Aliphatic & Related Natural Product Chemistry (v. 1)

A Specialist Periodical Report ~~ ~~ Aliphatic and Related Natural Product Chemistry Volume 1 A Review of the Litera...

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A Specialist Periodical Report ~~

~~

Aliphatic and Related Natural Product Chemistry Volume 1

A Review of the Literature Published during 1976 and 1977 Senior Reporter F.D. Gunstone, Department of Chemistry, University of St. Andrews Reporters R. A. Baker, University of Southampton D. A. Evans, University of Southampton D. H. Grayson, Trinity College, Dublin R. C. F. Jones, University of Nottingham A. K. Lough, Rowett Research Station, Bucksburn, Aberdeen P. R. Marsham, ICl Pharmaceuticals Division, Macclesfield, Cheshire R. E. Moore, University of Hawaii at Manoa, Hawaii V. Thaller, University of Oxford

The Chemical Society Burlington House, London W I V OBN

British Library Cataloguing in Publication Data Aliphatic and related natural product chemistry. (Chemical Society. Specialist periodical reports). VOl. 1 1. Natural Products I. Gunstone, Frank Denby 11. Series 547' .7QD415 ISBN 0-85186-642 5 ISSN 0142-7318

Copyright 0 1979 The Chemical Society

All Rights Reserved No part of this book may be reproduced or transmitted in any form or b y any means - graphic, electronic, including photocopying, recording, taping or information storage and retrieval systems - without written permission from m e Chemical Society

Printed in Great Britain by Henry Ling Ltd., at the Dorset Press, Dorchester, Dorset.

Foreword The Tertiary Publications Committee of the Chemical Society decided that after the appearance of Volume 5 the Specialist Periodical Report ‘Aliphatic Chemistry’ should be replaced by two new titles: ‘General and Synthetic Methods’ and ‘Aliphatic and Related Natural Product Chemistry’. This latter will be produced biennially and this represents the first volume in this series. The Reporters have been asked t o cover the years 1976 and 1977 and to emphasise those areas of natural product chemistry which relate t o aliphatic compounds o r to molecules with an important aliphatic or alicyclic component. The division of material is based partly on structural criteria and, in part, on the question of occurrence. These considerations have led to a work of eight chapters covering: natural acetylenic and olefinic compounds (V. Thaller), marine aliphatic natural products (R. E. Moore), acyclic terpenoids (D. H. Grayson), insect pheromones (R. A. Baker and D. A. Evans), olefinic microbial metabolites including macrocyclic compounds (R. C. F. Jones), prostaglandins (P. R. Marsham), fatty acids (F. D. Gunstone), and lipids (A. K. Lough). I thank the Reporters who, in response to my bullying, produced their contributions so promptly. Most of them have agreed to contribute to the second volume covering the years 1978 and 1979. June 1978

F. D. Gunstone

Contents

Natural Acetylenic and Olefinic Compounds excluding Marine Natural Products By V. Thaller

Chapter 1

1

1 Introduction and Scope of the Chapter

1

2 Natural Acetylenic Compounds

1 1

Introduction New Polyacetylenes from Plants Known Polyacetylenes from Plants Polyacetylenes from Fungi Non-Poly acetylenic Acetylenes Synthesis of Polyacetylenes Bio sy nt hesis Physiological Aspects of Polyacetylenes

3 Natural Olefinic Compounds Introduction New and Known Olefins Mixed Olefins Synthesis Biosy nt hesis Chapter 2

Marine Aliphatic Natural Products By R. E. Moore

2 9 10 11 13

14 15 16 16 16 17 18 19

20

1 Introduction

20

2 Non-isoprenoidalCompounds

21

3 Isoprenoidal Compounds Monoterpenes Sesquiterpenes Diterpenes Sesterterpenes Triterpenes and Steroids Carotenoids

32 32 37 41 55 58

V

65

vi

Chapter 3

A liph a tic and R ela t ed Na t u ral Product Che m is try

Acyclic Terpenoids By D. H. Grayson 1 Introduction

68

2 Isoprene Chemistry

68

3 Lavandulyl, Artemisyl, Santolinyl, and Chrysanthemyl Derivatives

70

4 2,6-Dimethyloctane Group

Ocimenes Myrcene Derivatives Cit ronelly 1 Derivatives Citral Linalyl Compounds Geranyl and Neryl Derivatives

74 74 74 77 80

81 84

5 Farnesyl and Nerolidyl Derivatives

93

6 Phytol

97

7 The Squalene Group

98 101

8 Polypeptides

Chapter 4

68

Insect Pheromones and Related Behaviourmodifying Chemicals By R. Baker and D. A. Evans

102

1 Introduction and Scope of Coverage

102

2 Pheromones Sex Pheromones of Lepidoptera Attractants for Lepidoptera 0ther Responses of Lep id opte ra Pheromones of Diptera Sex Pheromones of Coleoptera Other Pheromone Responses Pheromones of Social Insects and Related Species

102 102 106 106 109 109 110 112

3 Defence Chemistry of Insects

113

4 Plant-Insect

115

Interactions

5 Separation and Structure Elucidation Techniques

115

Contents

Vii

6 Synthetic Studies Mono-unsaturated Derivatives Di-unsaturated Derivatives Tri-unsaturated Derivatives Ketonic Derivatives Alcohols and Acetates Enantiomer Specific Synthesis

116 116 119 122 124 125 126

Chapter 5 Olefinic Microbial Metabolites including Macrocyclic Compounds By R. C.F. Jones

128

1 Non-macrocyclic Olefinic Microbial Metabolites

Pyran-Pyranoid Compounds But enolid e Metabolite s Pulvinones Miscellaneous N-Het erocy clic Compounds Pyrrolidines and Pyrroles Piperidines and Pyridines Other N-heterocycles Other N-containing Metabolites Miscellaneous Olefinic Microbial Metabolites Cyclopentene Metabolites Cy clohe xene Metabolites

2 Macrocyclic Olefinic Microbial Metabolites Macrocyclic Lactones: General and Synthetic Aspects Polyoxo Macrolides Picromy cin Platenomycins Leucomycins Carbomy cins Maridomy cin s Tylosin Juvenimicins Polyene Macrolides Tet r aene s Pentaenes Hep taenes Roridins and Verrucarins Vermicoline and Pyrenophorin Brefeldins Miscellaneous Macrocyclic Lactones Cytochalasans and Chaetoglobosins

128 128 132 134 136 136 136 137 139 140 143

145 146 147 147 150 15 1 15 1 15 1 152 152 153 154

155 155 156 156 156

158 160 161 162

...

Aliphatic and Related Natural Product Chemistry

Vlll

Chapter 6

The Ansamycins Rif amy cin s Halomy cins Strep t ovaricins Geldanamycins Other Macrocyclic Metabolites

165 165 165 166 167 168

Chemistry of the Prostaglandins By P. R. Marsham

170

1 Introduction

170

2 Synthesis of the Primary Prostaglandins Corey’s Bicyclo [ 2,2,1] heptane Route Modifications and New Routes to Intermediates The Bicyclo [ 3 , l , O ] hexane Route Mod if ications Routes via Conjugate Addition t o Cyclopentenones New Syntheses of Intermediates Miscellaneous Syntheses New Routes to Intermediates

170 17 1 17 1 175 175 177 177 180 180

3 Synthesis of Prostaglandin A2

18 1

4 Synthesis of 19 ( R ) -19-Hydroxy-prostaglandins

183

5 Synthesis of Prostaglandin I2 and its Analogues

183

6 Synthesis of Thromboxane B2

187

7 Synthesis of Modified Prostaglandins Deoxy-prostaglandins 9 -Deoxy -pro st aglandins 1 1-Deoxy-prostaglandins 9 , l l -Bisdeoxy-prostaglandins 15-De oxy-prost aglandins 1 1,15-Bisdeoxy-prostaglandins Cyclopentane Ring Variants Aza-prostaglandins Thia-pro staglandins Cyclohexane Ring Analogues Cyclobutane Ring Analogues Mercapto-prostaglandins Methyl-prostaglandins Hydroxymethy 1-prostaglandins Benzo-prost aglandins

190 190 190 190 194 194 197 198 198 202 203 203 204 206 208 210

ix

Conten ts

Upper Side-chain Variants Lower Side-chain Variants A Bicyclic Prostaglandin Epi-prostaglandins Fluorinated Prostaglandins Ace ty lenic Prostaglandins Simple Prostanoic Acid Analogues Endoperoxide Analogues Seco-prost aglandins Radiolabelled Prostaglandins

2 10 212 215 215 2 17 2 17 2 18 219 222 223

8 Prostaglandins in Cord

224

9 Prostaglandin E, Derivatives

224

10 Metabolism of Prostaglandins Natural Prostaglandins Modified Prostaglandins Thromboxane B2

225 225 226 227

1 1 Biosynthesis and Biochemistry of Prostaglandins

228

12 Conformational Analysis of Prostaglandins

233

13 Determination of Prostaglandins

233

Chapter 7

Fatty Acids By F. D. Gunstone

236

1 Introduction

236

2 Natural Acids Unsaturated Acids Branched-chain and Cyclic Acids Oxygenated Acids

236 236 2 37 2 38

3 Synthetic Compounds General Procedures Synthetic Acids Furanoid Acids Lactones

240 240 241 243 244

4 Physical Properties Gas Chromatography Thin Layer Chromatography

2 45 2 45 246


X

High Performance Liquid Chromatography Nuclear Magnetic Resonance Spectroscopy Mass Spectrometry Raman Spectroscopy Crystal Structure and Polymorphism Other Physical Properties 5 Chemical Reactions

Hydroperoxide Formation and Structure Secondary Reactions of Hydroperoxides Other Oxidation Reactions Double Bond Stereomutation and Migration Other Reactions

Chapter 8

247 2 47 247 2 48 2 48 249 249 249 252 254 255 256

6 Biological Reactions de novo Synthesis Elongation Desaturation Metabolism of Selected Acids

258 258 259 259 260

7 Books and Reviews

2 62

Lipids By A, K. Lough

263

1 Introduction

263

2 Occurrence and Identification of Lipids Animal Lipids Plant Lipids Bacterial Lipids Fungal Lipids Marine Lipids

263 263 264 265 '2 69 27 0

3 Chemical Synthesis Glycerol Esters Glycosidic Lipids Alkyl and Alkenyl Thioethers of Glycerol Phosphatidic Acid and Analogues Phosp hatidylcholines and Analogues Phosphatidylethanolamine and its Derivatives Phosphatidylserines and Analogues Phosphatidyl Inositols Phosphatidylgly cerol and Analogues

270 270 272 274 275 277 280 28 1 282 283

xi

Con ten ts

4 Physical Properties of Lipids Mass Spectrometry Electron Diffraction X-ray Diffraction Relaxation Studies Chirality and Pro-chirality in Lipids Lipid Meso-phases Lipids in Organic Solution Hydration of Phospholipids

285 285 287 287 288 288 289 289 290

5 Aspects of Lipid Chemistry Autoxidation Studies Hydrolysis of Sphingolipids Analysis of Long-chain Diols and Related Compounds Chemical Approach t o Lipid-Protein Interactions

29 1 291 291 292 292

Author Index

293

1 Natural Acetylenic and Olefinic Compounds excluding Marine Natural Products BY V. THALLER

1 Introduction and Scope of the Chapter

This Report covers developments in the chemistry of natural acetylenes and olefins during 1976-7 and can be regarded as part-successor t o G. Pattenden’s Chapters 3 in the Specialist Periodical Reports on Aliphatic Chemistry Volumes 2-5 for the years 1972-5. Whilst the scope of the acetylene part is reduced only by the omission of the relevant marine products, most of the olefin part is covered now by other chapters of this volume. The material discussed has been collected for ease of orientation under several sub-headings, although this sometimes leads to repetition of references and double citations.

2 Natural Acetylenic Compounds Introduction.-The very rapid expansion which has occurred in this field since the early fifties (7 compounds were known in 1950, over 700 are known today) has slowed down considerably. By far the greatest number of natural acetylenes belongs to the group of secondary metabolites known as natural polyacetylenes. They have been shown to originate in Nature from CI8 fatty acids by pathways which include a combination of desaturation, chain shortening, oxidation, rearrangement, cyclization, and other funtionalization processes. The many imaginable permutations have certainly not been exhausted, but their detection and isolation are more sporadic. Although the general principles of polyacetylene biogenesis are thought to be understood, many details still wait t o be confirmed, not least the biogenesis of the triple bond itself. The reason for polyacetylene formation, their role and fate in the economy of the plants, higher and lower, which produce them, still needs elucidation. Bohlmann, who with his co-workers contributed more than any other single group to the development of the natural acetylene field, always conscious of the chemotaxonomic implications of his work, has moved even further in this direction. He is now involved in a more general analysis of the secondary metabolites of species, mostly Compositae, the classification of which leaves open some doubts and investigates the contribution chemotaxonomy can make t o their reclassification. Thus Bohlmann’s long polyacetylene series increased during the two years under review by only eight publications (parts 237-244), but some information on polyacetylenes appears continuously in his series on natural terpenes, coumarins, etc. 1

2


The book on ‘Naturally Occurring Acetylenes’’ forms an invaluable basis for the study of this field. Pattenden’s reports have been keeping it up-todate, and this Report continues this trend.

New Polyacetylenes from Plants.-With the exception of the Anonaceae species and some Korean Umbelliferae species, which were screened for polyacetylenes, all plants investigated belong to various tribes of the Compositae family. The has been reported2 isolation of the sixteen Czl diynes and diynenes (1)-(4) from the roots and, to a lesser extent, the bark of the tree Alphonsea ventricosa Hook F. and Th. (Anonaceae family), a native of Assam. The discovery of CZl polyacetylenes, the longest polyacetylene chain found thus far in Nature, in the Anonaceae species has already been m e n t i ~ n e d ,but ~ details of the structures were not available. These consist of all possible permutations of four distal C6 fragments (R’) and four proximal oxygenated C4 fragments (R’) around a central Cl1 diyne. The root extract was readily separated into the four groups (la-d), (2a-d), (3a-d), and (4a-d), and of these only the first could be

(2) R2 = J(J/OA.

(3) R2 = K

O

H

OH OH (4)

R2 = &OH

further separated into (la,b) and (lc,d). ’H n.m.r., aided by shift reagents, and low and high resolution mass spectra indicated structures for the metabolites present in each group. A series of chemical transformations which were carried out on the mixtures enabled the separation and identification of the four distal F. Bohlmann, T. Burkhardt, and C. Zdero, ‘Naturally Occurring Acetylenes’, Academic Press, London and New York, 1973. K. W.Gopinath, P. K. Mahanta, F. Bohlmann, and C. Zdero, Tetrahedron, 1976,32, 737. c$ Ref. 1, p. 338.

Natural Acetylenic and Olefinic Compounds

3

C6 fragments, and interconversions of the mixtures established their relationships firmly. Pathways for the formation of these polyacetylenes have been proposed: the preferred one is a C18 + C3 + Czl chain elongation involving the condensation of the known (Santalaceae and Olacaceae) CI8 acids (Sa-d) with pyruvate. The analogy in the structure of the oxygenated proximal part of the CZl metabolites with those of the C17 metabolites from Persea gratissima seeds, the Lauraceae and Anonaceae being relatively closely related, stimulated the authors to speculate about a similar C14 + C3 pathway for the C17 compounds.

A

=

=

OR

(7) R = H (8) R = Ac

OR

A

=

= (9) R = H

(10) R = Ac

A

=

= OR (11) R = H (12) R = Ac

OR (13) R = H (14) R = Ac

The presence of thirty nine CI3-C17 polyacetylenes was established4 in the roots and green parts of eight representatives of the genus Dahlia. All contained varying amounts of polyacetylenes, but only the C I 3 hydrocarbon (6) was found to be present in all eight of them. The new CI6 alcohol (7) and its acetate (8) were isolated from D. scapigera (A. Dietr.) Link and Otto var. scapigera f . scapigera; the alcohol was synthesized. The new CI3 diol (9) and its diacetate ( l o ) , the C14 diol (1 1) and the diacetate (12), and the C17 alcohol (13) and the corresponding acetate (14) were isolated from the garden varieties. The spectra C. T. Bedford, D. Bhattacharjee, J. R. F. Fairbrother, Sir Ewart R. H. Jones, S. Safe, and V. Thaller, J.C.S. Perkin I , 1976, 735.

4


of the metabolites and simple transformation products established their structures. The alcohol (1 3) was synthesized. Two more benzenoid polyacetylenes have been isolated from Artemisia capillaris T h ~ n b Norcapillen .~ ( 15) was found to represent 0.1 76 of its essential oil and neocapillen (1 6 ) was identified as a minor component in the root extract. Spectral analysis, hydrogenation, and synthesis were used in both instances.

Known polyacetylenes were isolated from A . monosperma (from Israel)6 and A . dracunculus L. (seeds from Tashkent).' In the roots of the latter, the acetylenic isocoumarin ( 17) isolated from other A . dracunculus specimens gave place t o the olefin ( 1 8), an occurrence which might be of biogenetic interest.

A few of Bohlmann's publications appear to represent the rounding off of his intensive investigation of South African Compositae. Thus, amongst several known thiophene acetylenes, the new thiophene diol (19) was isolated from Platicarpa glomerata:' its structure followed from spectral data obtained from

the metabolite and its MnOZ-oxidation product. The majority of species Bohlmann has analysed recently seem, however, t o originate in the Americas. Several new thiophene acetylenes (terthienyls are included on biogenetic grounds) were found here too and identified by spectral methods. The roots and greenery of the Mexican Compositae Dyssodia anthemidifolia Benth.' M. Miyazawa and H. Kameoka, Phytochernistry, 1976, 15, 223, 1987. F. Bohlmann and D. Ehlers, Phytochernistry, 1977, 16, 1450. ' H. Greger, F. Bohlmann, and C. Zdero, Phytochernistry, 1977, 16, 795. F. Bohlmann and C. Zdero, Phytochernistry, 1977, 16, 1832. F. Bohlmann and C. Zdero, Chern. Ber., 1976, 109,901.


5

(20)

(21)

OAc

OAc

contained the terthienyls (20) and (21), the latter being obtained pure for the first time, and the green parts of D. setifolia (Lag,) Rob.g yielded the dithienyl acetylenes (22), (23), (24), and (25). The roots of D. acerosa" contained in addition to several known thiophenes, the new dithienyl diyne ( 2 6 ) whilst D. papposa (Vent.) Hitchc. yielded only known polyacetylenes. A score of known thiophenes were also isolated from the roots of Haploestes gregii var. texana" amongst them the two new metabolites (27) and (28), the former already known synthetically.

New polyacetylenic sulphoxides and sulphones have also been isolated and are always accompanied in the plants by many known polyacetylenes. From the roots of the Texan Baileya multiradiata Ham. et Gray." the sulphoxide (29) was isolated. Very little of the natural product was available and its stereochemistry was established by synthesizing the cis- and trans-isomers from the known sulphides. The greenery of the Mexican species Coreopsis parvifolia Blake (Sekt. lo

l1

F. Bohlmann, C. Zdero, and M . Grenz, Phytochemistry, 1976, 15, 1309. F. Bohlmann and C. Zdero, Chem. Ber., 1976, 109, 1964.

6


EZectra)12 contained the isomeric sulphoxides ( 3 0 ) and (31) and the sulphone (32). The latter is now known t o occur along with the cis-isomer in the roots of Helenium tenuifolium Nutt.

H

- - - I - - _ - SOde I - - CI7 polyacetylenes, amongst them dehydrofalcarinone and the new aldehyde (33) were isolated from the roots of the Mexican Heliantheae species Calea integrifolia Hemsl.13 In addition to'spectral identification, the new metabolite gave, on NaBH4 reduction, the corresponding known C1, alcohol.

(33) n = 4 (34) n = 5 (35) n = 3

A mixture of the related aldehydes (34) and (35) was isolated from the roots of the South African species Senecio deltoides Less.,14 the structures being assigned from spectral data. The analysis of further Senecio species established the presence of a considerable number of known polyacetylenes in many of the 12

l3

14

F. Bohlmann and C. Zdero, Chem. Ber., 1977, 1 1 0 , 468. F. Bohlmann and C. Zdero, Phytochemistry, 1976, 15, 1177. F. Bohlmann, C. Zdero, and M. Grenz, Chem. Ber., 1977, 1 1 0 , 474.


7

species investigated.” The green parts of S. chrysanthemoides D.C.” contained the new acetylenic angelicate (36), identified by its spectra and by transesterification t o methyl angelicate.

From the roots of the Compositae Jungia spectabilis D. Don.,16 a native of Ecuador, the new C15 polyacetylenes (37) and (38) were isolated and identified by their spectra. They represent the first Compositae polyacetylenes in which the terminal -CH=CH2, originally the proximal half of the CI8-precursors, is absent , presumably hydrogenated.

The Cynereae (Compositae) species Serratula wolfii Andrae was found17 t o contain a series of known CI3-C1, polyacetylenes and the two pairs of new epimeric C15 polyacetylenes (39) and (40). The structures were established spectroscopically, primarily by the 270 MHz ‘H n.m.r. spectra, and confirmed by the synthesis of the methyl ethers of the pair (40).

lS

l6 l7

F. Bohlmann, K. H. Knoll, C. Zdero, P. K. Mahanta, M. Grenz, A. Suwita, D. Ehlers, N. Le Vani W. R. Abraham, and A. A. Natu, Phytochemistry, 1977, 16, 965; F. Bohlmann, A. Suwita, and P. Mahanta, Chem. Ber., 1976, 109, 3570. F. Bohlrnann and C. Zdero, Phytochemistry, 1977, 16, 239. F. Bohlmann and H. Czerson, Chem. Ber., 1976, 109, 2291.

8


The stereochemistry of the new natural product (41) from Solidago altissima L. was established" by spectral comparison with the two synthetic 2-methylbut-2enoates. Atractylodinol (42) and its acetate (43) have been isolated in addition to atractylodin from A tractylodes Zancea de Condolle var. Chinensis Kitamura;" the structures were elucidated by spectroscopy and chemical transformations. Both were piscicidal.

OR (42) R = H (43) R = Ac

Wyerone epoxide (44) has been isolated2' and shown t o be the third component of the multiple phytoalexin response of the broad bean, Vicia faba L., t o fungal (Botrytis) infection. Its structure was confirmed by comparison with the synthetic epoxide obtained from wyerone and rn-chloroperbenzoic acid,

The C I 3 enetriynediene from Carthamus tinctorius L. has been shown t o exist in Nature as a mixture of the isomers (45) and (46) in a 83 : 17 ratio which is photoisomerized t o an equilibrium mixture of 37 : 63. The two isomers have A. Kobayashi, S. Konya, and K. Yamashita, Agric. Biol. Chem., 1976,40,2 2 5 7 (Chem. A h . , 1977,86, 089 126). l9 Y. Nishikawa, 1. Yasuda, Y. Watanabe, and T. Seto, Yakugaku Zasshi. 1976, 96, 1322. (Chem. A b s , 1977,86, 052 671) 20 J. A. Hargreaves, J . W. Mansfield, D. T. Coxon, and K. R. Price, Phytochemistry, 1976, 1 5 , 1 1 19. l8


9

now been prepared pure ('H n.m.r.) by high pressure liquid chromatography o n reversed phase.21 The hydrocarbon mixture is strongly nematocidal (for the test Apheleuchoides besseyi was used). Known Polyacetylenes from Plants.-As mentioned above, known polyacetylenes have been regularly detected along with new ones. In many species analysed for the first time only the presence of known polyacetylenes has been observed. As the allocation of several of these species t o genera and tribes appears to be in doubt, the polyacetylene containing species themselves are, with few exceptions, listed alphabetically; formulae and names of the polyacetylenes which have been detected have on the whole been omitted. Species already quoted in the section dealing with new polyacetylenes have not been cited again. Known polyacetylenes have been found in the following Compositae species: Ageratina exertovenosa (Klatt) King et Rob.22 and A . glabrata (HBK) King et Rob.;= Ambrosia cumanensis;% Arctotis aspera L., A . repens Jacq., and A . revoluta J a ~ q . ; ~Ayapana ' ecuadorensis King et Rob.;26 Berkheya radula (Harv.) De Willd., B. bipinnatifida (Harv.) Roessler, and B. rhapontica (DC) Hutch. et Burtt Davy ssp. platyptera (Harv.) R o e s ~ l e r(all ~ ~ Berkheya species contained thiophene acetylenes); Calea zacatechichi Schlecht. and C. scabra (Lag,) B. L. Robinson;28 Callilepis laureola DC.?' Centaurea s ~ a b i o s a(Centaurea ~~ species are ingenious polyacetylene producers; in the species discussed 25 polyacety~ ~D. aurantiaca lenes have been found); Dimorphotheca pluvialis M ~ e n c h .and H ~ r t . ;Elephantopus ~~ mollis HBK.;33 Erlangea rogersii S . Moore;M Felicia uliginosa (Wood et Evans) Gray ;7' Flourensia resinosa Blake and F. cernua DC.;36 Gymura ~ r e p i o i d e s ;Gynoxys ~~ sancto antonii H i e r ~ n ;Hebeclinum ~~ macrophyllum ( L . ) DC.;22 Heterotheca inuloides C a ~ s . Hymenopappus ;~~ scabiosaeus var. corymbosus;" h u l a viscosa AiLM (on an earlier investigation, the polyacetylene presence was not detected); Isocarpha oppositifolia (L.) R.B.?' the Liaburn group from Ecuador42 (all contain phenylheptatriyne which was found S. Kogiso, K. Wada, and K. Munakata, Agric. Biol. Chem., 1976, 40, 2085; Tetrahedron Letters, 1976, 109. 2 2 F. Bohlmann and M. Grenz, Chem. Ber., 1977, 110, 1321. 23 F. Bohlmann, J. Jakupovic, and M. Lonitz, Chem. Ber., 1977, 110, 301. 24 F. Bohlmann, C. Zdero, and M. Lonitz, Phytochemistry, 1977, 16, 575. 25 F. Bohlmann and N. Le Van, Phytochemistry, 1977, 16,487. 26 F. Bohlmann, C. Zdero, and M. Grenz, Chem. Ber., 1977, 110, 1034. 27 F. Bohlmann, N. Le Van, and J . Pickardt, Chem. Ber., 1977, 110, 3777. 28 F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 1065. 29 F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 1854. 30 A. B. Andersen, J . Lam, and P. Wrang, Phytochemistry, 1977, 16, 1829. 31 1;. Bohlmann and N. Le Van, Chem. Ber., 1976, 109, 1447. 32 F. Bohlmann, C. Zdero, and P. Mahanta, Phytochemistry, 1977, 16, 1073. 33 F. Bohlmann and C. Zdero, Chem. Ber., 1976, 109, 3956. 34 F. Bohlmann and C. Zdero, Chem. Ber., 1977, 110, 1755. 3 5 F. Bohlmann and C. Zdero, Phytochemistry, 1976, 15, 1318. 36 F. Bohlmann and M. Grenz, Chem. Ber., 1977, 110,295. 37 F. Bohlmann and c'. Zdero, Phytochemistry, 1977, 16,494. 38 F. Bohlmann, M. Grenz, and A. Suwita, Phytochemistry, 1977, 16, 774. 3 9 F. Bohlmann and C. Zdero, Chem. Ber., 1976, 109, 2021. 40 F. Bohlmann, H. Czerson, and S. Schoneweiss, Chem. Ber., 1977, 110, 1330. 41 I;. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochernistry, 1977, 16, 768. 4 2 F. Bohlmann, M . Grenz, and C. Zdero, Phytochemistry, 1977, 16, 285. 21

10


hitherto only in the Heliantheae); Ligularia hodgsoni Hook. f., L. brachyphylla Hand. Mazz., L. dentata (A. Gray) Hara, L. veitchiana Greenm., and L. japonica DC.;43 Macowania glandulosa N.E. Br. and M . cf. hamata;44 Melampodium Mutisia coccinea A. St. HiIl.;l6 Parthenium perfoliatum (Cam.) A. Gray:’ hysterophorus;= Perymenium equadoricum Blaket6 Picradeniopsis woodhousei Gray;” Pluchea odorata Cass. Podachaenium ern in en^;^' Polymnia fructicosa Benth. and P. pyramidelis Triana:9 Schistocarpha bicolor Less.;” Schkuhria ~ dombeyana DC.?l senecioides Ness. and S. pinnata (Lam.) K ~ n t z e ; ’Simsia Stevia serrata Cav. and S. ovata Willd.;52 Tanacetum tanacetioides (DC) T ~ v e l . ; ~ ~ Tessaria absinthioides (H. et A.) Cabr.;53 Verbesina angustifolia (Benth.), V. greenmanii Urb., and V. oncophora Rob. et Seat.;% twenty Vernonia species all contain very small amounts of tridecapentaynene;” Viguiera ~ t e n o l o b a ; ~ ~ Wedelia trilobata (L.) Hitch. and W. grandiflora Benth.56 Several papers concerned with the screening of Korean plants for polyacetylenes appeared in Korean journals. Although only one author is common to all publications, one paper” appears to cover all the species screened and found to contain polyacetylenes. They were detected in the Compositae Aster scaber and Chrysanthemum sibirzcum and the Umbelliferae Angelica decursiva and A . koreana, Heracleum moellendorfii, Peucedanum japonicum, Phellopterus littoralis, and Pleurospermum kamtschaticum. Korean workers also founds8 that fresh Ginseng extracts contained only two polyacetylenes but that their number increased on standing indicating the formation of polyacetylenic artefacts.

e7

Polyacetylenes from Fungi.-The new C8 hydroxy acid (47)has been isolated together with known polyacetylenes from cultures of the fungus Camarophyllus virgineus (Wulfen ex Fr.) K ~ m r n e r , ’This ~ belongs t o the Hygrophoraceae, a fungal family not previously reported as a polyacetylene producer. The isolation of five CZ2 diacetylenes from the sponge Reniera fulva, collected in the Bay of Naples, has been reported.60 Marine products are dealt with in Chapter 2 of this volume, but the question of chirality allocated to the marine 43 44

45 46

47 48

49 51

’*

s3 54

56 57

58

59

F. Bohlmann, D. Ehlers, C. Zdero, and M. Grenz, Chem. Ber., 1977, 110, 2640.

F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 1583. F. Bohlmann and C. Zdero, Chem. Ber., 1976, 109, 1670. F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 786. F. Bohlmann and C. Zdero, Phytochemistry, 1976, 109, 2653. F. Bohlmann and N. Le Van, Phytochernistry, 1977, 16, 1304. F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 492. F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 780. F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 776. F. Bohlmann, A. Suwita, A. A. Natu, H. Czerson, and A. Suwita, Chem. Ber., 1977, 110, 3572. F. Bohlmann, C. Zdero, and M. Silva, Phytochemistry, 1977, 16, 1302. F. Bohlmann and C. Zdero, Phytochemistry, 1976, 15, 1310. F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 778. F. Bohlmann and N. Le Van, Phytochemistry, 1977, 16, 579. D. S. Park, C. K. Moon, and N. S. Park, Soul Taehakkyo Yakhak Nonmunjip, 1976, 1, 132 (Chem. Abs., 1977,87,114 583). H. B. Han, B. J . Song, and H. S. R o , Soul Taehakkyo Saengyak Yonguso Opjukjip, 1976, 15, 128(Chem. Abs., 1978, 88,047 506). I. W. Farrell, V. Thaller, and J. L. Turner, J.C.S. Perkin I , 1977, 1886. G . Cimino and S. De Stefano, Tetrahedron Letters, 1977, 1325.


11

diynol (48) and diynediol (49)requires comment in the context of fungal polyacetylenes. The chiralities of the fungal C7 diynol (50) and the C8 diynediol (51), a transformation product of the fungal C9 trio1 ( 5 2 ) , have been determined by unambiguous chemical transformations.6’ The groups attached t o the

(48)

X

= Br, R = H

(49) X = H, R = C K O H

-

- R -

(SO) R = H (51) R = CH,OH

chiral centres in the two pairs of diynes are identical but for the length of the alkyl chain and the presence of distal double bonds [and bromine in (48)J in the marine products. Both fungal compounds show negative rotations and negative trends in their 0.r.d. curves from 589--365 nm. Negative rotations at 589 nm have been cited for the marine products and their chiralities have been assigned by Gilbert and Brooks’ gas chromatographic modification of Horeau’s method. The coincidence of the negative rotations itself, on which the authors made no comment, is in no way a sufficient indication for identical chiralities in the two pairs of compounds. This Reporter is, however, a little uneasy on account of this coincidence and feels that the chirality of the two marine alcohols merits further attention. Non-Polyacetylenic Acetylenes.-Most of these metabolites will certainly appear in other Report-volumes, but they are collected here for the sake of completeness. The structure of rubrynolide (53), a constituent of the trunk wood of the Lauraceae Nectandra rubra (Mez) C . K. Allen, a native of the Amazon Basin, was proposed years ago. The stereochemistry of the compound has now been determined with the help of ‘H n.m.r., o.r.d., Horeau’s method, and Hudson’s lactone rule as ( 2 S ) ( 4 R ) and (2’s); full supporting chemical and spectral evidence is provided.62 61

62

M. R. Otd, C. M. Piggin, and V. Thaller, J.C.S. Perkin I, 1975, 6 8 7 and unpublished work. N. C. Franca, 0. R. Gottlieb, and D. T. Coxon, Phytochemistry, 1977, 16, 257.


12

Structure (54)has been e ~ t a b l i s h e dfor ~ ~ frustulosinol, an antibiotic isolated from the culture fluids of the Basidiomycete fungus Stereum frustulosum; the structure for frustulosin, the corresponding aldehyde, also present in the fungal culture fluid extract, has now been corrected to (55). OH

R = CH,OH ( 5 5 ) R = CHO (54)

( 2 S ) (3R)-2-Amino-3-hydroxypent-4-ynoic acid has been isolated" from dried sclerotia of the fungus Sclerotium rolfsii (Sacc.). The stereochemistry of the acetylenic amino-acid was confirmed by X-ray crystallography. It is toxic t o chickens. The y-glutamyl peptides of the known acetylenic amino-acids L-2-aminohex4-ynoic acid and L-ery thro-2-amino-3-hydroxyhex-4-ynoicacid have been isolated6' from the fruiting body of the Tricholomataceae fungus Tricholomopsis rutilans (Fr.) Sing. The structure and stereochemistry df yet another acetylenic alkaloid from the skin extract of the Colombian frog Dendrobates histrionicus, gephyrotoxin, formerly referred to as HTX-D, has been established66 as (56) by X-ray crystallography .

63 64

65 66

M . S. R. Nair and M. Anchel, Phytochernistry, 1977, 16, 390. H. C. Potgieter, N. M. J . Vermeulen, D. J. J . Potgieter, and H. F. Strauss, Phytochernistry, 1977, 16, 1757. Y. Niimura and S. I. Hatanaka, Phytochernistry, 1977, 16, 1435. J. W. Daly, B. Witkop, T. Tokuyama, T. Nishikawa, and I. L. Karle, Helu. Chirn. Actu, 1977,60, 1128.


13

Synthesis of Polyacety1enes.-These have been mentioned where relevant in the section on new polyacetylenes. Standard methods were used in most instances, though the successful use of a hydroxytriphenylphosphonium iodide in a Wittig reaction4 had not been reported before, Bohlmann described6' the synthesis of (57) and the novel part of this synthesis is given in Scheme 1. A new approach

HO R-CHO

ThPo

0

0

-b RuNMe2

RuNMe2

(57) Reagents: i, LiCH,CONMe, ;ii, C,H,O; iii, EtMgBr; iv, H,SO, (40%);v,Me,CHCH,COCl-Py

Seheme 1

t o the synthesis of aryl-acetylenes is exemplified by the synthesis of junipal(58), one of the polyacetylenes from the culture fluid of the fungus Daedalea juniperina (Scheme 2 ) from 2-propionyl thiophene in 24% overall yield.68 Syntheses of labelled polyacetylene precursors have also been d e ~ c r i b e d . 6 ~ ~ ~

A

i ,Meo# 0

0

0

HN-NH

Reagents: i, (MeO),CO, NaH, C H,; ii, H,NNH2, MeOH; iii, Py,HBr,, AcOH; iv, NaOH, K,Fe(CN), ,H20; v, Bd'Li, 0 C; vi, DMF, -78 C

Scheme 2 67 68

69 70

F. Bohlmann and C. Huhn, Chern. Ber., 1977, 110, 1183. P. J. Kocienski, J. M. Ansell, and B. E. Norcross,J. Org. Chem., 1976, 41, 3650. K. Jente and E. Richter, Phytochemistry, 1976, 15, 1673. M. Ahmed, M. T. W. Hearn, Sir Ewart R. H. Jones, and V. Thaller, J. Chern. Research, 1977, ( S ) 125; (M) 1579.

