

C-7

46.3

C.18

26.5

C-8

49.8

C-19

74.8

C-9

39.0

C-20

80.3

C-10

54.2

C-21

67.2

C-11

28.9

C-22

7.8

T Zhapova and AA Semenov, Khim. Prir. Soedin., 888 (1993).

Carboii-13 and Proton NMR Shift Assignments

301

NOMININE (11-DEOXYKOBUSINE, NOMIBASE-1) C2oH27NO;MW: 297; mp 258-260"^, 260°' [a]D + 53.4''^ Aconitum zeravschanicum Steinb.', A. sanyoense Naka^^ A. Finetianum Hand-Mazz'. Preparedfromkobusine^ 'H NMR (CDCb)': 8 0.97 (3H, s, H-18), 2.37, 2.50 (each IH, d, J=12 Hz, H19A, H-19B), 2.49 (IH, s, H-20), 3.21 (IH, br*, J=7 Hz, H-6), 3.99 (IH, s, H-15), 4.93,4.95 (each IH, J, H-17). "C Chemical Shift Assignments (CDCI3/

1. 2. 3. 4. 5.

C-1

33.3

C-11

27.1

C-2

19.8

C-12

34.0

C-3

34.2

C-13

32.9

C-4

38.0

C-14

44.0

C-5

61.2

C-15

74.9

C-6

65.4

C-16

156.8

C-7

27.0

C-17

108.3

C-8

45.7

C-18

28.9

C-9

43.8

C-19

62.8

C-10

49.7

C-20

71.8

ZM Vaisov, BT Salimov, B Tashkhodzhaev and MS Yunusov, Khim. Prir. Soedin., 653 (1986). S Sakai, I Yamamoto, K Yamaguchi, H Takayama, M Ito and T Okamoto, Chem. Pharm, Bull, 30,4579 (1982). ZM Vaisov and MS Yunusov, Khim. Prir, Soedin., 407 (1987). S Sakai, I Yamamoto, K Hotoda, K Yamaguchi, N Aimi, E Yamanaka, J Haginiwa and T Okamoto, Yakugaku Zasshi, 104,222 (1984). RM Tian, YM Cheng, BR Chen, P Liu, SH Jiang, BN Zhou, PI Zheng and M Wang, Acta Chim. Sinica, 45,776 (1987).

BJS. Joshi, S.W. Pelletier and S.K. Srivastava

302 NORSONGORAMINE

C20H25NO3; MW: 327; mp 286-288° Delphinium tamarae Kem. Nath.', A. monticola Steinb.^ *H NMR (CDCb)^ 8 1.12 (3H, s, H-18), 4.63,4.85 (each IH, bw, H-17).

1.

LV Beshitaishvili, MN Sultankhodzhaev, KS Mudzhiri and MS Yunusov, Khim.

Prir.Soedin.,n, 199 (\9S\). 2.

EF Ametova, MS Yunusov and VA Telnov, Khim. Prir. Soedin., 18,504 (1982).

Carbon-13 and Proton NMR Shift Assignments NORSONGORINE C20H27NO3; MW: 329; mp 284-286° Aconitum monticola Steinb.

VE Nezhevenko, MS Yunusov and SY Yunusov, Khim. Prir, Soedin., 10,409 (1974).

303

B^. Joshi, S.W. Pelletier and S.K. Srivastava

304

ORJENTININE C2oH23N05;MW: 357.1566 [a]D+42.0*»(CHCl3) Aconitum orientate Mill. *H NMR (CDCI3): 8 1.02 (3H, 5, H-18), 2.00 (IH, d, J=9 Hz, H-9), 2.31 (IH, i J= 11 Hz, H.19A), 2.62 (IH, d, J=l 1 Hz, H1 IB), 2.90 (IH, bK, H-12), 3.47 (IH, bw, H-6), 4.24 (IH, brrf, J=9 Hz, H-1 Ip), 4.50 (IH, r, J=2 Hz, H.7p), 4.86,4.98 (each IH, hxs, H-17). '^C Chemical Shift Assignments C-1

46.0

C-11

70.0

C-2

214.1

C-12

49.5

C-3

51.5

C-13

211.4

40.3

C-14

79.1

C-5

60.0

C-15

37.0

C-6

65.3

C-16

146.1

C-7

69.8

C-17

108.2

C-8

44.2

C-18

24.2

C-9

54.9

C-19

62.7

C-10

48.2

C-20

68.6

A Ulubelen, AH Meri9li, F Meri9li and F Yilmaz, Phytochemistry, 41,957 (1996).

Carbon-13 and Proton NMR Shift Assignments

305

OVATINE C24H35NO3; MW: 385; mp 113-114« [a]D-79.4*>(CHCl3) Garrya ovata var. Hndheimeri Ton} *H NMR (CDCI3): 8 0.72, 0.80 (3H. s, H18), 2.15 (3H, 5, OAc), 2.60 (2H, bw. H19), 4.25, 3.95 (IH, bw, H-20), 4.88, 5.14 (eachlH,br
A

B

C-1

41.9

41.6

C-2

18.2

C-3

A

B

C-13

40.6

40.2

19.5

C-14

37.6

37.6

37.6

37.6

C-15

82.1

82.4

C-4

34.2

34.1

C-16

154.5

154.9

C-5

52.2

53.2

C-17

105.7

105.5

C-6

18.5

17.2

C-18

26.0

26.6

C.7

35.3

35.1

€-19

56.6

56.1

C-8

45.7

46.0

€-20

93.2

94.4

C-9

45.4

44.8

C-21

50.5

49.5

C-IO

40.8

40.3

C-22

64.6

59.0

C-11

22.8

21.9

COCH3

171.7

171.7

C-12

32.2

21.9

COCH3

21.3

20.4

*H-20 epimers A and B.

1.

SW Pcllctier, NV Mody and DS Seigler, Heterocycles, 9,1409 (1978).

2.

SW Pelleticr, NV Mody and HK Desai, J. Org, Chem., 46,1840 (1981).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

306 PALMADINE

C31H35NO5; MW: 501; mp269-27r [a]D+11.2^(CHCb) Aconitum palmatum Don. 'H NMR (CDCI3): 6 0.99 (3H, s. H-l 8), 2.02 (3H, 5. OAc), 3.27 (IH, brs, H-6), 3.84 (IH,5, H.20),4.24 (IH, brm. W„2=10.8 Hz, H-2p). 4.82, 5.00 (each IH, s. H-17), 5.19 (2H, d, J=9.5 Hz, H-l 1^, H - n j . 6.61, 7.86 (each IH, J, J=16.1 Hz, H-22, H-23), 7.39 (3H, m, Ar-H), 7.53 (2H, w, Ar-H). '^C Chemical Shift Assignments 32.0'

C.15

C.2

67.2

C-16

143.6

C-3

40.3

C-17

109.9

C-4

36.6

C-18

29.7

C.5

61.1

C-19

63.4

€-6

64.3

C-20

68.5

C-7

35.9

C-21

166.1

C-8

43.9

C-22

118.7

C-9

53.2

C-23

144.7

C-10

50.6

COCH3

170.6

C-11

75.9

COCH3

21.0

C-12

45.0

c-r

134.7

C.13

73.4

C-2',6'

128.9**

C-14

50.1

C-3', 5'

128.0*'

C-4'

130.2

C-1

••**Assignments may be interchanged. QP Jiang and SW Pelletier, Tetrahedron Lett., 29,1875 (1988).

33.9*

Carbon-13 and Proton NMR Shift Assignments

307

PALMASINE C29H33NO4; MW: 459; mp 252-254" Aconitum palmatum Eton. 'HNMR(CDCl3 + CD30D): 80.98(3H,s, H-18), 3.38 (IH, bra. H-6), 3.82 (IH, s. H20), 4.24 (IH, brm, W|/2=10.5 Hz, H-2p), 4.70,4.91 (each IH, s. H-17), 5.21' (2H, d, J=9.3 Hz, H-llp, H-13J, 6.57, 7.79 (each IH, d, J=16 Hz, H-22, H-23), 7.39 (3H, m, Ar-H),7.49(2H,m. Ar-H).

HO..

"C Chemical Shift Assignments

C-1

33.4*

C-15

C-2

66.5

C-16

144.9

C-3

39.9

C-17

108.6

C-4

36.4

C-18

29.5

C-S

61.2

C-19

62.9

C-6

64.3

C-20

68.4

C.7

35.8

C-21

166.5

C-8

43.7

C-22

118.3

C-9

55.2

C-23

145.1

C-10

50.8

c-r

134.6

C-U

75.2

C.2', 6'

128.7^

C-12

46.9

c-3', 5'

128.0*^

€-13

74.4

C-4'

130.1

C-14

50.0

'''*'*^Assignments may be interchanged.

QP Jiang and SW Pelletier, Tetrahedron Lett,, 29,1875 (1988).

33.7**

B^. Joshi, S.W. Pelletier and S.K. Srivastava

308 PANICUDINE

C20H25NO3; MW: 327; mp 249-250° Aconitum paniculatum Lam. 'H N M R (CDCI3): 8 1.29 (3H, 5. H-18), 2.20 (IH, s, W,/2=5 Hz, H-14), 2.22, 2.52 (each IH, dt, J=18 Hz, H-15), 2.74 (IH, btd. J=4 Hz, H-12), 2.95, 3.12 (each IH, d, J= 11.5, 2 Hz, H-19), 3.49 (IH, s, H-20), 4.02 (IH, m. Wi/2=10 Hz, H-2p), 4.76,4.87 (each lH,i:,W,/2=4,2Hz,H-17). "C Chemical Shift Assignments C-1

34.91*

C-11

23.41

C-2

66.1 d

C-12

54.0 d

C-3

43.31

C-13

210.8 s

C-4

37.7 s

C-14

C-5

62.5 d"

C-15

34.01*

C-6

99.7 s

C-16

144.9 s

C-7

44.41

C-17

110.31

C-8

44.2 s

C-18

32.0 q

C-9

49.7 d

C-19

61.91

C-10

49.7 s

C-20

70.2 d

61.9 d"

••^^Assignments may be interchanged.

lA Bessonova, SA Saidkhodzhaeva and MF Faskhutdinov, Khim. Prir. Soedin., 838 (1995).

Carbon-is and Proton NMR Shift Assignments

309

PANICULAMINE C22H35NO3; MW: 393; mp 222-224^ Aconitum paniculatum Lam. *H NMR (D2O): 8 0.82 (3H, 5, H-IS), 1.33 (3H, r, J=7.5 Hz, H-22), 2.78 (IH, q, J=7.5 Hz, H.21), 3.11, 3.36 (each IH, d, J=13 Hz, H-19), 3.67, 3.90 (each IH, d, J=12 Hz, H17), 3.97-4.10 (3H, m, H-1, H-15, H-20). X-ray structure

IM Yusupova, lA Bessonova and B Tashkhodzhaev, Chem. of Nat. Cmpds., 31,277 (1995).

310

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

PANICULATINE HO.

C31H35NO7; MW: 533; mp 260-263°' CH,

Aconitum paniculatum Lam.^'^ ' H N M R (CDCh)': 5 1.03 (3H, s, H-IS), 1.63 (IH, bw, OH-13), 1.63-1.83 (2H, m, H.7), 1.78-1.97 (2H, m, H-3), 2.03 (6H, s. 2 OAc), 2.05 (IH, 5, H-5), 2.08-2.35 (2H, AB, JAB=20 HZ, H-15), 2.26, 2.27,

2.29,

2.32 (3H,m, H-9,H-12, H-14), 2.51 (IH, t/. JAB=15 Hz, H.19), 2.88 (IH, d, JAB=14.5 HZ, H-19), 3.29 (IH, m, Wyi^l Hz, H-6), 4.19 (IH, m. W,/2=16 Hz, H-13), 4.30 (IH, s, H-20), 4.77,4.90 (each IH, s, H-17), 5.37 (IH, m, H-11), 5.55 (IH, m. W,/2=9 Hz, H-2), 5.84 (IH, d, J=3 Hz, H-1), 7.46, 7.58, 8.13 (5H, Ar-H). '^C Chemical Shift Assignments (CDCb)^

1. 2. 3.

C-1

71.6 d

C-14

50.0 d

C-2

70.9 d

C-15

36.3 t

C-3

34.lt

C-16

144.3 s

C-4

36.9 s

C-17

109.01

C.5

51.7d

C-18

29.4 q

C-6

65.6 d

C-19

64.01

C-7

33.lt

C-20

58.1 d

C-8

44.0 s

COCH3

170.1,171.4 s

C-9

64.2 s

COCH3

21.3, 21.8 q

C-10

54.6 s

ArCO

165.5

C-U

68.7 d

c-r

130.3

C-12

51.8d

C-2', 6'

129.9

C.13

75.3 d

C-3', 5'

128.6

C-4'

133.0

E Staehelin and A Katz, Pharm. Acta Helv., 55,221 (1981). A Katz and E Staehelin, Tetrahedron Lett., 23,1155 (1982). A Katz, J. Nat. Prod, 52,430 (1989).

Carbon-13 and Proton NMR Shift Assignments

311

PSEUDOKOBUSINE C20H27NO3; MW: 329 M'^+l 330.2069^ mp 273-274°^'^

HO,

Aconitum yesoense var. macroyesoense (Nakai) Tamura'*^ A. nasatum^^^ Fisch. Ex Reichb.'* ^HNMR(CDCl3:^8 1.60(1H, w, H-la), 1.36 (IH, m, H-lb), 1.57 (IH, m, H-2a), 1.39 (IH, w, H-2b), 1.43 (IH, m, H-3a), 1.30 (IH, m, H-3b), 1.44 (IH, J, H-5), 2.30 (IH, w, H7a), 1.54 (IH, w, H07b), 1.62 (IH, bw, H9), 3.94 (IH, d, J=4.84 Hz, H-11), 2.41 (IH, w, J=<2Hz,H-12), 1.72(lH,br5, wl/2 9.2 Hz, H-13), 0.85 (IH, d, J=9.2Hz H-13b), 1.72 (IH, m, H-14), 3.85 (IH, bw, H-15), 5.15, 5.05 (each IH, bw, H-17), 1.28 (3H, 5, H.18), 3.00, 2.26 (each IH, Jab=11.9Hz, H-19), 2.41(lH,5,H-20) .-ray structure * ^Chemical Shift Assignments (CDCb)"* C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

3. 4.

27.4 t 19.2 t 35.5 t 37.6 s 61.2 d 97.8 s 40.21 46.8 s 54.1 d 49.8 s

C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20

67.5 d 34.5 d 29.lt 40.7 d 70.3 d 149.3 s 114.9t 30.3 g 60.01 73.4 d

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocycles, 26,2623 (\9S7y H Takayama, A Tokita, M Ito, S Sakai, F Kurosaki and T Okamoto, Yakugaku Zasshi, 102,245 (1982). K Wada, H Bando and T Amiya, Heterocycles, 27,1249 (1988). AH Meri^li, F. Merigli, HK Desai, RS Joshi, Q Teng, K Bhattacharyya, G KU9tikislamoglu, A Ulubelen and SW Pelletier, Heterocycles, (in Press.)

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

312

PUKEENSINE Hj

V-{

*Q^

C44H64N2O3; MW: 688.4947 Aconitumpukeense V^,T.^ang. 'H NMR (CDCI3): 5 0.75. 0.96 (each 3H, s,2x CH3), 4.78 (IH, brs, H-15J, 5.02,5.07 (each IH, /, J=1.5 Hz, H-17).

-C

'^C NMR (CDCI3): 19.5, 20.6, 22.0, 23.5, 24.8 (C-18), 25.2, 26.0, 26.1 (C-18'), 26.6, 28.2,29.7,31.1,31.2,34.0,34.4,35.8,36.0,37.0,39.6,39.9,40.6,45.3,45.4,47.1,47.6, 48.8 (C'2i% 49.2, 51.7, 53.9, 56.0 (0-21), 57.1 (C-19), 58.7 (C-22'), 68.1 (C-17), 70.9 (C-20'), 71.4 (C-20), 72.6 (C-22). 76.4 (C-15), 94.2 (C-19'), 108.8 (C-17), 157.3 (C-16).

LS Ding, FE Wu and YZ Chen, Acta Pharmaceutica Sinica, 27,394 (1992).

Carboii-13 and Proton NMR Shift Assignments RYSOENAMTNE

313

C27H3,N04; MW 433; mp 213-215*' [a]„ + 96.8° (MeOH)'-^ Aconitum ibukiense Nakai '"^ HNMR(CDCI3):''6 1.06(3H,5. H-18), 2.62, 3.04 (each H i df, J=I2.5 Hz, H-19), 3.31 (IH, br5.H-20), 3.33 (Hi, bw, H-6), 4.12 (IH, 5, H15„), 4.97, 5.00 (Hi, A, H-17), 5.54 (IH, m, H-

2p), 7.43-8.03 (5H,Ar-H). '^C Chemical Shift Assignments (CDCI3)' C-1 C-2 C-3 C-4 C-5 C-6

29.2* 70.8 38.8 35.9 54.3 64.1

C-B C-14 C-I5 C.|6 C-17 C-18

33.6 42.0 72.5 155.2 109.6 29.5

C-7

29.1* 44.1 79.3 50.5 37.2 35.0

C-19 C-20 ArCO

63.7 74.2 166.0 130.4 129.4 128.6 133.0

C-8 C-9 C-10

c-n

c-12

c-r

C-2',6' C-3',5' C-4'

Assignments may be interchanged.

1. 2.

S Sakai, I Yamamoto, K Hotoda, K Yamaguchi, N Aimi, E Yamanaka, J Haginiwa and T Okamoto, Yakugaku Zasshi, 104,222 (1984). S Sakai, K Yamaguchi, I Yamamoto, K Hotoda, T Okazaki, N Aimi, J Haginiwa and T Okamoto, Chem. Pharm. Bull, 31,3338 (1983).

314

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

RYOSENAMINOL

C20H27NO3; MW 329; mp 287-290** ^'^ [alo + 66.8** (MeOH)*'^ Aconitum ibukiense Nakai*'^ X-ray structure**^

'^C Chemical Shift Assignments {C^^N)^

1. 2. 3.

C-1

32.7

C-11

39.6

C-2

66.7

C-12

36.1

C-3

41.1

C-13

34.0

C-4

36.6

C-14

42.9

C-5

55.7

C-15

74.3

C-6

64.9

C-16

156.7

C-7

30.2

C-17

109.1

C-8

44.6

C-18

30.1

C-9

80.0

C-19

64.5

C-10

51.6

C-20

72.7

S Sakai, I Yamamoto, K Yamaguchi, N Aimi, E Yamanaka, J Haginiwa and T Okamoto, Yakugaku Zasshi, 140,222 (1984). S Sakai, K Yamaguchi, I Yamamoto, K Hotoda, T Okazaki, N Aimi, J Haginiwa and T Okamoto, Chem. Pharm. Bull., 31,3338 (1983). S Sakai, Personal Communication, July 4,1986.

315

Carbon-13 and Proton NMR Shift Assignments SADOSINE C27H3,NO
17),5.4b(lH.m,H-2) X-ray structure

'^C Chemical Shift Assignments (CDjOD)^ C'\ C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-ll C-12

1. 2.

34.0 75.6 71.1 39.9 50.5 65.0 67.7 48.3 80.6 51.4 37.6 36.1

C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 ArCO C'V C-2',6' C-3\5' C-4'

25.6 41.7 71.3 155.4 110.1 25.7 62.3 74.6 166.5 131.0 130.1 129.5 134.2

T Okamoto, H Sanjoh. K Yamaguchi, Y litaka and S Sakai, Chem. Pharm. Bull, 31,360 (1983). H Sanjoh, T Okamoto and S Sakai, J. Pharm. Soc. Japan, 104,738 (1983).

BJS. Joshi, S.W. Pelletier and S.K. Srivastava

316 SANYONAMINE

C20H27NO2; MW 313; mp 276-278** [a]„ + 62.9"' Aconitum sanyoense NakaiM sanyoense, var. tonenze Nakai

HO.

'H NMR (CEX:i3):' 6 1.06 (3H. s, H-18). 2.77. 3.50 (each IH. d\ J=12.0 Hz, H-19). 3.63 (IH. brs, H-6). 3.67 (IH. .v, H-20), 4.07 (IH, 5. H15).4.31 (IH. br5. H.2). 4.96, 4.98 (each IH. s, H-17) X-ray structure *

'•'C Chemical Shift Assignments (CDClj)^ C-1 C-2 C.3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

1. 2. 3.

34.2 66.6 40.2 35.8 60.0 65.2 32.2 41.8 44.6 48.0

C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20

26.8 33.6 32.8 43.2 71.5 155.0 108.8 29.3 62.0 73.8

S Sakai. K Yamaguchi. H Takayama. I Yamamoto and T Okamoto, Chem, Pharm. Bull, 30.4576(1982). H Takayama. Y Hitotsuyanagi. K Yamaguchi, N Aimi and S Sakai. Chem, Pharm. Bull, 37.548(1989). M Reina, JA Gavin, A Madinaveitia, RD Acosta, and G de la Fuente, / Nat. Prod., 59,145 (1996).

Carboii-13 and Proton NMR Shift Assignments

317

SCZUKIDINE C2,H27N04;mp 119-121" Ia]D+ 87.1**(MeOH) Aconitum sczjukinii Turez IH NMR (C5D5N): 5 1.49 (IH, dd, J=14,4 Hz. H-l„). 1.54 (IH, 5. H.18). 1.57 (IH. dd, J=15, 4.6 Hz. H.3„), 1.76 (IH, m . H-11 J . 1.78 (IH, 5. H-5). 1.86 (IH, d. J=14.6 Hz. H-3«). 2.02 (IH. d, J=10 Hz. H-9). 2.08 (IH. dd, J=IO. 4 Hz. H-113). 2.15 (IH. d. J=14 Hz, H-1.). 2.30 (lH,5.A^-CH3).2.46(lH.cf, J=l 1 Hz, H.19„), 2.82 (IH. d, J=19 Hz. H-7J. 3.13 (IH. d, J=4 Hz. H-12), 3.15 (IH, s, H-14), 3.37 (IH. i J=19 Hz, H-73). 3.40 (IH. 5, H-20). 3.71 (IH. i J=ll Hz. H-I93), 4.26 (IH, brs, Wi/2=10 Hz. H-2), 4.35 (IH. 5. H-15). 5.26 (IH. 5, H-17J, 5.52 (IH, 5, H-17p).

'^C Chemical Shift Assignments (CjO^l^^^ C-1 €-2 C.3 C.4 C-5 C-6 C-7 C.8 C.9 C-10 C-11

39.7 65.2 47.8 37.3 59,9 205.1 49.0 44.7 48.0 47.0 22.4

C-12 C-B C-14 C-15 C-16 C-17 C-18 C-19 C-20 N-Me COCH3 COCH3

57,4 211.0 53.3 71.5 150.0 112.3 30.6 59.9 70.1 42.6 170.7 20.8

DH Chen, Q Chang, JY Si, M Yoshikawa and I Kitagawa, Acta Chimica Sinica, 51.825 (1993).

318

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

SCZUKININE C23H29NO5; MW 399. 2043; mp 272-275^* [ a ] p - 107.9° (MeOH) Aconituin sczukbiii Turcz 'H N M R (C5D5N): 6 1.46 (IH. dd, J=15. 5 Hz, H-3J, 1.49 (IH, dd, J=15, 5 Hz, H-IJ, 1.59 (IH. 5, H-18), 1.68 (IH, d. J=I1 Hz, H-11^,), 1.70 (1H, s. H-5). 1.78 (1H. m. H-3p), 1.99 (1H, s, OAc). 1.99 (IH, m, H-11^), 2.02 (IH, d. J=15 Me O Hz.H-lp),2.07(lH,J,J=ll Hz, H-9), 2.26 (IH,s, N-CH3). 2.52 (IH,d. J=12 Hz, H-19o). 2.63 (IH, J. J=12 Hz, H-I93), 2.73 (1H.4 J=I3 Hz, H-7„), 2.82 (IH. s, H-20). 3.09 (IH. d, J=2 Hz. H-14), 3.14 (IH, J, J=3 Hz, H12),3.44(IH, J.J=13Hz,H-7,j).4.54(lH,5. H-l5).5.l9(lH,bK, Wi/2=10Hz,H-2). 5.28 (IH, 5, H.17„),5.58(1H.5.H-17B)

C Chemical Shift Assignments (CDCl^) C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8

C-9 C-IO C-ll

35.9 68.5 43.8 37.1 59.4 203.6 48.8 44.3 47.6 46.9 21.9

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 N-Mc COCH3

58.2 210.9 52.0 71.5 147.6 113.4 31.2 60.4 70.7 43.1 169.9

COCH,

21.6

DH Chen, Q Chang, JY Si, M Yoshikawa and I Kitagawa, Acta Chimica Sinica, 51,825 (1993).

Carbon-13 and Proton NMR Shift Assignments

319

SCZUKITINE C28H37N06;mpll6-118" 5* 4' 2- 1 S-HjCMe-HjC-HC-^

[a]p - 66.6° (MeOH) °\^X>d3
Me M e -

, .,

,

,

Aconitiwi sczukmii Turcz'' ,

*H NMR (CDCI3): 6 0.93 (3H, r, J=7.0 Hz, H5), 1.16(3H,d. J=:6.7 Hz.H-3), 1.47 (1H, 5, H18), I.50(1H, JJ. J=15, 5 Hz, H-lot), 1.60 (IH, dd, J= 15,5 Hz, H-3a), 1.66 (IH, jr, H-5),l.70 (2H, nt, H-4'), 1.76(IH,d, J=15 Hz» H-3p), 1.87 (IH. m, H-l la). 2.00 (lH,c/, J=I5 Hz, H-I3), 2.05 (IH, m, H-^llp), 2.06 (IH, 5, OAc), 2.13 (IH, dd, J=IO, 2 Hz, H-9), 2.28 (IH, rf, J=18.4 Hz, H-7a), 2.38-2.43 (IH, m, H-2'), 2.57 (IH, d. 1=11 Hz, H-19), 2.69 (IH, brs , Wi/2=8 Hz, H-20), 2.72 (IH, d. J=l 1 Hz, H-19B), 2.79 (IH, d, J=18 Hz» H-7b), 2.81 (IH, ^, J=3 Hz, H-14), 2.99 (IH,
'^C Chemical Shift Assignments (CDCI3) C-l

35.3

C-ll

22.1

N'Mc

C.2

68.9

C-12

58.7

COCH3

169.4

C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

42.9

CI 3 C-14 C-15 C-16 C-17 C.18 C-19 C-20

212.7

COCH3

21.4 176.2,176.9 41.3,41.3 16.8,16.2 26.8,26.2 11.8.11.6

36.6 59.3 209.6 48.5 44.6 47.9 45.8

52.6 71.9 144.5 114.0 31.2 61.8 71.6

c-r

C-2' 03' C-4' . C-5'

43.2

DH Chen. Q Chang. JY Si, M Yoshikawa and I Kitagawa, Acta Chimica Sinica, 51,825 (1993).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

320 SEPTATISINE (SEPTEDININE)

Q2H31NO,; MW 357.2287; mp 129-130**'; ^02 124-126^ laJo + 30.55^CHa3) Aconitwn septentrionale Kocllc'*^ 'H NMR (CDCI3):' 62.20 (IH. m. H-la). 0.90 ( IH, ddd, J=13.3. 13.3. 5.4 Hz, H-lp), 1.55 (IH. m. H-2a). 1.45 (1H, ddd, H-2p), 1.25 (IH. m. H-3a), 1.11 (IH. dddM3.2, 13.2, 5.1 Hz. H.3p). 1.25 (IH. m. H-5). 2.28 (IH, ddd, J=13.4.13.3,8.7 Hz. H.6a). 2.10 (lH,m, H-6p). 4.21 (IH. cW, J=8.7.7.7 Hz. H-7). 1.45 (IH, m. H9).2.10(lH.m, H-llo), 1.55 (IH, ddd, H-llp), 2.20 (IH. br5. H.12). 1.98 (IH. m. H-13a). 1.36 (1H.£W^/J, J=13.4.12.2.2.2,2.0 Hz. H-13p). 2.01 (IH. m. H-14), 4.49 (IH, br5, H-15), 4.83 (IH, dd, J=2.1, 1.2 Hz, H-I7a). 4.94 (IH, J=2.6, 1.2 Hz. H-17p). 1.00 (IH. 5. H-IS). 2.35 (IH. ^/AB. J=11.4 Hz, H-19a), 2.58 (IH. dAB, J =11.4 Hz, H.19p), 2.81 (IH, ddd, J=12.4, 6.9, 2.2 Hz. H21a). 3.03 (IH, ddd, J=12.4.12.1.8.6 Hz, H.21p), 3.78 (IH, ddd, J=13.6,8.6.2.2 Hz. H-22a). 3.56 (IH. ddd, J=13.6,8.6,2.2 Hz, H-22p). '^C Chemical Shift Assignments (CDClj)^ C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

1. 2.

30.21 19.61 41.31 34.4 s 46.6 d 32.31 70.0 d 50.0 s 44.0 d 47.1s 29.21

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

34.51 27.41 49.6 d 68.7 d 157.9 s 103.81 28.6 q 57.31 104.6 s 51.51 61.71

BS Joshi, HM Saycd, SA Ross, HK Dcsai, SW PcUcticr, P Kai. JK Snyder and AJ Aascn, Can, J, Chenu, 72.100 (1994) SK Usmanova and lA Bessonova. Khim. Prir. Soedin., 77 (1996).

Carbon-13 and Proton NMR Shift Assignments SEPTEDINE

321

CzjHjiNOj; MW 357.2304; mp 160-161° Acotinum septentrionale Koelle (A. fycoctonum) 'H NMR (CDClj): 8 0.97 (3H. s, H-18), 1.04 (3H, d, J=12 Hz, H-17). 2.32, 2.60 (each IH, d, J=12.0 Hz, H-19), 2.87, 3.65 (each 2H. m. H-21, H-22). 4.07 (IH. t, J=9 Hz,H-7).

SK Usmanova, VA Tel'nov and ND Abdullaev, Khim. Prir. Soedin., 412 (1993)

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

C20H27NO4; MW 345; mp 168-170** Prepared from septenine

SK Usmanova, VA Tel'nov and ND Abdullaev, Khim, Prir. Soedin., 412 (1993)

323

Carbon-13 and Proton NMR Shift Assignments SEPTENINE

C22H29NO5; MW 387; mp 190-192'' Acolinum septentrionale Koelle

AcO^

' H NMR (CDCl,): 6 1.00 (3H, s, H-18), 1.99, (3H, J. OAc), 3.55 (IH, hvs\ 4.47 (IH, s, H19a),4,54,4.68 (each IH, br5, H-17), 4.95 (IH, bnv, H-2p).

'^C Chemical Shift Assignments C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

67.9 73.1 33.0 42.2 50.8 60.7 30.8 41.7 79.6 53.7

C-U C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20

39.2 36.2 33.9 43.9 31.1 150.6 104.7 22.2 91.2 67.9

COCH3

170.2

COCH3

21.6

SK Usmanova, VA TcFnov and ND Abdullacv. Khim, Prir, Soedin., 412 (1993)

324

BJS. Joshi, S.W. Pelletier and S.K. Srivastava

SEPTENTRIOSINE C20H27NO4; MW 345; mp 260-262**' [alo + 20.78^McOH) Acotinum septentrionale Koelle

HO.

*H NMR (CDCI3): * 5 1.02 (3H, 5, H-18), 3.30 (IH, br5. H-6), 3.60 (IH. brs, 20). 4.08 (IH. s, H-19). 4.48,4.65 (each IH. 5. H-17). X-ray structure*

'^C Chemical Shift Assignments (CDClj) ^^ C-1 €-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

69.0 d 70.4 d

69.lt 39.7 s 58.8 d 60.5 d 31.lt 42.1s 79.8 s 53.0 s

C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C.19 C-20

33.5 t 36.2 d 33.1't 43.3 d 30.71 150.3 s 104.81 28.4 q 95.2 d 60.5 d

Assignments may be interchanged.

1. 2.

BS Joshi. HK Desai, SW Pelletier. EM Holt and AJ Aasen, 7. Nat. Prod., 51.265 (1988) SK Usmanova, VA Tel'nov and ND AbduUaev, Khim, Prir, Soedin,, 412 (1993)

Carbon-13 and Proton NMR Shift Assignments

325

SONGORAMINE CzzH^^NO,; MW 355; nip 2I2-2I4'*\ 2112,2or H

[a]D-57**(EtOH) Aconitum napellus L.S. Str. (Syn. A. anglicum Stapf,' A. napellus L. subsp. castellanian J. Molero et C. Blanche', A. nagarum var. lasiandrum W.T. Wang^ and A. karakoUcum^ Rapaics, A, monticola^' Steinb.; A. barbatian Pers/

'H NMR (CDCI3):' 6 0.85 (3H, j . H-18), 1.03 (3H,/, J=7.2H2, H-22). 2.68.2.71 (each IH, ^, J=7.2Hz,H-21). 2.84 (IH. 5, H-20). 3.15 (IH, d. J=4.1 Hz, H-13). 3.71 (IH, j , H-19), 3.98 (IH, d, J=5.2 Hz, H-1), 4.40 (IH, /, J=2.1 Hz, H-15), 5.20,5.31 (each IH.5, H-17). "C Chemical Shift Assignments (CDCI3)' C-1 C-2 C-3 C-4 C-5 C-6 €-7 C-8 C-9 C-IO C-11 1. 2. 3. 4. 5. 6. 7.

67.9 29.9 24.4 37.9 48.7 24.9 46.1 50.4 31.6 51.9 31.4

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

209.0 53.3 37.5 77.1 149.9 111.9 19.0 93.1 66.4 48.5 14.4

G de la Fuente, M Reina and E Valencia, Heterocycles, 29,1577 (1989). MS Yunusov, YV Rashkes, SY Yunusov and AS Samatov, Khim. Prir. Soedin., 101 (1970). G de la Fuente, M Reina, E Valencia and A Rodriguez-Ojeda, Heterocycles, 27,1109 (1988). SY Chen, SH Li and XJ Hao, Acta Botanica Sinica, 28,86 (1986). VE Nezhevenko, MS Yunusov and SY Yunusov, Khim. Prir, Soedin., 409 (1974). EF Ametova, MS Yunusov and SY Yunusov, Khim. Prir. Soedin., 504 (1982). D. Batsuven, J Tunsag, N Batbayar, MH Meri9li, F Meri9]i, Q Teng, HK Desai, BS Joshi and SW PelleUer, Heterocycles, 49,327 (1998).

326

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

SONGORINE (NAPELLONINE, SHIMOBURO BASE I, BULLATINE G) C22H3|N03;mp212** Aconihnn soongaricum, slapf*, A. japomcunC A. karakoliamr Rapaics, A. moitticola^ Slcinb., A. nagarum var. lasiandrum W.T. Wang A. carmichaeli, Debeaux^, A. leucostomuni^'^\ A. harhatum^ Pcrs.

'^C Chemical Shift Assignments (CDCb)-^ C'l C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

70.1 31.5 a 31.9a 34.0 49.0 23.0 43,4 49.7 35.1 52.1

C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

37.3 209.6 53.6 38.0 76.9 150.3 lll.l 26.0 57.2 65.8 50.8 13.5

a Assignments may be interchanged 1. SR Yunusov, J. Gen. Chem, USSR (Engl transl.) 18. 515 (1948) 2. SW Pelletier and LH Keith in "The Alkaloids" (Ed. RHF Manske), vol 12, Chapter 2, Academic Press, New York, 1960; SW Pelletier and NV Mody, in "The Alkaloids" (Ed.) vol. 18, Chapter 2, Academic Press, New York (1981). 3. SY Chen, SH Li and XJ Hao, Aeta Botanica Sinica, 28, 86 (1986). 4. SW Pelletier, NV Mody, KI Varughese and SY Chen, Heterocycles, 18,47 (1982). 5. H. Takayama, A Tokita, M Ito, S Sakai, F Kurosaki and Tokamoto, J. Pharm. Soc, 102,245 (1982). 6. J Yue, J Xu, Q Zhao, H Sun and Y Chen, J, Nat. Prod., 54,277 (1996). 7. D Batsuren, J Tunseng, N Batbayar, AH Meri9li, F Meri^li, Q Teng, HK Desai, BS Joshi and SW Pelletier, Heterocycles, 49, 327 (1998).

Carbon-13 and Proton NMR Shift Assignments

327

SONGORINE-N-OXIDE C22H3,N04; MW 373; mp 253-255" Aconitum monticola'; A. harbatum Pcrs.^ 'H NMR: 6 0.84 (3H, s, H-18), 1.36. (3H. /. H-22),

1. 2.

EF Ametova, MS Yunusov and SY Yunusov, Khim. Prir. Soedin., 867 (1977). D Batsuren, J Tunsag, N Batbayar, AH Meri^li, F Meri9li, Q Teng, HK Desai. BS Joshi and SW Pelletier. Heterocycles, 49.327 (1998).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

328 SPIRADINE A

C20H25NO2; M W 311; mp 281 -2*; 271 -3 " ^'^ [a]D + 51.7**(CHaO Spiraea japonica L.fil; S. japonica \ar, fortimei (Planchon) Rehd; Tlialictrufn sessile Hayata^*^ 'H N M R (CDCI,): 5 1.23 (3H, 5. H-I8)

4.87 (each IH,br5,H-17)

^MeOH

4.73.

X-ray structurc^*^

"C Chemical Shift Assignments *'' CI C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-IO

1. 2. 3. 4. 5. 6. 7.

35.6 19.2 33.8 37.7 61.9 98.7 45.2 44.5 65.2 51.8

C-11 C.12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20

211.0 53.3 27.6 43.9 29.2 143.5 110.9 30.6 60.8 74.6

VI Frolova. AI Bankorskii. and MM Molodozhnikov, Med. Prom, SSR., 18,19 (1964). G Goto, K Sasaki, N Sakabe and Y Hirata, Tetrahedron Lett, 1369 (1968). K Sasaki, N Sakaba and Y Hirata, / Chem. Soc, (B), 354 (1971). F Sun and DQ Yu, Acta Pharmaceutica Sinica, 20,912 (1985). YC Wu, TS Wu. M Niwa, ST Lu and Y Hirata, Phytochemistry, 27,3949 (1988). YC Wu. TS Wu, M Niwa. ST Lu and Y Hirata, Heterocycles, 26,943 (1987) F Sun and DQ Yu, Youji Huaxue, 5,395 (1985).

Carbon-13 and Proton NMR Shift Assignments

329

SPERADINE B C20H27NO2; MW 313; mp 259-260** Spiraea japonica L. fil**^

^MeOH

1. 2.

VI Frolova, AI Bankovskii, AD Kuzovkov and MM Molodozhnikov, Med. Prom. SSR., 18,19(1964). G Goto, K Sasaki, N Sakabc and Y Hirata. Tetrahedron Lett., 1369 (1968).

B.S. Joshi, S.W. Pellctier and S.K. Srivastava

330 SPIRADINE C

AcO^ t

C22H29NO3; MW 355; mp 248-249^ Spiraea japonica L. fil

•^MeOH

G Goto, K Sasaki, N Sakabe and Y Hirata, Tetrahedron Lett., 1369 (1968).

Carbon-13 and Proton NMR Shift Assignments

331

SPIRADINE D C22H29NO2; MW 339; mp 134-135° 2 Spiraea japonica L. fil *H NMR (CDCI3): 8 1.44. 1.47 (3H. s, H-18), 4.22 (IH, s, H-19), 4.55 4.72 (each IH, s, H17).

21 22

J?\» II

G Goto and Y Hirata, Tetrahedron Utt., 2989 (1968).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

332

SPIRADINE F C24H33NO4; mp 114-117** (HCl) Spiraea japonica L. fil

M Toda and Y Hirata, Tetrahedron Lett, 5565 (1968).

Carbon-13 and Proton NMR Shift Assignments

333

SPIRADINE G C22H3,N03; MW 357; mp 168-170* [aJo - 137°(MeOH) Spiraea japonica L. fil ^H NMR (CEXrij): 8 1.17 (3H. 5. H-18). 2.47. 3.59 (each 2H, t\ J=5.5 Hz, H-21, H-22) 3.32. (IH. d, J=5 Hz. H.6). 3.30 and 4.46 (IH. 5, H19). 3.32 (IH. d, J=5 Hz, H-6). 3.80, 4.46 (each IH, 5. H-19, H-20), 4.58 (IH, bw. H-17). 4.60 (IH, /, J=5 Hz, OH-6), 4.72 (IH. bw, H-17)

M Toda and Y Hirata. Tetrahedron Lett, 5565 (1968).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

334 SPIRAMINE A

C24H„N04; MW 399; mp 137.5-139°' [al,, . | 0 3 . r ( C , H , ) OAc

Spiraea japonica L. fil var acuntinata Franch*' S.japonica L. fil ydxfortunei (Planchon) Rehd^

'H NMR iC^n^)'} 6 0.62 (IH, ddd, J=13. 2. 4 Hz, H-5), 1.18 (3H, s, H-18), 1.65 (3H. s. OAc), 1.80(1H.^^/, J=13, 15 Hz, H-6tt). 2.23(1 H, m, H-12), 2.63 (IH.Jc/rf, 3=5,15,4 Hz. H-6«), 3.01,3.24 (each IH,m. H-21). 3.54 (IH, J. J=5.0 Hz, H-7). 3.37, 3.81 (each IH, m. H22). 3.54 (1H. ^, J=5 Hz, H-7), 3.87 (1H, 5, H-19),0 4.47 (1H, J, J= 1.8 Hz, H-20), 5.04, 5.30 (each IH, bw. H-17). 5.46 (IH, bw, H-15). [-ray structure '

'^CCh '^C Chemical Shift Assignments (CDCI3)*

C-1

41.01

C.12

36.7 d

€-2

22.91

C.13

2\A^i

C-3

29.81

C-14

20.9**t

C-4 C-5 C.6 C-7 C-8 C-9

35.4* s 45.2 d 25.21 74.2 d 40.8 s 43.0 d

€-15 C-16 C-17 C-18 C.19 C-20

69.2 d 150.1 s 114.2t 26.0 q 95.2 d 85.8 d

C-IO

34.2's

C-11

23.51

C-21 C-22

51.0d 63.lt

•.b

'Assignments may be interchanged.

1. 2.

XJ Hao, M Node. T Taga, Y Miwa, J Zliou, SY Chen and K Fuji, Chem. Pharm. Bull., 35, 1670(1987). M Node, XJ Hao, J Zhou, SY Chen, T Taga, Y Miwa and K Fuji, Heterocycles, 30.635 (1990).

Carboii-13 and Proton NMR Shift Assignments SPIRAMINE B

335

C24H33NO4; MW 399.242; mp I29-I3r [ah ' 159.5^C,H,) Spiraea japonica L. fil var. acuminata Franch*'^ S.japonica L. fil var.fortimei (Planchon) Rehd^ 'H NMR (C^Hg): 6 0.75 (IH, ddd. J=I3, 2, 4 Hz, H-5), 0.97 (3H, 5. H-18). 1.66 (3H s, OAc), 1.85 (2H, m, H-6), 2.59 (IH, m, H-20). 2.70, 3.02 (each IH, m, H-21), 3.61 (IH, d, 3=5 Hz, H-7), 3.65. 3.73 (each IH, m, H-22), 4.27 (IH, 5, H-19), 4.69 (IH, d, J=2 Hz, H-20), 5.04, 5.30 (each IH,br5, H-17), 5.46(IH,brs, H-15).

"C Chemical Shift Assignments (dXTl,)* C-1 C-2 C-3 C-4 C.5 C-6 C-7 C-8 C-9 C-IO C-ll

•.b

1. 2.

33.91 22.91 29.81 35.4* s 42.4 d 25.31 74.3 d 41.0 s 43.9 d 34.9" s 23.lt

Assignments may be interchanged.

C-12 C-13 €-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22 COCH3 COCH3

36.4 d 21.2^ 20.8*'t 69.7 d 150.1 s 114.3t 25.9 q 91.3 d 83.5 d 45.7 d 64.91 171.1 20.8

XJ Hao. M Node, T Taga, Y Miwa, J Zhou, SY Chen and K Fuji, Chem. Pharm. Bull., 35, 1670(1987). M Node, XJ Hao, J Zhou, SY Chen, T Taga, Y Miwa and K Fuji Heterocycles, 30,635 (1990).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

336 SPIRAMINE C

C22H31NO3; MW 357; mp 167-169^ [aJD . 149.9^QH,) Spiraea japonica L, fil var. acuminata Franch''^ SJaponica L. fil \zx,fonunei (Planchon) Rchd^ 'H N M R (C^H^i): 6 0.67 (IH, m. H-5). 1.22 (3H.5,H-18). 1.52 (IH, m, H-6„), 2.22 (IH, m, H-12), 2.62 (IH, dd. J=5, 15 Hz, H-63), 3.00. 3.25 (each IH, m, H-21), 3.79 (IH, bw. H-15). 3.36,3.83 (each IH, m, H-22). 3.80 (IH, c/, J=5 Hz, H.7), 3.88 (IH. 5, H-19), 4.49 (IH. d, J=2 Hz, H-20), 4.90,4.98 (each IH. bw, H-17). X Chemical Shift Assignments (CDCI3) C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-IO C-ll

40.81 23.01 29.91 35.4* s 45.5 d 25.21 74.3 d 41.5 s 43.1 d 34.1* s 23.61

C-12 C-13 C-14 015 C-16 C-17 C-18 C.19 C-20 C.21 C-22

37.0 d 19.9S 20.4** t 69.0 d 155.3 s 112.0t 26.4 q 95.3 d 85.9 d 51.0t 63.lt

Assignments may be interchanged.

1. 2.

XJ Hao. M Node, J Zhou. SY Chen, T Taga, Y Miwa and K Fuji, Heterocycles, 36,825 (1993). X Hao, J Zhou, SY Chen, K Fuji and M Node, Acta Botanica Yunnanica, 13,452 (1991).

Carboii-13 and Proton NMR Shift Assignments

337

SPIRAMINE D

t X . xPH2

C22H31NO3; MW 357; mp 160-162'* [a)o - 169.0" (C,H,) Spiraea japonica L. fil var. acuminata Franch (Planchon) Rchd*'" 5, japonica L. fil var. fortunei (Planchon) Rehd' *H NMR (QH^): 6 0.77 (IH, m, H-5), 0.99 (3H. 5. H-18). 1.52 (IH, m, H-6J. 1.84 (IH, ddd, JsS. 15.4 Hz. H-63). 2.61 (IH.m. H-12). X 2.71. 3.04 (each IH. m. H-21). 3.66. 3.74 (each IH.m. H-22). 3.79 (IH. bw. H-15). 3.86 (IH. d, J=5 Hz. H-7). 4.29 (IH. 5. H-19). 4.72 (IH, ^. J=:2 Hz. H-20). 4.91,4.94 (each IH. bw. H-17).

'^C Chemical Shift Assignments (CDCIj)*'^ C-l C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

c-n

34.2't 23.01 30.01 35.6' s 47.3 d 25.51 74.5 d 41.9 s 44.3 d 34.2' s 23.lt

C-12 C-13 C-14 C.15 C-16 C-17 C-18 C-19 C-20 G-21 C.22

37.6 d 21.3** I 20.4** t 69.6 d 156.2 s 111.6t 26.9 q 91.5 d 83.6 d 45.71 64.91

•.b

Assignments may be interchanged.

1. 2.

XJ Hao. M Node. T Taga, Y Miwa, J Zhou, SYClien. and K Fuji, Chenu Pharm, Bull.,35, 1670(1987). M Node, XJ Hao. J Zhou. SY Chen. T Taga, Y Miwa and K Fuji Heterocycles,, 30.635 (1990).

338

B JS. Joshi, S.W. Pelletier and S.K. Srivastava

SPIRAMINE E

f X . J3H2

C2,,H„NO,; MW 443.269; amorphous'': [a]p - 97^CHCl3)

OAc

Spiraea japonica L. fil var. acuminata ' n NMR (Q,HJ' -: 5 0.63 (3H, j . H-IS), 1.68 (3H, s. OAc), 1.73 (IH, m, H-6„), 1.75 (3H. s, OAc), 1.80 (IH, m. H-6„). 2.55 (IH, m, H-12). 2.16, 2.60 (each IH, d. J=l I Hz. H-19), 2.64, 2.98 (each IH, J/, 6, 13.5 Hz, H-21), 3.60 (IH, J. J=5 Hz, H-7p), 4.16 (2H, /, J=6 Hz, H-22), 4.51 (IH, bnv, H-20), 5.03, 5.28 (each IH. /, J=1.5 Hz. H-17), 5.46 (IH, bw. H-15p).

'^C Chemical Shift Assignments (CDCIj)'*^ C-l C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-IO C-ll C-12

1. 2.

41.2 21.2 30.1 34.6 44.8 25.2 74.6 d 41.0 44.6 34.6 23.8 36.9

C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22 OCOCH3 OCOCH3

25.2 20.71 69.7 d 150.3 114.1 26.1 53.0 87.3 d 54.4 62.1 170.9,171.1 21.0,21.2

XJ Hao. M Node, J Zhou, SY Chen, T Taga, Y Miwa, and K Fuji, Heterocycles, 36,825 (1993). X Hao, J Zhou, SY Chen. K Fuji and M Node. Acta Botanica Yunnanica, 13,452 (1991).

Carboii-13 and Proton NMR Shift Assignments

339

SPIRAMINE F

t > ^ xPH2

C24H35NO4; MW 401.257; amorphous' M I , - lOrcCHCI,)

OAc

Spiraea japonica L. fil var. acwninata 'H NMR (QH^)'^ 6 0.60 (IH. m, H-5b). 0.61, (3H, 5, H-18), 1.71 (3H, 5. OAc), 1.78 (IH, m, H-6p), 1.78 (IH. m, H-6„), 235 (IH, m, H-12). 2.73, 2.81 (each IH, rf, J^ll Hz, H-19), 2.86, 3.42 (each IH, H-21), 3.53 (IH, ^, 1=5 Hz, H7p), 3.75 (2H, nu H-22), 4.49 (IH. bw, H-20), 5.02. 5.23 (each IH, brj, H«17). 5.38 (IH. br5. H-15p).

"C Chemical Shift Assignments (CHCl,)''^ C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-ll C-12

1. 2.

41.2 21.2 30.1 34,8 44.5 25.1 74.5 d 40.8 44.9 33.6 23.8 36.9

C-13 C-14 €-15 C-16

25.1 21.21 70.0 d 150.2 114.2 c-n C-18 26.0 C-19 51.9 C-20 87.4 d 57.7 C-21 C-22 57.9 OCOCH3 170.9, 171.1 OCOCH3 21.0,21.2

X Hao, M Node, J Zhou, SY Chen, T Taga, Y Miwa, and K Fuji, Heterocycles. 36,825 (1993). X Hao, J Zhou, SY Chen, K Fuji and M Node, Acta Botanica Yunnanica, 13,452 (1991).

BS. Joshi, S.W. Pelletier and S.K. Srivastava

340 SPIRAMINE G

CjjHjjNOj; MW 359.249; mp 160-162*'' [alo .I6**(CHC1,) Spiraea japonica var. acuminata 'H N M R (CHClj)*'^ 5 0.80 (3H, 5, H-18), 1.67. (IH. m. H-11). 1.95 (IH, m, H-U), 2.19 (IH, dd, J=3. 20 Hz. H-13„), 2.25 (IH. dt, J=2. 17 Hz. H-15„). 2.31. (IH. du J=3, 20 Hz. H.13«). 2.12.2.20.2.45.2.52 (each IH. 2xAB type, 2H-19,2H-20). 2.40(2H,m. H.21). 2.70(IH, m. H-12). 3.07 (IH.du J=2.5,11 Hz. H15p), 3.20, (IH. ddd, 1=6. 8. 11 Hz. H-7p). 3.48 (IH. d, J=8 Hz. OH). 3.60, (2H. m, H-22), 4.29. 4.74 (each lH.m.H-17). X-ray structure'

"C Chemical Shift Assignments (CHClj)'*^ C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

1. 2.

39.5 22.8 41.1 33.5 48.4 28.1 76.2 d 51.8 49.4 38.2 27.3

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

38.6 45.6 219.8 s 38.21 146.3 107.7 26.3 59.6 52.41 58.0 60.3

XJ Hao, M Node, J Zhou, SY Chen, T Taga, Y Miwa and K Fuji, Heterocycles, 36,825 (1993). X Hao, J Zhou, S Chen, K Fuji and M Node. Acta Botanica Yunnanica, 13.452 (1991).

Carboii-13 and Proton NMR Shift Assignments

341

SPIRAMINE H CjjH^NO,; MW: 359.247; mp 172-174" [alp - 68°(CHa3); Spiraea japonica var. acuminata •H NMR (CHCI,): 8 0.78 (3H. j , H-18) 1.16 (lH.m, H-11 J , i.86 (IH, m. H-1 Ip). 2.20 (IH. dd, J=3, 20 Hz, H.13„), 2.30 (IH, dt, J=3, 20 Hz. H-Bp). 2.62 (IH, dt, J=3, 13 Hz. H-l^l 2.79 (IH. m. H.12), 3.56 (2H, m. H-22), 3.93 ( l a J. H-15), 5.16 (2H, 5, H.17). '^C Chemical Shift Assignments (CHCI3) C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

39.9 22.9 41.4 33.6 45.1 17.6 27.3 53.2 49.3 38.1 27.6

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

36.9 44.6 213.8 79.4 151.9 111.6 26.4 59.6 52.4 57.8 60.2

XJ Hao, J Zhou, SY Chen. K Fuji and M Node, Acta Botanica Ymnanica, 13,452 (1991).

342

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

SPIRAMINE I C24H35N04;mp 168-170° [a]D-24^CHCl3) Spiraea japonica van acuminata

OAc

/i

C'\

39.2

C Chemical Shift Assignments C.12

37.2

C.2

22.9

C-13

44.4

C-3

41.2

C-14

212.2

C-4

33.6

C-15

78.5

C-5

45.6

C-16

147.7

C-6

17.6

C-17

113.7

C-7

27.3

C-18

26.3

C-8

52.2

C-19

59.6

C-9

49.3

C-20

52.2

C-10

38.1

C-21

58.1

C-11

27.4

C-22

60.4

COCH3

170.6

COCH3

20.9

XJ Hao, J Zhou, SY Chen, K Fuji and M Node, Acta Botanica Yunnanica, 13,452 (1991).

343

Carbon-13 and Proton NMR Shift Assignments SPIRAMINE J C23H33NO3; MW 371.248; mp 92-94" [alp - 95^CHCl3) Spiraea japonica var. aciuninata

'H NMR (CDCI3): 6 0.90 (3H, 5, H-18), 2.21 (3H,5.0Ac),2.73(2H.octa, J=7, 17 Hz, H-20), 3.59 (IH. ^ , J=5, 11 Hz, H-73). 3.94 (IH, dd, J=2.5,7 Hz, H-20), 3.98 (IH, br^, H-I5p), 5.03, 5.06 (each IH, br^, H-17), 7.94 (IH, e/, J=2.5 Hz. H I 9).

CH2COCH3 21

C-I C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-IO C-11

34.31 19.31 48.21 34.9 s 45.6 d 13.41 79.7 d 40.9 s 44.2 d 44.2 s 27.31

C Chemical Shift Assignments C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 CO CH3

35.5 d 30.61 25.91 77.5 d 154.9 s 109.lt 24.5 q 63.0 d 164.2 d 42.31 207.6 s 30.6 q

XJ Hao, J Zhou, K Fuji and M Node, Acta Botanica Yunnanica, 14,314 (1992).

344

B JS. Joshi, S.W. Pelletier and S.K. Srivastava

SPIRAMINE K C23H33N03;MW 371.244 Q^

[alo +18"(CHCI3) Spiraea japonica var. acuminata 'H N M R (CHCI3): 5 7.83 (IH, /, J=l Hz. H19), 5.02, 5.06 (each IH, br5, H-17). 3.98 (IH, bw, H-15(,), 3.95 (IH, //, J=l, 11 Hz, H-20), 3.66 (IH. dd, 1=5, 11 Hz, H-73), 2.51 (IH. dd, J=3, 15 Hz. H-2la). 2.59 (IH. dd, J=I 1. 15 Hz, H-21b). 2.29 (3H. 5, H-23), 0.89 (3H, 5, H-18).

H3COCH2C 23 22

21

' C Chemical Shift Assignments C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

37.21 19.71 34.11 34.6 s 47.5 d 13.41 80.0 d 41.1 s 44.3 d 44.1s 27.61

0-12 C-13 C-14 C.15 C-16 C-17 C-18 C-19 C-20 C-21 C-22 C-23

35.5 d 27.01 25.91 77.1 d 155.3 s 109.01 25.9 q 62.6 d 163.9 d 42.21 208.4 s 30.9 q

XJ Hao, J Zhou, K Fuji and M Node, Acta Botanica Yunnanica, 14,314 (1992).

Carboii-13 and Proton NMR Shift Assignments

345

SPIRAMINE L C25H35N04;MW 413.255

[alo - 77^CHCl3) Spiraea japonica var. acuminata ' H NMR (CDCI3): 8 7.94 (IH, d, J=2.5 Hz. H19), 5.36 (IH. d, J=2 Hz. H-15p), 4.95. 5.02 (each IH.br5. H-17). 3.93 (IH.dt, J=3.8 Hz. H20), 3.55 (IH. dd, J=5. 11 Hz. H-73), 2.72. (2H, octa, J=8. 17 Hz, H-21). 2.22. (3H. jr. H.23). 0.89(3H.5,H-18)

CH2COCH3 21 22 23

C Chemical Shift Assignments C-1 C-2 C-3 C-4 €-5 C.6 C-7 C-8 C-9 C-10 C-11

34.51 19.21 48.21 34.9 s 45.4 d 14.31 79.6 d 41.2 s 44.5 d 44.2 s 27.61

C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22 C-23

29.71 25.91 75.8 d 150.5 s 110.91 24.4 q 63.3 d 163.5 d 42.51 207.5 s 30.6 q

C-12

33.5 d

CDCH3

171.0 s

COC:H3

21.1 q

XJ Hao. J Zhou. K Fuji and M Node. Acta Botanica Yunnanica, 14 (3). 314 (1992).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

346 SPIRAMINE M

C25H35NO4; MW MH^ 414.261 [alo - 55°(CHCl3) Spiraea japonica van acuminata 'H N M R (CDCI3): 8 7.96 (IH, J, J=2 Hz, H-19), 5.02 (1H; bM, H-17), 4.94 (IH, bw,

H-I7), 4.83 (IH, tW, J=5, 11 Hz, H-7B),

3.93 (IH, dt, J=2.5,7 Hz, H-20), 3.98 (IH, s, H-15), 2.60 (2H, octa, J=8, 17 Hz, H-21), 2.24 (3H, s, H-23), 2.03 (3H, 5, OAc), 0.88 (3H,5,H-18).