14

Biosynthesis.-Jente

Aliphatic and Related Natural Product Chemistry and Richter69 have thrown further light on the biogenesis

of cis-dehydromatricaria ester (5 9) in higher plants by supplementing published information from Bohlmann's school with the results of additional biosynthetic experiments. The good incorporation of both [ 18-14C] (60) and [ 16-14C] (61)

0

0 OMe

(60)

into the ester (59) by Artemisia vulgaris L. is interpreted as excluding a direct Baeyer-Villiger-like oxidative cleavage of a convenient c18 precursor t o a Clo (dehydromatricaria ester) and a c8 fragment. They confirmed an already precursors in biosynthetic experiobserved loss of tritium from [ 9,l G3HI ments leading t o polyacetylenic acids of the type RC=CCH=CHCO*H. The involvement of crepenynate in the biogenesis of plant polyacetylenes has also been demonstrated in biosynthetic experiments with several plant species. The origin of the carbon skeletons of the antibiotic mycomycin ( 6 2 ) , one of the earliest and most spectacular fungal polyacetylenes and that of the drosophilins C (63) and D (64) has been established" in biosynthetic experiments with [9-l4c]and [ 18-14C] c18 precursors in cultures of the fungi


15

Resiniciu m (Odontia) b icolor and Drosop h ila (Psathy rella) subatrata, respectively : mycomycin was found to consist of C(5)-C(17) and the drosophilins of C(8)C(18). The incorporations were in the region of 3-6.5%. High pressure liquid chromatography helped enormously in the mycomycin work with the separation of stereoisomers. Analogous experiments with terminally-labelled C18 and C10 precursors in fungal cultures demonstrated7' the origin of the C8 polyacetylenes (65), ( 6 6 ) , (67), and (58) from the eight distal carbon atoms of the precursors. Incorporations were again in the region of 4-6.5%. The fungal experiments which were

0 -

-

-

OH

discussed also confirmed in each instance the involvement of the crepenynate pathway in the biogenesis of the fungal polyacetylenes examined. Ichihara and Noda carried out analyses of germinating seeds, seedlings, and tissue cultures of safflower (Carthamus tinctorius L.) for the known C13 polyacetylenes. Labelled acetate was incorporated and the activities at the various stages of growth were investigated. A possible metabolic sequence of the polyacetylenes in safflower is discussed. Physiological Aspects of Polyacety1enes.-The host-pathogen interactions of the well known cases of Vicia faba L. and Carthamus tinctorius L. in which polyacetylenes play a major role are the subject of continued investigations. The isolation of wyerone epoxide (44), another component of the V. faba phytoalexin complex has already been mentioned*' and further investigations of the V.fabaBotrytis interactions have been reported.72 In the case of C. tinctorius, the ability of the safflower polyacetylenic hydrocarbons t o stimulate the growth of Puccinia carthami teliospores has been tested.73 The discovery of the nematocidal activity of the C13 trienetriynes from C. tinctorius has already been mentioned.*' A novel development is the screening of polyacetylenes for ultraviolet-mediated antibiotic activity; many proved active in the tests used.74 71

Sir Ewart R. H. Jones, C. M. Piggin, V. Thaller, and J. L. Turner, J. Chern. Research, 1977,(S), 68;(M) 744. 7 2 J. A. Hargreaves, J . W. Mansfieid, and D. T. Coxon, Phytochernistry, 1976, 1 5 , 651; J. A. Hargreaves, J . W. Mansfield, and S. Rossall, Physiol. Plant.Pathol., 1977, 11, 227. 73 R. G. Binder, J. M. Klisiewicz, and A. C. Waiss, jun., Phytopathology, 1977,67, 472. 74 G. H. N. Towers, C . K. Wat, E. A. Graham. R. J. Bandoni, G. F. Q. Chan, J. C. Mitchell, and J. Lam., Lloydia, 1977,40, 487.

16


3 Natural Olefinic Compounds Introduction.-With acyclic terpenoids, pheromones, olefinic microbial metabolites (fungal olefins too), prostaglandins, fatty acids, and lipids dealt with elsewhere, this leaves only the olefins from higher plants. The long chain alkenes and polyenes are an obvious choice but beyond these the selection is very difficult. The former are often produced by polyacetylene producers and their biogeneses are possibly linked. Indeed, some fungi are known to produce both types of metabolites depending on the substrates on which they are grown. simultaneous occurrence of the CI7 olefins (68) New and Known 0lefins.-The (aph1otaxene)-(7 1) in Centaurea scabiosa L.30is intriguing and the hypothesis linking their formation with the corresponding CIS acids (P-oxidation and decarboxylation), is very attractive. The four compounds were identified in the

mixture by mass spectrometry and' 'H n.m.r. Compounds (69) and (70) are new ' metabolites which were also isolated from Cirsium japonicum ( N ~ a z a m i ) ~and identified by their spectra and ozonolysis. The hypothesis is put forward75 that (70) represents an intermediate in the biogenesis of C17 polyacetylenes from oleic acid, a possible but rather unlikely route. The known C15-C18 tetraene in the aldehydes (72)-(75) were also present in C. scabiosa3' and (72)-(74) green parts of Serratula wolfii Andrae.I7 The new C I 8 (76) and CI6 (77) polyene aldehydes were isolated from Pseudogynoxys sonchoides (HBK) C ~ a t r and .~~ the new C14 pentaene acetate (78) from the roots and green parts of P. engleri H i e r ~ n Their . ~ ~ structures were elucidated by spectral methods. The new CI4 tetraene ester (79) was isolated from Felicia ~liginosa.~'The CIS aldehyde (80) was isolated from the Cucurbitaceae Cucumis s a t i ~ u s ' ~and its structural relationship t o palmitoleic acid was noted. Rubrenolide (8 1) was isolated62 together with rubrynolide (53). The stereochemistry of the two compounds is identical. 75 76

K. Yano, Phytochemistry, 1977, 16, 2 6 3 . T. R. Kemp, Phytochernistry, 1977, 16, 1831.


(72) (73) (74) (75)

n n n n

17

= 4 = 5 = 6

= 7

(76) n = 5 (77) n = 3

0 OMe (79)

Mixed 0lefins.-A considerable amount of work has been published on amides from Piperaceae species. Most of them will certainly be reviewed with alkaloids and some, e.g. wisamine (82)77 and (83),78 with natural aromatic compounds, although a substantial part of their molecules consists of an aliphatic chain. Entirely aliphatic are the Cz0 isobutylamides (84) and (85) from Piper g ~ i n e e n s eand ~ ~P. officinarum,80 respectively. Argentilactone ( 8 6 ) from Aristolochia argentina Gris. (Aristolochiaceae) was identified" by spectral evidence and chemical transformations. The lactone had the (5R)configuration. 77

I. Addae-Mensah, F. G. Torto, and I. Baxter, Tetrahedron Letters, 1976, 3049. 0. P. Gupta, K. L. Dhar, and C. K. Atal, Phytochernistry, 1976, 15, 425. 79 I. Addae-Mensah, F. G. Torto, I. V. Oppong, I. Baxter, and J . K. M. Sanders, Phytochernistry, 1977, 16, 483. 80 0. P. Gupta, S. C. Gupta, K. L. Dhar, and C. K. Atal, Phytochernistry, 1977, 16, 1436. H. A. Priestap, J. D. Bonafide, and E. A. Rbveda, Phytochernistry, 1977, 16, 1579. 7*

18


0

The CI2 and CI4 acetates (87) and (88), as well as the macrocyclic lactone (89) were isolated82 from the steam distillate of the seeds of Hibiscus abelmoschus L. Spectral data, degradation, and synthesis of all three compounds established the structures. Partial reduction of triple bonds or stereoselective Wittig reactions with 2-hydroxytetrahydropyran were used in the syntheses. Synthesis.-All four isomeric 5,lO-pentadecadienals [the E,E-isomer is represented in structure (90)] were prepared by stereoselective routes.83 The four isomers are believed t o participate in the agreeable odour of turpentine oil from the European silver fir, Abies pecfinata DC, A synthesis of the above mentioned wysamine (82) has been described.w

82

83

a4

B. Maurer and A. Grieder, Helv. Chim. Acta, 1977, 60, 11 5 5 . G. Ohloff, C. Vial, F. Naf, and M. Pawlak, Hefu. Chim. Acra, 1977, 60, 1161. L. Crombie, G. Pattenden, and G. Stemp, Phytochemistry, 1977, 16, 1437.

Natural Acetylenic and Olefinic Compounds D

O

-

19 A

C

(87)

Biosynthesis.-Further experiments concerned with the biosynthesis of trans2 ,czs-6-nonadienal (9 1) from linolenic acid and trans-2-nonenal from linoleic acid were carried out with cucumber fruits (Cucurnis sativus) at different ripening stages.*’ The results suggest that homogenates of mid-ripening fruits produce the largest amounts of C9 aldehydes and that the presence of the 1,4-cis,cis-diene group and a free carboxy group were necessary for the transformations to take place.

The conversion of [U-14Cllinolenic and linoleic acids into trans-hexen-2-a1 (2%) (via cis-hexen-3-al) and hexanal (1 O%), respectively, was studied with chloroplasts of Thea sinensis (Theaceae) leaves; radio g.1.c. was used t o measure the activity of the volatile products (no activity was present in other volatile components).86

*’ 86

J. Sekiya, T. Kajiwara, and A. Hatanaka, Phytochemistry,

1977, 16, 1043. A. Hatanaka, T. Kajiwara, and J . Sekiya, Phytochemistry, 1976, 15, 1125.

2 Marine Aliphatic Natural Products BY R. E. MOORE

1 Introduction

This Report is mainly concerned with a review of the 1976-1977 literature on marine fatty acid metabolites, acetogenins, and terpenes. Included also are some lipophilic substances that arise from one-carbon substrates and acyclic amino acids. The five plenary lectures delivered at the First International Symposium on Marine Natural Products held at the University of Aberdeen in September 1975 have appeared in print. These papers deal with the chemistry of alcyonaceans (soft corals)' and sponges,2 biomimetic synthesis of marine natural product^,^ reactions of the aplysiatoxins (sea hare toxins): and a review of chemical research on Australian marine organisms for the period 1959- 1975,' All of the lectures presented at a NATO-sponsored conference on Marine Natural Products Chemistry held in Jersey, Channel Islands in October, 1976 have been published in a book edited by D. J . Faulkner and W. Fenical and the articles concerned with new marine aliphatic natural products are reviewed and referenced in the appropriate sections of this Report. The papers delivered a t the Symposium on Food-Drugs from the Sea held in Puerto Rico in November, 1974 have been published.6 A multivolume treatise, 'Marine Natural Products: Chemical and Biological Perspectives' edited by P. J. Scheuer has been initiated. Volume 1, published in December, 1977, contains five articles reviewing dinoflagellate toxins,' algal non-isoprenoids,8 algal sesquiterpen~ids,~ terpenoids from marine sponges," and uncommon marine sterols." Reviews on physiologically active substances from marine organisms,12 marine

B. Tursch, Pure A p p l . Chem., 1976, 48, 1. L. Minale, Pure A p p l . Chem., 1976, 48, 7. D. J. Faulkner, Pure A p p l . Chem., 1976, 48, 2 5 . Y. Kato and P. J . Scheuer, Pure A p p l . Chem., 1976, 48, 29. J. T. Baker, Pure A p p l . Chem., 1976, 48, 3 5 . 'Food-Drugs from the Sea: Proceedings 1974', ed. H . H. Webber and G. D. Ruggieri, Marine Technology Society, Washington, 1976. ' Y . Shimizu, in 'Marine Natural Prodacts: Chemical and Biological Perspectives', ed. P. J. Scheuer, Academic Press, New York, Vol. I, p. 1 . * R. E. Moore, in ref. 7, p. 4 3 . J. D. Martin and J. Darias, in ref. 7 , p. 125. l o L. Minale, in ref. 7, p. 175. l 1 F. J . Schmitz, in ref. 7 , p. 241. l 2 J. T. Baker, Austral. J. Pharm. Sci., 1976, NS5, 89.

20

21

Marine Aliphatic Natural Products

t o ~ i n s , ' ~ ' 'the ~ odour of chemotaxis in ~ e a w e e d , " ~ ' ~chemical communication of marine invertebrates," and natural products from sponges2' have appeared elsewhere. A review of some of the important contributions t o the field of marine natural products has been written.21

2 Non-isoprenoidal Compounds Seven sulphur compounds ( 1--7) have been isolated from the red alga Chondria caZifornica.22 The antibiotic activity of this rhodophyte is primarily due to the major component, the sulphone ( 6 ) . Polysulphide (3) is identical to lenthionine, S-

s-s

\s-s ) s-s

a constituent of the edible mushroom Lentinus edodes. The biosynthesis of lenthionine in the mushroom involves an enzymatic decomposition of lentinic acid (8).23The biogenesis of the algal sulphur compounds, however, is unknown. 0

It

0

0

0

0

HNCCH,CH,CHCOOH

II

6

I

NH,

(8 1 The essential oil of the Hawaiian variety of the red alga Asparagopsis taxiformis, is composed mainly of CHBr3, with smaller amounts of CHBr21, l3

l4

*'

l6 17

l9 20

21

22

23

P. J. Scheuer, Accounts Chem. Res., 1977, 10, 3 3 . R. E. Moore, Bioscience, 1977, 27, 797. R. E. Moore, Lloydiu, 1976, 39, 181. R. E. Moore, Accounts Chem. Res., 1977, 10, 40.

L. Jaenicke, Nuturwiss., 1977, 64, 69. L. Jaenicke, TZBS, 1977, 152. P. J. Scheuer, Bioscience, 1977, 27, 664. L. Minale, G. Cimino, S. de Stefano, and G. Sodano, Fortschr. Chem. Organ. Naturstoffe, 1976, 33, 1. D. J. Faulkner, Tetrahedron, 1977, 33, 1421. S. J. Wratten and D. J . Faulkner, J. Urg. Chem., 1976, 41, 2465. G. Hofle, R. Gmelin, H.-H. Luxa, M. N'Galamulume-Treves, and Sh. I. Hatanaka, Tetrahedron Letters, 1976, 3 129.

22


CHBr12, ICH2CH20H, CH3COCHBr2, CH3COCBr3, Br2CHCH=CBr2, and Br2C=CHCOCHBr2.In addition to these eight compounds, thirty-four related trace constituents, nearly all containing bromine and/or iodine, have been identified; ten of the components contain chlorine. The most unusual trace compounds are CHBrClI, C012, and the epoxide (9).2A Five 2,2-dihaloacetamides, twenty halogenated propan-2-01s (e.g. lo), and seven halogenated but-3-en-2-01s have been identified in the CH2C12 extract2' and nine halogenated acetic acids and nine halogenated acrylic acids have been found in the aqueous extract* of the vacuum-dried alga. 2,2-Dichloroacetamide was not detected in Hawaiian A . taxiformis (family Bonnemaisoniaceae), but it is a constituent of the red alga Margznisporurn aberrans (family Corallinaceae).26 The major halogenated acrylic acid in Hawaiian A . taxiformis is ( 1 l).' Br Br i ,

Br Br

H Br

Br

(10)

Br

(9) Br

B

0

r

A

Br

B

r

i_

Br J

1 Br

0

A

H Br

Br

(1 2)

(1 3)

Reagent: i, aqueous NaHCO,

Scheme 1

A . taxiformis from the Gulf of California and A . arm at^ from the Spanish Mediterranean coast elaborate the same types of compounds, except that more chlorinated metabolities and fewer iodinated ones appear t o be p r e ~ e n t . ~ ' Bromoform is the major volatile constituent in both seaweeds. Trace amounts of CHd, CHC13, and CC14, which have environmental significance, have also been detected in A . armata. 1,1,3-Tribromoacetone and (12) are the major halogenated components in the extract of air-dried Mexican A . taxiformis, whereas 1,1,3-trihaloacetones and 1,1,3,3-tetrahaloacetonescontaining bromine and/or chlorine are the major halogenated compounds in the extract of air-dried A . armata. In contrast to the Hawaiian variety, (1 3, isolated as the ethyl ester) is the major halogenated acrylic acid in Mexican A . taxiformis and A . armata. The biogenesis and biomimetic synthesis of the haloforms and halogenated acetic and acrylic acids in Asparagopsis from halogenated acetones has been 24 25

26 21

B. J . Burreson, R. E. Moore, and P. P. Roller, J. Agric. Food Chem., 1976, 24, 856. F. X. Wollard, R. E. Moore, and P. P. Roller, Tetrahedron, 1976, 32, 2843. K. Ohta and M. Takagi, Phytochemisrry, 1977, 16, 1085. 0. J. McConnell and W. Fenical, Phytochemkrry, 1977, 16, 367.

Ma rin e A liphat ic Na t u ral Products

23

discussed.8 Acid (1 1) is the sole product of the Favorskii rearrangement of (12) in aqueous sodium bicarbonate and (9) is formed when (10) is allowed t o stand in aqueous sodium bicarbonate (Scheme 1). A related alga, Bonnemaisonia nootkana, contains a dextrorotatory epoxide. (14), two alcohols (1 5 ) and (16), a ketone (1 7), and four acids (18-2 1).28 OH

H

Br H

Br

(15) R = Me (16) R = CH2CH2Me

(14)

Acids ( 18) and ( 19) are biomimetically synthesized by Favorskii rearrangements of (22) and (23), respectively. Acids (20) and (21), on the other hand, can be formed by Favorskii rearrangements of (24) and (17), respectively (Scheme 2).

br

Br

(22) R = Me (23) R = CH,CH,Me

(18) R = Me (19) R = CH2CH2Me

(24) R = Me (17) R = CH2CH2Me

(20) R = Me (21) R = CH,CH,Me

Reagents: i, Na,CO, in aqueous MeOH Scheme 2

Five polyhalogenated l-octen-3-ones, the major ones (25) and (26), have been isolated from Delisea fimbriata, another red alga belonging to the Bonnemaisone a ~ e a e . ~ ’ ~ ~Five ’ polyhalogenated 1-octen-3-ones are also present in Bonnemaisonia asparagoides, the major ketones being the (E) and ( 2 ) isomers (27) and (28).3’ Polybromo-1-octen-3-ones (29-3 1) have also been found in PtiEonia aus tralasica (Bonnemaisoniaceae).32 0. J. McConnell and W. Fenical, Tetrahedron Letters, 1977, 4159. J. J . Sims, J. A. Pettus, jun., and R. M. Wing, in ‘Marine Natural Products Chemistry’, ed. D. J . Faulkner and W. Fenical, Plenum Press, N e w York, 1977, p. 205. 30 A. F. Rose, J. A. Pettus, jun., and J. J. Sims, Tetrahedron Letters, 1977, 1847. 3 1 0. J . McConnell and W. Fenical, Tetrahedron Letters, 1977, 185 1. 32 R. Kazlauskas, P. T. Murphy, R. J. Quinn, and R. J . Wells, Tetrahedron Letters, 1977, 28 29

37.

24


X

61

Br

X = H (26) X = C1 (25)

cr

(27) Y = Br, X = Cl (28) Y = C1, X = Br Br

(29) R = CH&HCB~,CH,CH, (30) R = CHBrCH,CH,CH,CH, (31) R = CBr,CH,CH,CH,CH,

A series of interesting halogenated y-lactones called fimbrolides, hydroxyfimbrolides, and acetoxyfimbrolides have been reported from Australian32 and A n t a r t i ~ a nDelisea ~~ firnbiata and are responsible for the antibiotic activity of the algae. A total of three fimbrolides, seven hydroxyfimbrolides, and seven acetoxyfimbrolides have been detected in the Australian variety by g.c.-m.s. and the major representatives are (32), (33), and (34). Two hydroxyfimbrolides and two acetoxyfimbrolides contain iodine, Three acetoxyfimbrolides (34--36) have been isolated and fully ~ h a r a c t e r i z e d .Related ~~ compounds (beckerelides) have been found in the red alga BeckereEZa subcostatum (family G e l i d i a ~ e a e ) . ~ ~ ~

Y (32) R = H,X = Y = Br (33) R = OH, X = H, Y = Br

(34) X = Br, Y = H (35) X = H, Y = Br (36) X = H, Y = I

(+)-Multifidene (37), the male gamete attractant in the brown alga CutZeria multifida, and its stereoisomers have been synthesized.% The ring stereochemistry

3 3 J. A. Pettus, jun., K . M . Wing, and J . J . Sims, Tetrahedron Letters, 1977,41. 3 3 a K . 0 h t a , A g r i c .B i d . Chern., 1977,41,2105. 34 L. Jaenicke and W. Boland, Annalen, 1976, 1 1 35.

25

Marine A 1ip ha t ic Natural Products

of (37),which could not be rigorously deduced from spectral data, has been shown t o be cis. Another synthesis of fucoserratene (trans, cis-octa-l,3,5-triene), the sperm attractant produced by the eggs of the brown alga Fucus serratus, has been r e p ~ r t e d . ~ ’ The conversion of the previously synthesized (38) into (+)-laurencin (39), the first halogenated, non-terpenoid CI5 acetylene t o be found in a red alga of t h e genus Laurencia, has been This is the first synthesis of a representative member of the group.

Laurencia continues t o be a prolific source of novel metabolites. In an examination of a green variety of Hawaiian L. nidifica, six new C,’-enynes have been

(44) (45) 3s 36

R’ = Br, RZ = Et R’ = Et, RZ = Br

B. Wiedenmann and H. H o p f , Z. Naturforsch., 1977, 32b, 119. A. Murai, H. Murase, H . Matsue, and T. Masamune, Tetrahedron Letters, 1977, 2 5 0 7 .

26


found, all of which possess carbocyclic rings in addition t o the usual cyclic ether rings. Four of the compounds (40)-(43) are tricyclic and have been named maneonenes after the Hawaiian name for the seaweed.3798 The other two compounds (44), (45) are tetracyclic and are called i s ~ m a n e o n e n e s . ~ ~ Laurencia subopposita contains eight acetylenes which can be considered as four pairs of A3 isomers.39 Three pairs are the already known: cis- and transisoprelaurefucin , cis- and trans-laurefucin,and cis- and trans-acetyl-laurefucin. The acetylenes in the other pair, cis- and trans-dehydrobromolaurefucin (46), had not been described previously. Similar compounds are frequently found in sea hares as a result of diet. The trans-enyne isodactylyne (47) has been isolated from ApZysia dactylornela. 40 A novel bromoallene (48) has been found in the sea hare Aplysia brasiliana and

HO

(48)

named panacene after the collection site of the m ~ l l u s k . ~Most ' of the relative stereochemistry for panacene has been determined and the absolute configuration of the allene moiety has been tentatively assigned by application of Lowe's rule. Panacene is proposed to arise biogenetically from an algal CIS enyne, but whether this transformation occurs in the alga upon which the sea hare feeds or in the sea hare itself is an open question. The isolation of panacene provides evidence that metabolized enynes are probably present in Laurencia. (23-2Chloropentadec-2enal (49) has been isolated from Laurencia nidifica and its biogenesis from pentadec-3-en-1 -yne has been suggested.8

c1

(4 9) 37 38 39 40

41

H

S . M. Waraszkiewicz, H . H. Sun, and K. L. Erickson, Tetrahedron Letters, 1976, 3021. H. H. Sun, S . M. Waraszkiewicz, and K. L. Erickson, Tetrahedron Letters, 1976, 4227. S. J . Wratten and D . J . Faulkner, J. Org. Chern., 1977, 42, 3343. D. J. Vanderah and F. J. Schmitz, J. Org. Chem., 1976, 41, 3480. R. Kinnel, A. J . Duggan, T. Eisner, J. Meinwald, and I. Miura, Tetrahedron Letters, 1977, 39 13.


27

Five closely related acetylenes (50)--(54), referred t o as renierins, have been isolated from the sponge Reniera f ~ l v a The . ~ ~C-5 and C-6 positions of (52) and (54),respectively, have been proposed t o have ( R ) configurations. 0

0

Br

,

Br

(5 2)

(54)

(E)-1-Chlorotridec-1ene-6(R),8(R)diol (55) is reported t o be a constituent of a blue-green algal mixture identified as Oscillatoria nigroviridis and Schizothrix calcicola; experimental details of the structure determination? howOH

OH

(55)

R' R'

I I

Me(CH,), CHCH(CH,), COOH (56)

R', R2 = C1, OH or OH, C1 x = 5 , 7

42

y = 7 , 9

G. Cimino and S. de Stefano, Tetrahedron Letters, 1977, 1325.

28


ever, are not yet in print.8 Two C I 6 and four CIS fatty acid chlorohydrins of general formula (56) have been isolated from an edible jellyfish.43 An interesting peroxyketal chondrillin (57), has been isolated from a sponge of the genus Chondrilla.44 The absolute configuration of C-3 is proposed to be ( S ) . The interesting, quantitative conversions of (57) into (58) and (59) are summarized in Scheme 3. YOOMe

jii

(59) (5 8)

Reagents: i, 10M aqueous HC1; ii, Zn in HOAc

Scheme 3

The lipid-soluble extract of the brown alga Cystophora torulosa is composed of a complex mixture of polyketidederived alkyl and alkenyl resorcinols (e.g. 60), a phloroglucinol (61), and two straight chain Czl polyenes which had been HO

OH

(60)

Me0

43 44

R. H. White and L. P. Hager, Biochemistry, 1977, 16, 4944. R. J . Wells, Tetrahedron Letters, 1976,2637.


29

isolated previously from the brown alga Fucus ~ e s i c u l o s u sThree . ~ ~ 1 O-aryldeca(3E,SE,7E,9E)-tetraen-3-ones, navenones A ( 6 2 ) , B (63), and C (64), have been 0

0

0

identified as trail-breaking alarm pheromones from the opisthobranch Nauanax in ermis. Full details of the isolation and characterization of (1 5R)- and ( 155’)-prostaglandins A 2 and their esters from the sea whip Plexaura homomalla have appeared in the l i t e r a t ~ r e . 4Also ~ described are the details for converting the marine natural products into the primary, highly biologically active mammalian prostaglandins, PGE2 and PGF2a. 5,6-trans-PGA2 (65) has also been found in P. h omomalla. OAc

I

0

Me(CH,),,CHCHCH,OH

1

1

NHCMe

H (65).\OH

(66)

II

0

OH CH,-(CH,),

I

,--CH~CH-CH--CH-CH,OH

I

NH-CC-(CH,)~-CH,

ll

0 (67) n = 12, 14, 16, 21, 22, or 23 4s

4h

47

K. P. Gregson, K. Kazlauskas, P. T. Murphy, and K. J. Wells, Austral. J. Chem., 1 9 7 7 , 30, 2 5 2 7 . H. L. Sleeper and W . Fenical, J. Amer. Chem. SOC., 1977, 99, 2 3 6 7 . W. P. Schneider, G . L. Bundy, F. H. Lincoln, E. G. Daniels, and J . E. Pike, J. Amer. Chern. SOC., 1977, 99, 1222, 5 2 2 8 .

A I iph at ic and R e la te d Na t u ral Product Chem ist ry

30

2(S)-Acetamido-3(R)-acetoxyoctadecan-l-ol( 6 6 ) , a diacetate of dihydrosphingosine, has been isolated from Laurencia nidifica and several N-acylsphingosines ( 6 7 ) have been found in another red alga Amansia glomerata. A new antibiotic, aplasmomycin, has been isolated from a cultured marine strain of Streptomyces g r i ~ e u s .The ~ ~ structure and absolute configuration of aplasmomycin, named so because of its inhibitory activity against plasmodium in mice infected with Plasmodium berghei, has been elucidated by an X-ray crystallographic study of the silver salt (68)49 The antibiotic is unusual in that it is a natural boric acid complex.

'

The relative stereochemistries of aplysiatoxin (69) and debromoaplysiatoxin (70), two poisonous substances from the digestive gland of the sea hare

(

H

\

OMe X

0

Po (69) X = Br

(70) X = H

StylocheiZus longicauda, have been partially assigned on the basis of 'H n.m.r. and reactivity data.4 The toxins appear to be of algal origin since sea hares held in captivity and deprived of their natural diet lack t o ~ i c i t y . ' Debromoaplysia~ 48 49

Y. Okami, T. Okazaki, T. Kitahara, and H. Umekawa, J. Antibiotics, 1976, 2 9 , 1019. H. Nakamura, Y . Iitaka, T. Kitahara, T. Okazaki, and Y . Okami, J. Antibiotics, 1977, 30, 714.


31

toxin (70) is a constituent of the blue-green alga Lyngbya gracilis and is responsible for the antileukemia activity of the seaweed; it has also been found in an algal mixture of Oscillatoria nigroviridis and Schizothrix calcicola and in a dermatitis-producing strain of Lyngbya majuscula. Two non-toxic amides, stylocheilamide ( 7 1) and deacetylstylocheilamide (72), have been found in the sea hare Stylocheilus longicauda.13 Details of the structure determination have not been published yet. Like the above, amides (7 1) and (72) appear t o be of dietary origin and are probably metabolites of a bluegreen alga. trans-7-Methoxytetradec-4-enoic acid is a constituent of the cyanophyte Lyngbya majuscula.

Majusculamides A (73) and B (74) are two epimeric lipodipeptides that have been isolated from Lyngbya majuscula. 5 1

(73) R' = Me, R2 = H (74) R' = H, R2 =Me

Dysidin (75)"' ana dysidenin ( 76)52 are novel nitrogeneous compounds with trichloromethyl groups that have been isolated from the sponge Dysidea herbacea. J . S. Mynderse, R. E. Moore, M. Kashiwagi, and T. R. Norton, Science, 1977, 196, 5 3 8 . F.-J. Marnet, R. E. Moore, K. Hirotsu, and J . C1ardy.J. Org. Chem., 1977,42, 2815. s l a W.Hofheinz and W. E. Oberhansli, Helv. Chirn. A m , 1977,60, 660. 5 2 R. Kazlauskas, K. 0. Lidgard, K. J . Wells, and W. Vetter, Tetrahedron Letters, 1977, 51

3183.

32

Aliphatic and Related Natural Product Chemistry ,C“3

Me

cc1,

0

>HCH,CH Me

Q+-&

Me0

(75)

\NcOCH,CH /

‘Me

\CONHCH-Me

AS

N/

OMe

(76)

u

3 Isoprenoidal Compounds Monoterpenes.-The digestive gland of the sea hare Aplysia calijornica contains ( 7 7 ) and (78) which have not been previously detected in red algae of the genus Plocamium. The stereochemistry of (77) was not determined. Compound (78) was converted into (79), which has properties which are not identical with those reported for cartilagineal; direct comparison of (79) and cartilagineal, however, was not made.53 A new related monoterpene (80) has been found in A . limacina and n.m.r. data suggests that it has the threo c ~ n f i g u r a t i o n . ~ ~

# CH,OAc

/

B+Br

c1

/

C1

H

(77)

C1

(78) CHBr,

c1

c1

c1

C1

H

The diastereoisomers (8 1) and (82) (tentative structure) and the known dehydrohalo compounds (83) and (84) have been isolated from Plocamium ~regonium.~’Epimers (83) and (84) have also been found in a P. cartilagineum on the British coast along with ( 8 5 ) , one of the first halogenated monoterpenes t o be isolated from the sea hare A . californica and Californian P. cartilagineum. To date ( 8 5 ) is one of two acyclic monoterpenes from marine organisms whose structure, including absolute configuration, has been rigorously established by X-ray cry~tallography.’~A closely related compound, oregonene A (86), has also been found in P. oregonium.55

53 54

5s 56

C . Ireland, M . 0. Stallard, and D, J . Faulkner, J . Org. Cliem., 1 9 7 6 , 41, 2461. F‘. Imperato, L. Minale, and K. Riccio, Experientia, 1 9 7 7 , 33, 1273. P. Crews, J. Org. Chem., 1 9 7 7 , 4 2 , 2 6 3 4 . M. D. Higgs, D. J . Vanderah, and D. J. Faulkner, Tetrahedron, 1 9 7 7 , 33, 2 7 7 5 .

33


Br

Br

c1

The most interesting acyclic monoterpenes from Plocamium are the preplocamenes (87), (88), and (89) which have been isolated from P. viola~eum.~’ Their structures and stereochemistries have been established by detailed n.m.r.

analysis and comparison made with model compounds. It is proposed that the preplocamenes may be biogenetic precursors of cyclic monoterpenes such as plocamene D (90) in this seaweed (Scheme 4).

Scheme 4

Five new cyclic monoterpenes have been found in P. cartilagineuin on the British coast .56 The halogenated monoterpenes from the British samples are closely related t o the isoprenoidal violacene-1 (9 l ) , and the rearranged, nonisoprenoidal violacene-2 (92) and plocamene-B (93). A footnote of this paper reports that the structure of violacene-1 has been revised from (94) t o (91) by X-ray crystallography. The structures of the new monoterpenes (95-99), the

’’ P. Crews and E. Kho-Wiseman, J . Org. Chem., 1977, 42,2 8 1 2 .

34


a a

c1 (91) X = Cl (95) X = Br

(92)

I

Cl (93)

I

Cl (94)

major one being (96), were determined by comparison of spectral data with those of (9 1) and (92) and by chemical interconversion (Scheme 5 ) . The easy conversion of (96) into (97) suggests that (98) may be biogenetically formed from (96) by concomitant intrafacial migrations of the chlorovinyl group and C-2 bromine. Compounds (92) and (98) have also been isolated from Australian P. cartilagnieum.”

Reagents: i, AgOAc in HOAc; ii, heat in DMF Scheme 5

The structure of mertensene (100) from male P. mertensii has been proposed from 13C n.m.r. studies coupled with proton n.m.r. studies and a single chemical degradation.” 58

R. S. Norton, R. G . Warren, and R. J . Wells, Tetrahedron Letters, 1977, 3905.


35

Interestingly red algae belonging t o the genus Microcladia (Ceramiales) contain the same halogenated monoterpenes found in Plocamium gig art in ale^).'^

c1 (100)

An acyclic monoterpene, costalol (101), has been isolated from Australian P. costaturn.60 Also present in this alga is a related cyclic hemiketal, costatone ( 102).61 Some chemical reactions of costatone6081 are summarized in Scheme 6 . The lactone, costatolide (103), formed by reaction of (102) with DBU, is also a constituent of P. costatum.61 Costatone (102) may be formed from a precursor similar t o (101) by an S N 2 elimination of the C - 3 ( R ) chloro group by the hydroxy group on C-7.60

+

Reagents: i, DBU in ether; ii, 0, in CH,Cl, ; iii, NaOH in aqueous MeOH; iv, isomerization on standing ( f % = 7 days)

Scheme 6

Chondrococcus (Desmia) hornemanni and C. japonicus contain halogenated myrcenes in their essential oils. Two new derivatives (104) and (105) have been isolated from C. japonicus; the previously reported methoxy compounds (106)(109) are artifacts that are produced from (104) and (105) when the seaweed is

59

P. Crews, P. Ng, E. Kho-Wiseman, and C. Pace, Phytochernisrry, 1976, 1 5 , 1 7 0 7 .

'"R.

Kazlauskas, Y. T. Murphy, R. J . Quinn, and R. J . Wells, Tetrahedron Letters, 1976,

4451. 61

D. B. Stierle, R. M.Wing, and J . J . Sims, Tetrahedron Letters, 1976, 4455.

36


extracted with methanol.62 Halogenated myrcenes were not found in Sri Lankan

C.hornemanni; instead ( 1 10) is the major haloterpene in this variety.63

R'

H

(104) R' (105) R' (106) R' (107) R'

R2 = Br, R3 = H = C1, R2 = H, R3 = Br

(108) R'

= C1, =

=

OCH,, RZ = Br, R3 = H

(109) R' = OCII,, R2 = H, R3 = Br

OCH,, RZ = Br, R3 = H R2 = H, R3 = Br

= OCH,,

Seven bromine-containing prenylated hydroquinones, viz. c y m o p o l ( l l 1 ) and its monomethyl ether (1 12), cyclocymopol (1 13) and its monomethyl ether (1 14), cymopolone (1 15), isocymopolone (1 16), and cymopochromenol (1 17), have been isolated from the green calcareous alga Cymopolia barbam.@ The

(111) R = H (112) R = Me

(113)R = H (114)R = Me

OH

0 0

(115)

(117) 62

63

64

Y. Naya, Y . Hirose, and N. Ichikawa, Chem. Letters, 1976, 839. F. X. Woolard, It. E. Moore, M. Mahendran, and A. Sivapalan, Phytochemistry, 1976, 15, 1069. H.-E. Hogberg and K . H. Thomson, J.C.S. Perkin I , 1976, 1696.


37

structure and absolute configuration of the acetate of ( 1 6 5 ) nas been established by X-ray crystallography. Sesquiterpenes.--The carbonimidic dichlorides (1 18) and ( 1 19) have been isolated from the sponge Pseudaxinyssa pitys.65 Reductions of ( 1 18) and (1 19) gave unstable isonitriles (120) and (121) which could be hydrolysed t o formamides (122) and (1 23). The stereochemistry of (1 19) was deduced from a

fR c1 (118) R = -N=CCl, (120) R = -N'=C(122) R = -NHCHO

I

OH (119) R = -N=CCl, (121) R = -N"= -c(123) R = -NHCHO

lanthanide induced shift experiment, but the absolute configurations of ( 1 18) and ( 1 19) were not determined. Axinyssane is the proposed name for the carbon skeleton of ( 1 19). A biogenesis of ( 1 19) from (1 18) has been suggested. The furanosesquiterpenoidal acid ( 124) has been isolated from the soft coral Sinularia gonatodes.66 The compound bears resemblance t o the prenylated quinol (1 25).

Zonarol (126) and isozonarol ( 127), two naturally-occurring antifugal compounds from the brown seaweed Dictyopteris undulata, have been synthesized as race mate^.^^ The absolute configuration of avarol ( 128), a constituent of the sponge Disedea avera, has been determined from c.d. studies.68 This 9,4-friedodrimane type sesquiterpene, the first of its kind, is biogenetically related t o the S. J . Wratten and D. J. Faulkner, J. Amer. C'hem. SOC., 1977, 99, 7 3 6 9 . J. C. Coil, S. J . Mitchell, and G . J. Stokie, Tetrahedron Letters, 1977, 1539. 6 7 S. C. Welch and A. S. C. P. Rao, Tetrahedron Letters, 1977, 5 0 5 . 6 n S. d e Kosa, L. Minale, R. Riccio, and G. S o d a n o , J.C.S. Perkin I , 1976, 1408. 65 66


38

sponge metabolite, ent-chromazonarol (1 29), which is antipodal t o chromazonarol previously isolated from Dictyopteris undulata. HO

HO

DOH

OH

(131)

(1 30)

Scheme 7 6q

B. M . Howard and W. Fenical, Tetrahedron Letters, 1976, 2 5 19.


39

crystallography,70 but experimental details are not yet in print. Two biogenetic routes t o (130) have been proposed (Scheme 7). One pathway utilizes as an intermediate (B)-y-bisabolene (1 3 1), which is reported to be a constituent of a Laurencia sp. and the sole isomer of y-bisabolene in that ~ e a w e e d . ~Bromonium ' ion-induced cyclizations of ( 13 1) t o (+)-10-bromoiu-chamigrene have so far failed.72 The isolation of metabolites such as a-snyderol (1 32) and 0-snyderol ( 1 33) from Laurencia snyderiae,73 however, provides some evidence that favours the other biogenetic pathway. a-Snyderol and P-snyderol could not be converted into (1 30).n A third snyderol isomer (134) has been synthesized and successfully cyclized t o (?)-10-bromoiu-chamigrene; the stereochemistry of the synthetic chamigrene, however, was not e ~ t a b l i s h e d . ~ ~

(f)-P-Synderol has been synthesized from methyl trans, t r a n s - f a r n e ~ a t ebut ~~ no mention was made about the stereochemistry of the product as compared with the natural product. a- and 0-Synderol have been synthesized biomimetically by the bromonium ion-induced cyclization of nerolidol using 2,4,4,6-tetrabromocyclohexa-2,5-dione as the reagent; the synthetic ( 133), however, had [a],-4.6', whereas natural (133) had [a]D+14.6°.75

H

70

71 72

73 74 7s

T. Suzuki, A. Furusaki, N. Hashiba, and E. Kurosawa, Tetrahedron Letters, 1977,3731. L. E. Wolinsky and D. J . Faulkner, J. Org. Chem., 1976,41,697. L. E. Wolinsky and D. J. Faulkner, J. Org. Chem., 1976,41,597. B. M. Howard and W. Fenical, Tetrahedron Letters, 1976,41. A. G. Gonzalez, J. D. Martin, C. Perez, and M. A. Ramirez, Tetrahedron Letters, 1976, 137. T. Kato, I. Ichinose, A. Kamoshida, and Y . Kitahara, J.C.S. Chem. Comm., 1976, 5 1 8 .

40


PH

I

(141)

johnstonol

Reagents: i, oxalic acid in MeOH; ii, p-TsOH; iii, HBr in HOAc

Scheme 8

3o-Bromo-8-epicaparrapi oxide ( 135) from a British Laurencia o b t ~ s a the ,~~ rearranged, non-isoprenoidal alcohols ( 136) and ( 137) from a green variety of Hawaiian L. n i d i f i ~ aand ~ ~ (1 38) from the sea hare Aplysia d a ~ t y l o m e l aand ,~~ a cytotoxic compound, aplysistatin ( 139), from an Australian sea hare Aplysia angasi7’ appear t o be related t o the synderols. Br

c Me

-Me

C‘ ‘Cl

H Br (144)

R20 @ B P (145) R’ = Br, (146) R’ = H ,

R2 = H K2 = H

D. J. E’aulkner, Phytochemistry, 1976, 15, 1993. H. H. S u n , S. M. Waraszkiewicz, a n d K. L, Erickson, Tetrahedron Letters, 1976, 585. 7 8 E’. J. Schmitz, D. C. Campbell, K. Hollenbeak, D. J . Vanderah, L. S. Ciereszko, P. Stendler, J. D. Eckstrand, D. van der Helm, Y. Kaul, a n d S. Kulkarni, in ref. 29, p. 2 9 3 . 79 G. R. Pettit, C. L. Herald, M. S. Allen, R. B. Von Dreele, L. D. Vanelle, J . P. Y . Kao, a n d W. Blake, J. Amer. Chem. SOC., 1977,99,262. 76

I7


41

Analysis has shown that the absolute configuration of the spiro carbon atom is not the same for all chamigrenes. A (-)-a- or (-)-b-chamigrene skeleton with trans-diequatorial 2-bromo and 3-chloro groups is found in prepacifenol epoxide ( M O ) , ~(~141),53 ( 142),53 ( 143),80 nidifocene ( 144),8' ( 145),82 and ( 146).82 The same system is probably also present in (147); the absolute configuration of (147), however, was not determined.83 A (+)-chamigrene skeleton with transdiaxial 3-bromo and 2-chloro groups, on the other hand, is found in (148) and ( 149).82 The structures of (140) and (14 1) were secured by chemical correlation with johnstonol (Scheme 8).53 The structure of nidifocene has been revised t o (1 44).81 The structures and absolute configurations of (1 45), (146), (148), ( I 49), and a related compound (150) were obtained by chemical correlation with elatol ( 15 1) and c.d. studies.82 e

l

@Br

c1 y

Br Br H0 '

R20

/

(148) R' = Br, R2 = H (149) R' = H , R2 = H

(150) R' = H , RZ = H (151) R' = Br, RZ = H

A hypothetical biogenetic scheme has been proposed which explains the form~ ~ ~scheme ~ also ation of all of the known chamigrenes from a b i ~ a b o l e n e .This accounts for the biogenesis of caespitol (1 52) and isocaespitol (1 53). Another scheme utilizes (130) as the precursor of other chamigrenes and an unusual, related acetal(1 54).M) Br

(152) R' = H , R2 = Br, R 3 = M e , R4 = (71 (153) R' = C1, R 2 = H , R3 = Br, R4 = Me

'"T. Suzuki, A. Furusaki, N . Hashiba, and E. Kurosawa, Tetrahedron Letters, ''

R3

1977, 3 7 3 1 .

S. M. Waraszkiewicz, K. L. Erickson, J . Finer, and J . Clardy, Tetrahedron Letters, 1977, 2311. A. G. Gonzalez, J . Darias, A. Diaz, J . D. Fourneron, J . D. Martin, and C . Perez, Tetrahedron Z,etters, I97 6, 3 0 5 1 . W. Fenical, Phytochemistry, 1976, 1 5 , 5 1 1.

42


A synthesis of (f)-isocaespitol has been reported.M Perforene (155)," perforenone-C ( 156),% and perforenone (1 57)% are three new metabolites from Laurencia perforata. The structure of (203) was deduced from spectral and chemical data and confirmed by synthesis of a degradation product. Compound (1 57) was identified by a biomimetic chemical correlation with perforatone (1 58) (Scheme 9). The absolute configurations of these compounds are not known. A chamigrene is proposed t o be the biogenetic precursor of these r n e t a b o l i t e ~ . ~ ~ * ~

(157) Reagents: i, Zn in HOAc/ether, RT; ii, DBN in o-xylene; iii, NaBH,; iv, Br, in CH,Cl,,

-40 O C

Scheme 9

7-Hydroxylaurene ( 159) and 10-bromo-7-hydroxylaurene (1 60) are responsible for the antibiotic activity of Laurencia suboppositu. 39 Compound ( 160), also known as allolaurinterol, is the major constituent of L . filiformis f. heterodada and occurs in that seaweed with three other new laurene-related sesquiterpenes, dihydrolaurene (16 l ) , filiformin ( 162), and filiforminol ( 163)." Filiformin (162), however, may be an artifact since ( 1 60) is slowly converted into ( 162) on standing.39b87Dihydrolaurene ( 16 1) is readily air oxidized or de84 85

A. G. Gonzalez, J . L). Martin, and M. A. Melian, Tetrahedron Letters, 1976,2279. A. G. Gonzalez, J . M. Aquiar, J . D. Martin, and M. L. Rodriguez, Tetrahedron Letters, 1976, 2 0 5 .

13'

A. G. Gonzalez, J . Darias, and J . D. Martin, Tetrahedron Letters, 1977, 3375. R. Kazlauskas, P. T. Murphy, R. J . Quinn, and R. J . Wells, Austral. J. Chem., 1976, 29, 2533.

43


hydrogenated t o laurene (164), also a constituent of these two seaweeds. The gross structure and stereochemistry (tentative) of (163) was deduced from spectra1 and chemical data. Two related bromoethers (165) and (166) have been isolated from L . glandulifera and their structures determined by comparison with a known bromoether (167) which had been isolated previously froin n

(160) R = OH, X = Br (164) R = H, X = H

(162) R = Me (163) R = CH,OH

(161)

decomposed laurenisol.88 The stereochemistry and absolute configuration of aplysinol ( 1 68) has been rigorously established by X-ray ~ r y s t a l l o g r a p h y .The ~~ only other sesquiterpene in the cuparene group which has a known absolute configuration is laurinterol.

X

(165) X = Br, R = CH,Br (166) X = H, R = CHBr, (167) X = H, R = CH,Br

(168)

The cuparene sesquiterpenes have been proposed t o arise biogenetically from a ~ h a m i g r e n e .Cuparene ~ and chamigrene sesquiterpenes co-occur in Laurencia gland ulife ra. 8a New stereoselective syntheses of racemic debromoaplysin and aplysin have been reported.g0 Sinularene (169) is a novel sesquiterpene hydrocarbon from the soft coral Sinularia rnayi.91 Its structure was deduced from an X-ray analysis of a crystalline derivative and the absolute configuration was established from a c.d. study of the ozonolysis product. Sinularene is related t o (+)+?-copaene which is also present in S. rnayi. The same biogenetic precursor has been suggested for the formation of both ( 169) and (+)-P-copaene.

'' M. Suzuki and E. Kurosawa, Tetrahedron Letters, 1976, 48 17. 89

J . A. McMillan, I. C. Paul, S. Caccamese, and K. L. Rinehart, jun., Tetrahedron Letters, 1976, 4 2 19.

90 91

R . C. Ronald, Tetrahedron Letters, 1976, 441 3 . C. M. Beechan, C. Djerassi, J . S. Finer, and J . Clardy, Tetrahedron Letters, 1977, 2 3 9 5 .

44


Axisonitrile-3 ( 170), axisothiocyanate-3 ( 17 l ) , and axamide-3 ( 172) are constituents of the sponge Axinella cannabina. 92 Compound ( 17 1) was isolated as a thiourea derivative (173) which proved t o be identical with (227) produced from ( 170) (Scheme 10). A cubebene precursor has been suggested for the biogenesis of the novel spiro[ 43 ] decane system in ( 170)-( 172). \

\

(172) tii \

\

c-y

SCN

(170) Reagents: i, sulphur; ii, aqueous HOAc; iii, MeJH

r

(171)

Scheme 10

1(S)-Bromo-4(R)-hydroxy-(-)-selin-7-ene ( 174) and heterocladol ( 175)95 are two new selinane-type sesquiterpenes from Laurencia. The absolute configuration of ( 174) was determined by relating it t o o p l o d i ~ l and ~ ~ (>- )~- 6 - ~ e l i n e n e . ~ ~ Oppositol (176) and two related, epimeric diols (177) and (178) are constituents of Laurencia subopposita. 39 The absolute configurations of ( 177) and (178) were deduced by relating the two diols t o (176), but it was not possible t o decide the relative stereochemistry of the epimeric carbon. The structure assignments are therefore tentative. Two biogenetic pathways t o (176) have " 93 y4

9s

B. D. Blasio, E. Fattorusso, S. Magno, L. Mayol, C. Pedone, C. Santacroce, and D. Sica, Tetrahedron, 1 9 7 4 , 32, 4 1 3 . B. M. Howard and W. Fenical, J. Org. Chern., 1 9 7 7 , 4 2 , 2 5 18. A. F. Rose and J . J . Sirns, Tetrahedron Letters, 1 9 7 7 , 2 9 3 5 . K. Kazlauskas, P. T. Murphy, K. J . Wells, J . J . Daly, and W. E. Oberhansli, Austral. J. Chem., 1 9 7 7 , 30, 2 6 7 9 .

Marine A lip h at ic Natural Products

45

ITr

Br

Br

Br I

(177) (178)

R' = H, R2 = OH R' = OH, R2 = H

been suggested, one utilizing (1 75) as a precursor9' and the other a cyclopropane intermediate which could also lead t o (1 75).39 Axisonitrile-4 ( 179), axiso'thiocyanate-4 (1 80), and axamide-4 ( 18 1) are three minor sesquiterpenes from the sponge Axinella cannabina.% Compounds (179)-(181) were inter-related by the same reactions outlined in Scheme 10. The relative stereochemistry of axisonitrile-1 ( 182), axisothiocyanate-1 (1 83), and axamide-1 (1 84) was determined by X-ray analysis and the absolute configuration of the axane system for (1 79)-( 184) was established by a c.d. study of the ketone (1135),~~obtained by Na/NH3 reduction of (182) t o ( 186) followed by ozonolysis. Compound (186) was also obtained from Na/NH3 reduction of (179).

96 97

A. Iengo, L. Mayol, and C. Santacroce, Experientia, 1977, 33, 1 1 . M. Adinolfi, L. De Napoli, B. Di Blasio, A. Iengo, C. Pedone, and C. Santacroce, Tetrahedron Letters, 1977, 2815.

46


Two sesquiterpenes (187) and (188) from soft corals of the genera Lemnalia and Paralemnalia have been chemically correlated t o lemnacarnol (1 89) which has a known relative stereochemistry and absolute configuration (antipodal to the nardosinan sesquiterpenes of terrestrial origin) .98

(+)-Palustrol ( 190)99 allo-aromadendrene ( 19 l ) , (-)-viridiflorol ( 192), and (+)-led01 (193) are constituents of the soft coral Cespitularia aff. subviridis. loo (-)-Palustrol, (+)-viridiflorol, and ( 193) have been found in several terrestrial plants. (+)-Led01 constitutes the first exception t o the intriguing antipodal relationship between sesquiterpenes from marine coelenterates and their corresponding terrestrial forms."' 1-Hydroxyallo-aromadendrene (1 94) and another alcohol (1 95) have been isolated from Laurencia subopposita. 39 Oxidation of allo-aromadendrene with selenium dioxide gave an alcohol that was identical with (194) in every respect except sign of optical rotation. The relative stereochemistries of ( 194) and ( 195) were deduced from LIS studies. The absolute configurations were not secured. Dactylol (196) is a constituent of Aplysia dactylomela." Its structure appears to be related t o aromadendrene.

(191) (194)

98

99

loo

R = H R = OH

D. Daloze, J . C. Braekman, P. Georget, and B. Tursch, BulZ. SOC. chirn. belges, 1977, 8 6 , 47. C. J. Cheer, D. H. Smith, C. Djerassi, B. Tursch, J . C. Braekman, and D. Daloze, Tetrahedron, 1976, 32, 1807. J . C. Braekman, D. Daloze, R. Ottinger, and B. Tursch, Experientia, 1977, 33, 993. J . C. Braekman, in ref. 29, p. 5 .


47

Oplopanone (1 97) and a diol ( 198) have also been isolated from Laurencia subopposita. 39 The diol ( 198) undergoes dehydration and rearrangement when treated with phosgene in pyridine o r Moffatt oxidation conditions t o (1 99). Dehydration of (197) with phosphorus oxychloride in pyridine also gives (1 99).

Five sesquiterpenes with a novel, non-isoprenoidal skeleton (200, capnellane), i.e. (20 1)--(205), have been isolated from the soft coral Capnella i r n b r i ~ a t a . " ~ ~ ' ~ A biogenesis whereby a farnesol pyrophosphate isomer cyclizes and C-13 migrates from position five t o four has been suggested.

HoM HO

(202) R' = R3 = R4 = H, R2 = OH (203) R1 = R2 = R4 = H, R3 = OH (204) R2 = R3 = R4 = H, R' = OH

(205)

Diterpenes.-Free cis- and trans-phytol are present in the red alga Gracilaria andersoniana. ' 0 4 ( - ) - ( R ) - 1-0-geranylgeranylglycerol is a constituent of the brown alga Dilophus fasciola. lo5 Four terpenoidal compounds which may arise from degradation of geranylgeraniol have been isolated from marine organisms. trans, trans-Farnesylacetone (206) and hexahydrofarnesylacetone (207) are constituents of a bioactive lipid fraction from the androgenic glands of the male crab Carcinus rnaenas.'06B'07 102

Y. M. Sheikh, G. Singy, M. Kaisin, H. Eggert, C. Djerassi, B. Tursch, D. Daloze, and J. C. Braekman, Tetrahedron, 1976, 3 2 , 1171. Y. M. Sheikh, C. Djerassi, J. C. Braekman, D. Daloze, M. Kaisin, B. Tursch, and R. Karlsson, Tetrahedron, 1977, 33, 2 1 15 Io4 J. J. Sims and J. A. Pettus, jun., Phytochemistry, 1976, 15, 1076. lo' V. Amico, G. Oriente, M. Piattelli, C. Tringali, E. Fattorusso, S. Magno, and L. Mayol, Experientia, 1977, 3 3 , 989. ' 0 6 J-P. Ferezou, J . Berreur-Bonnenfant, A. Tekitek, M. Rojas, M. Barbier, M. Suchy, H. K. Wipf, and J. J . Meusy, in ref. 29, p. 361. lo'J. P. Ferezou, J. Berreur-Bonnenfant, J. J. Meusy, M. Barbier, M. Suchy, and H. K. Wipf, Experientia, 1977, 33, 290. 103

48


Oxocrinol acetate (208) and crinitol (209) are present in the brown alga Cystoseira crinita;'08 oxocrinol and (*)-crinitol have been s y n t h e ~ i z e d . " ~

The polyprenyl chromans (210) and (211) are minor constituents of the brown alga Cystophora t o r u l o ~ a .Compound ~~ (210) is the methyl ether of 6-tocotrienol, a settling factor for the metamorphosis of the swimming larvae of the hydrozoan Coryne uchidai on the brown alga Sargassum tortile. The position of the extra methyl group on the aromatic ring of (21 1) was not determined. (-)-Caulerpol (212), which is related t o retinol, is a major constituent in the green alga Caulerpa bro wnii. 'lo

109

""

E. Fattorusso, S. Magno, L. Mayol, C. Santacroce, D. Sica, V. Amico, G. Oriente, M . Piattelli, and C. Tringali, Tetrahedron Letters, 1976, 937. T. Kato, H . Takayanagi, T. Uyehara, and Y . Kitahara, Chem. I,etters, 1977, 1009. A. J . Blackman and K. J . Wells, Tetrahedron f,etters, 1976, 2729.

Marine A liph a t ic Na t u ral Products

49

Isoaplysin-20 (213) has been isolated from the sea hare Aplysia kurodai.'" The proposed structure is based on spectral data and co-occurrence with the known aplysin-20 (2 14).

Neoconcinndiol hydroperoxide (2 15) is a novel metabolite of Laurencin snyderiae. 11* The structure and relative stereochemistry of (2 15) were solved by X-ray analysis, but the absolute configuration could not be determined. The compound is biogenetically related t o concinndiol(2 16).

Di-isocyanoadociane ( 2 17) is a novel tetracyclic diterpenoid from a sponge of the genus Adocia. ' 1 3 Its structure and relative stereochemistry were determined by X-ray crystallography. The absolute configuration is uncertain. The formation of the perhydropyrene system might be accomplished by a unique cyclization of a geranylgeraniol residue and an accompanying methyl shift.

H

H

N

111 112

113

S. Yamamwayand Y . Terada, Tetrahedron Letters, 1977, 2 17 1 . B. M . Howard, W. Fenical, J . Finer, H. Hirotsu, and J . Clardy, J. Amer. Chem. Soc., 1977, 9 9 , 6 4 4 0 . J. T. Baker, K. J . Wells, W. E. Oberhgnsli, and G . B. Hawes, J. Amer. Chem. SOC., 1976, 98. 401 0.

50


Xenicin (218), isolated from the soft coral Xenia elongata, possesses a ninemembered carbocyclic ring trans-fused t o a dihydropyran ring."4 Acetoxycrenulatin (219), a metabolite of the brown seaweed Dictyota crenuzata, appears t o be biogenetically related."' The structure of (218) was secured by X-ray analysis, whereas the gross structure of (219) was proposed from spectral and chemical data.

os 0

AcO

Several diterpenes related to pachydictyol A (220) have been found in brown algae of the family Dictyotaceae. Four of these hydroazulenes, dictyol A, B, C, and D (221)-(224), have been isolated from Dictyota d i ~ h o t o r n a " ~ ' ~and ~ ' the

16

(220) R = H (222) a; R = OH b; R = OAc

(223)

'15 '16

'17

(224)

D. J . Vanderah, P. A. Steudler, L. S . Ciereszko, F. J . Schmitz, J . D. Ekstrand, and D. van der Helm, J. Arner. Chern. SOC., 1977, 99, 5780. F. J . McEnroe, K, J . Robertson, and W. Fenical, in ref. 2 9 , p. 179. E. Fattorusso, S . Magno, L. Mayol, C. Santacroce, D. Sica, V . Amico, G. Oriente, M. Piattelli, and C. Tringali, J.C.S. Chem. Cornm., 1 9 7 6 , 5 7 5 . B. Danise, L. Minale, R. Riccio, V. Amico, G. Oriente, M. Piattelli, C. Tringali, E. Fattorusso, S. Magno, and L. Mayol, Experientia, 1 9 7 7 , 33, 413.

51

Marine A lip hat ic Na t u ral Products

digestive gland of the mollusk Aplysia depilans'17y"8 which is known t o feed on

D. dichotoma. Dictyol E (225) is a major constituent of Dilophus ligulatus.l17 The stereochemistry of the chiral centres in the ring of (221)-(225) was deduced, but not of the side chain asymmetric carbon in (225). Dictyotadiol (226) and dictyol B acetate (222b) are also constituents of D. dichotoma.*19 Pachydictyol-A epoxide (227) has been isolated from D.jlabellata. 120 Dictyoxepin (228) and dictyolene (229), which is the first example of a naturally-occurring cis-decalin with a 1,3-diene system, are present in Dictyota

Scheme 11

'18

L. Minale and R. Riccio, Tetrahedron Letters, 1976, 2 7 1 1. D. J . Faulkner, B. N. Ravi, J . Finer, and J . Clardy, Phyrochernistry, 1977, 16, 991. K. J . Robertson and W. Fenical, Phytochemistry, 1977, 16, 1071.


52

acutiloba.121 A thermally allowed disrotatory ring closure of (230) to (229) and a [ 3,3 J sigmatropic shift of the epoxide (23 1) t o (228) have been proposed for the biogenesis (Scheme 11). Dilophol (232) is a constituent of the brown alga Dilophus ligulatus122and appears to be biogenetically related t o (220)-(229).

Fourteen diterpenes having a novel 5 ,1 1-bicyclic carbon skeleton (dolabellane) have been isolated from the digestive gland of the sea hare DolabelZa californica. One of the diterpenes, 10-acetoxy-18-hydroxy-2,7dolabelladiene, was shown by

(234) (235) (236) (237) (238) (239) (246)

12'

122

R = A c , X = OAc, Y = H R = H, X = OH, Y = H R = H , X = OAc, Y = OAc R = H , X = OAc, Y = OH R = Ac, X = OH, Y = OH R = H, X = OH, Y = OH R = H, X = H, Y = H

(240) (241) (242) (243) (244) (245)

R' R' R' R' R' R'

R2 = Ac, R' = Ac Ac, R2 = Ac, R3 = H Ac, RZ = H, R' = Ac H, R2 = Ac.R3 = Ac Ac, R2 = H, R3 = H H, R2 = H, R3 = H

= Ac,

= = = = =

H. H. Sun, S . M. Waraszkiewicz, K. L. Erickson, J . Finer, and J . Clardy, J. Amer. Chem. Soc., 1977,99, 35 16. V. Amico, G. Oriente, M. Piattelli, C. Tringali, E. Fattorusso, S . Magno, and L. Mayol, J.C.S. Chem. Comm., 1976, 1024.


53

X-ray analysis to have structure (233),'23 Twelve compounds (234)-(245) were chemically correlated to (233); the structure of (246) was determined from spectral data.124*125 Dolatriol (247a) and the 6-acetate (247b) are two cytotoxic compounds that have been isolated from DoZZabeZZa auricuzaria. 126 Both (247a) and (247b) show antineoplastic activity. The structure of (247b) was determined by X-ray crystallography.

OR (247) a; R = H b ; R = COMe

Several new cembranoid diterpenes have been isolated from gorgonians'*' and alcyonarians (soft corals).lol, 128-133 Asperdiol(248) is an antineoplastic agent from Eunicea asperuZu and E. tourneforti.127 Three anticancer agents, two of them, sinularin (249) and dihydrosinularin (250), new compounds and the third the previously reported sinulariolide (25 l ) , have been isolated from SinuZaria flexibizis. 12' Minor amounts of (252), (253), the already known R(-)-cembrene A (254), and the novel 1R ,3S,4S,llS,12S-diepoxycembrene A (255) have also been isolated from S. f l e ~ i b i 1 i s . lThe ~ ~ diepoxide ( 2 5 5 ) may be the biogenetic precursor of (25 l)!29 Lobolide (256), which is toxic t o fish, is a constituent of a Lobophytum s p . from the Red Sea.130 A related y-lactone (257), in which the ring fusion is tentatively assigned t o be cis, is present in Lobophytum crassurn. 131 Crassolide (258, stereochemistry unknown) is also a constituent of L . crassum!O1 A new cembranoid diterpene has also been isolated from Lobophytum michaelue. 132 A dehydro derivative of epoxynephthenol is reported from a

C. Ireland, D. J . Faulkner, J . Finer, and J . Clardy, J. Arner. Chern. SOC., 1976, 98, 4 6 6 4 . C. Ireland and D. J . Faulkner, J. Org. Chem., 1977, 4 2 , 3157. 12' D. J . Faulkner and C. Ireland, in ref. 2 9 , p. 23. l Z 6 G. R. Pettit, R. H. Ode, C. L. Herald, R. B. Von Dreele, and C. Michel, J. Arner. Chem. SOC., 1976, 98, 4677. 12' A. J . Weinheimer, J . A. Matson, D. van der Helm, and M. Poling, Tetrahedron Letters, 1977, 1295. 12* A. J . Weinheimer, J . A. Matson, M. B. Hossain, and D. van der Helm, Tetrahedron Letters, 1977, 2923. lZ9 M. Herin and B. Tursch, Bull. SOC. chim. belges., 1976, 85, 707. 130 Y. Kashman and A. Groweiss, Tetrahedron Letters, 1977, 1 1 59. 13' B. F. Bowden, J . A. Brittle, J . C. Coll, N. Liyanage, S. J . Mitchell, and G. J . Stokie, Tetrahedron Letters, 1977, 3661. 132 J . C. Coll, S. J . Mitchell, and G. J . Stokie, Austral. J. Chern., 1977, 30, 1859. 133 J . C. Coll, G. B. Hawes, N . Liyanage, W. Oberhansli, and R. J . Wells, Austral. J. Chern., 1977, 30, 1305. 123

124

54


(251) R = H (252) R = OH

Sarcophyton sp; its structure (259) has been deduced from spectroscopic

evidence and confirmed by X-ray a n a 1 y ~ i s . l ~ ~ Flexibilene (260) is an unprecedented fifteen-membered ring diterpene hydroAcetoxycladiellin (26 1) and carbon from the soft coral SinuZaria flexibilis. cladiellin (262) are two new diterpenes related t o eunicellin from a soft coral, CZadieZZa sp,; the structure of (261) was secured by X-ray analysis and chemical data.’35 Stylatulide (263), a chlorine-containing diterpene which is toxic to

134

135

M. Herin, M. Colin, and B. Tursch, Bull, SOC.chim. belges., 1976, 85, 801. K. Kazlauskas, P. T. Murphy, K. J . Wells, and P. Schonholzer, Tetrahedron Letters, 1977, 4643.

55


P H(262)OAc

AcO

OAc

I

0 '

OAc

,

I

(263)

larvae of a copepod, is a major metabolite of the sea pen Stylatula sp.; its structure was determined by X-ray ~ r y s t a l l o g r a p h y . ' ~A~related compound, ptilosarcone (264), which was found t o be toxic t o mice, has been isolated from the sea pen Ptilosarcus g ~ r n e y i ; ' ~ 'its structure was determined by spectral comparison with the closely related briarein A (265), a metabolite of Briareurn asbestinurn, whose structure was elucidated by X-ray analysis.

0

0

Sphaeracoccenol A'38 (266) and bromosphaer01'~~( 2 6 7 ) are rearranged bromo-diterpenes from the red alga Sphaerococcus coronopifolius. Both structures have been rigorously established by X-ray analysis. Sesterterpenes.-Many sponges of the order Dictyoceratida contain sesterterpenes. Two types have been found, one a group of tetra- or penta-cyclic sesterterpenes which appear t o be biogenetically derived from a geranylfarnesyl

136

S. J . Wratten, D. J . Faulkner, K. Hirotsu, and J . Clardy,J. Arner. Chem. SOC., 1977, 99, 2824.

137

S. J . Wratten, W. Fenical, D. J . Faulkner, and J . C. Wekell, Tetrahedron Letters, 1977, 1559.

138

W. Fenical, J . Finer, and J . Clardy, Tetrahedron Letters, 1976, 731. 1 3 9 E. Fattorusso, in ref. 29, p. 165.

56

Aliphatic and Related Natural Product Chemistry Br

precursor via a cyclization that is typical of triterpenes, and the other a series of linear sesterterpenes, which have a furan ring at one end and a tetraonic acid or a lactone ring at the other. The unusual C2, furanoterpenes that are present in some of these sponges are probably degraded sesterterpenes. lo Two minor sesterterpenes of Spongia nitens have been identified as C-12 epimers of scalarin (268) and deoxoscalarin (269)." With the aid of c.d. and H and 13C n.m.r. spectroscopy, the total relative stereochemistry and absolute configuration has been assigned t o (268), (269), and to the new compounds, 12epi-scalarin (270) and 12-epi-deoxoscalarin (27 1). Furanoscalarol, a metabolite of Cacospongia mollior, possesses a furan ring and has been assigned structure (272) on the basis of chemical and spectral evidence; the A dihydrofuran, heteronemin, stereochemistry of (272), however, is not is present in Heteronema erecta and is proposed to have structure (273) from QH

(268) R = w O A c (270) R = 0-OAc

140

14'

OH

(269) R = c~-OAC (271) R = B-OAC

G. Cimino, S. De Stefano, L. Minale, and E. Trivellone, J.C.S. Perkin I, 1977, 1587. F. Cafieri, L. De Napoli, E. Fattorusso, C. Santacroce, and D. Sica, Gazzetta, 1977, 107, 71.


57

chemical and spectral data;14* an all trans-anti-trans configuration has been assigned from I3 C n.m.r. a n a 1 y ~ i s . l ~ ~ Molliorin-A (274) and molliorin-B (275) are unique scalarin-like pyrroloterpenes from Cacospongia moblior. 144J45 Molliorin-A has been synthesized 144 from scalaradial (276), also a constituent of C. mollior, 14’ and de-2-methylbutylamine. The mass spectra of natural and synthetic (274) were identical, but comparison of the optical properties for the two products was not reported. Similarly (275) was synthesized from (276) and 1,4-diaminobutane.14’ Isoleucine, ornithine, and (276) are probably the precursors of (274) and (275).

N-CH,-CH,t

8 Ircinolide (277a) and 24-hydroxyircinolide (277b) are two major metabolites of Thorecta marginalis. 146 The difuranoterpenes were identified from spectral data. The absolute configuration at C-18 is not known. Ircinianin (278) is a novel polycyclic sesterterpenetetronic acid that has been isolated from an Australian Ircinia sp. Its structure was established by X-ray analysis .146a

R. Kazlauskas, P. T. Murphy, R. J . Quinn, and K. J . Wells, Tetrahedron Letters, 1976, 2631. ‘ 4 3 Y. Kashman and A. Rudi, Tetrahedron, 1977, 33, 2997. ‘44 F. Cafieri, L. De Napoli, E. Fattorusso, C. Santacroce, and D. Sica, Tetrahedron Letters, 1977,477. 14’ F. Cafiari, L. De Napoli, E. Fattorusso, and C. Santacroce, Experientia, 1977, 3 3 , 994. 146 R. Kazlauskas, P. T. Murphy, R. J . Quinn, and R. J . Wells, Tetrahedron Letters, 1976, 2635. 146a W. Hofheinz and P. Schonholzer, Helv. Chim. A c t a , 1977, 6 0 , 1367.

58


(277) a; R = Me b ; R = CH,OH

H I

Furospongenol (279) and furospongenone (280) are two new Czl furanoterpenes from an Australian Spongia. 14’ Jones oxidation converted (279) into (280). Tetradehydrofurospongin-1 (28 l ) , also from an Australian Spongia, is a closely related rnetab01ite.l~~

R

(279) R = H, OH (280) R = 0

Triterpenes and Steroids.-Over 1 00 sterols have been identified from marine o r g a n i ~ r n s . ~ ~Many ~ * ~ ’phytosterols ~ contain an alkyl group at C-24. In general algae produce sterols with the 24P-configuration, whereas in most higher plants the sterols have the 24a-configuration. C-24 epimers can be distinguished by 147

K. Kazlauskas, P. T. Murphy, R. J . Quinn, and R. J. Wells, Tetrahedron Letters, 1976, 1333. 148 R. Kazlauskas, P. T. Murphy, R. J. Quinn, and R. J. Wells, Tetrahedron Letters, 1976, 1331. 149 J . T. Baker and V. Murphy, ‘Handbook of Marine Science Compounds from Marine Organisms’, Vol. I, CRC Press, Cleveland, 1976. Is’ C. Djerassi, R . M. K. Carlson, S. Popov, and T. H . Varkony, in ref. 29, p. 1 1 1 .

59


n.m.r. spectroscopy. lS1 Many sterols have unusual side chains, but generally these non-conventional sterols1s2 are minor constituents in complex sterol mixtures.153 Two unprecedented acetylenic sterols, cholest-5en-23-yn-3P-01 (282) and 26,27-dinorcholest-5-en-23-yn-3~-01 (283), and a new unsaturated sterol (284) are minor sterols in the sponge Calyx nicaaensis.'Y1 The structures of (282) and (283) were rigorously established by synthesis from stigmasta-5,22dien-3P-ol. Several synthetic attempts to convert (282) into calysterol (285), the major sterol in this sponge, were unsuccessful. In a biosynthetic study of calysterol, however, [ 7-3Hlfucosterol was successfully converted into labelled (2841, but tritiated stigmasterol and 0-sitosterol did not serve as 19-Nor As-sterols (286)-(288) have been found for the first time in the gorgonian Pseudoplexeura porosa. lSs The three new sterols were isolated as

22

(286) R = H (287) R = Me (288) R = Et; A22 15' 152 153 154

155

I. Rubinstein, L. J . Goad, A. D. H . Clague, and L. J . Mulheirn, Phytochemistry, 1976, 15, 195. L. Minale and G. Sodano, in ref. 29, p. 87. S. Popov, R. M. K. Carlson, A. Wegmann, and C. Djerassi, Steroids, 1976, 28, 699. E. Steiner, C. Djerassi, E. Fattorusso, S. Magno, L. Mayol, C. Santacroce, and D. Sica, Helv. Chim. Acta, 1977,60, 475. S. Popov, R. M. K. Carlson, A-M. Wegmann, and C. Djerassi, Tetrahedron Letters, 1976, 349 1.

60

Aliphatic and Related Nutural Product Chemirtry

acetates (286)--(288) and identified by mass spectrometry. The structure assignments of (287) and (288) are tentative. 19-Norcholesterol has also been detected in Plexa ura h o m o rnalla. The sponge Axinella verrucosa contains exclusively 3P-hydroxymethylA-nor-Sa-cholestanes with conventional saturated and A2*-unsaturated C8 , Cg, and Clo side chains. The sponge does not incorporate acetate into the A-nor-steranes, but it readily converts [ 4-14 C]cholesterol into 3P-hydroxymethyl-A-nor-5a-cholestane labelled at C-3 (Scheme 12).l S 6

Scheme 12

Dinosterol (289) is an unusual (2% sterol from the toxic dinoflagellate Gonyaulax tamarensis.lS7 The chemical and spectral work did not define the geometry of the A22 double bond or the configuration at C-24. These two points however, have been solved by X-ray analysis. 15* A novel sterol with a modified bile acid side chain has been isolated as the acetate (290) from the sea pen Ptilosarcus gurneyi. l S 9 Three other sterols,

believed to be 5,6-dihydro, 22,23-dihydro, and 5,6,22,23-tetrahydro analogues of (290) have also been detected. The stereochemistry at C-20 in (290) is opposite to that in the bile acids. The structure of (290) was rigorously established by synthesis. Both C-20 epimers were synthesized.

156

15' 159

M. de Rosa, L. Minale, and G. Sodano, Experientiu, 1976, 32, 1 1 12. Y . Shimizu, M. Alam, and A. Kobayashi, J. Amer. Chem. SOC.. 1976, 98, 1059. J . Finer, K. Hirotsu, and J. Clardy, in ref. 2 9 , p. 147. D. J , Vanderah and C. Djerassi, Tetrahedron Letters, 1977, 6 8 3 .