CHgCCX^Hg 21

22

23

C Chemical Shift Assignments 34.41

C-13

27.01

C-2

19.21

C-14

25.61

C-3

48.21

C-4

34.9 s

C-15 C-16

155.2 s

C-5

45.5 d

C-17

108.91

C-6

14.3 t

C-18

25.6 q

C-7

78.2 d

C-19

63.1 d

C-8

40.8 s

C-20

163.6 d

C-9

44.5 d

C-21

42.21

C-10

44.1s

C-22

207.2 s

C-11

27.61

C-23

30.3 q

C-12

34.9 d

CH3

171.1s

CO

21.0 q

C-1

77.3 d

XJ Hao, J Zhou, K Fuji and M Node, Acta Botanica Yunnanica, 14 (3), 314 (1992).

Carbon-13 and Proton NMR Shift Assignments

347

SPIRAMINE P

.

Me

C22H33NO4; MW 375; mp 237-239*" [alo - 49^CHCl3) Spiraea japonica var. incisa Yu *H NMR (CDCI3): 8 1.16 (3H, j , H-18), 1.35 (3H, 5, H-17), 2.30 (IH, dd, 1=3, 12 Hz. H-12), 3.27, 3.59 (each IH. w. H-22), 3.40, 3.55 (each IH, m, H-21), 3.30, (IH, d, J=5 Hz, H-7), 3.84 (IH, brs, H-19), 4.52, (IH, J, H-20), 4.63 (IH, bw, H.15).

^^C Chemical Shift Assignments (CDCI3) C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

40.7 22.8 47.9 35.3 43.1 26.6 69.5 36.7 39.2 35.6 29.2

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

56.1 21.3 20.3 74.0 72.6 31.3 22.5 95,1 85.2 51.0 63.2

XJ Hao, X Hong, XS Yang and BT Zhao, Phytochemistry, 38, 545 (1995).

BS. Joshi, S.W. Pelletier and S.K. Srivastava

348 SPIRAMINE Q

.

9H

C22H33NO4; MW 375; mp 197-199° [alo - 70'*(CHCl3) Spiraea japonica var. incisa Yu, *H NMR (CDCI3): 8 LIS (3H, 5, H-18), 1.28 (3H, J, H-17), 2.70 (IH. bw, OH), 3.18.3.60 (each IH, m, H-22), 3.28,3.46 (each IH, m, H-21), 3.30 (IH, d, J=5 Hz, H-7), 3.50 (IH, br5, OH), 3.54 (IH, 5, H19), 4.52 (IH, s, H-20), 4.56, (IH, bw, H15).

'^C NMR Chemical Shift Assignments (CDCI3) C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

40.9 22.7 47.3 35.2 42.2 27.3 69.4 36.3 40.8 35.6 29.1

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

55.9 23.5 20.3 73.9 73.9 30.1 22.7 95.1 85.5 51.0 63.1

XJ Hao, X Hong, XS Yang and BT Zhao, Phytochemistry, 38,545 (1995).

Carbon-13 and Proton NMR Shift Assignments

349

SPIRAMINE R

22

C24H33NO5; MW 415; mp 190-192** [alo +180°(CHCl3) Spiraea japonica var. incisa Yu 'H NMR (CDCI3): 8 1.09 (3H. 5. H-18). 1.99 (3H. 5, OAc), 2.42 (IH, m, H-H), 3.22. 3.60 (each IH, m, H-21), 3.46 (each IH, d, J=4 Hz, H-7). 3.75, 3.90 (each IH, m, H-22), 4.77 (IH, J, J=2 Hz, H-20), 5.01 (2H, d, J=3 Hz, H-17), 5.17 (IH, brs, H15).

21

HOH2CH2C

13

C NMR Chemical Shift Assignments (CDCI3)

C-1 C-2 C-3 C^ C-5 C-6 C-7 C-8 C-9 C-10 C-U

39.4 20.6 29.4 44.4 45.2 25.3 69.4 40.7 45.2 33.2 29.1

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

36.5 25.6 19.8 74.0 149.3 114.7 21.1 175.5 86.7 51.6 61.8 OCXX:H3 171.0 0COCH3 21.1

XJ Hao, X Hong, XS Yang and BT Zhoa, Phytochemistry, 38,545 (1995).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

350 SPIRASINE I

C22H29NO3; MW 355; mp 250-251° ^^ [alp-Bl^'CCHCy^ Thalictrum sessile Hayata' and Spiraea japonica L.f\SiX,fortunei (Planchon) Rehd^ ^H NMR (CDClj):^ 8 1.86 (3H, s, H-17), 5.29(lH,br5,H-15).

'^C Chemical Shift Assignments {CHCl^f* C-1 C-2 C-3 C-4 C-5 C'6 C-7 C-8 C-9 C-10 C-11

49.4,49.0 20.7,18.6 31.6,30.1 36.5,35.9 56.1,55.6 206.2 47.9 41.0 82.1 47.2,46.5 37.1,36.2

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

40.0 40.6 44.4 125.0,124.0 147.0 19.6 30.5,23.4 97.8,93.9 69.9,69.8 52.1 64.7,62.6

Twin signals are due to epimers at C-19 which exist in solution in a ratio of approx. 1:1

1. 2.

YC Wu, TS Wu, M Niwa, ST Hirata, Phytochemistry, 27.3949 (1988). F Sun, XT Liang and DQ Yu, Heterocycles, 24,2105 (1986).

Carbon-13 and Proton NMR Shift Assignments SPIRASINE II

351

C22H29NO3; MW 355; mp 230-23 f *'^ [a]D -37.6^ (MeOH)* Thalictrum sessile Hayata' and Spiraea japonica L. f var.fortunei (Planchon) Rehd^ ^H NMR (CDCla)^: 8 4.52 and 4.62 (2H, H-17).

'^C Chemical Shift Assignments (CDCl^f* C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

48.7,48.4 20.5,18.4 32.6,32.3 35.7 55.9,55.4 209.0,204.0 48.1,47.9 42.6.42.2 78.0,77.8 47.1 36.8

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

38.1 35.1,34.8 43.0 29.0,28.2 150.9,150.7 102.8,102.6 29.3,23.4 97.2,93.2 70.6 51.8 64.2,62.1

*Twin signals are due to epimers at C-19 which exist in solution in a ratio of apporx. 1:1

1. 2.

YC Wu, TS Wu, M Ni wa, ST Lu and Y Hirata, Phytochemistry, 11,3949 (1988). S Fang, L Xiao-tian and Y De quan, Heterocycles, lA, 2105 (1986).

BJS. Joshi, S.W. Pelletier and S.K. Srivastava

352

SPIRASINE in

p\a C22H27NO4; MW 369.1858; mp 218-220'

[a]D-11.7*'(MeOH)**^ Thalictrun sessile Hayata Spiraea japonica L. tfortunei (Planchon) Rehd ^H NMR (CDCh)'} 8 1.49 and 1.53 (3H, s, H.18), 1.00-1.18 (IH, H-la), 1.78-1.82 (IH, H-lb), 1.53-1.62 (2H, H-2), 1.00-1.18 (IH, H-3a), 1.48-1.53 (IH, H-3b), 2.18, 2.01 (IH, H-5), 2.68, 2.33 (IH, H-7a), 2.54, 2.36 (IH, H-7b), 3.05 (IH, H-12), 2.11 (IH, H-Ba), 1.72 (IH, H-13b), 2.22 (IH, H-14), 5.00, 4.83 (each IH, H-17), 1.52, 1.46 (3H, H-18), 4.26, 3.75 (IH, H-19), 2.38, 2.31 (IH, H-20), 3.08-3.12; 3.30-3.38; 3.14-3.20; 2.48-2.58 (2H, H-21), 3.91-3.98; 3.78-3.84; 3.86-3.91; 3.62-3.68 (2H,H-22). 13

C Chemical Shift Assignments (CHCI3)

C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

48.6 20.4,18.2 32.1,31.9 36.6,36.2 55.5 206.9 45.3,45.1 47.3,46.8 85.5 49.0,48.1 214.3

39.5,36.0 20.4.18.2 32.1,31.9 41.5,36.6 55.5,54.9 206.9 47.3,40.8 45.8,45.3 86.0,85.5 49.0,48.1 214.3

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

53.2,53.0 39.5 54.9 29.8,29.5 143.6,143.5 s lll.l,110.9t 30.6,23.3 98.0,93.8 70.4 51.8 64.8,62.8

53.2 29.8 54.9 32.2 143.6 111.1 30.6,23.3 98.0,93.8 70.4 51.8,48.5 64.8,62.8

Twin signals are due to epimers at C-19 in solution.

1. 2. 3.

YC Wu, TS Wu, M Niwa, ST Lu and Y Hirata, Phytochemistry. 11,3949 (1988). F Sun, XT Liang and DQ Yu, Heterocycles, 26,19 (1987). F Sun, DQ Yu and XT Liang, Chinese J. Magn. Resonance, 7,415 (1990).

Carboii-13 and Proton NMR Shift Assignments SPIRASINE IV

353

C20H25NO; MW 295

Spiraea japonica L. f. vdx.fortimei (Planchon) Rehd^ *H NMR (CDCI3)*: 8 1.04 (3H, j , H-18), 2.46 and 2.72 (each IH. ^, J=l 1.5 Hz. H19), 3.40 (IH, bw, H-6), 4.84 and 4.96 (each lH,bw.H-.17).

'^C Chemical Shift Assignments (CDCI3) C-l C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

1. 2.

34.9 19.3 33.7 38.0 61.2 65.4 33.9 43.0 48.9 49.8

C-11 C-12 C-13 C-14 C-15 C.16 C-17 C-18 C-19 C-20

22.7 53.3 213.0 60.9 26.0 142.7 110.4 28.8 62.7 70.0

F Sun and DQ Yu, Acta Pharmaceutica Sinica, 20,913 (1985). F Sun and DQ Yu, Youji Huaxue, 5,395 (1985).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

354

SPIRASINE V

C22H3,N03;mpl77-179'' [a]D-47^CHCl3) Spiraea japonica L. f. var.fortunei (Planchon) Rehd

'^C Chemical Shift Assignments (CD3OH) C-1 C-2 C-3 CA C-5 C-6 C-7 C-8 C-9 C-10 C-11

40.4 17.3 33.8 38.9 59.8 104.8 26.3 39.9 34.4 47.8 22.8

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

47.6 24.4 39.3 40.1 68.5 27.2 21.3 104.8 73.3 43.3 68.5

F Sun, XT Liang, DQ Yu, CF Xu and J Clardy, Tetrahedron Lett., 27,275 (1986).

Carbon-13 and Proton NMR Shift Assignments SPIRASINE VI

355

CjzHjjNOa; MW 357; mp 202-203° [alo - 107**(CHCl3) Spiraea japonica L. f. vacfortunei (Planchon) Rehd X-ray structure

/i.

C Chemical Shift Assignments (CD3OH)

C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

41.4 17.3 34.5 40.9 60.4 105.6 27.0 40.9 35.3 48.5 27.6

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-I9 C-20 C-21 C-22

48.0 20.8 39.9 41.4 69.4 28.8 22.1 105.2 73.7 44.2 69.1

F Sun, XT Liang, DQ Yu, CF Xu and J Clardy, Tetrahedron Lett., 11 y 275 (1986).

B.S. JoshI, S.W. Pellctler and S.K. Srivastava

356 SPIRASINE Vn

C22H3,N04; mp 191-193° [aJo .78.0(CDCl3)

Spiraea japonica L. f. (Planchon) Rehd

var. fortunei

13

C Chemical Shift Assignments (C5D5H)*

C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

49.1,48.6 20.6,18.2 32.8,31.7 35.9 56.0,55.5 210.0,205.0 47.1 42.5 76.8 48.1,47.5 37.0

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

38.0 29.1,28.0 41.9 42.0,39.0 69.1 30.4 23.7 97.2,93.2 70.6 51.9 64.1,62.1

Twin signals are due to epimers at C-19 which exist in solution in a ratio ofapproxl:l.

F Sun, XT Liang and DQ Yu, Heterocycles, 24,2105 (1986).

Carbon-13 and Proton NMR Shift Assignments SPIRASINE Vm

357

C22H3,N04; mp 207-209° [alp - 57" (CDCI3) Spiraea japonica L. f. (Planchon) Rehd.

var. fortunei

13,

C Chemical Shift Assignments (C5D3N)

C-1 C-2 C-3 C-4 C-S C-6 C-7 C-8 C-9 C-10 C-U

50.3.49.8 21.6,19.4 30.5,30.1 36.9,35.9 557.2,56.7 211.5,208.0 49.3,48.0 41.7 78.1 48.6 37.9,36.5

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

39.0 29.8,29.2 43.1 42.8,40.8 70.2 31.3 24.4 98.5,94.3 71.0 52.6 65.2,63.1

Twin signals are due to epimers at C-19 which exist in solution in a ratio of 1:1 approx.

F Sun, XT Liang and DQ Yu, Heterocycles, 24,2105 (1986).

358

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

SPIRASINE IX

C20H25NO; MW 295; mp 157-158° [aJo + 135.5° (CHCIj)**^ Spiraea japonica L. f. (Planchon) Rehd^

var. fortunei

'H NMR (CDCl,)^ 8 1.08 (3H, 5, H-18), 2.72 and 2.89 (each IH, d, 1=11.5 Hz. H19), 3.72 (IH, br5, H-6), 4.82 and 4.92 (each lH.bw,H-.l7).

'^C Chemical Shift Assignments (CDCI3)* C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

1. 2.

35.2 19.3 33.9 38.0 61.0 65.6 35.2 44.2 65.3 51.0

C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20

211.2 53.4 28.3 45.0 28.4 144.1 110.1 28.8 63.1 75.7

F Sun and DQ Yu, Acta Pharmaceutica Sinica, 20,913 (1985). F Sun and DQ Yu, Youji Huaxue, 5,395 (1985).

Carbon-13 and Proton NMR Shift Assignments SPIRASINE X

359

C20H25NO2; MW 311.1853; mp 224-227°

HO.

[aJD + 51.0°(CHCl3) CHa

Spiraea japonica L. f. (Planchon) Rehd

var. fortunei

'H NMR (CDa3)V- 8 1.01 (3H. s, H-18), 1.68 and 1.87 (each IH, dd, H-7), 2.04 (IH, d, H-20), 2.26 and 2.32 (each IH. br^. H15), 2.41 (IH, q, H-14), 2.47 and 2.58 (each IH,
^^C Chemical Shift Assignments (CDCI3) C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

33.5 19.2 25.7 37.9 60.1 65.1 34.8 44.9 67.2 50.3

C-11 C-12 C-13 C-14 C-15 C-16

cn

C-18 C-19 C.20

F Sun, XT Liang and DQ Yu, 7. Nat. Prod,, SO, 923 (1987).

211.0 62.5 67.7 51.6 33.7 140.5 112.4 28.8 62.5 65.1

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

360 SPIRASINE XI

C20H27NO; MW 297 [alo -23.8°(CHCl3) Spiraea japonica L. f. (Planchon) Rehd

var. fortunei

*H NMR (CDCI3): 5 1.13 (3H, 5. H-18), 2.86 and 3.06 (each IH, d, J=11.5 Hz, H19), 4.13 (IH, q, J=9.4.3.0 Hz, H-Bp). 4.68 and 4.85 (each IH, bw, H-17).

i3,

C Chemical Shift Assignments (CDCI3)

C-1 C-2 C-3 C-4 C-5 C-6 C-T C-8 C-9 C-10

34.6 19.1 33.6 37.1 58.1 65.7 33.3 42.2 49.1 50.1

C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C.20

21.8 49.8 67.7 41.9 24.0 147.2 107.4 28.5 59.8 69.1

F Sun and DQ Yu, Acta Pharmaceutica Sinica, 20,913 (1985).

Carbon-13 and Proton NMR Shift Assignments

361

C20H25NO3; MW 327.1809; mp 226-228'* [alo + 17.9** (CHCI3) Spiraea Japonica L. fil var. fortunei (PI) Rehd. *H NMR: 8 1.32 (3H, 5, H-18), 2.83 (IH, d, 1=3.5 Hz), 4.12 (IH, q, J|=3.5, J2=10 Hz), 4.86,4.96 (each IH, bw, H-17).

Me OH

'^C Chemical Shift Assignments (C5D5N) C-1 C-2 C-3 C-4 C-5 C-6 C-7 €8 C-9 C-10

36.4 19.8 27.3 38.4 62.3 98.5 44.3 46.6 65.7 51.2

C-11 C-12 C-13 C-14 C-15 C-I6 C-17 C-18 C-19 C-20

F Sun, XT Liang and DQ Yu, 7. Nat. Prod,, 51,50 (1988).

210.8 64.3 67.3 51.7 33.9 142.8 111.3 31.2 61.9 68.9

362

BJS. Joshi, S.W. Pelletier and S.K. Srivastava

SPIRASINE XIII

C20H25NO3; MW 327.1858; mp 188-189** [alo + 25.7** (CHCI3)

Spiraea japonica L. f. var. fortunei (PI) Rehd. 'H NMR: 8 1.38 (3H, 5, H-18), 2.39, 3.11 (each IH, d, J=12 Hz), 2.94 (IH, s), 3.05 (IH, d, J=4 Hz, H-12), 3.65 (IH, J, J=4 Hz, H-13), 4.97,5.02 (each IH, bw, H-17), 4.57 (1H,^,0H-13).

'^C Chemical Shift Assignments(CDC]^) C-1 C-2 C'3 C.4 C-5 C-6 C-7 C-8 C-9 C-10

35.3 19.0 28.6 37.6 60.7 98.9 43.3 45.1 73.9 52.3

C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20

F Sun, XT Liang and DQ Yu, J. Nat Prod., 51,50 (1988).

209.2 61.9 67.4 56.0 32.8 137.6 114.9 30.5 61.1 72.0

Carbon-13 and Proton NMR Shift Assignments

363

SPIRASINE XIV

Ha

C20H27NO2; MW 313; mp 244-246° [alo - 18.8° (EtOH) Spiraea japonica L. f. var. fortunei Rehd.

(PI.)

*H NMR (CDClj): 8 1.36 (3H, 5, H-18). 2.08, 2.30 (each IH, J, J=12.6 Hz), 3.96 (IH, br^, J=10.0 Hz), 4.62, 4.77 (each IH, br5,H-17).

'^C Chemical Shift Assignments (CDCI3) 35.4

C-11

21.6

C-2

18.6

C-12

48.2

C-3

24.2

C-13

65.9

C.4

37.2

C-14

41.6

C-5

59.1

C-15

33.0

C-6

99.5

C-16

147.1

C-7

42.5

C-17

106.6

C-8

43.1

C-18

29.0

C-9

48.8

C-19

58.0

C-IO

49.4

C-20

69.0

C-1

F Sun, XT Liang and DQ Yu, 7. Nat Prod., 51,50 (1988).

BJS. Joshi, S.W. Pelletier and S.K. Srivastava

364 SPIRASINE XV

C20H27NO2; MW 313; mp 156-158^ Spiraea japonica L, f. var. fortunei (PI.) Rehd. *H NMR (CDCI3-CD3OD) 1.49 (3H, s, H18),4.85.(2H,br5.H-17).

^C Chemical Shift Assignments (CDClj-CD.OD) C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

35.1 18.3 26.1 37.3 58.2 101.5 41.2 41.2 47.5 49.4

C-ll C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20

F Sun, XT Liang and DQ Yu, J. Nat. Prod.. 51.50 (1988).

23.3 53.7 69.3 41.1 32.3 143.1 109.4 29.4 56.7 71.0

Carbon-13 and Proton NMR Shift Assignments SPIREDINE

365

C22H27NO3; MW 353; mp 160-162" '-^ taJo - 21»(CHCl3)'* Thalictrum sessile Hayata' and Spiraea japonica L. f. var.fortunei (PI.) Rehd. "^ 'H NMR (CF3COOD)' : 6 1.47 (3H, s. H18), 4.00 and 4.60 (2H, m, H-21), 5.04 (IH. s,H-l9). (CDClj)^ : 8 1.43 and 1.47 (3H, s, H-18), 3.00-3.50 (2H. m, H-21), 3.50-4.00 (2H. m, H-22), 4.10 (IH, *, H-19), 4.73 and 4.91 (eachlH.j,H-17).

Me O

"C Chemical Shift Assignments (CDCI3)' C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

49.8,48.9 20.3,18.3 33.9,18.3 36.8,36.7 61.5 206.6 50.9,50.3 43.3,42.1 64.7 42.6.46.7 210.1

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

53.4,53.3 39.7 45.2 30.0,29.6 143.4,143.2 110.3,110.2 30.2,23.1 97.6,93.3 73.1,72.5 52.2 64.8,62.8

The data reported are for the C-19 epimeric mixture.

1. 2. 3. 4.

YC Wu, TS Wu, M Niwa, ST Lu and Y Hirata, Phytochemistry, 27,3949 (1988). F Sun, XT Liang and DQ Yu, Heterocycles, 26,19 (1987). VD Gorbunov, VI Sheichenko and AI Bankovskii, Khim. Prir. Soedin., 12,124 (1976). F Sun and DQ Yu, Youji Huaxue, 5,395 (1985).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

366 STAPHIDINE

We*

.21'

i-"N,

C42H58N2O; MW 606; mp 213-216° [ a l o - 160^QH6)^ Delphinium staphisagaria ' ^HNMR (CDCI3)'' ^ : 8 0.91 (6H, H.18. 18'). 2.13 (3H, H-2r ). 2.21 (3H, H-21). 5.85(lH.H.ir).

13

C Chemical Shift Assignments (CDClj)

C-4 C-4'

34.2 s 34.4 s

c-ir

C-15'

112.7 77.6 d

C-5' C-8

135.6*8 37.6 s

C-16 C-16'

73.6 s 29.3 s

C-8'

41.6 s

c-19'

62.4^

C-9'

127.7" s

C-20

77.0 d

C-10

45.5 s

C-20'

64.5N

C-10'

135.8* s

C-21

43.5 q

c-2r

46.3 q

C-19 «.b

1. 2.

60.4

Assignments may be interchanged

SW Pelletier, NV Mody, Z Djarmati, IV Micovic and JK Thakkar, Tetrahedron Lett., 1055(1976). SW Pelletier, NV Mody, Z Djarmati and SD Lajsic, J. Org. Chem., 41,3042 (1976).

Carbon-ia and Proton NMR Shift Assignments STAPHIGINE

Me .21'

^^"N,

367

C43H58N2O3; mp 225-227° [a]D- n6°(C6H6) Delphinium staphisagaria 'HNMR (CDCI3) : 8 0.94, 1.12 (6H, H-

18, 18'), 2.13 (3H, s, H-2r), 2.98 (3H, s, H-21), 3.30 (3H, s, OMe), 5.85 (IH, H-

ir).

13.

C Chemical Shift Assignments (CDCI3)

C-4

44.6 s

c-ir

C-4'

34.5 s

C-15'

78.5 d

C-5'

135.6 s

C-16

72.2 s

C-8

38.4 s

C-16'

29.7 s

C-8'

41.8 s

C-19'

62.5*' t

C-9'

128.2' s

C-20

72.9 d

C-10

44.6 s

C-20'

64.7*' t

C-10'

136.1's

C-21

46.9 q

C-19

175.1 s

C-21'

46.4 q

C-13

90.3 d

OMe

57.0 q

113.7

^^ Assignments may be interchanged

SW Pelletier, NV Mody, Z Djarmati and SD Lajsic, J. Org, Chem., 41,3042 (1976).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

36S STAPHIMINE

Me

• 21'

^"N,

C41H54N2O; amorphous [a]D.58.5^C5H6) Delphinium staphisagaria^ *HNMR (CDCI3): 8 0.941.00 (6H, s, H-IS, 18'), 2.13 (3H, J, H-2r), 5.85 (IH. H-ll'). 7.30(1H.J,H-19).

1.2 ^^C Chemical Shift Assignments (CDCI3)''

C-4 C-4'

41.5 s 34.5 s

c-ir

C-5 C-8 C-8'

135.7* s 38.3 s 41.6 s

C-15' C-16 C-16'

77.9 d

C-9'

127.9's

C-19'

62.3'* t

C-10

43.7 s

C-20

75.8b d

C-IO'

135.7" s

C-20'

64.4''t

C-19

167.6 d

C-21

113.3 d

C-13 73.8 s 29.4 s

46.4 q a,b

1. 2.

Assignments may be interchanged

SW Pelletier, NV Mody, Z Djarmati, IV Micdvic and JV Thakhar, Tetrahedron Lett. ,1055^1976). SW Pelletier, NV Mody, Z Djarmati and SD Lajsic, J. Org. Chem., 41,3042 (1978).

Carbon-ia and Proton NMR Shift Assignments STAPHININE

Me

I 21*

«>/%,

369

C42H55N2O2; amorphous [a]D-57.5^C6H,) Delphinium staphisagaria ' ^HNMR (CDCI3): 8 0.94,1.00 (6H, 5, H-18. 18'), 2.13 (3H, J, H-2r), 3.30 (3H, jr, Ome), 5.85 (IH, H-ir), 7.30 (IH, s, H-19)

13

C Chemical Shift Assignments (CDCI3)1.2

C-4 C-4*

41.5 s 34.4 s

c-ir C-13

112.9d 91.2 d

C-5' C-8 C-8'

135.5's 38.1s 41.6 s

C-15' C-16 C-16'

78.5 d 72.3 s 29.5 s

C-9' C-10

127.7' s 44.3 s

C-19' C-20

62.5^ t 73.1 d

C-10'

135.5's 168.1 d

C-20'

64.7^ t

C-21' OCH3

46.3 q 56.4 q

C-19

1. 2.

SW Pclleticr, NV Mody, Z Djannati, IV Micovic and JV Thakkar, Tetrahedron Letters, 1055 (1916). SW Pelletier, NV Mody, Z Djannati and SD Lajsic, 7. Org. Chem,, 41,3042 (1978).

370

B^. Joshi, S.W. Pelletier and S.K. Srivastava

STAPHIRINE

Ye

.21*

^•N,

C42H56N2O2; mp 222-225** [alo -126^C,H6) Delphinium staphisagaria ' (CDCI3): 8 0.94, 1.12 (6H, H-18, 18'), 2.13 (3H. H-2r). 2.92 (3H, s, H-21). 5.85(3H,5,H-ir) 'HNMR

C Chemical Shift Assignments

a,b

1.

C-4 C-4' C-5' C-8 C-8'

44.7 s 34.5 s 136.4 s 38.7 s 41.9 s

C-ir C-15' C-16 C-16' C-19'

113.1 d 78.1 d 73.5 s 29.4 s 62.71

C-9'

128.1* s

C-20

77.0 d

C-10

44.3 s

C-20'

67.8^

C-10'

136.4's

C-21

46.6 q

C-19

175.0 s

C-2r

46.9 q

Assignments may be interchanged

SW Pelletier, NV Mody, Z Djarmati and D Ujsic. / Org, Chem., 41,3042 (1976).

Carbon-13 and Proton NMR Shift Assignments

371

STAPHISAGNINE V'

i

C44H52N2O2; amorphous

18'

[alo - 104.5^C6H,)

Me» Hi 1

20*

Delphinium staphisagaria *HNMR (CDCI3): 5 0.82, 0.93 (each 3H, 5. H-18, H-IB'), 2.21 (3H, 5, H-21), 4.06 (IH, H-20'),5.93(1H,H-11').

21

Me-

SW Pelletier. NV Mody and Z Djarmati, Tetrahedron Lett, 1749 (1976).

372

B JS. Joshi, S.W. Pelletier and S.K. Srivastava

STAPHISAGRINE C43H6oN202;mp 229-231^ [ a l o - 105.6^C,H6) Delphinium staphisagaria *HNMR (CDCI3): 5 0.82, 0.93 (each 3H, 5, H-18, H-18'), 2.21 (3H, s, H-21), 4.06 (IH, H-20'),5.93(1H,H-11').

SW Pelletier, NV Mody and Z Djannati, Tetrahedron Lett., 1749 (1976).

Carbon-13 and Proton NMR Shift Assignments STAPHISINE

373

21*

C43H6oN202;mp 211-213"o l , 2

•^'V^o'

[alD - 159' 1.3 Delphinium staphisagaria

Me

.0 2

'HNMR (CDCla)*'^: 6 0.91 (6H, s, H-18,

18'). 2.13 (3H, J, H-2r), 2.27 (3H, 5, H21), 3.30 (3H. J, H-23), 5.85 (IH. H-ll'), (QDg)^ 0.18 (IH, J, H-12'), 0.72 (IH, m, C-13'), 0.95 (3H, J, H-18). 2.03 (6H, s, H-21, 21% 2.20 (3H, s, H-23). 3.18 (2H, w, H-16'). 6.18 (IH,^, H-ll'). X-ray structure^ Me---|-

'^C Chemical Shift Assignments (CDCI3) **^ C-4 C-4' C-5' C-8 C-8' C-9' C-10 C-10' C-11' C-13 a.b

1. 2. 3.

34.2 s 34.5 s 135.6's 37.4 s 41.8 s 127.6" s 46.0 s 135.6's 112.9d 89.4 d

C-15' C-16 C-16' C-19 C-19' C-20 C-20' C-21 C-2r C-23

78.1 d 72.2 s 29.5 s 60.71 62.5** t 74.4 d 64.4** t 43.9 q 46.6 q 57.8 q

Assignments may be interchanged

SW Pelletier, NV Mody. Z Djarmati, IV Micovic and JK Thaldcar, Tetrahedron Lett,, 1055 (1976). SW Pelletier, AH Kapadi LH Wright, SW Page and MG Newton, J, Am. Chem, Soc, 94,1754(1972). SW Pelletier, NV Mody, Z Djarmati and SD Lajsic. /. Org, Chem,, 41,3042 (1976).

B.S. Joshi, S.W. Pelietier and S.K. Srivastava

374

STENOCARPINE C21HJ1NO3; MW 345; mp 179-182°

HO.

[a]D-44.3° Aconitella stenocarpa (Hossain and P.H Davis) Sojak., Syn. Consolida Stenocaipa Hossaii and P.H. Davis

Me-

'H NMR: 8 3.99 (IH, dd, J=l 1.6, 6.6 Hz, H Ip), 2.07 (IH, m, H-2„), 1.72 (IH, m, H-23) 1.48 (IH, ddd J=13.4, 4.4, 2.6 Hz, H-3„) 1.15 (IH, m, H-3p), 1.21 (IH, d, J=9.2 Hz, H 5), 1.15 (IH, m, H-6„), 2.69 (IH, dd, J=14.1, 7.8 Hz, H-6p), 2.15 (IH, d, J=5.4 Hz, H-7), 1.21 (IH, d, J=9.2 Hz, H-9), 4.25 (IH, d, J=9.: Hz, H-llc), 2.04 (IH, hxs, H-12), 1.60 (IH, ddd. J=15.0, 2.8, 2.8 Hz, H-13„), 1.34 (IH, m H-13p), 1.79 (IH, m, H-14a), 0.99 (IH, t, J=11.8 Hz, H-14p), 4.12 (IH, brs, H-I5a), 5.1( (IH, /, J=1.6 Hz, H-17„), 4.88 (IH, /. J=1.7 Hz, H-17p), 0.61 (IH, s, H-18), 2.47 (IH, a J=l 1.7 Hz, H-19„), 2.21 (IH,
69.5 d 30.01 37.91 33.7 s 51.1 d 22.61 41.3 d 43.6 s 53.3 d 51.1s

C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21

72.3 d 46.5 d 24.21 27.lt 77.3 d 153.0 s 109.21 25.5 q 58.91 68.7 d 43.2 q

G. de la Fuente and Mesia LR, Phytochemistry, 46,1087 (1997).

Carbon-13 and Proton NMR Shift Assignments SUBDESCULINE

375

C24H33NO4; MW 399; mp 135-145^ [alo + 7.3° (CHCI3) Aconitum japonicum Thunb. *H NMR (CDCI3): 6 0.81 (3H, 5, H-18), 1.02 (3H, /, H-z, H-22), 2.04 (3H. s, OAc), 3.69 (IH, s, H-19), 4.04 (IH, J, J=4.9, Hz, H-ljj), 4.24 (IH, brs, H-15„), 4.59 (IH, dd, J=8.0,6.0 Hz, H-12a), 5.23, 5.34 (IH, 5, H17).

13,

C Chemical Shift Assignments (CDCI3)

C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

61,1 29.7 24.4 37.7 45.9 23.9 48.7 50.2 32.2 51.8 26.3

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22 COCH3 COCH,

76.8 43.0 28.1 77.2 156.5 110.5 18.9 92.9 65.9 48.3 14.2 170.4 21.3

H Bando, K Wada, T Amiya, Y Fujimoto and K Kobayashi, Chem. Pharm. Bull, 36, 1604(1988).

376

B^. Joshi, S.W. Pelletier and S.K. Srivastava

TADZHACONINE Ca.H^jNO/, MW 533; mp 236-237* Aconitum zeravschanicum Steinb / ^ i Aco IJ I ^f ^>--C00.^ ^ A ^ ^ T T K N ^

'H NMR: 6 0.94 (3H, 5, H-18). 1.93 and 1.94 (each3H.j,20Ac).2.39(lH,diJ=l2.9Hz,Hl9b).2.79(IH,^,J=I2.0 Hz, H-19a). 3.18 (IH, brj. H-6). 4.08 (IH, brJJ=:9.0 Hz, H-13„), 4,21 (IH, s, H-20). 4.67. 4.78 (each IH, 5. H-H), 5.26 (IH. d, J=9.0 Hz. H-1 Ip). 5.46 (IH, /n, H2^), 5.77 (IH, €/. J=3.0 Hz, H-I J , 7.28 - 8.12 (5H.iii.OBz). X-ray structure

'"'C Chemical Shift Assignments C-1 C-2 C-3 C^ C-5 C-6 C-7 C-8 C-9 C-10

71.6 68.9 36.7 36.1 58.0 64.3 34.0 44.0 51.9 54.7

C-16 C-17 C-18 €-19 C-20 ArCo C-l C-2.6 C-3,5 CA

144.6 108.9 29.3 63.6 65.7 165.9 130.3 130.0 128.7 133.3

C-11

76.1

COCH3(l) 172.0

C-12

49.4

COCHjd)

C-13

70.4

COCH3(ll) 170.5

C-14

51.5

COCHjdl)

C.I5

33.1

21.6 21.4

IM Yusupova, BT Salimov and BT Tashkhodzhaev, Khim. Pnr. Soedin., 382 (1992).

Carbon-13 and Proton NMR Shift Assignments

377

TALASSAMINE C20H27NO2; MW 313; mp 208.210° Aconitwn ialassicum M. Pop •H NMR(CDCl3): 8 1.00 (3H, 5. H-18). 3.22 (1H, brv. H-20)/3.94 (IH, ^, J,=IO Hz,Lrr? Hz. H-7X 4.53 (IH, U J=l.5 Hz, H-15), 4.81, 4.92 (each 1H,5,H-17),7.31 (lH.brj,H-19).

AA Nishanov, MN Sultankhodzhaev, MS Yunosov, IM Yusupova, and B. Tashkhozhaev, Khim, Prir. Soedin., 93, (1991).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

378 TALASSIMIDINE

C22H29NO3; MW 355; mp 263.265" Aconitum talassicum M. Pop 'H N M R ( C D C I 0 : 5 !.00 (3H. 5, H-18), 2.12

(3H, J, OAc), 4.61,4.86 (each 1H, d, J=2 Hz, H17), 3.25 (IH, bw, H-20), 3.47 (IH, 17, J,=10 Hz, J,=7 Hz, H-7), 5.84 (IH, u J=1.5 Hz, H-I5), 7.88(br.T,H-19).

AA Nishanov, MN Sultankhodzhaev, MS Yunosov, IM Yusupova, and B. Tashkhozhaev, Khim. Prir. Soedin., 93. (1991).

Carbon-13 and Proton NMR Shift Assignments

379

TALASSIMINE C22H2yN03; MW 355; mp 242.245" Aconitum talassicum M Pop ' H NMRCCDCI,): 6: 0.98 (3H, s, H-18), 1.99

(3H. i'. OAc). 4.83.4.92 (each IH. 5. H-17), 3.24 (IH, bnv, H-20), 5.18 (IH, r/, J,=:IO Hz, J.=7 Hz, H-7). 4.20 (IH, r, J= 1.5 Hz, H-15), 7.82 (brA, H19). X-ray structure

AA Nishanov, MN Sultankhodzhaev, MS Yunosov, IM Yusupova, and B. Tashkliozhaev, Khim. Prir. Soedin., 93, (1991).

380

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

TALATISINE C20H27NO3

Aconitum talassicum M. Pop X-ray structure

Z. Karimov and MG Zhamierashvili, Khim. Prir. Soedin., 335 (1981).

Carbon-13 and Proton NMR Shift Assignments TANGIRINE

381

C49H52N2O7; MW 790; mp 266.268**

Aconitum tanguticum 'H NMR (CDCI3): 8 0.86 (SH. s, H18). 1.08 (3H. /, 1=7.2 Hz, H-21). 1.22 (IH. m, H-3,), 1.58 (IH, bw, H-S), 1.59 (each IH, w, H-3^). 1.82 (each IH. H15,X 1.83 (2H, H-16a), 2.04 (each IH, H-I5b). 2.13 (2H, m, H-2). 2.13-3.15 (2H, m, H.12). 2.19 (IH. tl J=12 Hz, H-I9,). 2.40 (each IH, H-16h). 2.45 (IH. H-10). 2.52 (2H. AB. J=7.2 Hz. H-20). 2.65 (IH. i J=:12 Hz, H-19p), 2.95 (IH. d, }=n2 Hz, H-7). 3.18 (IH. m. H-1). 3.29 (3H. 5. OAc-29). 3.60 (IH. bM. H-17). 4,19 (IH.rf.J=8.0 Hz. H-9). 4.73 (IH, £W. J=5.5 Hz. H-13). 5.64 (IH.rf.J=7.2 Hz. H-6). 7.43 (2H. r. J=7.1 Hz. H-25. 27). 7.53 (2H. /, J=7.1 Hz, H-26), 8.05 (2H. dSrf. J=7.0. 1.4 Hz, H-24. 28). 0.87 (IH, m. H-9). 1.00 (3H. 5. H.18). 1.05 (each, IH,m, H-13J, 1.07-1.32(2H. m, H.2), 1.18 (IH, bw, H.5). 1.22 (2H. m. H-3). 1.36(cach lH.m.H-7',). 1.42(2H.m.H-1'), 1.43-1.50(2H.m.H-11). 1.48 (each IH. m. H7b). 1.52 (each IH. m, H-13.), 2.00 (IH. m. H.12). 3.30 IH. br5. H-20). 3.82 (2H. AB. 1=12.0 Hz. H-17). 4.98 (IH. br5, H-15). 7.32 (2H.rf.J=2.5 Hz. H-19). '•^C Chemical Shift Assignments (CDCI3) C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-U C-12 C-2' C-14 C-15

82.3 d 26.71 36.31 34.7 s 55.9 d 74.0 d 44.7 d 78.7 s 48.2 d 43.0 d 48.8 s 29.21 27.41 173.2 s 31.2t

C-16 C-17 C-18 C.19 C-20 C.21 C-22 C-23 C-24,28 C-25.27 C-26 C-29

c-r C.2' C.3'

29.71 62.9 d 25.9 q 57.41 48.81 13.5 q 166.6 s 130.8 s 130.2 d 128.2 d 132.3 d 55.0 q 30.5 t 27.411 30.61

C-4' C.5' C-6' C-7' C-8' C-9' C-10'

c-ir C-12' C-13' C-14' C-15' C-IT C-18' C-19' C-20'

45,0 s 44.3 d 20.61 31.51 43.1 s 46.4 d 44.9 s 28.41 31.5 d 42.81 72.5 s 127.8 d 60.41 19.0q 169.2 d 80.3 d

BS Joshi, Y Bai, DH Chen and SW Pelletier, Tetrahedron Lett., 34.7525 (1993).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

382

C,oH.7N04; MW 345.1939; mp 310-315 ** (dec.)' Aconitiun tanguticum 'H N M R (DJO + 3 drop of CD3OD): 6 1.76 (IH. dd, J,5. ,„ = 15.4 Hz, J,3 234.1 Hz, H.I3), 2.97 ( H i bfi/. J,^ ,3 = 15.4 Hz, J,„. ^ 1.7 Hz. H-1 J . 4.21 (IH, bi.f, W,/2 = 10.4, H-20), 1.62 (IH. dd. J,3.,« 15.4 Hz. J^p 23= 4.3 Hz, H-33). l.92(lH.brJ.J^33= 15.4 Hz, J3„,,„= 1.7 Hz, J3^2 = 2.1Hz,H-3„).2.19(lH,5, W,^ = 4.0 Hz, H-5), 4.05 (IH, br^, W,^ = 6.8 Hz, H-6), 1.77 (IH, brc/, J73 ,„= 15.3 Hz, H-73), 2.10 (IH, dd, J73.7a= 15.3 Hz. ^ 6 = 3.4 Hz, H-7J, 2.31 (IH, d, J^, ,,3= 8.8 Hz. H-9), 4.33 (IH. J, J„3 9 8.8 Hz, i„3 ,33= 1.8 Hz, J„3, ,2<1.0 Hz, H-l I3). 2.55 (IH. d. J,2 ,30= 3.0 Hz. J,2, „3<1.0 Hz, H-12). 4.05 (IH. bw. W,;2= 6.8 HA H.I33). 2.26 (IH. AB. J.„„ = 18.1 Hz, H-I53). 2.06 (IH. AB. J^„= 18.1 Hz,H-15„),4.99(lH,bw, W,;2=7.0Hz, H-17,), 4.78 (IH, bw, H-17j,), 1.16 (3H, 5. H.18). 3.01 (IH. J. J ^ = 11.6 Hz. H-I93). 3-74 (IH. d. J ^ = 11.6 Hz. H-19^.4.50(IH. 5. W,^ = 3.9 Hz, H-20).

'^C Chemical Shift Assignments (DjO + CD3OD) C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

33.21 66.7 d 38.lt 36.4 s 57.4 d 66.0 d 30.3 t 44.9 s 53.7 d 46.9 s

C-11 C-12 C-13 C-M C-15 C-16 C-17 C-18 C.19 C-20

74.6 d 51.7 d 81.8 d 81.4 s 30.41 145.2 s 109.61 29.2 q 60.01 70.3 d

BS Joshi, DH Chen, X Zhang, JK Snyder and SW Pelletier. Heterocycles, 32,1793 (1991).

383

Carboii-13 and Proton NMR Shift Assignments TATSIRINE

HQ

C20H27NO3; MW 329; mp 260-263° Delphinium tatsienense Franch 'H NMR ( C A N ) ; 8 1.55 (3H, j . H-IS), 4.72. 4.85 (each lH;bw,H-17)

HO.

^MeOH

X Zhang, JK Synder, BS Joshi, JA Glinski and SW Pelletier, Heterocycles, 31,1879 (1990)

384

B JS. Joshi, S.W. Pelletier and S.K. Srivastava

2,11, 13, 14-0-TETRAACETYLTANGUnSINE Cj8H35NO,;MW513; Prepared from tangutisine ' H N M R (CDCI,): 6 1.00 (3H, 5. H-18). 2.04,

2.08,2.12,2.12 (each 3H, 5. OAc), 2.46,2.90 (each 1H, AB, J= 13 Hz), 3.30 (1H, brj, W,^ =7 Hz), 4.25 (1H, j,H-20), 4.83,5.05 (each IH', s, H-17). 5.03-5.16 (3H, m. H.2, H-l 1, H-13).

BS Joshi. DH Chem, X Zhang, JK Snyder and SW Pelletier. Heterocycles, 32,1793 (1991).

Carbon-13 and Proton NMR Shift Assignments

385

2,11.13,19-O'TETRAACETYLVAKHMATINE CigHssNOg; MW 513.2364 AoO. Prepared from vakhmatine «H NMR (CDCl,): 6 0.92 (3H, 5, H-18). 1.51 (lH.£/
AoO

OAc

C-1 C-2 C-3 C-4 C-5 C-6 C.7 C-8 C-9 C-10 C-11

29.4 69.3 35.7 .43.2 61.2 62.2 35.2 44.3 52.7 50.2 75.3

"C Chemical Shift Assignments C-12 C-13 C-14 C-15 C.16 C-17 C-18 C-19 C-20 OCOCH, OCOCH,

QP Jiang and SW Pcllctier, / Nat, Prod,, 54,525 (1991).

44.7 72.7 50.0 33.6 142.7 110.2 21.8 92.6 65.7 169.8,170.1, 170.3. 170.7 21.3, 21.6.20.7.20.9

386

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

TETRAHYDROUNCINATINE C22H37NO3

Prepared from uncinatine *H NMR: 8 1.12 (J, J=7 Hz, CH3-I7).

HC

C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-U

36.5 20.2 41.4 34.1 45.0 20.1 69.4 46.0 40.0 42.9 28.9

Chemical Shift Assignments C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 C-22

36.6 28.4 25.0 70.9 49.5 11.2 25.6 60.3 64.2 58.2 60.6

A. Ulubelcn, M Arafan, U Sonmez, AH Meri9li and F Merigli, Phytochemistry, 47, 1141(1998).

Carboii-13 and Proton NMR Shift Assignments

387

C22H,7N04; MW 369; mp 213-216'' [a]jy + in'^CCHCIj)'-^ Tfialictrum sessile Hayata'-^ *H NMR(CHCI,)'-^ 8 1.50 (3H. s, H-18), 2.85 (IH. f, 1=5.12 Hz, H-22). 3.45 (IH. ddd, J=14.16, 5.13, 3.41 Hz. H-2la), 3.62 (IH. ddd, J=14.I6,8.05,3.41 Hz,H-21b),3.78(lH,m, H22a), 3.88 (IH, m, H-22b), 4.85 (IH,
"C Chemical Shift Assignments (CHClj)*'^ C-1 C-2 C-3 C-4 C-5

39.81 20.61 34.21 46.5 60.0

C-12 C-13 C-14 C-15 C-16

63.7 d 33.31 47.0 d 35.11 141.9 s

C-6

207.6* s

C-17

lll.lt

C-7 C-8 C-9 C-10 C-11

51.51 43.9 s 75.6 42.9 208.9 s

C-18 C-19 C-20 C-21 C-22

25.5 q 177.1s 53.9 d 49.61 60.91

'Assignments may be interchanged

1. 2.

YC Wu, TS Wu, M Niwa. ST Lu and Y Hirata. Phytochemistry, 27.3949 (1988). YC Wu, TS Wu. M Niwa. ST Lu and Y Hirata. Heterocycles, 26,943 (1987).

388

B^, Joshi, S.W. Pelletier and S.K. Srivastava

THALICSILINE C24H35NO5; MW 417-2481; mp 183-186*' ^^ [aJo 4- 11.4*^ (McOH)'-^ Thalictrwn sessile Hayata^'^ 'HNMR(CHCIJ)*'^: 50.94. l.ll (3H, 5, H-18), 1.30, 1.31 (3H, 5, H-17), 2.05 and 2.06 (3H. 5. OCOC//5), 3.00-4.10 (5H, m, H-19, 21. 22), 3.86 {R), 4.11 (5) (IH. 5, H-19 ratio 3:1), 4.584.82 (IH, 5. H-20), 5.32, 5.67 (IH, d, J=2.40 Hz,H-6).

Me OAc

X-ray structure^

'^C Chemical Shift Assignments {CHO^y^ C-1 C.2 C-3 C-4 C-5 C-6 C.7 C-8 €-9 C-10 C-11 C-12

1. 2.

40.51 22.71 47.21 35-21 52.2 d 70.8 d 70.9 d 36.3 s 42.5 d 35.3 s 29.01 38.3 d

C-13 C.14 C-15 C-16 C-17 €-18 C-19 C-20 C-2I C-22 COCH3 COCH,

26.71 23.51 20.21 73.8 s 30.2 q 22.6 q 94.6 d 85.6 d 51.lt 63.31 169.7 s 21.4 q

YC Wu, TS Wu, M Niwa, ST Lu and Y Hirata. Phytochemistry, 27,3949 (1988). YC Wu, TS Wu, M Niwa, ST U , Y Hirata, DR McPhail, AT McPhail and KH Lee, Heterocycles, 27,1813 (1988).

Carbon-13 and Proton NMR Shift Assignments

389

TOROKONINE (GOMANDO BASE I) C27H„N05; MW 449.22341; mp 198.5-199** [a]o + 71.7^ (McOH) Aconitum suhcuneatwn Nakat 'H NMR (CD3OD): 8 1.11 (3H, s. H-18), 2.96 (1H, 5. H-20X 2.60 and 3.11 (each 1H,
C Chemical Shift Assignments (CDCI3) C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-ll C-12

28.9 70.2 39.2 35.4 51.5 69.764.3* 48.9* 79.6 49.8 36.9 34.6

C-13 C-14 €-15 C-16 C-17 €-18 C-19 C-20 AiCO

cr

C-2', 6' C-3'.5* C-4'

32.7 36.0" 66.6* 153.6 110.5 29.3 62.2 73.3 169.9 130.1 129.4 128.8 133.3

^ Assignments may be interchanged

S Sakai, T Okazaki, K Yamaguchi, H Takayama and N Aimi, Chem. Pharm. Bull., 35,2615 (1987).

B JS. Joshi, S.W. Pelletier and S.K. Srivastava

390 M 2 , I5-0-TRIACETYLUCICUL1NE OAC

C2«H39N06; MW 485; mp 153.!58"'-^ Prepared from lucidusculine •H N M R (CDCl,)l- 5 5.49 and 5.27 (each IH, .V), 5.03, (IH, (Id, J=11.0, 7.0 Hz), 5.00 (IH, 5,), 4.48 (IH, m\ 2.12, 2.06 and 2.02 (each 3H, s\ 1.08 (3H, /, J=7.0 Hz) and 0.73 [(3H, 5, H-18), 1.08 (3H, r, J=7 Hz, H-22), 2.02, 2.06, 2.12 (each 3H, 5, OAc), 4.48 (IH, m. ), 5.00 (IH, 5, ), 5.03 (IH, dd, J=n.7 Hz), 5.27,5.49 (each IH, 5,H-I7)]. '^C Chemical Shift Assignments'

1.

2. 3.

C-I C-2 03 C-4 C-5 C-6 C-7 C-8 C.9 C-10 C-ll

74.1 26.8 37.7 34.3 50.1 23.3 44.3 48.9 37.7 50.1 25.4

C.13 C-H C-15 C-16 C-17 C-18 C-I9 C-20 C-21 C-22 COCH3

C-I2

77.1

COCH3

45.0 29.1 76.9 151.6 111.2 25.8 57.1 65.1 50.6 13.4 170.1 21.2,21.6,21.8

H Takayama, A Tokita, M Ilo, S Sakai, F Kurosaki and T Okamoto, Yakugaku Zasshi, 102, 245, (1982); H Suginome, S Kakimoto, and J Sonoda, J. Fac. Sci. Hokkaido Univ. Ser. Ill Chem. Vol. IV, 25 (\950) H Bando, K Wada. T Amiya, K Kobayashi, Y Fujimolo and T Sakurai. Heterocycles, 26, 2623 (1987). K Wada, H Bando, T Amiya and N Kawahara, Heterocydes, 29,2141 (1989).

Carbon-13 and Proton NMR Shift Assignments

391

2,11, 13-TRI-O-ACETYLHETISINE CacHj^NOft. MW 455; amorphous

AcO,^ AcO.^

Prepared from hetisine

|>

' H NMR (CDCI3): 8 1.00 (3H, 5. H-18), 2.06, 2.10, 2.12 (each 3H, 5, -OAc). 3.80 (IH, s, H20). 4.85, 5.00 (each IH, brj, H-17), 5.14. 5.25 (each IH, br^, H.2p, H--11^ H-13p).

ACQ

'^C Chemical Shift Assignments (CDCI3)

C-10

29.6 70.1 36.5 36.6 61.1 64.2 36.1 44.1 53.1 50.4

C-12 C-13 C-14 C-15 C-16 C-17 C-IS C-19 C-20 COCH3

44.9 73,2 50.2 34.0 143.3 110.0 29.8 63.6 68.7 170.6.170.2,170.1

C-U

75.7

COCH3

21.9,21.6,21.1

C-1 C-2 C-3 C-4

C-5 C-6 C.7 C-8 C-9

J A Glinski, BS Joshi. QP Jiang and SW Pelletier, Heterocycles, 27.185 (1988).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

392 \a. 19-TRI-O-ACETYLSEPTENTRIOSINE

C26H3,N07; MW 471; mp 210.5-212.5'' Prepared from 2-acetylseptentiosine ACQ

'H N M R (CDCI3): 5 0.97 (3H, 5, H-18). 2.07, 2.10,2.13 (each 3H, s, OAc). 2.52 (IH. s, H-?). 3.08 (IH, J, H-20), 3.55 (IH, j , H-6), 4.58, 4.75 (each IH, j . H-17), 5.04 (IH. q, J=4.7 Hz, H-2), 5.30(1H,5,H-1).5.55(1H,5,H-19).

Aca

'^C Chemical Shift Assignments (CDCI3) C-1 C-2 C-3 C-4 C-5 C.6 C-7 C-8 C-9

69.5 70.9 39.2 42.4 52.0 62.7 30.7 42.4 79.2

C-12 C-13 C-14 C-I5 C-16 C-17 C-18 C-19 C-20

35.9 32.6 43.8 30.7 150.1 104.8 21.6 92.3 68.9

C-10

53.3

OCOCH3 170.2,169.2,169.0

C-11

33.4

OCOCH3

21.3.21.1,20.8

SA Ross, BS Joshi, SW Pelletier, MG Newton and AJ Aasen, / Nat Prod., 56.424 (1993).

Carbon-13 and Proton NMR Shift Assignments 2,3,13-0 -TRIACETYLVAKHM ADINE AcO.

393

C27H35NO7; MW 485; mp 261-262'' [a]^-37.8°(MeOH) Aconitum palmatum, Don

AcO.

'H NMR (CDCI3): 6 1.48 (3H, 5, H-18), 1.63 (IH.m, H-lip)/l.67 (IH, J. J=I5.3 Hz), 1.68 AcO' (IH, J. H-5), 1.76 (IH, br^, J=I0.7 Hz, H-9), 2.00,2.07, 2.08 (each 3H, 5. OAc), 2.11 (IH, 1/, J=12Hz,H.lla), 2.12(!H,
"C Chemical Shift Assignments (CDCI3) C-l C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-n

33.7 67.9 75.8 41.3 57,8 202.4 51,2 41.4 49.3 43.9 23.5

C-12 C-l 3 C-14 C-l 5 C.16 C-17 C-l 8 C-I9 C-20 C-21 COCH3

39.7 74.6 51.3 35.2 146.6 107.0 25.5 57.2 65.7 43.2 170.2,169.4,169.8

COCH3

21.3.20.7,20.9

QP Jiang and SW Pelletier, 7. Nat Prod., 54,525 (1991).

B.$. Joshi, S.W. Pelletier and S.K. Srivastava

394 2,11, 13-0-TRIACETM.VAKHMATINE

C26H33N07;MW 471; amorphous .

Aca ACQ..

b

Prepared from vakhmatine 'H N M R (CDC!,): 5 1.02 (3H, 5, H-18), 2.03. (6H, 5,2x OAc), 2.04 (3H,.?, OAc), 2.57 (IH, d, J=2.6 Hz, H-12), 2.83 (IH, J, J=I5.3 Hz, Hl(i), 3.54, (IH, 5, H-20), 3.60 (IH, bw. H-6), 4.63 (IH. s, H-I9), 4.80, 4.98 (each IH. bw, Hl7),5.IO(IH,£/,J=8.6Hz. H-Ilp), 5.13(1H, J, J=9.0 Hz, H-I3P), 5.15 (IH, brm, Wl/2=I2.0 Hz, H-2p).

AcO,

C-1 C.2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-IO C-11

"C Chemical Shift Assignments (CDCl,) C-12 44.8 29.8 73.3 C-13 69.8 C-14 35.4 49.9 C-15 42.5 33.9 143.0 61.4 C-16 110.2 C-17 60.7 C-18 22.2 35.5 91.4 C-19 44.8 65.0 €-20 52.9 COCH3 169.7, 169.7. 170.5 50.4 COCH, 21.0,21.4,21.7 75.7

QP Jiang and SW Pelletier, / Nat. Prod., 54,525 (1991).

Carbon-13 and Proton NMR Shift Assignments

395

TURPELLINE C22Hv,N04; MW 375.24095; mp 268-271" Aconitimi turczoniuowii 'H NMR: 8 0.62 (3H, s, H-18), 1.05 (IH. dd, J= 12.1,4.4 Hz, H-14.), 1.16(lH,m, H-3J, 1.34 (IH, dd, J=4.5. 3.5 Hz, H-6,). 1.36 (IH. m, H3,), 1.37 (3H, m, J=7.4 Hz, H-22), 1.56 (IH, brt/, J=7.9 Hz, H-5), 2.01 (IH, m, H-2). 2.09 (1H,^,J=I2.1 Hz, H I 4^), 2.23 (IH,£/, J=5 Hz, H-7). 2.31 (IH, J, J=10.3 Hz, H-9), 2.45 (br^, J=13.5 Hz. H-19,).2.81 (IH, brJ, J=4.4 Hz, H-13), 2.86(2H, w, H-21), 2.90 (IH, m, H2^). 2.90(IH, m, H-19b). 3.23 (IH.dd, J=8.3. 3.5 Hz, HW 3.90 (IH, br^, J=7.5 Hz, H-12), 3.98 (IH. brs. H-20). 4.45 (IH. r, J=2.4 Hz, H-15). 4.58 (IH. dd, J=7.1. 12.2 Hz, H I ) , 4.82 (IH, dd, J=7.8.10.3 Hz. H-l 1). 5.16 (IH. J. J=2 Hz, H-17,). 5.32 (IH, bw, H-17.).