61

Three free pregnane derived sterols (29 1)-(293) have been detected as minor constituents in the sponge Haliclona rubens. 16* The sterols were identified by g.c.-m.s. and comparison with authentic samples. The soft coral Gersemina rubiformis, also known as the sea raspberry, contains an usual steroid (294) with a vinyl side chain.'61 The structure of (294) was deduced from spectral data and verified by synthesis from progesterone. Dienone (294) has also been isolated from another, unidentified soft coral along with the three related pregnane derivatives (295)-(297).162

Ad''

H (296) R = H (297) R = OH

Lobosterol (298) is a novel sterol from the soft coral Lobophyturn pauciflorum. 163 It possesses a 3,4,5,6-oxidation pattern unprecedented for natural sterols and a cis A/B ring fusion which had not been previously reported for marine sterols. The structure and relative stereochemistry was determined by an X-ray analysis of 4-lobosterol p-bromobenzoate. The absolute configuration was solved by a c.d. study of (298), which showed a negative Cotton effect, typical of 6-ket osteroids with the 5P-configuration. 24-Methylenecholest-5-en-3@,7@, 19-trio1 (299) is a constituent of the soft coral Litophyton viridis. lWIts structure was established by X-ray crystallography. The trio1 is accompanied by the 7-monoacetate. This is the first example of a naturally-occurring 19-hydroxysterol, a possible intermediate in the formation of 1%nor steroids. Scu-Cholestane-3P,S,6/3,9-tetrol (300) has been isolated l6' 16' 16' 163

lh4

J . A. Ballantine, K. Williams, and B. A. Burke, Tetrahedron Letters, 1977, 1547. J. F. Kingston, B. Gregory, and A. G. Fallis, Tetrahedron Letters, 1977,4261. M. 0.Higgs and D. J . Faulkner, Steroids, 1977, 30, 379. B. Tursch, C. Hootele, M . Kaisin, D. Losman, and K. Karlsson, Steroids, 1976, 27, 137. M. Bartolotto, J . C. Braekman, D. Deloze, D. Losman, and B. Tursch, Steroids, 1976, 28,461.

62


from the gorgonian, Pseudopterogorgia elisabefhae and identified by spectral analyses and degradative studies.

OH

J"

II 0

HOW (298)

'OH (299)

The gorgonian Isis hippuris contains a novel polyoxygenated steroid, hippurin-1 (301), with a ketal f ~ n c t i o n a l i t y . 'Its ~ ~ structure was obtained by X-ray analysis of the acetate (302) and 0.r.d. studies of two ketones from oxidation of (301) showed that hippurin-1 had the normal absolute configuration found in sterols.

(301) R' = H , RZ = Ac (302) R', RZ = Ac

Thelothurins A (303) and B (304) are two defensive saponins from the sea cucumber Thelonata ananas. The structure and sequence of the carbohydrate moiety of the saponins has been established by degradation.166 The first sugar has an unidentified substituent ( X ) which is different from a sulphate group. Hydrolysis of thelothurins A and B with aqueous acetic acid yielded two aglycones, 23t-acetoxy-A8 -holostene-3&01 (305) and 2 3 , $ - a ~ e t o x y - A-holo~~' stadiene-3P-01 (306), which were identified by chemical interconversion and correlation with the already known seychellogenin ( 307)?j7 Six other triterpene 164aF. J . Schmitz, D. C. Campbell, and I. Kubo, Steroids, 1976, 2 8 , 2 1 1 .

'"

I66 16'

R. Kazlauskas, P. T. Murphy, R. J. Quinn, R. J. Wells, and P. Schonholzer, Tetrahedron Letters, 1977, 4439. A. Kelecom, B. Tursch, and M . Vanhaelen, Bull. SOC.chim. belges., 1976, 8 5 , 2 7 7 . A. Kelecom, D. Daloze, and B. Tursch, Tetrahedron, 1976, 32, 2313.

63


CH,OH I

OH

I

CH,OH

7

.'H

0

I

-0

I

OH

I

OH (303) R' = RZ = H (304) Rr = R 2 = c=c

OAc

I

CH,OH

X: unidentified substituent

genins, all considered t o be artifacts, were obtained by hydrolysis of thelothurins A and B with aqueous hydrochloric acid.'68 The structure and sequence of the oligosaccharide portion of the major saponin from the starfish Acanthaster planci has been determined.'69

Most of the echinoderm saponins are cytotoxic. Three saponins have been isolated from sea cucumbers which possess antineoplastic and cytotoxic activity , viz. stichostatin- 1 from Stichopus chloronotus, thelenostatin-l from Thelenota ananas, and actinostatin- 1 from Actinopyga mauritiana. Preliminary chemical evidence suggests that stichostatin- 1 contains a lanostane nucleus related to (308). Thelenostatin-1 and actinostatin-1 were found t o be half-esters of sulphuric acid similar to holothurin A. Holothurin A contains the lanostane system illustrated by (309). 168 169

170

A. Kelecom, D. Daloze, and B. Tursch, Tetrahedron, 1976, 32, 2 3 5 3 . I. Kitagawa and M . Kobayashi, Tetrahedron Letters, 1977, 859. G. R. Pettit, C. L. Herald, and D. L. Herald,J. Pharm. Sci., 1976, 65, 1558.

64


Echinoderms can utilize acetate for de novu sterol biosynthesis. The sea cucumber Stichupus califorizicus can biosynthesize labelled sterols from [ 2-3H] a ~ e t a t e . ' ~ '[ 1-l4C]Acetate has been incorporated into the aglycone moiety of thelothurins A and B; interestingly, radioactivity could not be detected in the sugars.'68 Tritiated acetate has also been incorporated into holotoxinogenin ( 3 10) from S. califurnicus. 172 [ 3-3H]Lanosterol, [ 1, z 3 H 2 ] cholesterol, and [ 3-3H] A7-cholestenol have been successfully transformed into As and A' sterols and labelled lanosterol has been converted into ( 3 10) in S. californicus. [ 4-I4C] Cholesterol is metabolized to labelled 30-hydroxy-Sa-pregnan-2-one ( 3 1 1), 5a-pregnane-3P,20gdiol ( 3 12), and Sa-cholestane-3P,6a-diol ( 3 13) in the starfish Asterias rubens.

j H d 0

A4-p

HO

H (310)

Y O H

&

HO

"' '"

H OH '

(313)

Y. M . Sheikh and C. Djerassi, Tetrahedron Letters, 1977, 31 11. Y . M . Sheikh and C. Djerassi, J.C.S. Chem. Comm., 1976, 1057. S. I. Teshima, K. Fleming, J . Gaffney, and L. J . Goad, in ref. 2 9 , p. 133.

I


65

Carotenoids.-The distribution of carotenoids in marine algae has been summarized in a review.'74 Caloxanthin ( 3 14) and nostoxanthin ( 3 15) are two carotenoids from the blue-green alga Anacystis nidulans. 175 Their absolute configurations have been determined from c.d. and n.m.r. data.

The absolute configuration of fucoxanthin ( 3 16), the characteristic pigment of brown algae, has been established as ( 3 S , 5R, 6S, 3'S, 5'R, 6'R), whereas the absolute configuration of the allenic isomer. which is present in some seaweeds and is formed on stereomutation, is (3S, 5R,6 S , 3'S, 5'R, 6'S).'76 Full details of the gross structure determination of peridinin ( 3 17), the characteristic major carotenoid of dinoflagellates, have appeared in print .177$178 The relative stereochemistry and absolute configuration of (3 17) has been solved by chemical correlation with ( 3 16) and violaxanthin, both of known ~ h i r a 1 i t y . l ~ ~ Ozonolysis of peridinin p-bromobenzoate ( 3 18) gives an allenic ketone ( 3 19) which is identical in all respects, including c.d. properties, with (319) from ozonolysis of ( 3 16). Ozonolysis of ( 3 18) also produces an aldehyde (320) which is identical in spectral and c.d. properties with (320) from ozonolysis of violaxanthin di-p-bromobenzoate (321) (Scheme 13). The pigment dinoxanthin (322) is also found in dinoflagellates and possesses the same end groups as (317). The absolute configuration of (322) has been determined by chemical correlation with neoxanthin of known ~ h i r a 1 i t y . l ~ ~ Dinoxanthin (322) is suggested t o be the biogenetic precursor of (316) and ( 3 17).

174 176

"* 179

S. Liaaen-Jensen, in ref. 29, p. 239. K. Bernhard, G. P. Moss, G. Toth, and B. C. L. Weedon, Tetrahedron Letters, 1976, 1 1 5 . R . Buchecker, S. Liaaen-Jensen, G . Borch, and H. W. Siegelman, Phytochemistry, 1976, 15, 1015. H. H. Strain, W. A. Svec, P. Wegfahrt, H. Rapoport, F. T. Haxo, S. Norgard, H. Kjgsen, and S. Liaaen-Jensen, Acra Chem. Scand., 1976, B30, 109. H. KjQsen, S. Nordgard, S. Liaaen-Jensen, W. A. Svec, H . H. Strain, P. Wegfahrt, H. Kapoport, and F. T. Haxo, Acta Chem. Scand., 1976, B30, 157. J. E. Johansen and S. Liaaen-Jensen, in ref. 29, p. 225.

66


Marine A lip hat ic Na t u ral Prod u ct s

67

Peridinin (317) is unusual in that it lacks three of the forty carotenoid carbons. Biogenetic schemes have been proposed for the loss of an acetylenic three-carbon unit via a photochemically allowed electrocyclic reaction and for the formation of the butenolide ring.lm

3 Acyclic Terpenoids BY D. H. GRAYSON

1 Introduction

This Chapter covers the main developments in the chemistry of acyclic terpenoids for the years 1976 and 1977. Inevitably, there will be some overlap with the relevant sections of the Specialist Periodical Reports on ‘Terpenoids and Steroids’ for these years. Acyclic terpene-derived natural products obtained from marine organisms, and terpenoid insect pheromones have been excluded from consideration as their chemistry is dealt with in Chapters 2 and 4 of this Volume. Every effort has been made t o take cognisance of all appropriate papers which have appeared during the period under review. However, some degree of selectivity has had t o be exercised owing t o spatial limitations, and the nonmention of any particular publication should not thereby be taken as implying its damnation with faint praise.

2 Isoprene Chemistry Methods for the specific oligomerization of isoprene (1) continue t o attract attention. The best yields and selectivity for the H-T dimerization of ( 1 ) to (E)-2,6-dimethylocta-1,3,7-triene (2) are obtained’ with bis-n-allylpalladium chloride and bis(tributy1phosphine)nickel chloride as catalysts in a 1 : 1 mixture of methanol and propan-2-01. Pd(acac)z o r Pd(OAc)2 together with tri-u-tolylphosphite in acetic acid solution catalyse the telomerization of (1) t o a mixture of dimeric acetates, including those of nerol (28%) and geraniol (23%).2 With Pd(acac)2/PPh3 and methanol as solvent, the H-H dimer ( 3 ) (60%) is formed together with the ethers (4) ( 1 5 % ) and (5) (1 2%).3 Substitution of Pd(OAc)2 for P d ( a ~ a c )alters ~ the product distribution to ( 3 ) (40%), (4)(22%), and ( 5 ) (33%). Using a nickel catalyst system, isoprene (1) has been selectively converted into the trimer ( 6 ) and the natural product 0-trans-farnesene (7): Co-oligomerization of ( 1) with methyl methacrylate using a soluble nickel catalyst yields (8) when one equivalent of diene is present, o r the mixture of isomers (9)-( 1 1) with two equivalents.’ Another nickel-catalysed co-oligomerization is that of ( 1) with acetone t o give the alcohols (1 2) and (1 3).6

’ H. Yagi, E. Tanaka, H. Ishiwatari, M . Hidai, and Y . Uchida, Synthesis, 1977, 334.

L. I. Zakharkin, S. A. Babich, and I. V . Pisareva, Zzvest, Akad. Nauk S.S.S.R.,Ser. Khim., 1976,1616 (Chem. Abs., 1976, 8 5 , 123 263). L. I. Zakharkin and S. S. Babich, Zzvest. Akad. Nauk S.S.S.R., Ser. Khim., 1976, 2099 (Chem. A h . , 1 9 7 7 , 8 6 , 167 98). S . Akutagawa, T. Taketomi, and S. Otsuka, Chem. Letters, 1976, 485. E. Klein, F. Thomel, H . Struwe, P. Heimbach, and H. Schenkluhn, Jusnts Liebigs Ann. Chem., 1 9 7 6 , 3 5 2 . ’ S. Akutagawa, Bull. Chem. SOC.Japan, 1976, 49, 3646.

68

A cyclic Terpenoids

69

(3) R = H ( 5 ) R = OMe

The ene-reaction between isoprene (1) and chloral proceeds well under mild ,~ ( 14) and the dihydropyran conditions when A1C13 is used as ~ a t a l y s t affording (15) in accord with earlier work using SnC14.8 The ether (15) possibly arises as a result of further reaction of (14) with the Lewis acid. The cyclic H-T isoprene dimer (1 6 ) and the trimer (17) have been selectively mono-ozonized followed by ozonide reduction over a Lindlar catalyst to yield the synthetically useful C0,Me

I

t

C0,Me

(8)

I

(9) R =

(11) R =

' G. B. Gill and B. Wallace,J.C.S.

*

R

A,0

(12) R' = Me; RZ = H (13) R' = H ; RZ = Me

?*'

Chern. Cornrn., 1 9 7 7 , 380. E. I . Klimova, E. G. Treschova, and Y. A. Arbuzov, Doklady Akad. Nauk S.S.S.R., 1968, 180. 865.

70


/

ketoaldehydes ( 18) and ( 19), respectively.' Aldehyde ( 18) was converted by direct Wittig reaction (Ph$=CMe,) into (2)-geranylacetone; similar treatment of (19) afforded (E,E)-farnesylacetone.

3 Lavandulyl, Artemisyl, Santolinyl, and Chrysanthemyl Derivatives

A CONGEN programme has been used t o demonstrate that there are 75 possible saturated acyclic isomers of formula CI&22.10 As expected, only three are fully isoprenoid. The mass spectra of a number of acyclic monoterpenoid alcohols have been measured and their characteristic ions tabulated." A number of new acyclic terpenes have been isolated from lavender [(20)(25)] and lavendine (26) oils.12 The ketoacetates (27) and (28) occur in both sources. The H-T alcohol (29), a constituent of Ledum palustre oil, has been obtainedf3 by reaction of 1-methylpropenal with 3-methylpentadienyl-lithium

V. N . Odinokov, W. K. Achunova, K. I. Haleeva, U . M . Djemilev, and H . A. Tolstikov, Tetrahedron I,etters, 1977, 657. D. H. Smith and K . E. Carhart, Tetrahedron, 1976, 3 2 , 25 13. J . Iwamura, K. Beppu, and N. Hirao, Buseki Kiki, 1976, 14, 162 (Chem. A b s . , 1976, 8 5 , 63 172). H. Kaiser and 0. Lamparsky, Tetrahedron Letters, 1977, 6 6 5 . S . K. Wilson, K. M . Jernberg,and D. T. Mao,J. Urg. Chem., 1 9 7 6 , 4 1 , 3209.

Acyclic Terpenoids

71

AcO

( 2 0 ) R1 = O H ; R'R3 = CH, ( 2 1 ) R' = H ; R2 = Me; R3 = OH

( 2 2 ) R L = H; R 2 = O H ; R3R4 = CH, (23) R I R z = 0;R3R4 = CH, (24) R'R' = 0;R3 = H ; R4 = Me

( 2 7 ) R'R2 = CH, ( 2 8 ) R' = H; Rz = Me

(30). The latter has a preferred W-conformation but the 2-methyl salt exists as a mixture of conformers and, with methylvinylketone, yields a I : 1 mixture of hotrienol(31) and the alcohol (32).

Several syntheses of artemisia ketone (33) have been reported. The sulphonium ylide route14 has received a further airing," and papers have appeared describing syntheses via alkylation of the thioacetal mono-oxide (34)16 and acylation of the prenyl chloridederived silene (35) (Scheme l)." Artemisia ketone (33) and artemisia acetate (36) are the main volatile constituents of the flowers and leaves of Achillea ageratum from central Italy," the ratio of acetate t o ketone altering from 0.12 in January t o 1.1 in June as the young leaves mature. 14 1s

l6 17 18

D. Michelot, G. Linstrumelfe, and S. Julia, J.C.S. Chern. Cornm., 1974, 10. D. Michelot, G. Linstrumelle, and S. Julia, Synth. Comm., 1977, 7 , 95. C. Huynh and S. Julia, Synth. Cornm.,1977, 7 , 103. J-P. Pillot, J. Dunogues, and R . Calas, Tetrahedron Letters, 1976, 187 1. R. Grandi, W. Messerotti, and U . M . Pagnoni, Phyrochemistry, 1976, 15, 1770.

*


72

(33) RLR2= 0 (36) R' = H; R2 = OAc (41) R' = H ; RZ = OH

SMe SMe

ii,iii,

+yy

JSM"

0

liV

(34)

(35) Reagents: i, H,O, ; ii, Pri NLi; iii, prenyl bromide; iv, HgC1,-MeCN-H,O; vi, Me,SiCl; vii, 3-methylbut-2-enoyl chloride-A1C13,-60 C Scheme 1

v, Mg-Et,O;

Methyl santolinate (37), isolated from Artemisia tridentata tridentata, has been synthesized stereoselectively using the ally1 siloxyvinylether modification of the Claisen rearrangement (Scheme 2).19 The new (-)-oxidosantolinatriene (38) has been obtained from the same Arternisia species.*'

iii, iv

OSiMe,Bu'

I

(1 2%)

(37) (88%)

Reagents: i, LiAlH, ; ii, (MeCH,CO),O; iii, lithium cyclohexylisopropylamide; iv, ButMe,SiC1-HMPT; v, 65 "C; vi, H,O+, then CH,N, Scheme 2 19

J . Boyd, W. Epstein, and G . Frgter, J.C.S. Chem. Comm., 1976, 380. T. A. Noble and W. W. Epstein, Tetrahedron Letters, 1977, 3933.

A cy clic Terp en0 ids

73

Poulter and his co-workers have made a detailed examination2' of the solvolyses of some chrysanthemyl derivatives (39) in water and have shown, inter alia, that yomogi alcohol (40), artemisia alcohol (41), and a little santolina alcohol (42) are formed. A trace product in the solvolysis of (39; R = N-MePyI) is the H-H compound 2,7-dimethylocta-2,6-dien-4-01(43). The stereochemistry of its formation has been studied22 as a model for the head-to-head rearrangement involved in the biosynthesis of squalene from presqualene pyrophosphate. Solvolysis of theN-methyl-4-[( lS, 1'R,3'R)-[ 1-3H]chrysanthemyloxy] pyridinium iodide (44) afforded a low (CQ. yield of labelled dienol (43) which was

isolated by dilution with cold, synthetic carrier. A series of oxidative reactions gave [3-3H]rnalic acid, which was resolved by addition of an excess of cold (S)malic acid, affording a specimen at least 85% S [malic enzyme]. Incubation of this with fumarase revealed it t o be a mixture of the (2S,3S)- and (2S,3R)diastereoisomers (45) and (46) in the ratio 83 : 17. It followed that the R : S

21

'*

C . D. Poulter, L. L. Marsh, J . M . Hughes, J. C. Argyle, D. M . Satterwhite, R. J . Goodfellow, and S. M. Moesinger, J . Arnev. Chem. SOC., 1 9 7 7 , 99, 3 8 1 6 . C. D. Poulter and J . M. Hughes, J. Arnev. Chem. Soc., 1977, 99, 3830, beware misprints in Scheme iv.

74


ratio at C-5 in the labelled dienol (43)was also 8 3 : 17 and, therefore, that rearrangement of the chrysanthemyl derivative (44)to (43) must have involved predominant inversion at its C-1. Thus (Scheme 3), ionization of the antiperiplanar rotamer of (44) leads to the ion (47) which, via a cyclopropylcarbinylcyclopropylcarbinyl rearrangement initiated by a stereospecific suprafacial bond migration, is converted into the ( R ) - [5-3H]dienol (48).

(47)

(44 )

1

3H

(48)

Scheme 3 4 2,6-Dimethyloctane Group

0cimenes.-A new synthesis of transa-ocimene (49) has been reported,= and a route to ocimenone mixtures has been described.% Allo-ocimene (50) undergoes the Prins reaction with formaldehyde t o give the ethers ( 5 1 ) and ( 5 2 ) . 2 5 Another synthesis of dihydrotagetone (53) has been published.26 Myrcene Derivatives.-N,N-Diethylgeranylamine (54) has been cleanly converted into myrcene (55) by treatment with a catalytic amount of n-butyllithium.*' Similar treatment of the neryl derivative affords (55) in a mixture with ocimene. Organohomocuprates (e.g. R2CuMgX) have been demonstrated t o add specifically to the triple bond of a conjugated enyne. This property has been FMO theory has made use of in a simple synthesis of myrcene (55) 23

0. P. Vig, S. D. Sharma, M. L. Sharma, and K. C. Gupta, Indian J. Chem., 1977, 15B, 25.

24

C. F. Garbers and F. Scott, Tetrahedron Letters, 1976, 1623.

25

K. Takabe, N. Ike, T. Katagiri, and J . Tanaka, Nippon Kagaku Kaishi, 1977, 1253 (Chem. Abs., 1978, 88,7073). J. F. Le Borgne, Th. Cuvigny, M . Larchevzque, and H . Normant, Tetrahedron Letters, 1976, 1379. M. Tanaka and G. Hata, Chem. and Znd., 1976, 370. H.Westmijze, H.Kleijn, J . Meijer, and P. Vermeer, Tetrahedron Letters, 1977, 869.

26

27 28

A cyclic Terp e no ids

75

(49)

been applied in an attempt t o rationalize the differing modes of attack by lo2 on ( 5 5 ) and a-myrcene ( 5 6 ) . Photoelectron spectroscopy showed that the ionization potentials of t h e buta-173dienyl moieties of (55) and ( 5 6 ) were, as expected, almost identical (8.48 and 8.63 eV).29 For a-myrcene (56), which

(54)

(55)

yields (57), this is the HOMO as the isolated n-bond has an IP of 9.13 eV. However, for the P-isomer (55) the IP of the isolated olefinic bond is raised t o 8.48 eV due t o its greater degree of substitution. The consequential orbital crossover leads t o it becoming the HOMO site and thus the formation of the eneproducts (58) and (59). The alcohol (60) has been converted into the 1 ,dendoperoxide ( 6 1) which, with But OLi followed by H 2 S 0 4 , affords the furanoterpene (62) in good yield.30 Nickel complex-catalysed cyclodimerization of myrcene (55) with butadiene leads to cyclo-octadiene derivatives such as ( 6 3 ) in addition t o Diels- Alder a d d ~ c t s . ~Similar ' results are obtained by using isoprene in place of b ~ t a d i e n e . ~ * 29 30

31

32

L . A. t'aquette, 1). C. Liotta, and A. D. Baker, Tetrahedron Letters, 1976, 2681. K. Kondo and M . Matsumoto, Tetrahedron Letters, 1976, 391. C . A. Tolstikov, U. M . Dzhemilev, G . E. Ivanov, and L. M . Zelenova, Zhur. obschei Khim., 1 9 7 6 , 4 6 , 1 8 9 (Chem. Abs., 1976,84,150 760). W. Eisfelder and P. Weyerstahl, Justus Liebigs Ann. Chem., 1977, 988.

76


R (57) R

(55)

10,

=

H

+Hoo&/k/ (61) R = OH

(56)

+

I

R

(59)

R = OOH (60) R = OH (58)

The dichlorocarbene species generated from chloroform and aqueous sodium hydroxide in the presence of tertiary amines shows high selectivity in product distribution when added t o polyolefinic substrates. Myrcene (5 5) yields only the mono-adduct (64) under these condition^.^^

Tricarbonylmyrceneiron (65) has been found t o yield (66) when treated with a catalytic amount of fluoroboric acid; in the presence of excess acid the salt (67) is obtained and this can be reduced t o (68) by borohydride.M Carbonyl-

33

Y. Kimura, K. Isagawa, and Y . Otsuji, Chem. Letters, 1977, 951.

34

A. J . Pearson, Austral. J. Chem., 1976, 2 9 , 1841.

A cyclic Terpenoids

77

ative annulation of (65) yields (69) and (70) (Scheme 4).35 Myrcene (55) reacts with magnesium in THF when a Lewis acid is present t o give ‘myrcenemagnesium’, 36*37 Evidence has been adduced37 for the structure (71). Acid hydrolysis of ‘myrcenemagnesium’ yields the dienes (72) and (73);36 the compound behaves nucleophilically towards aldehydes, ketones, epoxides, carbon

(65)

+ [mixture

Reagents: i, oxalyl chloride-AlC1,-CH2C1,, -78 “C; ii, AgN0,-EtOH

Scheme 4

dioxide, and a ~ e t o n i t r i l e .Reaction ~~ occurs at positions 2- and 3- of the initial 1,3-diene unit; with, for example, acetone, the products (74) and (75) are formed in a 31 : 9 ratio.37 When ‘myrcenemagnesium’ is treated with esters, acyl chlorides or carboxylic anhydrides, cyclic products may be ~ b t a i n e d . ~ For ’ example, treatment of (7 1) with ethyl pivalate yields the cyclopentenol (76), whilst its reaction with acetyl chloride leads t o the cyclopropane (77).3*

Citronellyl Derivatives.-Citronellol (7 8) has been synthesized via alkylation of the a-sulphinyl carbanion derived from (79) (Scheme 5 ) . 3 9 A synthesis of (78) utilizing H-T dimerization of isoprene has also been described?’ The reaction of (78) with BF3,Et20 affords a macrocyclic b i ~ e t h e r ,but ~ ~ with HFS03 at -78 O C it yields the oxacycloheptanes (80) and (8 1).42 The formation of (80) involves loss of a carbon atom, and a mechanism has been proposed 3s 36

37 38 39 40

A. J . Birch and A. J . Pearson, J.C.S. Chem. Comrn., 1976, 601. S. Akutagawa and S. Otsuka, J. Amer. Chem. SOC., 1976, 98, 7420. R . Baker, R . C . Cookson, and A. D. Saunders, J.C.S. Perkin I , 1976, 1809. R. Baker, R. C. Cookson, and A. D. Saunders, J.C.S. Perkin I , 1976, 181 5. M . Julia, I). Uguen, and A. Callipolitis, Bull. SOC. chim. France, (Part 11), 1976, 519. H. Yagi, M. Shirado, M. Hidai, and Y . Uchida, Yukagaku, 1977, 26, 2 3 2 (Chem. Abs., 1977, 87, 135 973).

41

42

K. Nagai, M. Nakayama, and S. Hayashi, Chem. Letters, 1973, 665. D. V. Banthorpe and 1’. A. Boullier, J.C.S. Perkin I , 1977, 114.

78


(71)

(72) R = H (74) R = Me$(OH)--

(73) R = H (75) R = Me2C(OH)-

on the basis of an experiment using I4C-labelled citronellol (Scheme 6)42 Onepot conversion of (-)-citronello1 into isopulegone (82) using unbuffered pyridinium chlorochromate is again rep0rted.4~ Photolysis of citronellyl iodide (83) in

i,ii. iii

iv,v,vi,

~

S0,Ph

&

OH

(79) (78) Reagents: i, PhSH-(PhCO,), ;ii, KOH; iii, NaOCl; iv, 2BuLi; v, prenyl bromide; vi, Na-Hg Scheme 5

heptane containing triethylamine leads t o (84) (52%) and trans-p-menth-8,9ene (85) (35%).@ Formation of the diene (84) is not a dark reaction. (+)-(3R)-Citronellic acid (86) is obtained in 95% yield when the dienoic acid (87) ( E : Z = 9) is hydrogenated in the presence of neomenthyldiphenylphospine-p,p’dichlorobis[ 1,5-cyclo-octadienylrhodium(I)].45 Methyl epoxycitronellate [racemate of 43 44

45

E. J. Corey, H , E. Ensley, and J. W. Suggs, J. Org. Chem., 1976, 41, 380. P. D. Gokhale, A. P. Joshi, R . Sahni, V. G. Naik, N. P. Damodaran, U . R. Nayak, and S. Dev, Tetrahedron, 1976, 32, 1391. Neth. Appl., 75 12 729 (Chern. A h . , 1977, 86, 5 5 597).

A cy clic Te r p e n o id s

79

(80) R = H (81) R = Me

Scheme 6

(88)l is efficiently converted into a mixture of the puleganolides (89), potentially useful in iridoid synthesis, by treatment with ButOK in DMF at 25°C.46 Optically active (88), obtained from (+)-methyl citronellate, reacts with catalytic amounts of perchloric acid in benzene t o give ( 9 0 ) , which hydrolyses t o (+)6-oxo-6,7dihydrocitronellic acid (9 1 ) , the epimer of naturally occurring material from Pelargon iu m graveole ns The benzylamine Schiff base (92) of (+)-(R)-citronella1 cyclizes with tin(1V) chloride in benzene t o a stereoisomeric mixture of unsaturated benzylamines (93).48 Catalytic reduction/debenzylation gives a mixture which is largely (73%) menthylamine (94). Additional experiments suggest that the observed stereoselectivity of product formation is due t o the chiral centre p- t o the imine group of (92).

46 47 48

J . Wolinsky, P. Hull, and E. M . White, Tetrahedron, 1 9 7 6 , 32, 1335. E. Klein and W. Rojahn, Dragoco Rep. (Ger. edn.), 1 9 7 7 , 24, 5 5 . G . Demailly and G. Solladie, Tetrahedron Letters, 1 9 7 7 , 1 8 8 5 .

80


Citra1.-The cyclization of citral (95) in aqueous acid has been r e - e ~ a m i n e d . 4 ~ Fourteen products have been identified, three of which [(96) and both epimers of (97)] were not previously detected in this reaction. Treatment of (95) with HFS03 affords (98) and (99).42 The structure of the product obtained when

(89)

(90) R = Me (91) R = H

citral is treated with anhydrous base has been confirmed as ( and structures have been assigneds1 t o the Diels-Alder adducts from citral enamines and acrylonitrile or methylvinylketone.

49

50

B. C. Clark, jun., C. C. Powell, and T. Radford, Tetrahedron, 1977, 3 3 , 2 1 8 7 . A. F. Thomas and R. Guntz-llubini, Helv. Chim. Acta, 1976, 5 9 , 2261. S. H . Mashraqui and G. K. Trivedi, Indian J. Chem., 1977, 15B, 3 0 5 .

A cyclic Terp e n o ids

3, (95)

4? qH

81

0

OH

(97)

Linalyl Compounds.-Linalool (101) and myrcene (55) have been found amongst the monoterpenes of the foliage of nine Juniperus specie^.'^ It is suggested that the monoterpene composition may be a useful taxonomic aid in the identification and classification of these plants. It seems important, however, t o examine the composition of oil from older leaves for this purpose, as the differences between species are very much less distinct in oils from juvenile fo~iage.’~

Lp” The i.r. spectrum of (1 01) has been the subject of a computer-assisted interp r e t a t i ~ n , ’ ~whilst dipole-dipole interactions, modulated by molecular tumbling and segmental rotation dominate the relaxation of all its carbon nuclei at up to 320 K for the neat liquid.” At higher temperatures, spin-rotation relaxation becomes a competitive process. 52

53 54 55

T. ,4. Fretz, T. D. Snydor, ond M . R . Cobbs, Sci. Hortic. (Amsterdam), 1976, 5 , 8 5 . K. P. Adams and A. Hagerman, Biochem. Syst. Ecol., 1 9 7 6 , 4, 7 5 . H . €3. Woodruff and M . E. Munk, Res./Dev., 1977, 28, 34. A. Olivson and E. Lippmaa, ‘Proceedings o f the 19th Ampere Congress’, 1976, p. 325.

82


Linalool (101) has been synthesized by alkylation of the a-sulphonyl carbanion derived from sulphone (1 02),56 and also by regioselective coupling of the dilithium salt of hydroxy-sulphoxide ( 103) with prenyl bromide57 (Scheme 7). The hydroxy-sulphoxide route affords nerolidol ( 104) when geranyl bromide replaces prenyl bromide.57 Linalool reacts with dichloro- and dibromo-carbenes exclusively at the trisubstituted double bond under phase-transfer condition^,^^ and linalyl acetate yields the substituted cyclopentane (105) with manganic acetate and dimethyl ma10nate.’~

SO, Ph

q-j$ S0,Ph OH (103) Reagents: i, BuLi; ii, Li- Et NH,

; iii, Na-Hg;

iv, PhSH-0, ; v, 2BuLi; vi, prenyl bromide; vii,

Scheme 7

The unidentified ‘diol’ formed by the oxidative hydroboration of linalool (101) (even when excess B2H6 is used) has been shown t o be a mixture of (106) and (1 07).60 Evidence has been presented for the hydroboration- rearrangement

56 57 58 59

60

M. Julia and D. Uguen, Bull. Soc. chim. France (Part I Z ) , 1 9 7 6 , 5 1 3 . P. J . R. Nederlof, M . J. Moolenaar, E . R. De Waard, and H . 0. Huisman, Tetrahedron Letters, 1 9 7 6 , 3 1 7 5 : Tetrahedron, 1 9 7 7 , 33, 5 7 9 . K. Kleveland, L. Skatteboel, and L . K . Sydnes, Acta Chem. Scand., 1 9 7 7 , B31, 463. F. J . McQuillin and M . Wood, J. Chem. Research ( S ) , 1 9 7 7 , 6 1 ; ( M ) , 0 7 5 2 . J . Wolinsky and R. H . Bedoukian, J. Org. Chem., 1 9 7 6 , 4 1 , 2 7 8 .

A cyclic Terpe no ids

83

of the oxaborinane intermediate (108) (Scheme 8), followed by either ‘normal’ attack of diborane on (109) to yield (106), or intramolecular attack at the tertiary position to give (107):’

3

(109)

Reagents: i, B,H, ;ii, [ O ]

Scheme 8

Dehydrolinalool (1 10) reacts with 2,4,4,6-tetrabromocyclohexa-2 ,5dienone [a source of B? via (1 1 l ) ] t o give the bromoether (1 12).61 The analogous acetoxyether (1 13) arises in low (5%) yield when dehydrolinalyl acetate is treated with zinc chloride in benzene.62 The major components of the reaction mixture are carvenone (1 14) and its enol acetate (1 15); the car-2ene derivative (1 16) is also formed. a-Acetylenic tertiary alcohols are very cleanly rearranged to the corresponding a P-unsaturated aldehydes on heating with tris(triphenylsilyl)vanadate(V) in

61

62

T. Kato, 1. Ichinose, T. Hosagai, and Y. Kitahara, Chem. Letters, 1976, 1 187. H. Strickler, J . B. Davis, and G. Ohloff, Helv. Chirn. Actu, 1976, 5 9 , 1328.

84

Aliphatic and Related Natural Product Chemixtry

hydrocarbon solvents.63 Dehydrolinalool ( 1 10) affords citral (95) in this way; a similar result is obtained with other poly(vanadiumorganosiloxanes).64

Geranyi and Neryl Derivatives.-The geranylhydroquinone alliodorin ( 1 17) has been isolated from the heartwood of Cordia alliodora, and its structure confirmed by ~ynthesis.~'New neryl derivatives from the roots of Schkuhria senecioides include (1 18) and (1 19);66 the isobutyrate (1 19) is also found in S. pinnata. Dehydroneryl isovalerate (120), found in the roots of Anthemis montana L., has been ~ynthesized.~'

fi CHO (1 17)

OH

R)./+ocoR1

(118) R' = Me; R2 = OAc (119) R' = Pr'; R' = OAc (120) R' = PrjCH,; R2 = H

Geraniol (121) has been obtained by low-temperature reaction of the prenyl Grignard reagent with (E)-4-chloro-3-methyl-2-buten-l-ol ( 122) in the presence of coppe41) iodide (without which the coupling fails).68 Both geraniol (1 2 1) and nerol (1 23) have been stereoselectively synthesized from isoprene and myrcene, r e ~ p e c t i v e l y . ~Another ~ synthesis of y-geraniol ( 124) has been reported.70 Geranyl bromide (1 25) affords citral (95) (80%) and geraniol(l2 1) (20%) when nucleophilically attacked in HMPT by potassium chromate where dicyclohexyl-18-crown-6 is present .71 Geraniol is not oxidized under these 63 64

'' 66 67 6M

69

70 71

H. Pauling, D. A. Andrew, and N. C. Hindley, Helv. Chim. Acta, 1 9 7 6 , 59, 1 2 3 3 . M. B. Erman, I. S. Aul'chenko, L. A. Kheifits, V. G . Dulova, Yu. N. Novikov, and M . E. Vol'pin, Zhur. org. Khim., 1 9 7 6 , 12, 921 (Chem. Abs., 1976, 85, 1 2 4 165). K. L. Stevens and L. Jurd, Tetrahedron, 1 9 7 6 , 3 2 , 665. F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 7 8 0 . G. Cardillo, M. Orena, and S. Sandri, Tetrahedron, 1976, 32, 107. F. Derguini-Boumechal, R. Lorne, and G. Linstrumelle, Tetrahedron Letters, 1977, 1 181. K. Takabe, T. Katagiri, and J . Tanaka, Chem. Letters, 1977, 1025. 0. P. Vig, S. L). Sharma, S. S. Bari, and S. D. Kurnar, Indian J . Chem., 1 9 7 7 , 15B, 9 3 . G. Cardillo, M . Orena, and S. Sandri, J.C.S. Chem. Comm., 1976, 190.

85

Acyclic Terpenoids

conditions. Hypochlorite oxidation of nickel oxide o n graphite gives a supported nickel peroxide which converts geraniol into citral in 89%yield.n 6o Co-radiolysis of geraniol at 100 Mrad leads t o a mixture containing 30% of the isomeric nero1.73 Pyridinium toluene-p-sulphonate is a mild and efficient catalyst for formation of the THP-ether of (1 2 l).74

cuR &OH

61 (121) R = OH (125) R = Br (126) R = OAc

(1 22)

(1 24)

Oxidations with selenium dioxide have lacked favour owing to difficulties encountered with the separation of reaction products from reduced forms of selenium. This disadvantage is eliminated when t-butyl hydroperoxide is incorporated into the reaction mixture to re-oxidize lower-valent states of Se.” Under these conditions, geranyl acetate ( 1 26) affords a mixture of the alcohol (1 27) and aldehyde (128) in the ratio 86 : 14.