C-l C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

68.9 30.2 31.2 36.8 48.4 23.6 45.8 55.2 46.8 55.5 73.5

'^C Chemical Shift Assignments C-12 C-13 C-14 C-15 C-16 C-17 C-l 8 C-19 C-20 C-21 C-22

82.7 46.8 37.2 77.4 158.6 109.8 25.6 59.2 66.8 51.5 10.7

N. Batbaryar. D Batsuren. AA Scmenov and MN Sultankhodzhaev, Khim. Prior Socdin.. 740 (1993).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

396 UNCINATINE

C22H33NO3; amorphous; MW 359.2445 Delphinium uncinatum Hook f. and Thomas *H NMR: 5 1.07 (3H, s, H-18), 1.20 (IH, M J=:3,12. H2 H-2p). 1.24 (IH,dd, J=2, 12, H2 H6J. 1.50 (IH. m. H-II3). 1.60 (IH. m. H^^). 1.70 (IH, m, H-1 J . 1.72 (IH. dd, J=2, 14. H5,j). 1.80 (IH. ddd, J=3, 10. 12, H-2J. 1.8 (IH. III. H-13J, 1.87 (IH, dd, 5, 14, H-3„). 1.90 (m, H-14).2.00(J^.3, 12,H-11J, 2.05(m,H-13p),2.10(JtW,5,12,14,H-3p),2.20(J,3,H-9),2.40(^,3. H-12J, 2.8 (brJ, 14, H-lp), 3.45 {d, 10, H-19p), 3.60 (J, 10, H.19„). 3.90 (^, 5, H-7p), 4.15 (J, 12, H.20), 4.20 (J, 3, H.15^. 5.02 (bw, H-17^,). 5.12 (bw. H-17p), 6.75 (d, 8,5, H-22). 7.08 (d, 8,5, H-21).

C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11

'^C Chemical Shift Assigmnents 35.41 C-12 19.51 C-13 41.61 C.14 34.1s C-15 44.2 d C-16 20.01 C-17 68.8 d C-18 46.9 s C-19 40.4 d C-20 43.5 s C-21 28.91 C-22

36.7 d 28.51 24.81 70.8 d 155.8 s 110.5t 25.8 q 60.31 64.91 132.4 d 116.7d

A Ulubclen, M Arafan, U Sonmcz, AH Meri9li and F Mcri9li, Phytochemistry 47,1141 (1998).

Carboii-13 and Proton NMR Shift Assignments

397

VAKHMADINE C2,H3oNO/ OH"; MW 359.2091; mp 263.273* [alo -37.8**(McOH) Aconitum palmatum Don. ' H NMR (D2O): 61.40(3H. 5, H-18), 2.58 (3H, 5, H-21). 2.97. 4.05 (IH. each, d, J=U.7 Hz, H-19), 3.33 (IH, d, 5=4.3 Hz. H-3p), 3.93 (IH, d, J=I1.0 Hz. H-I3p). 3.97 (IH, brm, H2o), 4.22 (IH, 5, H-20), 4.59. 4.73 (each IH. 5. H-17).

"C Chemical Shift Assignments (DjO) C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-ll

30.0 69.3 73.5 40.6 58.9 105.0 40.1 41.5 45.3 45.2 21.4

C-12 C-13 C-14 C-15 C-16

c-n

C-18 C-19 C-20 C-21

QP Jiang and SW Pclleticr. /. Nat Prod., 54,525 (1991).

41.5 67.8 48.1 31.8 148.1 107.2 25.3 66.7 73.2 36.3

B.S. Joshi, S.W. Pellctier and S.K. Srivastava

398

C20H27NO4; MW 345; mp 170.5-174.5" la),5+I2.6*'(MeOH) Aconitum palmatum Don. 'H NMR (CD3OD): 6 1.04 (3H. 5, H-18), 1.55 (IH. dd, J,=15.2, J2=4.8 Hz, H-33), 1.91 (IH. dd, J,=9.0. J,=2.0 Hz. H-9). 1.99. 2.25 (each IH. brJ. J=17*'.7 Hz, H-IS). 2.12 (IH.dd, J,=9.3. J2=1.8 Hz. H-14). 2.35 (IH. J. J=2.6 Hz. H-12). 3.00(IH. brJ, J=15.3 Hz, H-IJ, 3.38 (IH. bw, H-6). 4.02 (IH. brm. H-23). 4.11 (IH, d^, J,=9.3, J2=2.3Hz.H-13p).4.18(lH.5.H-19).4.22(lH. d, J=9.1 Hz, H-II3). 4.67. 4.84 (each IH. bw. 2H-17)

"C Chemical Shift Assignments (CD3OD) C-l C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

35.1 62.9 38.5 42.4 60.6 61.6 36.8 45.3 56.8 51.5

C-11 C-l 2 C-l 3 C-l 4 C-l 5 C-16 C-l 7 C-l 8 C-l 9 C-20

QP Jiang and SW Pellctier. J. Nat Prod, 54.525 (1991).

76.9 52.4 73.0 53.2 34.5 148.2 107.6 27.5 95.5 66.1

Carbon-13 and Proton NMR Shift Assignments

399

VAKOGNAVINE C34H,7NO,o; MW 298" 1.3 Aconitum palmatum Don

'H NMR (CDCl,):'-^-' 6 1.05 (3H, 5, H-18), 2.01» 2.03, 2.13 (each 3H, .v, 3xCOCH,), 2.27 (3H, 5, H-21), 3.13 (IH. brr, H-6), 3.84 (IH, .v, H-20), 5.24 and 5.37 (each !H, brj. H-17), 5.40 (JH, d, J=3.2 Hz, H-l„), 5.46 (IH, .v, H-15,,), 5.56 (IH, d, J=8.8 Hz, H I Ip), 5.69 (I H, brm, W,^=I2.0 Hz, H-2.), 7.43 (2H, /, J=7.5 Hz, ArH), 7.55 (IH, f. J=7.3 Hz, Ar-H), 7.90 (2H, J, J=7.8 Hz, Ar-H), 9.27 (IH, s, H-19). X-ray structure^

C-I C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-IO C-11 C-12 C-13 C-14

1. 2. 3.

70.5 67.2 29.3 44.2 59.9 57.1 28.3 48.3 50.7 56.8 70.5 58.7 206.0 51.7

mgnments (CDCI,)* C-15 C-16 C-17 C-18 C-I9 C-20 C-21 COCH3 COCH3 Ar-CO

c-r

C-2',6' c-3', 5' C-4'

71.3 137.5 120.7 26.6 195.9 66.5 33.1 169.3, 170.7,170.7 21.2,21.2,21.5 165.3 129.6 129.6 128.6 133.3

QP Jiang and SW Pelletier, Tetrahedron Lett., 29,1875 (1988). SW Pelletier, KN Iyer, LH Wright and MG Newton and N Singh. / Am Chem. Soc, 93, 5942(1971). N Singh and SS Jaiswal, Tetrahedron Lett., 2219 (1968).

400

B^. Joshi, S.W. Pelletier and S.K. Srivastava

C22H33N02;mp 125.5-128.5° [a]D- 67.5%CHCl3) Garrya veatchine Kellogg ^H NMR (CDCI3/: 8 0.77. 0.82 (3H, 5, H-18), 3.65, 3.95 (2H. m, H-22). 4.28 (IH, 5, H-20), 5.08 and 5.21 (each IH, br5,W,/2=4.5Hz,H-17). X-ray structure'2.3 ^^C Chemical Shift Assignments {CDCI3)* ^'^

C-1 C-2 C.3 C-4 C-5 C.6 C-7 C-8 C-9 C-10 C-U

A 41.7 18.6 37.1 34.1 52.8 18.2 33.9 47.3 51.6 40.6 22.7

B 41.3 19.2 37.1 34.1 52.3 17.4 33.9 47.5 51.1 40.3 21.8

C-12 C-13 C-14 C-15 C-16 C-17 C-18 C.19 C.20 C.21 C.22

A 31.2 42.4 35.1 82.5 160.7 107.4 25.9 56.4 92.6 50.2 64.3

B 30.3 42.4 35.1 84.3 161.2 107.8 26.4 55.9 93.3 49.8 58.8

*A and B are H-20 epimers

1. 2. 3. 4. 5. 6.

K Weisner, SK Figdor, MF Barlett and DR Henderson, Can. J. Chem,, 30,608 (1952). WH Decamp and SW Pelletier. Science, 198.726 (1978). SW Pelletier, WH Decamp and NV Mody, J. Am. Chem. Soc, 100. 7976 (1978). SW Pelletier and TN Oeltmann, Tetrahedron, 24,2019 (1968). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978). SW Pelletier and NV Mody. J. Am. Chem. Soc, 99,284 (1977).

Carbon-13 and Proton NMR Shift Assignments

401

VEATCHINE-Ar. 20-AZOMETHINE C2oH29NO;mp 186-188^ [aJo -109.7° (CHCI3) Prepared from veatchine'

'^C Chemical Shift Assignments ^ C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-IO

1. 2.

42.3 18.3 34.9 32.9 49.7 18.3 32.9 47.3 49.7 45.5

C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20

SW Pclletier and DM Loche. /. Am. ChemSoc, 87.761 (1965). NV Mody and SW Pelletier, Tetrahedron, 34,2421 (1978).

20.9 32.9 42.3 34.6 80.6 159.7 107.9 26.0 58.9 165.8

402

BJS. Joshi, S.W. Pelletier and S.K. Srivastava

VENUDELPHINE AcO.

C26H3,NO^,;MW 455.2316 Delphinium venulosum Boiss. 'H N M R (CDCI,): 6 1.05 (3H. 5, H-18), 1.98

(3H, s. OAc). 2.01 (3H, .v, OAc), 2.09 (3H, j . OAc), 2.45 (IH. buL J=10 Hz. H-M). 2.55. 2.82 (each IH. brJ, J=:14 Hz, H-19). 3.32 (IH. brs, H-6), 3.86 (IH. s, H-20), 4.82 (IH. brj. H-17). 4.99 (IH. brs. H-17). 5.07 (IH. du J=10.0. 1.5 Hz. H-13p). 5.31(1 H. dd, J=3.5 and 5.00 Hz, H2p).5.72(lH.J.J=3.5Hz.H-l„).

Aca

C-1 C-2 C-3 C-4 C-5 C-6 C-7 C.8 C-9 C-10

C Chemical Shift Assigmnents (CDCI3) 73.1 d C-11 29.21 49.4 d 71.1 d C-12 74.9 d 36.71 C-13 51.6d 37.4 s C-14 34.lt 54.7 d C-15 142.1 s 67.1 d C-16 110.6t 35.71 C-17 29.2 q 43.9 s C-18 64.lt 63.2 C-19 60.3 d 52.2 s C-20 COCH3 COCH,

170.8.169.9. 169.7 s 21.0.21.2,21.5 q

A Ulubelcn. AH Men?!! and F Mcri^li, / Nat. Prod., 56.780 (1993).

403

Carbon-13 and Proton NMR Shift Assignments VENULOL C2oH27N02;MW 313.2013 HO^.

[a]p + 19.7^ (MeOH) Delphinium venulosum Boiss. 'H NMR (CDCI3-CD3OD): 81.37(3H, s, H18), 2.03 (3H, 5), 2.07 (3H, s\ 2.30 (IH, d, J=4.5 Hz, H-9), 2.50 (IH, br^, J=4.6 Hz, H-12), 2.86, 3.28 (each IH, e/, J=12.5 Hz, H-19), 3.97 (IH. d, J=4.5 Hz, H-11), 4.70, 4.71 (each IH, bw,H-l7).

^MeOH

'^C Chemical Shift Assignments (CDCIj) C-1 C-2 C-3 C>4 C-5 C-6 C-7 C-8 C-9 C-10

30.2 19.6 38.6 42.3 59.4 102.2 35.9 43.2 42.9 57.9

C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20

72.6 42.8 27,3 47.7 36.1 146.3 109.8 29.2 59.8 68.1

A Ulubelen, AH Mcri^li, F Meri^li, R Ilarslan and SA Matlin, Phytochemistry, 31. 3239 (1992).

B JS. Joshi, S.W. Pelletier and S.K. Srivastava

404 VENULUSON

C2oH25N03;MW 327.1819

HO.

[alo + 27.3* (McOH) Delphinium venulosum Boiss. 'H N M R (CDOJ): 5 1.02 (3H. 5, H-18), 2.03 (3H, s\ 2.75 (1H;^, 1=9 Hz, H-14), 3.10 (IH, 5,

H-20), 4.05 (IH, bnv» H-15), 4.20 (IH. J=9 Hz. H-13). 4.71 (each IH. bw. H-17).

' C Chemical Shift Assignments (CDCI3) C-l C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

31.5

C-11

27.8

212.5 41.5 42.7 59.9 63.7 35.7 44.2 45.1 60.7

C-12 C-13 C-14 C-15 C-16 C-17 C-l 8 C-19 C-20

42.1 70.1 49.6 75.4 155.3 109.3 28.7 60.7 70.2

A Ulubelen, AH Meri^li, F Meri^li, R Ilarslan and SA Matlin, Phytochemistry, 31,3239 (1992).

Carbon-13 and Proton NMR Shift Assignments

405

15-VER ATRO YLPSEUDOKOBUSINE C29H35NO6; MW 493.2463; amorphous [alo - 6.7** (EtOH) Aconitum yesoense var, macroyesoense (Nakai) Tamura.

Me

'H NMR (CDCI3): 6 1.35 (3H. 5. H-18), 3.92, 3.94 (each 3H, 5, OMe), 4.06 (IH,
H Bando. K Wada, T Amiya, K Kobashi. Y Fujimoto and T Sakurai. Heterocycles, 26, 2623 (1987).

406

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

VILMORRIANONE C23H27NO5; MW 397; mp 253-255f> [ a b -1220{Mc0H) Aconitum vilmorrianum Kom.' Delphinium denudatum Wall^ >H NMR (CDCI3)*: 5 1.42 (3H, 5, H-18), 2.08 (3H, .V, OAc), 2.28 (3H, 5, H-21), 2.43, 2.83 (each IH. J, J=12 Hz, H-15), 2.53, 3.11 (each IH, bxd, J=20 Hz, H-19), 2.96 (IH, d, J=2 Hz, H-20), 3.00 (IH, 5, H-5), 4.96, 5.06 (each HI, brj,H-17),5.23(lH,m,H.2).

'MeO

X-ray Struclurc''^

"C Chemical Shift Assignments (CDCb)' C-l C-2 C-3 C-4 C-5 C-6 C-? C-8 C-9 C-10 C-11

35.lt 67.9 d 42.61 54.1s 64.1 d 187.0 s 192.9 s 44.5 s 47.4 d 40.0 s 22.41

C-12 C-13 C-14 C-l 5 C-16 C'M C-18 C-19 C-20 C-21 OCOCH3

52.0 d 208.3 s 58.8 d 27.81 140.1 s 112.71 31.0q 60.71 69.0 d 41.9 q 169.6 s

OCOCH3 21.5 q

1. 2.

LS Ding, YZ Chen and FE Wu, Planta Med,, 57,275 (1991). A Rahman, A Nasrcen, F Akhtar, MS Shekham, J Clardy, M Parvez and MI Cloudhury, y. Nat. Prod., 60,472 (1997).

Carbon-13 and Proton NMR Shift Assignments

407

C25H35NO4; MW 413.2598; amoiphous CH2 Me23

! OCQC-CHaMe I

^MeOH

( H

[aJo -9.4%CDCl3)

Aconitum yesoense var. macroyesoense (Nakai) Tainurd 'H NMR (CDCI3): 80.91 (3H, /, J=7.3 Hz), 1.16 (3H. d. J=6.9 Hz). 1.34 (3H, s\ 4.00 (IH, d, J=4.6 Hz), 5.23 and 5.33 (each IH, s\ 5.59 (IH,5).

'^C Chemical Shift Assignments (CDCI3) C-1 C-2 C-3 C-4 C.5 C-6 C-7 C-8 C-9 C-10

37.7 s 100.0 s 44.8 s 49.9 s

C-11 C-12 C-13 C-H C-15 C-16 C-17 C-18 C-19 C-20 C-21

67.3 d 41.9 d

70.3 d 144.2 s 118.7t 30.0 q 58.41 72.3 d 175.8 s

(Not assigned) 60.0(d). 55.4(d). 41.3(d). 41.1(d). 40.4(d). 39.5(1), 35.3(t).28.0(t). 27.l(t), 26.8(0, 19.1(t), I6.6(q), 11.6(q).

K Wada, H Bando and N Kawahara, Heterocycles, 31.1081 (1990).

408

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

YESOLINE C3(,H37N06; MW 507-263; amorphous (a)p . 10.6*' (ElOH) Aconitum yesoense var. macroyesoense (Nakai) Tamura ' H NMR (CDCl,): 6 1.45 (3H. s\ 2.45 (3H, s\ 3.92 (3H. s\ 3.93 (3H. s\ 4.16 (IH, d, J=5.0 Hz). 5.23 (IH, s\ 5.41 (IH, s), 5.66 (IH. 5), 6.86 (IH. ^, J=8.6 Hz). 7.52 (IH. J. J=2-0 Hz). 7.59(lH,iW.J=2.0.8.6Hz).

C Chemical Shift Assignments (CDCI,) C-1 C-2 C-3 C-4 C-5 C-6

38.1s 203.1 s

C'l C'S

C-9 C-10 C-11 C-I2 C-13 C-14

C-14 C-15 C-16 C-17 018 C-19 C-20 C-21

c-r

c-2'

67.6 d

C-3' C-4' C-5' C-6'

70.9 d 144.5 s 117.lt 30.7 q 61.0 42.8 q 122.1 s 112.1 d 148.7 153.2 s 110.2 123.4 d

(Not assigned) 165.8 {s, C=0). 78.1(d). 60.5(d), 56.7(d). 55.9(q. 20Mc). 46.1(t), 45.2(s). 43.3(s). 42.7(d), 41.3(d). 40.3(t). 31.8(t). 31.4(t). 18.9(t).

K Wada, H Bando and T Amiya, Heterocycles, n, 1249 (1988).

Carboii-13 and Proton NMR Shift Assignments

409

YESONINE C21H29NOV MW 343.2152; amorphous Ia]D + 2.4* (EtOH) Aconitum yesoense var. macroyesoense (Kao) Tamura *H NMR (CHCI,): 6 1.47 (3H. s\ 2.46 (3H, 5), 3.95 (IH. 5), 4.08 (IH, J, J=5.0 Hz), 5.15 (IH,5),5.26(1H.5),

MeO

C Chemical Shift Assignments (CDCl,) C-1 C-2 C-3 C-4 €5 C-6 C-7 C-8 C-9 C-IO

37.9 s 191.2 s

C-ll C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21

67.5 d

69.1 d 149.1 s ll3.9t 30.6 q 60.4 d 41.3 q

(Not assigned) 77.6(d). 61.9(t). 60.4(d), 55.1(d), 45.3(s x 2 and 0, 41.2(d), 40.8(d), 39.3(0,31.2(t), 31.1(t),l8.7(t).

K Wada, H Bando, T Amiya and N Kawahara, Heterocycles, 29,2141 (1989).

B.S. Joshi, S.W. Pelletier and S.K. Srivastava

410 YESOXINE AcOs

C25H35NO6; MW 445-2444; mp 184" [alp - 37.5" (EiOH)

^r

Aconitiim yesoense var. macroyesoense (Nakai)' Tamiira, and ^4. dephinifolium DC. 'H N M R (CHCl,): 80.71 (3H, 5. H-18). 2.06 (6H, 5, OAcX 2.30 (3H, 5, H-21), 2.42, 3.10 (each IH, d^ J=4.9 Hz, H-17), 4.21 (IH, 5, H13),4.85 (IH, dd, J=8.3, 4.3 Hz, IM or H-15). 5.05 (IH, dd, J=10.9.6.3 Hz, H-1 or H-15). X-ray structure'

('^CNMR Chemical shifts; CDCl,) 170.7(s). 170.6(s), 70.3(d), 74.0(d). 71.4(d), 71.4(d), 69.0(d), 64.0(s), 59.1(1), 52.4(d), 48.2(s), 45.5(t), 43.3(s), 41.4(d), 41.0(d), 38.5(d), 37.9(t), 36.0(t), 33.5(s). 26.4(t), 25.6(q), 23.4(t), 22.9(t), 21.9(q)and21.3(q).

1. 2.

H Bando, K Wada, T Amiya, K Kobayashi, Y Fujimoto and T Sakurai, Heterocycles, 26, 2623(1987). P Kulanthainel and MN Benn, Phytochemistry, 27,3998 (1988).

Carboii-13 and Proton NMR Shift Assignments

411

ZERACONINE C3oH4i,N20; MW 444; mp 130-131" ^ Aconitum zeravschanicum Steinb.'

skyJar(^H2

/ \

Me 3"

'H NMR (CHClj): 8 0.90 (3H, s. H-18), 2.19 (6H, A\ H-3*\4");3.10 (IH. bis). 4.38 (2H. brs. H-17), 5.69 (IH, brs. H-15). 6.68 and 6.95 (each2H.£/,J=8.5Hz,Ar-H).

Me 4"

^C Chemical Shift Assignments (CDCI3) C'V C-2\6' C>3'. 5' C-4' C-1" C-2"

C-2 C-3 C-4 C-5 C-6

27.7 29.8 33.2 37.4 48.6 65.5

C-11 C-12 C-13 C-14 C-15 C-16

C-7

34.2*

C-17

69.0

C-3"

45.5

C-8 C-9 C'lO

50.0 31.2 44.

C-18 C-19 C.20

28.9 63.1 74.2

C-4"

45.5

C-l

34.2' 61.9 33.5 50.1 114.8 132.5

157.4 129.4 128.7 144.2 19.6 61.8

q: 28.9.45.5 (2c) t: 19.6,27.7.29.8, 33.2,33.5,34.2 (2c) (1:31.2,48.6.50.1,61.9,65.5 s: 37.4,44.9,50.0

1. 2.

ZM Vaisov and MS Yunusov, Khim, Phir. Soedin., 407 (1987). ZM Vaisov, BT Salimov and MS Yunusov, Khim, Prir. Soedin., 800 (1984).

B^. Joshi, S.W. Pelletier and S.K. Srivastava

412 ZERACONINE N-OXIDE

C30H40N2O2; MW 460; mp 94-95** Aconiium zeravschanicum Steinb. *H NMR (CHCI3): 5 0.93 (3H, s\ 3.14 {6H, s\ 4.42 (2H, bw), 5.72 (IH. bw), 6.73 and 7.03 (each 2H.^. 1=7.5 Hz).

ZM Vaisov and MS Yunusov, Khinu Phir, Soedin., 23.407 (1987).

Carbon-13 and Proton NMR Shift Assignments

413

ZERAVSHANISINE Cj^HjjNO^; amorphous; mp 287-289" (HCi04)

BzO., HO.

:>. . ^OHl

Aca

^CHg

Aconitum zeravschaniciun Steinb. ' H NMR (CHCI3): h 0.90 (3H, 5. H-18), 1.13 (3H.5, OAc). 2.40.2.67 (each IH,d. J=I2H2. H-19). 3.23 (IH, 5. H-20), 4.34 (IH. J, J=9Hz. IH-11),4.70,4.80(each IH, bw, H-17),5.15 (IH.m, H-2). 5.46 (IH. bw. H-13). 7.35-8.10 (5H.m.Ar-H) X-ray structure

BT Salimov, B Tashkhodacv, IM Yusupova, S V Li ndeman and T Struchkov, Khim, Priv. Soedin. 375 (1991).

415

Chapter Two

Supercritical Fluid Extraction of Allcaloids Jinwoong Kim and Young Hae Choi College of Pharmacy Seoul National University Seoul 151-742, Korea Ki-PungYoo Department of Chemical Engineering Sogang University Seoul 121-742, Korea

CONTENTS 1. 2. 3. 4.

Introduction Characteristics of Supercritical Fluids Applications of Supercritical Fluid Extraction for the Extraction of Alkaloids Supercritical Fluid Extraction of Alkaloids Using Basified Modifiers 4.1. Solubilities of the Alkaloidal Free Bases and Salts in Supercritical CO2 4.2. Modifying Effect of Methanol and Water on the Solubility of Alkaloidal Salts 4.3. Effect of Modifiers Basified with Diethylamine on the Solubility of Alkaloidal Salts 4.4. Effect of Modifiers on Desorption of Alkaloidal Salts from Matrix 4.5. Supercritical Fluid Extraction of Target AlkaloidsfromPlant Materials 5. Conclusions 6. Acknowledgement References

416 416 418 420 421 423 424 426 426 430 430 430

416

J. Kim, Y.H. Choi and K. Yoo

1. INTRODUCTION The first report on the characteristics of a supercritical phase, different from either a gas or a liquid, was made by Baron Cagniard de la Tour in 1822 [1]. He noted that the gas-liquid boundary disappeared when the temperature of certain materials was increased by heating them in a closed glass container. Even though the dissolving capacity of a supercritical fluid was known by 1879 to be determined by its density to a first approximation, the extraction of mixtures with supercritical fluids aroused little interest. The first workers to demonstrate the solvating power of supercritical fluids for solids were Hannay and Hogarth in 1879 [2]. In this experiment, the solubilities of cobalt (II) chloride, iron (III) chloride, potassium bromide, and potassium iodide in supercritical ethanol were measured. They found that the concentrations of the metal chlorides in supercritical ethanol were much higher than their vapor pressures alone would have predicted. Later, Buchner reported that the solubilities of certain nonvolatile organic materials in supercritical COj were also much higher than would be expected from vapor pressure considerations alone [3]. The historical aspect of supercritical fluid extraction (SFE) has been well reviewed in detail in the literature [4]. The promise shown by supercritical fluid extraction led to the development of the Solexol process for the purification and separation of vegetable and fish oils. This process concentrated the polyunsaturated triglycerides in vegetable oils and the "so-called vitamin A values'* from fish oils using propane as a selective solvent [5]. A significant development in supercritical fluid extraction was ZoseFs patent for decaffeination between 1964 and 1981, which reported a procedure for the decaffeination of coffee beans with COj [6-10]. Also, a number of patents of some food companies have been reported that concern the decaffeination of coffee [11]. The American Food Company, for example, has constructed an extraction vessel 7 fl in diameter and 70 fl tall for supercritical COj decaffeination of coffee at the Houston, Texas plant. The current annual U.S. market for decaffeinated coffee is $2-$3 billion [4]. Since 1980, there has been rapid development of SFE, for the extraction of fossil fuel and environmental samples such as pesticides, hydrocarbons, phenolics [12,13], food products including hops, fats and lipids from butter, perfumes and flavors from natural products [14], and oligomeric materials or additives from polymers [15]. Among these applications of SFE, extraction of natural products is one of the most widely investigated fields. In particular, alkaloids have been considered as target materials of SFE owing to their intensive and diverse bioactivity. In spite of much efforts by previous investigators, however, SFE is not recognized as an extraction method alternative to organic solvent extraction. The purpose of this chapter is to review the SFE method as an extraction technique for alkaloids emphasizing the usage of basic modifiers. 2. CHARACTERISTICS OF SUPERCRITICAL FLUIDS A supercritical fluid is in a state where matter is compressible and behaves as a gas (i.e., it fills and takes the shape of its container), which is not the case when it is in a liquid state (an incompressible fluid that occupies the bottom of its container). Moreover, a supercritical fluid has the typical density of a liquid (between 0.1 and 1.0 g/mL), which results in its characteristic dissolving power. Thus, a supercritical fluid can be defined as a heavy gas with a controllable dissolving power or as a form of matter in which the liquid and gaseous state are indistinguishable [16-18]. A typical phase diagram for a pure substance (Figure 1) shows the temperature and pressure regions where the substance occurs as a single phase, such as solid, liquid, or gas.

Supercritical Fluid Extraction of Alkaloids

417

Such regions arc bounded by curves indicating the coexistence of two phases, which are involved in sublimation, melting and vaporization equilibria, respectively. At a constant pressure, a phase transition takes place at a transition temperature. Phase transformations involve enthalpy changes. Thus, in the absence of external influences, two phases can coexist indefmitely at a transition temperature for each pressure. However, only one phase will be stable at such a pressure and at a temperature above or below the transition value. For example, the line that represents the pressure (P) and temperature (T) at which the liquid and gas phase coexist in equilibrium, known as the vapour pressure curve divides the P, T plane into two regions, namely, one in which the liquid is the stable phase and the other in which the gas prevails. The coexistence curve representing the equilibrium between two phases with a different internal symmetry tends to infinity or eventually intercepts another coexistence curve. This is not the case with the liquid-gas equilibrium since the vapour pressure curve suddenly breaks at a point called the critical point (CP), which can thus be defined as a point in the phase diagram designated by a critical temperature (Tc) and a critical pressure (Pc) above which (a) no liquefaction will take place on raising the pressure and (b) no gas will be formed on increasing the temperature. This latter property allows for a new definition of supercritical fluids: materials are above their critical pressure and temperature [4,16-18]. A supercritical fluid is thus a gas which has been heated above its critical temperature and simultaneously compressed above its critical pressure. Some properties of a liquid (e.g., density, viscosity) subjected to a pressure above its Pc change gradually as the temperature is raised; likewise, a gas which has been heated above its Tc becomes a supercritical fluid on gradually increasing the pressure.

Melting

Pressure

Solid

Pc Sublimation/ /

Supercritical Fluid

Liquid

i^"Zy

\ CP

VaporlzatioM

Gas

Temperature

Tc

Figure 1. Solid-liquid-gas-supercritical fluid phase diagram. TP' triple point, CP = critical point, Pc = critical pressure, Tc - critical temperature. The critical point is characteristic for a given substance. Table 1 lists the critical pressure and temperature for various solvents classified according to their chemical nature, as well as thefluiddensity at the critical point, which is called the critical density. Among the supercritical fluids used as solvents listed in Table 1, carbon dioxide has been utilized the most extensively for extracting phytochemicals from natural plants because it is nontoxic, environmentally acceptable, inexpensive, and its Tc and Pc are easily controlled compared with other solvents. Owing to the advantages of carbon dioxide, it has been widely used in SFE of natural products [19-21].

418

J. Kim, Y.H. Choi and K. Yoo

3. APPLICATION OF SUPERCRITICAL EXTRACTION OF ALKALOIDS

FLUID

EXTRACTION

FOR THE

Up until now, most of the published work on the SEE of natural products has been concerned primarily with nonpolar substances such as essential oils, lipids, flavor, and fragrance ingredients. However, recent reports have shown that some polar plant constituents (e.g. flavonoid glycosides, proteins, and steroidal glycosides) can be extracted by SEE as effectively as conventional organic solvent extraction. Examples of SEE applications for natural products are well reviewed in several literature sources [19-22]. Table 1. Features of selected solvents at the critical point. « . Acetone Acetonitrile Ammonia Benzene Carbon dioxide Diethyl ether Ethane Ethanol Ethylene Helium Hydrogen Isopropyl alcohol Methane Methanol /i-Butane /i-Hexane Nitrogen dioxide Nitrous oxide Propane Pyridine Tetrahydrofuran Toluene Water

Critical temperature (*C) 235 275 132.5 288.9 31.1 193.6 32.3 243.4

11 •268 -240 235.3

-82 239 152 234.2

158

36.5 96.7

347 267 319 374.2

Critical pressure (bar)

Critical density (g/mL)

47.0 47.0 109.8 98.7

0.28 0.25 0.23 0.30 0.47 0.27 0.20 0.28 0.20 0.07 0.03 0.27 0.17 0.27 0.23 0.23 0.27 0.45 0.22 0.31 0.32 0.29 0.32

72 63.8 47.6

72 50.5

2.2 12.6 47.6 46.0 78.9 70.6 28.9 98.7 70.6 42.4 56.3 50.5 41.1 214.8

Few, if any, classes of plant secondary metabolites have played a greater role in the evolution of organic chemistry than the alkaloids. The biological activities exhibited by many alkaloids ensured that the plants containing them were highlighted in folklore and herbal medicine and consequently many were of importance to man before any thought was given as to what it was that caused their bioactivity. Therefore, many alkaloids have been targeted as compounds of interest for SEE. Certain classes of alkaloids have been extensively investigated using SEE, while many others are yet to be investigated. In the 1970s when natural products were paid great attention as target materials for SEE, Stahl and Willing reported screening tests using SEE with direct TLC for alkaloid constituents of several plant genus, including .^reca, Atropa, Catharanthus, Colchicum, Conium, Ephedra, Ipecacuanha, Nicotiana, Opium, and Rauvolfia [23]. In this qualitative work, supercritical COj or N2O show the greatest utility as solvents for alkaloids [23]. However, caffeine is the most frequently examined alkaloid which has been extracted by SEE. Elisabeth et al. isolated

Supercritical Fluid Extraction of Alkaloids

419

caffeine from coffee powder using SFE and preparative supercritical fluid chromatography [24]. Sugiyama et al. reported on-line coupled SFE-SFC for the extraction and analysis of green coffee beans and extraction conditions such as pressure, temperature, water content and extraction time for caffeine extraction [25]. The optimum conditions were determined to be 20 MPa and 40 *"€ for 15 min with 20% of water content. Caffeine has also been extracted from kolanuts by supercritical COj [26]. With carbon dioxide at 60 "*€ and ca. 7 MPa (density of 0.160 g/mL) the extraction yield was found to be 53.7%, whereas with tetrahydrofuran and methanol the yields were 99.0% and 99.4%, respectively. The low SFE recovery was thought to be the comparatively low density of COj at the operating condition and low water content of dried samples before extraction. Schaeffer et al. successfully extracted monocrotaline, a hepatoxic pyrrolizidine alkaloid, from the seeds of Crotalaria spectahilis using supercrtical carbon dioxide with 5-10 % ethanol (mol/mol) at 10.34 MPa and 22.15 MPa and 35-55 'C. In order to improve the yield, they incorporated a cation-exchange resin trap after the SFE to selectively trap the alkaloids in preference to the co-extracted lipid material. The reported yield of monocrotaline using this technique increased to 95% [27]. Off-line SFE capillary GC analysis has been investigated for the isolation of pyrrolizidine alkaloids, including senecionine and seneciphylline, from two Senecio species, S. cordatus and S, inaequidens, SFE was performed on a home-made apparatus using carbon dioxide modified with methanol at 55 *C and 15 MPa. Compared with the Soxhlet extraction with methanol, SFE required a smaller amount of sample and gave a quicker extraction, a simplified fraction clean-up procedure, and a higher recovery [28]. Thebaine, codeine and morphine from poppy straw (Papaver somniferum) were extracted with carbon dioxide and various polar modifiers at 20 MPa and 40.5 °C. Kinetic extraction curves for morphine showed that 50% methanol in carbon dioxide was necessary in order to achieve quantitative yields in less than 20 min. A mixture of 25% methanol, 0.22% methylamihe and 0.34% water had the same effect as 50% methanol in the carbon dioxide. However, it was also reported that, in spite of its strong extraction power, the methylaminewater mixture had a major drawback in that morphine in the presence of the amine degraded in the presence of light. Hence, carbon dioxide-methanol-water mixtures were investigated: increasing the water content in the extraction fluid dramatically enhanced the extraction rate for thebaine [29]. The extraction of moist snuff {Nicotiana tabacum) has been investigated using supercritical carbon dioxide at 60 °C and 54.4 MPa over a 20 min period. A variety of compounds including nicotine were identified in the extracts by GC-FID and GC-MS. When 1.0 mL of methanol was directly added to the snuff before SFE, compounds such as benzyl alcohol, benzothiazole and cotinine were identified. These compounds were not present in extracts obtained using pure carbon dioxide [30]. Bugatti et al, used supercritical carbon dioxide in the extraction of the isoquinoline alkaloids, a-allocryptopine, califomidine, chelerythine, escolzine, 0-methylcariachine, protopine, and sanguinorine, from the aerial parts o( Eschscholtzia californica [31]. Extractions were performed at 40 °C using pressures from 8 to 30 MPa. A reversed-phase HPLC separation with UV photodiode detection was used for the identification of components in the SFE fraction. Paclitaxel, a diterpenoid alkaloid, has been extracted using supercritical COj or NjO [32-34]. Supercritical NjO modifred with 11.5% (mol/mol) of ethanol could recover about 100% of paclitaxel present in the barks of Taxus brevifolia, while pure or modified CO2 could extract below 50%. Regardless of the SFE yield of paclitaxel from plants, both the supercritical solvents could greatly improve the selectivity of paclitaxel in the extract than organic solvent extraction. The HPLC chromatograms of paclitaxel from the needles of T. ctispidata using supercritical CO2 and methanol are presented in Figure 2 (unpublished data obtained by the authors).

J. Kim, Y.H. Choi and K. Yoo

420

luJJLW A

B

Figure 2. HPLC chromatogram of paclitaxel from the needles of 7: cuspidata obtained by (A) supercritical COj and (B) methanol.*: paclitaxel. Of the useful supercritical fluids, CO2 has been most widely employed for the extraction of alkaloids, due to its low critical point, low toxicity, and chemical inertness. However, most alkaloids are too polar to be sufficiently extracted by pure CO2. Accordingly, a polar solvent such as methanol or water is required as a modifier in the SFE of alkaloids. In addition, other supercritical fluids such as NjO and CHF3 have been utilized for the purpose of enhancement of SFE efficiencies of alkaloids. For example, the extraction of a range of alkaloids from the plants in the family of Amaryllidaceae using modifled nitrous oxide instead of carbon dioxide has been reported [35]. Recently, ion-pairing reagent such as 1-heptanesulfonic acid was also used to enhance the recovery of pseudoephedrine from spiked sand or tablets [36]. However, these SFE methods for alkaloids have several problems including the limitation of adding percentage of modiflers, residual organic solvent in the flnal product, and the environmental hazard of the alternative supercritical solvents such as NjO and CHF3. These problems have led to development of another SFE method before it became universally accepted as an extraction method for alkaloids. 4. SUPERCRITICAL FLUID EXTRACTION OF ALKALOIDS USING BASIHED MODIFIERS Certain free bases of alkaloids were found to be quite soluble in pure supercritical CO2 even under mild supercritical conditions. However, the alkaloids were not extracted as much as expected from their solubilities [37]. This discrepancy was assumed to be due to the fact that most alkaloids exist in the form of salts in the plant. Alkaloids have been extracted from plant materials traditionally by extraction processes with the addition of ammonia or calcium hydroxide. Accordingly, the use of basifled modiflers in SFE, rather than simple polar modiflers was investigated, in the hope that the extraction efficiencies of alkaloids from their plant of origin would be enhanced. This chapter documents enhancements of the efficiency of SFE extraction of alkaloids from plant matrices using basifled modiflers. Hence: (I) The pure compound solubility of some free bases in pure supercritical CO2 has been measured by investigating the effects of temperature, pressure or density of COj; (2) The solubilities of the alkaloidal salts were compared with those of their free bases in order to evaluate the difference of their solubilities influenced by a changing from free bases to salts; (3) Polar solvents such as methanol and water, as initial modiflers, were used for the enhancement of the solubilities; (4) The solubilities of the salts by non-basifled modiflers such as neat methanol or water were compared with those of methanol or water basifled with diethylamine; (5) The effect of modiflers employed on the desorption of the compounds from a matrix were measured and compared with each other; (5) On the basis of the results of pure compound extractability, SFE was performed on alkaloids from the plant

421

Supercritical Fluid Extraction of Alicaloids

matrix. The alkaloids dealt with in this section of the chapter are hyoscyamine (1), scopolamine (2), methylephedrinc (3), norephedrine (4), cphedrine (5), pseudoephedrine (6), and cephalotaxine (7).

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J. Kim, Y.H. Choi and K. Yoo

422

relatively low polarity (e.g., esters, ethers, lactones, and epoxides) can be extracted in the lower pressure range (i.e., 7.0-10 MPa). (2) The introduction of more strongly polar functional groups (e.g., -OH, -COOH) makes the extraction correspondingly more difficult. For benzene derivatives, substances with three phenolic hydroxyls are still capable of being extracted, as are compounds with one carboxyl and two hydroxyl groups. Substances in this range that cannot be extracted are those with one carboxyl and three or more hydroxyl groups. (3) More strongly polar substances (e.g., sugars and amino acids) cannot be extracted in the range up to 40 MPa. In addition to this general rule, the formation of the target compound has to be considered. In particular, alkaloids do not always exist in the free base state but also occur in salt forms, which are insoluble in nonpolar solvents such as COj because of their own characteristic basicity. Opium alkaloids such as codeine, thebaine, papaverine, and noscapine exhibit high solubility (0.09-0.9 mg/g) in supercritical fluids including COj, NjO, CHF3 [37]. However, in spite of their high solubilities, they were not extracted from plant material by pure CO2 to the degree expected [29], possibly because these alkaloids exist as their salt forms in plant tissue. In this chapter, the examples that show the difference of the solubilities between alkaloidal free bases and salts are presented. For this comparison, the solubilities of the free bases of hyoscyamine (1), scopolamine (2), pseudoephedrine (6) were measured and compared with those of their hydrochloride salts (Figures 3 and 4).

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Supercritical Fluid Extraction of Alkaloids

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Figure 4. Pseudosolubilities of pseudoephedrine (6) free base in supercritical CO2 [41]. Reproduced with permission from Vieweg Publishing © 1999. 4.2. Modifying Effect of Methanol and Water on the Solubility of Alkaloidal Salts To improve supercritical COj solubilities of target alkaloidal salts, an appropriate modifier to raise the polarity of COj had to be used. As previously mentioned, the most common modifier used in SEE is methanol because of its high solvation parameters, which can greatly increase the resultant polarity of COj. Water has been chosen as another modifier because some alkaloidal salts are freely soluble in water as well as methanol. Moreover, the addition of water into CO2 has been reported to improve the extraction yield of some alkaloids [29]. Methanol or water as a modifier was added into the extractor at the concentration levels of I, 5 and 10% (v/v), respectively. The effect of methanol and water on the solubilities of hyoscyamine (1) and scopolamine (2) is shown in Figure 5. Analogous information on ephedrine derivatives such as methylephedrine (3), norephedrine (4), ephedrine (5), and pseudopehedrine is illustrated in Figure 6.

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424

While increasing the concentration of water did not show any significant influence, the addition of a greater proportion of methanol yielded great enhancements in the resultant solubilities of the alkaloids, except for methylephedrine (3). These observations may be due to the fact that water is not so miscible as methanol in CO2 (Figure 7). Therefore, water was less effective than methanol in terms of the enhancement of the SFE efficiency. Even though the addition of methanol in CO2 resulted in slight improvements in solubilities, they were still poor; hence another modifier to enhance the solubilities of the alkaloidal salts was required. 80 70

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Figure 6. Effect of methanol (A) and water (B) as a modifier on the solubilities of the hydrochloride sahs of ephedrine derivatives in CO2 at 80 T and 34.0 MPa. ME = methylephedrine (3); NE = norephedrine (4); E = ephedrine (5); PE = pseudocphedrine (6) [41]. Reproduced with permission from Vieweg Publishing © 1999. 4.3. Effect of Modifiers Basified with Diethylamine on the Solubility of Alkaloidal Salts Generally, alkaloidal salts are insoluble in nonpolar solvents but their free bases are quite soluble in the solvents. Therefore, the basified modifler should be introduced into the SFE to solubilize alkaloids in COj. For the evaluation of the effects of basified modifiers, diethylamine was added to methanol or water at a 10% (v/v) concentration level. Then, the basified modifiers were continuously incorporated into the extraction cell at concentrations of 1, 5, and 10 % (v/v). The effects of methanol basified with diethylamine as a modifier on the solubilities of hyoscyamine (1) and scopolamine (2) are shown in Figure 8. The addition of diethylamine (10% v/v) into methanol dramatically enhanced the solubilities of the alkaloidal hydrochloride salts compared with those of pure methanol alone. This may be due to the fact that methanol basified with diethylamine changed the salts to the free bases.

A B Figure 7. Comparison of the phase in the mixtures of methanol-COj (A) and water-CO, (B) using a view cell at 60 "*€ and 34.0 MPa.

425

Supercritical Fluid Extraction of Allcaloids

When the extractabilities using diethylamine/methanol as a modifier were compared with diethylamine/water, the former was more effective on the extractabilities of hyoscyamine (1) and scopolamine (2) salts than the latter, as seen in the comparison of pure methanol and water. Although the water with added diethylamine was less effective than basified methanol, it could largely increase the solubilities when compared with pure water, similar to the comparison of basic methanol with pure methanol (Figure 9).

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Figure 9. Comparison of the extractabilities of hyoscyamine (A) and scopolamine (B) hydrochloride using water basified with diethylamine (10% v/v) with those of pure water. SEE conditions at 60 *C, 34.0 MP [39]. Reprinted from J. Chromatogr. A, 863, Y. H. Choi et al.. Strategies for supercritical fluid extraction of hyoscyamine and scopolamine salts using basified modifiers, 47-55,1999, with permission from Elsevier Science. For ephedrine derivatives, basified methanol or water showed solubilities greater than for neutral conditions (Figure 10), similar to the results for hyoscyamine (1) and scopolamine (2).

J. Kim, Y.H. Choi and K. Yoo

426

ME

NE

E

PE

ME

NE

Figure 10. Effect of methanol (A) and water (B) basified with diethylamine (10% v/v) as a modifier on the solubilities of ephedrine derivative hydrochloride salts in CO2 at 80 "C and 34.0 MPa. ME = methylephedrine (3); NE = norephedrine (4); E = ephedrine (5); PE = pseudoephedrine (6) [41]. Reproduced with permission from Vieweg Publishing © 1999.

4.4. Effect of ModiFiers on Desorption of Alkaloldal Salts from Matrix In addition to the effect of modifiers on solvation power, they also play other very important roles, especially for matrices, where the analyte is strongly bound through chemisorption and physisorption. Another advantage of using a polar modifier is swelling of the matrix, thereby increasing the internal volume, which in turn increases the surface area accessible to the near supercritical solvents [42,43]. Therefore, prior to SFE, the effect of modifiers on a matrix should be evaluated together with that on solubility. For this evaluation, the alkaloidal salt (0.2 mg) was spiked onto filter paper disks. Then, the spiked samples were extracted with pure or modified supercritical COj. In this experiment, the best modifier was also found to be methanol basified with diethylamine. It could recover 61% of hyoscyamine (1), 79% of scopolamine (2), 43% of methylephedrine (3), 11% of norephedrine (4), 36% of ephedrine (5), and 14% of pseudoephedrine (6) from the spiked filter papers. Thus, extraction efficiency was enhanced 2 to 6 times more than any other modifiers evaluated. Therefore, these results suggest that diethylamine in methanol is most effective in improving SFE efficiencies of the alkaloidal salts by increasing desorption from the matrix as well as enhancing solubilities. 4.5. Supercritical Fluid Extraction of Target Alkaloids from Plant Materials In both results of solubility and desorption from filter papers, diethylamine in methanol as a modifier was found to offer greater efficiency for SFE of the alkaloids than any other modifiers employed. The yields of hyoscyamine (1) and scopolamine (2) fi-om the roots and aerial parts by SFE and conventional organic solvent extraction are listed in Tables 2 and 3. The SFE yields from both plant parts were greatly enhanced by the addition of methanol basified with diethylamine. From the results of solubility and desorption fi^om filter paper, methanol and diethylamine/methanol (10% v/v) were much more efficient for both compounds than water and diethylamine/water (10% v/v) because of their low miscibility with CO2. The extraction profile of hyoscyamine (1) when present in plant material was in good agreement with that when extracted as a pure compound. However, in the case of scopolamine (2), there

427

Supercritical Fluid Extraction of Allcaloids

was not a great difference between the initial data and results using methanol and water-based modifiers. Morrison et al. reported that basified water was more effective in SFE of cocaine, another tropane alkaloid, from several matrices than basified methanol and they hypothesized that it was not limited by analyte solubility, but rather, by the desorption of cocaine from the matrices [44]. Thus, in the case of scopolamine (2), it was also hypothesized that the main factor of the modifiers in SFE is not the solubility, but the interaction with the plant matrix. Table 2. Effect of different volumes of modifiers on the SFE yields (mg/g) of hyoscyamine (1) and scopolamine (2) from the roots of S.Japonica at 60 °C and 34.0 MPa [39]. Reprinted from J. Chromatogr. A, 863, Y. H. Choi et al., Strategies for supercritical fluid extraction of hyoscyamine and scopolamine salts using basified modifiers, 47-55, 1999, with permission from Elsevier Science. SFE (mg/g) Methanol

Water Hyoscyamine Scopolamine Hyoscyamine Scopolamine 0.15 (±0.057) 0.12 (±0.026) 0.38 (±0.041) 1% 0.20 (±39) 5% 0.15 (±0.012) 0.34 (± 0.0078) 1.9 (±0.063) 0.23 (± 34) 0.16 (±0.0081) 10% 0.14 (±0.024) Not detected 3.4 (±0.22) Diethylamine in methanol (10% v/v) Diethylamine in water (10% v/v) 0.18 (±0.025) 0.14 (±0.0043) 1% 0.73 (± 0.048) 0.53 (±0.078) 0.23 (±0.021) 5% 4.6 (±0.38) 0.23 (± 0.025) 0.66 (±0.059) 10% 0.22 (±0.029) 6.2 (±0.14) 0.24 (±0.015) 0.20 (±0.028) Organic solvent extraction' Scopolamine 0.26 (± 0.027) Hyoscyamine 6.4 (± 0.72) 'Extraction solvent was chlorofrom-methanol-28% NH4OH (15:5:1). % of modifier

Table 3. Effect of different volumes of modifiers on the SFE yields (mg/g) of hyoscyamine (1) and scopolamine (2) from the aerial parts of S. Japonica at 60 °C and 34.0 MPa [39]. Reprinted from J. Chromatogr. Ay 863, Y. H. Choi et al.. Strategies for supercritical fluid extraction of hyoscyamine and scopolamine salts using basified modifiers, 47-55, 1999, with permission from Elsevier Science. SFE (mg/g) % of modifier

Methanol

Water Hyoscyamine Scopolamine Hyoscyamine Scopolamine 1% 0.081 (± 0.029) 0.13 (± 0.035) 0.11 (± 0.0091) 0.32 (± 0.039) 5% 0.23 (±0.058) 0.28 (±0.11) 0.081 (± 0.0050) 0.30 (± 0.034) 10% 0.49 (±0.076) 0.26 (±0.052) 0.093 (± 0.0072) 0.38 (± 0.028) Diethylamine in methanol (10% v/v) Diethylamine in water (10% v/v) 1% 0.44 (±0.062) 0.39 (±0.13) 0.092 (± 0.010) 0.53 (± 0.064) 5% 0.62 (±0.033) 0.51 (±0.041) 0.61 (±0.17) 0.69 (±0.18) 10% 1.2 (±0.089) 0.69 (±0.022) 0.26 (±0.039) 0.53 (±0.023) Organic solvent <extraction' Hyoscyamine 1.6 (±0.15) Scopolamine 0.65 (± 0.015) 'Extraction solvent was chlorofrom-methanol-28% NH4OH (15:5:1).

Although there are some differences in the degree of enhancement of extractability, among the modifiers employed in this study, 10% methanol basified with diethylamine was found to be optimal for the extraction of hyoscyamine (1) and scopolamine (2) from both the roots and aerial parts of Scopolia japonica. While the recoveries from the roots and aerial parts of S.

428

J. Kim, Y.H. Choi and K. Yoo

Japonica were only in the range of 10-54% relative to the organic solvent extraction method using conventional modifiers such as methanol or water, methanol basified with diethylamine improved the recoveries of hyoscyamine (1) and scopolamine (2) to 98% and 84%, respectively. In the case of ephedrine derivatives from Ephedra sinica, diethylamine in methanol was also obviously effective in improving the SFE efficiencies of all the ephedrine derivatives from plant materials, as revealed by the results of solubility and desorption from filter papers. In particular, above 80% of methylephedrine (3) could be extracted using 10% of this modifier when compared with a conventional organic solvent extraction. Although diethylamine in methanol among the modifiers was most effective on the SFE efficiencies of ephedrine derivatives from plant materials, the yields of norephedrine (4), ephedrine (5), and pseudoephedrine (6) were still below 60% relative to liquid-liquid extraction. Thus, a means of enhancing SFE yields of ephedrine derivatives proved necessary. For this purpose, increase of extraction time, temperature, and modifier percent were carried out. Unfortunately, extraction time and temperature did not show any significant effect on them. However, when adding diethylamine in methanol up to 20%, the extraction yields of ephedrine derivatives were dramatically improved. In the case of methylephedrine (3) and ephedrine (5), they were completely recovered by SFE using this modifier. The yields of ephedrine derivatives by COj modified with 20% of diethylamine in methanol were compared with those by the conventional extraction in Table 4. Table 4. Yields of methylephedrine (ME), norephedrine (NE), ephedrine (E), and pseudoephedrine (PE) obtained by organic solvent extraction and SFE. Resuhs are mg/g [41].'*^ Reproduced with permissionfromVieweg Publishing © 1999. ME

NE

E

PE

Organic solvent extraction

0.25 (±0.003)

0.12 (±0.020)

3.22 (±0.190)

1.1 (±0.066)

SFE

0.37 (±0.001)

0.046 (±0.012)

3.44 (±0.076)

0.40 (±0.034)

Extraction method

'Extraction solvent was 0.5 M H2SO4 followed by basifying with 6M NaOH and diethyl ether extraction 'Mixture was COj-methanol-diethylamine (80:18:2).Tempenitiire and pressure were 80 "C and 34.0 MPa, respectively.

Pseudoephedrine (6), which is the diastereomer of ephedrine (5), was extracted only by 44%, while ephedrine (5) was 106% when compared to the organic solvent extraction. TTiese results might not be caused by differences in their solubilities but desorption from the plant matrix. The yield of pseudoephedrine (6) extracted with CO2 modified by diethylamine in methanol from filter papers was about half of that of ephedrine (5), whereas there was no significant difference in their solubilities. A gas chromatogram obtained by SFE and liquid extraction is provided in Figure 11. These results indicate that SFE may extract selectively a target compound from its stereoisomers. The selective extraction of ephedrine (5) from its stereoisomer, pseudoephedrine (6), may be due to the difference in conformation, that is, the OH and NH groups of ephedrine (5) are located in the same plane, so the hydrogen of the hydroxyl group and nitrogen may be hydrogen-bonded to each other. However, in the case of pseudoephedrine (6), the hydrogens of OH and NH rotate more freely than in ephedrine (5), so they are more likely to bind to the matrix. The results of molecular modeling (Sybyl 6.5, Tripos) support this proposal. The distance between hydrogen of OH and nitrogen in ephdrine was closer than that of pseudoephedrine (6). They were measured as 3.24 A for ephedrine (5) and 3.95 A for pseudoephedrine (6), respectively (Figure 12).

429

Supercritical Fluid Extraction of Alkaloids

PE

PE

L Figure 11. Comparison of the gas chromatograms obtained by (A) 0.5 M H2SO4 extraction and (B) SFE at 80 "C and 34.0 MPa using 20% diethylamine in methanol as a modifier. E = ephedrine (5), PE = pseudoephedrine (6) [41]. Reproduced with permission from Vieweg Publishing© 1999.

Matrix

Matrix

3.24 A Ephedrine

3.95 A Pseudoephedrine

Figure 12. Difference of chemical conformations of ephedrine (5) and pseudoephedrine (6) and distance between hydrogen and nitrogen measured by molecular modeling (Sybyl 6.5,

Tripos).

Another example for SFE of alkaloids using basified modifiers was reported for cephalotaxine (7) from Cephalotaxus wilsoniana leaves [45]. Li this report, basified methanol was found to greatly enhance the extraction efficiency relative to any other modifiers (Figure 13).

J. Kim, Y.H. Choi and K. Yoo

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•

120

•

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Figure 13. Relative extraction yields (%) of cephalotaxine (7) from C. wihoniana leaves by SC-CO2 by added modifiers when compared with methanol extraction [45]. Reproduced with permission from the Pharmaceutical Society of Korea © 1999. 5. CONCLUSIONS There have been reported numerous advantages of SFE for the extraction of natural products including reduction of extraction cost and time, environmental acceptance, and lack of toxicity to human health compared with conventional organic solvent extraction. However, the high polarity of alkaloids due to salt formation in plant tissue has made it difficult to extract them using SFE. In order to develop a universally acceptable SFE method for alkaloids present in plant materials, a basified modifier has been introduced to the SFE of selected alkaloids. On the basis of these resuhs, it is believed that SFE using basified modifiers can be used as an alternative to conventional solvent extraction for alkaloids from plant material. 6. ACKNOWLEDGEMENT We are grateful to Prof. A. Douglas Kinghom of College of Pharmacy, University of Illinois at Chicago for helpful comments. The works described in the author's laboratory were supported in part by the Korean Science and Engineering Foundation (KOSEF).

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.

C Cagniard de la Tour, Ann. Chim. Phys. 21.127 (1822). JB Hannay and J Hogarth, Prvc. Roy. Soc. Lond. 29,324 (1879). EH Buchncr, Z. Phys. Chem. 54,665 (1906). LT Taylor, Supercritical Fluid Extraction, John Wiley & Sons, New York, 1996. NL Dickcrson and JM Meyers, / Am. OH Chem. Soc. 29,235 (1952). K Zosel. Belgium Patent No. 646641 (1964). K Zosel. French Patent 2,079,261 (1971). K Zosel, US Patent 3.806,619 (1974). K Zosel. US Patent 3.969,196 (1976).

Supercritical Fluid Extraction of Alicaloids 10. 11.

431

K ZoscI, US Patent 4,247,570 (1981). E Lack and H Seidlitz, Commercial scale decaffeination of coffee and tea using supercritical CO,. In Extraction of Natural Products using Near-critical Solvents; MB King and TR Bott, Ed., Chapman & Hall, London, UK, 1993, pp 101-139. 12. B Van Bavcl and G Lindstrom, Organohahgen Compd. 11, lA'h (1996). 13. M Gartner, A Loibncr, E Nasahl, and R Braun, Soil Environ. Sen 608,281 (1995). 14. N Sanders, Food legislation and the scope for increased use of near-critical fluid extraction operations in the food, flavouring and pharmaceutical industries. In Extraction of Natural Products using Near-critical Solvents; MB King and TR Bott, Ed., Chapman & Hall, London, UK, 1993, pp 34-49. 15. JM Bruna, Rev Plast Mod. 21,448 (1995). 16. MA McHugh and VJ Krukonts, Supercritical Fluid Extraction, 2nd ed. Butterworth-Heinemann, Boston, 1994. 17. T Clifford, Fundamentals of Supercritical Fluids, Thomas Press, Chennai, India, 1999. 18. MD Luque de Castro, M Valcarcel, and MT Tena, Analytical Supercritical Fluid Extraction, SpringerVerlag, Berlin (1994). 19. WK Modey, DA Mulholand, and MW Raynor, Phytochem. Anal. 7, 1 (1996). 20. AP Jarvis and ED Morgan, Phytochem. Anal. 8, 2 i 7 (1997). 21. CD Bevan and PS Marshall, Nat. Pmd Rep. 11,451 (1994). 22. TL Chester, JD Pinkston, and DE Raynie, Anal. Chem. 70,301R (1998). 23. E Stahl and E Willing, Planta Med. 34,192 (1978). 24. P Elisabeth, M Yoshioka, Y Yamauchi, and M Saito, Anal. Sci. 7,427 (1991). 25. K Sugiyama, M Saito, T Hondo, and M Senda, / Chromatogr. 332,107 (1985). 26. DP Ndiomu and CF Simpson, Anal. Chim. Acta 213,237 (1988). 27. ST Schaeffer, LH Zalkow, and AS Tcja, AlChE Journal 34,1740 (1988). 28. C Bicchi, P Rubiolo, C Fratini, P Sandra, and F David, / Nat. Prod. 54,941 (1991). 29. JL Janicot, M Caude, and R Rosset, J. Chromatogr. 505,247 (1990). 30. AK Sharma, B Prokopczyk, and D Hoffmann, / Agric. Food Chem. 39,508 (1991). 31. C Bugatti, ML Colombo, and A Mossa, Planta Med. 59,626 (1993). 32. DW Jennings, HM Deutsh, HZ Leon, and AS Tcja, J. Supercrit. Fluids 5,1 (1992). 33. MK Chun, HW Shin, H Lee, / Supercrit. Fluids 9, 192 (1996). 34. V Vandana, S AS Teja, and L Zalkow, Fluid Phase Equilib. 116,162 (1996). 35. OR Qucckenberg and AW Frahm, Pharmazie 49, 159 (1994). 36. PR Eckard and LT Taylor, / High Resol. Chwmatogr. 11,469 (1999). 37. E Stahl, KW Quirin, and D Gerard, Dense Gases for Extraction and Refining, Springer-Verlag, Berlin, 1988. 38. E Stahl, W Schilz, E Schutz, and E Wiling, Angew. Chem. Int. Ed Engl. 17,731 (1978) 39. YH Choi, YW Chin, J Kim, SH Jeon, and KP Yoo, J. Chromatogr. y< 863,47 (1999). 40. DW Hughes and K Genest, In LP Miller (Ed.), Phytochemisiry 11, Van Nostrand Reinhold, New York, 1973. 41. YH Choi, J Kim, YC Kim, and KP Yoo, Chormatographia 50,673 (1999). 42. TM Fahmy, ME Paulaitis, DM Johnson, and MEP McNally, Anal. Chem. 65, 1462 (1993). 43. WN Moore and LT Tayor, / Nat. Prvd. 59,690 (1996). 44. JF Morison, SN Chesler, WJ Yoo, CM Selavka, Anal. Chem. 70, 2368 (1998). 45. YH Choi, J Kim, JY Kim, SN Joung, KP Yoo, and YS Chang, Arch. Pharm. Res. 23,163 (2000).

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433

Chapter Three

Recent Advances in the Total Synthesis of Amaryllidaceae A\\i2\o\A% Sundaresan Prabhakar Department of Chemistry Faculty ofScience and Technology New University ofLisbon 2825-114 Monte de Caparica, Portugal M. Regina Tavares Department of Technology of Chemical Industries INETI 1649-038 Lisbon, Portugal

CONTENTS 1. Synthesis l.L Introduction 1.2. Classification of Alkaloids 1.3. Biphenyl Alkaloids 1.4. Tricyclic Alkaloids 1.4.1. Phenanthridine and Related Alkaloids 1.4.2. Narciclasine Related Alkaloids 1.4.3. Dibenzo[c,e]azocine Alkaloids 1.5. Tetracyclic Alkaloids 1.5.1. Pyrrolophenanthridines / Pyrrolophenanthridones 1.5.2. Lycorine and Related Alkaloids 1.5.3. Galanthamine and Related Alkaloids 1.5.4. Crinine and Related Alkaloids 1.5.5. Tazettine and Related Alkaloids 1.5.6. Morphanthridine Type Alkaloids 1.6. Pentacyclic Alkaloids 2. Recently Isolated Alkaloids (1987-1998) 3. Biological Activity 4. Addendum 5. Abbreviations Used 6. References

434 434 434 437 440 440 444 474 476 476 498 508 515 523 532 549 550 558 559 562 564

434

S. Prabhakar and M.R. Tavares

1.

SYNTHESIS

1•1•

Introduction

Amaryllidaceae alkaloids [1] constitute an important class of naturally occurring bases and neutral substances. The last ten years have witnessed increased activity in the synthesis [2] of these alkaloids. This is undoubtedly largely driven by the fact that, besides academic interest, certain members of the family possess interesting and very useful biological properties [23]* Occasionally recourse to synthesis was undertaken in order to confirm structures that were proposed on less than secure spectroscopic grounds. Many elegant syntheses, chiral or otherwise, of structures incorporating a multiplicity of asymmetric centres have relied on electrocyclic reactions because of their predictable stereochemical outcome. Organometallic chemistry also featured prominently in achieving regiospecific reactions under extremely mild conditions, with often remarkable functional group selectivity. The present survey is divided into three sections. The first reviews only the completed syntheses, formal or otherwise, of Amaryllidaceae alkaloids reported during the decade 1968 to 1998. Interesting, but as yet unsuccessful synthetic approaches are only referred to when appropriate. The second part lists new alkaloids isolated during the same period, followed by a brief third section dealing with the biological activity associated with some of them. 1.2.

Classification of Alkaloids The variety of structural types that are encountered in alkaloids belonging to the

Amaryllidaceae family can be conveniently classified, from the point of view of their basic skeleton, along the following lines (see Figure 1): —Biphenyl Alkaloids —Tricyclic Alkaloids Phenanthridine and Related Alkaloids Narciclasine Related Alkaloids Dibenzo[c,^]azocine Alkaloids —Tetracyclic Alkaloids Pyrrolophenanthridines and Related Alkaloids Lycorine and Related Alkaloids Galanthamine and Related Alkaloids Crinine and Related Alkaloids Tazettine and Related Alkaloids

Recent Advances in the Total Synthesis of Amaryllldaceae Allcaloids

435

Morphanthridine Type Alkaloids -Pentacyclic Alkaloids.

Biphenyl Alkaloids

crinasiadine (phenanthildine related)

trisphaeiidine (phenanthfidlne type)

2^

OH

^3

MeO

MeO

7-deoxynarciclasine (narciclasine related)

buflavin (dlbenz[c.e]azocine type)

Figure 1. Examples of maior Amaryllidaceae alkaloid group (continued next page).

S. Prabhakar and M.R. Tavares

436

MeO,

vasconine (pyrrotophenarrthridine type) OH

oxoassoanine (pyrrolophenanthridine type) 2 1 O"

Pentacyclk Alkaloid O

7

6

pancracine

(morphanthridine type)

Figure 1. Examples of major i4mary//{d!aceae alkaloid group.

augustamine

N" Me

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

437

1.3. Biphenyl Alkaloids Ismine, Ismine (1) [4], the catabolic end product and the simplest member of Amaryllidaceae family of allcaloids, has been synthesised by two different routes. The first due to Snieckus [5] involved Suzuki's reaction between the boronic add 2 and the ^-bromobenzamide 3 (Scheme 1). The former was obtained from the carbamate 4 via o-lithiation, followed by conversion of the resulting aryllithium 5 into the boronic ester 6 and thence by acid hydrolysis to 2. The coupling product 7 was methylated and chemoselectively reduced to the benzylalcohol 8. However, attempts to remove the nitrogen protecting group in the usual manner, with trifluoroacetic acid to furnish ismine, were of no avail, because of the ease of cyclisation to the dihydrophenandmdine 9. The difficulty was neatly overcome by reacting 8 with tbutyldimethylsilyltriflate followed by desilylation d* the product, presumably 10, with aqueous tetra-n-butylammonium fluoride.

L NHBOC

+ 2

^L

4

XsH

5

XsU

J

B(0Me)3

2

X = B(0H)2

Pd(PPh3)4/ NagCOa ^ DMEA-enux 75%

NHMe

Scheme 1. Synthesis of ismine (continued next page).

NHBOC

S. Prabhakar and M.R. Tavares

438

1) NaH/Mein-HF >95% 2)UBEt3H/rHF NHBOC 0*'C-rt/72%

BOC

O OH 1)TBDMSOTf/CH2a2 2,6-iutidineM 2)TBAF/H20/rHF

/

^COaTBDMS

Scheme L Synthesis of ismine. The second synthesis [6], based on radical chemistry to achieve the crucial Caryi-Caryt bond, required as the starting material the 2-bromobenzyl-2'-aminophenyl ether (11) (Scheme 2). It was secured by alkylation of o-nitrophenol with 2-bromo-4,5-methylenedioxybenzyl chloride, followed by catalytic reduction of the resulting nitrophenyl ether. 11 when subjected to the action of tri-n-butyltinhydride in the presence of 2,2'-azobisisobutyronitrile furnished a

Recent Advances in the Total Synthesis of Amaryllidaceae All^aloids

439

mixture of compounds from which, N-norismine (12) and the aminopyran 13 were isolated in 27% and 10% yields respectively. The N-monomethylation of 12 to ismine (1) in 80% yield had been earlier reported [7]. The preponderance of N-norismine over the aminopyran 13 was attributed inter alia to the kinetically favoured 1 ^addition product 14 (Scheme 3) of the initial o radical to the proximate phenyl group undergoing aromatisation by unimolecular fragmentation to the alkoxyl radical 15 at a rate faster than the bimolecular oxidative aromatisation of the isomeric radical 16 to 13 (Scheme 3).

1)NaH/MeCN reflux/26h/66% 2) PtA^2/EtOH 2 atm/tt/24h/77%

11 TBTH/AIBN benz/ reflux 13h

NHa

13 Scheme 2. Synthesis of N-norisminc.

-*•

S. Prabhakar and M.R. Tavares

440

r^^^^

13

Scheme 3. Synthesis of N-/K7rismine 1«4.

Tricyclic Alkaloids

1.4.1.

Phenanthridine and Related Alkaloids

Trisphaeridine, [8]. The synthesis [9] of trisphaeridine (17) (Scheme 4) involved the known aryl boronic acid 18 and the sterically unencumbered {7-bix>mophenylcaibamate 19 as coupling partners in the Suzuki reaction. The biaryl 20, thus obtained in customary good yield, underwent

a Bischler-Napieralsky cyclisation with phosphorus oxychloride to afford the

chlorophenanthridine 2 1 . The latter on catalytic dechlorination furnished 17.

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

441

.B(0H)2

NHCOaMe

18

19

\P6iPPt\^)4f2M aq. Hoi^COz >£tOH/ben2/80'*C/8h NT 90%

NHCO2M6

Scheme 4. Synthesis of trisphaeridine.

3-Hydroxy'8,9'methylenedioxyphenanthridine, [10]. The method developed by Kessar ct al. [11] for phenanthridines and related compounds was applied to the synthesis [10] of 3hydroxy-8,9-methylcnedioxyphcnanthridine (22) (Scheme 5). Thus, the benzylidene aniline 23, prepared from 6-chloropiperonal and 3-benzyloxyaniUne, was reduced to the secondary amine 24. Treatment of 24 with excess lithium diisopropylamide furnished, on work-up, the benzyl ethers 25 (22%) and 26 (6%) respectively. Catalytic debenzylation of the former generated 22.

S. Prabhakar and M.R. Tavares

442

OBn

OBn

25

26

Pd/C(10%)/MeOH 1 alm/20X/3h 71%

Scheme 5. Synthesis of 3-hydroxy-8,9-methylenedioxyphenanthri
Recent Advances in the Total Synthesis of Amaryilidaceae Allcaioids

443

Me30BF4 CH2CI2 reflux/12h

iTf20/DMAP/CH2a2 O'^-IS^'C/IOh 92%

NaH/Mel/THF NHC02Me

90%

20

Me02C

Me

30

Scheme 6. Synthesis of crinasiadine and N-methylcrinasiadine. Thus, whilst acid-hydrolysis of 21 provided 27, N-methylation of the former followed by treatment of the resulting chloroiminium salt 29 with aqueous alkali generated 28. A later report [14] described a shorter route to 28 which involved a mild Bischler-Napieralsky reaction of the tertiary carbamate 30 secured from 20 by N-methylation, with a mixture of trifluoro-

S. Prabhakar and M.R. Tavares

444

methanesulphonic anhydride and N,N-dimethylaminopyridine. It is worthy of note that phosphorus oxychloride failed to achieve the same cyclisation under a variety of conditions. Narciclasine Related Alkaloids

1.4.2.

i^-yi-Deoxynarciclasine [(•^)'Lycoricidine], [15]. A

chiral

synthesis of

(+)-7-

deoxynarciclasine (31) (Scheme 7). reported by Ogawa et al [16,171, utilised methyl-2-azido-6bromo-2,6-dideoxy-a-D-altropyranoside (32), as the starting material, a known compound derived from D-glucose, in seven steps. Protection of the hydroxy groups as the methoxymethylethers, followed by dehydrohalogenation of the halides 3 3 formed in the reaction furnished the enopyranoside 34. Application of a modified Ferrier reaction with catalytic amount of mercury (II) trifluoroacetate induced an enolether-ketone rearrangement of 34 to the aldol 3 5 which was dehydrated to the carbocyclic enone 36.

=4i-"-xx OH

OMOM MOMCt/DtEA CHaOa/A/ISh

OH

MeO^

MeO

N3

D-glucose

32 (XsBr)

33

OMOM % 33 (X = a.Br)

Hg(OCOCFa)2/H20^ Me2COm/20h OMOM HO^

DBUAol/A/15h

Na

34

Scheme 7. Synthesis of (-»-)~7-deoxynarciclasine (continued next page).

N3

35

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

445

^IL^OMOM MsCI/EtaN CH2a2

HO'"'"^V''''^OMOM N3

N3 36

35

1) CeQdJHeO/MeOH crC/NaBH4/0.5h/86% 2) NaHA)MF/MPMClAt/18h

OMPM

69%

OMOM

OMPM

JL^OMOM

^XS. T V

^ A ™ ..XXL.™ coyH

N3

Js^ OMOM

,X^-,

DMFAy»C/D.25h 89%

37

NaH/DMF/MPMC rt/5h/100%^

38

OMPM

DMOM

OMOM

Pd(0Ac)2 DPPEn-IOAc DMF/7h/14(rC 68%

OMPM OMOM

MPM OMOM MPM

40

Scheme 7. Synthesis of (•f)-7-deoxynarcic]asine (continued next page).

S. Prabhakar and M.R. Tavares

446

OMPM PMOI^

OMOM ,OMOM

MPM CH2Cl2/(rC/3h 53%

OMOM

^^^

PPh3/PhC02H lEAD PMOK

41

0M0^ 1) NaOMe/MeOH/THF/I.Sh/tt 99% 2)1NHCI(aq),50*C/23l 3) Ac20/pyr/rt/3h

MPM

pAc-

OAc

1)TFAyCHa3 rt/1.5h 53% if 2) methanolysis •

OH s

MPM

fT

k X)

1

^OH 1 ^OH 1

0"

0 31 (+)-7-deoxynarclclaslne V^BHHB

Scheme 7. Synthesis of (-h)-7-deoxynarciclasine.

MHJ

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

447

Since 1,4 addition of a variety of appropriate aryl carbanions to 36 failed, an intramolecular version of the Heck reaction was examined. With this end in view, the ketone 36 was reduced stereospecifically to the corresponding allyl alcohol which was then protected as its p-methoxybenzyl ether 37. The amine, obtained on reduction of the azide 37, was condensed with 6-bromopiperonylic acid to furnish the amide 38. Whilst, not unexpectedly, the secondary amide 38 failed to undergo a 6-exo trig addition with palladium(O) complex, the corresponding tertiary amide 39 did so, when subjected to Heck reaction conditions, to furnish styrene 40 in good yield. Mechanistically, the absence of enol ether in the reaction is of interest because it implied that the palladated syn addition product A (Figure 2) underwent an unusual trans elimination of palladium, possibly due to more acidic character of the benzylic hydrogen. Alternatively, such a result was the consequence of the intervention of palladocycle B as the intermediate torn which the C-C bond formation occurred with the extrusion of Pd(0). OMPM OMPM

OMOM

OMOM

OMOM

MPM I Br

Figure 2. The 'Vrong" stereochemistry at C(2) was corrected at this stage by selective oxidative cleavage of the O-benzylether followed by inverting the resulting P-alcohol 41, by Mitsunobu reaction to the corresponding a-benzoate 42. Sequential hydrolysis of 42, first by basic methanol, and then with acid provided a triol which was converted into the corresponding triacetate 43. Exposure of 43 to trifluoroacetic acid liberated tri-O-acetyl-7-deoxynarciclasine, the methanolysis of which furnished (+)-7-deoxynarciclasine (31). Pseudomonas putida mediated cf5-dihydroxylation of bromo or chlorobenzene supplied the requisite chiral starting material 44 for a second synthesis of (+)-7-deoxynarciclasine reported by Hudlicky [18,19]. Subsequent to protection of the diol as the acetonide 45 (Scheme 8), its cycloaddition reaction with the N-acylnitroso compound derived from benzyl-Nhydroxycarbamate 46 by in situ oxidation, occurred with complete regio and stereospecificity togive the bromo adduct 47. In a similar fashion, the chloro compound 48 was obtained.

448

S. Prabhakar and M.R. Tavares

Reduction of die bromide and subsequent cleavage of the N-0 bond was achieved by the action of aluminium amalgam on 47 and led to cis 1,4-hydroxyurethane 49. Deprotonation of 50 followed by acylation of the resulting caitmmate anion with ^bromopiperonyl chloride provided the key bicydic intermediate 51. Palladium catalysed Heck cyclisation of 51, performed in anisole, furnished the allylsilylether 52. Catalytic transfer hydrogenolysis of the benzyl group of 5 2 followed by acid treatment of the resulting Oprotected tricyclic 5-lactam 53 furnished (+)-7deoxynarcidasine (31). Br

47 48

Ri = CBZ: X = Br Ri = CBZ ; X = a

.^ i CISIMeal-Pr lmld/CH2a2A)*C

98%

Ri Ri=:CBZ:R2 = R3 = H

49

50 RisCBZ :R3sH;R2 = SiMe2i-Pr

OR2 1)n-BuU/rHF

-zs'C-crc 2)<

\XX^o 77%

51 Ri s CBZ; R2 ' SiMe2i-Pr Scheme 8. Synthesis of (+)-7>deoxynarciclasine (continued next page).

Recent Advances in the Total Synthesis of Amaryllidaceae Alicaloids

449

OR2

'.xxS^'' / - ^ ^ ^

^

Pd(0Ac)2 (cat). TI(OAc)/ani90le DPPE 135'»C/7h 27%

51 RirrCBZ; R2=:SiMe2i-Pr

52 Rt:sCBZ;R2sSiMe2i-Pr

EtOH I

reflux y2h 99% L - ^ 5 3

R^ g, H : R2 = SiMe2l-Pr

Scheme 8. Synthesis of (+)-(7)-deoxynarciclasine. ("yi'Deoxynarciclasine, Following their easier synthesis of (-»-)-7-deoxypancratistatin (67) (vide irrfrd) Keck et al, [20] had applied a cascade radical cyclisation to achieve the total synthesis of non-natural (-)-7-deoxynarciclasine for biological assay (Scheme 9). The requisite chiral starting material, the oxime ether 54 was obtained as a mixture of geometric isomers from D-lyxose 55 by the set of reactions depicted. Subsequent to conversion into the lactol-O-benzyl ether and protection of 1^-diol as its acetonide, the remaining hydroxyl group was transformed to the silyl ether 56. Reductive cleavage of the benzyl ether regenerated the lactol functionality, which on reaction with hydroxylamine-O-benzyt ether furnished 54. Oxidation of the primary alcohol 54 to

the

aldehyde

followed

by

successive

treatment

of

the

latter

with

tetrabromomethane/triphenylphosphine and butyllithium furnished the acetylene 57. Palladium catalysed coupling of 57 with 6-bromopiperonal yielded the disubstituted acetylene 58.

450

S. Prabhakar and M.R. Tavares TBDMSO 1) BnOH/rsOHy81% 2) DMP/Me2COArsOH/90%' 3)TBDMSCt/imid/95%

1)LI/NH3 2) BnONHaHCI/pyr 93% TBDMSO

TBDMSO

f

^

1)TPAP/NM0

2)CBr4/PPh3n'EA 3)n-BuU(2eq) 4)H20

OH

Y"V

N

OBn

OBn

57

54

1

A OMe 1)HF/|3yr/88% 2) Mn02/NaCN/MeOH/81%

Scheme 9. Synthesis of (-)-7-deoxynarciciasine (continued next page).

59

451

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaioids

"'nJ^

^ ^

OBn

OMe

OH

PhSHAol

^

T II

I 1

\ X / \

v ^ f

61

OH

„...*0H 1

V KXXr

-^'"^OH

o

3 1 (-)-7-deoxynarclclaslne

1 1

Scheme 9. Synthesis of (-)-7-deoxynarciclasine. The derived hydioxy-aldehydc was selectively oxidised vw its cyanohydrin derivative to the corresponding hydroxy-methyl ester 59» Thinyl radical, generated photolytically from thiophenot, attacked, due to steric reason, regioselectively the terminus of the arylacetylene unit

452

S. Prabhakar and M.R. Tavares

of 59 to initiate a S-exo radical addition that tenninated with the formation of the N-benzyloxy aminoester 60. Reductive cleavage of both the thioether group and the N~0 bond, achieved in a single operation with samarium (II) iodide, provided the lactam acetonide 61, from which the (-)-alkaloid was secured in 11% overall yield, from D-lyxose, by acid hydrolysis. (•¥)'7'D€oxy''trarU'dihydronarciclasine, (+)-7-deoxy-//'aft5*dihydronarciclasine

(62)[21 ]

(Scheme 10) was synthesised [22] from the olefinic phenanthridone 40 that had served as an advanced intermediate for (+)-7-deoxynarciclasine (31) (vide supra). Thus, catalytic hydrogenation of 40 occurred with high a-stereoselectively and with concomitant cleavage of the 0-benzylether to provide alcohol 63. Its triflate derivative was converted, with inversion of configuration, into the acetate 64 and thence, to diol 65. Subsequent to transformation of 65 into triacetate, the removal of N-benzyl group furnished the secondary amide 66 which on methanolysis liberated the alkaloid with an overall yield of 46% from 40. ('¥)'7'Deoxypancratistatm, [23]. A sp^ carbon radical addition in a 6-6X0 mode to an appropriately functionalised chiral imine constituted the key reaction in the synthesis of (+)-7deoxypancratistatin (67) reported by Keck et al. [24]. The requisite starting material, the Oprotected hydroxyaldehyde 68 with absolute stereochemistry at the four contiguous centres correctly correlating with C(l), C(2), C(3), C(4) of the alkaloid, was obtained from Dgulonolactone 69 as shown in the Scheme 11. Oximation of the carixmyl group of 68 with Obenzylhydroxylamine followed by protection of the hydroxyl group as the methoxymethylether yielded the fully Oprotected oxime ether 70. The carboxylic acid 71, obtained by selective desilylation of 70 and oxidation of the primary alcohol thus formed, was coupled with the bromoalcohol 72 by Mitsunobu method to furnish bromoester 73. Generation of aryl caibanion from 73 by halogen-metal exchange resulted, via an intramolecular alkoxide displacement reaction, the unstable o-ketoalcohol. Oxidation to the corresponding aldehyde, followed by fluoride ion promoted desilylation yielded the cyclic hemiacetal 74 as a diastereomeric mixture, which was resilylated to 75. The key intermediate, the thianoamide 76, which was secured from the ketone 75 by reduction and subsequent thioacylation of the resulting alcohol with N,N'thiocarbonyldiimidazole, when subjected to radical generating conditions, underwent 6-6X0 ring closure to furnish the tricycle 77. Noteworthy was the observation that a favourable conformation for the new C-C bond formation with the indicated geometry was only obtained when the radical precursor was cyclic. Conversion of 77 into the 0-benzylhydroxamicacid derivative 78 followed by O-desilylation and oxidation of the resulting lactol furnished the lactone 79. The trifluoroacetamide 80 obtained by successive treatment of 79 with samarium (II) iodide and acidic Dowex resin, on exposure to methanolic potassium carbonate generated, (+)-7-deoxypancratistatin (67). The overall yield of the alkaloid starting from D-gulonolactone was 7%.

453

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

OMPM PMOM

OMOM

pWM

MPM OMOM

1)Tf2O/CH2a2/0''/i3yr 2) K0Ac(5eq)/ 18-crown-6(2eq) benz/tt

OAc

I

63 OAc

81% (40-•65; pMOM

OMOM^)^^^[^N«^

5(rc MPM

64 OAc

P <

1)Ac20-pyr 93% ^2)TFA^HF 85%

_ .—

OH

H

0 66

^OAc MeONa/MeOM

1

^A^^OH 1

^OAc

00

r^s > < ^OH 1 L

H ^ NH

1 1

0

1

62 (-i-)-7-deoxy-trans-dihydronarciclasine 1

Scheme 10. Synthesis of (+)-7-deoxy-trans-dihydronarciclasine.

S. Prabhakar and M.R. Tavares

454 H.

o

HO

HO

V ° v ^o

.0 1) MeaCO/DMP/TsOH (cat.) N2/36h/82%

4

Q

X

OH

HO

69

^4.

HOAc-HjO (7:1] 30''C/16h/79^

.0. 1)TBDMSCI/imid 2)DIBAL/-78*'C

I

/ TBDMSO

^ § OTBDMS O

68

/

^ '6

\ 1)BnONH2 ^ 2)M0Ma/DIEA

MOMQ TBDMSO,

MOMQ 1) HF/pyr 2)TPAP/NM0 TRHM^n ^ n 3)NaCI02 TBDMSO^^.%s,^^0

Scheme 11. Synthesis of (+)-7-dcoxypancratistatin (continued next page).

.

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

455

OMOM

1)NaBH4-MeOH 2)TCDI/DMAP JCICH2)2 OBn 74 RsH 75 R=TBDMS

OMOM TBDMSO,

O TBTH/AIBN/

'v^

OMOM

70%/^

r

OBn

V—O

n

^*

^ =0

TBDMSO.

1)TBAF/rHF .2)TPAP/NM0

78 R = C0CF3 .^—l

TFAA/DMAP/pyr

Scheme 11. Synthesis of (+)-7-deoxypancratistatin (continued next page).

C—N

/S555,K,

J

456

S. Prabhakar and M.R. Tavares OMOM O.^

^O 1)Sml2 ^ IDowex-MeOH

r

sr

lOH 1

/ ^

<

OH

V

OH

h

^

1)K2C03/dryMeOH 2) amberiite

3|

'OH 1 ^*^*%-^N>^ H 1

1

0

<>7

(+)-7-deoxypancratistatir

)

1

Scheme 11. Synthesis of (+)-7-deoxypancratistatin. The chiral bromoacetonide 45 once again served as the starting material for a convergent synthesis [25,26] of (+)-7-deoxypancratistatin (67) (Scheme 12). Thus N-carbomethoxynitrene addition to 45 occurred, due to blocking by the P-dioxolane group, from the a-face to provide aziridine 81. SN2 ring opening of the debromo compound 82 derived from 81 with arylcuprate 83 proceeded in modest yield to furnish the trans arylcarbamate 84. Acid hydrolysis to diol 85 and its subsequent oxidation produced, owing to the directing effect of the adjacent p-hydroxy group, the epoxide 86 of the same configuration. The latter on heating with water containing catalytic quantity of sodium benzoate provided via trans diaxial ring opening, the carbamate cyclitol 87. Peracetylation followed by cyclisation of the resulting acetoxy carbamate by the mild method of Banwell [14], furnished the 0-acetylated compound 88 from which the alkaloid 67 was liberated by methanolysis.

457

Recent Advances in the Total Synthesis of Amaryllidaceae Alitaloids

O

/

02N-(3"S03NHC02Me

\ / /

TEBAC \

NaHCOsAHgO 51%

r*"

VTBTH/AIBN THF/i^v 82% ^

1

45

COaMe

(Xf-.Cu(CN)U2 2

82

30% H

O

I

HOAC/H2O THF/65X

NHCOaMe

94<)^

^

84 t-Bu02H/VO(acac)2 benz/7(rC/3h

O

<

NHC02Me

85 H2O/NaCX5OPh/100'»C OH

82«/

^

OH

NHC02Me

NHC02Me

87 Scheme 12. Synthesis of (+)-7-deoxypancratistatin (continued next page).

S. Prabhakar and M.R. Tavares

458

OH

NHCOaMe 1)AC20/DMAP/pyr rt/16h/84% 2)Tf20/DMAP CHaOa/S^C/ieh 61%

87

Scheme 12. Synthesis of (+)-7-deoxypancratistatin. Yet another total synthesis of (-•-)-7-deoxypancratistatin, which involved the use of the 2-aacetate 64 was reported by Ogawa et al, [22] (Scheme 13). To achieve the end 64 was subjected to basic methanolysis to furnish the corresponding alcohol 89 which was converted via its triflate into the C(l)-C(2) olefm 90 using potassium acetate as the base. Utilisation of a stronger base, such as triethylamine, resulted in significant formation of the C(10b) epimer of 90. Phosphatebuffered peracid oxidation of diol 91 derived from 90, occurred exclusively from the p-face to furnish the epoxide 92. Tron^-diaxial ring opening of 9 2 with acetate ion and subsequent acetylation of the resulting monoacetate with zinc chloride as catalyst provided tetraacetate 93. The use of Lewis acid in esterification was found to be essential. Otherwise, elimination of elements of acetic acid became significant. Compound 93 on N-debenzylation followed by exposure of the resulting secondary amide to methanolic methoxide furnished (+)-7deoxypancratistatin (67).

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

459

OAc

PMOM

OMOM

PMOM 1)Tf20/rEA/D'»C 2) KOAc/18-Crown-6/benz/rt 81% OMOM MPM

N aq. HCI/THF/SO'C 92»^ O

90

m-CPBAyCHgCIs 46% OAc AcO,

OAc

OAc MPM 1) NaOAc/DMF/HaO/BCrC 2) Ac20/ZnCl2/rt 85%

^^ ^^ I

Scheme 13. Synthesis of (+)-7-deoxypancratistatin (continued next page).

S. Prabhakar and M.R. Tavares

460

1)H2/Pd/C(5%) 1Naq.HCI(cat)/EtOHyrt :) NaOMe/MeOH ^ 85%

93

Scheme 13. Synthesis of (+)-7-deoxypancratistatin. (±yPancratistatm, The first total synthesis of (±)-pancratistatin (94) (Scheme 14), the structurally most complex of narciclasine alkaloids, was achieved by Danishefsky [27]. The requisite starting materia], the substituted benzaldehyde 95 prepared from pyrogallol in six steps in 18% overall yield, was converted via the homoallylic alcohol 96 into the diene 97. Reaction of 97 with 2-nitrovinylsulphone yielded the cycloadduct 98, which on treatment with tributyltinhydride and 2,2*-azobisisobutyronitrile furnished the cyclohexadiene 99. Whilst the cyclisation of the silylether 99 or the derived phenol, under the influence of iodine, could not be accomplished, the more nucleophilic stannylether did participate in the desired ring closure and provided via the iminium salt, the iodolactone 100 on aqueous work-up. The original synthetic plan contemplated the use of the diene of the type A (Scheme 14) as the pivotal intermediate for pancratistatin by selective modification of one of the double bonds. However, the propensity of the benzylether 101 to undergo facile aromatisation to the diphenylcarboxylic acid 102, necessitated hydroxylation of the olefin 101 prior to base-induced elimination of elements of hydroiodic acid. The c/s-diol 103, thus secured, was converted via the olefin 104 into /r^i/is-a-bromoacetate 105 in an unusual reaction studied by Moffat [28], involving the use of 2-acetoxyisobutyrylbromide. The new diol 106 secured from 105 by osmylation protocol was converted into the corresponding stannylene 107 that on successive

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaioids

461

treatment with p-methoxyphenylmethyl bromide and benzyl bromide furnished the cis-diol differentially protected 108. Selective oxidative removal of the p-methoxyphenylmethyl group, followed by exposure of the resulting hydroxybromoacetate 109 to zinc, reestablished the double bond at the original C(l)-C(2) position to give the allylalcohol 110. The derived trichloroimidate ester 111 on heating underwent a 3,3 suprafacial sigmatropic rearrangement to provide the p-acetamido olefin 112. C/s-hydroxylation of 112 occurred from the less hindered a-face of the molecule to afford the diol 113. Basic hydrolysis of the lactone 113 and subsequent carbodiimide induced lactamisation of the resuhant aminoacid 114 furnished 2,7-di0-benzylpancratistatin (115) from which the racemic alkaloid 94 was released by catalytic hydrogenation. HO.

1)NaH/Et2NCCI DMAP 2) MeOH/TsOH 86%

1)s-BuLin-HF 58% 2) TBDMSCi/imid. CHjCt/O'^rt

s-BuLin'MEDA THF/DMF >78'C-»rt

TBDMSO

Scheme 14. Synthesis of (i:)-pancratistatin (continued next page).

S. Prabhakar and M.R. Tavarei

462

Et20A7yC 92%

i)Msa/rEA CH2CI2 2)0BU 54%

SPaPh

coir TBDMSO

.NO2

CHOsA-eflux 12h/96% SOaPh

NEt2

TBDMSO

98

97

AfBN/TBTH/lol reflux/3h , 72%

1)TBAF/rHF/79% 2) (Bu3Sn)20M)ol sieve sA 3) l2n"HF 4) aq. work-up 67% TBDMSO

NEt2 99

Scheme 14. Synthesis of (±)-pancratistatin (continued next page).

Recent Advances in the Total Synthesis of Amaryllidaceae Allialoids

100

101 OH

HOj^

463

Js.

OSO4/NMO/H2O CH2a2/rHF rt/20h..,--^^-^^

90%

105 Scheme 14. Synthesis of (±>pancratistatin (continued next page).

\Base

S. Prabhakar and M.R. Tavares

464 Br

Br

BnO

O 110

Scheme 14. Synthesis of (±)-pancratistatin (continued next page).

465

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

.cas OBn

^^

1)NaH/THF

2)CCl3CNArC-rt 74%

|

I ^^

^^^

OBn 110 O, *^

/

H

100-105X y high vac/1.2h/^

BnO

56% X

-^

111

OBn NMO/OSO4/H2O rxjc: ^ THF/45hM ^ 75% OBn 112

( 1)K2C03/MeOHl O reflux/8h [ 82%/ 2)amberllte J / OH /

^ ^

113

f

>0H

gR ^As. ^ O H

HO^

H

1

OH 'CO2H BnO

^OBn 1)DCC 2)H2/Pcl/EtOAc 90%

114

^

cY ^ Y

\

H

\ '

N<^OH a

1

^NH

RO ^^mmm

Scheme 14. Synthesis of (±)-pancfatistatin.

115 RsBn 94 R=H

(±)-pancratistatin 1

466

S. Prabhakar and M.R. Tavares (+)'Pancratbtatm, [29]. The first asymmetric total synthesis of (+)-pancratistatin (94) was

reported by Hudlicky [30,26]. Thus the bromo olefin 116 (Scheme 15), obtained by a-addition of copper nitrenoid generated from (N-tosylimino) phenyliodinane to 45, was debrominated to the olefinic aziridine 117. The latter underwent trans 1,2-ring opening with diarylcyancuprate 118 to furnish the penta substituted aromatic 119. Conversion of the secondary sulphonamide 119 into its carbamoyl derivative 120 facilitated the reductive removal of N-tosyl group by sodium in anthracene and afforded a mixture of phenol 122 and its silyl ether 121 due to restricted rotation around the central biaryl axis (Figure 3). The latter on exposure to fluoride ion provided further quantities of 122.

icx

1) AIBNATBTHATHF/A 78%

45

BFaEtgO/THF -78-C — ft 75% RiO

O

118 Rir:TBOMS

117

X p

OR1

NMe2

NR2R3

11^ Ri=TBDMS:R2 = nH:R3 ,n2 = , n 3 ==iTs s

1

120 Ri=TBDMS ;R2 = BOC:R3 = T s ^

Scheme 15. Synthesis of precursor of (-i-)'-pancratistatin.

S-lBuLiATHF

(BC>:)20 (B

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

RiO

NMea

121 Ri=TBDMS:R2 = BOC:R3 = H

RiO

467

NMes

122 R i = H : R 2 = BOC:R3 = H

Figure 3. On treatment with sodium bis (2-methoxyethoxy)aluminium hydride (Scheme 16), 122 gave the aldehyde 123, which was converted by standard synthetic operations, into the methylObenzylester 124. Acid hydrolysis of 124 followed by allylic epoxidation of the diol furnished the P'Oxirane 125. On heating 125 in water containing sodium benzoate a remarkable chain of chemical events took place that resulted in the generation of (+)-pancratistatin (94) in 2% overall yield starting from bromobenzene. It was shown by monitoring the reaction by NMR spectroscopy that the overall process to involve the following steps: firstly, a ring closure of 125 to the phenanthridone 126 (Scheme 17), secondly, the formation of 127 by thermal loss of the N-protecting group, thirdly, diaxial opening of the oxirane 127 to the triolbenzoate 128, fourthly, hydrolysis of 128 to the tetrol 129 and finally, a slow dealkylation of the 0-benzyl ether 129 to (-i-)-pancratistatin (94). The elegant asymmetrization methodology of a meso compound, achieved in high enantioexcess under chiral environment, was the highlight of the total synthesis of (4-)pancratistatin (94) reported by Trost and Pulley [31]. The synthesis commenced with (±)conduritol-A (130), obtained fromp-benzoquinonc, (Scheme 18) which was converted into the acetonide 131 and thence, via the dialkoxide to the cis-bis carbonate 132 (Scheme 19). The chiral TC-allyl palladium complex A formed on treatment of 132 with the catalyst generated from chiral 6i5-amide 133 and Jt-allyl palladium chloride underwent azide substitution from the less hindered face of the molecule to provide the monocarbonate 134 in excellent yield and with high optical induction. An anti SN2 addition of the Grignard reagent 135 derived from 136 to the allylic ester 134 followed by cis hydroxylation of the resulting aryl olefm 137 furnished the hexasubstituted cyclohexane 138. Subsequent to protection of the hydroxyl groups as silylethers, bromination of the aromatic ring with N-bromosuccinimide, which incidentally occurred surprisingly with high

S. Prabhakar and M.R. Tavares

468

OH

RiO

*^, 123

O

\

1) BnBr/K2C03ADMF rt/4d/83% ^ , \ 2) NaCIOa/KHPOV W/rt \3)CH2N2

NMe2

122 R,=H:R2«BCX:;R3 = H

OMe

OBn OH / i ) H0AcA^2cyrHF 6CrCV73% 2) VO(acac)2A)en2 6(rC/53% OH H

i ^ " ^

OBn

124

OMe

\phC0fNf>(cat)/H20 , 100*C/6d/51%

/ '

125

OH

•

H04

cY^ Av ^ OH

>•••••

Scheme 16. Synthesis of (+)-pancratistatin.

^***s^^^^

H

^OH 1

"^OH 1

£ NH

0

94 (+)-pancratJslatJn

mmmmJ

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

469

OH

^

m

^OH 1

HO^

^OH 1

K:

H ^NH OH

^•^•1

Scheme 17. Synthesis of (+)-pancrati$tatin.

0

94 (+)-pancrall8tatln

^HMJ

470

S. Prabhakar and M.R. Tavares

+ anthracene-

- • Diels-Alder adduct

1)MeOH/CH2Cl2 NaBH4-CeCl3.8H20 97% 2)NMO/Os04(cat.) t-BuOH/HjO/pyr N2/24h/reflux 87% 3) A/460"/0-1 mm (retro Diels-Alder) ^ 100%

+ anthracene

Scheme 18.

regioselectivity, provided the aryl bromide 139 in 75% yield. The azide group in 139 was transformed to the amine 140 by a Staudinger reaction and thence to the bromoisocyanate 141. The derived carbanion, obtained by halogen-metal exchange underwent smooth intramolecular cyclisation to the tricyclic lactam 142. Fluoride ion induced desilylation generated the acetonide of the 0-methylether of l-wopancratistatin (143). The stereochemical correction at C(1) was achieved at this stage by forming the cyclic sulfate 144 first and then subjecting it to nucleophilic opening with benzoate ion. In situ acid hydrolysis of the resulting acetonide gave the (+)-pancratistatin derivative 145. The observed regioselectively in the introduction of the benzoate group was attributed to ring C in 144 assuming a lower energy twist-boat conformation thereby favouring nucleophilic attack at C(l). Base hydrolysis of benzoate 145 followed by demethylation of the resulting anisole derivative, furnished (+)-pancratistatin with an 11% overall yieldfromthe meso diol. Other interesting approaches yet to culminate in successful chiral syntheses of narciclasine alkaloids are reported in the recent literature [32-40].

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids OH

471

OCOaMe O. O'

/

i)n-BuU(2eq) THP/Q^ 2) CICO2M6 \ 87%

•

gC02Me

CHaOa 82%

OH

N3 131

134

0C02Me

135. CuCN THF/Et20

£CX complex A

138

OMe MgBr

Scheme 19. Synthesis of (
S. Prabhakar and M.R. Tavares

472

1) TBDMSOTI / 2.6-lutidine CH2a2/100% 2) NBS/DMF/75%

OMe

0

142

Scheme 19. Synthesis of (+)-pancralistatin (continued next page).

OMe

O

143

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

473

1)S0Cl2/rEA 2)RuCl3.H20(cat) Nai04 Ca4/MeCN/H20/rt 72%

SO2--Q

^'^-. .A^^O,

1) CsOCOPh/DMF 2)THF/H20/H2S04(cat) OMe

O 144

•

^

OH HO^

VT ^

^L

1)MeOH-K2C03/rt

0^

<

OH

^^^^^^^^^

^OHI

H

*.

^^OH 1 2) UI/DMF/BO^g..-^

^NH

0

9 4 (•t-)-pancratistatin

Scheme 19. Synthesis of (+)-pancratistatin.

OMe j4g

474

S. Prabhakar and M.R. Tavares

1.4.3.

Dibenzo[c,^]azocine Alkaloids

Buflavine [41]. S-O-Demethylbuflavine, [41], The ability of lithium tetiamethylpiperidide to selectively deprotonate the methyl group of N,N>dimethylarylamides and the in situ capture of the resulting carbanion by a silyl chloride to form a,a-^/5-silyl derivatives had been put to good use in a neat synthesis [42] of buflavine (147) and 8-0-demethylbuflavine (146) (Scheme 20). The a,a>disilylamide 148, thus secured from 149, was i7-metallated and thence converted, by standard synthetic operations to the boronic acid 150. The Suzuki cross coupling product 151 obtained from 150 and ^-bromobenzaldehyde on exposure to caesium fluoride furnished, via in situ capture of the resulting carbanion 152 by the proximate aldehyde group, the Peterson elimination product, the enamine 153 in 54% yield. Saturation of the double bond and subsequent reduction of the resulting amide provided 80-isopropylbuflavine 154. Chemoselective removal of the protecting group with boron trichloride afforded 8-0-demethylbuflavine (146), which on methylation furnished buflavine (147).

MeO.

TMSCI

l-PrO'

1)n-BuLin-MEDA/ THFAZe^C 2) B(0Me)3 • 3)H;MeO, CH(TMS)2 l-PrO O

150

^®

2M NagCOy^ M«0' DME/reflux 70%

^CH(TMS)2

i-PrO'

Scheme 20. Synthesis of buflavine, S-O-demethylbuflavine (continued next page).

475

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

C8F/DMF/110°C 54% MeO. ^CH(TMS)2 MeO.

l-PrO'

l-PrO'

MeO,

i-PrO*

1)H2/Pd(OH)2/C 2)LAH

MeO.

y*

' '

MeO^

r MeO^

T^ J^

MeO'^

HO^

y\

II II

NaH/Me2S04

Me 1 ^^••M^

147

[

DMF/O'C 84%

buflavine ^^^^^J

Scheme 20. Synthesis of buflavine, 8-0-demethylbuflavine.

146

s^^:^^

11

J < ^ s ^ II

^^

N \

11 11 1

Me 1

8-O-demethylbuflavine

1

476

S. Prabhakar and M.R. Tavares

1.5.

Tetracyclic Alkaloids Pyrrolophenanthridines/Pyrrolophenanthridones

1.5.1.

(±)'J I'Hydroxyanhydrolycorine, 11 Jl-Dehydroanhydrolycorine,

Dehydroanhydrolyco-

line (155) [43] and 11-hydroxyanhydrolycorine (156) [44] were synthesised by Rigby et al, [45] making use of a method developed by them for quick assembly of hydroindole systems. Relevant to the present synthesis was the pivotal observation that vinyl isocyanates react with isonitriies in a formal (4f 1) sense, represented as occurring in discrete steps, to furnish heterocyclic derivatives (Scheme 21).

CtL

C^N—R

N=C=rO Scheme 21.

Accordingly, the cyclic isocyanate 157, derived from cyclohexene-l-<;arboxylic acid and cyclohexylisocyanide in acetonitrile under reflux, led, via the hydroindolone 158, to 159 in good yield (Scheme 22).

^y^NHCy

157 Scheme 22. Selective

alkylation

of

the

enamidic

nitrogen

in

159

with

2-iodo-4,5-

methylenedioxybenzyl bromide afforded the enamino-enamide 160 (Scheme 23). Application of Heck's oxidative coupling method to 160, generated by G-endo addition, the tetracyclic enamide

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

477

161, the acid hydrolysis of which furnished the a-
NHCy ^ Pd(0Ac)2/ O TBAC/DMF. 10(rC.2h 71%

Scheme 23. Synthesis of (±)-l l-hydroxyanhydrolycorine, 11,12-dehydroanhydrolycorine.

478

S. Prabhakar and M.R. Tavares Assoanine, [46]. An interesting synthesis of assoanine (164) reported by Moore [47]

(Scheme 24), involved the thennolysis of the hydroxycyclobutenone 165 obtained from dimethylsquarate (166) and lithium salt of N-propargylindoline, which led directly to 7,10dihydroxyassoanine (167) and the N-benzylindole 168 in 43 and 50% yields respectively. Conversion of 167 into its diethylphosphate ester, followed by reductive cleavage of the latter with sodium in liquid ammonia furnished assoanine (164) in low yield (25%). The transformation (165 - • 167) is believed to occur via electrocyclic ring opening of the cyclobutenone 165 to enynylketone 169 and its ring closure to the biradical 170. A subsequent 1,6-addition of the carbon centred o radical to the proximate aromatic ring generated the cyclohexadienyl radical 171 that abstracted a hydrogen atom from the nearby hydroxyl group to generate/'-benzoquinone 172 and thence, by prototropy, to 167.

MeO^

MeO^

MeO

OH

M«'^~^0 165

166

J p-xylene/reflux ^N2

MeO

MeO

MeO

MeO OH

168 Scheme 24. Synthesis of assoanine by Moore (continued next page).

167

Recent Advances in the Total Synthesis of Amaryllidaceae Aiicaioids y"

MeO

2) (EtO)2P(0)CI/(y»C 3) Na/NHa (I)

MeO

167

" '

MeO^

1)NaH/rHF/3h/tt

479

T ^ 11

M e O ^\ v^^^^^^

|f^ ] 1 1 ^r\

^

164 assoanine

I

MeO, MeO MeO MeO 170

169

MeO

MeO

MeO

MeO

171

172

Scheme 24. Synthesis of assoanine by Moore. Assoanine via Vasconine, A similar intramolecular addition of an aiyl a radical generated in a more conventional manner to an aryl ring constituted an alternative approach [6] to the synthesis of 164 (Scheme 25). Thus, o-bromobenzylaniline 173 obtained by sodium borohydride reduction of the Schiffs base derived from 6-bromoveratraldehyde and the

S. Prabhakar and M.R. Tavares

480

commercially available o-aminophenethylalcohol, on exposure to the combined action of 2,2'azobisisobutyronitrile and tri-n-butyltinhydride afforded the phenanthridine alcohol 174 in 27% yield. The latter on treatment with phosphorus tribromide was converted into the quaternary salt, vasconine (175) [48], which on reduction with sodium borohydride provided 164.

MeO

AlBNn-BTH benz/ reflux 27%

MeO

^^

MeO

174

173

PBryEt20/hex reflux/6.5h

/ MeO^

r

Pi IT

T

MeO^

7I

L J^

NaBHVMeOH/rt ^ 88%

MeC^ ^^^^^^

^

164 assoanine

Y^\r KJ

(T^

^

V \

MeO'^

1

175 vasconine ^^BHB

1

•••I^HMHHHB^BMldi

Scheme 25. Synthesis of assoanine via vasconine. In an another approach [49] to assoanine, again via vasconine (Scheme 26), a room temperature Ullmann reaction featured as the key reaction, after it was found the 7lithioindoline urethane 176 failed to participate in the anticipated chelate assisted nucleophilic aromatic addition to the imine 177. Thus the copper derivative 178 derived from 176, underwent smooth coupling with the iodoimine 179 to provide the biaryl 180 which on, in situ, hydrolysis led to the aldehyde 181. Deblocking of the N-protecting group with gaseous hydrogen chloride furnished vasconine (175) and thence by reduction, assoanine (164).

Recent Advances in the Total Synthesis of Amaryllidaceae Alicaloids

481

MeO

177R = CH(CHMe2)2 |CuI/P(0Et)3 jEt20/-45«C

MeO N-Cy MeO

179 1)Et20/-78«-2(rC v2)1NHa MeO

MeO

,65r9

MeO

MeO HCI (g)yCHCl3

1oo?^•

181 /•

n1

180 '"

f

[r 1^ 1

NaBH4/EtOH

MeO^

Y**^

MeO-^ " V,^^^^^

% ^

JL

93%/

11

i'L ^ - - ^ 1

164 assoanine

MeO^

1

Scheme 26. Synthesis of assoanine vUx vasconine.

MeO-^

^

r^

K}

it >w ^ N . — y 1

175 vasoonine

1

S. Prabhakar and M.R. Tavares

482

Ungeremine. The anti-tumour betaine alkaloid ungeremine (182) [50] was synthesised by Snieckus et al. [51] (Scheme 27) utilising their useful modification of the cross-coupling methodology of Suzuki forbiaryl compounds. OMs 1) MsCin-EA/CH2Cl2 99% 2) NaCNBHyHOAc 74% 3) Br2/CH2Cl2 89% O

184

/Pd(PPh3)4/ /NazCOa/DME 183

OMs

o©

K;

Y*^^r

OMs

]

f\

T

-^^^^^

v^^^^^_

182

ungeremine

1

Scheme 27. Snieckus* synthesis of ungeremine.

187

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

483

One of the starting materials, the bromoindolinemesylate 183 was obtained from the commercially available 5-hydroxyindole by mesylation followed by successive treatment of the resulting indole derivative with sodium cyanoborohydride and bromine. Coupling of 183 with the known boronic acid 184 in the presence of zero valent palladium complex led directly to the lactam 185, the intermediate carbinolamine 186 formed initially in the reaction suffering facile aerial oxidation during work-up. On reduction with sodium (2-methoxyethoxy)aluminiumhydride, the amide 185 yielded the aminophenol 187 which on chromatography underwent oxidative aromatisation to 182 in 54% yield. A multi-step synthesis [52], reportedly amenable to large scale preparation of ungeremine (182), was based on the chemistry of an aryl radical generated in an unusual manner, and employed the 1-aroyl bromonitroindoline 188 as the starting material (Scheme 28). On thermolysis in dimethylsulfoxide containing potassium carbonate and benzyltriethylammonium chloride, the substance 188 underwent cyclisation, via radical 189, to give a 1:1 mixture of two regioisomers from which the requisite nitrophenanthridone 190 was isolated in 27% yield. The phenol 191 secured from 190 by standard chemical reactions ie, catalytic reduction to the amine, formation of diazonium fluoborate and subsequent introduction of hydroxyl group was alkylated to the 0-benzylether 192. The amine 193 obtained on treatment of 192 with lithium aluminium hydride was 0-debenzylated to the corresponding phenol, which on oxidation, furnished 182 in 9% overall yield startingfrom188. NO2

Scheme 28. Synthesis of ungeremine (continued next page).

-1

S. Prabhakar and M.R. Tavares

484

191 NaHADMF/BnBr 51% OBn

OBn

193

1)Pd/C/H2/EtOH

7(rc

2) H202-Mn02

192

25*C/2h 80%

Scheme 28. Synthesis of ungeremine. Roserine, The unusual presence of three methoxyl groups at C(8), C(9) and C(10) in the structure suggested for roserine 194 on spectroscope basis [53] and the paucity of natural

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

485

substance prompted Flippin to undertake the syntheses [54] of both (±)-194 and its regioisomer (±)-195 (Scheme 29). With this end in view, the keto-ketal ester 196 obtained by alkylation of known a,a-dimethoxycyclohexanone, was condensed with benzylamine 197 and the resulting imine reduced in situ to the cw-amine 198. The latter on cyclisation with hydrochloric acid followed by exposure of the resulting dihydrophenanthridine derivative to oxygen led to the phenanthridinyl acetic acid 199. Reduction to alcohol 200 and its subsequent treatment with phosphorus tribromide furnished 195 as the bromide salt. In an analogous manner the quaternary salt 194 was also prepared. However, both the ^H and the ^^c NMR spectra of synthetic 194 were found to be different from those reported for the alkaloid. On the other hand, although no direct comparison of 195 with the natural product could be made, the NMR spectrum of 195 was more in accord with that recorded for roserine.

C02l-Pr OMe

198 Scheme 29. Synthesis of (±)-roserine (continued next page).

S. Prabhakar and M.R. Tavares

486

NH

COai-Pr

MeO

MeO

^ ^

r

-V

HI

MeO^

MeO^

)pC

\^^^^^^

OMe 195 (±)-

PBra/beiij

1® / 1 X®

OMe

reflux/20 min 60%

200

1

X^Br©

Scheme 29. Synthesis of (±)-roserine. Anhydrolycorinone [55], Hippadine [56], Oxoassoanine [46], Pratosine [57]. The syntheses of alkaloids, incoqx>rating the pyrrolophenanthridone nucleus, in the majority of cases followed the A + CD - • ACD -» ACDB sequence, in which organometallic chemistry featured prominently in this transformation. Simple syntheses of anhydrolycorinone (201), hippadine (202), oxoassoanine (203) and pratosine (204) described by Black [58], involved direct intramolecular oxidative coupling of appropriate N-aroylindoline derivatives. The indolines were chosen instead of the corresponding indoles to avoid ring closure occurring at C(2) of the indole nucleus. Thus, N-piperonyl indoline 205 in acetic acid, on heating with a stoichiometric quantity of palladium acetate furnished anhydrolycorinone (201) in a low yield (15%) and the 9,10-methylenedioxy isomer 206 (10%). The former on oxidation provided quantitatively hippadine (202) (Scheme 30). The dimethoxy analogue 207, on the other hand, underwent the same oxidative cyclisation to

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

487

oxoassoanine (203) in higher yield, 50% (Scheme 31). The latter on oxidation with dichlorodicyano-p-benzoquinone afforded pratosine (204). In the approach of Snieckus [51] (Scheme 32), 201 was obtained in one step by palladium(0) promoted coupling of the known boronic acid 208 and 7-iodoindoline 209. The latter was prepared from N-acetylindoline via iodination of its 7-thallo derivative followed by hydrolysis of the resulting iodoamide. The initial product of coupling, the carbinol amine 210 readily suffered aerial oxidation to 201, which on dehydrogenation yielded 202. Pd(0Ac)2. HOAc. A 115-12(rC/5h/15%

DDQ

206 Scheme 30. Black's synthesis of anhydrolycorinone and hippadine.

S. Prabhakar and M.R. Tavares

488

-^ 1

f

iT MeO

MeO^

MeO

MeO*^

^^Hx^1

1^^r\ yti^^^

1

0 V^HHHMi

203 oxoassoanine

/^D\DDQ

Scheme 31. Black's synthesis of pratosine.

1)TTFA/rFA N \ Ac

2) KKHaO) (70%) 3) aq. NaOH/EtOH 95%

Scheme 32. Snieckus* synthesis of anhydrolycorinone (continued next page).

1

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

489

210

Scheme 32. Snieckus' synthesis of anhydrolycorinone. Oxoassoanine, Meyers* approach [59] to oxoassoanine was based on the observation that aryloxazolines incorporating an e>-methoxy group undergo SNAr reaction with aryl Grignard reagents to form biaryls in good yields. The regiospecificity observed was ascribed to chelate controlled nucleophilic addition of metallated aromatics to the carbon bearing the methoxy group (Rgure 4).

Figure 4.

S, Prabhakar and M.R. Tavares

490

Thus, the N-protccted indotine 211 (Scheme 33), on regiospecific metallation followed by bromination with dibromotetrafluoroethane provided the 7-bromoindoline 212. Removal of the urethane functionality and subsequent benzylation of the free amine formed, furnished the tertiary amine 213. Addition of oxazoline 214 derived from 2,4,5-trimethoxybenzaldehyde to the Grignard reagent prepared from 213, followed by acid hydrolysis of the resulting biaryl 215 afforded the 2-substituted isobutylbenzoate 216. Catalytic N-debenzylation of the methylester 217 obtained by transesterification of 216 yielded oxoassoanine (203).

Br s-BuLi/ TMEDAH-HF {BrF2C)2/-78XO'C /68% BOC—N

BOC—N

1)TFA/CH2Cl2 2)n-BuLi/BnBr^ Bn--^N^^'^^^^'V^

• \J

99%

MeO.

MeO

MeO.