R (127) R = H , OH (128) R = 0

(129) R = C0,Me (131) R = S0,Ph

(130) R = C0,Me (132) R = S0,Ph

Tetrakis( triphenylphosphinepal1adium)-catalysed alkylation of ( 126) with diethyl sodiomalonate gives a 90% yield of the primary substitution product ( 1 29) with no disturbance of olefin geometry.76 The remaining product (1 30) (10%) results from y-attack on the allylic system. This ratio improves to at least 97 : 3 when the anion of PhS02CH2C02Meis used t o produce (1 3 1) and (132). Lower selectivity was observed with neryl acetate; this afforded (133) (37%) and (1 30) (63%), or ( 134) (90%) and (1 32) ( Similar a-selectivity

72

73 74

7s

76

J . D. Surrnatis, U.S.P. 4 005 031 (Chem. Abs., 1 9 7 7 , 86, 140 297). U. D. Bregvadze,Izwest. Akad. Nauk Gruz. S.S.S.R., Ser. Khim., 1976, 2, 89 (Chem. Abs., 1976, 8 5 , 1 2 4 169). M. Miyashita, A. Yoshikoshi, and P. A. Grieco, J. Org. Chem., 1 9 7 7 , 42, 3772. M. A. Umbreit and K. B. Sharpless,J. Amer. Chern. SOC., 1 9 7 7 , 99, 5526. B. M . Trost and T. R. Verhoeven,J. Org. Chern., 1976, 4 1 , 321 5.


86

and retention of 2-geometry are observed when geranyl acetate (1 26) is treated with tri-isobutyl aluminium in hexane at -78 "C t o yield (1 35).77 (Z)-3,7-Dimethylocta-2,6-dienyltriphenylphosphonium bromide ( 136), obtained from nerol, condenses with aldehydes with retention of configuration about the 2 , 3 - b 0 n d . ~The ~ isomeric (E)-salt from geraniol behaves analogously.

(133) R = C0,Me (134) R = S0,Ph

Geranyl acetate (1 26) reacts with thiyl radicals (hv-PhSSPh-C& -Pyrex) to give a 5 : 1 ratio of cyclic and acyclic product^.'^ The cyclic fraction is a mixture of stereoisomers of ( 137). Hydroboration of (1 26) followed by silver ioninduced cyclization affords trans-p-menthane (1 38) (83%); linalyl acetate under the same conditions gives trans-1-hydroxy-p-menthane ( 139) and the cis-isomer (140) in equal amounts.80 Using thexyl borane, geranyl acetate yields the diol

(1 37)

(138) R' = Me; R2 = H (139) R' = Me; R2 = OH (140) R' = OH;R1 = Me

( 14 1) via rearrangement of (1 42), after oxidative work-up.81 The THP-ether (143) is not prone to this rearrangement and the derived cyclic borane undergoes carbonyl insertion to yield the epimeric ketones (144)?' Direct hydroboration of geranyl acetate (126), followed by Br,-hv and then oxidation, yields the trans-p-menthan-4-01(1 45).81 77

78

79

8o 8'

S. Hashimoto, Y. Kitagawa, S. Iemura, H . Yamamoto, and H. Nozaki, Tetrahedron Letters, 1976, 261 5. L. Barlow and G. Pattenden, J.C.S. Perkin I , 1976, 1029. M. E. Kuehne and R. E. Damon, J. Org. Chem., 1 9 7 7 , 4 2 , 1825. R. Murphy and R. H . Prager, Tetrahedron Letters, 1 9 7 6 , 4 6 3 . R. Murphy and R. H , Prager,Austrul. J. Chem., 1976, 29, 617.

Acyclic Terpenoids

87

(142)

0-THP

f

TxBH,,

i.CO

ii. H,@

*

The ( W a c t o n e (146), derived from L-glutamic acid by nitrous acid deamination, has been used by a Japanese group as a synthon for (+)-(R)-6,7epoxygeraniol (1 47) (Scheme 9).82 Racemic 6,7epoxygeraniol is formed in a 5 : 1 ratio with the 2,3epoxide (148) when geraniol is treated with benzene peroxyseleninic acid ( P h S e O g ) generated in situ by hydrogen peroxide oxidation of benzeneseleninic acid.83 The reagent is used in a phosphate buffer (pH 7) and must be followed by a silica gel treatment (!) if starting material is not t o be largely recovered. Similar treatment of linalool(lO1) affords the epoxide (149). The position of epoxidation of geraniol is reversed, giving (148) as the major product, when molybdenum or vanadium catalysts are used. Thus, with the optically active hydroxamic acid (1 50) and V O ( a ~ a c )geraniol ~, yields (2S,3S)(148) in 30% enantiomeric excess and with 86% conversion,M whilst with the (acetylacetonato) [ (-)-N-alkylephredrinato] dioxomolybdenums ( 15 1) and cumene hydroperoxide, (2R,3R)-( 148) is formed in 33% enantiomeric excess and 57% chemical yield.'' The mechanisms of Mo- and V-catalysed epoxidations

'* 84

S-i. Yamada, N. Oh-hashi, and K. Achiwa, Tetrahedron Letters, 1976, 2557. P. A. Grieco, Y . Yokoyama, S. Gilman, and M. Nishizawa, J. Org. Chem., 1977,42, 2034. R . C. Michaelson, R. E. Palermo, and K. B. Sharpless, J. Amer. Chem. Soc., 1977, 99, 1990.

85

S-i. Yamada, T. Mashiko, and S . Terashima, J. Amer. Chem. Suc., 1977, 99, 1989.

88


ta 0

(146)

i'ii'u+

J.0 0 -%

H

(147)A

OH

+OAc

)I..H

MsO

Reagents: i, SOc1, ; ii, CH,N, ; iii, HI-H,O; iv, piperidine; v, MeMgI; vi, acetone-PTSA; vii, trimethylphosphonacetate-NaH; viii, LiAlH, ; ix, Ac,O-Py ; x , 90% HOAc 50°C; xi, MsCl-Py,-2O0C; xii, NaOMe,O"C

Scheme 9

of geraniol (121) by alkyl hydroperoxides have been probed using "0 labelling techniques.% The results suggest that the intact hydroperoxide is involved in the oxidation step.

An interesting oxidative cyclization of geraniol ( 1 2 1 ) to the mixture of epimers ( 152) occurs on reaction with o-nitrobenzeneselenylcyanide and tributylphosphine followed by treatment with hydrogen peroxide;" (1 53) is an intermediate. Geraniol reacts with T1(C1O4)3 in aqueous solution t o give the cyclic hydroxyethers (1 54)-( 156).88 A new method for the stereoselective 1,3-transposition of allylic alcohols has been published (Scheme [ 3,3] Sigmatropic rearrangement of allylic tri-

86

89

A. 0. Chong and K. B. Sharpless, J. Urg. Chem., 1977, 4 2 , 1587. T. Kametani, H. Nemoto, and K. Fukumoto, Heterocycles, 1977, 6, 1365. Y. Yamada, H . Sanjoh, and K. Iguchi, J.C.S. Chem. Comrn., 1976, 997. A. Yasuda, H. Yarnamoto, and H . Nozaki, Tetrahedron Letters, 1976, 2621.

A cyclic Terp en o ids

89

(151) R = Me or Et

(150)

chloroacetimidatesgOor pseudoureasg' effects the conversion of allylic alcohols into the transposed amines (Scheme 11). Rearrangement of the O-trichloroacetimidate (1 57) is greatly accelerated in the presence of mercury(I1) trifluoroacetate; the intermediacy of (1 58) is then possible. SeC,&NO,

r-J R' = Me; R' = OH (155) R' = OH;R2 = Me (154)

-0

(156)

The basic polymerization step in polyterpenoid biosynthesis is catalysed by the enzyme prenyltransferase. This reaction involves condensation of C-4 of isopentenyl pyrophosphate (1 59) with the C-1' of an allylic ester (1 6 0 ) , leading t o elimination of PPi and formation of (161), the five-carbon homologue of the

88% Reagents: i, V O ( ~ C ~ C ) , - B U ~ O O ii,HNEt ; ,-MsC1-CH2Cl,,-26

OC; iii, Na-NH,-THF

Scheme 10 90 91

L. E. Overrnan,J. Amer. Chem. SOC.,1976, 9 8 , 2901. S. Tsuboi, P. Stromquist, and L . E. Overman, Tetrahedron Letters, 1 9 7 6 , 1 1 4 5 .

90

Aliphatic and Related Natural Product Chemistry NHCOCl,

i, uf

(121)

p

3

&

p

(157)

\

9

NHCONQ

pN &F

/

FH2

Reagents: i, NaH; ii, CCl,CN; iii, 140 "C; ivy3M-NaOH; v, Ncyanopyrrolidine-KH-THF; vi, 137°C 80h Scheme 11

allylic substrate. Either Mg2+ or Mn2+ are obligatory for enzymic activity, their possible role being to assist in the ionization of (160) thereby initiating an ionization-condensation-elimination mechanism, The rate of solvolysis of

geranyl pyrophosphate (1 62) (to yield geraniol and linalool in the ratio 1 : 5) has now been foundx t o depend strongly on cation concentration once sufficient has been added t o form the mono-metal salt of (162). This suggests the for-

4'L

O2

P

P

(159)

+

Prenyltransferase

-TR PP,, H'

R

92

OPP

(161)

D. N. Brems and H.C . Rilling, J. Amer. Chem. SOC.,1977, 99, 8351.

Acyclic Terpenoids

91

mation of, for example, M2-geranyl pyrophosphate which then exhibits an enhanced rate of decomposition. As it is known93 that two MZ+ions are bound per catalytic site in prenyltransferase when substrate is present, this observation provides added evidence for such a reaction sequence.

2-Fluoro-3-methylpyridinium methyl toluene-p-sulphonate ( 163) effects nonenzymic biogenetic-like cyclization of nerol ( 123) to yield the p-menthadiene ( 1 64) (83%) and terpinolene (1 65) (1 5%).* When geraniol(l21) is the substrate it would appear that the intermediate allylic cation preserves its stereochemical integrity to some extent as, together with (164) (41%) and (165) (3%), the

acyclic trienes myrcene (55) (7%) and ocimene (166) (7%) are obtained.* This effect is much more marked in the heterolysis of the corresponding diethylphosphate esters with t r i e t h y l a l ~ m i n i u m . The ~ ~ neryl derivative affords ( 164), (165), and (167), but the geranyl ester yields only a 9 : 1 mixture of the substituted acyclic products (168) and (169). Acetolysis of the neryl 2,4dinitrophenyl ether has an unusually negative entropy of activation.%

93 94 95

96

H. L. King, jun., and H. C. Rilling, Biochemistry, 1977, 16, 381 5 . S. Kobayashi, M. Tsutsui, and T. Mukaiyama, Chem. Letters, 1976, 1 1 3 7 . Y. Kitagawa, S. Hashimoto, S. Iemura, H . Yamamoto, and H. Nozaki, J. Amer. Chem. SOC.,1976, 98, 5030. K. B. Astin and M . C. Whiting, J.C.S. Perkin 11, 1976, 1160.

92


Meou 0-THP

v, vi, vii

Me0,C

*

Me0,C

(171)

II'

iviii, ix,x

0-THP

xi, ix, xii, ix

(1 70)

E = C0,Bu' Reagents: i, bromodi-t-butyl malonate-(Me,N),C=NH-DMF; ii, Ph,S' -95% yield (Scheme 6 ) . = When the cyclopropylglycol system was opened via the orthopropionate (45) the yield was improved, but more importantly the (2-15 (PG numbering) stereochemistry of the cyclopropyl precursor (43) was retained in the product

(41)

+

ar i ,

CN

(47)

(25)

Reagents:

i, hexamethylphosphortriamide; ii, HCO, H; iii, aq.H, SO, ;iv, aq. NaHCO,

Scheme 7 23

24 25

V. Van Kheenen, K. C. Kelly, and D. Y . Cha, Tetrahedron Letters, 1976, 1 9 7 3 . R. C. Kelly and V. Van Kheenen, Tetrahedron Letters, 1976, 1067. D. R. White, Tetrahedron Letters, 1976, 1753.

Chemistry of the Prostaglandins 177 (46).% As an additional refinement, the purification of (46) was effected through the corresponding crystalline hydroxy-acid. White2' has described a simple and efficient synthesis of the enone (25) via the masked acyloin (48) (Scheme 7). Solvolysis of (48) followed by acidic hydrolysis of the resulting formate ester afforded the cyanohydrin (49). The latent carbonyl of (49) was revealed on treatment with aqueous sodium bicarbonate. The overall yield of (25) from (41) was 74%.

HO Reagents:

(5 2)

i, KOBd -BufOH; ii, 48% HBF, -MeCN; iii, aq.NaHC0, ; iv, LiOH-Adogen 464-benzene Scheme 8

Routes via Conjugate Addition to Cyclopentenones. -New Syntheses of Intermediates. Several new methods have been devised for the preparation of the intermediate (52) to PGEl (ref. 1, Vol. 3, p. 325). In one approach the 0-methylthio-y-keto-aldehyde (5 1) was constructed as shown in Scheme 8 and cyclized with lithium hydroxide under phase-transfer conditions to give (5 2) directly .26 A related route elaborated (53) into (54).27 The t-butyl ester corresponding to

(53)

(54)

(52) was formed in 95% yield by an alumina-mediated isomerization of the hydroxycyclopentenone (55),28 itself readily available from 2-furyl-lithium and t-butyl 8-formyloctanoate followed by an acid-catalysed rearrangement of the 26

27

*'

G. R. Kieczykowski, C. S. Pogonowski, J . E. Richman, and R. H. Schlessinger, J. Org. Chem., 1977, 42, 175. G. K. Cooper and L. J. Dolby, Tetrahedron Letters, 1976, 4675. G . Piancatelli and A. Scettri, Tetrahedron Letters, 1977, 1 1 31.


178

0

0

Hi)

(55)

(56) R = Me (57) R = H

resulting carbinol. Selective epoxidation of (5 8) followed by hydrogenation and Jones oxidation furnished the epoxy-ketone ( 5 9 ) , which was transformed into (52) by known methods (Scheme 9).29 The PGEz precursor (56) was obtained

-

*C02Me

b(cH2)6c02Me

(58)

Reagents:

--+

(52)

0

(59) i, BufOOH-VO(acac), ;ii, H, -Pd/C-MeOH; iii, Jones oxidation

Scheme 9

when the hydrogenation step in Scheme 9 was omitted, Another new synthesism of ( 5 6) exemplified an efficient general preparation of 2-alkyl-4-hydroxycyclopentenones from t-butyl 2-furylacetate.

1-0~~

H

OR2 (62)

(61)

(+)-(52)

&

p

cvii-ix -- R20@M ;M I

OH

OR2

(641 Reagents:

29 30

(63)

MM = methoxymethyl; R' = (CH,),CH%HC,H,,; R2 = ethoxyethyl i, 10% aq.H, SO, -THF; ii, TsCl-pyridine, 0 "C;iii, DIBAL, -40 " C ; iv, HCN-NH, -EtOH; v, ethyl vinyl ether-Ha; vi, NaN(SiMe,), ; vii, KMnO, NalO,; viu, H,O+; ix, CH, N, ;x, 2%NaOH-Eta-THF: xi, 0.1 M-HCl Scheme 10

M. Kobayashi, S. Kurozumi, T. Tom, and S. Ishimoto, Chem. Letters, 1976, 1341. T. Shono, H. Hamaguchi, and K. Aoki, Chem. Letters, 1977, 1053.

Chemistry of the Prostaglandins

179 0

0

(65 1

A neat way of preparing (+)-(52), the precursor to nat-PGEl, produced the correct absolute configuration from D-gly~eraldehyde.~~ Isopropylidene Dglyceraldehyde was added t o the anion of methyl oleate and the resulting aldol protected as the methoxymethyl ether ( 6 0 ) . Aqueous acid removed the isopropylidene group and formed the y-lactone. Tosylation of the free hydroxygroup gave (61) (Scheme 10). The other key features of this synthesis are the

OH

I

OR

(67)

(68) /iii

TMSO

,%& TMSO

CN OR

OR (69)

(70)

viii, ix

OR OR

Reagents:

OR

i. silylation; ii, propynal, aldol reaction; iii, Me, SiCN-KCN-dicyclohexyl-18crown-6-CC1,; iv, 250 OC, toluene; 10" M-HC1-THF: vi, Ac, 0-pyridine; vii, NaBH, -MeOH; viii, K, CO, -aq.MeOH; ix, Jones oxidation

Scheme 11

,*G. Stork and T. Takahashi, J. Amer. Chem. SOC.,1977,99,1275.

180


cyclization of the protected cyanohydrin (62) and the unmasking of the latent C-1 carboxy-group by periodate-permanganate oxidation of the side-chain double bond in (63). The reduction of trione (65) to (R)-(66) has been achieved chemically in 54% optical yield, using LiAlH4 (LAH) partially decomposed with (-)&-methylephedrine.32 This step, a key feature of Sih’s synthesis of PGEl , was originally performed microbiologically (ref. 1, Vol. 3, p. 325). The methylenecyclopentanone (7 2) has been prepared33 from the vinylogous aldol (67) via the thermal ene reaction of the enyne (69) (Scheme 11). This represents a new approach to intermediates of the type (72) which can be converted into (+)-PGF2, (ref, 1, Vol. 5, p. 257). Miscellaneous Syntheses.-New Routes to Intermediates. Vandewalle and coworkersM have used their approach from 2,3-dialkyl- 1,4-~yclopentenediones (ref. 1, Vol. 5, p. 249) t o obtain the PGFla precursor (75) (ref. 1 , Vol. 2, p. 272) from (73). The key epimerization of the diester (74) to (75) was carried out with potassium acetate in methanol. The same group3’ have modified their route from the cyclopentene-173-dione (76) (ref. 1, Vol. 4, p. 245) to yield the Corey intermediate (46).

kPh &/R

KOAc, MeOH

\CO,Me

0

OAc

(73)

OAc

*

a;” ,

C0,Me

OAc

(74)

(75)

R = (CH,),CO,Me 0

0

(76)

In an elegant new synthesis of (46) from (77), HoltonSb utilized the amino function to establish the four stereocentres about the cyclopentane ring through the formation of palladium complexes (Scheme 12). Treatment of (77) with 32

33 34

35

36

S. Yamada, M. Kitamoto, and S. Terashima, Tetrahedron Letters, 1976, 3 1 6 5 ; M . Kitamoto, K. Kameo, S. Terashima, and S. Yamada, Chem. and Pharm. Bull. (Japan), 1977, 2 5 , 1273. G. Stork and G. Kraus, J. Amer. Chem. SOC., 1 9 7 6 , 9 8 , 6747. P. De Clercq, R. Coen, E. Van Hoof, and M. Vandewalle, Tetrahedron, 1976, 32, 2747. M. Vandewalle, P. De Clercq, M. Desmet, K. Legein, and F. Vanhulle, Bull. SOC. chim. belges, 1976, 8 5 , 5 0 3 . R. A. Holton, J. Arner. Chem. SOC.,1977, 9 9 , 8083.

Chem&try of the Prostaglandins

181

lithium tetrachloropalladate and sodium diethyl malonate followed by decomposition of the resulting palladium complex with di-isopropylethylamine led t o the olefin (78). A second complex (79) was then made, and it reacted with n-pentyl vinyl ketone to give the desired enone (80). After the reduction of the enone the synthesis of (46) was completed by hydrolysis of (8 1) with base.

(77)

E = C0,Et

(46) +--

(81)

Reagents:

(80)

i, Li, PdC1, -NaCH(CO, Et), -THF; ii, EtPriN; iii, Li, PdC1, -Cl(CH,), OHDMSO; iv, H,C=CHC(O)C,H,, Scheme 12

3 Synthesis of Prostaglandin A2

In their aesthetically appealing synthesis of (+)-1 5(S)-PGA2 Stork and Raucher3’ have produced the first route t o a natural PG from a simple sugar (Scheme 13). The route chosen featured the use of two Claisen rearrangements to achieve the correct stereochemistry. The reaction of 2,3-isopropylidene-L-erythrose (82) with vinylmagnesium chloride gave the vinyl carbinol (83), the primary alcohol function of which was selectively protected as its methyl carbonate (84). This was submitted to the first of the Claisen rearrangements by heating with trimethyl orthoacetate, producing the necessary trans geometry of the double bond in (85). The choice of a methyl carbonate protecting group for the primary alcohol function in (84) and (85) was an essential feature of the synthesis since hydrolysis of the acetonide followed by cyclic carbonate formation selectively made available the allylic alcohol in (86). The second Claisen rearrangement was then carried out by heating (86) with the orthoester (87). This step served to transfer the chirality of the allylic carbon-oxygen bond in (86) to that of a 3’

G. Stork and S. Raucher, J. Amer. Chern. Sac., 1976, 98, 1583.

182

HoyoiH


H

& y o H F 0 R 1

O

O

X

X

\,

CO,Me

(83) R' = H

(82)

i i 6 ( 8 4 ) R1 = C0,Me

OC0,Me

~

O X 0 (85)

Me0,C

MeozcY-y----o RzYco2Me * M

e

o

2

C

K

o

H

I

(89) I

+ I

PGA,

Rz = CH1C-C(CH,),C0,Me Reagents:

i , H C=CHMgCl; ii, ClC0,Me-pyridine, -30 "C; iii, MeC(OMe), -EtCO, H, 140 'C iv, aq.HOAc, 120 "C; v, Et, N; vi, K, CO, -MeOH

Scheme 13

non-adjacent carbon-carbon bond in (89), thus defining the absolute stereochemistry of C-12. This crucial rearrangement took place via the chair transition state (88). This gave, after deprotection, the diol (90) containing all the stereochemical features required for further elaboration into PGAz. Two independent have developed a route (Scheme 14) to the intermediate (94) to PGAz (ref. 1, Vol. 2, p. 278) from the ketoester (91) 39

D. F. Taber, J. Amer. Chem. SOC., 1 9 7 7 , 9 9 , 3 5 1 3 . K. Kondo, T. Umemoto, Y. Takahatake, and D. Tunemoto, Tetrahedron Letters, 1 9 7 7 , 113.

183

Chemistry o+fthe Prostaglandins

via a copper-catalysed diazoester cyclization, giving (92). The stereochemistry of (92) dictated that of the PG lower side-chain in (94). This conversion involved a ring opening with thiophenoxide to sulphide (93) followed by reductive rearrangement of the corresponding sulphoxide.

(92)

I

SPh

(93) liv, v

I

(94) Reagents:

i, TsN, -MeCN; ii, C u bronze-toluene-A; MCPBA; v, (MeO),P-EtOH-A

OH

iii, PhSH-KOBut -EtOH; iv,

Scheme 14

4 Synthesis of ( 1 9R )-19-Hydroxy-prostaglandins

The major PG components of human semen are the ( 19R)-19-hydroxy-derivatives of PG’s Ez , E l , F2a, and F l a . All four of these have been obtained by standard methods from the common intermediate (97).% In this synthesis pent-1 en-4-ol (95) was resolved via the brucine salt of the phthalate ester. Elaboration of (-)-(95) into (96) was followed by a Grignard coupling t o the aldehyde (98) t o furnish (97) (Scheme 15).

5 Synthesis of Prostaglandin Iz and its Analogues The potent biological activity (p. 229) of PG12 (99) has prompted its synthesis by several g r o ~ p s . ~ ’Each - ~ route follows essentially the same approach, namely 40 41

42

4’

*

J. C. Sih, Prostaglandins, 1977, 13, 831. E. J. Corey, G. E. Keck, and I. Szgkely,J. Amer. Chem. Soc., 1977, 99, 2006. K. C. Nicolaou, W. E. Barnette, G. P. Gasic, R. L. Magolda, W. J. Sipio, M. J. Silver, J. B. Smith, and C. M. Ingerman, Lancet, 1977, i, 1058. K. C. Nicolaou, W. E. Barnette, G. P. Gasic, R, L. Magolda, and W. J. Sipio, J.C.S. Chem.

Comm., 1977,630.

K . A. Johnson, F. H. Lincoln, J. L. Thompson, E. G. Nidy, S. A. Mizsak, and U. Axen, J. Amer. Chem. SOC., 1977,99,4182. 45 N. Whittaker, Tetrahedron Letters, 1977, 2805. 46 I. TiimGskozi, G. Galambos, V. Simonidesz, a n d G. Kovacs, Tetrahedron Letters, 1977, 2627.

184

Aliphatic and Related Natural Product Chemistry 0

OTHP Reagents:

(98) i, dihydropyran-H'; ii, B, H, -H,O,; iii, TsCI; iv, LiBr-DMF; v, Mg-Et,O; vi, (98)

Scheme 15

P G F 2 a or a derivative is cyclized t o a halo-ether (101), which affords a PGI, derivative on dehydrohalogenation. In the Upjohn approachM PGFza methyl ester was allowed t o react with iodine-potassium iodide in the presence of sodium carbonate t o give the iodo-ethers (101 and 102; R = Me, X = I) in a 9 : 1 ratio. The major isomer, which was assigned stereochemistry (101), on treatment with 1,5-diazabicyclo[4,3,0] non-5-ene (DBN) in benzene, yielded PG12 methyl ester. The crystalline sodium salt of PG12 was obtained by alkaline hydrolysis of the methyl ester.4345 Corey et aL41 proposed the opposite configurations at C-5 and C-6 [i.e. (102; R = H, X = Br)] for the major product formed when PGFzQ-ll,lS-bis-THP ether was allowed t o react with N-bromosuccinimide and then depyranylated. Again, the major halo-ether was the one that yielded the correct PG12 double-bond isomer on dehydrohalogenation (potassium t-butoxide) whereas the minor isomer yielded the (4E)-isomer (1 03) of p r o ~ t a c y c l i n .Fried ~ ~ and Barton48D49have presented a rationale in support of the major cyclization product having stereochemistry (1 01). The formation of the (5Z)-isomer can be rationalized as an internal abstraction of the endo6-hydrogen by the hydroxy-group at C-11 (Scheme 16). In the (102) series, such a mechanism is impossible, and the more accessible 4-pro-S-hydrogen is abstracted. A corollary t o these stereochemical conclusions was the conversion of 5-transPGF2a into the (95)-isomer (104) of PGIz methyl ester by these procedures.Mss0 47

4R 49 50

I. Sze'kely, Prostaglandins, 1977, 14, 217. J . Fried, Prostaglandins, 1977, 14, 219. J. Fried and J. Barton, Proc. Nat. Acad. Sci. U.S.A., 1977, 74, 2199. E . I. Corey, I. Szdkely, and C. S. Shiner, Tetrahedron Letters, 1977, 3 5 2 9 .


x x

(99) (100)

I

OH

185

OH

= 0 =

s

I

OH (101)

I

OH

In addition, the (5E)-acid (105) was derived from the bis-THP ethers of the mixture of the bromo-ethers (101 and 102; X = Br, R = H).50 The necessary inversion of configuration at C-5 was achieved on treatment with potassium superoxide. A comparison of the C-5 proton signals in the n.m.r. spectra of PG12 methyl ester and (1 04) confirmed the assignment of the (5Z)-configuration in the former.

OH

Scheme 16

Alternative s y n t h e s e ~ ~ of~ (*103) ~ ~ involved intermediate phenylselenoethers (1 02; R = H or Me, X = SePh). The corresponding selenoxide underwent a spontaneous rearrangement involving elimination of the syn-C-4-hydrogen (far less hindered than the 6-endo-hydrogen) t o form the (4E)-olefin. The two C-6 epimers of ( 103) were separated chromatographically. Reduction of (101; R = Me, X = I) and (102; R = Me, X = I) with tributyltin hydride provided both isomers of dihydro-PG12 methyl ester (101 and 102; R = Me, X = H).44 Alternatively, the free acids (101 and 102; R = X = H ) were ”

K. C . Nicolaou and W. E. Barnette,J.C.S. Chem. Comm., 1977, 3 3 1 .

186


obtained by an oxymercuration-demercuration sequence on PGF2a-l 1,15-bisTHP ether.41 The endo-configuration of the carboxy side-chain in (1 02 ; R = X = H) has been proven by its unambiguous synthesiss2 from lactone (106). The term PGIl 52 has been introduced t o describe (101 and 102; R = X = H).

(104) R = M e (105) R = H

A silica-gel-mediated rearrangements3 of (1 07) followed by deprotection resulted in the 5-hydroxy-PGI1 isomers (101 and 102; R = H, X = OH). Neither of these derivatives is an intermediate in the biosynthesis of PGlz by dog aorta micros~rnes.~~

0 I

OH

I

ODMBS

DMBSO

(107)

(106)

The 13,14-dehydr0-~~ and 5,6-methylene4’ (1 08) analogues of PG12 have also been reported. 6,9-Thia-PG12 (100) has been made from 9-thio-PGF20 methyl ester (258) via the iodination-dehydroiodination procedure.H It is considerably more stable than PG12 but retains the platelet aggregation inhibitory activity. A Japanese working in this area observed that the bis-THP ether of (258) cyclized X

I

HO

52

53 54

’’

OH (108)

THPO

I

OTHP (10%

N. A. Nelson, J. Amer. Chem. SOC., 1977, 99, 7362. F.-C. Huang, M. Zmijewski, G. Girdaukas, and C. J . Sih, Bioorg. Chem., 1977, 6 , 31 1. K. C. Nicolaou, W. E. Barnette, G. P. Gasic, and K. L. Magolda, J. Amer. Chem. SOC., 1977, 99, 7 7 3 6 . M. Shibasaki and S. Ikegami, Tetrahedron Letters, 1977, 4 0 3 7 ; 1978, 559.

187


spontaneously t o the protected 9-thia-PG11 (109; X = H ) and also readily autoxidized to a disulphide. The sulphenyl bromide derived from this disulphide cyclized to (1 09; X = Br), from which (1 00) was easily obtained.

?< *OF’.

CHO

HO OH

(1 10)

(111)

(112) R = H (113) R = TMS

,‘ (115) R = H /

H’

OH

I

OH (1 16) TXB, Reagents:

i, NaBH, ; ii, p-PhC, H, COCl-pyridine; iii, OsO, -N-methylmorpholine Naxide. iv, HIO, ; v, Me, SiC1; vi, Collins oxidation; vii, 0.25 M-HC1-MeOH; viii, NaOMe-MeOH Scheme 17

6 Synthesis of Thromboxane B2 Three discrete syntheses of TXBz ( 1 16) were simultaneously reported by workers at the Upjohn C ~ m p a n y . ’ ~ - ’Each ~ of these started from known PG intermediates and involved different procedures for the cleavage of the 1 1,12carbon-carbon bond. In the first approach Nelson and Jacksons6 obtained the

’6

57

N. A. Nelson and R. W. Jackson, Tetrahedron Letters, 1976, 3 2 7 5 . R. C. Kelly, 1. Schletter, and S. J. Stein, Tetrahedron Letters, 1976, 3279. W. P. Schneider and R. A. Morge, Tetrahedron Letters, 1976, 3 2 8 3 .

188


ao-unsaturated aldehyde ( 1 10) by treating the Corey aldehyde (1 3) with Florisil. After reduction of the aldehyde and protection of the resulting alcohol, the cyclopentene ring was opened via the d i o l ( l l 1 ) and the product reduced to afford diol (112). Selective oxidation of the primary alcohol in (1 12) was

Ro, 04

% o&o, ?$ iii-v_

HO

I

HO

Ph

Ph

Ph

+ (1 15)

Reagents:

i, Jones oxidation; ii, MCPBA; iii, DBU; iv, DIBAL; v, CH,N, Scheme 18

achieved via Collins oxidation of the bistrimethylsilyl ether (1 13). Direct treatment of this oxidation product with methanolic HC1 yielded the mixture of methyl acetals (1 14). Each isomer of ( 1 14) was converted by conventional procedures into TXB2 (Scheme 17). Kelly e t al.” also utilized the intermediate (1 15). This they obtained from the hydroxy-lactone (1 17), which was oxidized t o the crystalline dilactone (1 18). The elaboration of ( 1 18) into TXBz as shown OAC

OAc I

in Schemes 18 and 17 confirmed that the stereochemical integrity was maintained at C-8 and C-12 in the rearrangement of the endoperoxide into T X A 2 . PGF2 a methyl ester 9,15diacetate (1 20) was transformed into TXB2 in four stages.58 In this synthesis the crucial ring-opening step was accomplished by the action of lead tetra-acetate on the 1 1-hydroxy-group of (1 20), affording 1 1,12seco-1 2P-hydroxy-PGD2 methyl ester triacetate, which was protected as its dimethylacetal ( 12 1). Ester hydrolysis followed by treatment with aqueous phosphoric acid yielded TXBz . A completely novel total synthesis of racemic TXBz started from 4,4-di-nbutylthiobut-3-en-2-one, which was converted into the enone (1 22).59 Depyranylation and acid-catalysed ring closure followed by formation of the

’’ E. J . Corey, M. Shibasaki, J. Knolle, and T. Sugahara, Tetrahedron Letters, 1977, 785.


189

kv

RS

OH

OTHP

(1 22)

OTHP (1 23)

R = n-butyl

liv

OH

JJv+Q.v (1 24)

3 Meo kVii

9T0

?*

~

viii,ix

Me0

OH

OH

(1 26)

Reagents

(1 25)

i, aq.HOAc-THF; ii, TsOH-CH,C1, ; iii, dihydropyran-H+; iv, NaBH, ; v, &NO, -Ag, 0-MeCN; vi, DIBAL; vii, BF,,Et, 0-MeOH; viii, OsO, -pyridine; ix, NaIO, -aq.dioxan Scheme 19

tetrahydropyranyl ether furnished the mixture of isomeric ketones ( 123). This was reduced by sodium borohydride t o a separable mixture of alcohols. The 9a-alcohol ( 124) was further elaborated as shown in Scheme 19 into ( 126) and thence into (-f)-TXB,. Two very neat procedures6'@ have been reported for the conversion of D-glucose into TXB2 via ( 1 15), thus avoiding a resolution step in the synthesis. In the first of these methods6' the known sugar (127) underwent a Claisen rearrangement o n heating with dimethylacetamide dimethylacetal, affording the amide

60 61

E. J . Corey, M. Shibasaki, and J. Knolle, Tetrahedron Letters, 1977, 1625. S. Hanessian and P. Lavallee, Canad. J. Chern., 1977, 5 5 , 562.

190


(1 28), which after iodolactonization and de-iodination yielded ( 1 15). In the second method6' the benzoate ( 129) of 4,6-0-benzylidene-2deoxyiu-D-ribohexopyranoside was sequentially hydrogenolysed, silylated, and oxidized t o give ( 130) (Scheme 20). Condensation of (1 30) with trimethylphosphonoacetate anion followed by hydrogenation gave (1 3 l ) , which afforded ( 1 15; R = BDPS). This intermediate was further modified by standard PG chemical steps, yielding crystalline TXBz. 0Bz

OBZ

OBz

OBDPS

MeO'

OBDPS

MeO' (129)

(1 30)

(131)

1. (115) R = BDPS

BDPS = ButPh$i-

Reagents:

i, H, -Pd(OH), /C; ii, Bu'Ph SiCI; iii, Hitzner-Moffatt (MeO), P(O)CH, CO, Me-KOBu'; v, K, CO, -MeOH

oxidation; iv,

Scheme 20

7 Synthesis of Modified Prostaglandins

Deoxy-prostaglandins.-A considerable amount of effort is still being directed towards the preparation of deoxy-PG's, particularly in the 1 1-deoxy series, where a number of novel syntheses have increased the variety of these analogues. 9-Deoxy-prostaglandins. Photolysis of (40; R = Me) gave the cyclopentene aldehyde (1 32) in good yield. This was readily converted into 9deoxy-9a-methoxyPGC2 (1 33).62

11-Deoxy-prostaglandins. The May and Baker have published full details of their previously reported synthesis of 11-deoxy-PG's E l , F 1a,and F 1p (ref. 1, Vol. 2, p. 284 and Vol. 4, p. 255).

62

N. M . Crossland, S. M. Roberts, and K. I;. Newton, J.C.S. Chem. Comm., 1977, 886. T. S. Burton, M. P. L. Caton, E. C. J . Coffee, T. Parker, K. A. J . Stuttle, and C. L. Watkins, J.C.S. Perkin I , 1976, 2 5 5 0 .

191

Chemistry of the Prostaglandins 0

(134) R = H, Me, or Et 0 OHC

(CH,),CO,R

(136) R = H or Me

Novhk e t al. have described modifications to their synthesis of the versatile 1 1-deoxy-PG intermediate (134) (ref. 1, Vol. 4, p. 255) that yield the corresponding cis-A4- and cis-A5-compounds.64 Two new routes to 4-keto-aldehydes have been employed in efficient preparations of (1 34) via (136) from azelaic acid6’ and ( 135)66 respectively, 0

,‘

(1381,1576 (13 I ! , 3370

Y

e_r,

&Hz)6c02Me-

H

‘t7 O (139)

Reagents:

CHO I

(140)

i, Me, S=CHCO, Na-DMSO; ii, Li-NH,; v, c, HI, MgBr Scheme 21

OH

(141) R = Me iii, CH, N, ; iv, Collins oxidation;

In a novel approach a Russian group6’ have utilized the reaction of sodium dimethylsulphuranylideneacetate with ( 134; R = Me) to form the cyclopropylcarboxylic acids (137) and (138) (Scheme 21). The predominant isomer (137) was converted into the epoxide (1 39). This underwent regiospecific reductive cleavage of the cyclopropane ring followed by Collins oxidation to give the aldehyde ( 140), which on treatment with pentylmagnesium bromide yielded the methyl ester (141) of 1 1-deoxy-PGE I . 64

65 66

61

L. Novik, C. Szintay, Z. Visky, and J . Marosfalvi, Synthesis, 1977, 575. P. Bakuzis and M . L. F. Bakuzis, J. Org. Chem., 1977, 42, 2362. E. Wada, T. Nakai, and M. Okawara, Chem. Letters, 1977, 112 1.

V. I. Melnikova, A. E. Grigorev, and K. K. Pivnitskii, Zhur. obshchei Khim., 1976, 46, 1425.

192


The synthetic utility of nucleophilic ring-opening reactions of the bicyclo[ 3,l ,O]hexanone (1 42) was illustrated by its conversion into the precursor (144) (ref. 1 , Vol. 5, p. 261) of 1 1-deoxy-PGEl (Scheme 22).68

A group from Roussel-Uclaf have produced the versatile 1 1deoxy-PG intermediate ( 146p9 and have used it to prepare a series of 1643-thieny1oxy)analogues. The key step in their route to (146) was the bicarbonate-catalysed cyclization of (1 45).

The Ayerst group have modified two of their previous procedures (ref. 1, Vol. 2, p. 287 and Vol. 3, p. 335) t o produce l l - d e o x y - l @ - m e t h y l - P G F ~ ~ from 1 1-deoxy-1 5-keto-PGF1a methyl ester and the corresponding PGEl analogue from (147)." A Lederle group have synthesized a series of methylated

(148)

(149)

OH

(150) R = CH,Ph (151) R = H

Me0,C C0,Me

'' K. Kondo, E. Hiro, and D. Tunemoto, Tetrahedron Letters, 1976,4489. 69 70

J. Buendia and J . Schalber, Tetrahedron Letters, 1977, 4499. J . E'. Bagli, K. Greenberg, N. A. Abraham, and K. Pelz, Prostaglandins, 1976, 1 1 , 981.


193

lower side-chain analogues of 1 1deoxy-PGEl 71 and 1 1 deoxy-3-thia-PGEl by the conjugate addition of alanate and cuprate reagents t o ( 134)-type enones.

(156) X = CN (157) X = CH(CO,CH,Ph),

(158) n = 0 (159) n = 1

A high-yield four-stage route t o the intermediate (1 50) (ref. 1, Vol. 2, p. 283) has been described" which has as its key step a Nef reaction on the Diels-Alder adduct (148). This smoothly yielded the hydroxamic ester (149). Selective hydrogenation (5% Pd/C in dimethoxyethane) of the olefinic bond followed by a thermal extrusion of nitrous oxide from the N-nitroso-derivative of the hydroxamic ester afforded the required lactone (1 50). Two new syntheses have given the lactone alcohol (151) (ref. 1, Vol. 2, p. 285) from (152)74 and the Diels-Alder adduct" of (1 53) with methyl 0-acetoxyacrylate.

I

ODMBS (160)

OH (161) X = C0,Me (1-series) (162) X = SPh (1-series) (163) X = SPh (2-series)

The enone (1 54), prepared from 2-carboethoxycyclopentanone, was the common starting material for the synthesis of trans-A2-l ldeoxy-PGE, and its C13 homologue (1 55).76 Conjugate addition of hydrogen cyanide and dibenzyl malonate, respectively, gave the two precursors (1 56) and (1 57) to the aldehyde 71

J. S. Skotnicki, R. E. Schaub, K. F. Bernady, G. J . Siuta, J . F. Poletto, M . J . Weiss, and F. Dessy, J. Medicin. Chern., 1977,2 0 , 1551. J. S. Skotnicki, R. E. Schaub, M. J . Weiss, and F. Dessy, J. Medicin. Chern., 1977, 2 0 , 1662. 73 S. Ranganathan, D. Ranganathan, and R. Iyengar, Tetruhedron, 1976,32, 961. I4 K. Inoue and K. Sakai, Tetrahedron Letters, 1976,4107. 7 5 T. Ogino, K. Yamada, and K. Isogai, Tetrahedron Letters, 1977, 2445. 76 W. Bartmann, G . Beck, R. Kunstmann, U. Lerch, and H. Teufel, Tetrahedron Letters, 1977,2563. 72

194


( 1 5 8 ) and (1 59). After standard elaborations of the lower side-chains, the dithioacetals were deprotected (MeI-CaC03 in aqueous DMF) and the A’-acid functions introduced by Wittig reactions with methoxycarbonylmethylenetriphenylp hosphorane. The intermediate enolate anion formed on conjugate addition of (160) tt, (1 53) has been trapped with methyl chloroformate and diphenyl disulphide. Further elaboration of the products gave respectively the 8-methoxycarbonyland the 8-phenylthio-1 ldeoxy-PGE’s (1 6 1),77 ( 162),78 and (1 63).79 The application of a new desulphurization method, using zinc-trimethylsilyl chloride, t o the silyl ether of (1 63) represents an additional synthesis of 1 ldeoxy-PGE2 .79 CrabbC et a/. have derived the 1 la-substituted-1 l-deoxy-PGE2 analogues (1 64)-( 167) by conjugate addition of the appropriate lithium organo-cuprate t o PGAz methyl ester 15-tetrahydropyranyl ether. An alternative synthesiss0 of (1 64) illustrates the application of the same group’s synthon (1 68) (ref. 1, Vol. 5 , p. 261) to 2-series PG’s. Addition of lithium dimethylcuprate t o (168) furnished ( 169). Minor modifications of the published method converted ( 169) into (164).

’’

R

I

OH (164) R = methyl (165) R = n-butyl (166) R = benzyl (167) R = phenyl

H

(168)

(169)

9,1l-Bisdeoxy-prostaglandins.A versatile synthon (1 72)81 for 9,ll-bisdeoxy-PG’s was prepared from the hydrindanone (170). This was converted into the acyloin (171) and thence into (172) on cleavage with lead tetra-acetate (Scheme 23). The use of (1 72) was illustrated by its transformation into methyl 1SO-hydroxy2-trans,4-cis, 8,13-trans-prostatetraenoate( 173). 15-Deoxy-prostaglandins. A separable mixture of 15-deoxy-PGF2a and its A14 isomer was formed from the tris(t-butyldimethylsilyl) ether of PGF2a by

T. Toru, S. Kurozumi, T. Tanaka, S. Miura, M. Kobayashi, and S. Ishimoto, Tetrahedron Letters, 1976,4087. 7 8 S. Kurozumi, T. Toru, T. Tanaka, M. Kobayashi, S. Miura, and S. Ishimoto, Tetrahedron Letters, 1976, 409 1. 79 S. Kurozumi, T. Toru, M. Kobayashi, and S. Ishimoto, Synthetic Comm., 1977, 7 , 427. NJ P. Crabbe‘, E. Barreiro, H. Sook Choi, A. Cruz, J . P. DeprGs, G . Gagnaire, A. E. Greene, M. C. Meana, A. Padilla, and L. Williams, Bull. SOC. chim. belges, 1977, 86, 109; P. Crabbe‘, In$ Chim., 1976, 160, 229. A. Barco, S. Benetti, G. P. Pollini, P. G . Baraldi, M . Guarneri, and C. B. Vicentini, Synthetic Comm., 1977, 7 , 13. 77


195

reduction of the C-15 oxygen function (lithium-neopentyl alcohol-methylamine, at -30°C) followed by deprotection.82

(1 70)

I

i

I

OH Reagents:

(173) i, DBN; ii, K, CO, -MeOH; iii, Pb(OAc), -MeOH; iv, H, SO, -MeOH Scheme 23

In an extension of their work on 15deoxy-16-hydroxy-PGEl analogues (ref, 1, Vol. 5, p. 268, for which full details have now been published=), the Searle groupsq have described the synthesis of the cyclopentenone (1 74) and its conversion, by the addition of the appropriate organo-cuprate reagents, into the 15 -deoxy- 16-hydroxy-PGE2 analogues ( 17 5) and ( 17 6 ) .

OH (175) R = H (176) R = Me

Pirillo and T r a v e r s ~ , ~ working ~@ in the 9- and 1 ldeoxy-series, have synthesized the first examples of modified PG's containing the isomeric 16-hydroxy-trans lower side-chain. They have described two routes to the 9-deoxy-PGD analogue (1 79) which involve the conjugate addition of a C2 aldehyde precursor R. R. Gorman, ti. L. Bundy, D. C. Peterson, F. F. Sun, 0. V. Miller, and F. A. Fitzpatrick, Proc. Nut. Acad. Sci. U.S.A., 1977, 74, 4007. 83 P. W. Collins, E. Z. Dajani, D. R. Driskill, M . S. Bruhn, C. J . Jung, and R. Pappo, J. M e d i c i n Chem., 1977, 2 0 , 1152. 84 M. Bruhn. C. H. Brown, P. W. Collins, J . R. Palmer, E. 2. Dajani, and K. Pappo, Tetrahedron Letters, 1976, 2 3 5 . G . Traverso and D. Pirillo, Farmuco, Ed. Sci., 1976, 31, 3 0 5 . ~6 G. Traverso and D. Pirillo, Famzaco, Ed. Sci, 1976, 31, 438.

82

196


(177) a; R = CH,CH=CH, b; R = CH,C=CH

(178)

(1 79)

Scheme 24

(methyl cyanoacetate) to the cyclopentenones ( 177a) and ( 177b) (Scheme 24). The resulting aldehydes ( 178a) and ( 178b) were elaborated by conventional reactions into (179). The aldehyde (178b) also furnished 14,15-dehydro-( 179).85 Modification of the synthesis of (179) as outlined in Scheme 25 gave the 11deoxy-PGE analogue (1 82).87

(182)

-L

Scheme 25

A group led by Ireland8’ have published a new convergent approach to the synthesis of the PG skeleton. This incorporates a connection of the two halves of the molecule, using the ester enolate modification of the Claisen rearrangement to form the key bond between C-8 and C-12. In practice this had limited success. Of the target molecules, only Al4-l5-deoxy-PGAl (187) was obtained. The components were assembled as shown in Scheme 26 to give the keten acetal (184). This underwent a facile Claisen rearrangement, the product of which, on acidification, furnished the lactone (1 85). The reduction of ( 185) with DIBAL gave the keto-aldehyde (186). This yielded the PGAl analogue (187) on cyclization in the presence of piperidinium acetate, The analogous keto-aldehydes (188) and (189) were similarly prepared but could not be cyclized to the corresponding PGA derivatives. I” 88

D. Pirillo and G. Traverso, Farmaco, Ed. Sci., 1976, 31, 468. R. E. Ireland, K . H. Mueller, and A. K. Willard, J. Org. Chem., 1976,41,986.


Reagents:

197

i, trans-dec-4enyl chloride-Et,N-C€I,Cl, ; ii, LiNPr; iii, Me, But SiC1; iv, 67 "C; v, NaOH-MeOH, reflux and then neutralize; vi, DIBAL; vii, piperidiniunl acetate-benzene, reflux Scheme 26

11,15-Bisdeoxy-prostaglandins.The conjugate addition of the Stork protected cyanohydrin reagent (1 90) t o cyclopentenone has been applied to the synthesis of 5,6-dehydro-l1,15-bisdeoxy-l 3-hydroxy-PGE2 (1 92).89 The intermediate enolate anion (1 9 1) was treated with methyl 7-iodo-5-heptynoate to incorporate

the upper side-chain, Bartmann et al. have prepared 1 1,15-bisdeoxy-l3hydroxy-PGE, (196) from the keto-ester (193). The allylic rearranger. ent at C-13 was effected by acid-catalysed lactonization of (194) (Scheme 27). The 14-cis-isomer of (196) was reported earlier (ref, 1, Vol. 5, p. 263). The related ester ( 197)" and acid (198)= were obtained from 1-octanol on radical addition and benzophenone-sensitized photoaddition, respectively, t o a cyclopentenone of the type (134). 89

J. A. Noguez and L. A. Maldonado, Synthetic Comm., 1976, 6 , 39. W. Bartmann, G. Beck, R . Kunstmann, U. Lerch, and H. Teufel, Tetruhedron Letters, 1977, 3879.

S. Dolezal, Coll. Czech. Chem. Comm., 1976, 41, 2755. 92 A. Wissner, J. Org. Chem., 1977, 42, 356. 91

198

9--

Aliphatic and Related Natural Product Chemistry CO,H

CN

&C5Hll

\ -

RO CN

(190)

R = ethoxyethyl

OH

(191) (192)

9-Keto-13-trans-prostenoic acid and its 13-cis-isomer were converted in high yields into their 18- and 19-hydroxy-derivatives by cultures of Microascus trigonosporus. 93

I

I

OTHP

OTHP (193)

1

(194)

R = (CH,),CO,Et

ACH,

+--

\ I

OH (196)

(195)

Scheme 27

The conjugate addition of geranyl-copper to ( 134) gave the 1 1deoxy-PGE analogue ( 199) with an isoprenoid lower side-chain.” Cyclopentane Ring Variants.-Aza-prostaglandins. The range of aza-prostaglandin analogues reported has grown to include substitution by nitrogen in positions 9, 10, and 12. A new synthesis of 1 1-deoxy-8-aza-PGE2 (ref, 1, Vol. 5, p. 269) from pyroglutamic acid proceeded via the acetylenic oxazolidine ( The related compound 1 1-deoxy-8-aza-13,14-dihydro-PGE (203) was obtained from a sequence in which the conjugate addition of the nitro-ketal (201) to methyl vinyl ketone followed by catalytic reduction of the nitro-function afforded

93 94

95

R. P. Lanzilotta, D. G. Bradley, K. M. McDonald, and L. TokCs, A p p l . Environmental Microbiol., 1976, 32, 726. B. Crammer, 2. Aizenshtat, and R. Ikan, Org. Prep. Proced. Znternat., 1975,7 , 297. P. A. Zoretic, N. D. Sinha, and B. Branchaud, S y n t h e t i c C o m m . , 1977,7 , 299.

199

(197) R = Me (198) R = H

the intermediate pyrrolidone (202).% In an alternative synthesis9' of (203) the pyrrolidinone ring was formed by reductive amination of (204) with 7aminoheptanoic acid in the presence of sodium cyanoborohydride. The preparations of some analogous 8,ll-diaza- and 8-aza-l l-thia-PG's were also described in this paper. 0

0

II

(200)

The conjugate addition of aziridine to diethyl 7-cyanoheptylidenemalonate followed by a ring-opening reaction with ethyl chloroformate formed an Nethoxycarbonyl-2-chloroethylamine. This underwent ring closure to give (205), which was used t o prepare the 9-aza-PG (206).98 The 1 la-hydroxy-analogue (207) was subsequently obtainedw in eight steps via (208) from ethyl N-ethoxycarbonylglycinate and diethyldec-2enedioate. 9-Aza-9,ll -bisdeoxy-1 O-ketoPGF2 methyl ester (252) was derived from 1 l-nor-PGE2 (248) methyl ester (see p. 2O3).'Oo 96

P. A. Zoretic and J . Chiang, J. Org. Chem., 1977, 42,2103. R. L. Smith, T. Lee, N. P. Gould, E. J . Cragoe, jun., H . G. Oien, and F. A. Kuehl,jun.,J. Medicin. Chem., 1977, 20, 1292. 9 8 G . P. Rozing, T. J . H. Moinat, H. d e Koning, and H. 0. Huisman, Heterocycles, 1976, 4,719. 99 G. Y. Rozing, H. de Koning, and H. 0. Huisman, Heterocycles, 1976, 5, 325. I00 A. E. Greene, J . P. DeprZs, H. Nagano, and P. Crabbe', Tetrahedron Letters, 1977, 2365. 37

200


m

CO,E t

C02Et

I

C02Et

qlOzEt +COzEt X

CO,E t

bH

OH

(206) X = H (207) X = OH

(205)

R = (CH,),CO,Et

A facile synthesis of 10-aza-l l-deoxy-l 0-methyl-PGE2 methyl ester ( 2 13) commenced from the pyrrolidone ester (209) via ( 2 10).'O1 Two alternative sequences introduced the upper side-chain uia (2 1 1) and (2 12) respectively.

kRl

MeN

\

---+ M e N

- - + MeNh y R 2

CH,OTHP I

(209) R' = C0,Me (210) R' = CH,OTHP

(211) RZ = CHO (212) R2 = CEEEC(CH,),CN

A closely analogous sequence produced 10-aza-l l deoxy-1 0-methyl-PGE .Io2 Extension of this work led t o 10-aza-l l-methoxy-PGE analogues, e.g. (2 16).Io3 Methoxylation at C-1 1 was achieved by anodic oxidation of the intermediate (214) (Scheme 28).

(214) OH

Co2Me

-;k /'

/'

OMe

(215)

OH (216)

Reagents:

101

102

'03

i, Me, N BF, -MeOH, at Pt anode Scheme 28

K. Kuhlein, A. Linkies, and D. Reuschling, Tetrahedron Letters, 1976,4463.

P. A. Zoretic and F. Barcelos, Tetrahedron Letters, 1977, 529. D. Reuschling, M, Mitzlaff, and K. Kuhlein, Tetrahedron Letters, 1976,4467.


201 (CH,),CO,Me

1

X

OH (217) X = H, (218) X = 0

(CH,),CO,Me

Efficient routes to the 12-aza-PGEo methyl esters (2 17)'04 and (2 18)"' were described by Scribner, starting from 2-aminoazelaic acid. 12-Aza-9,llbisdeoxy-A' -PCo methyl ester (220)'06 was synthesized from 3-pyrroline by reaction with 1-chloro-oct-1 en-3-one and potassium carbonate in DMF. The resulting enamino-ketone (21 9) was alkylated (7-iodo-l,1,1 -trimethoxyheptanelithium di-isopropylamide), reduced (NaBH4), and finally hydrolysed t o yield (220).

Pailer and Gutwillinger have described the synthesis of two PG analogues (221)lo7 and (222)lo8 in which the cyclopentane ring is substituted by imidazole. The skeleton of (221) was formed by conjugate addition of methyl 2-imidazoleheptanoate to oct-1-yn-3-one. Methyl 1-imidazoleheptanoate was hydroxymethylated at C-2 and oxidized (Mn02) to the aldehyde precursor t o (222). In an attempt to find PG-like compounds as devoid of stereochemical features as possible, Bennett et al. lo9 have synthesized a series of l-aryl-3-pyrazolidinones, 104

105 106

R. M . Scribner, Tetrahedron Letters, 1976,3853.

R. M. Scribner, Prostaglandins, 1977, 1 3 , 677.

3. C. Lapierre Armande and U.K. Pandit, Tetrahedron Letters, 1977, 897. M . Pailer and H. Gutwillinger, Monatsh., 1977, 108, 653. ' 0 8 M. Pailer and H. Gutwillinger, Monatsh., 1977, 108, 1059. 109 G. B. Bennett, W. J . Houlihan, R. B. Mason, and J . B. Roach, jr., J. Medicin. Chem., 1977, 19, 715. 107

202


exemplified by (223). None of these compounds had any desirable PG-like activity in a variety of biological screens. A Russian group"' have made the piperazine (224) as an unusual diaza-PG analogue.

Thia-prostaglandins. In an alternative procedure for the preparation of 9-deoxy9-thia-PGEl (ref. 1, Vol. 4, p. 259) Vlattas e t al. '11 have devised two syntheses of the intermediate aldehyde (225). The reaction of (225) with the anion of diethyl thiophenylmethyl phosphonate gave (226). This underwent a novel regiospecific aldol condensation t o produce a mixture of the epimeric aldehydes (227), which was elaborated by standard techniques into the PGEl analogue. A new efficient procedure for the Dieckmann cyclization has been used t o convert (228) into (229). This ketone was elaborated via (230) and (231) into 9 , l l bisdeoxy-9-thia-PGE .*12 The application t o PG synthesis of the ketovinylation of 0-dicarbonyl compounds has been illustrated in the preparation of the 9-thia-PG analogue (233),

(225) X = 0 (226) X = CHSPh

OH (227)

R2

(229) R1R2= 0 (230) R'R2 =

4

(231) R' = H, R2 = CHO

110

"'

112

E. I. Levkoeva, G. Y. Shvarts, M. D. Mashkovskii, and L. N. Yakhontov, Khim. Farm. Zhur., 1976, 10, 64. I. Vlattas, L. Della Vecchia, and A. D. Lee,J. Amer. Chem. Soc., 1976, 98, 2008. W. J . Vloon, E. R. De Waard, and H. 0. Huisman, Heterocycles, 1977,6, 1097.

Chemistry o f the Prostaglandins

203

obtained in 47% yield when the anion of the 0-keto-ester (232) was treated with octyn-3-0ne.l~~

Cyclohexane Ring Analogues. The preparations of (+)-9a-homo-PGF10 ethyl ester (237) and its 8,12-bisepi-isomer were described from the respective intermediates (235) and (236).l14 These were in turn derived from the Diels-Alder ,3-diene via adduct of dimethyl fumarate and trans,trans-174-diacetoxybuta-l the diol (234). Syntheses of (238), its 8-epi-isomer, and the aromatic analogue (239) have also been reported.'"

x

OTHP ,CH,OR'

(J I

CH,OR' I

I

X

OTHP

I

OH (237) X = OH (238) X = H

(234) R' = R2 = H (235) R1 = H, RZ = CH,Ph (236) R' = CH,Ph, R2 = H

; (CH,),CO,H OH

Cyclobutane Ring Analogues. Crabbe"s have reported an elegantly simple synthesis of 1 l-nor-PGE2 (247) and 1 l-nor-PGF2a (248) (Scheme 29), starting from the readily available dichlorocyclobutanone (240). This was successively reduced ( t o 242) and cleaved to furnish the lactone acid (243). After incorporation of the lower side-chain, the 8,12-trans stereochemistry was achieved via equilibration of the enone (245) with DBU. A modification

114

'15 116

K. J . K. Taylor and I. T. Harrison, lttrahedron Letters, 1976, 4793. T. A. Eggelte, H, de Koning, and H. 0. Huisman, Chem. Letters, 1977, 433. T. A. Eggelte, H. de Koning, and H . 0. Huknian, Rec. Traw. chim., 1977,96,271. A. E. Greene, J . P. DeprGs, M. C. Meana, and P. CrabbC, Tetrahedron Letters, 1976, 3755.

204

A 1ip h at ic and R e la t ed Natural Product Che m is try

A

4 o f i

H O \ \ f i

A * la;

1

cl

iii,i"

R

\

H

R H il(240)

R

= C1/

(241)

R

=

'C0,H

(24 2)

'CHO

(243)

(244)

1

H

(.

x

*--

+'

OH II (247) XY = 0 (248) X = OH,

8 /

0

Y = H

(245) 8,124s vii

[I

(246) 8 , 1 2 - t ~ ~ ~

Reagents:

i, Zn-HOAc; ii, LiAlH, -THF, -78 OC; iii, 0, ; iv, I i , 0, --HCO, H; v, B, H, THF; vi, pyridinium chlorochromate; vii, DBU

-

Scheme 29

of this synthesis proceeded from (242) via (249), which was epimerized t o (250).l17 Routine ring-expansion reactions on (247) methyl ester have provided the novel cyclopentane ring variants (251), (252), and (253).'O0 Mercapto-prostaglandins.-The first examples, (254)-(258), of PG analogues in which hydroxy-groups have been replaced by thiols have been OMe ?

4 I

I

I

CHO (249) aCHO (250) PCHO

OH (251) X = 0 (252) X = NH (253) X = CH,

D. Reuschling, K. Kuhlein, and A. Linkies, Tetrahedron Lerters, 1 9 7 7 , 17.

-


X Y L

7

. I

I

OH

(254) X

I

OH =

205

x &YCOzH

H

H, Y = OH

II

i

Y

(256) X = OH, Y = SH (257) X = SH, Y = OTHP (methyl ester)

(255) XY = 0

SH

2 C0,Me

OH

OH

reported. 54*114119 Their preparation involved the tosylation, mesylation, or bromination of a suitable PG precursor followed by SN 2 displacement with thioacetate or hydrosulphide and finally completion of the syntheses by standard methods.

OH (261)

I

OH

I

I

OH

(263) R = Me (264) R =

H Scheme 30

'"S. '19

Ohki, N. Ogino, S. Yamamoto, 0. Hayaishi, H. Yarnamoto, H. Miyake, and M. Hayashi, Proc. Nat. Acad. Sci. U.S.A., 1977, 74, 144. M. Miyake, S. Iguchi, H. Itoh, and M. Hayashi, J. Arner. Chern. Soc., 1977, 9 9 , 3536.

206


Methyl-prostaglandins.-The methyl ester (263) of 10,l O-dimethyl-PGE 1 has been reported (ref. 1, Vol. 5, p. 274) in a synthesis which utilized the cyclic diketone (259) as starting material. In another approach from (259) an Organon group'20 have prepared (263), from which the acid (264) was derived (Scheme 30). A key feature of this synthesis was the selective reduction of the cuo-unsaturated 15-ketone by lithium tri-s-butylborohydride in the presence of an unprotected 9-ketone.

4 h' 9

&L

i ,

HO

Me

0

/

I

/ / /

+

OCOEt

+1 lct-methyl isomer

I

/

/

H?

0

HO

Me

I

Me

OH

I I

OH (270)

Reagents:

i, aq. chromic acid-Et, 0;ii, Me, Al-toluene

Scheme 31

The synthesis of the 11-methyl-PG methyl esters (268), (269), and (270)12' was achieved from (265) via the reaction of the unstable 11-ketone (266) with trimethylaluminium (Scheme 3 1). The 1 lp-methyl intermediate (267) was isolated by high-performance liquid chromatography (HPLC) of the C-1 1 epimer mixture. lZo

lZ1

A. Hamon, B. Lacoume, G. Pasquet, and W. R. Pilgrim, Tetrahedron Letters, 1976, 211. C. H. Lin, Chem. and Ind., 1976, 994.


207

Me (27 1 )

(272)

Mc i

(273) 96% optical purity I

I

.I 4---

BzO Reagents:

Me

P ' C 0 2 H CH,OTHP 0

Me (275)

THPO

(276) i, D-proline; ii, TsOH-benzene, A

Me (274)

Scheme 32

Grieco and his collaborators'22 have now published a full, detailed paper on their syntheses which had been reported previously (ref. 1 Vol. 5 p. 273) of (+)-12-methyl-PGF2, (277) and (+)-12-methyl-PGA2 The same group have subsequently described an asymmetric synthesis of the optically active form of

HO Me

OH (277) X = OH (278) X = H

the key intermediate aldehyde (276).'23 This route was based on the catalytic asymmetric cyclization of the triketone (271) by D-proline t o give the alcohol (272) followed by dehydration t o the enedione (273) (96% optically pure) (Scheme 32). The introduction of the C-9 oxygen function into (274) was effected through the cyclopentenone acid (275) but the procedure proved lengthy and laborious. The aldehyde (274) was also transformed into 9-deoxy12-methyl-PGF2a (278).'23 The Sankyo group'% have adapted one of their routes to hydroxymethylPG's to prepare 1 1-deoxy-12-methyl-PGE2 (279) and its 8,12-cis-isomer (280) from the bicyclic lactone (292b).

123 124

P. A. Grieco, C . S. Pogonowski, S. D. Burke, M. Nishizawa, M. Miyashita, Y . Masaki, C.-L. J. Wang, and G . Majetich,J. Amer. Chem. Soc., 1977, 99, 41 11. P. A. Grieco, N. Fukamiya, and M. Miyashita, J.C.S. Chem. Comm., 1976, 5 7 3 . N. Nakamura and K. Sakai, Tetrahedron Letters, 1976, 2049.

208


Hydroxymethyl-prostaglandins.-The first total synthesis of 9-deoxy-9ahydroxymethyl-PGF2a (284) has been developed by Kojirna and Sakai. 12' The functionalized cyclopentanone (28 1) was constructed by a known method (ref. 1, Vol. 2, p, 272) and stereospecifically reduced by sodium borohydride, affording, after acetylation, the 1 la-acetoxy-derivative. Reduction of the

Me

I

I

OH (279) a-upper side-chain (280) p-upper side-chain

corresponding mixed anhydride followed by cleavage of the phenylpropyl side-chain (via an intermediate styryl compound) furnished the necessary lactol, protected as its methyl acetal (282). The synthesis of (284) was readily completed after protection of the hydroxy-group and conversion of the ester into aldehyde (283) (Scheme 33).

Reagents:

i, dihydropyran-H'; ii, LiAlH, ;iii, Collins oxidation

Scheme 33

This group's synthesis of 1 1deoxy-1 la-hydroxymethyl-PGE was reported last year (ref. 1, Vol. 5 , p. 265). They have now prepared 1 l-deoxy-llo-hydroxymethyl-PGEl (286) and its 8P-isomer by a completely novel approach.'26 This 125

lZ6

K. Kojima and K. Sakai, Tetrahedron Letters, 1976, 101. J. Ide and K. Sakai, Tetruhedron Letters, 1976, 1367.


209

twenty-four-stage synthesis, starting from (285), proceeded via a cleavage of the olefinic bond followed by a Dieckmann cyclization to form a suitably functionalized cyclopentane ring. A further modification in this series by the Sankyo group'% was 1 l d e o x y 12-hydroxymethyl-PGE2 (293). The key intermediate lactone (292c) in the synthesis of (293) was produced by an ingenious approach (Scheme 34) from (287a). This, on reduction with sodium borohydride followed by elimination of the alcohol, furnished the cyclopentenyl ester (288a). This was converted into the malonate diazo-ester (289a). The intramolecular cyclopropanation of (289a)

i-iii

R

C0,Me

(292)

(29 1)

I

+

a; R = CH,OCH,Ph b; R = CH, c; R = CH,OH

I

R OH (293) Reagents:

i, NaBH,-MeOH, -15 O C ; ii, MeS0,Cl; iii, HMPA, 145 OC; iv, LiAlH,; v, ClC(O)CH, CO, Me; vi, TsN, -Et, N-MeCN; Vii, Cu-octane, A ; vui, HOAcH, SO, (40: l ) , 90 " C ;ix, K,CO, -MeOH; x, Collins oxidation, xi, BP,, Et,, 0ethylene glycol Scheme 34

210


gave the crystalline tricyclic ester (290a) in 67% yield, thus introducing stereospecifically the upper side-chain precursor. Cleavage of the cyclopropane ring occurred on heating (290a) in an acetic-sulphuric acid mixture, giving the 9cyacetoxy bicyclic lactone (291a) as the sole product. Conversion into the 9-ketal (292a) followed by debenzylation afforded (292c). $,

,CH,OH

HOCH,.

,

The anion derived from the bicycloheptane ester (294) was treated with formaldehyde to yield a 1 : 1 mixture of the hydroxymethyl derivatives (295) and (296). Each of these was separately converted into (2)-12-hydroxymethylPGF2a methyl ester.I2' Benzo-prostaglandins.---A remarkably facile synthesis of 1 0 , l l -benzo-PGA2 (298) has been developed via the lactone (297).'28 This was obtained in two steps from indene [alkylation with chloromethyl methyl ether followed by lactonization with manganese(II1) triacetate] . The approach was modified t o afford 13,14-dihydro-l0,11 -benzo-PGA2, commencing with the Grignard reaction of 1-(2'-bromoethyl)indene with n-hexanol.

Upper Side-chain Variants.-Full details of the synthesis of the cis-A4 -PG analogues (299) and (300) (ref. 1, Vol. 3, p. 348) have appeared.'29 The C-1 alcohol (303) corresponding t o PGEl was formed by the addition of the organo-cuprate reagent (302) to (3O1).l3O A similar addition of (302) to (304) led to benzo[ 5,6]-PGE2, -PGA2, and -PGF2a.131

127

P. A. Grieco, C.-L.J . Wang, and F. J . Okuniewicz, J.C.S. Chem. Comm., 1976, 939. A. Sugie, H. Shimomura, J. Katsube, and H. Yamamoto, Tetrahedron Letters, 1977, 2759.

lZ9 130

13'

K. Gre'en, B. Samuelsson, and B. J. Magerlein, European J. Biochem., 1976, 6 2 , 527. H. C. Kluender and G. P. Peruzotti, Tetrahedron Letters, 1977, 2063. K. T. Buckler, F. E. Ward, H. E. Hartzler, and E. Kurchacova, European J. Medicin. Chem., Chim. Ther., 1977, 1 2 , 4 6 3 .

21 1


The carboxylic acid function at C-1 can be degraded by a Curtius reaction t o give a 2-amino-l-nor-PG, which may be further modified to a thiourea derivative, 132

I

I

OH

I

OH

(299) X = OH, Y = H (300) XY = 0

Tanaka e t al. 133 have published the experimental details of their synthesis of 7-keto-PGEl ethyl ester from the synthon (305) (ref, 1 , Vol. 5, p. 277). The same group have now prepared both enantiomers of (305) from a mixture of cis- and dl-trans-3,5-diacetoxycyclopentene,using the differential rates of hydrolysis by baker’s yeast t o effect the resolution.134

j m8 R

= THP or ethoxyethyl

e

I

OH

I

OH

OR

ODMBS

Treatment of 2,3epoxycyclopentanone with methyl 6-mercaptohexanoate and triethylamine afforded ( 3 0 6 ) , the precursor to 1l-deoxy-7-thia-PGEl methyl ester (308).13’ Extension of this work resulted in the corresponding

132

133 134

135

G. Tronconi, G. d’Atri, and C. Ycolastico, Prostaglandins, 1977, 13, 1067. T. Tanaka, S. Kurozumi, T. Toru, M. Kobayashi, S. Miura, and S. Ishimoto, Tetrahedron, 1977, 33, 1105. T. Tanaka, S. Kurozumi, T. Toru, S . Miura, M. Kobayashi, and S. Ishimoto, Tetrahedron, 1976, 32, 1713; S. Miura, S . Kurozumi, T. Toru, T. Tanaka, M. Kobayashi, S. Matsubara, and S. Ishimoto, Tetrahedron, 1976, 32, 1893. S. Kurozumi, T. Toru, M . Kobayashi, and Y . Hashimoto, Chern. Letters, 1977, 331.

21 2


1 1-hydroxy-enone (307) and a series of 7,13dithia-PG’s, for example (+)-methyl

7,13dithia-l5-methy1-9,1 1,l S-trihydroxypr~stanoate.~~~ The coupling of PG’s E l and E2 with phosphatidylethanolamine gave amide derivatives having a delayed onset of action on various smooth-muscle preparations. 13’

X

(306) X = H (307) X = OH

Lower Side-chain Variants.-A Searle has reported a series of omegahornologues of PGEl , prepared by their previously published route (ref. 1, Vol. 3, p. 323). Although less potent than PGEl itself, the homologues showed some interesting separation of biological activities; for example, (5)-2Oethyl-PGE1 had a comparable hypotensive potency to PGEl but showed a much lower smooth-muscle-stimulating activity.

QH

0 II

In the continuing search for PG analogues with a lower affinity for the 15-dehydrogenase enzyme an Ono have prepared 16-methylene-PGF2a (309a), 16,16-ethano-PGF2a (309b), and the PGE methyl esters (310a) and (310b), using a modified Corey route. Owing t o the acid-sensitive nature of these lower side-chains, the synthesis of the PGF’s was carried out without protection of the hydroxy-groups at C-1 1 and C-15. The PGE’s were prepared as methyl esters from the PGF’s by the selective silylation, oxidation, and desilylation procedure.

136

S. Kurozumi, T. Toru, M. Kobayashi, and Y . Hashimoto, Synthetic Comm.,1977, 7 ,

137

H. B. Kunze, R. B. Ghooi, E. Bohn, and D. Le-Kim, Prostaglandins, 1976, 12, 1 0 0 5 . E. Z. Dajani, L. F. Rozek, J. H. Sanner, and M. Miyano, J. Medicin. Chem., 1976, 19,

169. 13*

1007.

H. Miyake, S. Iguchi, S. Kori, and M . Hayashi, Chem. Letters, 1976, 21 1.


I

213

1

H O OR (314) R = (315) R = Me144

OH (3 1 7)14’

HO OH (316)143

The conjugate additions of organo-cuprate reagents t o the appropriate cyclopentenones have resulted in a variety of PGE analogues with the novel lower side-chains, e.g. ( 3 11)-(3 17),’40-’45 An ICI group’46 have prepared a series of 17-phenyl-PGF’s ( 3 18)-(32 1) to investigate the effect on luteolytic activity of structurally rigid linking groups

OH (318) R = (319) R =

(320) R =

I

OH

mph =

Ph

A P”

cis

Ph

(321) R =

trans

(322) R = CMe,CH,Ph (323) R = CMe’OPh 140

14’ 14’

H. C. Arndt, W. G. Biddlesom, G. P. Peruzotti, and W. D. Woessner, prostaglandins, 1976, 11, 569. H. C . Arndt, W. G. Biddlesom, E. Hong, C. Myers, G. P. Peruzotti, and W. D. Woessner, Prostaglandins, 1977, 13, 837. J. S. Skotnicki, R. E. Schaub, M. J. Weiss, and F. Dessy, J. Medicin. Chem., 1977, 2 0 ,

1042. W. A. Hallett, A. Wissner, C. V. Grudzinskas, and M . J . Weiss, Chern. Letters, 1977,51. 144 W. A. Hallett, A. Wissner, C. V. Grudzinskas, R. Partridge, J . E. Birnbaum, M. J . Weiss, and F. Dessy, Prostaglandins, 1977, 13, 409. 14’ W. Bornatsch and K. G. Untch, Prostaglandins, 1977, 14, 617. 146 D. G. Fletcher, K. H. Gibson, H, R. Moss, D. R. Sheldon, and E. R . H. Walker, Prostaglandins, 1976, 1 2 , 493. 143

214


between C-15 and the phenyl ring. In the potent alkynyl series the replacement of the phenyl ring by furan, thiophen, and cyclohexane was also examined, Upjohn workers14' have outlined the synthesis of the 16,16dimethyl-l7-phenyl analogues (322) and (323). Fried e t ~ 1 . have ' ~ ~incorporated the allene moiety into the lower side-chain to produce the four isomers of (327). A modification of the standard Corey route was used, in which condensation of (324) with aldehyde (13) afforded (325). Acetylation and rearrangement (Me2CuLi) of the ynol fragment yielded the key allenic intermediate (326). LiCECCH(OTHP)C,H, (324)

I

OPB

OH

(325) R = CH(OH)CECCH(OTHP)C,H, , (326) R = CH=C=CHCH(OTHP)C,H,

OH (327)

The 14-cyclohexyl-PG methyl esters (330) and (33 1) were synthesized from aldehyde (29) and the 0-oxido-ylide (328) via an acid-catalysed rearrangement of the secondary allylic alcohol (329).149

" P

h

,

P

C

0

,

M

e

5

y THPO

-0

W

OH

OH (329)

HO (330) X = H, Y = OH (331) XY = 0

Further examples have been described of analogues in which the hydroxygroup at C-15 is shifted to other positions of the lower side-chain, Wissnerg2 obtained (+)-9-keto-ll,13dihydroxy-5-cis-prostenoicacid as a mixture of isomers on benzophenone-photosensitized addition of 1-octanol to the cyclopentenone (57). The alcohol (332) was transformed into (333) by addition of

'41 14* 149

F. A. Kimball, J. W. Lauderdale, N. A. Nelson, and R. W. Jackson, Prostuglandins, 1976, 12, 985. J. H. Fried, J. M. Muchowski, and H. Carpio, Prostaglandins, 1977, 14, 807. H. Niwa and M. Kuronn. Chem. Letters, 1977, 121 1.