1)NaOMe/MeOH A/3h 2)Pd/C/HOAc/MeOH H2 (1atm)

MeO

/

^

216 R=CH2

C

^1

sxA A r^ K) j^^-^ 1

MeO>^

MeO'^ 217

R = Me

\^^^__ Scheme 33. Meyer's synthesis of oxoassoanine.

0 203 oxoassoanine

1

wmmmmmmmmmmmmmS

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

491

Anhydrolycorinone, Hippadine, Kalbretorine, Qxoassoanine, Pratosine, The efficient coupling of 7-stannylated indoline 218 and 6>bromopipeix>nal promoted by Pd(0) complex provided another route [60] to anhydrolycorinone (201), hippadine (202) and the phenolic alkaloid, kalbretorine (222) [61]. Thus, the tricyclic urethane 219 (Scheme 34), obtained in 63% yield, on acid hydrolysis led to the carbinolamine 220 which, without purification was oxidised to anhydrolycorinone (201).

Scheme 34. Synthesis of anhydrolycorinone.

492

S. Prabhakar and M.R. Tavares Metailation of 201, which occurred regiospecifically at the position peri to the carbonyl

group, followed by successive treatment of the resulting 7-lithio compound with trimethylborate and hydrogen peroxide in acetic acid furnished dihydrokalbretorine (221) (33%) (Scheme 35). Subsequent dehydrogenation furnished the alkaloid, kalbretorine (222). Anhydrolycorinone could be similarly oxidised to hippadine (Scheme 36). Starting with appropriate obromobenzaldehyde and 218, both oxoassoanine (203) and pratosine (204) were also accessible by this method.

1)t-BuU/rHF/-78*C 2) B(OMe)3/THF/-78'C - rt 3) 30% H202/HOAc/rt/33%

221 (33%) r

f^

< ;

li^^^^_

W

OH 0 222 kalbretorine

1 A 1 j\

DDQ/dio: refluxMOh

^ ^ J

Scheme 35. Synthesis of kalbretorine from anhydrolycorinone.

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

493

Scheme 36. Synthesis of hippadine from anhydrolycorinone. Anhydrolycorinone, Hippadine,

Oxoassoanine, The

recent

syntheses

[14]

of

anhydrolycorinone (201), hippadine (202) and oxoassoanine (203) once again made use of the Suzuki reaction and a very mild and efficient reagent for effecting Bischler-Napieralsky type cyclisations (Scheme 37). Thus the 7-arylindole 223 obtainedfromthe arylboronic acid 224 and the bromoindole 225 in high yield, was reduced with sodium cyanoborohydride in acetic acid to provide the indoline 226, which was converted into the methylcarbamate 227. An optimum yield (76%) of oxoassoanine (203), contaminated with the regioisomer (228 ; 7%) was realised, presumably via the intermediate 229, when a mixture of 227 (1 eq.) and 4(N,N-dimethylamino)pyridine (3 eq.) was treated with trifluoromethane sulfonic anhydride (5 eq.). Similarly the methylenedioxy analogue of 224 and 225 led to anhydrolycorinone (201) which, on oxidation, provided hippadine (202). Pratosine. The utilisation of the cyclic hydroxamic acid 230 as a late precursor of pratosine has also been described [62] (Scheme 38). The preparation of 230 was achieved in excellent yield by photocyclisation of the borate ester 231 itself obtained from hydroxamic acid 232. Aqueous hydrolysis of the cyclic borate furnished 230, which underwent a smooth Michael addition to methyl propiolate to form the 0-vinyl ester 233. The latter, on thermolysis in wet dimethylsulfoxide provided, via a 3,3-sigmatropic rearrangement, pratosine (204, 17% yield) and methyl pratosine'4-carboxylate (234,35% yield). Anhydrolycorinone. Two recent methods embodying the AB -^ ABCD strategy for the synthesis of anhydrolycorinone have been reported. The first synthesis due to Guitian et al [63] (Scheme 39) involved the pyrone 235 as the key intermediate and was secured as follows: 4,5methylenedioxyhomophthalic anhydride 236 was opened with 3-butyn-l-amine to the amide

494

S. Prabhakar and M.R. Tavares

Pd {PPh3)4Aol B(0H)2

MeO

MeO

MeO

MeO 225

224

NaBHaCN/HQ

MeO 1) NaHH-HF ^ 2)CIC02Me/15*C/16h , , -, 96% ^^

MeO

Tf20/DMAR

f

MeO^

T

MeO-^' ^ ' * ! ^

r^ 1

T M 4-

i/i-y 0

^•••••1

MeO

1

203 oxoassoanine

J

MeO

MeO

Scheme 37. Synthesis of oxoassoanine.

228

495

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

MeO

1) BF3Et20/Et20 reflux^.5h/rt/24h

86%

MeO

1 /

benz/hv/30h/37*C pyrex filter/>92%l

.BF2 0~-—BFo 231

232

MeO

MeO reflux/24h 99%

MeO

MeO

S--C02Me/MeCS TEA/3h/rt 97% .C02Me DMSO/H2O (0.5V/V) reflux/4h

MeO MeO

233

MeO C02Me

MeO

234

Scheme 38. Synthesis of pratosine.

230

496

S. Prabhakar and M.R. Tavares

carboxylic acid salt that on heating provided the N-alkynyl imide 237. Short heating of 237 and diethyl ethoxymethylenemalonate at 220®C furnished via Michael addition, 235. On thermolysis it underwent an intramolecular Diels-Alder reaction and generated the unstable 1,4dihydrobenzene-5-lactone 238 that extruded carbon dioxide to provide the phenanthridone carboxylic ester 239. The latter on hydrolysis and subsequent copper mediated decarboxylation of the resulting acid provided anhydrolycorinone (201).

Scheme 39. Guitian's synthesis of anhydrolycorinone.

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

497

In a recent report, Padwa [64] disclosed a general method of wide applicability for constructing a variety of heterocyclic systems. It involved an amino furan ester as a more reactive four carbon component vis a vis a pyrone in intramolecular Diels-Alder addition to an unactivated olefin. This method as applied to the synthesis of anhydrolycorinone consisted of the preparation of the tertiary amide 240 (Scheme 40) and its subsequent thermolysis to the N> o-bromoaroylindoline 241. It is believed that the initially formed cycloadduct 242 opened to the acyl iminium oxyanion 243, which by prototropy and dehydration generated 241. The latter, on photolysis in the presence of bis (tri-«-butyltin), furnished the tetracyclic ester 244, which was hydrolysed and decarboxylated to anhydrolycorinone as in the previous synthesis.

C02Me

C02Me

C02Me

COaMe

240

242

Scheme 40. Padwa's synthesis of anhydrolycorinone (continued next page).

498

S. Prabhakar and M.R. Tavares COaMe

C02Me

243

242

COaMe

COaMe

241 anhydrotycorinone

Scheme 40. Padwa's synthesis of anhydrolycorinone. Oxoassoanine. Vasconine (175) had also been converted into oxoassoanine (203) by oxidation either with alkaline hydrogen peroxide [6] or alkaline permanganate [49].

1.5.2.

Lycorine and Related Alkaloids

(±)-Lycorine. Boeckman's particularly elegant synthesis [65] (Scheme 41) of the most abundant >4mary//idbc*eae alkaloid, (•)-lycorine (245) [66], known since 1877 [67], involved an intramolecular Diels-Alder reaction of an appropriately functionalised azatrienic system. This approach (A + D - • AD - • ADCB) somewhat reminiscent of the one used by Stork for (±)-7oxo-a*lycorane [68], possessed the virtue of establishing the correct stereochemistry of four

Recent Advances in the Total Synthesis of Amaryllidaceae Allialoids

499

contiguous carbon centres C(l), C(2), C(4a), C(lOb) generated during the cycloaddition and required a minimum of functional group modifications thereon to achieve the final structure of the (±)-alkaloid. The requisite starting materials for the advanced intermediate, the E,E-dienamide 246 were the o-substituted piperonyloyl chloride 247 and the cyclopropane carboxyaldehydeimine 248. The latter was prepared from the commercially available cyclopropyl cyanide 249 in six steps as follows: treatment of the lithium carbanion of 249 with dimethylallyl bromide followed by reduction of the resulting nitrile with diisobutylaluminium hydride furnished the aldehyde 250. The derived dimethylacetal, on ozonolysis, provided the acetaldehyde 251 which was converted into the enol acetate and thence, by acidic hydrolysis into the requisite aldehyde 252. The latter on condensation with 2,4-dimethoxybenzylamine, generated from the corresponding azide by a Staudinger reaction, provided 248 which was used in situ for the ensuing reaction with 247 {vide infra).

1)HC(0Me)3 (MeOfeCH,

AT

A v 2)>^v.Br 249 ^'^'^^^

250

Scheme 41. Synthesis of (±)-lycorine (continued next page).

500

S. Prabhakar and M.R. Tavares .OH

1)Jl^/r90Hy25'C/15h 2) NBS/DMF/23*C/20h 74% (from safroie)

1) n-BuUgHF/-78'CA).5h 2) ^ ^

^

/rHF/-78*C/1h

23*aih/80%

HsIOe/INHCin-HF 2(rC/3.5h

255 (t-Bu-&)20/rEA/23*C/15h O

t-Buccnl

Scheme 41. Synthesis of (±)-lycorine (continued next page).

501

Recent Advances in the Total Synthesis of Amaryllidaceae Ailcaloids O II t-BuCO^

M

Pd(PPh3)4/ C^ ^ CH2a2/23'C/1h

/EtOAc/89%

OAc

260

Scheme 41. Synthesis of (±)-lycorine (continued next page).

261

S. Prabhakar and M.R. Tavares

502

Pd(MeCN)2a2A).25eq. tol(0.1M)/23*'C/5h

OAc

0

II

OAc

t-BuCO^

c

DBU/CHCI3 70% (from 261)' ^ ^ - ^

^ 246

6

u

/reflux/56h r

1)LAHn-HF 2)A/2h

'—

C >«HHMI

263 Scheme 41. Synthesis of (±)-lycorine.

OH

1

14 A

245

H

1

(±)-lycorine

D >

1

J

Recent Advances in the Total Synthesis of Amaryilidaceae Allcaloids

503

The synthesis of 247 commenced with the diol 253 itself prepared from safrole, which when subjected to successive reactions with acetone and N-bromosuccinimide furnished the bromoarylacetal 254. Transformation of the bromide into the 0-protected carboxylic acid derivative 255 was achieved by the reaction of the derived aryllithium with allyl chloroformate. Unmasking of the acetal functionality and the oxidation of the resulting diol was accomplished in one step with periodic acid in aqueous hydrochloric acid. The unstable phenylacetaldehyde 256, thus generated, was converted stereoselectively to the cis-enol ester 257 with pivalic anhydride and triethylamine. The observed geometry was ascribed to kinetic deprotonation of the preferred ground state conformation of the reactive acyloxonium ion intermediate 258. Deprotection and regeneration of the carboxylic acid as its potassium salt 259 was accomplished

with

catalytic

amount

of

palladium

zero

complex

and potassium

ethylcyclohexane carboxylate. Slow addition of the acid chloride 247, derived from 259 with oxalyl chloride, to the imine 248 resulted in the formation, via N-acylation and subsequent nucleophilic opening of the cyclopropyl ring, the dienamide 260 with the undesired Z,Egeometry. The all important E,E-geometry of the diene required for the planned Diels-Alder reaction was, however, secured firstly by releasing the secondary dienamide 261 and secondly by subjecting it to the action of palladium (II) salt. The latter process caused isomerisation, presumably via a-allyl complex, to a 1:1 mixture (90%) of the E,E-isomer 262 and recovered 261. The mixture on exposure to base yielded the azadecatrienic amide 246, which was separated from the recyclisable and unreacted 261. The key intermediate 246, on thermolysis, underwent a smooth intramolecular (4 + 2) cyclo exo addition to furnish the oxolycorine 263. A fmal reduction with lithium aluminium hydride delivered the (±)-alkaloid 245. A recently published full account of another synthesis [69] of the same alkaloid starting from the /ra/w-cinnamic ester 264 represented a different approach (ACD -» ACDB) to {±y lycorine (Scheme 42). An intramolecular Diels-Alder reaction of 264 in o-dichlorobenzene furnished the two diastereomeric lactones 265 (86%) and 266 (5%) involving the endo and exo modes of addition respectively. The transposition of the carbonyl group of 265 to 267 was achieved by reduction with lithium aluminium hydride, followed by treatment of the resulting diol with Fetizon's reagent, which selectively oxidised the less substituted alcohol to give isomeric 6-lactone 267. On exposure to iodine in alkaline medium 267 underwent iodolactonisation to afford the iodo-hydroxy y-lactone 268. The derived tetrahydropyranyl ether 269, on treatment with base afforded the olefin, which was hydrolysed to the primary alcohol 270. Jones's oxidation of the latter furnished the carboxylic acid 271 which on treatment with diphenylphosphorylazide in tert. butanol was converted, with retention of configuration, into the /-butylcarbamate 272. The free amine liberated from 272, on exposure to methanolic methoxide, underwent cyclisation to afford the key intermediate, the c/5-lactam 273, which was

S. Prabhakar and M.R. Tavares

504

268 269

R=H —iDHPA-sOH rt/4h/87% RsTHP^

270 RsCHaOH—ijones oxldatlonArC/0.25h r^^^ ^""^^"^ TEA/DPPA t-BuOH/reflux/4h 78% L ^ 2 7 2 R=HNBOC

«-xx:>

1)TFAA3H2a2 ^ lrt/1h/98% 2) NaOMe/ MeOH/rt/3h 97%

Scheme 42. Synthesis of (±)-lycorine (continued next page).

505

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids Q//^.,.

DTBDMS

1) TBDMSCi/lmid/DMFm/8r)/98% — • 2) m-CPBAA5H2a2/rt/42h/85% ^^N^*

274 1)TBAF/rHF/ttA).5h

77% 2) hz^fpf( OAc iiAlSePh

1) (PhSe)2/NaBH4 EtOH/reftuxA).25h

AcO,

2)Ac20/^)yr/tt/21h 98%

276 1) SMEAHAol/irefiux/0.5h 2) CH2=»N(Me)2p/rHF/i'eflux/1h 43% OH

Scheme 42. Synthesis of (±)-lycorinc. taken to the final product, (±)-iycorine, as follows: subsequent to protection of hydroxyl group as the silyl ether, a-epoxidation was accomplished with peracid to give 274 which, when treated with fluoride ion, generated the p epoxide isolated as its acetyl derivative 275. The latter on

S. Prabhakar and M.R. Tavares

506

nucleophilic ring opening with sodium phenylselenate furnished, after acetylation, the diacetoxy lactam 276. Reduction with SMEAH, followed by cyclisation of the resulting pyrrolidine with Eschenmoser salt, furnished the tetracyclic base 277. Oxidative c/5-elimination of phenylseleno group effected with sodium periodate led to (±)-lycorine (245). (+)'Trianthine. Central to Oppolzer's synthesis [70] of (+)-trianthine (278) [71] (Scheme 43) was the observation that appropriately substituted N-pentenylhydroxylamines undergo thermal suprafacial

cyclisations to 2-substituted pyrrolidine derivatives, wherein

the

stereochemistry of the newly created asymmetric centres is found to be determined exclusively by the geometry of the starting olefms. Thus the E-olefm A, on thermolysis, yielded only B. None of its stereoisomer C was formed in the reaction (Figure 5).

Rgure 5. The requisite starting material for the synthesis was the commercially available (IS, 2S)-3chlorocyclohcxa-3,5-diene-l,2-diol (279) which was converted into the enantiomerically pure hydroxyacetonide derivative 280 by the method of Hudlicky et a! [72] and thence to the corresponding acetate 281. The y^cetoxyenone underwent an interesting deacetoxylation reaction when treated with tetramethyldisiloxane in the presence of zero-valent palladium catalyst to furnish a mixture of ketones 282 and 283, which was isomerised by triethylamine to the pure (2S3S)-enone 283. A 1,2-addition of 3,4-methylenedioxyphenyllithium, followed by trapping of the resulting alkoxide with acetic anhydride provided the tertiaiy acetate 284. Anti-selective SN^' substitution of the acetate was achieved with vinylmagnesium chloride in the presence of cuprous bromide to provide exclusively the vinylcyclohexene 285 from which the key intermediate, the hydroxylamine 286, was secured in 75% overall yield by a standard set of reactions, namely, by hydroboration, oxidation, oximation and reduction respectively. Thermolysis of 286 in degassed benzene proceeded as anticipated, with stereospecificity to provide the cis-hydroindole 287. Reductive cleavage of the N-0 bond followed by PictetSpengler cyclisation of the resulting amine with Eschenmoser*s salt provided the acetonide 288, from which the (+)-alkaloid was generated by trans ketalisation.

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

507

OH

282 TEA/CH2CI2 reflux/1 h 66%

1) ArU/Et20-THF/-78*»C - O'^C

OAc 284

"'i^C

CuBr.MeaS 95%

1)9-BBN-H, H2O2 2) (C0CI)2. DMSO 3) NH2OH: 4) NaBHaCN 75%

285

Scheme 43. Synthesis of (+)-trianthine (continued next page).

283

508

S. Prabhakar and M.R. Tavares

benz/70h

reflux 93%

IjRaneyNI-wetEtp 2) CH2=N^ r7THF/40'C/16h Me 89% •

HO^

288

r

OH

^

JL

1

T i "^ / 278

(•i')-trianthine

1

SMNM

Scheme 43. Synthesis of (+)-trianthine. 1.5.3. Galanthamine and Related Alkaloids (±)-Narwedine, The biomimetic synthesis of narwedine type compounds involving oxidative cyclisation of substances incorporating the norbelladine structural unit is invariably beset by occurrence of preferential phenolic p,p-coupling. The desired regioselection is usually achieved by a blocking-deblocking protocol as exemplified in the synthesis of (±)-galanthamine {vide infra). However, Holten et al [73] showed that such an approach can be dispensed with, by the use of appropriate palladocycles. Thus, the methylthiomethylether 289, derived from the protected isovanillin and tyramine (Scheme 44), furnished, with Pd(II) salt, regiospecifically, the sandwiched organometallic compound 290.

509

Recent Advances in the Total Synthesis of Amaryllidaceae Ailialoids MeO, 1)NaBH4/D"C/1h 2) CHSFO / MeOH / NaBHsCN

MTMO

MeO

MeO

U2Pda4/MeOH ^ DIEA/-78«C 95%

MTMO

289

CH2Ci2-TFA (2:1) 1)TTFA(2eq) -10*C/1.5h PPh3(2eq)/ 25V14h 2) aq. work-up

MeO,

Scheme 44. Synthesis of (±)-narwedine.

290

S. Prabhakar and M.R. Tavares

510

The latter on treatment with thallium trifluoroacetate, under carefully defined conditions followed by aqueous work-up, led direcdy to narwedine (291) [74] in 51% yield. The remarkable transformation is believed to occur via the cationic intermediate 292, formed by an oxidative process, undergoing a 1,2 C-C shift to generate the carbenium ion 293. Aromatisation involving the cleavage of C-Pd bond, followed by hydrolysis of the resulting sulphonium salt 294 liberated the phenol, which smoothly underwent Michael addition to the proximate enone system, furnishing (±)-narwedine (291) in 44% overall yield. (±)'Galanthamine, In a recent synthesis [75] of galanthamine (295) [76] (Scheme 45), it was observed that the dibromoderivative of N-benzyl-N-formyltyramlne 296, on oxidation with potassium ferricyanide and sodium bicarbonate in chloroform afforded the dibromo Nn^marwedine derivative 297. The comparatively high yield (as 40%) obtained in tiiis o, pcoupling reaction, vis a vis the didebromo and the monobromo analogues was also attributed to increased lipophilicity of 296, as well as to its diminished tendency to form sterically bulky metal chelates that cause reduction in yield. Selective reduction of 297 with activated zinc in ethanol gave the arylbromide 298, which furnished stereoselectively the P-alcohol 299 on treatment with L-selectride. Reduction of the N-formyl group to N-methyl with concomitant debromination was achieved with lithium aluminium hydride to provide (±)-galanthamlne, the overall yield from 296 being 27%. Facile resolution of the racemate to optically active isomers, achieved via camphanate esters, provided a practical method for large scale preparation of the (+) and (-)-alkaloids.

MeO

296 Scheme 45. Synthesis of (±)-galanthamine (continued next page).

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

511

MeO

MeO \ ^^^

K3Fe{CN)6/CHa3 HgO/NaHCOa

6(rC/2h 39%

296

297 Ri = R2 = Br X

|Zn/EtOH

L-selectrideATHF 298 R^ = Br: R2 = H ^ 9 8 % ^ -78'»C/76% r

y^^s.

jP^

01 MeO^

MeO

1^^^^

\lcf\J

C1

^\

^.>

295 (±)-galanthamine

1

299 Scheme 45. Synthesis of (±)-galanthamine. In the light of great therapeutic importance of (-)-galanthamine in the treatment of Alzheimer's and other related mental disorders [see Section 3], any economical process that assures reasonable supply of the substance should be welcomed. In this regard, a recent report achieving such a result, which involved the total resolution of (±)-narwedine (291) (based partially on an earlier observation of Barton \T1\) into its (-)-enantiomer, followed by stereospecific reduction to (-)-galanthamine (295) with 99% ee, has been published [78]. (±)'Lycoramine, Lycoramine (300)[79] synthesised by Parker et al [80] utilised an intramolecular 5-exo radical addition to an appropriately located double bond to generate the quaternary carbon centre (Scheme 46). The starting material, the silyloxybromo ketone 301, was secured initially as a mixture of isomers from 4-methoxy-3-cyclohexen-l-ol (302) by silylation to 303 followed by bromination. On standing or in contact with silica, the mixture was converted essentially into 304. The overwhelming preference for the substance 3 0 1 to exist

S. Prabhakar and M.R. Tavares

512 ^OH

^- S ^ ^ ^ O T B D M S

TBDMSCI/PMF^

|

Br.

1

NBS/NaOAc ^

1

THF/HaO/O'C^

.OTBDMS

MeO 303

302

OTBDMS

tc

301

PTBDMS

OH

MeO 304 +

TBAB/H2O

Ph3P=CHC02Men-HF

64%

reflux/72h 77%

MeNBOC

305 .OTBDMS

PTBDMS

MeO

MeO TBTH/AIBN COoMe ^

COaMe

benzA'eflux/2d/Ar 61%

MeNBOC 307 1)TFA/H20 2)10%aq.NaOH

^' '

^''-

01 MeO^

V-^__

NA

k^i > 300

MeO

Me

(±)-lycoramJne

1 J

Scheme 46. Synthesis of (±)-Iycoramine.

refiux/22h 75%

309

.OH

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

513

as 304, which placed the bromine atom equatorial, was attributed to a favourable dipole interaction in that conformation. Reaction of the bromide 304 and the phenol 305, prepared from bromoisovanillin, under phase transfer conditions furnished the d5-2,4-disubstituted cyclohexanone 306. A Wittig olefination of 306 led to the p,P-disubstituted acrylic ester 307, which on heating with /i-tributyltinhydride and 2,2*-azobisisobutyronitrile underwent smooth 5exo addition to provide the cis-dihydrobenzofuran 308. Acid hydrolysis of the carbamate 308, followed by basification, resulted inringclosure to (±)-oxolycoramine (309). Finally, reduction with lithium aluminium hydride furnished (±)-lycoramine (300). Based on the observation that 1,4-dimethoxycyclohexadiene cationic iron complex 310 undergoes regiospecific nucleophilic addition at C(l) and not at C(5) Stephenson et d

[81]

developed a new formal synthesis of (±)-lycoramine (300) (Scheme 47). Thus, the arylcarbanion311, derived from the bromocompound 312 by halogen-metal exchange, reacted with 310 to provide the ipso addition product 313. Oxidative elimination of the C(l) methoxyl group generated the salt 314. OMOM

OMOM

MeO

MeO

315 R = CH(CN)C02(CH2)2TMS 316 R=:CH2CN

Scheme 47. Synthesis of (±)-lycoramine (continued next page).

^C02(CH2)2TMSn-HF/(rC 81%

S. Prabhakar and M.R. Tavares

514 MOMO MeO

MesNO/DMACAt 316 RsCHaCN

85%^

MOMO MeO.

MeO

(COOH)2/MeOH/H20^ 10%H2SO4/MeOH/rt'

318 R = CH2CN

MeO.

319 R=:CH2CN

Scheme 47. Synthesis of (±)-lycoraniine. This compound bearing an o-methoxymethyi substituent in the aryl ring, unlike other structurally related compounds lacking such an ortho substituent was found to undergo nucleophilic addition with the carbanion derived from silylethyl cyanoacetate to furnish the ipso product 315. The observed regioselectivity was attributed to K electronic interactions between the dienyl moiety and the o -alkoxyalkyl substituent of 314, which by causing the flattening of the structure, allowed the reaction to occur at the otherwise sterically more hindered C(l) to generate the quaternary carbon. The carbanion, formed by fluoride ion induced C-desilylation of 315, suffered fragmentation into ethylene, carbon dioxide and the cyanide 316, which on oxidation released

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

515

the metai-free diene 317. On exposure to acidic conditions, the latter furnished the phenolic enone 318, which underwent base catalysed Michael additicm to afford the tricyclic ketone 319, that had served as an advanced intermediate in Pinhey's earlier synthesis [82] of (±)-lycoramine. Crinine and Related Alkaloids

1.5.4.

(±)-Elwesm€, The starting material for a synthesis [83] of elwesine (320) [84] (Scheme 48), the O-protected cyclohexene derivative 321, itself obtained from 4-benzyloxycyclohexanone, was converted into a 1:4 diastereomeric mixture of bromohydrins 322 and 323 with N-bromosuccinimide and thence by dehydration to a mixture of a-allyl bromide 324 and the pisomer 325.

OBn

QBn

1) ArMgBr/rHF/(rC~* reflux/2h

NBS/MeCN/H20

2)TsOH/ben2/i'eflux/1h 73%

,.;X

322 OBn

OBn

OBn

OBn

Br^'

Br^

^ v ^

TsOH/benz reflux/1 h ^%«*77% BT

323

OBn

OBn

NH

326

98%

(rC-*rt/1h 94%

327

Scheme 48. Synthesis of (±)-elwesine (continued next page).

'

N—Bn

516

S. Prabhakar and M.R. Tavares

OBn OBn

OBn

N-BH TBTH (2eq.) N""Bn AlBNAol 0'*C-reflux/ 1h

OBn

OBn

|1)B2H6/THF

(TC-reflux/1 h AA^^' 74% ^' A\OBn

333

334

r

r ^1 1 0^

A

^•••^

320 ±)-elwesine

Scheme 48. Synthesis of (±)-elwesine.

I

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

517

A syn displacement of the bromine by benzylamine in the presence of triethylamine led, by a SN2' reaction, to the a and p amino compounds which were separated into 326 (18%) and 327 (81%) respectively. The dichloroacetamide 328 derived from the latter, when subjected to the action of tri-w-butyltinhydride (2eq) and 2,2'-azobisisobutyronitrile underwent a S-exo ring closure to furnish via the radical 329, the hydrooxindole 330 (51%) and significant amount of the rearrangement product 331 (30%). The latter is believed to be formed by fragmentation of the cyclohexadienyl radical 332 generated from the cyclohexyl radical 329. On diborane reduction, 330 provided the cis hydroindole 333, which on 0,N-debenzylation afforded (±)-cwfused bicyclic aminoalcohol 334, a compound that had been previously cyclised with formaldehyde to (i:)-elwesine (320) by Stevens et al [85]. (±)'Epielwesme. Intramolecular addition of vinylsilanes, catalysed by acid to an appropriately sited carbon-nitrogen double bond, which featured as the key step for the efficient construction of a variety of heterocycles, [86] was successfully applied to the synthesis of (:i:)epielwesine (335) (Scheme 49) by Overman et al, [87]. The requisite starting material, the

1) LDAn-HFATOX/lh-^rt/ISmin. 2)Br^"'^^-^ 77%

/

3) Had*

\

TMS 1) LDAn-HF/-60*'C/1h->23X/1h 2) CICH2CH2Br

1) DIBAUolZ-aOX/ 1h->rt/0.76h 2)0X/NaF/1h/ H2O/0.75h 81%

TMS 2) 1N NaOH 95%

O

Scheme 49. Synthesis of (i:)-epielwesine (continued next page).

S. Prabhakar and M.R. Tavares

518

1)Hg(OAc)2/H20 THF/25'C/24h 2) NaBH4 NaOH/0.6h 99%

338

339 1) formalin (37%) MeOH/0.26h/rt 2)6MHCI/12h 58%

1

^

1)DEAD PPh3 HCOOH/rt 72h

II

N

|l)NaOH (2N) 60%

320 (±)-elw BSine

Scheme 49. Synthesis of (±)-epielwesine. C-silyl cw-alkcne 336 was prepared by successive base promoted alkylation of commercially available 3,4-methylenedioxyphenylacetonitrile with c/5-(4-bromo-l-butenyl)trimethyIsilane and chlorobromoethane. Reduction of the nitrile group with diisobutylaluminium hydride, followed by deprotonation of the resulting aldimine with sodium fluoride, induced cyclisation to the l-pyrroline 337 containing the cw-alkenyl side chain. The latter, in acetonitrile containing an equivalent of trifluoroacetic acid under reflux, rapidly generated the cw-arylhydroindole 338 in excellent yield at a rate nearly 7000 times faster than its trans counterpart. The remarkable ease of cyclisation was attributed to the most favourable stabilisation, offered by the silicon atom in the cis olefin, to the developing positive charge at the P-carbon atom in the chair like transition state leading to 338 (Scheme 50).

H NH

Scheme 50.

-xx:>

Recent Advances in the Total Synthesis of Amaryllidaceae Allcalolds

519

However, various attempts to introduce stereospecifically the a-hydroxyl group at the desired position of the double bond by hydroboration were unsuccessful. Eventually hydration of the double bond was accomplished by mercuration-reduction protocol, which although occurring both with high regio and stereoselectivity furnished only the p hydroxy compound 339. The conversion of the latter with formaldehyde into (±)-epielwesine (335) constituted in a formal sense, the synthesis of (±)-elwesine (320) as well, since Sanchez etal\S8\ had shown that the inversion of the hydroxyl group in 335 could be accomplished with diethylazodicarboxylate, triphenylphosphine and formic acid. (•^yMaritidine, It was observed that a variety of alkoxyl or silyloxy phenols 340 (Scheme 51), on oxidation with the non-toxic phenyliodo-^/5-trifluoroacetate, instead of customary heavy metal reagents such as trivalent thallium or pentavalent vanadium salts, in the weakly nucleophilic solvent, trifluoroethanol at low temperature, furnished consistently improved yields of cyclisation products 341 [89].

PIFA/CF3CH20^^ -40*0

COCF3 340 Ri=:R2-Me. R3=:H RiR2=CH2, R3=H Ri=:TBDMS. R2=Me. Ra^H Ri=R2=TBDMS. R3=H

341 Ri=R2=Me. R3=H Ri.R2=CH2,R3=H RiaTBDMS. R2=Me, R3=H Rl=R2=TBDMS. R3=H

342 Ri=R2=Me, R3=C02Me

343 Ri=:R2=Me. R3=C02Me

••

— " " • " ^

..x\OH

f***^^ MeO^

y^

MeO^^

^

,cf

JL

N

345 (+)-maiitldine V^MBIMI

MeO

H3i

MeO 344 •MiJ

Scheme 51. Synthesis of (+)-maritidine.

S. Prabhakar and M.R. Tavares

520

Application of the above procedure to the known N-protected phenol 342, derivedfromLtyrosine and veratraldehyde, resulted in smooth oxidative cyclisation to the dienone 343 in 66% yield. Since the latter had been previously converted [90] via (4-)-epimaritidine (344) into (+)maritidine (345) [91] in six steps with an overall yield of 1.26% , the preparation of 343 constituted a formal synthesis of the alkaloid. (')'Amabiline, [92]. An efficient and a concise enantioselective synthesis of (-)-amabiline (346) described by Pearson [93,94] involved the generation of an aza allyl anion appropriately located in a a-substituted styrene derivative (Scheme 52). This arrangement of atoms resulted in a cycloaddition, to furnish a c/s-hydroindole derivative in high yield. The key intermediate 353 was obtained through the following sequence of reactions: addition of aryllithium derived from 4-bromo-l,2-methylenedioxybenzene to the commercially available 2,3-0-isopropylidene-Derythronolactone (347) generated the alkoxide 348, which on in situ Wittig olefmation provided the styrene alcohol 349. Alkylation of the N-cyclohexylaldimine anion 350 with the trifiate 351 followed by mild acid hydrolysis of the resulting Schiffs base, furnished the aldehyde 352. The latter on condensation with aminomethyl tri-/i-butylstannane yielded 353, thus setting up the molecule for the ensuing crucial cycloaddition reaction. On addition to /i-butyllithium at low temperature, the compound 353 underwent the anticipated ring closure via 354 to produce, on aqueous work-up, a 5:1 diastereomeric mixture of 355 and 356 respectively.

P'":.

^

bDAf-LtfTH^

1)CH2=PPh3

2)H30© 99%

348 OTf

%

N—Cy

350 Scheme 52. Synthesis of (-)-amabiline (continued next page).

352

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

521

H

BuaSnCH^NHg ^ mol.sieve/EtaO

J

^N-CH2SnBu3 353 BuLi/

1)H20

e.Mee

2)CH2=K

Me

I nAeCWH

3S4

Scheme 52. Synthesis of (-)-amabiline. The observed exclusive cis fusion and the predominance of the product 355 over 356 was ascribed to the reaction occurring via the preferred, transition state 354, wherein steric repulsion between one of the methyl groups of the dioxolaneringand the methylene group p to nitrogen is minimised. Final introduction of one carbon atom to achieve the crinane skeleton was accomplished with Eschenmoser salt. The product, the 0-isopropylidene derivative of the alkaloid, on acid catalysed deketalisation furnished (-^amabiline with an impressive overall yield of 43%.

522

S. Prabhakar and M.R. Tavares (±)'Crinine, The JC4S + K2S electrocydisation which featured as the pivotal step in the

synthesis of (-)-aniabiline {vide supra) was put to good use for the synthesis |941 of crinine (357) [95] as well (Scheme 53). 1)n-BuU 2) ZnOa

.OMOM

OTBDMS

3) 359

^yAr^

^OMOM OTBDMS

4) (Ph3P)2Pda2 65%

Ar ^OMOM

359 TBAF

^;^s.

OMOM

Swem^ oxid OH 99%

79%

362

361 ^^s^^

^ 90%

360

Br

358

H2/Pd CaCOa Pb

OMOM UMU BuaSnCHaNHo

/

^

^^ 363

^ s s ^ ^ mol.sieve4A T

EtgO

H

100%

r^^'^''

365

A>OR

1

CH20/MeOH 1)aq.CH20/l^ 2) 6M HCI/SO"'

2) CsOAc

3SR=fSSnine;]^^^^3^^ Scheme 53. Synthesis of (±)-crinine.

366

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

523

The known, differentially 0-protected acetylenic diol 358 was converted into zinc acetylide and thence, by a palladium promoted coupling with the known a-bromostyrene 359 formed the disubstituted enyne 360. The latter, on reduction to the cis diene 361, followed by removal of the silyl group furnished the alcohol 362, which was oxidised by Swem's method to the aldehyde 363. Condensation with aminomethylstannane afforded the corresponding Schiffs base 364, which on exposure to butyllithium generated the bicyclic secondary amine 365 as the sole product of the reaction in 80% yield. The observed diastereospecificity of the reaction was ascribed to the involvement of the preferred conformation of 364 in which severe steric interaction between the aryl group and the ether functionality was minimised vis a vis the alternative arrangement 367 during the cyclisation reaction. Pictet-Spengler cyclisation of 365 occurred with concomitant removal of the 0-protecting group to furnish (±)-epicrinine (366). Compound 366 was converted into the corresponding mesylate which on treatment with caesium acetate provided (±)-0-acetyl crinine 368. Subsequent mild basic hydrolysis afforded (±)-crinine (357). 1.5.5. Tazettine and Related Alkaloids (±)'Pretazettine. Ishibashi's formal synthesis [96] of the alkaloid 369 [97] (Scheme 54) in the racemic form commenced with 4-methoxy-l-(3',4'-methylenedioxyphenyl)-cyclohex-l-ene (370), which was converted into a mixture of P-bromohydrin 371 and the a-isomer 372. OMe OMe OMe

^•xx:>

NBS/MeCN/HoO

MeOH

Ar

OH 374

1^

Ar 373

Scheme 54. Synthesis of (±)-pretazettine (continued next page).

S. Prabhakar and M.R. Tavares

524 OMe

OMe

,H

OMe

TsQHA?enz/i"efluv 76%

377

376

RuClo-PPha benz/i50*C 57%

OMe

OMe

OMe

^ "

1)m-CPBA CH2a2 ^2)sat.NaHC0^ g^'''N-Me 87% a

''N-Me

380

1)TFAA/lutidlne/CH2a2 "^ reflux 2) sat. NaHCOa

OMe

Scheme 54. Synthesis of (±)-pretazettine (continued next page).

OMe

525

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids OMe

I

OMe

N—Me

LAH/THF

N—Me

reflux 63% 383 R=H O 384 RsMesC—C—

Scheme 54. Synthesis of (±)-prctazettine. The latter, on reaction with methylamine yielded via the ^-epoxide 373, the trans-aaminoalcohol 374, which was N-acylated to the amide 375. Acid-catalysed dehydration of the teitiaiy alcohol 375, led to the olefin 376, from which the key radical precursor, the chlorothioether377 was secured in quantitative yield by reaction with N-chlorosuccinimide. In keeping with the eariier results recorded for structurally related compounds, 377 on heating in the presence of ruthenium dichloride and triphenylphosphine also underwent a S-exo radical addition to generate the cyclohexyl radical 378 which recaptured the chlorine atom to furnish the a-chloro-ci5-hydroindolone 379. Oxidation of thioether 379 gave the corresponding sulfoxide 380, which on successive treatment with trifluoroacetic anhydride and aqueous bicarbonate led to the chloro-a-ketoamide 381. The olefm 382 resulting from base induced dehydrochlorination of 381, was reduced to the hydroxy-amine 383, which was obtained as the sole diastereoisomer

S. Prabhakar and M.R. Tavares

526

in 63% yield. The derived pivaloyi ester 384 had been eariier converted, via (±)-haemanthidine (385) by Maitin etal [98] into (±)-pretazettine (369). (±)'Tazettine, The elegant method [99] for the construction of ds-arylhydroindoles B (X = H) (Scheme 55) involving tandem azaCope rearrangement - Mannich cyclisation from appropriate cyclopentane A (X = H) was examined for the substrate A (X =: SiRs; X/Ar trans) as means of possible entry into cis -arylhydroindole B (X = SiRy, X/Ar trans) potentially capable of subsequent direct conversion into pretazettine.

9-membered enol

Scheme 55. C/s-Aiylhydroindoles. With this end in view, phenyldimethylsilyl tri-/i-butylstannane was added under the influence of zero-valent palladium compound with high regioselectivity and in excellent yield to the acetylene 386 to give the metallated olefin 387 (Scheme 56). The vinyl lithium carbanion 388 generated therefrom, was then converted by reaction with cerium(III) chloride into an equilibrium mixture (1 : 1) of the cerium salts 389 and 390 respectively. However, the 1,2addition of 389 to the carbonyl of 391, which in principle would have eventually led to (±)pretazettine, did not occur due to steric reasons — instead, only deprotonation of 3 9 1 was observed. On the other hand, 390 did function as a suitable nucleophile to provide the olefmic product 392. Exposure of 392 to copper(n) triflate induced its transformation via the nine membered enol (Scheme 55) to the requisite C-silyl hydroindole 393. On treatment with tetrafluoroboric acid diethyl ether complex in dichloromethane, compound 393 suffered

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaioids

527

protodq>henylation and furnished the silyl fluoride 394. The replacement of the dimethylfluorosilyl

/v= A

%5j^^

functionality by hydroxyl group with retention of

configuration

Ar Bu3SnSiMe2Ph Pd(PPh3)4

I

n-BuLJH'HF -78'C/1h

^ BU3S1 THF/60X/8h/95%

u - ^

0'C/5mln CeCK

SiMeaPh

SJMejPh

387

388

"•xx:^

386

Ar

+

ClaO

^SiMe2Ph

ClaO

SiMe2Ph

NC"

I Me

390

391 PhMe2Si

/.^J^A..

PhMeaSi, Cu(0Tf)2/THF nux/2h \ reflux/2h

94%

Ji

HBF4-OEt2 J

rt/2h

'i' l ^ ^ ' ^ Me

393

392

TMSO .SePh

1)TMS0Tf TEA/CH2CI2 0X/1h/95% ^ H) PhSeCI/CH2Cl2 0X/1h/78%

H2Q2/KF/DMF 60X/7h/76%

395 Scheme 56. Synthesis of (±)-tazettine (continued next page).

396

528

S. Prabhakar and M.R. Tavares TMSO

TMSO

.SePh

SePh DIBAL/lol

-78*C/0.25h/81%

397 1)m-CPBA/CH2a2 -78'C/075h

2) xyleneA-eflux 0.25hmi%

y^ ^

2)MeOH/TEA reflux/0.25h 3)TBAF/rHF rtA).25h

™S0

.

W"

398

Scheme 56. Synthesis of (±)-tazettine. was cleanly achieved, despite the presence of a basic nitrogen atom, by oxidation, with hydrogen peroxide and potassium fluoride to afford 395, with the hydroxyl and the aryl group cis to each other. The seleno-silyl ketone 396 obtained from the 0-silylether of 395 in the usual maimer, on treatment with diisobutylaluminium hydride suffered reduction from the less hindered a-face of the molecule to provide the ^-alcohol 397, which on oxidative elimination of the phenylseleno group yielded the allyl alcohol 398. The derived mesylate on methanolysis followed by Odesilylation of the resulting methyl ether furnished the bicyclic amine 399 (cf. 383) that had

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

529

been eariier used as the advanced intermediate [100] by Danishefsky in the synthesis of {±y tazettine(400)[101]. (±)'Tazettine, In a subsequent study [102], again directed towards the synthesis of pretazettine (Scheme 57), the known ketal-aldehyde 401 was converted into the 1,2aminoaicohol 402 via its cyanohydrin derivative. Giemoselective 0-alkylation of the alkoxide of 402 with 3,4-methylenedioxy-6-iodobenzyl chloride furnished the amino ether 403, which was converted into the corresponding carbamate 404. On heating widi a catalytic quantity of palladium(0) complex and silver caii)onate, the aryl iodide 404 underwent smooth oxidative addition to the double bond to provide the pyran 405 as the sole product (63-70% yield). It should be noted that the stereochemistry of the newly created asymmetric cai1x)n adjacent to the pyran ring oxygen corresponds, not to that c^ pretazettine (369), but, instead to its C(ll) epimer. The observed stereochemistry was explained by invoking a preference for boat-like transition state (Figure 6) with the substituted aminomethyl group equatorially disposed in the developing benzopyran ring in which the a-aryl palladium and the olefmic 7C-bonds were eclipsed for the ensuing syn-6-exo addition.

H

1)TMSCN/KCN/ 18-cr6wn-6-ether CH2a2A3.5h/rt ^

Q

2) UH/EtaO/tyC-rt/ 16h/72%

403 R=:H 404 R=C02Me

Z\

Scheme 57. Synthesis of (±)-tazettine (continued next page).

CIC02Me/K2C03/CH2a2 91%

S. Prabhakar and M.R. Tavares

530

NHCOaMe F Pd(OAc)2/PPh3/Ag2C03 THF/l-efliix/IShi

oOo NHC02Me

404

405 2N HCI/THF reflux/2h/94%

407 1) CeClaTHaO MeOH/-78^C 2)NaBH4/10min 95% ^

OMe

COaMe N 1) KH/THF

1 O

H

2) Mel/O**- rt/5h 75%

P \ (

409 Scheme 57. Synthesis of (±)-tazettine (continued next page).

531

Recent Advances in the Total Synthesis of Amaryllidaceae Allialoids OMe

OMe CrOa^.S-dlmethylpyrazole CH2a2/-4(rCABh n

OH 412 ll-epipretazettine Scheme 57. Synthesis of (±)-tazettine.

S. Prabhakar and M.R. Tavares

532

Deketalisation of 405 under acidic conditions also induced Michael addition to occur on the enone system generated, to furnish the hydroindole 406 with H(C-4a) and the aryl group (C> 10b) in cis arrangement. Introduction of C(l)-C(2) double bond was effected via the enol silyl ether which on oxidation with palladium diacetate furnished the enone 407. The P-allyl alcohol 408 produced by stereoselective reduction of 407 with borohydride - eerie chloride involved a hydride ion delivery from the less hindered a face and was transformed via its alkoxide to the methyl ether 409. Low temperature oxidation of 409 with chromium trioxide - 3,5dimethylpyrazole complex afforded the isocoumarin derivative 410. Reduction of 410 with lithium aluminium hydride gave the tertiaiy amine, (±)-tazettinediol (411), which by judicious selection of oxidant permitted the completion of the synthesis of either (±)-tazettine (400) or (±)11-epipretazettine (412).

*9

^^ CH^NHCOaMe

l2NHC02Me

\-i Figure 6. Thus, in line with earlier observation, the use of dimethylsulfoxide and trifluoroacetic anhydride led, by preferential oxidation of the secondary alcohol, to the hemiketal (±)-tazettine (400). On the other hand, application of the Dess-Martin method furnished, by selective oxidation of the primary alcohol group, (±)-ll-epipretazettine (412) (also known as (±)-6aepipretazettine), in 73% yield, previously converted into (±)-tazettine [100]. 1.5.6.

Morphanthridine Type Alkaloids

(±)'Coccinine, (±)'Pancracine, (±)'Montanine, (±)-Brunsvigine, (-)-Coccininc (413) [103], (-)-pancracine (414) [91], (-)-montanine (415) [103] and (-)-brunsvigine (416) [104] constitute a group of structurally closely related alkaloids incorporating the 5,11methanomorphanthridine skeleton. Hoshino*s synthesis [105] (Scheme 58) of these alkaloids in their racemic forms started with a ring opening reaction of c/s-cyclohexenecarboxylic anhydride 417 with piperonyl magnesium bromide to furnish the c/s-keto carboxylic acid 418. The latter

Recent Advances in the Total Synthesis of Amaryllidaceae Allialoids

533

was conveited widi retention of configuration, by Curtius rearrangement, into the tertiary butyl carbamate 419. Acid hydrolysis of the latter and tosylation of the resulting amine followed by hydroxylation with osmium tetroxide furnished the diol, which was isolated as the diacetyl derivative 420 in high yield.

1) CIC02Etn"EA/(rCMq acetone 2) NaN3/H20/1h 3)t-BuOH/reflux/16h

96%

94%

1)TFA/CH2a2/tt/1h 2)TsCIArEAyCHCl3/tt/1h 3) Os04/NMO/l1/2h 4) AC2O/PMAP

92%

H N - | x ^ ,

BOC

Ts 420

419

B2H6nrHF/rt/1h 2) 30% H2O2-3N NaOH/rt/40mln • 100%

PhaPsCHgn-HF/rt/aomin ft/D.5h

71% Ts 421

dec Ts

422

Ac20/t>yrm/1h 100%

-XO

Scheme 58. (continued next page)

Ts 423

S. Prabhakar and M.R. Tavares

534

OAc

OAc

(CHaOWAcaO/MeSOaH (CH2a)2M/2h

OAc

NaOMe/MeOH/20min 100%

.N

H Ts

PhCH(0Me)2

N

Scheme 58.

H

OH

429

Recent Advances in the Total Synthesis of Amaryllidaceae Alicaloids

535

Hydroboration of the styrene 421, obtained by Wittig olefmation of 420, occurred from the less hindered face of the molecule to provide on oxidation with alkaline hydrogen peroxide, the a-alcohol 422. The N-sulfonyltriacetate 423 derived from 422, when subjected to a modified Pictet-Spengler reaction furnished the tricyclic sulfonamide 424, which was hydrolysed to the m-diol 425 and thence converted into the acetal 426. The dioxolane 426 on heating with sodium ^i5-<2-methoxyethoxy) aluminium hydride underwent a novel reductive cyclisation to furnish the tetracyclic base 427. The latter on exposure to diisobutylaluminium hydride afforded the cis-p-hydroxy benzyl ether 429, the formation of which occurred through aluminium (11!) promoted ring opening of the acetal group and subsequent reduction of the resulting oxenium ion intermediate 428. 429 thus obtained as the major diastereoisomer (74%) served as a versatile substrate for the synthesis of (±)-coccinine (413), (±)-pancracine (414), (±)-montanine (415) and (±)-brunsviginc (416). Thus two successive oxidations of 429 (Scheme 59) involving the Jones reagent and dichlorodicyano-/7-benzoquinone respectively led to the enone 430. A similar reductive cleavage as above of the derived dimethyl acetal 431 with diisobutylaluminium hydride occurred from the less hindered a-side to furnish the P-methoxyether 432 as the major isomer. Selective Odebenzylation of 432, achieved with iodotrimethylsilane led to (±)-coccinine (413).

Ortn ^) Jones reagent/O'C/l Omln/54% 2) DDQ/Na2HP04/dioxane/l-eflux/1h N

H

P

OBn

OBn

N

Scheme 59. Synthesis of (±)-coccinine (continued next page).

H

S. Prabhakar and M.R. Tavares

536

pMe OBn N

H

JTMSI^HCIaM^Jj^ 432

Scheme 59. Synthesis of (±)-coccinine. (±)-Pancracine was synthesised from 429 as follows (Scheme 60). The tiiflate 433 of the alcohol 429 on treatment with t-butoxide ion provided the allylic benzylether 434. The latter, on treatment with phenylselenylchloride, in methanol under ultrasound irradiation, followed by oxidative elimination of selenium from the resulting addition compound, furnished the aallylchloride 435. The ^-epoxide 436 secured from 435, underwent acid catalysed ring opening to furnish (±)-alkaloid 414. Methanolysis of the epoxide 436, in the presence of borontrifluoride etherate, provided (±)-montanine (415) in excellent yield. Oeoxygenation of the allylic epoxide 436 (Scheme 61) with iodotrimethylsilane resulted in the formation of the diene 437, which underwent the expected o.'his hydroxylation of the C(2)-C(3) double bond only in poor yield possibly due to flattening of the ring D. Nevertheless the reaction mixture could be processed to give (±)-diacetyl brunsvigine (438) in 12% yield, from which the (±)
537

Recent Advances in the Total Synthesis of Amaryllidaceae Allialoids PSO2CF3

OBn

N

436 BF3.Et20/MeOH. 15-2(yC/20mlf 94 V f

f^ ]

'"

L ^ ^

0

s

\

V-^OHJ

\

415 (±)-montanine

J

H

3N H2SO4 sJHF/|-eflux5h ^78%

^''

L^-^ 1^

r

10

1

iijiay If 5

^^•IHi

Scheme 60. Synthesis of (±)-pancracine, (±)-montanine.

**

1

1

Via 4/

1

H

1

6 5 414 (±)-pancractne

1 1

^ % X ^ \ J . ' N 7

\

538

S. Prabhakar and M.R. Tavares

TMSCI/NaI/MeCN/rt/A).5h

12%

1)0904/NMO dioxaneAtA3h 2) AC20/pyr DMAP/rt/19h

N

H

437 ;PAc

""»/OAc NaOMe/MeOH/rtA).3h

N

438

H r

^ / s

\

1

/""'OH 1

' ^ i X \,_____^

416

(±)-brunsviglne

J

Scheme 61. Synthesis of (±)-brunsvigine. followed by alkylation of the resulting aniine 442 with 4-bronio-cyclohexen-2-one (443) furnished the enone 444 as a diastereomeric mixture. The radical 445 generated therefrom under carefully defined conditions, underwent a 5-exo addition to provide 8,9-methylenedioxy-5,llmethanomorphanthridin-2-one (446) in 77% yield. Oxidation of 446 furnished the enone 464 an intermediate in Overman's synthesis of (±)-pancracine (vide infra). The ketone 446 also served as a suitable starting material for the syntheses of (±)montanine (415) and (±)-coccinine (413). Accordingly, the olefm 448 admixed with the A^*^ isomer was obtained from the tosylhydrazone 447 by base catalysed elimination. Bishydroxylation of the double bond of purified 448 achieved by the usual osmylation protocol

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

539

furnished the cis diol, which was converted into the corresponding benzylidene acetal 427. The latter had also been previously transformed {vide supra) [105] to (±)-montanine (415) and (±)coccinine(413).

CHa3/30mln/rt 78%

NH

C(XF3 440

439

PhSH/Znl2/(CH2CI)2|

rt/lh/98%1

SPh

SPh 5%aq. K2CO3 ,MeOH refiux/30min 99%

P

'\.

o

CCX^Fa

442

441 SPh

TEA/TEAI MeCNfr9flU?
^ ,.

^.

Vx'"'^^

H^nr

o 1

o-xylene

AIBN

I TTBTH

refiux/lh 77%

^--^x^o 444

445 Scheme 62. Synthesis of (±)-coccinine, (±)-pancracine, (±)-montanine (continued next page).

540

S. Prabhakar and M.R. Tavares

JsNHNH2/MeOH/i^eflu}(/1h 91% N—NHTs

+ 0 K /DMSO/10CrC/2h N

H

447 1) Os04/NMO/dioxane/H20A1/1h 2) PhCH(OMe)2/rsOH/CHCl3A1/1h 75%

o

N

448 415 (±)-montanine 413 (±)-cocJclnJne

Scheme 62. Synthesis of (±)-coccinine, (±)-pancracine, (±)-montanine.

H

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

541

(-yPancracine. The first enantioselective synthesis of (-)-pancracine (414) characterised by high stereoselectivity and excellent overall yield was reported by Overman et aL [107]. The starting material, the enandomerically pure (2S)-aminoketone 449 (Scheme 63), prepared in three steps from cyclopentene epoxide, reacted chemoselectively with the cerium salt of 3,4methylenedioxyphenylacetylene 450 to furnish die cis-aminoalcohol 451. Silver ion promoted solvolytic removal of the cyano group by a retro-Mannich reaction, under ultrasound irradiation in aqueous ethanol, generated besides, the secondary amine 452, the acetylenic oxazolidine 453 in ca. equal amounts. Further sonication of the latter, in aqueous ethanol containing nitric acid, provided additional quantities of 452, the overall conversion of 451 to 452 being 95%. Pftftial reduction of the triple bond of 452 with sodium £'i5(2-methoxyethoxy)aluminium hydride provided the tranS'Siyrtnt 454, which was converted into the styrene oxazolidine 455 with formaldehyde. Exposure of 455, free of acidic impurities, to borontrifluoroetherate, induced an extremely facile cationic aza-dbpe rearrangement via the iminium ion intermediate 456 to furnish the 9-membered enol 457, which underwent cyclisation to the cis-hydroindolone 458. Catalytic N-debenzylation furnished the enantiomerically pure secondary amine 459, which afforded the tetracyclic aminoketone 460 on treatment with formaldehyde. Ar

i

THF/-78^C/2h/DXj KH2P04/93%

CeCl2

450

Ars AgN03/EtOH/H20 23*»C/2h/)))/48h

449 Rr

467 RsCHaPh

X)

f

Ar

Ar

HCV/,,

m^^'^

454

SMEAH/tol/Et20 23*C/0.5h 100%

EtOH/H20/HN03 )))/72h HNW*^

452

Scheme 63. Synthesis of (->-pancracine (continued next page).

<

Ar

D 453

S. Prabhakar and M.R. Tavares

542

463 Scheme 63. Synthesis of (-)-pancracine (continued next page).

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

543

1) Se02/ceiite/dioxane 85^C/4h

Scheme 63. Synthesis of (-)-pancracinc. The axial a-alcohoi 461 obtained stereospecifically by reduction, furnished a 3:1 mixture of the olefms462 and 463 on dehydration with thionyl chloride. Sequential oxidation of the mixture with dioxides of selenium and manganese led to the enone 464. Introduction of a p-hydroxyl group adjacent to the carbonyl group at C(3) was achieved in high yield, by first converting 464 into the enol silyl ether 465 and then subjecting it to oxidation with osmium tetraoxide. The product 466 on reduction with triacetoxy sodium borohydride furnished (-)-pancracine (414) in 14% overall yield starting from the (2S)-aminoketone 449. In a similar fashion, starting with the (±)-aminoketone 467 (R=Bn) the synthesis of racemic pancracine was achieved.

S. Prabhakar and M.R. Tavares

544

(')'Coccinine, (')-Montanine, ('yPancracine. The second enantioselective syntheses [108] of coccinine, montanine and pancracine (Scheme 64) commenced with the known chiral epoxyalcohol 468 which was 0-benzylated and the resulting oxiiane opened with cyanide ion to furnish the benzyloxycyanoalcohol 469. The latter was converted into its silyt derivative to provide a l,2-d5-diol differentially protected 470. The vinyl group of 470 was transformed via regioselective hydroboration - oxidation to the primaiy alcohol and thence to the aldehyde 471. Treatment of 471 with ethynyl magnesium bromide yielded a 2:1 diastereoisomeric mixture of acetylenic alcohols 472 and 473. The .S-acetylenic acetate 474, derived from 472 by acetylation, and also available from the R-alcohol 473 by Nfitsunobu inversion method, underwent an exclusive anti-SN2* reaction on treatment with silacuprate reagent 475 to furnish the R-alXenyl silane 476. The nitrile 476, on reduction with diisobutylaluminium hydride gave the aldehyde 477, which reacted at 150®C with the iminophosphorane 478 obtained in situ from 2-bromo^,5-methylenedioxybenzyl azide and triphenyl phosphine to provide via a concerted imino-ene cyclisation, the ds-aminosilylacetylene 479. C-protodesilylation of 479 followed by partial reduction of the resulting acetylene yielded the amino olefin 480, which underwent smooth Heck cyclisation to provide the aminostyrene 481 isolated as the sulfonamide 482. Bn 1) BnBr/NaH TBAI/THF

CN

-2CrC-rt/96% 2) KCN/MeOH reflux/93%

468

469

OH

pen

OBn

TBDMSCI/imId DMFy(rC-rt/94%

OTBDMS

_^, 1) dJsiamylborane CN THF/CrC-rt

^ OTBDMS

^

2) NaOH/H2CV88% 3) Swem oxkJation/96%

ON

470

471 pBn OTBDMS

^

-MgBr/CH2a2l

-78*C-(rC 89%

472

Scheme 64. Synthesis of (-)-coccinine, (->montanine, (-)-pancracine (continued next page).