215

n-hexylmagnesium bromide t o the derived aldehyde. Further elaboration of (333) by standard procedures afforded the 14-hydroxy-PG’s (334) and (335).”*

0-4 WOH X

OAc

(332) R = H (333) R = nC6H,,

Y

bH

OH (334) X = H, Y = OH (335) XY = 0

The first published synthesis of 15-thia-PG analogue^'^' involved a homologation of the alcohol (20) into (332) and its conversion via the mesylate and (336) into (337). This was oxidized t o afford the sulphoxide and sulphone derivatives. Examples of 20-dimethylamino-PG’s have also been rep01-ted.I~~ OH

Q

OTHP

OH

I

(336)

(337)

A Bicyclic Prostaglandin.-The importance of the ‘hairpin’ configuration of the two PG side-chains has been discussed previously (ref. 1, Vol. 5, p. 288). In following this concept, a Yamanouchi have prepared the bicyclo [4,3,0]nonane PG derivative (34 l ) , in which conformational constraints are imposed o n the side-chains by a direct bond between C-6 and C-14 (Scheme 35). A Dieckmann cyclization of (338) effected the formation of the required ring-system in (339). This underwent an aldol condensation with n-hexanal to complete the lower side-chain in (340), but in only 8.5% yield. Standard procedures then realized the PGF analogue (341).

Epi-prostaglandins.-A Syntex group have employed the hydroxyl moiety at C-11 to direct an intramolecular delivery of hydride ion (A1H3-Et3N) t o the carbonyl group at C-9 in highly stereoselective preparations of PGFzp and 1 l-epi-PGF2a from the methyl ester 15-acetates of PGE2 and 1 lepi-PGE2 150 J. 15’ 152

J. Plattner and A. H. Gager, Tetrahedron Letters, 1977,2479.

J. J. Plattner and A. H. Gager, Tetrahedron Letters, 1977, 1629. N. Inukai, H. Iwamoto, T. Tamura, I. Yanagisawa, Y. Ishi, T. Takagi, K. Tomioka, and M. Murakami, Chem. and Pharm. Bull. (Japan), 1976,24, 1414.


216

OTHP E

OTHP M

e C02Et

1

~THP

QTHP

- -J Q ~-

i, ii

I

OTHP

(338)

(339)

(340)

OH

Reagents:

P

iv

(341 1 i, aldol (n-C, H,, CHO); ii, dihydropyran-H+; iii, Ph,P=CH(CH,), CO, Na; iv, aq. HOAc-THF Scheme 35

r e s p e c t i ~ e l y . ' ~The ~ reaction of a secondary alcohol with benzoic acid (mediat ed by trip heny lphosphine-diet hy 1azodicarboxy lat e) , which gives este rif icat io n with inversion of configuration has found application in the synthesis of 9 , l l bisepi-1 5deoxy-PGFza methyl esters2 and a number of PGF20 analogueslS from suitably protected PGF2a-type precursors.

(343)

f--

Reagents:

(346) (345) (344) i, LiNPri, -THF,-78 "C, then FClO;, ii, LiAIH; iii, DBU; iv, Collins oxidation; v, (MeO),P(O)cHC(O)C, H , i ; vi, NaBH, -EtOH, -20 "C; vii, aq.HOAc

Scheme 36 153 154

E. Martinez, J. M. Muchowski, and E. Velarde, J. Org. Chem., 1977, 42, 1087. K. Ceserani, and J. Franceschini,

C. Gandolfi, A. Fumagalli, R. Pellegata, G. Doria, Farmaco, Ed. Sci., 1976, 31, 649.


217

Fluorinated Prostaglandins.-Substitution by fluorine at C-2 has produced PG analogues that are resistant t o degradation by P - ~ x i d a t i o n . ’These ~ ~ derivatives are, however, still substrates for the 15-dehydrogenase enzyme. The synthesis of (-+)-12-fluoro-PGF2a methyl ester (346) (Scheme 36) by Wang, Grieco, and O k ~ n i e w i c z ’provides ~~ a further example of the use of the bicycloheptane ester (294) as a precursor to 12-substituted PG’s. Fluorination was achieved by the action of perchloryl fluoride on the enolate anion. The resulting 1 : 1 mixture of a-fluoro-esters (342) and (343) was separated by chromatography. Reduction of (342) followed by dehydrobromination afforded the alcohol (344), which was transformed via ketone (345) into (346).

L r ,

{+ ?J

ODMBS

I

OR

OR

bR

(347)

5, Y

(348)

ODMBS H s c-BMD ;

y

I

I

OH

I

OH

I

OR

(350) X = OH, Y = H (351) XY = 0 Reagents:

I I

OR

I

OR (349)

R = DMBS or THP

i, LiC=C(CH, ) 3 OSiMe, But; ii, Me, Bu*SiCl-imidazole; iii, NaBH, -MeOH; iv, mesylation; v, LiAlH, -Et, 0

Scheme 37

Ace t ylenic Prostaglandins.-Upjo hn chemists 15’ have prepared 5,6acetylenicPG’s from PGF2a methyl ester tribenzoate, employing the greater steric hindrance of the 13,14-d0uble bond to allow selective 5,6-bromination (Br2 -CHCl,, at -20 “C). Dehydrobromination (DBU) and hydrolysis yielded 5,6-dehydro-PGF2a methyl ester, Selective silylation of the 11,15-hydroxygroups permitted oxidation to the 9-ketone, from which, 5,6-dehydro-PGE* and -PGA2 were obtained. The conversion of the cis-A4-PG (299) into 4,5-acetylenic PG’s can also be accomplished by this p r ~ c e d u r e . ” ~An alternative approach U. Axen, Prostaglandins, 1976, 11, 438. C.-L. J. Wang, P. A. Grieco, and F. J. Okuniewicz, J.C.S. Chem. Comm.,1976,468. C. H, Lin, S. J . Stein, and J . E. Pike, Prostaglandins, 1976, 11, 377. C. H. Lin and S. J. Stein, Synthetic Comm.,1976,6 , 503.

”’ 15’

21 8


starts from the lactone (347) (Scheme 37),lS8 which was opened with dimethylt-butylsilyloxy-pent-4-ynyl-lithium, affording the hydroxy-ketone (348). After silylation of the hydroxy-group, the keto-group in the upper side-chain was sequentially reduced via the corresponding alcohol and mesylate to the protected tetrol (349). Hydrolysis of the silyl ethers in (349; R = DMBS) followed by selective oxidation of the primary alcohol yielded the PGF analogue (350). The removal of the silyl groups from (349; R = tetrahydropyranyl) afforded a diol from which the 4,5-dehydro-PGE (35 1) was obtained. The Carlo Erba have outlined some improvements t o their route (ref. 1, Vol. 3, p. 346) to 13,14dehydro-PG's.

(352)

(353)

Simple Prostanoic Acid Analogues.-Sakai and his colleagues16' have synthesized (+)-prostanoic acid (352) from the intermediate (+)-(353). This correlation showed the previous assignment of the absolute configuration of (352) (ref. 1, Vol 5, p. 283) t o be incorrect. A series of simple PGA-type compounds, e.g. (358), were prepared by Weil and Rouessac161 from endo-dicyclopentadiene (354) V ~ Qthe endo-ketone (35 5)

(354)

y44 (358) Reagents:

160

16'

(357)

i, SeO, ; ii, Jones oxidation; iii, n-C, HI, MgBr-CuCl; iv, MeO, C(CH, )s CHO; v, TsOH-benzene, A ; vi, LiA1(OBuf),H; Vii, 500 OC, 0.01 Torr Scheme 38

C. Gandolfi, R. Pellegata, E. Dradi, A. Forgione, and E. Pella, Faumaco, Ed. Sci., 1976, 31, 763. K. Sakai, K. Inouye, and M. Nakamura, Prostaglandins, 1976, 12, 399. J.-B. Weil and F. Rouessac, J.C.S. Chem. Comrn., 1976,446.

219


(Scheme 38). The method involved the use of the bicyclo[2,2,1] heptane moiety as a protecting group for the enone system in (358). In connection with their interest in developing efficient stereospecific olefination reactions for projected PG syntheses, Evans et al. 162 have investigated the boron-mediated cross-coupling process outlined in Scheme 39. The boronic ester (359) was added t o a solution of the vinyl-lithium reagents (364) or (365). Rearrangement of the resulting boron ate-complexes (360) and (362) followed by removal of the protecting groups furnished the allylic alcohols (361) and (363).

Li ODMBS (364)

Reagents:

7 OTHP (365)

i, (364); ii, NaOMe-1, -MeOH; iii, Bu, NF-THF; iv, (365); v, aq.HOAc Scheme 39

Endoperoxide Analogues.-The chemical synthesis'63 of the methyl ester of the endoperoxide PGHz (367) has been achieved in 3% yield by the treatment of dibromide (368) with potassium superoxide. The continuing interest of Corey's group in analogues of PGHz has resulted in the synthesis of the stable bicycloheptene (f)-(374) (Scheme 40).'@ The addwct (369) of cyclopentadiene and methyl propiolate underwent reaction with the mixed cuprate (370), affording the addition product (371). The 162

164

D. A. Evans, R. C. Thomas, and J . A. Walker, Tetrahedron Letters, 1976, 1427;D. A. Evans, T. C. Crawford, R. C. Thomas, and J. A. Walker, J. Org.Chem., 1976,41, 3947. R. A. Johnson, E. G. Nidy, L. Baczynskyj, and R. R. Gorman, J. Amer. Chem. SOC., 1977,99,7738. E. J. Corey, M. Shibasaki, K. C. Nicolaou, C. L. Malmsten, and B. Samuelsson, Tetrahedron Letters, 1976,737.

220


'-?

Br

0.-

bx PGG, (366) X = OH PGH, (367) X = H

aldehyde derived from (371) was homologated via the enol ether (372), which on acidification was converted into a mixture of the hydroxy-aldehyde (373) and its C-15epimer. A standard Wittig reaction on (373) completed the synthesis of (374). An alternative synthesis of (374) by an ICI group'65 starts from the ester (375). Homologation of (375) t o the aldehyde (377) was achieved via the nitrile (376). Elaboration of the upper side-chain yielded (378), which on hydrolysis gave the aldehyde (379). Standard procedures then afforded (374) ODMBS

(369)

ODMBS (371)

ji-iv OH (374) Reagents:

OH (373)

i, Et, 0, -78 " C ; ii, DIBAL-CH, Cl,, -78 "C;iii, pyridinium chlorochromate; iv, Ph,P=CHOMe; v, aq.HOAc-THF; vi, Ph,P=CH(CH, ),CO, Na

Scheme 40

(Scheme 41). In addition, this route was readily modified by hydrogenation of (376; X = C02Me) t o give the bicycloheptane analogue (380) with a saturated nucleus. A series of analogues of (374) with modifications at C-1 were also reported.16' In a third synthesis of (374) a group from SurnitomolM converted the cis-diol (382) into the key intermediate lactone (383), which could be elaborated by conventional PG chemistry (Scheme 42). The required stereochemistry of the side-chains was achieved via epirnerization of the aldehyde 16'

T. J. Leeney, P. K. Marsham, G. A. F. Ritchie, and M. W. Senior, Prostaglandins, 1976, 11,953.

H. Shimomura, A, Sugie, J . Katsube, and H. Yamamoto, Tetrahedron Letters, 1976, 4099.


&b 1. b:aCH0

,(%Me l:QcH(oMe,,i?i (375)

'%HO

-.

[*(-JYX

CH(OMe), (376) X = CN

8 ' W C 0 , H

(374)

Reagents:

+--

221

++

CH(OMe1, (377)

8 8 W C O z H

CH(OMe), (379) (378) i, LiAlH, -Et, 0; ii, TsC1-pyridine; iii, NaCN-DMSO; iv, DIBAL, -15 " C ; v, Ph, P=CH(CH, ),CO, Na; vi, conc. HC1-CHCl, Scheme 41

(384). The 8P,12a-isomer (381) was also obtained by similar procedures. Both isosteres (374) and (380) of PGHz were potent inhibitors of PGEz biosynthesis in vitro. 16' The Diels-Alder adduct (386) was developed into the endoperoxide analogue (38'77, which incorporates a cis-A13 bond.16' The elaboration of the lower sidechain exemplified the use of the vinylborane rearrangement (p. 219).

The 9 , l I-azo-analogue (389), previously derived from PGAz (ref. 1, Vol. 5 , p. 282), has now been prepared by total synthesis.'68 The success of this

approach depended on the stereochemistry achieved in the product of the conjugate addition of nitromethane to the key intermediate (388). A further variant in this series (390),82 was obtained by an established procedure (ref. 1 ,

(382)

a-CHoTli

(385) P-CHO (384)

(374) Reagents: i, piperidine-HOAc-benzene,

A

Scheme 42 167

A. G. Abatjoglou and P. S. Portoghese, Tetrahedron Letters, 1976, 1457.

222


Vol. 5 , p. 282) from the bis-mesylate of 9,ll-bisepi-1 5-deoxy-PGFza methyl ester. The compound (390) is a potent inhibitor of the enzyme that converts PGH2 into TXA2.

\

yeN---

(388)

X

(389) X = OH (390) X = H

The endodisulphide analogue (39 1) of PGH2 methyl ester was readily derived from the 9a,l lcwdithiol(257) on oxidation with manganese dioxide followed by hydroly~is."~The same overall procedure also gave the 9,l lepimer (392), starting from PGFzcw.

The acetal (393), formed on treatment of PGFzcwwith acetaldehyde and 0.1% HC1, was a weak PGG2 mimic in several biological tests.169 2,3-Dioxabicyclo [ 2,2,1 J heptane (394), the bicyclic nucleus of the PG endoperoxides, has been prepared in three independent syntheses. Seco-prostaglandins.-The continuing search for PG analogues with metabolic stability and differing tissue specificities has resulted in the synthesis of four series of 11,12-seco-PC's, exemplified by (395),"' (396),ln (397),ln and 16'

170

17* 172 173

E. J . Corey, K. Narasaka, and M. Shibasaki, J. Amer. Chem. SOC.,1976,98,6417. P. S. Portoghese, D. L. Larson, A. G. Abatjoglou, E. W. Dunham, J. M . Gerrard, and J. G. White, J. Medicin. Chem., 1977, 2 0 , 320. R. G. Salomon and M. F. Salomon, J. Amer. Chem. Soc., 1977, 99, 3501; N. A. Porter and D. W. Gilmore, ibid., p. 3503;W. Adam and H. J . Eggelte, J. Org. Chem., 1977,42, 3987. J . B. Bicking, C. M . Kobb, R . L. Smith, F. J . Cragoe, jun., 'F. A. Kuehl,jun., and L. K. Mandel, J. Medicin. Chem., 1977, 2 0 , 3 5 . J . H . Jones, W . J . Holtz, J . B. Bicking, E. J.Cragoe,jun., L. K. Mandel, and F. A. Kuehl, jun., J. Medicin. Chem., 1977,2 0 , 4 4 . R. L. Smith, J . B. Bicking, N. P. Gould, T.-J. Lee, C . hl. Robb, F. A. Kuehl,Jun., L . R . Mandel, and E. J . Cragoe, jun., J. Medicin. Chem., 1977, 2 0 , 540.

223


(398).'% The preparation of (395) was achieved by successive alkylation of t-butyl acetoacetate with ethyl 7-bromoheptanoate and (399). The resulting P-ketoester was heated with acid to effect elimination and decarboxylation. Saponification then yielded (395). The amide isostere (396) resulted from the alkylation of ethyl 7-acetamidoheptanoate with (399) followed by saponification. The ester (403) of the sulphone analogue (397) was obtained from (400) via (401 and (402), using routine chemical manipulations. The intermediate diethyl acetal (404) in the route to (398) was assembled from 2,2diethoxyethylamine by mesylation and alkylation of the resulting sulp honamide with ethyl 7-bromo-5-heptynoate. Radiolabelled Prostaglandins.-Two examples have been reported of preparative procedures for radiolabelled PG's that involve stereospecific enzymic reductions. 0

OH

OH

(395) X = CH (396) X = N

(397)

/\CO,H -

I OH (398)

C0,Et

xF MeSO,I'/ /-&02E

OAc (400) X = (401) X = (402) X = (403) X =

'" J .

t

CH,CH (OEt),

C0,H Br

(404)

SMe SO,Me

H. Jones, W. J . Holtz, J . B. Bicking, E. J . Cragoe, jun., L. R . Mandel, and F. A. Kuehl, jun., J. Medicin. Chem., 1977, 20, 1299.

224


In the first of these [ 1-14C J PGF20 was obtained from either [ 1-14C] arachidonic acid or [ 1-14C] PGE2, exploiting the reduction of PGE2 by PGE, -9-ketoreductase from rabbit renal cortex.17' Tritium was transferred from D-[ 1-3H]galactose to 1 5-keto-compounds by a mixture of NAD+, P-D-galactose dehydrogenase, and swine renal 15-hydroxyprostaglandindehydrogenase,yielding 15(S)-[ 15-3H] PGE2 and -F2a.176 The l4 C-labelled 16-aryloxy-PGF, QI analogues ICI 80996 and ICI 8 1008 (ref. 1, Vol. 5 , p. 241) were prepared by White from chloro[ l-I4C] acetic acid (giving the label at C-15) and potassium [ l4 C] cyanide (label at C-1).'77 8 Prostaglandins in Coral The Upjohn group have published the full experimental details of the isolation and chemical conversions of PG's from the coral Plexaura homomalla. 178 Several improvements t o earlier methods (ref. 1, Vol. 2, p. 301 and Vol. 3, p. 350) were described in this paper. Further investigationslm have shown that extracts of this coral contain derivatives of 13,l 4-dihydro-PGA2 and 13,l 4-cis-PGA2. From the latter, 13,l 4-cis-PGE2 15-acetate methyl ester, 13,l 4-cis-PGFz0, and 13,14-cis-PGF2flwere synthesized.

OH

I

OH (405)

9 Prostaglandin E2 Derivatives In order t o improve the chemical stability of PGE,, its ethylene ketal (405) was prepared by direct ketalization with ethylene glycol in benzene.lm Kinetic results demonstrated that (405) should be hydrolysed back t o PGE, in the stomach without appreciable dehydration t o PGA, . Other approaches t o this problem have resulted in the preparation of the bisulphite adduct'" and the carbamoylmethyl ester 182 of PGE, .

K. J . Stone and M . Hart, J. Labelled Compounds Radiopharm., 1976, 12, 5 3 . H. H. Tai, Biochemistry, 1976, 1 5 , 4586. 17' D. F. White, J. Labelled Compounds Radiopharm., 1977, 13, 2 3 . 178 W. P. Schneider, G. L. Bundy, F. H. Lincoln, E. G. Daniels, and J . E. Pike, J. Amer. Chem. Soc., 1977, 99, 122. W. P. Schneider, R. A. Morge, and B. E. Henson, J. Amer. Chem. Soc., 1977, 99, 6062. 180 M. J. Cho, G. L. Bundy, and J. J . Biermacher, J. Medicin. Chem., 1977, 2 0 , 1525. 1 8 1 M. J . Cho, W. C. Krueger, and T. 0. Oesterling, J. Pharm. Sci., 6 6 , 149. l S 2 R. G. Stehle and R. W. Smith, J. Pharm. Sci., 1976, 6 5 , 1844. 175


225

10 Metabolism of Prostaglandins

Natural Prostaglandins.-The metabolism of PG's has been reviewed. 129 The principal metabolite of PGEl in the cat lung is 13,14-dihydro-1 5-keto-PGEl .la Oxidative cleavage of the carboxyl side-chain was a major metabolic pathway of both PGAl 184 and 6-keto-PGF1~lasin the rat. The chief products (406) and (407) of the latter have been characterized by g . l . ~ . - m . s . ' ~6,l ~ 5-Diketo-PGFla and 13,14-dihydro-6,1 5-diketo-PGF1a have been identified in other tissues. lg6

O H o y c o z H I

1

HO

I I

OH

X

(406) X = H (407) X = OH

G.c.-m.s. methods have been developed for the quantitative determination of 15-keto-13,l 4-dihydro-PG-E2 and -F2(Y in plasma18' and of the metabolites (408),18' (409),189b190and (410)19' in human urine, employing the stable isotope-dilution techniques (see p. 2 34). Radioimmunoassay (RIA) procedures have also been described for most of these and for 15-ketoPGEz .la The rapid formation of pyrazoline adducts at C-13-C-14 is a serious B. 0. Cozzini and C. A. Dawson, Canad. J. Physiol. PharmacoL, 1977,5 5 , 31 1. A. J. Wickrema Sinha and S. R. Shaw, J. Pharm. Pharmacol., 1977, 29, 99. C. R. Pace-Asciak, M. C. Carrara, and Z. Domazet, Biochem. Biophys. Res. C o m m . , 1977,78, 115. ( a ) A. F. Cockerill, D. N. B. Mallen, D. J. Osborne, J. K. Boot, and W. Dawson, Prostaglandins, 1977, 13, 1033; ( b ) C. R. Pace-Asciak, Z. Domazet, and M. Carrara, Biochirn. Biophys. Acta, 1977,487,400, W. C . Hubbard and J. T. Watson, Prostaglandins, 1976, 12, 21. 18' J. A. Oates, B. J. Sweetman, K. Gre'en, and B. Samuelsson, Analyt. Biochem., 1976, 74, 546. 189 H. E. Seyberth, B. J. Sweetman, J. C. Frohlich, and J. A. Oates, Prostaglandins, 1976, 11, 381. I 9 O W. J. A. Vandenheuvel, V. F. Gruber, F. J. Wolf, and R. W. Walker, J. Chromatog., 1977, 143, 401. 191 A. R. Brash, G. H. Draffan, R. A. Clare, and T. A. Baillie, Biochem. SOC. Trans., 1976,4, 706;Biochem. Med., 1976, 16, 77. D. Gordon, L. Myatt, A. Gordon-Wright, J. Hanson, and M. G. Elder, Prostaglandins, 1977, 13, 399. L. Levine, Prostaglandins, 1977, 14, 1125; E. Granstrom and H. Kindahl, ibid., 1976, 12, 759; S. Ohki, Y. Nishigaki, K. Imaki, M. Kurono, F. Hirata, T. Hanyu, and N. Nakazawa, ibid., 1976, 12, 181; M. D. Mitchell, A. P. F. Flint, and A. C. Turnbull, ibid., 1976, 11;319; R. V. Haning, jun., F. X. Kieliszek, S. P. Alberino, and L. Speroff, ibid., 1977, 13, 455; S. Kitamura, Y. Ishihara, and K. Kosaka, ibid., 1977, 14, 961;B. M. Peskarand B. A. Peskar, Biochim. Biophys. Acta, 1976,424,430;H. Sors, J. Maclouf, P. Pradelles, and F. Dray, ibid., 1977, 486, 553; S. Kitamura, Y. Ishihara, and K. Kosaka, Prostaglandins, 1977,14,961.

183

Ia4

226


side-reaction in the esterification of 15-keto-PG metabolites with diazomehave suggested that the measurement of (409), the thane.'% Seyberth et al. major urinary metabolite of PG's El and E i , would provide a useful indicator of PG biosynthesis in man. The I3C n.m.r. spectrum of (409) has been described.19' A double isotope derivative dilution method'" represents a further assay procedure for (409) and (410).

1 . ( OH

I

OH

OH (408)

(409) (410)

XY = 0 X = OH, Y = H

CO,H

OH (411)

D

0

D

(412) X = D or T

The synthesis of (409) and (410) has been realized by Lin19' in a versatile route from (98) that would allow isotopic labelling as well as variations giving metabolites of modified PG's. A sample of (409), doubly labelled with deuterium and tritium (412), has been obtained chemically from the synthetic intermediate (41 l).19' Owing t o its high capacity for PG metabolism, human foetal membrane at term was found t o be useful for the preparation of milligram quantities of the PGF,Q, metabolites 15-keto-PGF2a and 13,14-dihydro15-ket0-PGF~~.'~~ Modified Prostaglandins,-The metabolism in the rat of (299), the A'-&analogue of PGF2a, has been i n v e ~ t i g a t e d . 'The ~ ~ shift in position of the double bond in the upper side-chain resulted in a considerably reduced rate of degradation by &oxidation; 10-20% of (299) was excreted unchanged in the urine. The major metabolite of 15(S)-1 5-methyl-PGFZa in the human female is the product (413) of p-oxidation.200 Its synthesis has been accomplished using a A. F. Cockerill, N. J. A. Gutteridge, D. N. B. Mallen, D. J . Osborne, and D. M . Rackham, Biomed. Mass Spectrometry, 1977, 4, 187. 1 9 5 D. M. Rackham, S. E. Cowdrey, N. J. A. Gutteridge, and D. J . Osborne, Org. Magn. Resonance, 1977, 9 , 160. 19' Y . Aizawa, K. Yamada, and M . Hata, Prostaglandins, 1977, 14, 1165. C. H. Lin,J. Org. Chern., 1976, 41, 4045. 19' A. Rosegay and D. Taub, Prostaglandins, 1976, 12, 785. M. J . N. C. Keirse and A. C. Turnbull, Brit. J . Obsret. Gynaec., 1976, 83, 146. 2oo S. Bergstrom, K. Gre'en, and M . Bygdeman, Prostaglandins, 1976, 12 (Supplement), 17; K. Grgen, E. GranstrBm, M. Bygdeman, and N . Wiqvist, ibid., 1976, 11, 699. 194


227

OH

Wittig reaction with a Corey-type lactol to introduce the py-unsaturated carboxyl side-chain.201 16,l 6-Dimethyl-PGF2* (4 14) undergoes a similar fate in both the cynomolgus monkey and human, giving (415) and the products (416) and (417) of further oxidation (Scheme 43).202 The introduction of the 15-methyl or the 16,16-dimethyl groups results in a much longer plasma halflife than PGF2*, and completely inhibits degradation by oxidation at C-15. In addition to &nor and hydroxylated products, (414) is formed as a metabolite of 16,l 6dimethyl-PGE2 by rat liver in vitro. 203

-1

OH H

OH

] I

OH

I

I

OH

bH

OH

(414)

(41 5 )

4/11I/

OH

?H

pzL+L+ OH

OH

(41 7)

, -CO,H

OH

(416)

Pathways in the metabolism of 16, 16dimethy1-PGF2

Scheme 43

Thrornboxane B2 .-Several urinary metabolites of TXBz (1 16) in the monkey204 and man205 have been characterized. The two most abundant ones are dinor-TXB2 (4 18) and 1 1-dehydro-TXB2 (4 19). The side-chains of the latter then suffer the same metabolic fate as those of the PG's. A group from Lilly J. C . Sih and S. A. Nash, Prostaglandins, 1977, 14, 407. E. Granstrom and G. Hansson, Biochem. Med., 1976, 15, 95. *03 F. M. Vane, D. H. Ellis, and G. W. Holland, Pharmacologist, 1977, 19, 169.

201 ,02

204 '05

H. Kindahl, Prostaglandins, 1977, 13, 619; L . J . Roberts, B. J . Sweetman, J . L. Morgan, N. A. Payne, and J . A. Oates, ibid., 1977, 13, 631; L. J . Roberts, ibid., 1977, 14, 189. L. J . Roberts, B. J . Sweetman, N . A. Payne, and J . A . Oates, J . Biol. Chem., 1977, 252,7415.

2 28


have identified 15-keto-TXB2 and 13,14-dihydro-15-keto-TXB2 in guinea-pig lung. 'w*

1 1 Biosynthesis and Biochemistry of Prostaglandins Porter et aL207 have extended their studies (ref. 1, Vol. 5 , p. 287) on model peroxy-radical cyclizations of relevance to PG biosynthesis. The iron(11)-induced rearrangement2'$ of 1,4-endoperoxides t o 1,4-hydroxy-ketones may serve as a model for the transformation of PGGz or PGH2 under the influence of an iron(I1)-iron(II1) redox-based enzyme system.

Bovine seminal vesicle PG synthetase has been solubilized and resolved into two fractions.209 Fraction I has cyclo-oxygenase and peroxidase activity and requires haem as a cofactor. The peroxidase activity also requires tryptophan. Fraction I1 catalyses the conversion of the endoperoxide moiety into the PGE nucleus. Cyclo-oxygenase from sheep seminal vesicles has also been solubilized and partially characterized as a complex of four subunits of molecular weight 70 000, which achieves full activity when two subunits bind haem.210 O'Brien and Rahimtula2" have suggested that the cyclo-oxygenase step in PG biosynthesis involves a peroxidase mechanism in which a singlet oxygen-rnetalenzyme complex reacts with the unsaturated fatty acid precursor t o form an unconjugated hydroperoxide. The hydroperoxide reacts further with the peroxidase part of the synthetase complex t o form a peroxy-radical, which could then yield the endoperoxide by a two-stage radical-cyclization reaction. Experiments were reported2I2 which support a role for hydroxy-radicals in the formation of the singlet oxygen complex. Glutathione peroxidase was shown t o regulate cyclo-oxygenase by destroying an essential activator (as yet ~ n i d e n t i f i e d ) . ~ ~ ~

W. Dawson, J. R. Boot, A. I;. Cockerill, b. r4. B. Mallen, and

L). J. Osborne, Nature, 1976, 262,699. ' 0 7 N. A. Porter, M. 0. Funk, D. Gilmore, R. Isaac, and J. Nixon, J. Amer. Chem. Soc., 1976, 98,6000. J. A. Turner and W. Herz, J. Org. Chem., 1977, 42, 1895. ,09 T. Miyamoto, N. Ogino, S. Yamamoto, and 0. Hayaishi, J. Biol. Chern., 1976, 251, 2629; 1977, 252, 890. 'lo F. J. van der Ouderaa, M. Buytenhek, D. H. Nugteren, and D. A. van Dorp, Biochim. Biophys. Acta, 1977, 487, 315; M . E. Hemler and W. E. M . Lands, Lipids, 1977, 12, 591. P. J. O'Brien and A. Rahimtula, Biochem. Biophys. Res. Comm., 1976, 7 0 , 8 3 2 , 893. 212 R. V. Panganamala, H. M . Sharma, R, E. Heikkila, J. C. Geer, and D. G. Cornwall, Prostaglandins, 1976, 11, 599. 2*3 H. W. Cook and W. E. M. Lands, Narure, 1976, 260, 630.


229

The irreversible self-deactivation of cyclo-oxygenase appears t o be due to its oxidation by oxygen-centred radicals formed as a result of the reductive breakdown of the 1 5 - h y d r o p e r o ~ i d e . ~ ' ~ Conformational analysis of some inhibitors of PG biosynthesis has led t o the formulation of a hypothetical model of the active site of cyclo-~xygenase.~'~ Simple biochemical methods have been described for the preparation of milligram quantities of the endoperoxides PG's G2 , H I , and H2 .216 In the presence of glutathione the major pathway in the enzymatic conversion of PGG2 into PGE2 (by Fraction I1 above) involves the intermediate formation of 15-hydroperoxy-PGE2,whilst the route via PGH, is of minor i m p ~ r t a n c e . ~ ' ~ There is further evidence2I8 that 19-hydroxy-PGE's are the major PG's in human semen. These compounds are also present in the semen of a variety of primates but were undetectable in that of other laboratory and domestic animals. 219 A series of isomeric methyl-substituted 8,11,14-eicosatrienoic acids were converted into PGEl analogues by bovine vesicular PG synthetase.220 In all cases the rate of PG biosynthesis was lower than that of PGEl itself. The widespread importance of PGE-9-ketoreductase is becoming recognized. This enzyme provides a mechanism for the inactivation of PGE2, in various tissues, by its conversion into PGF2a.221 Lipoic acid stimulates the nonenzymatic reduction of PGH2 to PGF2 a in vesicular gland microsomes.222 A further significant advance in PG biochemistry has been made by Vane and his colleague^.^^^-^^^ They have isolated microsomal preparations from arteries, veins, and rat stomach fundus, which transform PGG2 and PGH2 into an unstable substance, PG12 (prostacyclin, PGX), which inhibits the aggregation of human blood platelets (with thirty times the potency of PGE1), stimulates platelet adenyl cyclase, giving increased c-AMP levels,228 and relaxes vascular

214 215

'16

219

220

221

222

223 224 225

226 227 228

R. W. Egan, J . Paxton, and F. A. Kuehl, jun., J . Biol. Chem., 1976, 251, 7329.

P. Gund and T. Y. Shen, J. Medicin. Chem., 1977, 20, 1146. R. R. Gorman, F. F. Sun, 0. V. Miller, and R. A. Johnson, Prostaglandins, 1977, 13, 1043;F. Ubatuba and S. Moncada, ibid., p. 1055. A. Raz, M. Schwartzman and R. Kenig-Wakshal, Fed. Proc., 1976, 35, 1380;European J. Biochem., 1976, 7 0 , 89;Biochim. Biophys. Acta, 1977,488,322;J. L. Humes, K. W. Egan, and M. Galavage, Fed. Proc., 1977,36,767. H. T. Johnson, jr., B. S. Middleditch, M. A. Schexnayder, and D. M. Desiderio, J. Lipid Res., 1976, 17, 1. R. W. Kelly, P. L. Taylor, J. P. Hearn, R. V. Short, D. E. Martin, and J. H. Marstoil, Nature, 1976, 260, 544. U. H. Do and H. Sprecher, J. Lipid Res., 1976, 17, 424. Y. Friedman, S. Levasseur, and G. Burke, Biochim. Biophys. Acta, 1976, 431, 615; P. Y.-K. Wong, D. A. Terragno, N. A. Terragno, and J . C. McGiff, Prostaglandins, 1977, 13, 1113;A. Hassid and L. Levine, ibid., p. 503;K. J. Stone and M. Hart, ibid., 1976, 12, 197;L. P. Thuy and M. P. Carpenter, Fed. Proc., 1977,36, 375. L. J. Marnett and M. J . Bienkowski, Biochemistry, 1977, 16, 4303. S. Moncada, R. J . Gryglewski, S. Bunting, and J. R. Vane, Nature, 1976, 263, 663. R. J. Gryglewski, S. Bunting, S. Moncada, R. J. Flower, and J . R. Vane, Prostaglandins, 1976,12, 685. S. Moncada, K. J . Gryglewski, S. Bunting, and J. R. Vane, Prostaglandins, 1976, 12, 715. S. Moncada, E. A. Higgs, and J . R . Vane, Lancet, 1977,i, 18. S. Bunting, R. J. Gryglewski, S. Moncada, and J . R. Vane, Prostaglandins, 1976, 12, 897. J. E. Tateson, S. Moncada, and J . R. Vane, Prostaglandins, 1977, 13, 389;K. R. Gorman, S. Bunting, and 0. V. Miller, ibid., 1977, 13, 377.

230

A fiphatic and Related Natural Product Chemistry

smooth muscle. PG12 is also the major PG synthesized by the rabbit and rat hearts.229 An important role was suggested for the conversion of the PG endoperoxides into TXA2 (420) by platelets and PG12 by blood-vessel walls in the control of the blood clotting mechanism. Thus in normal blood vessels there is a balance between these pro- and anti-aggregatory substances. Vascular PG12 synthesis has been localized in the endothelial cells.230 The generation of PG12 is strongly inhibited by 15-hydroperoxyarachidonic and tranylcypromine.230

1 CO,H

I I

OH (420) TXA,

The structure of PGIz, i.e. 6,9aepoxy-l lc~,l5c~-dihydroxyprostalo0 mg per 100 The major volatile constituents of the marmoset scent mark are

’ Lipids, 1977, 12, 455;European J. Biochem., 1977, 7 9 , 1 1 .

Dommes, F. Wirtz-Peitz, and W. H. Kunau, J. Chromatog. Sci., 1976, 14, 360. D. Plattner, G. F. Spencer, and R. Kleiman, Lipids, 1976, 11, 2 2 2 . Paradis and R. C . Ackman, Lipids, 1976, 11, 8 6 3 , 8 7 1 . D. Plattner and R. Kleiman, Phytochemistry, 1977, 16, 2 5 5 . E. Pearce and L. W. Stillway, Lipids, 1976, 1 1 , 247. 13. R. Body, Biochem. J . , 1976, 157, 741.