Recent Advances In the Total Synthesis of Amaryllldaceae Alkaloids

545 pBn

^C

V*"OTBDMS

DEAD/PPhs HOAcn-HF

CN

473

OBn

PBn

78%

OTBDMS + I Ph—SI—buCNUa Me/2

475

474 HU//^^^^SJMe2Ph

^^

1HF_

Z-96»i

|

S

476

^

DTBDMS

CN blBALAol. -78»C-(rC f74% OBn

OTBDMS

>p^Hiv/;^^SIMe2Ph mesitylene 2h SiMeaPh OTBDMS

!

PBn AN

479

i

OTBDMS

OTBDMS 1)TBAF 2) Undlar reduction

Scheme 64. Synthesis of (-)-coccininc, (-)-montanine, (-)-pancracine (continued next page).

S. Prabhakar and M.R. Tavares

546

pBn

OTBDMS

TsCI p 481 R=H DMAP Pyf U-482 R=Ts

120*C/48h/74%

OTBDMS

485

^ o / 1)H2/Pd-C/MeOH/rt/24h ° ^ ^* 2) Na/haphthalene/DME/-78''C

OTBDMS

487 Scheme 64. Synthesis of (-)-coccinine, (-)-montanine, (-)-pancracine (continued next page).

547

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

l2/PPh3A)*C imid MeCN/Et20 82%

OTBDMS TPAP/NMO/CHgOaMA). 16h mol. sieve 4 / "96% H

488

OTBDMS

489

1) LDA/TMSCI/THF; -78*C/rEAA)*'C ^ Pd(OAc)2/MeCN/50h/i1 67%

OTBDMS CH(OMe)3/rsOH MeOH/CrC — rt/2h 91%

490

OMe

OTBDMS

Scheme 64. Synthesis of (-)-coccinine, (-)'niontanine, (-)-pancracine (continued next page).

548

S. Prabhakar and M.R. Tavares

OTBDMS

DIBALAol/(rC -* rt/27h

PIPAL » tol/rt/12h 81%

415

413 (O-ccwcinine

+

(-)-montanine

413 (-)-cocclnlne

492

TBAF/D«C/2h-rt/2h 98%

9

OTBDMS

H

490

^NaBH(OAc)3

466

-35'C/62% 414 (-)-pancracin6

Scheme 64. Synthesis d'(-)-coccinine, (-)-montanine, (-)-pancracine. A mixture of epoxides 483 obtained on oxidation of 482 with dimethyldioxirane, when exposed to ferric chloride provided, as the kinetically controlled product, the a-aldehyde 484, which without purification was reduced to the a-alcohol 485. The exclusive formation of 484 is believed to occur via the benzyl cation 486, generated by Lewis-acid opening of the oxirane ring, suffering a stereospecific kinetic 1,2-hydride shift The amino alcohol 487 obtained after sequential removal of 0-benzyl and N-tosyl groups from 485, on treatment with triphenylphosphine and iodine in the presence of imidazole furnished the tetracyclic base 488, which was oxidised to the ketone 489. Trapping of the kinetically generated enolate of 489 as the silylether, followed by palladium diacetate oxidation yielded the enone 490. The derived

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaioids

549

dimethylketal 491 on reduction with diisobutylaluminium- hydride furnished with concomitant cleavage of the O-silyl group, essentially (-)-coccinine (413). On the other hand, removal of the bulky silyl group from 491 prior to reduction, exposed the ring D of the resulting ketal alcohol 492 for hydride attack to occur from both faces of the molecule with equal facility and as a consequence, furnished a separable 1:1 mixture of (-)-montanine (415) and (-)-coccinine (413). Desilylation of the enone 490 generated the hydroxyketone 466 which had been previously transformed to (-)-pancracine (414) by Overman [107] (vide supra), A formal enantioselective synthesis of (-)-brunsvigine (416) was also available by Odebenzylation and 0-desilylation of 485 to the known triol 425, the racemic form of which had been utilised in the preparation of the (±)-alkaloid by Hoshino etal [105] (vide supra),

1.6.

Pentacyclk Alkaloids (')'AugU5tamine, [109]. The stannylated imine 353 utilised in the synthesis of (-)-

amabiline (346) also served as the advanced intermediate for the preparation (Scheme 65) of (-)augustamine (493) [93,94]. Thus, treatment of the mixture of the lithium salts 355 and 356 with iodomethane furnished a 4.3:1 mixture of the two tertiaiy amines 494 and 495 respectively. The ci5-diol, obtained on acid hydrolysis of the former was converted into the ortho ester 496, which on exposure to methanesulphonic acid underwent cyclisation via the carbenium ion 497 to (-)-augustamine (493) in 76% yield.

355

356

Scheme 65. Synthesis of (-)-augustamine (continued next page).

494

495

550

S. Prabhakar and M.R. Tavares

1 ' /-----^H 1 1 N Me

1 493 (-)-augustamJne

1 1 I

Scheme 65. Synthesis of (-)-augustainine. 2.

RECENTLY ISOLATED ALKALOIDS (1987-1998) The Amaryllidaceae alkaloids recently isolated are listed in Figure 7.

They largely

originate in Nature from condensation of two simple biogenetic precursors, namely tyramine (C6-C2-N unit) and isovanillin (Ce-Ci unit) to the corresponding SchifFs base, followed by reduction to the substituted benzylamine. It subsequently undergoes, prior to or after Nmethylation, extensive catabolism initiated by phenolic oxidation to generate a diversity of substances. A vast majority of these new alkaloids fall into previously known structural types, with only minor variations noted in the nature of the nitrogen atom and the positions occupied by common substituents such as OH, OMe within each group. General synthetic methodologies leading mainly to racemic alkaloids within each group already exist. There are as yet, no syntheses reported for the new alkaloids isolated possessing complex structures such as those encountered in galasine (529), (+)-10b-hydroxygalwesine (530), (-)-obesine (570) and cripowellins A (572) and B (573).

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

551

Alternative skeletal numbering is employed for the alkaloids 155, 156, 506, 507, 508, 525, 527, 530, 5 3 1 , 5 3 3 and 540 in the references cited.

© P 22 3-hydroxy-8.9-methylenedioxyphenanthridine [10]

28 Ri=H. R2=Me. R3R4=-OCH20N-methylcfinasladlne 113] ^

^ ^ ^ ^ ^ ^ ^ ^ ^ - ^ ^ ^ ^ - ^ ^ ^ ^ pnamine p i i j

498 X = not Identified bicolorine[110]

175 Ri=R2=H. R3=:R4=OMe, x snot Identified 500RXRSe.R.=H,iP=no.identHied tortuosjne [112] 501 Ri=0F>R2=H.R3=OMe.R4=OH zefbetaine[113] £s 502 Ri=R2=H, R3=OH. R4=:0fy/le, ) r = not Identified 8-0-demethytvasconlne (114]

MeO

MeO

Me a ^

503 assoanine methochloride [115]

156 11-hydroxyanhydrolycorine [44]

Figure 7. Amaryllidaceae alkaloids recently isolated (continued next page).

552

S. Prabhakar and M.R. Tavares

MeO

MeO

MeO

MeO

504 oxoassoanineN-oxid6[110]

^ OMe 195 )P= not Identified roserine [53]

OH

509 (•)-2-epllyoorine [118]

Ha

505 R , = R 2 = - ° ^ 4 : ^ (+)-1 -0-p-D,2-0-p-D-bisglycoside of pseudoiyoorine [116] R3=0Me. R4=0H 506 RisR4sOH.R2=H.R3s:OMe (+)-9-norpluviine [117] 507 Ri=OAc. R2=H. R3=0Me. R4=0H (+)-1-0-acetyl-9-norpluviine [117] 508 RirrR4sOAc. R2=:H. Rs^OMe (+)-1,9-cli-0-acetyl-9-norpluvline [117]

MeO

HO' 510 (-i-Hortuclne [119]

OMe

MeO

MeO 511 Incartine [120]

512 Ri=0H.R2=p-0Me R3=0Ac, R4=R5=OMe (-)-3-0-acetylnarcissldine [121] 513 Ri=:R3=0H. R2=a-0H R4R5=-OCH20(-)-2-eplpancrassidine [118]

Figure 7. Amaryllidaceae alkaloids recently isolated (continued next page).

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

553

OMe .^OH

514

515 Ri=R3=0H, R2=p-0Me. R4R5=-OCH20ungiminorine-a-N-oxide [123] 516 Ri=OH. R2=p-0Me, R3=0Ac R4sR5=sOM (.)-3-0-acetylnarcissldine N-oxWe [124]

(•)-siculinine[122] 12

MeO

517 Ri=R2=H, R3=a-0Me, R4R5=-OCH20-. R6=Me (+)-a-6-0-methylodullne (125) 518 Ri=R2=H, R3=p-0Et, R4R5=-OCH20-. R6=Me eugenine [126] 519 RisOH. R2=H. R3=a-OMe. R4R5=-OCH20Re^Me (+)-2-a-hydroxy-6-a-0-methylodullne [127] 521 522 523 524 525

MeO OMe 520

(•f)-0-methyltycorenine NH3Xide[123]

Ri=R2=H. R3=0Ac. R4=0Me, Rs^Me (+)-8-0-acetylhomolycoi1ne [48] Ri=R2=H. R3R4=-CX)H20-, R5=H (+)-N-norma9onlne [125] Rt=OAc. R2=H, RgsOMe R4=-OCCX)H2CH(OH)Me. R5=Me dubiusine[129] Ri=OH. R2=H, R3=0Me R4=0H. R5=:Me (+)-2a-hydroxy-9-0-demethylhomolycorine [130] Rt=R4=0Me. R2=H. R3=OH, R5=Me (+)-2a-methoxy-8-0-demethythomolyoorine[131]

Figure 7. Amaryllidaceae alkaloids recently isolated (continued next page).

S. Prabhakar and M.R. Tavares

554

MeO

OMe

MeO

526

529 galasine [131]

R i s : R 2 s H . R3rrR4s:OMe. Rs^sMe

(+)-homolycorJne N-oxIde [123] 527 Ri=R2=H. R3=0H, R4=0Me. R5=Me (+)-8-0-demethylhomolycorJne -a-N-oxlde[1281 528 Ri=:OH, R2=H, R3R4S-OCH20R5=Me (+)-hippeastrineN-oxlde[1321

534 nobllisine[133]

530 R1=R3=R4=OMe, R2=OH, R sssMe (+)-10b-hydroxygalwesine [131] 531 Ri=:R4=0Me, R2=R3:=OH. Rs^^Me (+)-10b-hydroxy-8-Odemethylgal weslne[ 131] 532 Ri=R3=R4=OMe. R2=H. Rs^Me (+)-galweslne [131] 533 Ri=R4=0Me, R2=H. R3=OH. R5=Me (+)-8-0-demethylgalweslne [131] 535 Ri=p-OH. R2=H, R3=0H (-)-N-norsanguJnine [134] 536 Ri=p-CX:(XH2CH(0H)Me, R2=H. R3=0H (-)-N-norbutsanguinJne [134] 537 Ri=a-OH, R2=H. R3=0Me (+)-epl-N-norgalanthamJne [135] 538 Ri=p-OAc. R2=Me. R3=0Me (-)-O-acetylgalanthamjne [117] 539 Ri=p-OH. R2=Ac. R3=0Me (-)-narcislne [136] 540 Ri=p-OAc. R2=Me. R3=0H (.)-3-0-acetylchlldanthine [137]

Figure 7. Ainaryllidaceae alkaloids recently isolated (continued next page).

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

555

l^eO

541 Ri=p-OH. R2=a-Me. R3=0Me (-)-galanthamine N-oxide [138] 542 Ri=p-OH. R2=a-Me. R3=0H (-)-sanguinihe N-oxide [138]

543

(+)-epi-N-noriycoramine [135] R2 Ri-

01 MeO

Me 544 (-)- lycoramine N-oxide [138]

346 Ri=:R2=a-0H R3=R4=R5=R6=H R7R8=-CX)H20- (-)-amablllne [92] 545 Ri=a-OH, R2=p-0Ac R3=R4=R5=R6=H R7R8=-OCH20- (-)-josepliinine [139] 546 Ri=R2=p-0Ac. R3=:R4=:R5=:H R6=OMe, R7R8=-OCH20(+)-epibowdenslne [140] 547 Ri=R2=p-OH. R3=R4=R5=H R6=0IVIe. R7R8=-OCH20(+)-1-epideacetylbowdensine [140] Ri=a-OMe, R2=R3=R7=H 548 Ri=R2=p-OAc.R3=R4=R5=H R4=OMe. R5R6=-OCH20RgsH, R7R8=-OCH20* R8=OAc (encfe?) (-)-ll-O-acetylambelline [142] (+)-1-epi-7-demethoxybowdensine [140] Ri=p-OMe. R2=R3=:R8=H 549 Ri=R2=R4=a-OH,R3=R5=H R4=0Me. R5R6=-OCH20-. R7=OH (exo) R6=0Me, R7R8=-OCH20- crinisine[141 (-)-brunsbeHine[142] Ri=:p-OH. R2=R3=R4=R8=H R5R6=-OCH20-, R7=0H (exo) (-)-3p, 11 a-dihydroxy-1,2-dehydrocrJnane [143] Ri=a-OH. R2=R3=R4=R7=R8=H R5=0H. R6=0Me (-)-8-liydroxy-9-methoxycrinine [143] RB

550 551 552 553

R7

Figure 7. Amaryllidaceae alkaloids recently isolated (continued next page).

S. Prabhakar and M.R. Tavares

556

Re R5 554 Ri=:R2=R4=R5=R6=H R3=P-0H. R7=0H. R8=0Me (-)-maritinamine [144] 555 R-|s:R2=R4=R5=R5=H R3=a-0H. R7=0H. Re^OMe (-)-epimarltlnamine [144] 556 Ri=R2=R4=R5=R6=H R3=a-0Ac. RysOMe, R8=0H (-)-cantabricine [145] R2

557 Ri=p-OMe, R2=R3=R4=R7=R8=H R5R6==-0CH2O (•i-)-buphanisine [144] 558 R^=a-OH, R2=R3=R4=R7=R8==H RsxOH. R6=0Me (-)-siculine [144] 559 Ri=:p-OH. R2=:R3=R4=R7=R8=H R5=0Me, R6=0H 9-0-demethylmaiitldine[146] 560 Ri=p-OMe. R2=R3=R4=R8=H R5=0H, R6=0Me. R7=0H [exo) (+)-narcidine [147] 561 Rt=:R3=:p-0Me. R2=:R4=R8=H R5Re=-0CH2O. R7=0H (exo) (-)-O'methyihaemanthidine [148] 562 Ri=R3=:p-0Me. R2=R4=R7=R8=H R5=Re=OMe (-)-O-methylpapyramine [128] 563 Ri==p-OMe. R2^-0H. R3=:R4=R8==H R7=OH(exo) (+)-albiflomanthine [149]

OH

564 R,=R3=R4=R5=OH

''-'°:2^'

OH OH

67 62

(+)-pancratiside [23] R,=:R2=R3=:R4=OH. R5=H (+)-7-deoxypancratistatln [23] R^=R5=H. R2=R3=R4=OH (+)-7-deoxy- frans-dlhydronarciclasine [21] ,0H

565 Ri: . H OHO

566 R=:

HO'

^^OH

4-0-p-giycopyranoside of narciclasine [151]

NHAC

R2=R3=R4=OH, R5=H (•i-Heiastaside [150]

Figure 7. Amaryllidaceae alkaloids recently isolated (continued next page).

557

ecent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

coa

567 (-f^d-demethyitazettine [152] OMe

OMe

HO 569 pattidiflorine [154]

568 tmoraline [153]

11 2.o<0^OH

OMe 6 H 571 (4-)-montabuphine [41]

570 (-)-obesine [155]

MeO 572

147 RsOMe

146 RsOH

bufiavine(41]

R=

573 R =

8-ademethytbuftavine[41]

Figure 7. Amaryllidaceae alkaloids recently isolated.

OM*

y^'^^^^^^^^^ 'OH (-)-cripoweliin A [156]

J^^T^o:^^ (-)-cripowellin B [156]

558 3.

S. Prabhakar and M.R. Tavares BIOLOGICAL ACTIVITY Extracts of Amaryllidaceae alkaloids have long been used in traditional medicine for the

treatment of a variety of illnesses. As early as the fourth century B.C., Hippocrates had reputedly advised the use of preparations of Amaryllidaceae plants to control uterine tumours [157]. More recently, a systematic bioassay of these alkaloids of different structural types has revealed a diversity of interesting biological properties. Thus, (+)-pretazettine (369) [158,159], and ungeremine (182) [160] show anti-leukemic activity. Cytotoxicity was observed for (-)• lycorine (245) [161], (-)-pseudolycorine (574) [162], 6-a-hydroxycrinamine (575) [163], ,\\OMe

MeO

OH 6-a-hydroxycrinamine 575 [174]

(-)-pseudolycorine 574 [173]

,,^OMe -OH

(+)-crinamlne 577 [176] kxxOMe

MeO

6-hydroxybuphanisine 578 [177]

pratorinine 579 [178]

Figure 8. Biologically active Amaryllidaceae alkaloids (continued next page).

Recent Advances in the Total Synthesis of Amaryllidaceae Ailcaloids

559

oH-hippeastrine 580 [179] Figure 8. Biologically active Antaryllidaceae alkaloids. (-)-augustine (576) [92], (+)-crinainine (577) [92], 6-a-hydroxybuphantsine (578) [164], pratorinine (579) (Figure 8) [164] and kalbretorine (222) [61]. Hippadine (202) has the interesting property of inducing reversible infertility in mice [165]. The analgesic properties of lycorine and haemanthidine (385) are reported to be superior to that of aspirin in a modified Koster's test [166]. While sharing with augustine the anti-malarial properties [92], crinamine (577) exhibits anti-bacterial activity as well [167]. (-)-Lycorine and (+)-hippeastrine (580) are reported to be virostatic alkaloids [168] due to their ability to reduce viral DNA synthesis. Medicinally by far the most exciting alkaloids are (->-galanthamine (295) and (-»-)-pancratistatin (94). Galanthamine, known to selectively inhibit human acetylcholinesterase in

vivo, has

successfully entered, as its hydrobromide salt, phase III clinical studies for the treatment of Alzheimer disease [169]. Although the majority of alkaloids belonging to narciclasine type, such as (+)-7-deoxynarciclasinc (31), (+)-pancratistatin (94), (+)-7-dcoxypancratistatin (67) and (+)/mn5-7-deoxydihydronarciclasine (62), all show consistent in vitro anti-viral activity [170], it is their anti-cancer properties that has evoked considerable medical interest. In fact (+y pancratistatin, the most potent cytotoxic alkaloid amongst its congeners [171], is under preclinical development as an anti-cancer drug [172]. 4.

ADDENDUM Since the completion of the manuscript the following woric on the synthesis and isolation

of new Amaryllicaceae alkaloids (c/. following page) was reported. Large scale syntheses [180,181] of (±)-narwedine (291) and (-)-galanthamine (295) have been reported. Kita and coworkers have described [182] the use of hypervalent iodine(III) compounds to achieve the total syntheses of (±)-sanguinine (535; R2=Me), (±)-ga]anthamine (295), (±)-narwedine (291) and (±)-lycoramine (300).

560

S. Prabhakar and M.R. Tavares

,OMe CH2OAC

583 5 8 1 Ri=H.R2=0H. R3=0Me (•i-)-6a-hydroxyci1namidine 5 8 2 RirsMe. R2=0H. R3=0Me (•f)-6a-hydroxyundulatine

(•i-)-bujeine

OMe

R2585 586

RiR2ss-OCH20(•i-)-delagoensine R^s:R2=0Me (-i-)<delagoenine

588

5 8 9 R=H S9Q RsOAc

(-fj-graciline (+)-11-acetoxygracillne

(-)-secopticamine

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

561

A substantially improved enantioselective synthesis [183] of {+)-7-deoxypancratistin (67) involving a significant modification of the previously reported [24] S-exo radical addition reaction to an oxime ether is described by Keck. A full account [184] of his earlier work on the synthesis of the same alkaloid [24] is now available. Magnus has successfully applied the reagents iodosylbenzene and trimethylsilylazide for p-azidonation of an enol-ether in a neat synthesis of (+)-pancratistatin (94) [185]. An interesting six-step preparation [186] of {±y epimaritidine (344) by Ley's group describes exclusive use of polymer supported reagents that circumvents all the customary techniques of laboratory purification of synthetic intermediates. A formal synthesis [187] of (:l:)-pancracine (414), involving the use of/ri5-trimethylsilylhydride as the radical initiator for a phenylthioacetamide derivative, has been reported by Oceda et al (+)-6a-Hydroxycrinamidine (581) and (•f)-6a-hydroxyundulatine (582) have been shown [188] to be C(l)-C(2)-P-epoxycrinane derivatives. An interesting variant of the crinane based structure occurs in (-f)-bujeine (583), isolated along with (-)-ll-O-acetylhaemanthamine (584) [189]. The former contains an acetoxymethyl substituent at C(ll) and an oxygen atom between C(ll) and C(12) of the ethanobridge. The presence of a C(12) hydroxyl group in the azacarbocyclic framework of maritinamine is a novel structural feature of both (+)-delagoensine (585) and (+)-delagoenine (586) [190]. (•f)-Egonine is shown [191] to be tazettine diol (411), epimeric at the carbon bearing the secondary hydroxyl group. Structures for (+)-plicamine (587) and (-)-secoplicamine (588) have been proposed [192]. (+)-Plicamine is a modified tazettine molecule with an additional nitrogen atom. The second nitrogen atom in (+).plicamine forms an isocarbostyril ring system. (+)-Graciline (589), (+)-ll-acetoxygraciline (590) and (+)-3,4dihydro-3-hydroxygraciline have all been shown to possess novel structures based on an ethanoiminodibenzo[6,(/]pyrane [193]. (+)-l-0-(3'-Hydroxybutyryl)pancratistatin and (+)-l-0(3'-0-P-D-glucopyranosylbutyryl)pancratistatin have been isolated [194].

Acknowledgement. We wish to express our deep gratitute to Dr. V. Sudarsanam (formerly of CIBA, Bombay, India), for many useful discussions and wise counsels that made this review possible. Our sincere thanks are also due to Dr. S. N. Swami (Pfizer, UK) and Professor A. M. Lobo (New University of Lisbon, Portugal) for their unflagging interest shown. We are indebted to Ms. F. Lopes da Silva for the painstaking attention in the preparation of the manuscript.

562

S. Prabhakar and M.R. Tavares

S.

ABBREVIATIONS USED

A Ac

angstrom units acetyl

acac

acetylacetonate

AC2O

acetic anhydride

AIBN

2,2*-azobisisobutyronitrile

Ar

ary!

9-BBN.H

9-borobicyclo[33.1 Jnonane

benz

benzene

Bn

benzyl

BOC

tert-butoxycarbonyl

(BOChO s-Bu

BOC anhydride

t-Bu

tert-butyl

sec-butyl

CBZ

carbobenzyloxy

m-CPBA

m-chloroperoxybenzoic acid

CSA

camphorsulphonic acid

Cy DABCO DBN DBU DCC DDQ DEAD DECPH

cyclohexyl 1,4-diazabicyclo[2.2.2]octane 1,5-diazabicyclo[4.3.0]non-5-ene l,8-cliazabicyclo[5.4.0]undec-7-ene dicyclohexylcarbodiimide 23-
DHP

dihydropyran

DIBAL

diisobutylaluminium hydride

DIEA

diisopropylethylamine

DMAC

dimethylacetamide

DMAP

4-dimethylaminopyridine

DME

1,2-dimethoxyethane

DMF

dimethylformamide

DMP

2,2-dimethoxypropane

DPPA

diphenylphosphoroylazide

DPPE

l,2-bis(diphenylphosphino)ethane

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids DMSO

dimethylsulphoxide

hex

n-hexane

hept

n-heptane

HMPA

hexamethylphosphoric triamide

HOAc

acetic acid

imid

imidazole

LAH

lithium aluminium hydride

LDA

lithium diisopropylamide

LHMDS

lithium hexamethyldisilazane

L-selectride

lithium tri-s-butylborohydride

Me

methyl

MOM

methoxymethyl

fAFM

4-methoxyphenylmethyl

Ms

methanesul phony1

MS2O

methanesulphonic anhydride

MTM

methylthiomethyl

NBS

N-bromosuccinimide

NCS

N-chlorosuccinimide

NMO

N-methylmorpholine N-oxide

PIFA

phenyliodobistrifluoracetate

i-Pr

isopropyl

pyr

pyridine

SMEAH

sodium bis(methoxyethoxy)aluminium dihydride

TBAB

tetra-n-butylammonium bromide

TBAC

tetra-n-butylammonium chloride

TBAF

tetra-n-butylanunonium fluoride

TBDMS

t-butyldimethylsilyl

TBDMSOTf

t-butyldimethylsilyltrifluoromethane sulphonate

TBTH

tri-n-butyltinhydride

TQ)I

1,1 '-thiocarbonyldiimidazolc

TEA

triethylamine

TEBAC

triethylbenzylammonium chloride

TEAI

tetraediylammonium iodide

Tf

trifluoromethanesulphonyl

TFA

trifluoroacetic acid

TFAA

trifluoroacetic anhydride

563

564

S. Prabhakar and M.R. Tavares

TfzO

trifluoromethanesulphonic anhydride

THF

tctrahydrofuran

THP

tctrahydropyranyl

TKfBAC

trimethylbenzyiammonium chloride

TMEDA

tetramethyiethylenediamine

TMSOTf

trimethylsilyltrifluoromethane sulphonate

td

toluene

TPAP

tctra-n-propylammonium pemithenate

Tr^BF4"

triphenylmethyl tetrafluoroborate

Ts

p-toluenesulphonyl

TsOH

p-toluenesulphonic acid

TTFA

thallium trifluoioacetate

6.

REFERENCES

1.

C Fuganti. The Alkaloids. New York: Academic Press, 1973. chapter 3 (RHF Manske, ed. vol XV).

2.

SF Martin. The Alkaloids. New York: Academic Press, 1987: chapter 3 (A Brossi, ed. vol XXX). R Polt Organic Synthesis: Theory and Applications. Lx)ndon: Jai Press, 1996: pp 109-148 (T Hudlicky, ed. vol 3). RJ Highet. J. Org. Chem. 1961 ;26:4767-4768. MA Siddiqui, V Snieckus. Tetrahedron Lett. 1988;29:5463-5466. AM Rosa, AM Lobo, PS Branco, S Prabhakar, M S^-da-Costa. Tetrahedron 1997;53:299306. S Prabhakar, AM Lobo, MM Marques, MR Tavares. J. Chem. Res. (S) 1985:394-395. K Allayarov, K Abduazimov, SY Yunusov. Uzb. Khim. Zh. 1964;8:46-51 (Chem. Abstr. 1964;61:4407a). MG BanwcU, CJ Cowden. Aust. J. Chem. 1994;47:2235-2254.

3. 4. 5. 6. 7. 8. 9.

10. J Razafimbelo, M Andriantsiferana, G Baudouin, F Tillequin. Phytochemistry 1996;41:323-326. 11. SV Kessar. R Gopal, M Singh. Tetrahedron 1973;29:167-175. 12. S Ghosal, KS Saini, S Razdan, Y Kumar. J. Chem. Res. (S) 1985:100-101. 13. R Suau, AI Gdmez, R Rico. Phytochemistry 1990;29:1710-1712. 14. MG Banwell, BD Bisset, S Busato, CJ Cowden, DCR Hockless, JW Holman, RW Read, AW Wu. J. Chem. Soc. Chem. Comm. 1995:2551-2553.

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

565

15. T Okamoto, Y Torii, Y Isogai. Chem. Pharm. Bull. 1968;16:1860-1864. 16. N Chida, M Ohtsuka, S Ogawa. Tetrahedron Lett. 1991 ;32:4525-4528. 17. N Chida, M Ohtsuka, S Ogawa. J. Org. Chem. 1993;58:4441-4447. 18. T Hudlicky, HF Olivo. J. Am. Chem. Soc. 1992;114:9694-9696. 19. T Hudlicky, HF Olivo, B McKibben. J. Am. Chem. Soc. 1994;116:5108-5115. 20.

GE Keck, TT Wager. J. Org. Chem. 1996;61:8366-8367.

21.

GR Pettit, GR Pettit ffl, RA Backhaus, MR Boyd, AW Meerow. J. Nat. Prod. 1993;56:1682-1687.

22. N Chida, M Jitsuoka, Y Yamamoto, M Ohtsuka, S Ogawa. Heterocyles 1996;43:13851390. 23.

S Ghosal, S Singh, Y Kumar, RS Srivastava. Phytochemistry 1989;28:611-613.

24.

GE Keck, SF McHardy, JA Murray. J. Am. Chem. Soc. 1995; 117:7289-7290.

25.

X Tian, R Maurya, K KOnigsberger, T Hudlicky. Synlett 1995:1125-1126.

26.

T Hudlicky, X Tian, K K6nigsberger, R Maurya, J Rouden, B Fan. J. Am. Chem. Soc.

27.

S Danishefsky, JY Lee. J. Am. Chem. Soc. 1989;111:4829-4837.

1996;118:10752-10765. 28.

S Greenberg, JG Moffatt. J. Am. Chem. Soc. 1973;95:4016-4025.

29.

GR Pettit, V Gaddamidi, GH Cragg, DL Herald, Y Sagawa. J. Chem. Soc. Chem. Comm.

30.

X Tian, T Hudlicky, K K6nigsberger. J. Am. Chem. Soc. 1995;117:3643-3644.

31.

BM Trost, SR Pulley. J. Am. Soc. Chem. 1995;117:10143-10144.

1984;1693-1694.

32.

M Khaldi, F Chretien, Y Chapleur. Tetrahedron Lett. 1995;36:3003-3006.

33.

JH Rigby, V Gupta. Synlett. 1995:547-548.

34.

TM Doyle, D VanDerveer, J Haseltine. Tetrahedron Lett. 1995;36:6197-6200.

35.

TK Park, SJ Danishefsky. Tetrahedron Lett. 1995;36:195-196.

36.

JL Acefta, O Arjona, F Iradier, J Plumet. Tetrahedron Lett. 1996;37:105-106.

37.

DR Gauthier,Jr., SL Bender. Tetrahedron Lett. 1996;37:13-16.

38.

GK Friestad, BP Branchaud. Tetrahedron Lett. 1997;38:5933-5936.

39.

SR Angle, T Wada. Tetrahedron Lett. 1997;38:7955-7958.

40.

G Mehta, N Mohal. Tetrahedron Lett. 1998;39:3281-3284.

41.

F Viladomat, J Bastida, C Codina, WE Campbell, S Mathee. Phytochemistry

42.

PA Patil, V Snieckus. Tetrahedron Lett. 1998;39:1325.1326.

43.

S Ghosal, Y Kumar, DK Chakrabarti, J Lai, SK Singh. Phytochemistry 1986;25:1097-

1995;40:307-311.

1102.

S. Prabhakar and M.R. Tavares

566

44. ZTrimino, I Spengter, C Iglesias, J Borrego. Rev. Cubana Quim. 1989;5:55-57 (Chcm. Abstr. 1991; 115:203303). 45. JH Rigby, ME Mateo. Tetrahedron 1996;52:10569-10582. 46. JM Llabres, F Viladomat, J Bastida, C Codina, M Rubiralta. Phytochemistry 1986;25:2637.2638. 47. Y Xiong, HW Moore. J. Org. Chem. 1996; 61:9168-9177. 48. J Bastida. C Codina, F Viladomat, M Rubiralta, J-C Quirion, B Weniger. J. Nat. Prod. 1992;55:122-125. 49. JS Fames, DS Carter, U Kurz, LA Flippin. J. Org. Chem. 1994;59:3497-3499. 50. S Ghosal, Y Kumar, SK Singh, A Singh, A Kumar. J. Chem. Res. (S) 1986:112-113. 51.

MA Siddiqui, V Snieckus. Tetrahedron Lett. 1990*31:1523-1526.

52. U Lauk, D DUrst, W Fischer. Tetrahedron Lett. 199132:65-68. 53. J Bastida, C Codina, F Viladomat, M Rubiralta, J-C Quirion, B Weniger. J. Nat. Prod. 1992;55:134-136. 54. AE Bunnell, LA Flippin, Y Liu. J. Org. Chem. 1997,62:9305-9313. 55. S Ghosal, H Rao, DK Jaiswal. Y Kumar, AW Frahm. Phytochemistry 1981;20:20032007. 56. AA All, MK Mesbash, AW Frahm. Planta Med. 1981 ;43:407.409. 57.

S Ghosal, KS Saini, AW Frahm. Phytochemistry 1983;22:2305-2309.

58.

DC Black. PA Keller, N Kumar. Tetrahedron Lett. 198930:5807-5808.

59. AI Meyers, RH Hutchings. Tetrahedron Lett. 1993,34:6185-6188. 60. M Iwao, H Takehara, S Obata, M Watanabe. Heterocyclcs 1994;38:1717-1720. 61.

S Ghosal, R Lochan, Ashutosh, Y Kumar, R Srivastava. Phytochemistry 1985;24:18251828.

62. MMA Pereira, S Prabhakar, AM Lobo. J. Nat. Prod. 1996;59:744-747. 63. D P^rez, G Bur6s, E Guitidn, L Castedo. J. Org. Chem. 1996,61:1650-1654. 64. A Padwa. J. Chem. Soc. Chem. Commun. 1998:1417-1424. 65.

RK Boeckmanjr., SW Goldstein, MA Walters. J. Am. Chem. Soc. 1988; 110:82508252.

66. K Allayarov, A Abdusamatov, SY Yunusov. Khim. Prir. Soedin. 1970,6:143-144 (Chem. Abstr. 1970;73:69771). 67. JW Cook, DJ Loudon. The Alkaloids. New York: Academic Press, 1952: chapter 2 (RHF Manske, HL Holmes, ed. vol XI p. 331). 68. G Stork, DJ Morgans,Jr. J. Am. Chem. Soc. 1979;101:7110-7111. 69. O Hoshino, M Ishizaki, K Kamei, M Taguchi, T Nagao, K Iwaoka, S Sawaki, B Umezawa, Y litaka. J. Chem. Soc. Perkin 1 1996:571-580.

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids

567

70. W Oppolzer, AC Spivey, CG Bochct. J. Am. Chem. Soc. 1994;! 16:3139-3140. 71. FM Dabire, DA Muraveva. Khim. Prir. Soedin.

1982;4:534 (Chem. Abstr.

1982;97:107078). 72. T Hudlicky, H Luna, HF Olivio, C Andersen, T Nugent, JD Price. J. Chem. Soc. Perkin 1 1991:2907-2917. 73. RA Holton, MP Sibi, WS Murphy. J. Am. Chem. Soc. 1988; 110:314-316. 74. HG Boit, W Dopke, A Beitner. Chem. Ber. 1957;90:2197-2202. 75. J Szewczyk, JW Wilson, AH Lewin, H Caroll. J. Het. Chem. 1995;32:195-199. 76. T Shingu, S Uyeo. Chem & Ind. 1956:177-178. 77. DHR Barton, GW Kirby. J. Chem. Soc. 1962:237-242. 78. W-C Shieh, JA Carlson. J. Org. Chem. 1994;59:5463-5465. 79. S Uyeo, S Kobayashi. Chem. Pharm. Bull. 1953; 1:139-142. 80. KA Parker, H-J Kim. J. Org. Chem. 1992;57:752-755. 81.

EJ Sandoe, GR Stephenson, S Swanson. Tetrahedron Lett. 1996;37:6283-6286.

82.

DJ Ackland, JT Pinhey. J. Chem. Soc. Perkin 1 1987:2695-2700.

83.

H Ishibashi, TS So, K Okochi. T Sato. N Nakamura, H Nakatani, M Ikeda. J. Org. Chem. 1991;56:95-102.

84. HG Boit, W D5pke. Naturwissenschaftan 1961 ;48:406. 85. RV Stevens, LE DuPree,Jr., P Loewenstein. J. Org. Chem. 1972;37:977-982. 86. TA Blumenkopf, LE Overman. Chem. Rev. 1986;86:857-873. 87. RM Burk, LE Overman. Heterocycles 199335:205-225. 88. IH Sanchez, FJ L6pez, JJ Soria, MI Larraza, HJ Flores. J. Am. Chem. Soc. 1983;105:7640-7643. 89. Y Kita, T Takada, M Gyoten, H Tohma, MH Zenk, J Eichhom. J. Org. Chem. 1996;61:5857-5864. 90.

K Tomioka, K Koga, SI Yamada. Chem. Pharm. Bull. 1977;25:2681-2688.

91.

F Sandberg, KH Michel. Lloydia 1963;26:78-90.

92.

K Likhitwitayawuid, CK Angerhofer, H Chai, JM Pezzuto, GA Cordell, N Ruangrungsi. J. Nat. Prod. 1993;56:1331-1338.

93.

WH Pearson, FF Lovering. J. Am. Chem. Soc. 1995; 117:12336-12337.

94. WH Pearson, FE Lovering. J. Org. Chem. 1998,63:3607-3617. 95. LH Mason, ER Puschett, WC Wildman. J. Am. Chem. Soc. 1955;77:1253-1256. 96. H Ishibashi, H Nakatani, S Iwami, T Sato, N Nakamura, M Ikeda. J. Chem. Soc. Chem. Comm. 1989:1767-1769. 97. WC Wildman, DT Bailey. J. Org. Chem. 1968;33:3749-3753. 98.

SF Martin, SK Davidsen, TA Puckette. J. Org. Chem. 1987,52:1%2-1972.

568 99. 100. 101. 102. 103. 104. 105. 106.

S. Prabhakar and M.R. Tavares

LE Overman, H Wild. Tetrahedron Lett 1989;30:647-650. S Danishcfsky, J Morris, G Mullen, R Gammil. J. Am. Chem. Soc. 1982;104:7591-7599. RJHighet,PF Higher. Tetrahedron Lett. 1966;7:4099-4101. MM Abelman, LE Overman, VD Tran. J. Am. Chem. Soc. 1990; 112:6959-6964. WC Wiidman, Q Kaufman. J. Am. Chem. Soc. 1955;77:1248-1252. U Dry, M Foynton, ME Thompson, FL Warren. J. Chem. Soc. 1958:4701-4704. M Ishizaki, O Hoshlno, Y litaka. J. Org. Chem. 1992;57:7285-7295. M Ishizaki, K-i Kurihara, E Tanazawa, O Hoshino. J. Chem. Soc. Perkin 1 1993:101110. 107. LE Overman, J Shim. J. Org. Chem. 1993;58:4662-4672. 108. J Jin. SM Weinreb. J. Am. Chem. Soc. 1997; 119:5773-5784. 109. AA Ali, H Hambloch, AW Frahm. Phytochemistry 1983;22:283-287. 110. F Viladomat, J Bastida, G Tribo, C Codina, M Rubiralta. Phytochemistry 1990;29:13071310. 111. W Dopke, LH Pham, E Grundemann, M Bartoszek, S Flatau. Panta Med. 1995;61:564566. 112. J Bastida, JM Fernandez, F Viladomat, C Codina, G de la Fuente. Phytochemistry 1995;38:549-551. 113. AHA Donia, A-A Abid, AS el Din, A Evidente, M Gaber, A Scopa. Phytochemistry 1992;31:2139-2141. 114 J Bastida, C Codina, P Peeters, M Rubiralta, M Orozco, FJ Lugue, SC Chhabra. Phytochemistry 1995;40:1291-1293. 115 R Suau, AI Gomez, R Rico. An. Qufmica 1990;86:672-674 (Chem. Abstr. 1991;114:98281). 116. W Dopke, E Scwerin, Z Trimiiio, I Spcnglcr, C Iglesias. Z. Chem. 199030:375. 117. M Kreh, R Matusch, L Witte. Phytochemistry 1995,40:1303-1306. 118. S Ghosal, S Unnikrishnan, SK Singh. Phytochemistry 1989;28:2535-2537. 119. GM Tokhtabaeva, VI Sheichenko, IV Yartscva. ON Tolkachev. Khim. Prim. Soedin. 1987;6:872-875 (Chem. Abstr. 1988; 109:89687). 120. M Kihara, LXu, K Konishi, K Kida, Y Nagao, S Kobayashi, T Shingu. Chem. Kiarm. Bull. 1994;42:289-292. 121. J-C Quirion, H-P Husson, B Weniger, F Jimenez, TA Zanoni. J. Nat. Prod. 1991;54:1112-1114. 122. P Richomme, V Pabu99Uoglu, T Gozler, AJ Freyer, M Shamma. J. Nat. Prod. 1989;52:1150-1152.

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

569

123. R Suau, AI G6mez, R Rico, MPV Tato, L Castedo, R Riguera. Phytochcmistry 1988;27:3285-3287. 124. M Kihara, T Ozaki. S Kobayashi. T Shingu. Chem. Phamn. Bull. 1995;43:318-320. 125. M Kreh, R Matusch. Phytochcmistry 1995;38:1533-1535. 126. C Codina, F Viladomat, J Bastida, M Rubiralta. Planta Med. 1989;55:116. P2-60. 127. GR Almanza, JM Fernandez, EWT Wakori, F Viladomat, C Codina, J Bastida. Phytochcmistry 1996;43:1375-1378. 128. R Suau, R Rico, AI Garcia. AI Gomez. Hetcrocycles 199031:517-522. 129. J Bastida, JM Llabr6s, F Viladomat, C Codina, M Rubiralta, M Feliz. Phytochemistry 1988;27:3657.3660. 130. J Bastida, C Codina, F Viladomat, M Rubiralta, J-C Quirion, H-P Husson. Phytochemistry 1990;29:2683-2684. 131. A Latvala, A Ontlr, T G5zler, A Linden, B Kiv9ak, M Hesse. Phytochemistry 199539:1229-1240. 132. M Kihara, K Konishi, LXu, S Kobayashi. Chem. Pharm. Bull. 1991,39:1849-1853. 133. PW Jeffs, L Mueller, AHA-Donia, AAS el-Din, D Campau. J. Nat. Prod. 1988;51:549554. 134. OMAbdallah. Phytochemistry 1995;39:477-478. 135. J Bastida, F Viladomat, S Bergoiion, JM Fernandez, C Codina, M Rubiralta, J-C Quirion. Phytochemistry 1993;34:1656-1658. 136. OMAbdallah. Phytochemistry 1993^4:1447-1448. 137. OM Abdallah, AA AH, H Itokawa. Phytochemistry 1989;28:3248-3249. 138. S Kobayashi, K Satoh, A Numata, T Shingu, M Kihara. Phytochcmistry 199130:675677. 139. F Viladomat, J Bastida, C Codina, WE Campbell, S Mathee. Phytochcmistry 1994;35:809-812. 140. F Viladomat, GR Almanza, C Codina, J Bastida, WE Campbell, S Mathee. Phytochemistry 1996;43:1379-1384. 141. RJ Tang, NJ Bi, GE Ma. Chin. Chem. Lett. 1994;5:855-858 (Chem. Abstr. 1995;122:128545). 142. F Viladomat, C Codina, J Bastida, S Mathee, WE Campbell. Phytochemistry 1995;40:%l-%5. 143. B Sener, S KOnUkol, C Kruk, UK Pandit. Nat. Prod. Lett. 1993;1:287-291. 144. V Pabu990uoglu, P Richomme, T Gozler, B Kiv9ak, AJ Freyer, M Shamma. J. Nat. Prod. 1989;52:785-791.

570

S. Prabhakar and M.R. Tavares

145. J Bastida, JL Contrcras, C Codina, CW Wright, JD Phillipson. Phytochemistry 1995;40; 1549-1551. 146. J Bastida. JM Llabr^s, F Viladomat, C Codina, M Rubiralta, M Feliz. Planta Med. 1988;54:524-526. 147. ETojo. J. Nat. Prod. 1991;54:1387-1388. 148. MPV Tato, L Castedo, R Riguera. Heterocyclcs 1988;27:2833-2838. 149. G Baudouin, FTillequin, M Koch. Heterocyclcs 1994;38:965-970. 150. S Ghosal, K Datta, SK Singh, Y Kumar. J. Chem. Res. (S) 1990:334-335. 151. AHA-Donia, A de Giulio, A Evidente, M Gaber, A-A Habib, R Lanzetta, AAS el Din. Phytochemistry 1991;30:3445-3448. 152. J Wagner, HLPham,WDopke. Tetrahedron 1996;52:6591-6600. 153. L-Z Lin, S-F Hu, H-B Chai, T Pengsuparp. JM Pezzuto, GA Cordell, N Ruangrungsi. Phytochemistry 1995;40:1295-1298. 154. C Codina, F Viladomat, J Bastida, M Rubiralta, J-C Quirion. Phytochemistry 1990;29:2685-2687. 155. F Viladomat, J Bastida, C Codina, M Rubiralta, J-C Quirion. J. Nat. Prod. 1992;55:804806. 156. R Velten, C Erdelen, M Gehling, A Gohart, D Gondol, J Lenz, O Lockhoff, U Wachendofff, D Wendisch. Tetrahedron Lett. 1998-39:1737-1740. 157. JB Gardeli (translator). Oeuvres M^icales d*Hippocrates. Toulouse: Pages, Meilhec et Cie, 1801: 4 vols, cited in [170]. 158. E Furusawa, S Furusawa. Oncology 1988;45:180-186 (Chem. Abstr. 1988; 109:47934). 159. B Weniger, L Italiano, JP Beck, J Bastida, S Bergofion, C Codina, A Lobstein, R Anton. Planta Med. 1995;61:77-79. 160. RKY Cheng, SJ Van, CC Cheng. J. Med. Chem. 1978;21:199-203. 161. E Furusawa, S Furusawa, S Morimoto, W Cutting. Proc. Soc. Exp. Biol. Med. 1971;136:1168-1173 (Chem. Abstr. 1971;74:139262). 162. E Furusawa, H Irie, D Combs, W Wildman. Chemotherapy (Basel) 1980;26:28-37 (Chem. Abstr. 1980;92:69310). 163. A Jimenez, A Santos, G Alonso, D Vazquez. Biochim. Biophys. Acta 1976;425:342-348. 164. MA Abd Hafiz, MA Ramadan, ML Jung, JP Beck, R Anton. Planta Med. 1991;57:437439. 165. SC Chattopadhyay, U Chattopadhyay, PP Mathur, KS Saini, S Ghosal. Planta Med. 1983;49:252-254. 166. M Tanker, G ^itoglu, B GUmUsel, B Sener. Int. J. Pharmacog. 19%;34:194-197 (Chem. Abstr. 1996; 125:316966).

Recent Advances in the Total Synthesis of Amaryllidaceae Allcaloids

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167. SA Adesanya, TA Olugbade, 0 0 Odebiyi, JA Aladesanmi. Int. J. Pharmacog. 1992;30:303-307 (Chem. Abstr. 1993;119:113351). 168. JR Nozaki. T Kim, Y Imakura. M Kihara. S Kobayashi. Res. Virol. 1989;140:115-128 (Chem. Abstr. 1989; 111:49925). 169. HAM Muckc. Pharmaceutical News 1998;5:10-14. 170. B Gabrielsen, TP Monath, JW Huggins, DE Kefauver, GR Pettit, G Groszek, M Hollings head, JJ Kirsi. WM Shannon, EM Schubert, J DaRe, B Ugarkar, MA Ussery, MJ Phelan. J. Nat. Prod. 1992;55:1569-1581. 171. GR Pettit, V Gaddamidi, DL Herald, SB Singh, GM Cragg. JM Schmidt, FA Bocttner, M Williams, Y Sagawa. J. Nat. Prod. 1986;49:995-1002. 172. GR Pettit, GR Pettit III, G Groszek, RA Backhaus, DL Doubek, RJ Barr, AW Meerow. J. Nat. Prod. 1995;58:756-759. 173. S Ghosal, Y Kumar, S Singh. Phytochemistry 1984;23:1167-1171. 174. Y Tsuda, N Kashiwaba, V Kumar. Chem. Pharm. Bull. 1984;32:3023-3027. 175. AA Ali, H Kating, AW Frahm, AM El-Moghazi, MA Ramadan. Phytochemistry 1981;20:1121-1123. 176. S Kobayashi, T Tokumoto, M Kihara, Y Imakura, T Shingu, Z Taira. Chem. Pharm. Bull. 1984;32:3015-3022. 177. AA Ali. H Kating, AW Frahm. Phytochemistry 1981,20:1731-1733. 178. JA Madry, BS Joshi, AA Ali, MG Newton, SW Pelletier. Tetrahedron Lett. 1985;26:4301-4302. 179. S Kobayashi, K Yuasa, Y Imakura, M Kihara, T Shingu. Chem. Pharm. Bull. 1980;28:3433-3436. 180. DA Chaplin. N Eraser, PD Tiffm. Tetrahedron Lett. 1997;38:7931-7932. 181. L Czollner, W Frantsits, B KUenberg. U Hedenig, J Frohlich, U Jordis. Tetrahedron Lett. 1998; 39:2087-2088. 182. Y Kita, M Arisawa, M Gyoten, M Nakajima, R Hamada, H Tohma, T Takada. J. Org. Chem. 1998;63:6625-6633. 183. GE Keck, TT Wagner, SF McHardy. J. Org. Chem. 1998;63:9164-9165. 184. GE Keck, SF McHardy, JA Murry. J. Org. Chem. 1999;64:4465-4476. 185. P Magnus, IK Sebhat. Tetrahedron 1998;54:15509-15524. 186. SV Ley, O Schucht, AW Thomas, PJ Murray. J. Chem. Soc. Perkin 1 1999; 10:12511252.

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187. M Ikeda, M Hamada, T Yamashita, K Matsui, T Sato, H Ishibashi. J. Chem. Soc. Perkin 1 1999;14:1949-1956. 188. A Machocho, SC Chhabra, F Viladomat, C Codina, J Bastida. Phytochcmistiy 1999;51:1185-1191. 189. J Labrafia, G Choy. X Solans, MF Bardia, G Fucnte, F Viladomat, C Codina, J Bastida. Phytochemistry 1999;50:183-188. 190. JJ Nair, WE Campbell, DW Gammon, CF Albrecht, F Viladomat, C Codina, J Bastida. Phytochemistry 1998;49:2539-2543. 191. LH Pham, E Griindemann, J Wagner, M Bartoszek, W Dopke. Phytochemistry 1999;51:327.332. 192. N Onver, T Gozler, N Walch, B Gozler, M Hesse. Phytochemistry 1999;50:1255-1261. 193. S Noyan, GH Rentsch, MA OnUr, T Gozler, B Gozler, M Hesse. Heterocycles 1998;48:1777-1791. 194. K Kojima, M Mutsuga, M Inoue, Y Ogihara. Phytochemistry 1998;48:1199-1202.

573

Chapter Four

Applications of Radical Cyclization Reactions in Total Syntheses of Naturally Occurring Indole Alkaloids JieJackLI Pfizer Global Research and Development 2800 Plymouth Road Ann Arbor, MI 48105 U.S.A. CONTENTS 1. Introduction 2. Five-Membered Ring Formation 2.1. The "disfavored" S-endo-trig Mode 2.2. The 5-6X0 Mode 3. Six- Membered Ring Formation 3.1. The e-endo'trig Mode 3.2. Intramolecular Caryi-Caryi Bond Formation 3.3. The e-exo'trig Mode 4. Seven- and Eight-Membered Ring Formation 5. Tandem Cyclization 6. Concluding Remarks 7. Acknowledgments 8. References

574 574 574 577 592 592 595 599 609 612 618 618 618

574

J.J. LI

1. INTRODUCTION Since the resurgence of free radical chemistry two decades ago, its utility has grown exponentially, thanks to mild reaction conditions, tolerance of a wide variety of functional groups, and good stereoselectivities. The formation of a C-C bond through a free radicalmediated cyclization approach has emerged as a highly versatile and often indispensable method. A host of books [1-3], book chapters [4-6], and reviews [7-9] have been published to summarize the development of radical chemistry in organic synthesis. However, except for the excellent review by Jasperse, Curran, and Fevig titled ''Radical Reactions in Natural Product Synthesis'' published in 1991 [7], the applications of radical chemistry to the synthesis of heterocycles, which have great importance to the pharmaceutical industry, have not been treated. This account will address this topic by highlighting accomplishments in the total syntheses of naturally occurring indole alkaloids where radical cyclization reactions have played a central role in the synthetic approach. This chapter is divided according to the size of the rings formed by radical cyclization: (1) Five-membered ring formation, (2) Six-membered ring formation, (3) Seven- and eightmembered ring formation, and finally (4) Tandem cyclization. 2. FIVE-MEMBERED RING FORMATION 2.1. The "disfavored" S-endo-trig Mode According to Baldwin's rules [10], the S-endo-trig mode of cyclization is disfavored stereoelectronically. As a result, most five-membered ring formations employing intramolecular radical cyclization proceed via the 5-exo-trig path. The few exceptions to Baldwin's rule occur when substrates possess structural moieties (e.g. an amide bond) that conformationally bias the substrates in favor of the S-endo-trig mode. Erythrina alkaloids, possessing curare-like activity, are a large class of natural products found in Erythrina plants (Leguminosae). In a study towards construction of the erythrina skeleton, "disfavored" S-endo-trig cyclizations were achieved by Ikeda et al. by BujSnHmediated radical cyclization of an ^-vinylic a-chloroacetamide to give five-membered lactams [11]. As depicted in Scheme 1, the carbamoylmethyl radical, generated fi-om precursors la-b underwent a "disfavored" 5-endo-trig cyclization to give the corresponding lactams 2a~b in good yield. The Ikeda group also demonstrated the sensitivity of this type of radical cyclization to the structures of the precursors. For example, when the carbonyl group was not incorporated into the precursor, no cyclization product was observed, instead, reduction of the starting material predominated. Furthermore, depending upon the electronic stability and/or the steric congestion of the radical intermediate, 4-^jco-ring closure could be a competing outcome. In another example, a synthesis of (db)-cotinine, a metabolite of nicotine was realized using the same approach [12]. As an extension of the Dceda group's carbamoylmethyl radical

Applications of Radical Cyclizatlon Reactions

575

cyclization methodology, a new synthesis of the erythrinane framework was accomplished [13]. The substrate 3 was easily prepared by treatment of 2-(cyclohex-l-enyl)ethylamine with chloroacetyl chloride in benzene and pyridine. When enamide 3 was allowed to react with Bu3SnH and 2,2'-azobisisobuyronitrile (AIBN) in toluene, perhydroerythrinone 5 was obtained in 44% yield. The formation of 5 may involve a S-endo-trig cyclization of the carbamoylmethyl radical intermediate to give a-acylamino radical intermediate 4, which subsequently undergoes a S-endo-trig cyclization to afford 5. This convenient route to erythrinane skeleton (6) opens the way to the synthesis of naturally occurring and biologically important erythroidine-type (non-aromatic) Erythrina alkaloids.

O-Jk

1.1 eq. n-BujSnH, cat. AIBN, Tol. reflux

Me l a : R = Me lb:R==Ph

H

1

\^

^R

I

N-^^O U Me

2a :R = Me,73% 2b :R = Ph., 75% n-BujSnH AIBN, 44%

CO

o

H

eg, erythrinane skeleton (6) Scheme 1. "Disfavored" S-endo-trig radical cyclization and application to erythrinane framework 3-Demethoxyerythratidinone (10), one of the simplest of the erythrina alkaloids, was isolated in 1973 by Barton et al. fh)m Erythrina lithosperma [14]. A concise approach to such Erythrina alkaloids using a "disfavored" S-endo-trig radical cyclization mediated by nickel powder was described by Zard and coworkers [15]. 7^-Alkenyl trichloroacetamide 7 was

J J. Li

576

prepared from cyclohexadione monoethyleneketal in three steps. As outlined in Scheme 2, substrate 7 was subjected to nickel powder promoted radical cyclization: upon refluxing 7 with nickel powder and acetic acid in 2-propanol, exclusive 5-endo-trig cyclization was observed to produce the unsaturated lactam 8 in 49% yield, along with 25% of reduced (monodechlorinated) 7. Exposure of 8 to p-toluenesulfonic acid in refluxing benzene accomplished the desired tetrahydroquinoline cyclization to furnish compound 9 in 84% yield. Finally, reduction of the amide moiety with a combination of LiAlHVAlCh in cold ether (86%) and deprotection of the ketone (^-chlorosuccinimide/AgNOa, 40%) with concomitant double bond migration provided 3-demethoxyerythratidinone (10). Worth noting is the difficult task of engineering the unsaturation on the more substituted side of the ketone, which was accomplished via an ingenious double bond migration of the p,Y>double bond to the desired a,P-unsaturated ketone. Danishefsky and Panek devised a different strategy to accomplish the same purpose employing an intramolecular radical cyclization with the fragmentation method [16] (vide infra).

•rm.

MeO Ni/AcOH MeO

^^.r^^y MeO

^N

2-propanol reflux, 2 h

P l.LiAIH4,AICl3 THF, ether, 86% ^. 2.NCS,AgN03 CH3CN/H2O,40%

O 3-demethoxyerythratidinone (10)

Scheme 2. Nickel powder promoted 5-endo-trig radical cyclization in erythrina alkaloid synthesis

Applications of Radical Cyclization Reactions

577

2.2 The S-exo Mode For the simple 5-hexenyl radical intermediate, S-exo-trig cyclization is kinetically preferred over G-endo-trig cyclization. The former is 50 times faster than the latter, translating to a -98:2 preference of five-membered ring formation over six-membered ring formation. Nonetheless, if the usually favored S-exo-trig regioselectivity of 5-hexenyl radical cyclization is retarded by substitution at the 5-position, the S-endo-trig mode of cyclization prevails (Section 3.1). Danishefsky and Panek [16] reported a total synthesis of (i:)-3-demethoxyerythratidinone (10) involving a novel S-exo-trig radical cyclization route to a site specific enol derivative. As illustrated in Scheme 3, the target substrate 13 was derived fh)m the coupling of the BOC derivative of dopamine methyl ether (11) and enone ketal 12. When substrate 13 was subjected to radical forming conditions, the internal "Michael-like" free radical cyclization led to compound 14 which constituted a formal total synthesis of 10. More importantly, they further established a site-specific enol derivative (enol acetate) directly through a free radical cyclization paradigm. Thus, enone 13 was treated with tri-/i-butyllithiostannane and the resultant hydroxystannane was immediately acetylated with acetic anhydride to afford an 83% yield of ca. 1:1 mixture of stereoisomers 15. Treatment of 15 with /i-BuaSnH in the presence of catalytic AIBN (5-10 mol%) provided 16 as a single stereoisomer. The net outcome was generation of an enolate at the more substituted side of the ketone. Advantage was then taken of the site-specific enol acetate: enolate generation using methyl lithium, quenching with phenylselenium chloride, followed by oxidation employing Nal04 with concomitant E2 elimination at room temperature produced 3-demethoxyerythratidinone (10). This synthetic sequence suggests a high susceptibility for a-oxygenated, a-stannylated allylic systems to undergo free radical attack at the 5-carbon. In substrate 15, the radical source was tethered to the allylic residue by a nitrogen atom attached to the 6-carbon. Jones et al. achieved an efficient formal total synthesis of geneserine (20) also using a 5-exO'trig radical cyclization strategy [17a]. The radical cyclization precursor 17, an Nacryloyl derivative of 2-bromoaniline, was prepared from 3-bromophenol in five steps. As summarized in Scheme 4, treatment of 17 with one equivalent of /t-BuaSnH and a catalytic amount of AIBN in refluxing toluene for 30 minutes led to clean cyclization to the 3substituted oxindole 18 in 63% yield with no observable six-membered ring product. The success of this cyclization reaction demonstrates that electron-donating substituents on the benzene ring do not hamper the radical cyclization. Interestingly, the other N-suhstituent (Nmethyl) did not undergo the theoretically possible competing reaction—1,5-hydrogen transfer reaction. Thanks largely to work by Jones and Storey [17b], Togo [17c], and Curran [I7d], we have a better understanding of the origins of chemoselectivity in radical reactions of axially twisted anilides. In aryl amides, the selectivity of short-lived aryl radical is determined by the relatively high rotational barrier of the C—^Nbond. AsaresuUofthe well-known preference

JJ.U

578

o

YY^

MeO

x^:;^ MeO 11

NHBoc

M

V"

O

O

2-4 eq. /i-Bu3SnH 5-10 mol% AIBN

»•

MeO'

r

J

^gph

YY^.

MeO MeO

/ * ^ ^ % ^ N" ^ ^

^

PhH, reflux, 88% 14

Me 1. H-Bu3SnLi,Et20,-78''C

MeO''^'''\X^~\

2.AC20,DMAP,CH2CI2,83%

L J 15

cat. n-BujSnH 5-10 mol% AIBN 69%

AcO

SePh

SnBu3

[4 AcO (SnBu3 Mel

M

•^^^^Y^ L X N-i MeO^^^'^'^ -^ 16

f\,

OAc

l.MeUTHF 2. PhSeCI, -78 "C 3.NaI04,aq.THF 64% overall

MeO"'^^"^''

O 3-demethoxyerythratidinone (10)

Scheme 3. S-exo-lrig Radical cyclization in the total synthesis of 3-demethoxyerythratidinone

Applications of Radical Cyclization Reactions

579

of M^aryl amides to exist in an E (Ar and O anti) geometry, the small amount of aryl radical generated from 17 cannot suffer a 1,5-hydrogen transfer because the C—N bond is fixed. In the event, fomiation of the enolate of 18 using lithium hexamethyldisilazide in THF at -78 **C followed by quenching with allyl bromide gave oxindole 19 in 88% yield, establishing the quaternary center at the C{3) position. Since the conversion from oxindole 19 to geneserine (20) was known [18], this constitutes a formal total synthesis of the natural product.

MeO

-OCX

1 eq. n-BusSnH »i

cat. AIBN, tol. reflux, 63%

Me 17 MeOI

"-Xxx N ^O Me

M e

^^

LIN(TMS)2,THF,-78°C, N ^O Me

allyl bromide, 88%

18

Me

MeHNOC

Me

5 steps

N • O nil" Me geneserine (20) ^^

Me 19

Me

Scheme 4. A formal total synthesis of geneserine In early applications of S-exo-trig radical cyclizations to indole alkaloid syntheses, a variety of dihydroindole systems were synthesized from Mallyl substituted o-bromoacetanilide in connection with the synthesis of koumine, a Chinese medicinal alkaloid [19]. In a similar manner, the Jones group further elaborated their chemistry developed in the synthesis of the 3substituted oxindole 18, and achieved a formal total synthesis of physovenine (26), a calabar bean alkaloid

that

acts

upon

the parasympathetic

nervous

system

by

inhibiting

acetylcholinesterase [20]. Analogous to the aforementioned approaches, substrate 21 was prepared by treating the corresponding aniline with tigloyl chloride in the presence of triethylamine, followed by A/-methylation (Scheme 5). To avoid the use of toxic organotin

JJ. LI

580

compounds, the cycHzation of o-bromoacryloylanilide 21 was achieved by a cobalt(I) salenmediated radical process, furnishing a mixture of dihydroquinolone 22 and the desired vinyloxindole 23 in a 1:3 ratio. Hydroboration of 23 using 9-BBN, followed by basic oxidative workup, gave alcohol 24 in 60% yield. Reductive cyclization of 24 by the action of diisobutylaluminum hydride in toluene yielded a 4:1 mixture of the desired furo[2,3-^]indole 25 and the dihydroindole from reduction of the oxindole carbonyl. Since the transformation from oxindole 25 to physovenine (26) was reported by Kametami ct al. [18], Scheme 5 constitutes a formal total synthesis of the natural product (26).

Me MeO^^Y^Me

Co(III)Br, PPh3,

MeO

l%Na/Hg,THF,40%

I

Me 22 MeOv^^:^^

9.BBN,THF, reflux, 2 h

1

thenH202,NaOH,61%'

^ ^ N ^ O

Me \—\

^^Y^^^^^il

^ ^ N " ^ 0 I

Me

24

23

Me DIBAL, tol. -78''C,92%

T

ll

MeHNOzC

Me

1 Me 25

Me" physovenine (26)

Scheme 5. The cobalt(I) salen-mediated radical cyclization Another application of a flve-membered ring radical cyclization in the total synthesis of indole alkaloids is that of (^)-m-trikentrin A (34), reported by Macleod and Monahan [21-23]. Trikentrins are a series of biologically active metabolites isolated from the marine sponge Trikentrionflabelliforme.As detailed in Scheme 6, the Macleod and Monahan synthesis began with the preparation of radical cyclization precursor 28 by reaction of o-bromoacetophenone (27) with allylmagnesium bromide. Treatment of 28 with /i-BujSnH led, after KF workup led to a mixture of c/5- and /ra;i5-indanols, which upon exposure to acid readily eliminated water to give dimethylindene 29. Notably, the yields for the radical cyclization were not consistent, particularly when carried out on a multigram scale due to polymerization of the product.

^"

Applications of Radical Cyclization Reactions

581

Generating tin hydride in situ by using a catalytic amount of tributyltin chloride and sodium cyanoborohydride [24] did not solve the problem. Although this method inherently produces the desired low concentration of/i-BuaSnH to promote cyclization over direct reduction of the starting material and reduces drastically the amount of tin residue, a displacement reaction between solvent and the benzylic hydroxyl group takes place. Eventually, the best method was the use of high dilution conditions at approximately 70 ®C in benzene followed by the KF workup.

^=^^^ MgBr

a

88%, 3 steps

l. fi-BujSnH, AIBN.PhH

CH2Cl2,85% 30

l.NaBH4,MeOH 2. H2, Pd/C, CHCI3 79% 3. CI2HCOCH3, TICl4,CH2Cl2,

CHO

»

1. Et02CCH2N3, NaOEt, EtOH 2. toluene, 95% 2 steps

74%

C02Et

l.K0H,H20, dioxane, 74% 2.FVP,600"C, 0.003 mmHg, 89%

Scheme 6. Total synthesis of (±)-cu-trikentrin A via a 5-exo-trig cyclization

582

J J. Li

With the cyclized product 29 in hand, hydrogenation provided predominantly (cis.trans 9:1) the c/5-dimethyl indene 30, which underwent a Friedel-Crafts reaction when treated with CH3COCI/AICI3, giving regiospecifically the desired 5-acetylindane 31 presumably due to steric effects. Double reduction, followed by regiospecific formylation with dichloromethyl methyl ether and titanium tetrachloride, gave a single regioisomer, 6-ethyl-l,3-dimethylindan5-carbaldehyde (32). Condensation between aldehyde 32 and excess azidoacetate, followed by the 1,5-electrocyclization of the resulting unsaturated azide under thermolytic conditions in toluene at reflux for 2 h, produced the indole ester 33. Finally, hydrolysis of 33 followed by decarboxylation via flash vacuum pyrolysis gave (±)-n5-trikentrin A (34). A total synthesis of (±)-rrfl/i5-trikentrin A was also accomplished via a similar route [22]. (±)-Mesembranol (40) belongs to the Sceletium alkaloid family, many of which possess the c/5-3a-aryloctahydroindole skeleton. A stereoselective total synthesis of (i:)-mesembranol (40) was realized by Ishibashi et al. via a radical cyclization of a,a-dichloroacetamides [2526]. The key precursor for the S-exo-trig radical cyclization, dichloroacetamide 38, was derived from cyclohexene 35 by four steps in 44% overall yield. As illustrated in Scheme 7, treatment of 35 with ^-bromosuccinimide in aqueous acetonitrile resulted predominantly in bromohydrin 36, along with 10% of the undesired diastereomer. Heating bromohydrin 36 with methanolic methylamine in a sealed tube at 100 °C provided amino-alcohol 37 with complete retention of configuration, presumably via the epoxide intermediate. Subsequent acylation of 37 afforded the amide, which upon exposure top-toluenesutfonic acid, underwent dehydration to give radical precursor 38. The key cyclization was conducted by treating 38 with 2.2 equivalents of/i-BujSnH and a catalytic amount of AIBN in refluxing toluene (6.5x10"^ M) for >3 h to afford the expected lactam 39, along with 26% of the reduced starting material. Reduction of lactam 39 with borane-THF furnished a pyrrolidine, which was deprotected by a catalytic hydrogenation to give (±)-mesembranol (40). Carbazomycin B (47), along with carbazomycins A, C-H, belongs to a family of carbazole alkaloids isolated from Streptoverticillium ehimense. Carbazomycin B (47) is a 5lipoxygenase inhibitor and inhibits the growth of some phytopathogenic fungi. Kndlker et al. reported an elegant synthesis of carbazomycin C, G, and H by utilizing an oxidative cyclization strategy with catalytic PdCh and cupric acetate [27]. The Clive group executed a S-exo-trig radical cyclization of the sulfonamide 45 in their total synthesis of carbazomycin B [28]. As summarized in Scheme 8, Baeyer-Villiger oxidation of arylmethyl ketone 41 provided the acetate, which subsequently underwent nitration and hydrogenation to give aminoacetate 42. Bromination and tosylation yielded toluenesulfonamide 43, which was alkylated with 3-bromo1-cyclohexene to produce two rotamers (3:2, resulted from restricted rotation about at least one bond) of structure 44. Replacement of the acetate group by an 0-benzyl ether (45) was achieved by hydrolyzing 44 to the corresponding phenol followed by benzylation. The pivotal radical cyclization was realized by treating substrate 45 with triphenyltin hydride in refluxing benzene to form the desired tricyclic indoline 46 in 39% yield (only one of the rotamers in 45

Applications of Radical Cyclization Reactions

9"^'

^^k^OMe ^

Y

^

Duvr

a

NBS,H20

*J9 Ar ,C X B"0'^^NHMe 37

^V^j

• N^O Me 38

HQ

f^^^*"

MeCN,83% *

MeNH2,MeOH 100»C,83»/o '

583

BnO^^^'^^Br

1- CI2CHCOCI, EtjN, CH2CI2,79% Lp-MeCH^SOaH, PhH, reflux, 80%

ii-Bu3SnH,(2.2eq.) AIBN, tol. reflux, 51%

^^^"1 BnO'^'^^N^O Me 39

l.BH3-THF,THF,0V, then reflux, 81% 2. Hj ( 4 Kg/cm^), 5% Pd/C HCl, EtOH, 68%

Scheme 7. Total synthesis of (±)-mesembranol via a S-exo-trig cyclization cyclized, suggesting that trapping by BuaSnH was faster than rotamer interconversion), along with a major by-product resulting from direct reduction of the starting material. The S-exo-trig radical cyclization product, sulfonamide 46, was treated with sodium naphthalenide to remove the ^-tolylsulfonyl and 0-benzyl groups concurrently. Finally, aromatization with Pd/C gave carbazomycin B (47).

JJ. Li

584

1. w-MCPBA, CH2CI2, 85%

MeO

^ 2.HN03,H2S04,CH2Cl2 3.H2/Pd-C,EtOAc,74%

OAc

Me

^^ 42

OAc MeO Me

NH Me Ts

.-O K2CO3, acetone, 56°C,93%

43

l.KOH,EtOH

> 2. BnBr, NaOH CH2Cl2,H20 Bu4NI,94%

MeO,

OBn

1. Br2, dioxane, CHCb, 86%

MeO

OBn MeO>J«v^Br ^j?>.

Me-'^Y^N'

NH2 2.TsCI,Pyr. CH2Cl2,4d, 85%

OAc MeOsJs^^Br

Me Ts 44 Ph3SnH,AIBN double syringe pump ^ PhH, reflux, 39%

Me Ts 45 1. Na-naphthalene THF,65% ^ 2. Pd/C, triglyme 120 ^^C, 71%

Scheme 8. Total synthesis of carbazomycin B via a S-exo-trig cyclization (±)-Gelsemine (55) was isolated from Gelsemium sempervirens (Carolina jasmine) in 1870. Due to its intriguing bridged polycyclic structure, coupled with its strychnine-like CNS stimulating activity, (i:)-gelsemine (55) has elicited intensive synthetic interest. Several total syntheses have been reported. In their total synthesis, Hiemstar and Speckamp [29] utilized Overman's "ligandless" intramolecular Heck conditions and achieved the spiro-oxindolc synthesis in a 2:1 ratio, with the major product being the desired diastereomer. In Johnson's total synthesis, photolysis of alkoxy-substituted-1-alkenylbenzotriazoles was introduced as a

Applications of Radical Cyclization Reactions

585

new route to make the spiro-oxindole [30-31]. Fukuyama et al stereoselectively constructed the bicyclo[3.2.1] framework by means of a divinylcyclopropane-cycloheptadiene rearrangement [32]. Among all the total syntheses of (i:)-gelsemine (55), the one documented by the Hart group is notable due to its successful incorporation of a radical cyclization strategy [33-35]. As summarized in Scheme 9, the Hart synthesis began with the assembly of a bicyclic perhydroindole framework using a Diels-Alder cyclization between diene 48 and Nmethylmaleimide (49). The Diels-AIder adduct was further manipulated, via seven additional functional group conversions, to give the thiophenoxy perhydroindole 50 as the key cyclization precursor in a 21% overall yield. The tricyclic core structure 51 was secured by a 5-hexenyl radical cyclization of 50 via an a-acylamino radical intermediate. Exposure of ester 51 to phenylmagnesium bromide resulted in a tertiary alcohol that was subsequently methylated. The resulting methyl ether was treated with PPTs in acetone to give ketone 52. Treatment of 52 with sodium hydride along with a catalytic amount of potassium hydride in refluxing THF generated the enolate that was quenched by o-bromophenylisocyanate to install the obromophenyl amide moiety. The radical precursor 53 was obtained by treating the P-ketoamide with an excess of acetic anhydride. Free-radical cyclization of several derivatives of 52 was examined, and it was eventually determined that 53, prepared in 79% yield from 52, provided the most usei^l results in terms of stereochemistry. Thus, treatment of 53 with nBusSnH under photochemical conditions produced oxindole 54 in 40% yield, along with 25% of the epimer at the quaternary oxindole chiral center. From oxindole 54,21-oxogelsemine was synthesized in seven additional steps with a 15% overall yield. Finally, (±)-21-oxogelsemine was easily transformed into (±)-gelsemine (55) by an allane reduction (50%) [29]. Competitive S-exo-trig and S-endo-trig cyclization processes occur for conjugated amide substrates. An example is found in the synthesis of spiropyrrolidinyl-oxindole frameworks, which are the core structures of several indole alkaloids such as (-)spirotryprostatine A-B, (+)-elacomine (61) and (-)-horsfiline. Cossy envisaged formation of the spiropyrrolidinyl-oxindole skeleton using an enecatbamate [36]. As illustrated in Scheme 10, the target precursor, enecarbamate 57, was derived from rer/-butyl-lpyrrolidinecarboxylate (56) in 5 steps and 38% overall yield. The radical cyclization of 57 provided the desired spiropyrrolidine 59 and the pyrrolidino quinolone 58 in a 7:3 ratio with a yield of 81%. Separation of the two isomers could be achieved after removing the carbamate group reductively. Upon exposing the pure isomer to trifiuoroacetic acid, the spiropyrrolidinyloxindole 60 was delivered in quantitative yield.

J J. Li

586

TMSOv^

48

\

8 steps • 21% 50

^v^,^^,OTHP

^ OBn CO^Et

OBn fi-Bu3SnH,AIBN PhH, reflux, 61%

l.PliMgBr,TIIF 2. NaH, Mel, DMF 1*.

)

3. PPTs, acetone, 8 1 % 51

^OBn

C02Et

1. NaH/KH,THF, reOux, <»-BrC6H4NCO »• 2. AC2O, EtsN, DMAP, DMF, 79% 2 steps

C(OMc)Ph2

n-BusSnH, AIBN * •

PhH,Av,40%

Scheme 9. Total synthesis of (±)-gelsemine 5-exo-dig Radical cyclization was the pivotal operation in Boger's indolone assembly in the total synthesis of CC-1065 (62, Fig.l). This antitumor-antibiotic tetrapeptide, isolated fVom cultures of Siepiomyces zelensis, possesses exceptionally potent in vitro cytotoxic activity, broad-spectrum antimicrobial activity, and confirmed in vivo antitumor activity. The

Applications of Radical Cyclization Reactions

587

left-hand unit, l,2,7,7a-tetrahydrocycloprop[l,2c]indol-4-one (CI), is crucial for biological activity because the electrophilic cyclopropane alkylates DNA. Boger's group explored two

r^

5 steps

1. Mg, MeOH

O O 0 = ^ >Ky—.

ii-Bu3SnH,AIBN

jT^

2.TFA,59%

Scheme 10. Concurrent S-exo-trig and ^-endo-thg process alternative radical cyclization strategies [37] in their synthesis of the left-hand unit, the cycloprop[c]pyrro[3,2-e] indol-4-(5//)-one. The first strategy involved implementation of a 5exo'dig aryl radical-alkyne cyclization (Scheme 11). Bromoindole 63 was prepared by standard indole synthesis, followed by selective bromination. A^-Alkylation of 63 with 3bromopropyne provided the 5-hexynyl free radical cyclization precursor 64. S-exo-dig Aryl radical-alkyne cyclization of 64 was effected by treatment with w-BuaSnH to afford the unstable methylidenindoline 65 as the predominant reaction product. 65 was subjected immediately to hydroboration with basic oxidative workup affording 3-(hydroxymethyl)indoline 66, completing the construction of the parent l,2-dihydro-3//-pyrrolo[3,2-e] ring system. Utilizing a radical carbocyclization-fragmentation methodology developed by Ueno et al. [38], Boger also explored an alternative approach to introduction of the 3(hydroxymethyl)pyrrolidine ring of the left-hand segment [37]. The allyl sulfide 68 was the

588

JJ. LI

precursor for a self-terminating aryl radical-alkene cyclization. Allyl sulfide 68, derived from ^-alkylation of 63 with 4-bromo-2-butenyl sulfide, underwent a clean S-exo-trig radical

(+)-C;C-1065 (62)

o^-J-^-^nrS O

\V H

OH OCH3

Figure 1. (+)-CC-1065, an potent antitumor-antibiotic

SOjPh

2.1 eq. n-BujSnH cat.AIBN,PhH,

^ PhCO'^^'y^

80°C,4h

BnO

SOzPh

6eq.BH3-SMe,THF then2NNaOH, »i

30%H2O2,45*'C 40% from 64 S02Ph

HN,

66

SOjPh

Scheme 11. S-exo-dig Cyclization of a 5-hexynyl radical

O^

67 ^S^^^^H

Applications of Radical Cyclization Reactions

589

cyclization-fragmentation process, affording 3-vinylindoline 69 in 95% yield (Scheme 12). The concurrently released thiophenoxy radical acts as the chain propagator [39]. Unfortunately, even though an ozonolysis/reduction sequence worked very well for model compounds [40, 41], it failed to deliver the desired alcohol 66. Eventually, 69 was subjected to a three-8tq> sequence comprising osmylation to give the diol, treatment with lead tetraacetate to afford the aldehyde, and reduction with sodium borohydride to furnish alcohol 66. The cyclization-fragmentation strategy using allyl sulfide 68 is more effective than the aryl radical-alkyne cyclization strategy using 5-hexyne substrate 64. With regard to the synthesis of alcohol 66, however, the 5-exo-dig aryl radical-alkyne cyclization has proven most expedient. Therefore, that was the method of choice in the total synthesis of (+)-CC-1065, although many analogs of 62 were prepared by the cyclization-fragmentation strategy using allyl sulfide 68. SPh

N

OBn

"SOiPh

2.05eq.«-Bu3SnH cat.AIBN,PhH, ». 80 "C, 2.5 h, 95%

p.^^.N *^"^" BnO 69

68

SOjPh

.CH3 1.1.2 eq. OSO4, pyr. 2.1.0 eq. Pd(OAc)4, PhH, 29% from 69 3.NaBH4,EtOH

PhCO' BnO

66 Scheme 12. Self-terminating S-exo-trig aryl radical-alkene cyclization

SOjPh

In the foregoing examples, indole alkaloids were synthesized using radical cyclization reactions as the central theme. However, none involved an indole radical intermediate. Mitosenes, close analogs of the mitomycins, received much synthetic attention due to their antitumor activities. In a rapid route to mitosenes reported by Jones and coworkers [42], a bona fide indole radical intermediate was involved. As depicted in Scheme 13, selective bromination of the indole was achieved using an ortho lithiation technique to give 2-bromoindole (70). During this process, carbon dioxide was employed as a temporary protecting group for nitrogen while introducing the bromine at the C(2) position using 1,2-dibromotetrafluoro-ethane. NAlkylation was realized by simply treating 70 with an excess of bromoalkene in the presence of

590

J J. LI

3-5 equivalents of potassium carbonate in acetone to give the goal substrate 71. After submitting 71 to normal radical reaction conditions, the S-exo-trig product 72 was formed exclusively. Generally, for a simple 5-hexenyl radical intermediate, substitution at C(5) leads to formation of a mixture of a cyclopentane via a S-exo-trig cyclization and a cyclohexane via a 6'endo-trig cyclization. In this particular case, only the S-exo-trig cyclization product was observed when substrate 71 had additional substituents on the double bond. The authors argued that the outcome was governed by the bond angles involved in the 5-membered ring of the indole.

H

BrF2CCF2Br,81%

3-5 eq K2CO3, acetone 12-36 h, reflux, 81%

H 70

if-Bu3SnH,AIBN

•

tol, reflux, 12 h, 79%

Scheme 13. Indole radical intermediacy in the total synthesis of a mitosene Bonjoch and coworkers [43] observed an intriguing radical cyclization reaction in the synthesis of Strychnos alkaloids of the curan type (78). When ^-substituted 3aarylhexahydroindol-4-one 73 was subjected to the normal radical cyclization conditions, the desired bridged azatricycle 74 was not observed (Scheme 14). Instead, 77 was isolated in 45% yield. Similar to Parsons' observation [44], the pyrrolidine ring on 77 was formed by a 1,5hydrogen atom abstraction, followed by a S-exo-trig cyclization of the resulting allylic radical to give the pyrrolidine 77. In radical cyclization reactions, the most commonly seen intermediates are aryl, vinyl and alkyl radicals. Nevertheless, a host of heterocyclic radical intermediates have been utilized in many synthetic approaches. The Ziegler group has taken advantage of intramolecular cyclization reactions of aziridinyl [45], oxiranyl [46], and dioxolanyl [47] radicals in the synthesis of indole alkaloids. A chiral aziridinyl radical was the pivotal intermediate in their synthesis of the core nucleus of the antitumor agent FR-900482 (81), a mitomycin-like antitumor agent isolated from Streptomyces sandansis [48]. Alkylating the corresponding indole with the aziridinylmethyl triflate assembled the precursor 79, shown in Scheme 15. The bromoaziridine, in turn, was derived from the corresponding thiohydroxamic acid anhydride and BrCCb via photolysis. Substrate 79 was then subjected to reductive cyclization conditions: a solution of w-BujSnH and ACCN [l,r-azobis(cyclohexylcarbonitrile)] was added via a

591

Applications of Radical Cyclization Reactions

syringe pump to a solution of 79 in refluxing toluene. As a result, dihydroindole alcohol 80 was isolated in 51% yield after the desilylation with TBAF, along with 5% 2-epi-80. The key cyclization reaction involved the generation of a carbon-centered aziridinyl radical that underwent an intramolecular addition to the indole nucleus. This specific example was successful although the indole ring was devoid of an electron-withdrawing group at C(3). Transformation of 80 to FR-900482 (81) was then achieved employing a double oxidation as the key step to install the remaining two oxygen atoms.

Jk. I

"' BujSnH AIBN

^

O2N

O2N

O

O

77 Scheme 14. Pyrrolidine ring formation via cyclization involving radical translocation TTF (tetrathiafulvalene) and related compounds have been the subject of intense interest in the materials chemistry community because of their semi-conduction and superconduction properties. Recently, TTF has emerged as a unique radical initiator because its radical cation can be easily formed. The ease of formation is presumably derived from the favorable structure of the radical cation that incorporates an aromatic disulfonium salt and a very delocalized radical [49a]. Murphy et al. demonstrated a novel one-pot reaction cascade

592

J J . Li

^

OBn

.CH20Si*BuMe2

^J

MeOiC

Kr"' N Boc

^ 80

^

2,TBAF,51%

79 OCONH2

OBn

MeOiC

l.ii.Bu3SnH,ACCN

.CH2OH OHC

N NBoc

FR-900482 (81)

Scheme 15. An application of chiral aziridinyl radicals to the synthesis of FR-900482 featuring (a) aryl radical generation, (b) cyclization, (c) radical trapping on sulfur with the radical-cation of TTF to form a sulfonium salt, and (d) SNI substitution—a sequence of reactions which was named a radical-polar cross-over sequence [49b]. By taking advantage of the unique properties of the radical-polar sequence in allowing direct neopentyl alcohol 85 formation, Murphy et al. completed a total synthesis of (db)-aspidospermidine (87). As summarized in Scheme 16, when diazonium salt 82 was treated with TTF, a TTF-mediated radical-polar crossover reaction took place. Thus, electron transfer from TTF to the diazonium salt is followed by loss of nitrogen, and the resulting alkyl radical couples with TTF+* to give a sulfonium salt 83. Subsequent regeneration of TTF gave cation 84, which underwent solvolysis in moist acetone to give the corresponding alcohol 85. This was one of the direct ways to introduce an alcohol via radical chemistry [50]. With the important tricyclic intermediate 85 in hand, functional group manipulations produced vinyl iodide 86, which underwent an intramolecular Heck reaction to establish the pentacyclic core structure leading to the conclusion of the total synthesis of (±)-aspidospermidine (87) [51]. 3. SIX-MEMBERED RING FORMATION 3.1. The S-endo-trig mode In contrast to the large body of data available on S-exo-trig cyclizations in indole alkaloid

Applications of Radical Cyclization Reactions

593

NHCOCF3

Scheme 16. Application of "radical-polar crossover" reaction in the total synthesis of (±)aspidospermidine syntheses, there are relatively few examples of those using the 6-endo-trig cyclization. When a radical cyclization reaction involves the 5-hexenyl radical intermediate, the reaction proceeds preferentially in the S-exo-trig mode. However, when the 5-exo-trig mode of cyclization is stereoelectronically disfavored, the d-endo-trig cyclization mode predominates. In the literature on indole alkaloid syntheses, there are few examples that feature 6-endO'trig radical cyclizations as the main theme. In all cases, the usually favored S-exo-trig regioselectivity of 5hexenyl radical cyclization was suppressed by a substituent (bromine or ethyl) at the 5position. In Kuehne's total synthesis of vincadifformine (89), the pentacyclic natural product was obtained when tetracyclic phenylselenide 88 was treated with 2.5 equivalents of/t-BuaSnH and the radical initiator AIBN in refluxing benzene [52]. The stereochemistry of the phenylselenyl substituent in the tetracyclic precursor had no impact on the product yield. After the tertiary radical intermediate 90 was generated (Scheme 17), the S-exo-trig cyclization was prohibited

J J . LI

594

because of the steric hindrance of the bromine substituent. Therefore, the 6-endo-trig cyclization took place to give intemicdiale 91 that undcnvent a hydrogen abstraction and then bromine reduction to funiish the desired natural product 89. As anticipated, in the absence of the bulky bromine atom, the five-membered products (93) were observed when substrate 92 was subjected to the cyclization conditions.

/i-BuaSnH, AIBN PhH, 85 X 71-85% CO2CH3 88

\

^ \

. ^ I

/f-BuaSnH, AIBN

XS^^"^^^ PhH, 85X71-72% H XCO2CH3 ^ „ 92 07

^^^^

^^N '^

CO2CH3

Scheme 17. Bromine substituent was required for the S-endo-tng cyclization mode An analogous strategy was applied for annelation of ring D in Kuehne's syntheses of 20-e/i/-^vincadifformine (96) and ^-vincadifformine (97). Upon slow addition of/i-BuaSnH and AIBN via syringe pump to the phenylselenyl ether 94, 20-epi-y^vincadifrormine (96) and ^vincadifformine (97) were formed in a 1:2 ratio. The separated products did not epimerize under the reaction conditions, indicating a facial preference in the hydrogen transfer to the pentacyclic radical intermediate 95. The ethyl substituent blocked S-exo-trig cyclization.

Applications of Radical Cyclization Reactions

1

595

II if-Bu3SnH,AIBN '^ Pii syringe pump, 0.015 M PiiH, 8 5 X 6 8 %

96/97 = 1:2

Scheme 18. Ethyl substituent was required for the 5-ewi Bond Formation Radical cyclization does not only occur with simple oleflns, but also with dienes, as well as aromatic rings. A few examples of radical additions to aromatic rings in indole syntheses are found in the literature. For radical processes that involve intramolecular C.ryr Caryl ^ond formation to form six-membered rings, it is difficult to categorize them as either 6endO'trig or 6-exo processes. Nonetheless, syntheses of pyrrolophenanthridone alkaloids employing such a strategy are summarized here. Ungeremine (101), vasconine (104), oxoassoanine (105), pratosine, and hippadine (107), belong to a family of pyrrolophenanthridone alkaloids isolated from the bulbs of Crinum pratense (Amaryllidaceae) collected at flowering time. Their biological importance emerged when some of them showed reversible inhibition of fertility among male rats as well as antitumor activities. Intensive synthetic efforts have been focused on Amaryllidaceae alkaloids recently. Total syntheses have been accomplished using transition metal chemistry, especially palladium chemistry, photochemistry, and intramolecular electrocyclic reactions. In the midst of these synthetic endeavors, Lauk's synthesis of ungeremine (101) [53] is unique because it entails an intramolecular radical CaryrCaryi bond formation to install the biaryl moiety. As outlined in Scheme 19, the nitrophenyl radical was generated from the bromonitrophenyl precursor 98 at elevated temperature in DMSO in the presence of potassium carbonate and benzyl triethylammonium chloride (BTAC). The derived radical was quenched by the reaction with an adjacent phenyl

group to form both regioisomers of the corresponding

596

JJ . LI

pyrrolophenanthridinones (99 and 100). Finally, pyrrolophenanthridinone 100 was transformed into ungeremine (101) using conventional methodology.. Even though the aromatization mechanism from the putative cyclohexadienyl radical intermediate is not well understood (oxidation by the adventitious air is one possibility), the radical addition to an aromatic ring strategy does possess some advantages: (a) no transition metal catalysis is required, (b) better yields are obtained than with similar procedures although the reaction is not regiospecific, (c) readily available starting materials may be used.

NO2

NO2 K2C03,BTAC DMSClSS'^CeOVo

O

100

Scheme 19. Radical cyclization onto an aromatic ring Intramolecular radical Caryi-Caryi bond formation was the key feature in the total syntheses of several other pyrrolophenanthridone alkaloids [54]. As illustrated in Scheme 20, aminoalcohol 102 and /f-BujSnH in refluxing benzene were treated slowly with AIBN in benzene until the reaction was complete (12-13 h), affording the phenanthridine alcohol 103. During radical addition to the arene to firom 103, concurrent oxidation of the amine to the corresponding imine took place. The low yield may be ascribed to the poor chain propagation capacity of the cyclohexadienyl radical. Conversion of alcohol 103 into vasconine (104), was achieved by the use of PBra. Oxidation of 104 with alkaline hydrogen peroxide yielded the lactam, oxoassoanine (105). Vasconine (104) also served as an intermediate for the total synthesis of pratosine and ismine. Although the yield for the key radical cyclization was low, it provided quick access to vasconine (104) in only three steps from commercially available starting materials.

Applications of Radical Cyclizatlon Reactions

OH MeO"

102

if-Bu3SnH AIBN PhH, reflux 27%

597

McO

OH

MeO 103

PBra ^ 65%

Scheme 20, Stannyl-mediated radical addition to the arene was low yielding possibly because of poor chain propagation l-Aroyl-7-bromoindole (106) was easily assembled by aroylation of 7-bromoindole with the corresponding aroyl chloride (Scheme 21). Treatment of 106 with w-BuaSnH in the presence of AIBN in refluxing benzene for 10 h resulted in radical cyclization with concurrent oxidation to give the regioisomenc pyrrolophenanthndones 107 (hippadine) and 108, along with the direct reduction product 109. It is interesting to note a related reaction, which might have more important synthetic utility. As delineated in Scheme 21, a S-exo-trig radical cyclization of l-(2-bromobenzoyl)-3-methylindole (110) without concurrent oxidation furnished 1,7-fused cj5-10,U-dihydro-6//-ll-methylisoindolo[2,l-a]indol-6-one (111) as the major product in 83% yield. A 6'exo radical cyclization onto an indole ring was applied to construct the isoquinoline ring (B-ring) of (i:)-cryptaustoline (116, Scheme 22), a dibenzopyrrocolinc alkaloid [56]. Indole 114 was assembled from 4-benzyloxy-2-bromo-5-methoxyphenylacetic acid (112) and 3,4-dimethoxyaniline (113) in 4 steps and 40% overall yield. When treated with w-BuaSnH in the presence of AIBN in benzene under reflux, indole 114 was cyclized into an unstable intermediate 115 in good yield. Quatemization of 115 with methyl iodide produced (±)-(9benzylcryptaustoline (72% yield from 114 in 2 steps) which was heated with concentrated hydrochloric acid, followed by potassium iodide in ethanol, to furnish (db)-cryptaustoline (116).

598

J J. LI

\_5

Me

r~Z ^^

[ no

109,20%

N

Br

^^=^

/f-Bu3SnH AIBN PhH, reflux 83%

^. 111

"v^

Scheme 21. Another example of radical cyclization onto an aromatic ring In summary, intramolecular radical cyclization reactions onto aromatic rings can provide quick access of otherwise not so easily assembled Caryi-Caryi bonds, although the yields are generally low and the process suffers from a lack of regioselectivity. Noticeably, Crich found that a catalytic amount of benzeneselenol, which can also be generated in situ reduction of diphenylselenide with stannane [57]. This method should find synthetic utility in intramolecular radical addition to arenes.

Applications of Radical Cyclization Reactions

599

4 steps

MeO

40% yield

BnO

McO 112

OMe 113

/i-Bu3SnH AIBN, PhH ^. reflux

BnO ""^

MeO

OMe

115

I^^O

OMe

1, Mel, 72% from 114

^ 2. HCI, then KI/EtOH,66% Scheme 22. Radical cyclization to construct the B-ring of (:i:)-cryptaustoline 3.3. The ^-exo'trig Mode 6-HeptenyI radical cyclizations proceed about 40 times slower than the 5-hexenyl counterpart. Therefore, in most cases, a rate-enhancing factor is required to achieve a synthetically useful reaction. The most common rate-enhancing factors are a,P-unsaturated esters, nitriles, and ketones, or other electron withdrawing groups. a,p-Unsaturated esters are the most widely employed precursors. One of the first examples of radical cyclization reactions in the total syntheses of indole alkaloids was Stork's approach towards (±)-gelsemine (55) [58] featuring a mixed acetal 6-6x0 radical cyclization as the pivotal step (Scheme 23). Thus, exposure of cyclopentene bromide 117 to standard radical cyclization conditions led to the c/5-fused bicyclic ester 118. A relatively dilute concentration (0.02 M) was needed to minimize possible intermolecular reactions although the intramolecular reaction was kinetically more favored. Diastereomeric phenylselenides were easily obtained by treating 118 with LDA and quenching the enolate with diphenyl diselenide. The a,p-unsaturated ester 119 was secured when the selenide underwent

600

J.J. LI

the usual oxidation-elimination process. Conversion of 119 into the somewhat strained lactone 120 as a single isomer involved a transannular alkylation at the anomeric center as the key operation. Eventually, a Claisen rearrangement involving a silyl ketene acetal assembled a significant portion of the carbon framework of gelsemine in the form of 121.

ii-Bu3SnH, AIBN EtOjC

Br

^OEt

0.02MinPhH reflux, 3 h, 95%

H*^ s " ^ ^OEt EtOjC ^

117

118

1. LDA, THF, -78 to -30 ^C

y^5^\

-78XPhSeSePh,93%

2. MCPBA, CH2CI2,1 h, -40 ^C; EtjN, rt, 1 h, 98%

^Tl

^ _ / ^ O^t ^^^^^ 119

LDA,THF,TMSC1 ^ -78°Ctort,24h, 96% 120

?

HO2C 121

Scheme 23. Application of S-exo-trig radical cyclization in Stork's approach to (db)-gelsemine Taking advantage of the 6'exo-trig radical cyclization approach, Fukumoto et al. developed a method to synthesize lactone 123 from bromoacetate 122, and acetals 126-127 from bromoacetal 125 [59]. The resulting lactone 123, in turn, served as a versatile building block in their total synthesis of several indole alkaloids. As depicted in Scheme 24, when bromoacetate 122 was subjected to radical cyclization by heating with /t-BusSnH in the presence of AIBN in refluxing benzene, lactone 123 was obtained as a single isomer in 35% yield, together with 65% of the corresponding reduced product. Alternatively, radical cyclization of bromoacetal 125 produced a remarkable 96% yield of a mixture of the four possible diastereomers of cyclic acetals 126 and 127. Conventional transformations comprising of deacetalization (dilute HCl, THF) and Jones oxidation (CrOj, dil. H2SO4, acetone) converted 126 and 127 into lactones 123 and 124 in a 4:1 ratio.

Applications of Radical Cyclization Reactions

601

0,t^0

EtOzC

jl

reflux PhH,35%

122

EtOzC

u rv i-i*^*"2^

123

124

EtOv ^O. AIBN reflux PhH,96%

EtOiC

I

LH

H'J EtOjC"^

125

HI EtOjC

126

127

Scheme 24. Six-membered lactones or lactals prepared using 6-exo-trig radical cyclization

0*^0 H^

1. tryptaniine, heat LMeSOjCUEtaN

cxjd.

3. KH, 18-crown-6 70%

N H

129

OBn

1. POCI3, MeCN 2. NaBH4 3.H2,PdCl2, CHCl3,MeOH 74%

(±)-dihydrocorrylnantheol (130) OH

Scheme 25. The total synthesis of (±)-dihydrocoTTylnantheol This method was successfully applied to the total synthesis of (±)-dihydrocorrylnantheol (130). As detailed in Scheme 25, substrate 128 was derived from 126. Condensation of 128 with tryptamine, mesylation of the resulting hydroxy amide, and then ring closure using KH and 18-ciown-6 in DME (1,2-dimethoxyethane) led to lactam 129 in 70% overall yield.

J J . LI

602

Lactam 129 was then stereoselectively converted into (±)-dihydrocorrylnantheol (130) in 74% overall yield. Despite the successful formation of lactam 129 from 128 and tryptamine, heating lactone 123 and tryptamine did not generate the desired lactam 134 [60-61]. In the synthesis of racemic and optically pure tacamonine (135), Fukumoto and coworkers envisaged a 6-exO'trig radical cyclization of advanced intermediate 133. As outlined in Scheme 26, optically pure bromide 131 was sequentially treated with tryptamine and fumaric acid monoester to furnish amide 132. The silyl group of 132 was removed, and the resulting primary alcohol was converted into the corresponding bromide 133. The 6-exO'tng radical cyclization was best achieved by treating bromide 133 with (TMS)3SiH and AIBN in refluxing benzene to furnish the desired lactam 134 as a diastereomeric mixture. Subsequently, 134 was manipulated to produce tacamonine (135) as a diastereomeric mixture in a 9% overall yield from 131. This route provides a good example of the application of radical cyclization chemistry for construction of a relatively intricate precursor. The biggest pitfall of this synthesis is the lack of stereoselectivity observed at the newly formed chiral carbon center.

1. tryptamine

131

DCC, DMAP 60%

Et02C

OTBDMS 132

1. dil. AcOH 2. MsCl

(TMS)3SiH AIBN, PhH

3. LIBr, 88%

reflux, 72% EtOiC

CxyV.

Br 133

1. POCI3 2. NaBHjCN 9

3. MeONa 9%

Scheme 26. Asymmetric total synthesis of tacamonine

Applications of Radical Cyclization Reactions

603

An asymmetric version of the aforementioned radical cyclization strategy was developed to address the issue of stereoselectivity. Diastereofacial selectivity was achieved by using a chiral auxiliary to control the 6-exo-trig radical cyclization. In the event, the sixmembered ring skeleton was synthesized with excellent 1,2-asymmetric induction [62-63]. When the a,p-unsaturated ester bromide 136 bearing {\R, 3R, 45)-8-phenylmenthol as the chiral auxiliary was submitted to the radical cyclization conditions, the diastereoselectivity was governed by preference for the s-trans conformation in the transition state (Scheme 27). As illustrated in Scheme 26, in the presence of a Lewis acid, the s-cis conformer 137 is disfavored due to steric interactions. The best selectivity (>98% de) was achieved via the s-trans conformer 138 to give acetal 139 as a single diastereomer when methylaluminum bis(2,6-di/er/-butylmethylphenoxide (MAD) was used as the Lewis acid. In contrast, when (45)-4benzyl-2-oxazolidinone was used as the chiral auxiliary, no significant diastereoselectivity was observed. Deacetalization and oxidation of 139 furnished chiral lactone 140. This diastereoselective radical cyclization provided a novel synthesis of chiral synthons to be employed in the asymmetric synthesis of natural products.

6~, /1\

OEt BuaSnH, EtaB, MAD, tol.

^

-40 °C, 1.5 h, 38%, >98% de 136

Ph

»«L. A.

j l s-irans _

_

/

^

O

%

137

138

OEt

po

OEt

1.10% HCIO4, THF, rt 2. Ag2C03-CeIlte, PhH, reflux, 70%

X Ph

^ 140

Scheme 27.6-exo-trig Radical cyclization with excellent 1,2-asynunetric induction

604

J J . Li

One application of lactone 140 as a chiral synthon may be found in the asymmetric synthesis of (+)-12b-epidevinylantirhine (143), a cleaved product of geissoschizol (Scheme 28) [62-63]. Treatment of 140 with tryptamine in hot toluene afforded 142, which cyclized to lactam 142 by mesylation and an SN2 displacement. The Bischler-Napieralski reaction of 142, followed by reduction of the resulting iminium salt with NaBIl*, produced stereoselectively, the indolo[2,3-a]quinolizine as a single isomer, which was further reduced with DIBAL to give (+)-12b-epidevinylantirhine (143).

140

tryptamine, toL lWC,7.5h,72%

N

jjO 1 r ^

H II

H ^^f Ph-MenOjC

•

Q liiiT nw NH^OH

LPOCl3,MeCN, reflux 2.NaBH4,MeOH,0''C

l.MeS02Cl,Et3N PhH,20°C,lh 2. KH, 18-crown-6, DME,1.5h,69%

^

3.35%, DIBAL, tol. 0 ""C, 0.5 h 3 steps

142

(+)-12b-epidevinylantirhine (143)

Scheme 28. Total synthesis of (+)-12b-epidevinylantirhine Hart's synthesis of the pyrrolo[2,3-i]isoquinoline substructure of the manzamine family alkaloids entails a 6-exO'trig radical cyclization where a 3-aza-6-heptyl substrate was essential for its stereoselective approach [64]. 1,4-Dihydrobenzoic acid 144 was prepared by the reductive alkylation of benzoic acid using 2-bromoethyl methyl ether in 95% yield. As summarized in Scheme 29, treatment of 144 with diphenylphosphoryl azide and 2(phenylseleno)ethylamine in the presence of HUnig*s base afforded amide 145. Reduction of the amide using lithium aluminum hydride in refluxing THF gave the corresponding amine (49% yield) which was acetylated to furnish the radical precursor 146. Slow addition of a benzene solution of/i-BuaSnH (2.0 equiv.) and AIBN (0.05 equiv.) to a 0.05 M solution of 146 in refluxing benzene afforded a 4:1 mixture of two diastereomeric cyclization products in 67% combined yield. The major isomer was assigned as the c/5-fused octahydroisoquinoline 147, and the minor isomer was assumed to be either the corresponding trans-fased

Applications of Radical Cyclization Reactions

605

octahydroisoquinoline or the product derived from a l-endo cyclization. The desired cw-fused octahydroisoquinoline 147 was further manipulated to the pyrrolo[2,3-i]isoquinoline 148, which served as an intennediate in the synthesis of manzamine A (149), a cytotoxic alkaloid isolated from a marine sponge. (PliO)2PON3, PhScCHzCHjNHj

^ HOv

^

/PrjNEt, 87%

144

SePh ^ ^

O

^ • ' - ' ^ " " 4 ' ^^^ reflux, 49%

^—OMe 145

2. CH3COCI, Et3N,84%

SePh

/f.BujSnH, AlBN PhH, reflux, 67% 146

^ > — /OMe

r"Y^ -OMe

V-NCOjEt 148

Scheme 29. Pyrrolo[2,3-i]isoquinoline substructure synthesis via a 6'exo-tng radical cyclization Since the monumental accomplishments of Woodward's total synthesis of reserpine in 1958, synthesis of the formidable yohimbane alkaloids continues to attract the fascination of organic chemists. Using a silylamido-cyclohexadienone photoinduced ^-exo-trig radical cyclization, Mariano et a/.[65] synthesized a highly frmctionalized yohimbane £-ring. As highlighted in Scheme 30, the cyclization precursor, cyclohexadienone 152, was easily constructed from mesylate 150 and methyl dihydrobenzoate (151) in 4 steps and 37% overall yield. The key photocyclization step was promoted by irradiation of an acetonitrile solution containing 9,10-dicyanoanthracene (DCA) as a photosensitizer and 152. The single-electron transfer (SET)-induced photocyclization process frimished the TV-tryptophylhydroisoquinoline

J.J. Li

606

154 in 24% yield with the expected cw-stereochemistry. Attempts to improve the yield of this crucial cyclization step using /i-BuaSnH mediated radical cyclization of the a-thioamide 153 were unsuccessful. The inefficiency of such processes may be due to fragmentation of the radical intermediate to produce methyl-p-hydroxybenzoate. The iV-tryptophylhydroisoquinoline 154 was transformed into alloyohimbenone stereoisomer 155 in 5 steps and 21% over yield. The SET-induced photocyclization chemistry has provided a new, concise strategy for the assembly of functionalized yohimbane £-rings.

a

PhOzS

OSOiPh

/ = \ ( >-C02Me \=/

150

4 steps 37% yield

>•

151 Av,DCA CH3CN, 24%

PhOjS

MeOjC

152,X = TMS 153,X = SPh

5 steps 21% yield

Scheme 30. Photoinduced radical cyclization in alloyohimbenone synthesis One of the few examples of a synthetically useful G-exo-trig cyclization from 3-aza-6heptenyl radicals is found in the total synthesis of (±)-melinonine-E (159, Scheme 31) by Bonjoch et al [66]. The cyclization precursor, a,P-unsaturated nitrile 157 was prepared from 1,4-cyclohexanedione monoethylene acetal (156) and tryptamine in 5 steps with 41% overall yield. Initially, when 157 was treated with 1.1 equiv. of w-BusSnH and 0.1 equiv. of AIBN in toluene for 16 h, the expected cyclization to the 2-azabicyclo[3.3.1]nonane ring took place to give 158 only as a minor product, along with its C(14) chloro- and dichloro-substituted derivatives as major products. An additional treatment of the crude mixture with 2.2 equiv. of BujSnH brought about the reduction of the C-Cl bonds to provide nitrile 158 in 38% yield over

Applications of Radical Cyclization Reactions

607

two steps. When the cyclization was conducted in the presence of an excess of BuaSnH (3.3 equiv.), the cyclization product 158 was obtained directly in 46% yield. However, the best results in this radical cyclization were achieved when tris(triniethylsilyl)silane (TTMSS, 3.5 equiv.), a poorer hydrogen atom donor, was used as the radical mediator. Under these conditions, after an additional treatment with BuaSnH-AIBN, the required 2azabicyclo[3.3.1]nonane 158 was isolated in 70% yield. The synthesis continued with the formation of the 2-azabicyclo[3.3.1]nonane ring (D, E-rings), and epimerization of the cyano group at C-20 to an axial position. Closure of the C ring using a Bischler-Napieralski cyclization gave the quaternary indole alkaloid, (±)melinonine-E (159). A closely related analog, (±)-strychnoxanthine, was also synthesized by a similar method [67].

/^O^

5 steps

^-^O-^ 156

410/0 yield

(SiMe3)3SiH (3.5 eq.) PhH,AIBN,(0.3eq.),16h

L 1

fq\ „

l^,XX 'CN

1

then BusSnH (1 eq.) AlBN (0.3 eq.), 7 h, 70%

6 steps 31% yield

^ 2»^ CHjOH H

(±)-melinonine (159) Scheme 31. A 6-exo-trig cyclization from a 3-aza-6-heptenyl radical in the total synthesis of (±)-melinonine-E Two alternative strategies employed by the Kuehne group for the synthesis of strychnos and aspidospermatane alkaloids include an intramolecular Diels-Alder reaction and a sigmatropic rearrangement sequence. Besides those two strategies, a third strategy, based on final installation of the D bridge by a radical cyclization, was successfully applied in construction of the pentacyclic strychnos framework.

608

JJ . LI

N ^ N ^ * ^ AcOCHiCHCtol.

1^^ j r ~ j r

CO2CH3

reflux, 2 h, 93% ^

160

COR

CO2CH3 161

(PhScO)20,PhH reflux, 30 min, 63%

H CO2CH3 162, R - A c 163, R = H

CO2CH3 164

Bu3SnH,AIBN. 1.5-1.8:1 PhH,85''C,51%

H

CO2CH3 165£

« CO2CH3 165

NaBH4,CeCl3 MeOH/THF(l:l) » 96%

H

CO2CH3

(db)-mossanibine (166)

Scheme 32. A 6-exo-trig radical cyclization in the total synthesis of (i:)-mossambine Scheme 32 illustrates an application of a 6-exo-trig radical cyclization in the total synthesis of (±)-mossambine (166) [68-69]. Indoloazepine 160 was obtained from tryptamine in four steps (30% overall yield). Pyrolysis of 160 in refluxing toluene in the presence of 2acetoxyacetaldehyde led to transient generation of an enamine acrylate 161, which stereoselectively formed the tetracyclic vinylogous urethane 162. Hydrolysis of the acetate

Applications of Radical Cyclization Reactions

609

gave the corresponding alcohol 163 (95%) and oxidation of the resulting vinylogous urethane with phenylseleninic anhydride provided the imino enone 164. A 6'exo-trig radical cyclization was induced by treating the tetracyclic iodide 164 with /i-BujSnH in refluxing benzene in the presence of a catalytic amount of AIBN. The pentacyclic vinylogous urethane product was reproducibly obtained in at least 51% yield as a 1.5-1.8:1 E:Z mixture of the olefin isomers \6SE and 165Z. Notably, attempted radical cyclization of the bromo and the chloro analogs of 164 failed to yield more than a trace of the pentacyclic products 165J^ and 165Z. Likewise, attempted cyclization of the vinyl iodide 164 with Mn^*, or with Pd(OAc)2/Ph3P also failed to provide the desired pentacyclic products. After separation, Luche reduction of the major ketonic olefin isomer 165i? with sodium borohydride and eerie chloride gave racemic (±)mossambine (166) and its hydroxy epimer (14-e/?i-166) in a 5:1 ratio (96%). A Corynanthe-type alkaloid, (±)-geissoschizine (175) is the biogenetic precursor to virtually all other families of monoterpenoid indole alkaloids. Since 175 is a very important natural product for biosynthetic studies as well as a useful precursor for biomimetic transformation to many other skeletal types of indole alkaloids, many synthetic studies and total syntheses have been conducted. Among the nine total syntheses in the literature, one of the latest was described by Rawal et al [70] involving Jeffery's "ligand-free" modification [Pd(0Ac)2, K2CO3, and Bu4NBr] of a 6-exo Heck cyclization. A concise synthesis of 175 featuring the construction of a Corynanthe-skeleton via a 6-exO'trig radical cyclization was reported by Takayama et al. [71]. As detailed in scheme 33, the M>-inonosubstituted tryptamine derivative 168 was prepared from alkylation of tryptamine with allylbromide 167 in acetonitrile. Condensation of the secondary amine 168 with alkoxy diester 169 in methanol afforded the enamine 170, which was subjected to Pictet-Spengler cyclization with 1.4 equiv. of camphor sulfonic acid in CH2CI2 to give the tetrahydro-P-carboline derivative 171 in 60% yield. The unstable indole 171 was subsequently protected at its TV^-function using (B0C)20 and DMAP in CH2CI2 to give 172. The key radical cyclization of the vinyl iodide 172 was conducted according to the conditions developed by Oshima [72]. Thus, treatment of 172 with w-BuaSnH (1.5 eq.), EtaB (0.4 eq.) in toluene at room temperature produced two 'Hmdesired" indoline derivatives 173^ and 173Z (32% total yield), and the desired tetracyclic product 174 possessing the C(3)/C(15) cw-relationship as the major product in 33% yield, along with 17% of the 19(2) isomer. Finally, (±)-geissoschizine (175) emerged after removal of the N^-BOC group in 174 using formic acid, and subsequent partial reduction of the resultant diester to the monoaldehyde with DIBAL. 4. SEVEN- AND EIGHT-MEMBERED RING FORMATION The rate constant measured for l-endo closure in the simple heptenyl radical is near the lower limit for synthetic utility (kj^ndo-^l x 10^ s"^) [73]. Nonetheless, 7-endo and S-endo cyclizations do occur when the (conformationally restrained) intermediate radicals possess

610

J J. Li

geometrical restrictions, i.e. less degrees of freedom relative to normal heptenyl radicals. During their studies towards the synthesis of the erythrinane ring system, Rigby et al.

Br Me

^'•^p^^'""". OUON-

CH3CN,82%

I

168

167

»69

VMe

H

MeOH, 90% Me02C

= \

\\ J^ COiMe

EtaB, if-BuaSnH toluene, rt

MeOiC

}=\

CSA, CH2CI2 J

60%

170 MeObC t^:^^^ T O I _ _ _ _ JL I ly ^^^ *' ^^.J^O

COjMe

171, R = H 172,R-BOC

19

HI I MeOiC C02Me 174,33% Scheme 33. A d-exo-trig geissoschizine

1. Formic acid 2. DIBAL, 72%

radical cyclization in the stereocontrolled synthesis of (±)-

developed a relatively rare l-endo radical cyclization process to construct the hydroepoerysopine ring system [74]. As detailed in Scheme 34, a novel [ 1 + 4 ] cyclization of cyclohexenyl isocyanate (176) with cyclohexyl isocyanide (177) provided an efficient entry into the highly functionalized hydroindole intermediate 178. Selective formation of the endocyclic enamide anion of 178 with NaH followed by addition of the readily available

Applications of Radical Cyclization Reactions

611

bromo mesylate 179 delivered the key N-alkyhied lactam 180 in 80% yield. Although palladium chemistry failed to effect the desired spirocyclization to produce the erythrinane skeleton, treatment of 180 with w-BuaSnH and AIBN in refluxing benzene cleanly afforded the hydroepoerysopine derivative 181 via a l-endo cyclization mode. In this case, not only is the product radical stabilized, there are only 3-dcgrees of freedom in molecule 180 which facilitates the cyclization.

r ^

NHC

T NC NC 177

MeO

84%

OMs

MeO 179

^\:5**^N H 178 NHCy

NaH THF 80%

f\ kJL N n-BuaSnH, AIBN 1

PhH, reflux, 65%

1

r\-

H O - \ j HO apoerysopine (182) j

Scheme 34. Construction of the hydroapoerysopine ring system via a l-endo radical cyclization process A very unusual ^-endo radical cyclization strategy was successfully applied in Sundberg*s synthesis of analogs of 5,6-homoiboga alkaloids [75]. Scheme 35 outlines the key eight-membered ring forming process. The precursor, indolylisoquinuclidine 183, was readily available from indole-2-acrylate and dihydropyridine derivatives. Substrate 183 offers a favorable SOMO-LUMO interaction between the electron-rich indol-3-yl radical and an electron-poor ^-allyl moiety. Thus, addition of w-BuaSnH to 183 in benzene containing AIBN

612

JJ.LI

at 80 °C led to two diatereoisomeric cyclization products 184. Again, the unusual S-endo radical cyclization occurred because of the high degree of conformational restraint. Like substrate 180, there are only 3-degrees offreedomin substrate 183. The absence of the l-exo cyclization product is again ascribed to the relative rates of formation of the radical intermediates: the intermediate for the S-endo cyclization is the tertiary radical 185, whereas the 7'exo cyclization intermediate 186, as a primary radical, is much slower to form. The Sundberg synthesis also involves the first synthetic application of the intramolecular addition ofS-indolyl radicals.

pCHa bCHj

ff-BuaSnH AIBN

PCH3 OCH3

PhH,80''C CO2CH3

CO2CH3 183a,R = H , Z = C02Et 183b,R = C H 3 , Z - C 0 2 E t 183c,R = H , Z = S02Ph

R

CO2CH3

184a, R = H, Z = C02Et, 48% 184b, R = CH3, Z = C02Et, 42«M 184c, R = H, Z = S02Ph, 70%

R

CO2CH3

185 186 Scheme 35. Synthesis of analogs of iboga alkaloids via a S-endo radical cyclization process 5. TANDEM CYCLIZATION Fraser-Reid's stereocontroUed synthesis of the Woodward reserpine precursor 195 relied upon a tandem 5-exo/6-exo radical cyclization of pyranose-derived dienes [76-77]. As outlined in Scheme 36, a,P-unsaturated ester 188 was prepared hy free radical coupling of iodide 187 with a tin acrylate. After hydrolysis of 188 (MeONa, MeOH, 100%) to give primary alcohol 189, the silicon tethered diene 190 was installed by silylation. Treatment of 190 with nBujSnH led to the desired cage molecule 192 in high yield via a 5-exo-trig cyclization to intermediate 191 followed by a 6-exo cyclization. Tamao oxidation of tricycle 192 led to diol

Applications of Radical Cyclization Reactions

613

193, which possesses all but one [C(7)] of the stereocenters found in an optically pure form of Woodward's densely fimctionalized caibocyclic precutsor 194. After transforming 193 to 194 using conventional methods, the unstable aldehyde 194 was condensed with tryptamine and transformed into the Woodward reseipine precursor 195.

COaEt BuaSii C02Et O. \ = *y^^ AIBN, PhCHa, 89%

AcO

187

RO,

^

OEt 188,R = Ac 189, R = H

COiEt BujSnCI, NaCNBHa

/ EtjN, CH2CI2

1

^Sl

/

-Br

OEt

AIBN

i

190

H202,KHC03

Scheme 36. A tandem 5-exo/6-exo radical cyclization of a pyronose-derived diene

614

J J . LI

The ergot alkaloids are metabolites of the parasitic fungus Claviceps with unique structures and pharmacological properties. Aside from the well-known hallucinogen lysergic acid diethylamide (LSD), many ergot alkaloids are biologically active and are in clinical use for the treatment of inter alia hypertension, migraine attacks, and Parkinson's disease. Due to its wide biological profile, lysergic acid (199) has stimulated much synthetic interest. There are eight total syntheses to date [78]. The Parsons group has conducted synthetic studies towards the total synthesis of lysergic acid (199) utilizing a tandem radical cyclization strategy [79-81]. Scheme 36 illustrates an early example [79]. Addition of BujSnH (1 equiv.) in benzene containing AIBN (10 mol%) to a refluxing benzene solution of enamine 195 produced the tetracyclic amine 197 (70%) as a mixture of diastereomers at C(8). Unfortunately, the D-ring formed was a five-membered ring instead of the desired six-membered ring. This problem was easily overcome by switching the methylphenylmethoxy- (MPMO-) group to a phenylthio group, which would act as a leaving group. Indeed, exposure of 196 to the same radical cyclization conditions led to the desired tetracyclic indoline 198 (20%) as the only isolable product.

"^^f

MPMO Bu3SnH,AIBN

a

PhH, reflux

195,R = OMPM 196,R = SPh HOiC^ 9

N^.

T% T>^ ^J\H 1 1 4 1

c1 1

^ ^

mx H 1

lysergic: acid (199) 1 Scheme 37. Synthesis of the lysergic acid framework via a S'exol6-endo-trigl6-endo-trig triple radical cyclization

Applications of Radical Cyclization Reactions

05»iMeBu

615

2.AcCI,THF 3.HF,MeCN,H20,83%

MeOjC l.Mn02,THF,94% 2.Ph3P=CH(OMe),85%

^CXY

3.HCI,THF,H2O,90%

NI

ra'

203

PhMe, MS 4A, 4 h, reflux

Ac 202 Me02C

MeOjC.

204

Bu3SnH,AIBN PhMe, reflux 20 h, 74%

Scheme 38. Synthesis of lysergic acid framework via a 5-exo/6-endo-trig double radical cyclization As described in section 3.1, when a radical cyclization reaction involves the S-hexenyl radical intermediate, the 6-endo-trig radical cyclization will prevail when the usually favored 5-exo-trig regioselectivity is suppressed by substitution at the S-position. Such a tactic was

616

J J. LI

applied in Parsons* synthesis of lysergic acid derivatives [80-81]. As detailed in Scheme 38, synthesis commenced with the readily available aniline 200. Treatment of the substituted aniline 200 with one equivalent of LDA in THF at -75 **C followed by the sequential addition of allyl bromide and acetyl chloride gave, after work-up with aqueous HF in acetonitrile (2%), the alcohol 201. After oxidation of 201 with MnO:, the resuhing aldehyde was treated with methoxymethylenetriphenylphosphorane to give the homologated aldehyde 202. Exposure of aldehyde 202 to the allylic amine 203 in dry toluene containing 4A molecular sieves furnished the key cyclization precursor, enamine 204. There are two advantages of this substrate over previous radical cyclization precursors: firstly, the electron deficient a,P-unsaturated ester will direct the radical addition to the requisite d-endo-trig mode, and secondly, having no bulky substituent at the terminal alkenic carbon atom will accelerate the S-endo-trig mode of cyclization in the fmal stage. When 204 was subjected directly to the triple radical cyclization, a 2:1 mixture was obtained with methyl tetrahydrolysergate 206 as the major isomer. The minor isomer was the undesired kinetic product from the triple tandem radical cyclization via a S-exo/S-endO'trig/S-exo pathway. Therefore, 205 was prepared by allowing the uncyclized enamine 204 to cyclize in boiling toluene for 5 h before the radical cyclization step. When the pure cyclized enamine 205 was treated with /i-BusSnH in boiling toluene, methyl tetrahydrolysergate 206 was obtained in 75% yield, as a 3:1 mixture of the two epimers at C(10). Although dehydrogenation at C(9)-C(10) was problematic, this approach assembled the lysergic acid skeleton with great efficiency. A fused tetracyclic a presursor of indole alkaloids was constructed via a S-exo-dig/Sendo'trig tandem double radical cyclization [82]. When the erythro isomer 207 was subjected to radical cyclization, the tetracyclic cis fused carbamate 208 was obtained. Interestingly, the corresponding threo isomer failed to cyclize due to the formation of a transoid ate complex of silicon during the cyclization process.

BusSnH/AIBN

.

COiMe

. S-N^

>

48% OTBDMS 207

Scheme 39. An indole alkaloid precursor via a 5-exo-dig/6-endo-trig double radical cyclization Pseudocopsinine (215) was isolated from Vinca erecta. Parsons et al. devised a concise synthesis of the pseudocopsinineframework214 utilizing a 5-exo/5-exo double tandem radical cyclization [83-84]. The cyclization precursor 213 was readily accessible via a [3 + 2] nitrone cyclization. As depicted in Scheme 40, reaction between the pyrrolidine aldehyde 210 ando-

Applications of Radical Cyclization Reactions

617 ,C02Me

^COzMe -N

Br

NHOH

CHO

MeOH/H20 3 days in dark 86%

210

209 O

,C02Me Ph3P=CH2, THF 1

-78X83%

sealed tube 105 ^C, 38% .COiMe

N-COiMe BuaSnH/AIBN PhH, reHux, 22%

Scheme 40. Synthesis of a model for pseudocopsinine via a S-exo/S-exo double tandem radical cyclization bromophenylhydroxylamine (209) installed nitrone 211, which reacted smoothly with 1-buten3-one to afford the 5yw-adduct 212 in 39% yield, along with the an//-adduct in 41% yield. Wittig methylenation of 212 proceeded uneventfully at low temperature to give the radical cyclization precursor 213. After much experimentation, it was found that prolonged exposure of 213 to tri-«-butyltin bromide caused stereo-randomization. When all the reagents were

618

J.J. Li

premixed together in benzene and heated at reflux, the requisite tandem radical cyclization occurred, furnishing the pentacyclic model for pseudocopsinine synthesis 214 in 22% yield. Even though the yield is modest, the S-exolS-exo double tandem radical cyclization delivered the pentacyclic skeleton in one step, demonstrating the tandem radical cyclization strategy as a powerful tool in organic synthesis. 6. CONCLUDING REMARKS In the indole alkaloid arena, the general rules of radical cyclizations apply. For example, radical cyclization via the S-endo-trig mode is usually disfavored unless the substrate possesses a structural setup (e.g. 7V;^-disubstituted amides, but not 7V-phenyl or iV^-allyl [17d]) that conformationally favors the S-endo-trig mode. Radical cyclizations via the S-endo-trig mode do occur for some substrates, such as 1,3, and 7. In contrast to the large body of data pertaining the S-exo and 6-ero cyclization modes, the 6'endo'trig mode has limited applications. This is simply because the S-exo-trig cyclization is kinetically favored for 5-hexenyl radical intermediates. Nevertheless, when the usually favored S-exo-thg regioselectivity is surpressed by a substituent (e.g. bromine or ethyl) at the 5-position, the d-endo-trig cyclization mode prevails. Generally, most radical cyclizations proceed kinetically in an exo fashion to provide the smaller of the two possible rings. Nonetheless, as an important exception, l-endo and S-endo cyclizations do occur when the (conformationally restrained) intermediate radicals possess geometrical restrictions, i.e. less degrees of freedom relative to normal heptenyl radicals. It also should be noted that the rate constants for l-exo and S-endo cyclization of 7-octenyl radical are almost identical—the preference for ero-closure decreases as the rings get bigger [86]. Finally, although a practical total synthesis of a naturally occurring indole alkaloid using a tandem radical cyclization strategy has yet to be demonstrated this strategy has shown great potential as a powerful tool in indole synthesis. 7. ACKNOWLEDGMENT: The author is indebted to Drs. Gary F. Filzen and Peter L. Toogood for proofreading the manuscript. Insightful comments and suggestions from Prof David Crich are greatly appreciated. 8. REFERENCES: 1.

DP Curran, NA Porter, B Giese, Stereochemistry of Radical Reactions, Concepts, Guidelines, and

2.

WB Motherwell, D Drich, Free Radical Chain Reactions in Organic Synthesis, Academic Press, London,

Synthetic Applications, VCH Weinheim, Germany, 1996. 1992.

Applications of Radical Cyclization Reactions 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

619

B Giese, Radicals in Organic Synthesis, Formation of Carbon-Carbon Bonds, Pergamon, Oxford, 1986. DP Curran, In Comprehensive Organic Synthesis, BM Trost and I Fleming, Ed., Pergamon: Oxford, 1991, Vol. 4, p 715 and p 779. T-L Ho, Tandem Organic Reactions, John Wiley & Sons, Inc. New York, 1992. C Thebtaranonth, Y Thebtaranonth, Cyclization Reactions, CRC Press, Boca Raton, 1994. CP Jasperse, DP Curran, TL Fevig, Chem Rev 91: 1237 (1991) DP Curran, Synthesis, 417 and 489 (1988). B Giese, Angew Chem Int Ed Engl 24: 553 (1985). JE Baldwin, J Chem Soc, Chem Comm 734 (1976). H Ishibashi, N Nakamura, T Sato, M Takeuchi, M Ikeda, Tetrahedron Lett 32: 1725 (1991). T Sato, N Machigashira, H Ishibashi, M Ikeda, Heterocycles 33:139(1992). H Ishibashi, N Nakamura, K Ikeda, M Okada, H Ishibashi, M Ikeda, J Chem Soc, Perkin Trans 1, 2399 (1992). DHR Barton, AAL Guntilaka, RM Letcher, AMFT Lobo, DA Widdowson, J Chem Soc, Perkin Trans 1, 874(1973). J Cassayre, B Quiclet-Sire, J-P Saunier, SZ Zard, Tetrahedron Lett 39: 8995 (1998). SJ Danishefsky, JS Panek, J Am Chem Soc 109: 918 (1987). (a) C Wright, M Shulkind, K Jones, M Thompson, Tetrahedron Lett 28: 6389 (1987). (b) AJ Clark, K Jones, C McCarthy, JNfD Storey, Tetrahedron Lett 32: 2829 (1991). (c) H Togo, O Kikuchi, Heterocycles, 28: 373 (1989). (d) DP Curran, NC DeMello, J Chem Soc, Chem Comun, 1314 (1993). K Shishide, K Hiroya, H Fukumoto, T Kametami, J Org Chem 51: 3007 (1986), JP Dittami, H Ramanathan, Tetrahedron Lett 29: 45 (1988). AJ Clark, K Jones, Tetrahedron 48: 6875 (1992). JK Macleod, LC Monahan, Tetrahedron Lett 29: 391 (1988). JK Macleod, LC Monahan, Aus J Chem 43: 329 (1990). P Wicdcnau, B Monse, S Blechert, Tetrahedron 51: 1167 (1995). G Stork, PM Sher, J Am Chem Soc 108: 303 (1985). T Sato, Y Wada, M Nishimoto, H Ishibashi, M Ikeda, J Chem Soc, Perkin Trans 1, 879 (1989). H Ishibashi, TS So, T Sato, K Kuroda, M Ikeda, J Chem Soc, Perkin Trans 1, 763 (1989). H-J Kndlker, N O'Sullivan, Tetrahedron 50: 893 (1994). DU Clive, N Etkin, T Joseph, JW Lown, J Org Chem 58: 2442 (1993). NJ Newcombe, F Ya, RJ Vijin, H Hiemstra, WN Speckamp, J Chem Soc, Chem Comm 767 (1994). Z Sheikh, R Steel, AS Tasker, AP Johnson, J Chem Soc, Chem Comm 763 (1994). iftiV/, 765 (1994). T Fukuyama. G, Liu, J Am Chem Soc 118: 7426 (1996). DJ Hart, SC Wu, Tetrahedron Lett 32:4099 (1991). D Kuzmich, SC Wu, D-C Ha, C-S, Lee, S Ramesh, S Atarashi, J-K Choi, DJ Hart, J Am Chem Soc 116: 6943(1994). S Atarashi, J-K Choi, D-C Ha, DJ Hart, D Kuzmich, C-S, Lee, S Ramesh, SC Wu, J Am Chem Soc 119: 6226(1997). J Cossy, M Cases, DG Pardo, Tetrahedron Lett 39: 2331 (1998). DL Boger, RS Coleman, J Am Chem Soc 110:4796 (1988). Y Ueno, K Chino, M Okawara, Tetrahedron Lett 23: 2575 (1988). D Crich, Q Yao, J Org Chem 60: 84 (1995). (a) DL Boger, T Ishizaki, RJ Wysocki, Jr, SA Munk, J Am Chem Soc 111: 6461 (1989). (b)DL Boger, RJ Wysocki, Jr, J Org Chem 54: 1238 (1989). DL Boger, RJ Wysocki, Jr, T Ishizaki, J Am Chem Soc 112: 5230 (1990). AP Dobbs, K Jones, KT Veal, Tetrahedron Lett 39:4857 (1995).

620

J J . LI

43.

J Bonjoch, D Sole, S Garcia-Rubio, J Bosch, J Am Chem Soc 119: 7230 (1997).

44.

DC Lathbury, PJ Parsons, I Pinto, J Chem Soc, Chem Comm 81(1988).

45.

FE Ziegler, M Belema, J Org Chem 59; 7962 (1994).

46.

FE Ziegler, PG Harran, Tetrahedron Lett 34:4505 (1993).

47.

FE Ziegler, PG Harran, J Org Chem 58: 2768 (1993).

48.

FE Ziegler, M Belema, J Org Chem 62:1083 (1997).

49.

(a) R Fletcher, C Lampard, JA Murphy, N Lewis, J Chem Soc, Perkin Trans 1,6: 623 (1995). R Fletcher, M Kizil, C Lampard, JA Murphy, SJ Roome, J Chem Soc, Perkin Trans 1,2341 (1998).

50.

For other methods of introducing an alcohol via radical chemistry, see (a) DHR Barton, D Crich, WB Motherwell, Tetrahedron Lett 41: 3901 (1983). (b) S Moutel, J Prandi, Tetrahedron U t t 35: 8163 (1994). (c) J D^sir^, J Prandi, Tetrahedron Lett 38: 6189 (1997). (d) T Bamhaoud, J Prandi, J Chem Soc, Chem Comm 1229 (1986).

51.

(a) O Callaghan, C Lanqjard, AR Kennedy, JA Murphy, Tetrahedron Lett 40: 161 (1999). (b) O

52.

ME Kuehne, T Wang, PJ Seaton, J Org Chem 61:6001 (1996).

Callaghan, C Lampard, AR Kennedy, JA Murphy, J Chem Soc, Perkin Trans 1,995 (1999). 53.

U Lauk, D Durst, W Fischer, Tetrahedron Lett 32: 65 (1991).

54.

AM Rosa, AM Lobo, PS Branco, S Prabhkar, M Sa-da-Costa, Tetrahedron 53: 299 (1997).

55.

O Tsuge, T Hatta, H Tsuchiyama, Chem Lett 155 (1998).

56.

S Yasuda, T Hirasawa, S Yoshida, M Hanaoka, Chem Pharm Bull 37:1682 (1989).

57.

D Crich. J-T Hwang, J Org Chem 63:2765 (1998).

58.

(a) G Stork, RA Mook, SA Biller, SD Rychnovsky, J Am Chem Soc 105: 3741 (1983). (b) G Stork, ME Kraft, SA Biller, Tetrahedron Lett 28: 1035 (1987).

59.

M Ihara, N Taniguchi, K Fukumoto, T Kametani, J Chem Soc, Chem Comm 1438 (1987).

60.

M Ihara, F Sctsu, M Shohda, N Taniguchi. K Fukumoto. Heterocycles 37: 289 (1994).

61.

M Ihara, F Setsu, M Shohda, N Taniguchi, Y Tokunaga, K Fukumoto, J Org Chem 59: 5317 (1994).

62.

M Ihara, A Katsumata, K Fukumoto, J Chem Soc. Perkin Trans 1.991 (1998).

63.

A Katsumata, T Iwaki, K Fukumoto, M Ihara, Heterocycles 46: 605 (1997).

64.

DJ Hart, JA McKinney, Tetrahedron Lett 30: 2611 (1989).

65.

SY Jung. PS Mariano, Tetrahedron Lett 34:4611 (1993).

66.

J Quirante, C Escolano, J Bosch, J Bonjoch, J Chem Soc, Chem Comm 2141 (1995).

67.

J Quirante, C Escolano, A Merino, J Bonjoch. J Org Chem 63: 968 (1998).

68.

ME Kuehne, T Wang, D Seraphin, Synlett 557 (1995).

69.

ME Kuehne, T Wang, D Seraphin, J Org Chem 61: 7873 (1996).

70.

VB Birman, VH Rawal. Tetrahedron Lett 39: 7219 (1998).

71.

H Takayama, F Watanabe, M Kitajima, N Aimi, Tetrahedron Lett 38: 5307 (1997).

72.

K Nozaki. K Oshima, K Utimoto, J Am Chem Soc 109:2547 (1987).

73.

ALJ Beckwith, GJ Moad, J Chem Soc, Chem Comm 472 (1974).

74.

JH Rigby, MN Qabar, J Org Chem 58:4473 (1993).

75.

RJ Sundberg, RJ Chemey, J Org Chem 55:6028 (1990).

76.

AM Gomez, JC Lopez, B Fraser-Reid, J Org Chem 59:4048 (1994).

77.

AM Gom^z, JC Lopfe, B Fraser-Reid. J Org Chem 60: 3859 (1995).

78.

I Ninomiya. T Kiguchi. The Alkaloids, ed. A Brossi. Academic Press: New York. 1990, vol. 38, p p l -

79.

DE Cladingboel, PJ Parsons, J Chem Soc, Chem Comm 1543 (1990).

156. 80.

Y Ozlu, DE Cladingboel, PJ Parsons, Synlett 357 (1993).

81.

Y Ozlu. DE Cladingboel, PJ Parsons, Tettahedron 50:2183 (1994).

82.

JJ Jenkinson, PJ Parsons, SC Eyley, Synlett 679 (1992).

83.

PJ Parsons, CS Penkett, MC Cramp, RI West, J Warrington, MC Saraiva, Synlett 507 (1995).

Applications of Radical Cyclizatlon Reactions 84. 85. 86.

PJ Parsons, CS Penkett, MC Cran^, RI West, ES Warren, Tetrahedron 52: 647 (1996). DP Curran. C-T Chang, J Org Chcm 54: 3140 (1989). AU Beckwith, CH Schiesscr. Tetrahedron 41:3925 (1985).

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623

Subject Index

Note: Bold page numbers refer to illustrations. There are often textual references on the same pages.

2-Acetoxyisobutyrylbromide 460 l-O-Acetylacofine 13,31,48 15-O-Acetylatisine-A^,20-azomethine 13, 23,49 7-0-Acetylbarbaline 13, 35, 50 ll-O-Acetylbarbisine 13,35,51 11-O-Acetylcardionine 13, 31, 44, 45, 52 15-O-Acetylcardiopetamine 13, 32, 37, 40, 44, 53 3-C?-Acetylcardiopine 13, 35 3-O-Acetylcardiopinine 13, 35, 54, 55 Acetylcholinesterase 559 13-O-Acetyl-15-dehydrocardiopetamine 13, 32. 56 15-O-Acetyl-13-dehydrocardiopetamine 13,32,37,40,57 11 -O-Acetyl-1,19-dehydrodenudatine 13, 37,58 11-O-Acetyl-l 1,19-dehydrodenudatine 28 3-O-Acetyl-2,20-dehydro-16,17-dihydro(14,20-5eco) hetidine 13, 28, 59 2-O-Acety I-13-dehydro-11 -epi-hetisine 13, 26, 60 12-O-Acetyl-1,19-dehydrolucidusculine 13, 30, 42, 61 12-€f/7i-0-Acctyl-1,19-dehydronapelline 13,28,40,62 7-0-Acetyldelgrandine 13, 36, 63 15-0-Acetyldenudatine 186 13-Acetyl-9-deoxyglanduline 13, 33 13-0-Acetyl-9-deoxyglanduline 43, 45, 64 14-Acetyl-9-deoxyglanduline 13, 33 14-0-Acetyl-9-deoxyglanduline 43, 45, 65

11 -O-Acetyl-2,13-didehydrohetisine 13, 26,66 13-0-Acetyl-2,11 -didehydrohetisine 13, 26, 67, 208 13-0-Acetylfissumine 13, 28, 68 13-O-Acetylglanduline 13, 33, 43, 45, 69 13-O-Acetylgomandonine 13,28,37,70 7-O-Acetylgrandine 45 2-O-Acetylhetisine 13, 26, 71 11-O-Acetylhetisine 66 13-O-AcetyIhetisine 13, 26, 45, 67, 72 13-0-Acetylhetisine-2-one 13, 26, 44-^6, 73,194 2-Acetyl-3-hexahydrobenzoyl-16,17dihydrohetidine 13 2-0-Acetyl-3-hexahydrobenzoyl-16,17dihydrohetidine 33, 74 15-0-Acetyl-9-hydroxynomininc 13, 22, 75 11-Acetylisohypognavine 31 11-O-Acetylisohypognavine 13,38,76 11-O-Acetyllepeninc 13, 28, 39, 77 NO-Acetylluciculine 13, 28, 42, 78 12-O-Acetyllucidusculine 13, 30, 38, 42, 79 12-O.Acetylnapelline 13, 28, 39, 80 12-0-Acetylnapelline-^-oxide 13, 29, 39,81 15-O-Acetylryosenamine 13, 31, 82 15-O-Acetylsczukinine 14, 30, 83 2-Acetylseptentnosine 27, 392 2-0-Acetylseptentriosine 14, 41, 84 15-O-Acetylsongoramine 14,28,85 6-(9-Acetylspiradine A 14, 24, 87 A^-Acetylspiradine A 14, 24, 86 Acofine 2, 14, 30, 39, 48, 88

624 Acoridine 14,28,39,89 Acorientine 14,23,40,90 Acorine 27 Acozerine 14, 32, 42, 91 Acsinatidine 14,23,92 Acsinatine 14, 26, 39, 92, 93 a-Acylamino radical 574 Acylaxaniutn ion 503 Acyl iminium oxyanion 497 ^-Acylnitroso 447 1,5-Addition 439 l,6.Addition 478 syn-S-exo Addition 529 Ajaconinc 14,25,43,44,46,94,95,254 Ajaconium chloride 14, 28, 95 Albovionitine 3, 14, 27, 37, 96 Alkaloidal free bases, solubilities 421-423 Alkaloidal hydrochloride salts 424 Alkaloidal salts 420, 422 -, desorption from matrix 426 -, solubilities 423-426 Alkaloids 416, 418-437 -, cephalotaxine 421 -, ephedrine 421 -, hyoscyamine 421,422 ~, methylephedrine 421 -, norephedrine 421 -, pseudoephedrine 421, 422 ~, scopolamine 421, 422 a-Allocryptopine 419 Alloyohimbenone 606 Alzheimei^s disease 559 Amino fiiran ester 497 Aminomethyl tri-/t-butylstannane 520 Andersobine 14, 26, 43, 97, 99 Andersobine-19-/^iV,^dimethylaminobenzoate 14, 33, 99 Anhydrolycorinone 486 Anopterimine 14, 28,42,100 Anopterimine-iV-oxide 14, 29, 43,101 Anopterine (Anopteryl-ll,12-ditiglate) 14, 33, 42, 43,102 Anopteryl-1 la,4'-hydroxybenzoate 12a-tiglate 14, 34, 43,103 Anopteryl-12a-tiglate (1 la-Destigloylanopterine) 14, 31, 42, 43,104 Anti SN2 addition 467 Anti SN2' reaction 544

Subject Index Anti-viral activity 559 Apomiyaconine 14, 24,105 S^Ar reaction 489 Aryloxazolines 489 (±)-Aspidospermidine 592, 593 Assoanine 480 Asymmetrization 467 Atidine 14, 25, 38, 106,180 Atisanes 2 Atisine 14, 24, 38, 40, 42, 46, 49, 107-^111,188,210,211,286,289,290 Atisine-Ar,20-azomethine 14, 22,109 Atisine-15-one 14, 23,108 Atisinium chloride (Guan Fu Base G) 14, 27,110 (-)-Augustamine 549 p-Azidonation 561 Azitine 14, 22, 111 Barbaline 2, 14, 35, 43, 50, 112 Bart>isine 2, 14, 34, 44, 51, 113 Basic modifiers 416 Basified modifiers 420^27,437 Benzothiazole 419 6-Benzqyl heteratisine 4 1 la-Benzoyl-7p-hydroxy-l la-destigloylanopterine (7P-Hydroxyanopteryllla-benzoate 12a-tiglate) 14, 34, 42, 43, 114 11-Benzoylkobusine 14,29,115 15-Benzoylkobusine 14, 29, 116 6-Benzoylpseudokobusine 14, 30, 117 11-Benzoylpseudokobusine 14, 30,118 15-Benzoylpseudokobusine 14, 30, 42, 119 Benzyl alcohol 419 Bischler-Napieralsky cyclisation 440, 493 Bischler-Napieralsky reaction 443 cij-(4-Bromo-l-burenyl)trimethylsilane 518 4-Bromo-cyclohexen-2-one 538 2-Bromo-4,5-methylenedioxybenzyl azide 544 6-Bromopiperonal 491 Brunonine 14, 25,44,120 (±)-Brunsvigine 536 Buflavine 474 /er/-Butyldimethylsilyltrif1ate 437

Subject Index Caffeine 418, 419 Califomidine 419 Carbamoylmethyl radical 574 Carbazomycin B 582, 583, 584 Caibenium ion 510, 549 ^-Caibomethoxynitrene 456 Carbon dioxide 416, 417, 419-422, 424, 426,428 Cardiodine 14,36,44,121 Cardionidine 3, 14, 26, 44,122 Cardionine 14,29,44,45,123,181,182 Cardiopetamine 14, 30, 37, 40, 44, 45, 124,148,149,174, 183 Cardiopidine 35, 44, 125 Cardiopimine 15, 35, 44,126 Cardiopine 15, 35, 44,127,152,176 Cardiopinine 15, 35, 44, 54, 55, 128, 150,153 Cationic aza-Cope rearrangement 541 (4.).CC-1065 588,589 CC-1065 586 Cephalotaxine 421 ~, extractabilities 429 - , yields 437 Chelerythine 419 Chellespontine 15, 24, 43,129, 210 (lS,25)-3-Chlorocyclohexa-3,5-diene-l,2diol 506 Chuanfunine 15, 27, 37,130, 269 Cocaine 427 (-)-Coccinine 549 (±)-Coccinine 535 Codeine 419,422 Coffee 416, 419 (±)-Conduritol-A 467 Contorine (2-0-Acetyl-3-anisoylhetidine) 15, 33, 37,131 Contorsine (2-0-Acetyl-3-isobutyrylhetidine) 15,31,37,132 Contortine (2-Acetyl-3-(25)-methylbutyrylhetidine) 15, 31, 37,133 Coryphidine 4, 15, 32, 39, 134 Coryphine 4, 15, 31, 39,135 Cossonidine 15, 22, 44, 136,151, 184, 207 Cossonine 15, 33, 44,137 Cotinine 419 (±)-Cotinine 574 Crassicauline B 15, 30, 37,138,185

625 Crinasiadine 442 (±)-Crinine 523 Critical density 418 Critical pressure 418 Critical temperatures 418 (db)-Cryptaustoline 597,599 Cuauchichicine 15,24,46,139,140,265 16-€y7/-Cuauchichicine 15, 24,140 Cuauchichicine-N,20-azomethine 15, 22, 141 Curtius rearrangement 533 1 l,12,16-Cyclopropyl-16,17-dihydrohetisane 15, 22,142 Cytotoxicity 558 Deacetoxylation 506 2-Deacetylheterophylloidine 15, 23, 37, 43, 143 12-Deacetylspiramine F 144 15-Deacetylspiramine 25 15-Deacetylspiramine F 15 15-Deacetyl^ognavine 2, 15, 34, 40, 145 Decaffeination 416 A^.Deethyl.N-acetyl.l.l2,15-0triacetylnapelline 15, 32,146 iV-Deethyl-l,19-dehydrolucidusculine 15, 26, 42,147 Dehydroanhydrolycorine 476 13-Dehydrocardiopetamine 15, 30,148 15-Dehydrocardiopetamine 15, 30, 56, 149 2-Dehydrocardiopimine 15, 35,150 15-Dehydrocossonidine 15, 22,151 3-Dehydro-1 -desacetoxy-1,2-dehydrocardiopine 15, 34,152 3-Dehydro-l -dcsacetoxy-1,2-dehydrocardiopinine 15, 34,153 2-Dehydro-11,13-O-diacetylhetisine 15, 28,154 13-Dehydro-l,ll-0-diacetylhetisine 28 13-Dehydro-2,ll-0-diacety]hetisine 15, 60,155 2,20-Dehydro-16,17-dihydro-( 14,20-5eco) hetidine 15, 25,156 15,16-Dehydro-16,17-dihydrotatsirine 15, 23,157 11-Dehydrohetisine 15, 23, 158

626 1,19-Dehydrolucidusculine 15, 28, 42, 159,162 n-^/^i-1,19-Dehydrolucidusculine 15, 28, 39, 160 1,19-Dehydronapelline (1,19-Dehydroluciculine) 15, 25, 38, 42,162 12-epi-l,19-Dehydronapclline 15, 25, 39, 40, 161 13-Dehydropaniculatine 16, 33,163 15-Dehydroryosenamine 16, 30, 164 Delatisine 16, 23, 44,165 Delbidine 16, 24, 44,45,166 Delfissinol 16,23,44,167 Delgrandine 2, 16, 36,45,168 Delnudine 4, 16, 23, 44,169 Delnuttalinc 16, 27,45,170 Delnuttidine 16, 23,45,171 Delnuttine 16, 26, 45, 172 (i:)-3-Demethoxyerythratidinone 577 3-Demethoxyerythratidinone 574, 578 Denudatine 16, 23, 38,39,44,173,186 (-»-)-7-Deoxy-//ti/ff-dihydronarciclasine 452 (•f)-7-Deoxynarciclasine 444,448 (~)-7-Deoxynarciclasinc 449 (+)-7-Deoxypancratistatin 452 11-Desbenzoylcardiopetamine 16,24, 174 ^-Desethylsongoramine (Norsongoramine) 16,23,40,46,175 2-Desmethylbutyrylcardiopine 16, 33, 176 A^-Desmethyl-M6-5eco-6-hydroxyepiscopalidine-6-cathylate 16,34,177 Desorption from matrix 427,428 1 la-Destigloylanopterine (Anopteryl-12atiglate) 16,31,42,43,178 9,19-O-Diacetylacsinatine 16, 31, 39, 179 12-0,22-A^-Diacetylatidinc 30 15-0,22-iV-Diacctylatidinc 16,180 6,11-O-Diacetylcardionine (basic) 16, 32, 181 N, 11 -0-Diacetylcardionine (neutral) 16, 32, 182 13,15-O-DiacetyIcardiopetamine 16, 33, 183 1,15-0-Diacetylcossonidine 16,28,184 1,7-O-Diacetylcrassicauline 16

Subject Index 1,7-0-Diacetylcrassicauline B 33,185 11,15-0-Diacetyldenudatine 16,29,186 11,13-0-Diacetyl-9-deoxyglanduline 16, 34, 43, 45, 187 15-0,22-A^-Diacetyldihydroatisine 16, 29, 188 1,15-0-Diacety 1-16,17-dihydrosongorine 16, 29,189 15-0,22-A^-Diacetyldihydroveatchine 16, 29, 190 6,13-O-Diacetylgeyerine 16, 32,191 2,11-0-Diacetylhetisine 16,29,155,192 11,13-O-Diacetylhetisine 16, 29, 154, 193 ll,13-0-Diacctylhetisine-2-one 16, 28, 194 11,15-O-Diacetylisohypognavine 16, 33, 38.195 1,15-O-Diacetylluciculine 16, 30, 196 7,11-O-Diacetylorientinine 16, 28, 197 2,15-O-Diacetylryosenaminol 16, 29, 198 6,11-O-Diacetylvenulol 16,28,199 13,15-O-Diacetylvenuluson 16, 28, 200 11,15-0-Dibenzoylkobusine 16,33, 201 6,11 -O-Dibenzoylpseudokobusine 16, 33, 202 6,15-O-Dibenzoylpseudokobusine 16, 33, 203 Dictyzine (Dictysine) 16, 24, 37, 44, 46, 204 Dictyzineacetonide (Dictysineacetonide) 16, 27, 44, 206 1,15-Didehydrocossonidine 16, 22, 207 2,11-Didehydrohetisine 17,23,208 Diels-Alder addition 497 Diels-Alder reaction 496, 498 Dihydroajaconine 17, 26,43, 209 Dihydroatisine 17, 25, 38, 210 ^,20-Dihydroatisineazomethine 17, 22, 211 (±)-Dihydrocorrylnantheol 601,602 Dihydrocuauchichicine 17, 25, 212 16,17-Dihydro-15,16-dehydro. episcopalidine 17,32,213 16,17-Dihydro-2,20-dehydro-( 14,20.5^co) hetidine 17,25,214 16,17-Dihydroepiscopalidine 17,32,215 Dihydrogarryfoline 17, 25, 216

Subject Index 16,17-Dihydrohetidine 17, 25, 217 Dihydrolaurifoline 212 Dihydroovatine 17, 27, 218 Dihydrosongorine 17, 25, 39, 189, 219 Dihydroveatchine 17, 25, 220 ^,20-Oihydroveatchineazomethine 17, 22, 221 4',7p-Dihydroxyanopterine (7p-Hydroxyanopteryl-l la-(£)4'-hydroxy-2'-mcthylbut-2'-enoatc 12a.tiglate) 17,34,42,43,222 2,4-Dimethoxybenzylaiiiine 499 1,4-Dimethoxycyclohexadiene cationic iron complex 513 a,a-Dimethoxycyclohexanonc 485 M^-Dimcthylarylamides 474 Dimethyldioxirane 548 Dimethylsquarate 478 Diterpenoid alkaloids 2, 419 D-Chilonolactone 452 (-f-)-EIacomine 585 (i:)-Elwesinc 517 Ephedrine 421, 423, 424, 426, 428 - , chemical conformation 429 ~, extractabilities 428, 429 - , selective extraction 428 - , solubility 425, 426 - , yields 428 (db)-Epicrinine 523 (+)-12b-Epidevinylantirhine 604 (i:)-EpieIwesine 517 11-Epipretazettine 532 Episcopalidine 17, 32, 37, 38, 59, 74. 156,177,213-215,223,243,252,253 Eschenmoser*s salt 506 Escolzine 419 Ferrier reaction 444 Finetianine 17, 24, 38, 224 Fissumine 17, 26, 45, 68, 225 Flavadine 38, 42, 226 Flavamine 17,27,38,227 Flavidine 17,29 FR-900482 590, 591 Free base 420, 422, 423, 424 Galanthamine 510

627 Garryfoline (Laurifoline) 17, 24, 43, 46, 141, 212, 228, 229, 291 Garryfoline-M20-azomethine 17, 22, 229 Garry ine 17,24,46,230 (i:)-Geissoschizine 609, 610 (i)-Gelsemine 584, 585,586, 599, 600 Geneserine 577, 579 Geyeridine 17,27,44,45,231 Geyerine 17.29,45,191,232 Geyerinine 17, 45, 233 Glanduline 17, 32, 43, 45, 234 Gomandonine 17, 26, 37, 41, 235 Guan Fu Base A 17, 29, 37, 39, 236 Guan Fu Base F 17, 31, 39, 237 Guan Fu Base G 17,27,31, 37,39,238 Guan Fu Base Y (Acorine) 17, 27, 37, 39, 239 Guan Fu Base Z 17, 29, 39, 240 (±)-Haemanthidine 526 Hanamisine 17, 31, 41, 241 Heck cyclisation 448 Heck reaction 447 1-Heptanesulfonic acid 420 Heterophylloidine (Panicutine) 17, 27, 38, 41, 143, 242 Hetidine 17, 25, 38, 40, 217, 243 Hetisine (Delatine) 17, 23, 38, 40, 43-46, 71, 72, 158, 192. 193, 244. 246, 391 Hetisine-2^ne 17, 23, 38, 44-46, 73, 246 Hetisinc-3-one 44 5-Hexynyl radical 588 High-resolution mass values 22 Hippadine 486, 597 l,2.Hydride shift 548 Hydrochloride salts 422, 423, 424 11-Hydroxyanhydrolycorine 476 7P-Hydroxyanopterine (7p-Hydroxyanoptery 1-11 a, 12a-ditiglate) 17, 34, 42, 43, 248 7P-Hydroxyanopteryl-l la,12a-ditiglate 17, 34, 42, 43, 249 7P-Hydroxyanopteryl-l la-benzoate 12a-tiglate 17,34,43,250 7P-Hydroxyanopteryl-11 a-(£)-4'-hydroxy2'-methylbut-2'-enoate 12a-tiglate 18, 34, 43, 251

628 ^,6-Hydroxyepiscopalidine-6-cathylate chloride 18,252 iV,6-Hydroxyepiscopal]dine chloride 18, 33, 253 7a-Hydroxyisoatisine 18, 209, 254 7p-Hydroxyisoatisine 25 3-Hydroxy-8,9-methylcnedioxyphenanthridine 441 9-Hydroxynoiiiinine 18,22,38,75,255 Hyoscyamine 421, 422, 423, 424, 426 - , extractabilities 425,427, 428 - , solubility 425 ~, yields 427 Hypognavine 18, 30,41, 256, 257 Hypognavinol 18, 24, 257 Iboga alkaloids 612 Ignavine 18,30,37,38,41,258 Ignavinol (Anhydroignavinol) 18, 24, 259 3-£/7f-Ignavinol 18, 24, 38, 260 Ignivine 259 6-O-Imidazoylthiocarbonylpseudokobusine 18,30,261 Iminium ion 541 Imino-ene cyclisation 544 Indole radical intermediate 589 3-Indolyl radicals 612 7-Iodoindoline 487 lodolactonisation 503 lodosylbenzene 561 Isoatisine 18,24,38-40,42,262,264 Isoatisinone 18, 24, 264 Isocuauchichicine 18, 24,46, 265, 266 16-£/'i-Isocuauchichicine 18, 266 Isogarryfoline 18, 24,46, 267 Isohypognavine 18,30,38,40,268 Isonitriles 476 1-Isopancratistatin, 0-methylether 470 2,3-O-Isopropylidenc-D-erythronolactone 520 Isopropylidine chuanfunine 18, 30, 269 Isoquinoline alkaloids 419 Jynosine (15-0-Acetyldenudatine) 18, 27, 38, 270 Kalbretorine 491 ent'KauTzne 2

Subject Index Kauranes 2 KirinineB 18,25,39,271 KirinineC 18,26,39,272 Kobusine 18, 22, 38, 41, 42, 115, 116, 142, 201, 273, 301 Koumine 579 Lassiocarpine 18, 32, 39, 275 Laurifoline 24 Lepedinc 18,27,41,276 Lepenine 18, 25, 39, 41, 277 Liangshanine 2, 18, 27, 39, 278 Liangshanone 2, 18, 26, 39, 279 Lindheimerine 18,23,46,141,229,280 Luciculine (Napelline) 18, 26, 37-40, 42, 281 Lucidusculine (15-0-Acetylnapelline) 18, 28, 38, 39, 42,159,196, 283, 390 12-e/7i-Lucidusculine 18, 28, 39, 282 Lycoramine 511 Lysergic acid 614 JD-Lyxose 449 Macrocentrine 18,27,45,284 Manzamine A 605 Matrix 426 (±)-Melinonine-E 606,607 (±)-Mesembranol 582,583 4-Methoxy-3-cyclohexcn-1 -ol 511 Methyl-2-azido-6-bromo-2,6-dideoxy-aD-altropyranoside 444 0-Methylcariachine 419 ^-Methylcrinasiadine 442 iV-Methyl-M20-dihydroatisineazomethine 18,22,286 ^-Methyldihydroveatchineazomethine 18, 22, 287 4,5-Methylenedioxyhomophthalic anhydride 493 Methylephedrine 421, 423, 424, 426 ~, extractabilities 428 - , yields 428 ;^-Methyl-6-oxospiradine A 18,23,288 A^-Methyl-iV,6-5eco-6-dehydropseudokobusine 18,24,285 16a-Methyltetrahydroatisine 18,24,289 16P-Methyltetrahydroatisine 18,24,290 16a-Methyltetrahydrogarryfoline 24

Subject Index 16p-Methyltetrahydrogarryfoline 18, 291 16a-Methyltetrahydroveatchine 18, 23, 292 16P-Methyltetrahydroveatchine 18, 24, 293 Mitosene 590 Mitsunobu inversion method 544 Mitsunobu reaction 447 Miyaconine 19,26,294 Miyaconitine 19, 29,40,105, 294, 295 Miyaconitinone 3, 19, 29, 40, 296 Modifiers 420, 423, 424, 426-429,437 -, basified 420^27, 437 Molecular formulas 22 Monocrotaline 419 (-)-Montanine 549 (±)-Montanine 536 Morphine 419 (±)-Mossambine 608,609 Napelline 146 l.e/7i-Napelline 19, 26, 38, 297 12.e/7i.Napelline 19, 26, 37-40, 298 Napelline Af^xide 19, 27, 39, 299 12-epi-Napelline ;^-oxidc 19, 27, 37, 300 (±)-Narwedine 510 Nicotine 419 Nitrogen dioxide 422 Nitrogen oxide 420 Nitrous oxide 420 Nominine (11-Deoxykobusine, Nomibase-1) 19, 22, 38, 41, 42, 301 Norditerpenoid alkaloids 2 Norephedrine 421, 423, 424, 426 -, yields 428 Norsongoramine 19, 23, 40, 46, 302 Norsongorine 19, 23, 40, 303 Noscapine 422 Opium alkaloids 422 Orientinine 19, 25, 40,197, 304 Ovatine 19, 27, 46, 141, 216, 218, 229, 267, 305 Oxoassoanine 487, 596 (±)-Oxolycoramine 513 Paclitaxel 419,420

629 Palmadine 19, 32, 40, 306 Palmasine 19,31,40,307 (-)-Pancracine 541, 543 (±)-Pancracine 536 (+)-Pancratistatin 466 (±)-Pancratistatin 460 Panicudine 19, 23, 41, 308 Paniculamine 19, 27, 41, 309 Paniculatine 19,33,41,163,310 Panicutine 27 Papaverine 422 Phenyliodo-6i5-trifluoroacetate 519 Physovenine 579 Pictet-Spengler cyclisation 523 Pictet-Spengler reaction 535 Plant matrix 421,427,428 Polymer supported reagents 561 Potassium ethylcyclohexane carboxylate 503 Pratosine 492,493 (db)-Pretazettine 526 Protopine 419 Pseudocopsinine 616, 617 Pseudoephedrine 420-422, 423,424, 426, 428 -, chemical conformation 429 -, extractabilities 428,429 -, yields 428 Pseudokobusine 19, 23, 40, 42,117,118, 202,203,261,311 Pseudokobusine methiodide 285 Pukeensine 4, 19, 35, 41, 312 Pyrrolizidine alkaloids 419 Retro-Mannich reaction 541 Roserine 485 Ruthenium dichloride 525 Ryosenamine 19, 30, 38, 82, 164, 313 Ryosenaminol 19, 23, 38, 198, 314 Sadosine 19,31,38,41,315 Salts 420 -, solubilities 420-423 Samarium (II) iodide 452 Sanguinorine 419 Sanyonamine 19, 22, 41, 316 SC-CO2, see Supercritical carbon dioxide Scopolamine 421, 422, 423, 424, 426, 427

630 -, extractabilities 425, 427, 428 - , solubility 425 -, yields 427 Sczukidine 19,25,41,317 Sczukinine 19, 41, 83, 318 Sczukitine 19,31,41,319 Senecionine 419 Seneciphylline 419 Septatisine (Septedinine) 2, 19, 25, 41, 320 Septedine 2, 19, 41, 321 Septenidine 19,24,322 Septenine 19, 25, 27, 41, 322, 323 Septentriosine 19, 24, 41, 324 3,3-Sigmatropic rearrangement 493 Solubilities 416,420,426-428 -, alkaloidal free bases 421-423 - , alkaloidal salts 423-426 - , salts 421-423 Solvents 418 Songoramine 19,25,37,39,40,85,325 Songorine (Bullatine-G, Napellonine, Shimoburo Base 1) 19, 25, 37-41,189, 219, 326 Songorine AT-oxide 19, 27, 37, 40, 327 Spiradine A 19, 22, 46, 47, 86, 87, 288, 328 Spiradine B 19, 22, 46, 329 Spiradine C 19, 25, 46, 330 Spiradine D 19, 23, 46, 331 Spiradine F 19, 28, 46, 332 Spiradine G 19, 25, 46, 333 Spiramine A 19, 28, 46, 144, 334 Spiramine B 19, 28, 47, 335 Spiramine C 19,25,47,336 Spiramine D 19, 25, 47, 337 Spiramine E 19, 30, 47, 338 Spiramine F 20, 28, 47,144, 339 Spiramine G 20,25,47,340 Spiramine H 20,25,47,341 Spiramine I 20, 28, 47, 342 Spiramine J 20, 26, 47, 343 Spiramine K 20, 26, 47, 344 Spiramine L 20,29,47,345 Spiramine M 20,29,47,346 Spiramine P 20,27,47,347 Spiramine Q 20, 27, 47, 348 Spiramine R 20, 29, 47, 349 Spirasine I 20, 25, 47, 350

Subject Index Spirasine II 20, 25, 47, 351 Spirasine III 20, 26, 47, 352 Spirasine IV 20, 22, 47, 353 Spirasine V 20, 25, 47, 354 Spirasine VI 20, 25, 47, 355 Spirasine VII 20, 27, 47, 356 Spirasine VIII 20, 27, 47, 357 Spirasine IX 20, 22, 47, 358 Spirasine X 20,22,47,359 Spirasine XI 20, 22, 47, 360 Spirasine XII 20, 23, 47, 361 Spirasine XIII 20, 23, 47, 362 Spirasine XIV 20, 22, 47, 363 Spirasine XV 20, 22, 47, 364 Spiredine 20,24,47,365 Staphidine 4, 20, 34, 45, 366 Staphigine 4, 20, 35, 45, 367 Staphimine 4, 20, 34, 45, 368 Staphinine 4, 20, 35, 45, 369 Staphirine 4, 20, 35, 45, 370 Staphisagnine 4, 20, 35, 45, 371 Staphisagrine 4, 20, 35, 46, 372 Staphisine 4, 20, 35, 46, 373 Stenocarpine 20, 24, 37, 43, 374 Subdesculine 20, 28, 38, 375 Supercritical carbon dioxide 416, 419-421, 422, 423, 437 Supercritical fluid chromatography 419 Supercritical fluid extraction (SFE) 416-424,425,426-428,429,430-437 - , efficiency 424,426,428 - , yields 427, 428 Supercritical fluids 416, 417, 420, 422 Supercritical nitrogen dioxide 419 Supercritical solvents 419, 420 Suzuki*s reaction 437, 440 Tacamonine 602 Tadzhaconine 20, 33, 42, 376 Talassamine 20,22,41,377 Talassimidine 20, 25, 41, 378 Talassimine 20, 25, 41, 379 Talatisine 20, 23, 41, 380 Tangirine 4, 20, 36, 41, 381 Tangutisine 20, 24, 41, 382, 384 Tatsirine 20, 23, 46,157, 383 (±)-Tazettine 529, 532 (±)-Tazettinediol 532

Subject Index 2,11,13,14-O-Tetraacetyltangutisine 21, 33,384 2,11,13,19-O-Tetraacetylvakhmatine 21, 33, 385 Tetrahydrouncinatine 21, 26, 386 Tetramethyldisiloxane 506 Thalicsessine 21,26,47,387 Thalicsiline 21,29,47,388 Thebaine 419,422 Thermal suprafacial cyclisations 506 MN'-Thiocarbonyldiimidazole 452 Torokonine (Gomando Base I) 21, 30, 41, 389 (^-Tosilimino) phenyliodinane 466 2,11,13-Tri-O-acetylhetisine 21, 3*1,391 1,12,15-0-Triacetxlluciculine 21, 32, 390 1,2,19-Tri-O-acetylseptentriosine 21, 31, 392 2,3,13-O-Triacetylvakhmadine 21, 31, 40, 393 2,11,13-O-Triacetylvakhmatine 21,31, 394 (4-)-Trianthine 506 Trifluoromethane 420,422 (±)-ci5-Trikcntrin 580, 582 (±)-ci5-Trikentrin A 581 (±)-rm/i5-Trikcntrin A 582 2,4,5-Trimethoxybenzaldehyde 490 Trimethylsilylazide 561 /r/5-Triinethylsilylhydride 561 Trisphaeridine 440 Tropane alkaloids 427 TTF (tetrathiafulvalenc) 591

631 Turpelline 21,26,42,395 Ullmann reaction 480 Uncinatine 21,26,46,386,396 Ungeremine 482, 595 Vakhmadine 21.26,40,397 Vakhmatine 21, 24, 40, 385, 394, 398 Vakognavine 2, 21, 35, 40, 399 Vasconine 480, 596 Veatchine 21, 24. 46, 141, 190, 220, 287, 292, 293, 400. 401 Veatchinc-^,20-azomethine 21, 22, 221, 401 Venudelphine 21,31,46,402 Venulol 21,22,46,199,403 Venuluson 21, 23, 46, 200. 404 15-Veratroylpseudokobusine 21, 32, 42, 405 Vilmorrianone 21, 28, 42, 44, 406 Vincadifformines 593, 594 Vinyl isocyanates 476 Vinylsilanes 517 Wittig olefination 513, 520 Yesodine 21, 29, 42, 407 Yesoline 21, 32, 42, 408 Yesonine 21,24,42,409 Yesoxinc 21, 30, 37, 42, 410 Yohimbane 605 Zeraconinc 4, 21, 30, 42, 411 Zeraconine A^-oxide 4, 21, 31, 42, 412 Zeravshanisine 21, 32, 42, 413

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633

Organism Index

Aconitella stenocarpa 37, 374 Aconitum 2,41,258,315 A. alboviolaceum 37, 96 A. anglicum 37, 53, 57, 124, 325 A, baicalense 37, 298, 300 A, barhatum 37, 58, 'ilS-Zll A. bullatifolium van homotorichum 37, 236, 238, 239 A, carmichaeli 37, 130, 258, 326 A, contortum 37, 131-133, 223 A, coreanum 134, 135 A. crassicaule 37, 138 A, czekanouskyi 37, 281, 298, 300 A. delphinifolium 37, 70, 204, 235, 410 A, episcopale 37, 143, 223 A.finetianum 38,224,301 A.flauum 38, 162, 226, 227, 281, 283, 297, 298 A, gigas 38, 107 A, gymnandrum 110 A, heterophylloides 38, 107, 242 A, heterophyllum 38, 106, 107, 210, 243, 244, 246, 262 A, ibukiense 38, 255, 258, 313, 314 AJaponicum 38, 76, 195, 258, 268, 273, 315, 326, 375 var. montanum 38, 260, 273 A, jinyangense 38, 173,270 A, kamkolicum 39, 80, 81, 88, 219, 281, 298, 299. 325, 326 A. fdrinense 39, 271, 272 A, kojimae var. lassiocarpum 39,275 A. komamvii 39, 239, 240 A. koreamm 39, 89, 236-240, 262 A. kmnezoffii 39, 173, 277 A. leucostomum 39, 77, 93, 179, 277, 326 A, liangshanium 39, 160, 161, 278, 279, 282, 298

lucidusculum 39, 283 lycoctonum 39, 321 majimaii 40, 268 miyabei 40, 295, 296 monticola 40, 175, 302, 303, 325-327 A. nagarum var. lasiandrum 40, 325, 326 A. napellus 40, 53, 57, 124, 161, 281, 298, 325 ssp. castellanum 40, 62, 161, 325 A. nasatum 40, 311 A, orientate 40, 90, 304 A, palmatum 40, 107, 145, 243, 244, 262, 306, 307, 393, 397-399 A, paniculatum 40, 242, 308-310 A. pseudohuiliense 41,110, 276, 277 A.pukeense 41, 312 A. sanyoense 41, 241, 256, 258, 301, 316 var. tonense 41, 241, 316 i4. sczukinii 41, 317-319 A. septentrionale 41, 84, 320, 321, 323, 324 A. soongaricum 41, 326 A, subcmeatum 41, 235, 389 A. talassicum 41, 273, 377-380 A. tanguticum 41, 381, 382 i4. turczaninowii 41, 395 A. uilmorrianum 42, 406 A. yesoense 42, 78, 79, 281 var. macroyesoense 42, 61, 78, 79, 119, 147, 159, 162,226,273,283, 311,405,407-410 A, zemvschanicum 42, 91, 107, 262, 281,301,376,411-413 Amaryllidaceae 420, 595 Anoptems glandulosus 42, 102, 104, 114, 178, 222, 248, 249 A. A. A, A, A,

Organism Index

634 A. macleayanus 42, 100-104, 114, 178,222,248-251 Areca 418 Atropa 418 Brachycaudus aconiti 42, 161, 298 Catharanthus 418 Cephalotaxus wilsoniana 429, 447 Cocculus laurifolius 43, 228 Colchicum 418 Conium 418 Consolida 2 C. ambigua 43, 94, 209 C axiUiflom 43, 94. 244 C glandulosa 43,64,65,69,187,234 C hellespontica 43, 111, 129 C stenocarpa 43, 374 Crinum pratense 595 Crotalaria spectabilis 419 Delphinium 2 D. ajacis 43, 94, 209 D. albiflorum 43, 143 Z). andersonii 43, 97 Z). axilliflorum 43. 94. 244 D. ^ar^cyi 43. 112, 113, 166, 231 D. brunonianum 44, 94, 120, 204 D. cardinale 246 D. cardiopetalum 44, 52, 53, 73, 121-128, 136.246 Z>. carolinianum 44, 94 D. coreanum 110 D. corumbosum 44, 204 Z). cossnianum 44, 136, 137 D. delavayi var. pogonanthum 44, 94, 244, 246 D. demdatum 44. 169, 173. 246,406 D. dictyocarpum 44. 204. 206 D. Wa/wm 44, 94, 165 D.fissum ssp. anatolicum 44,167,225 Z). geveri 45,231-233 D. glandulosum 45, 64, 65, 69, 187, 234 D. gracile 45, 52, 73, 110, 123, 124, 246 D. grandiflonm 45, 63. 168 D. hellespontica 111 D. macrocentrum 45. 72. 284

D. nudicaule 45, 244, 246 D. nuttalianum 45, 72, 170-172, 244 D. occidentale 45, 166, 175,244,246 D. peregrinum var. elongatum 45. 73 D. staphisagria 4, 45, 366-373 D. tamarae 46. 302 D. tatsienense 46. 94. 204. 244. 246. 383 D. tomentosum 111 D. uncinatum 46, 396 D, venulosum 46, 244, 402-404 D. uerdunense 46, 73 D. uirescens 46 Ephedra 418 E. 5/mca 428 Erythrina lithosperma 575 Eschscholtzia californica 419 Garrya 2 G. laurifolia 46. 139. 228, 265, 267 G. ovata var. lindheimeri 46, 139, 228, 280, 305 G, ueatchii 46, 230, 400 Gelsemium sempervirens 584 Zffw/a 2

Ipecacuanha 418 Lycotonum gigas 46, 107 Nicotiana 418 Af. tabacum 419 0/7ifim 418 Papauer somniferum 419 Pseudomonas putida 447 Rauuolfia 418 Scopolia japonica 427, 428 Senecio 419 5. cordatus 419 5^. inaequidens 419 Spiraea 2 S. japonica 46, 328-333 var. acuminata 46, 334-346

Organism Index

635

y&r, fortune! 47, 328, 334-337, 350-365 var. incisa 47, 347-349 Streptomyces sandansis 590 S. zelensis 586 Streptouerticillium ehimense 582

T cuspidata 419, 420 Thalictrum 2 T. sessile 47, 328, 350-352, 365. 387, 388 Thkentrion flabelliforme 5 80

Taxus hreuifolia 419

Vinca erecta 616

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