V. R. M. R. R.

236

Fatty A cids

237

reported t o be squalane and fifteen esters of butanoic acid and saturated monoene (n-7 and n-9) and diene (n-6) alcohols in the CI6-CZ4 range.* Several reports on polyene acids deserve mention. The conjugated decatrienoic acids present as triterpenoid esters in the latex of Euphorbia pulcherrima include the 2t4t6c and possibly the 2c4t6t, 3t5t7c, and 3c5t7t isomers.' The seed oil of Leucas cephalotes with -28% of labellenic acid (18:2 5e6e) is the richest known source of this allenic acid." Marine dinoflagellates produce the very unsaturated 18: 5 (n-3) acid, which then occurs in decreasing amounts through the food chain." The N-isobutylamide uf 20 : 2 (2t4t) is reported t o be the major dienamide in Piper guineense fruit.12 Acids present in the livers of rats fed on a fat-free diet from the 30th-90th day after birth belong mainly t o the well known n-3, n-6, n-7, and n-9 families but the following non-methylene interrupted acids were also identified: 18 : 2 (9, 13; 6 , l l ; 5,11; and 6,12), 20 : 2 ( 5 , l l and 7,13), and 2 0 : 3 (5,11,14).13 Polyene acids of this type are being recognized increasingly, including some CZO,CZl and Czz d i m e acids in the white ~ h r i m p . ' Sponges ~ contain C24-C30 acids (34-79%). These are mainly polyunsaturated and include several A5y9 acids such as 2 4 : 2(5,9), 25 :2(5,9), 26 : 2(5,9), 26 : 3(5,9,17 and 5,9,19) and 27 : 3(5,9,19 and 5,9,20).'5 Branched-chain and Cyclic Acids:-2,4,6,8-Te t ramet hylunde cy 1 2,4,6,8-t e tramethylundecanoate from kingfisher preen gland wax is the most highly branched wax ester yet reported. l6 Branched-chain acids of medium chain length in ovine tissue lipids are important .for flavour and 4-methyloctanoic acid (hircinoic) is the major component among a group of C6-C9 acids present at levels u p t o 200 p.p.m." In a capillary g.c.-m.s. study of Vernix caseosa lipid, Nicolaides et al. recognized 35 monomethyl- and 46 dimethyl-branched C11 --CIS acids. Except for the is0 series the methyl groups occur on even carbon atoms and especially o n C-4. The cyclopropane acid (1 ; cascarillic) in the essential oil of Crofon eluteria is shown t o have trans stereochemistry and has been synthesized." Litchi sinensis seed oil is probably the richest source of dihydrosterculic acid (4176, 2a) and its lower homologue (876, 2b).20 By comparison with synthetic material the mycolic acid obtained from a human strain of M. tuberculosis is assigned structure ( 3 ; z = mainly 1 1 and 13 with some 15 and possibly 17). 2'

''

lo

'' l2 l3 l4 l5 l6

I7 l8

l9

''

A. B. Smith, R. G. Yarger, and G. Epple, Tetrahedron Letters, 1976,983. F. Warnaar, Lipids, 1977, 12, 707. S. Sinha, A. A. Ansari, and S. M. Osman, Chem. and Ind., 1978,67. P. Mayzaud, C. A. Eaton, and R. G. Ackman, Lipids, 1976,11, 858. I. Addae-Mensah, F. G. Torto, I. V. Oppong, I. Baxter, and J . K. M. Sanders, Phytochemistry, 1977, 16,483. B. Schmitz, U. Murawski, M . Pfluger, and H. Egge, Lipids, 1977,12, 307. R. E. Pearce and L. W. Stillway, Lipids, 1977, 12, 544. R. W. Morales and C. Litchfield, Biochem. Biophys. Acta, 1976,431,206;C. Litchfield, A. J . Greenberg, G. Noto, and K. W. Morales, Lipids, 1976, 11, 567. J . Jacobs, 2.physiol. Chem., 1976,3 5 7 , 609. C. B. Johnson, E. Wong, E. J . Birch, and R. W.Purchas, Lipids, 1977, 1 2 , 340. N. Nicolaides, J. M. B. Apon, and D. H . Wong, Lipids, 1976,11, 781. S. R. Wilson and K, A. Prodan, Tetrahedron Letters, 1976,4231. M. S. F. Lie Ken Jie and M. F. Chan, J.C.S. Chem. Comm., 1977, 78. W.J. Gender and J. P. Marshall, Chem. Phys. Lipids, 1977, 19, 128.

238


CH, /\ Me(CH,),CHCHCH,CO,H

Me(CH,),CHCH(CH,),CO,H (2) a; n = 7 b;n = 5

(1)

Oxygenated Acids.-Several oxygenated acids, including some not previously reported, have been the subject of investigation in the period under review. Pseudomonic acid A (and its 8-hydroxy derivative) from Pseudomonas fluorescens has structure (4).22 During biosynthesis, acetate, propionate, and methionine are incorporated into this acid but not formate or mevalonate. It appears to comprise three sub-units indicated by the vertical lines in (4). The 9,14dihydroxystearic acid in Peganurn harma2a seed oil is unusual in the distribution

H,OC-O

Me

0

of the hydroxy-groups along the chain,23 Isano oil, which contains several unusual oxygenated and non-oxygenated acids, has been re-examined and hitherto unknown hydroxy (9L-OH 18:0, 8-OH 18:2 1Oa12a, 8-OH 1 8 : 3 1Oa 1% 17e) and 0x0 acids (8-0x0 18 : 2 9a 1 la and 8-0x0 18 : 3 90 1la 17e) have been identified.% The acids oxygenated at C-8 with unsaturation starting at C-10 are especially unusual. Non-oxygenated acids with a cis enediyne chrornophore are also present but no individual compound was i~olated.~'Effective use is made of n.m.r. ('H and. 13C) and m.s. in these studies. The 3-hydroxy acids present in lipopolysaccharides from various bacterial groups have D-configuration regardless of their chain-lengt h, branching, 3-0 -substit ut io n , and whether they occur in ester or amide form.% Two groups have proved the

22

23 24

25 26

Sir E. B. Chains and G. Mellows, J.C.S. Perkin I , 1977, 294, 318; T. C. Feline, R. B. Jones, G. Mellows, and L. Phillips, ibid., p. 309. I. Ahmad, E. Ahmad, and S. M. Osman, Phyrochemistry, 1977, 16, 1761. R. W. Miller, D. Weisleder, R. Kleiman, R. D. Plattner, and C. R. Smith, jun., Phytochemistry, 1977, 16, 947. R. W. Miller, D. Weisleder, R. D. Plattner, and C. R. Smith, jun., Lipids, 1977, 12, 669. E. T. Rietschel, European J. Biochem., 1976, 64, 42 3.

Fatty Acids

239

oxygenated acid in Argemone rnexicana t o be a mixture of %OX0 28 : 0 and 1 I-0x0 28 : 0 and 30 : 0.27 Several new epoxy acids have been reported. The w-oxygenated epoxy acids ( 5 ) are present in cork,28 whereas Crepis conyzaefolia seed oil contains cis-12,

?\

X(CH2)7CHCH(CH,)7C0,H ( 5 ) X = HO,C or HOCH,

13ep0xy 1 8 : 2 (6t9c and 6c9c) in addition to other known acids.29 Alchornea cordifozia seed oil is very rich ( 5 1%) in (+)-cis-14,15-epoxyeicos-cis-llenoic acid (alchornoic). This is the C20 homologue of vernolic acid.30 Soybean phosphatidylcholines contain a number of oxygenated acids including 15 ,I 6epoxy 18:2 (9,12), 12,13-epoxy 18: 1 (9), and other oxygenated acids with hydroxy, 0x0, and mixed oxygenated function^.^' These are probably formed by homolytic decomposition of linoleate hydroperoxide or result from interaction of this hydroperoxide with unsaturated acids. Furan acids, first discovered in the pike, are widely distributed in fresh water and marine fish, albeit at low c ~ n c e n t r a t i o n .The ~ ~ proportion of these acids increases in starved fish and at certain times during the sexual cycle. Some natural hydroxy acids occur as lactones (for a review see ref. 241). Commonly these are y- or &-lactonesbut the macrocyclic lactones are of greater interest. Rubrenolide and r ~ b r y n o l i d eare ~ ~y-lactones ( 6 ) whilst new 6 -1actones include those based on the hydroxy derivatives of 2-methylhexanoic acidM and of the four Clo acids 10 : 10 : 1(7)?’ 10 : 2(2,6),% and 10 : 2(2,7).35 The 14membered lactone, (-)-(S,S)-l2-hydroxy-l3-octadec-cis-9-enolide, present in Crepis conyzaefolia, is the third macrocyclic lactone isolated from seed Other unusual acids include the polybasic acids (7) from rat (8) from

27

28 29 ’O

’’ 32

33 34

35 36

3‘ 38

S. B. Mahato, W. P. Sahu, A. Narayanaswami, R. N. Chakravarti, and D. Chakravarti, J. Indian Chem. SOC., 1975, 52, 6 2 6 ; (J. Amer. Oil Chemists’Soc., 1977, 54, 251A); F. D. Gunstone, J . A. Holliday, and C. M. Scrimgeour, Chem. Phys. Lipids, 1977, 2 0 , 331. E. Seoane, M . C. Serra, and C. Agull6, Chem. and Ind., 1977. 662. G . F. Spencer, Phytochemistry, 1977, 1 6 , 2 8 2 . R. Kleiman, R. D. Plattner, and G. F. Spencer, Lipids, 1977, 12, 610. D. J . Sessa, H. W. Gardner, R. Kleiman, and D. Weisleder, Lipids, 1977, 12, 61 3. F. D. Gunstone, R. C. Wijesundera, R. M . Love, and D. Ross, J.C.S. Chem. Comm., 1976, 6 3 0 ; R. L. Glass, T. P. Krick, D. L. Olson, and R. L. Thorson, Lipids, 1977, 12, 828. N. C. Franca, 0. R . Gottlieb, and D. T. Coxon, Phytochemistry, 1977, 16, 257. J . W. Wheeler, S. L. Evans, M . S. Blum, H . H. W. Velthius, and J . M. F. de Camargo, Tetrahedron Letters, 1 9 7 6 , 4 0 2 9 . R. Kaiser and D. Lamparsky, Tetrahedron Letters, 1976, 1659. H. A. Priestap, J . D. Bonafede, and E. A. Rliveda, Phytochemistry, 1977, 16, 1579. G. F. Spencer, R. D. Plattner, and R . W. Miller, Phytochernistry, 1977, 1 6 , 764. B. Eliasson, S. Lindstedt, and G. Steen, J. Lipid Res., 1976, 17, 637.


240

Unsea a l i p h a t i ~ a ,and ~ ~ (9) from Unsea meridensis.40 Alkyl and alkenyl resorcinols are present in the seed lipids of Rapanea l a e t e ~ i r e n s .Jelly ~ ~ fish lipids contain both chlorine (0.48%) and bromine (0.0034%). About 30% of the former is present as monochloro monohydroxy acids and six compounds were identified: the chlorohydrins of 16 : 1(9), 18 : 1(9), and 18 : l(1 1).42

(6) R = CH,=CH-

or HC=C-

(7) n = 4 , 5 , or 6

3 Synthetic Compounds General Procedures.-Ery thro and threo vic-diols are converted stereospecifically into cis and trans alkenes by thermal decomposition of an acetal (Scheme 1)?3

CHEt Reagents: i, CH(OEt),,H+,-12O0C; ii, 2 1 0 ° C Scheme 1

Hydroxy selenides, available from carbonyl compounds, furnish alkenes by trans elimination (Scheme 2),44 and alkene synthesis via 0-functionalized organo silicon compounds has been reviewed (see ref. 242). A stereoselective synthesis of 1,4-dienes, of possible value for preparing cis trans isomers, has been reported (Scheme 3)45 and the Homer variant of the Wittig reaction may be used to prepare single geometrical isomers of 1 , 3 - d i e n e ~ .A~ ~ new synthesis of conjugated

39 40

41

M. F. Keogh and M . E. Zurita, Phytochemistry, 1977, 16, 134. M. F. Keogh and I. Duran, Phytochemistry, 1977, 16, 1605. R. V. Madrigal, G. F. Spencer, R. D. Plattner, and C. R. Smith, jun, Lipids, 1977, 1 2 , 402.

45

R. H . White and L. P. Hager, Biochem., 1977, 16, 4944. H. Rakoff and E. A. Emken, Lipids, 1977, 12, 760. J . Ke'mion, W. Dumont, and A. Krief, Tetrahedron Letters, 1976, 1385. Y . Yamamoto, H . Yatagai, A. Sonoda, and S . I. Murahashi, J.C.S. Chem. Comm., 1976,

46

A. H . Davidson and S. Warren, J.C.S. Perkin I , 1976, 6 3 9 .

42

43 44

452.

Fa t t y A cids RiC-0

R;C(SeR'),

ii, iii

24 1 R;C(SeR')C(OH)R:

R:C=CR:

+ R2SeSeRZ

Reagents: i, R'SeH; ii, BuLi; iii, R:C=O; iv, H+

Scheme 2

trans enones (Scheme 4) might be of interest to prepare compounds of the type R' CH=CHCH(OH)CH=CHR2 derivatives of which have long been sought as autoxidation products?' Yet another route t o alkynes has been reported (Scheme 5): the acetylenic carbon atoms are derived from CF2=CC12!' Chiral 2-oxazolines are employed to prepare R and S 2-alkylalkanoic acids4' (for a R'C-CR'

1 ,(R'CH=CRZ),BC1

ii iii + R'CH=CR2CH,CH=CHR3

Reagents: i, BH,CI; ii, MeCu; iii, XCH,CH=CHR3 Scheme 3

review see ref. 243) and MeCdCl has been shown t o be superior to Me2Cd in the conversion of acyl halides into methyl ketones. This has been exploited in a synthesis of the w-labelled fatty acids Me(CH2),+ 1COzH from the dibasic acid derivative C1CO(CH2)&02Me." Coupling of the Grignard reagent RMgBr with the o bromo acid derivative Br(CH2)&02MgCl occurs in high yield in the

Reagents: i, HgCl,; ii, R2COC1, AlCl,, CH2C1,

Scheme 4

presence of the lithium tetrachlorocuprate (Li2CuC14).51 One-carbon homologation (Scheme 6 ) converts aldehydes or ketones into the higher acid, ester, or amide.s2 Synthetic Acids.-9-Oxodec-2-enoic acid (Queen substance) has been prepared (Scheme 7) from butadiene ( 2 moles) and diethyl m a l ~ n a t e . ' ~There are two independent reports of the synthesis of (+)-cerulenin (lo), a compound of CF,=CCl,

A

R'CF=CCl,

R'C=CLi

-!% R ' C E C R 2

Reagents: i, R'Li or R'MgBr; ii, BuLi; iii, R2X

Scheme 5

47 48 49

50

R. C. Larock and J . C. Bernhardt, Tetrahedron Letters, 1976, 3097. K. Okuhara,J. Org. Chem., 1 9 7 6 , 4 1 , 1487. A. I. Meyers, G. Knaus, K. Kamata, and M . E. Ford., J. Amer. Chem. Soc., 1976, 9 8 , 567. K. M. Patel, H . J . Pownall, J . D. Morrisett, and J . T. Sparrow, Tetrahedron Letters, 1976,4015.

51

52

53

T . A. Baer and R. L. Carney, Tetrahedron Letters, 1976, 4697. S . E, Dinizo, R. W. Freerksen, W. E. Pabst, and D. S. Watt, J. Amer. Chem. SOC., 1977, 99, 182. J . Tsuji, K. Masaoka, and T. Takahashi, Tetrahedron Letters, 1977, 2 2 6 7 .

242

Aliphatic and Related Natural Product Chemistry R2C=0

-b R,C=C

\

/CN

R,C=C

-%

R,CHCOZ

‘O*C

OBut

Reagents: i, (EtO),POCH(CN)OBut; ii, ZnCl,, A d ; iii, solvolysis (2 = OH, OR’,or NR:) Scheme 6

interest because it inhibits lipid synthesis.% Erythro-5,6-diacetoxyhexadecanoic acid, a novel fatty acid present in mosquito eggs, has been synthesized by condensation of a C5 0x0 ester with the required CI1 Wittig reagent (Scheme 8)? Phloionic acid (threo-9,1 Odihydroxyoctadecanedioic) is available from cork and \

‘CH(CO,Et),

Reagents: i, CH,(CO,Et),, Pd(OAc),, PPh,; ii, several steps

Scheme 7

has been converted into a compound identical with natural civetone (cis isomer) in an overall yield of 2.8%.The trans isomer has also been prepared. The surplus carbon atom is lost during a benzilic acid type of rearrangements6

There is considerable interest in derivatives of Czo acids and the following have been prepared: 2-bromo 20 : 3( 8c 1 l c 14c) from the corresponding Czo triene acid;” 20 : 4(5t8cl lc14c), 20 : 4(5c8cl lc14t), and 20 : 5(2t5c8cl lc14c) via acetylenic intermediate$’ the 5-, lo-, 13-, 17-, 18-, and 19-methyl branched derivatives of 20: 3(8cl l c 1 4 ~ ) , ~ ’and 13,13-dimethyleicosa-cis-8,cis-l4dien11-ynoic acid which is of interest as an inhibitor of prostaglandin cyclo-oxygenase (Scheme 9).60 The success of this last synthesis depends on the selective partial hydrogenation of the less hindered triple bond in the diyne chloride. 54

55 56 57

59

6o

A. A. Jakubowski, F. S. Guziec, jun., and M . Tishler, Tetrahedron Letters, 1977,2399; R. K. Boeckman, jun., and E. W. Thomas, J. Amer. Chem. SOC., 1977, 99,2805. A. N. Starratt, Chem. Phys. Lipids, 1976, 16,215. E. Seoane, A. Arnd, J. R. Pedro Llinares, and J . Sanchez Pararedo, Chem. and Ind., 1978, 165. L. van der Wolf and H. J. J . Pabon, Rec. Trav. chim., 1977, 96,72. G. J . N. Egmond, H. J . J. Pabon, and D. A. van Dorp, Rec. Trav. chim., 1977,96,172. U. H. D o and H. Sprecher, Chem. Phys. Lipids, 1976, 16,255. C. L. Yeh, M . Dawson, M. E. Hemler, and W. E. M. Lands, Tetrahedron Letters, 1977, 4257.

Fatty Acids 243 The most exciting synthesis in this field during the period under review is of methyl (+)-meromycolate (14), a c 5 6 degradation product of mycolic acids (Scheme 10). Imaginative use is made of metallated dithianes as chain extenders.61 Me (CH,),CH=i(Ph,

Br-

A

Me(CH,),CH=

CH (CH,),CO,Et

7 Me (CH, ),CH (0H)CH (OH)(CH,),CO,H Reagents: i, OHC(CH,),CO,Et; ii, KMnO, Scheme 8

Novel fluorescent labelled fatty acids (1 5 and 16; R = saturated o r unsaturated alkyl chain) have been prepared. These are incorporated into lipids and used as probes to study lipid-lipid and lipid-protein interactions.62 A synthesis of ginkgolic acid ( 17) has also been reported.63 The deuteriated compounds methyl 8,8,11,11-*H4 - and 8,8,13,13,14,142H@1eate64 and several dideuterio 18 : 0 and 0x0 18 : 0 esters have been prepared.65 Tulloch has also prepared methyl 16,16,16-2H3-hexadecanoate.66

A

HOCH,C(Me),OCH,Ph

Me (CH,),CH& CHC(Me),C=CH

7

cis

Me(CH,),CH =CHC(Me),C~CCH,C~C(CH,),CI u i

Me(CH,)&H=

Cis

CHC(Me),C=CCH,CH

&H(CH,)6Cl

iv{

Me (CH,),CH&CHC

(Me),C=CCH,CH&H(CH,),CO,

Reagents: i, severaI steps; ii, BrCH,=(CH,),Cl, iv, Mg, CO,, H,O+

H

EtMgBr, CuC1; iii, H, , Lindlar's catalyst;

Scheme 9

Furanoid Acids.-Lie Ken Jie and Lam6' synthesized several furanoid acids from synthetic octadecadiynoic acids by acid-catalysed cyclization of the derived 1,4dioxo compounds, from diepoxy acids by reaction with PrI, NaI, and DMSO, and from the oxygenated acids (1 8a-d) themselves obtainable from ricinoleic acid. One of these procedures is duplicated by an Indian group68 61 62

63 64 65

66 67

W. J. Gensler, J. P. Marshall, J. J. Langone, and J. C. Chen, J. Org. Chem., 1977,42, 1 1 8. W. Stoffel and G. Michaelis, 2. physiol. Chem., 1976,357, 7. J. H. P. Tyman, J. Org. Chem., 1976,41,894. W. J. Dejarlais and E. A. Emken, Lipids, 1976, 11, 594. A. P. Tulloch, Lipids, 1977, 12, 92. A. P. Tulloch, Chem. Phys. Lipids, 1977, 18, 1. M. S. F. Lie Ken Jie and C. H. Lam, Chem. Phys. Lipids, 1977,19, 275;1977,20, 1. S . Ranganathan, D. Ranganathan, and M. M. Mehrotra, Synthesis, 1977,838.

/c\H2

Me (CH,),,CHCH (CH,),Br

(12) + (13)

*

/c\",

/YZ

Me(CH2),,CHCH(CH2)14CHCH(CH2),,~) m . . v

/c? /c\"2 Me(CH,), ,CHCH(CH,), ,CHCH(CH,), ,C02Me (14) Reagents: i, 0,; ii, NaBH,; iii, dihydropyran, H+; iv, TsC1, pyridine; v, LiBr, COMe,; vi, 2-lithio-l,3dithiane; vii, compound (11);viii, Raney Ni; ix, €ICYaq; x, BuLi, PPh,, 1,8-bisthianyloctane; xi, HO(CH,),OH, H+; xii, BuLi, PPh,, 1, 4-bisthianylbutane; xiii, BuLi, PPh,; xiv, MeOH

Scheme 10

who converted methyl ricinoleate into a CI8 furanoid acid in >60% overall yield (Scheme 11). Synthetic approaches t o similar 2,5disubstituted furans have been patented.69 Lactones.-Some lact ones of long-chain acids with small and medium sized rings have been prepared. y-Lactones are conveniently obtained by photolysis 69

P. Nedenskov and K. Alster, B. P., 1 466 256.

Fatty Acids

245

.CH,C=CR

OH

o r thermolysis of N-chloroamides and the lactone (19) has been obtained in this way from oleic acidsm Corey and his colleagues have described a procedure for lactonization of hydroxy acids requiring dipyridyl disulphide (or a related acid, disulphide) and triphenylph~sphine.'~(~)-ll-Hydroxydodec-trans-8-enoic

?\

R1CH(OH)CH2CH=CHRZ

R'COCH,CHCHRZ

(1W

(18b)

R'COCH,CH =CH RZ

R'COCH=CHCH(OH)R'

(1 8 d

(1 8d)

R' = CH,(CH,),

R2 = (CH,),CO,Me

itself prepared from acetylenic precursors, was thus converted into the lactone (20).n Japanese workers lactonized the w-hydroxy acids (2 1) by reaction with triphenylphosphine and diethyl a~odicarboxylate.'~ 4 Physical Properties

Gas Chromatography.-Progress has been made in the continuing search for simple gas chromatographic conditions for separating cis and trans isomers and

R*CH(OH)CH,CH=CHR*

L R~COCH,CH=CHR~

?\

i i ,R~COCH,CHCHR~

R'

R' = Me(CH2I5--

RZ = (CH,),CO,Me or (CH,)7C0,H

Reagents: i, CrO,, pyridine, CH,Cl,; ii, rnClC,H,CO,H; iii, HC1, CHC1,

Scheme 11

70 71

'* 73

M . Benn and K. N. Vohra, Canad. J . Chem., 1976, 5 4 , 136. E. J . Corey, D. J . Brunelle, and P. J . Stork, Tetrahedron Letters, 1976, 3405; E. J . Corey and D. J . Brunelle, Tetrahedron Letters, 1976, 3409. E. J . Corey, P. Ulrich, and J . M . Fitzpatrick, J. Amer. Chem. SOC., 1 9 7 6 , 9 8 , 2 2 2 . T. Kurihara, Y . Nakajima, and 0. Mitsunobu, Tetrahedron Letters, 1976, 2 4 5 5 .

246


Me (CH,),CH=CH

(CH,),CH

\ 0-c

(19)

HO (CHJ CO,H (20)

(21) n = 5 , 7 o r 11

phases such as Silar 1OC and SP2340 show promise even on packed columns.74 It is claimed that with glass capillary columns cis trans isomers and positional isomers can be separated.75 Other papers devoted t o gas chromatography contain useful retention data on the complete series of diunsaturated C18 esters of ~ ~methyl-branched 2 0 : 3 the type (22),76 some C18 and Cz0 e n y n ~ a t e s ,six esters,59 iso-, anteiso-, and long-chain esters containing a three-, four-, five-, or six-membered ring,78 and the complete series of CI8 furan esters ( 23).79

Me(CH,), X(CH,),X(CH,),CO,Me

(22) C,, esters where X represents acetylenic or cis or trans olefinic centres

(23) x + y = 12

An improved analysis of fatty acid-resin mixtures in tall oil by capillary g.1.c. makes it possible to follow changes occurring during processing.m Haken continues his wider studies of retention data” and another potential g.1.c. difficulty has been reported: thq presence of ethyl esters resulting from ethanol present in chloroform used as a lipid extracting solvent.82

Thin Layer Chromatography.-The Ag+ chromatographic behaviour of esters of type (22) has been reported” and the same research group have demonstrated that acetylenic esters are separable from olefinic and saturated esters by chromatography on silica not impregnated with silver.% V. von Imhoff, G. Kelbeh, and A. Pastura, Fette, Seifen, Anstrichm., 1977, 7 9 , 4 8 0 ; D. M. Ottenstein, D. A. Bartley, and W. R. Supina, J. Chromatog., 1977, 119, 401; D. M. Ottenstein, L. A. Wittings, G. Walker, V. Mahadevan, and N. Pelick, J. Amer. Oil Chemist’s SOC., 1977, 54, 207; H. Heckers, K. Dittmar, F. W. Melcher, and H. 0. Kalinowski, J. Chromatog., 1977, 135,93; H. Heckers, F. W. Melcher, and U. Schloeder, J. Chromatog., 1977, 136, 311; E. G. Perkins, T. P. McCarthy, M. A. O’Brien, and F. A. Kummerow, J. Amer. Oil Chemists’ SOC.,1977, 54, 279. H. Jaeger, H. U. Klar, and H. Ditschuneit, J. Lipid Res., 1976, 17, 185. l6 C. H. Lam and M. S. F. Lie Ken Jie, J. Chromatog., 1976, 117, 365; 1976, 121, 303; M. S. F. Lie Ken Jie, J. Chromatog., 1977, 131, 239. G. R. Jamieson and E. H. Reid, J. Chromatog., 1976, 128, 193. T. Kaneda, J. Chromatog., 1977,136, 323. l9 M. S. F. Lie Ken l i e and C. H. Lam, J. Chromatog., 1977, 138, 373; 446. 80 B. Holmbom, J. Amer. Oil Chemists’ SOC., 1977, 54, 289. J. R. Ashes a n d J . K. Haken, J. Chromatog., 1977, 135, 61; 67; J. K. Haken, in ‘Advances in Chromatography’ ed. J . C. Giddings, Dekker, New York, 1976, Vol. 14, p. 367. 82 A. R. Johnson, A. C. Fogerty, R. L. Hood, S. Kozuharov, and C. L. Ford, J. Lipid R e x , 74

1976, 17, 431. 83 84

M. S. F. Lie Ken Jie and C. H. Lam, J. Chromatog., 1976, 124, 147. M. S. F. Lie Ken Jie and C. H. Lam, J. Chromatog., 1977, 136, 178.

Fatty A cid s

247

High Performance Liquid Chromatography.-This new technique is applied more particularly to lipid separation but there is a report on pre-column derivatization of fatty acids for HPLC8’ and, in particular, the formation and separation of p-met hdxy anilide s.%

Nuclear Magnetic Resonance Spectroscopy.-The period under review has seen the appearance of valuable information from four laboratories on the 13C n.m.r. spectra of a wide range of saturated and unsaturated long-chain Each group has furnished fairly consistent numerical data showing the influence of functional groups on the chemical shift for nearby carbon atoms. These effects are apparent through four t o six carbon atoms and are generally additive so that it is possible t o predict the resonance of all or most of the carbon atoms in a long-chain ester. This information has been employed in interpretating the spectra of the enediyne acids of isano oil2’ and the complex ether lipids of Calderia bacteria.” The characteristic 13C n.m.r. signals associated with butyric esters permit quantitation of this acid in milk fats and demonstrate that it is absent from the sn-2 position.% Analytical 13C n.m.r. has been used as a rapid nondestructive method of determining the cis-trans composition of partially hydrogenated polyene mixtures.93 The ‘Hn.m.r. spectra of the furan esters (23) have been rep0rted.6~

Mass Spectrometry.-Reference has already been made to the application of mass spectrometry to the structure determination of unsaturated acids,2s3 methyl meromycolate,21 and the new dihydroxy acid in Peganum h a r m a k B It is claimed that double bond position and configuration can be determined by c.i.-m.s.“ New studies report the fractionation by g.c.-m.s. of several di- and tetradeuteriated derivatives of tetracosanoic and the mass spectra of branched acids/esters (a-iso-, and anteiso-)% and of isomeric doxylstearic acids (24).97

M. S. F. Ross, J. Chromatog., 1977, 141,107. N. E. Hoffman and J. C. Liao, Analyt. Chem., 1976,48,1104. 87 F. D. Gunstone, M. R. Pollard, C. M. Scrimgeour, N. W. Gilman, and B. C. Holland, Chem. Phys. Lipids, 1976, 17, 1 ; F. D. Gunstone, M. R. Pollard, C. M. Scrimgeour, and H. S. Vedanayagam, Chem. Phys. Lipids, 1977, 18, 115. J . Bus, I. Sies, and M. S. F. Lie Ken Jie, Chem. Phys. Lipids, 1976, 17, 501;J. Bus, 1. Sies, and M . S. F. Lie Ken Jie, Chem. Phys. Lipids, 1977,18, 130. 89 A. P. Tulloch and M. Mazurek, Lipids, 1976, 11, 228; A. P. Tulloch, Canad. J. Chem., 1977,55,1135. 90 S. R. Johns, D. R. Leslie, R. I. Willing, and D . G . Bishop, Austral. J. Chem., 1977, 30, 813. 9 1 M. de Rosa, S. de Rosa, and A. Gambacorta, Phytochemistry, 1977, 16, 1909. 9 2 P. E. Pfeffer, J . Sampugma, D. P. Schwartz, and J. N. Shoolery, Lipids, 1977, 12, 869. 9 3 P. E. Pfeffer, I?. E. Luddy, J. Unruh, and J. N. Shoolery, J. Amer. O il Chemists’ Soc., 1977,54, 380. 94 T. Ariga, E. Araki, and T. Murata, Chem. Phys. Lipids, 1977,19,14. 9 5 R. A. Stein, Chem. Phys. Lipids, 1976, 17,22. 96 T. A. Foglia, P. Heller, and C . J. Dooley, J. Amev. Oil Chemists’ Soc., 1976, 53, 45; J . J . Boon, B. van de Graaf, P. J . W. Schuyl, F. de Lange, and J . W. de Leeuw, Lipids, 1977,12, 717. 97 L. Marai, J . J. Myher, A. Kuksis, L. Stuhne-Sekalec, and N. Z. Stanacev, Chem. Phys. Lipids, 1976,17,21 3. 86

248

Aliphatic and Related Natural Product Chemiktry

Cyclopropane esters are better identified after oxidation t o the a-0x0 derivative than by formation of the acyl p y r r ~ l i d i d e .Acetylenic ~~ esters are less prone to bond migration than olefinic compounds and give characteristic cleavage fragments. They can, however, be converted into 0x0 esters by oxymercuration and characterized in this form or as trimethylsilyl ethers after reduction of the 0x0 functiomW

Japanese workers'00 have discussed the interesting possibility of analysing triglyceride mixtures by a combination of g.c. and c.i.-m.s. The molecular and fragment ion peaks give information about the number of carbon atoms and the number of double bonds in each chromatographic fraction. For example, the c62 component in rape and mustard seed oils contains mainly one CI8 and two CzZ chains each of which is predominantly monounsaturated. Raman Spectroscopy.-The Raman spectra of deuteriated C 18 acids"' diunsaturated C18 acids of type (22) have been examined.'02

and

Crystal Structure and Polymorphism.-Precht lo3 has reviewed the crystal structure of fatty alcohols (cl2-c26) and acids (CIS only) by electron and X-ray diffraction and has offered a statistical model to explain the mixed crystal forms and melting behaviour of binary fatty acid mixtures such as 16 : 0 and 18 : 0. Other compounds examined include anhydrous sodium oleate, alkyl esters of elaidic (18 : 1 9 t ) and petroselinic (18 : 1 6c) acids, and methyl 1 2 - D - h y d r o ~ y s t e a r a t e .The ~ ~ crystal structure of cholesteryl 17-bromoheptadecanoate and of cholesteryl myristate'05 have been described along with the thermal properties of cholesteryl stearate, oleate, and linoleate.lM The thermal

98 99

loo

W. J. Gensler and J. P. Marshall, J. Org. Chem., 1977, 42, 126. R. Kleiman, M . B. Bohannon, F. D. Gunstone, and J . A. Barve, Lipids, 1976, 11, 599. T. Murata and S. Takahashi, Anulyt. Chem., 1977, 49, 728; T. Murata, Analyt. Chem., 1977,49, 2209.

S. Sunder, R. Mendelsohn, and H. J. Bernstein, Chem. Phys. Lipids, 1976, 17, 456; S. P. Verma and D. F. G . Wallach, Biochim. Biophys. Actu, 1977,486, 217. lo2 M. S. F. Lie Ken Jie and C. H. Lam, Chem. Phys. Lipids, 1977, 18, 105. lo3 E. Frede and D. Precht, Fette, Seifen, Anstrichm., 1976, 7 9 , 69, 270; J. Amer. Oil Chernists'Soc., 1976, 5 3 , 668; D. Precht, Fette, Seifen, Anstrichm., 1976, 7 8 , 145, 189. J. L. Curat and R . Perron, Chem. Phys. Lipids, 1977, 19, 301; A.V. Bailey, D. Mitcham, V. W. Tripp, and G. Sumrell, J. Amer. Oil Chemists' Soc., 1976, 5 3 , 89; I3. M. Lunde'n, H. Lijfgren, and I. Pascher, Chem. Phys. Lipids, 1977, 20, 263. 105 S. Abrahamsson and B. Dahle'n, J.C.S. Chem. Comm., 1976, 117; Chem. Phys. Lipids, 1977, 2 0 , 4 3 ; B. M . Craven and G. 'r. de Titta, J.C.S. Perkin 11, 1976, 814. lo6 B. Lundberg, Actu Chem. Scand., 1976, B30, 150.

2 49

Fatty Acids

properties of some cyclopropene and cyclopropane esters and some palmiticoleicelaidic glycerides have been examined. lo' Other Physical Properties.-Fluorescent fatty acids and their lipid derivatives continue to be used as membrane probes. These include parinaric acid (18 : 4 9,11,13,15), azido and anthryl fatty acids, and acyl derivatives prepared from 4-bromomethyl-7-methoxycoumarin.1~ The effect of branching in the 0.r.d. and c;d. of saturated glycerides in reportedlW and novel microtechniques fpr the measurement of acoustic properties have been described."' The behaviour of mixed monolayers of saturated ( 1 8 : 0 , 20 : 0) and unsaturated acids (18 : 1 9c and 9t) has been examined."* 5 Chemical Reactions

Oxidation under both enzymic and nonenzymic conditions continues to attract a good deal of attention. Hydroperoxide Formation and Structure.-Chan and his colleagues reinvestigated the autoxidation of methyl oleate, methyl linoleate, and methyl cu-linolenate making use of HPLC to separate the resulting hydroperoxides or the hydroxy esters formed by NaBH4 reduction. Autoxidation of oleate gave seven peaks representing the eight hydroperoxyoctadecenoates: 1 1-00H 9c and 9 t , 10-00H 8c and 8 t , 9-00H 1Oc and l o t , 8-00H 9c and 9t (the 9-00H 1Oc and 10-00H 8c isomers are not separated) and, after reduction of both hydroperoxide and double bond, the 8-, 9-, lo-, and 11-hydroxystearates were separated.'12 Photolytic oxidation sensitized by erythrosine gave only 1O-OOH 8c and 8t and 9-00H 1Oc and 10t andl after reduction, only the 9- and 10-hydroxystearates.'12 Autoxidation of methyl linoleate furnished four hydroperoxyoctadecadienoates and, after reduction with sodium borohydride, four hydroxyoctadecadienoates viz. 13-OH 9c 1 I t and 9t 1 1t and 9-OH 1Ot 12c and lOtl 2t,'13 After autoxidation and reduction methyl linolenate gave eight hydroxyoctadecatrienoates with the 9- and 16-oxygenated derivatives in larger amount than the 12- and 13-oxygenated acids thus: 9-OH 10t12c15c (30%), 9-OH 10t12t15c (3%), 12-OH 9c13t15c (8%), I2-OH 9c13t15t (2%), 1 3 4 H 9 c l l t 1 5 c (lo%), 13-OH 9 t l l t 1 5 c (2%), 16-OH 9c12c14t (38%) and 16-OH 9cl2t 14t (6%).'14 'ol

108

lo9 IJo 'I'

'14

J . L. White, A. Zarins, and R . 0. Feuge, J. Amer. Oil Chemists' Soc., 1977, 54, 335; N. V. Lovegren, M . S. Gray, and R. 0. Feuge, J. Amer. Oil Chemists' SOC., 1976, 5 3 , 5 19. F . Schroeder, J . F. Holland, and P. R . Vagelos, J. Biol. Chem., 1976, 251, 6739; L. A . Sklar, B. S. Hudson, M . Petersen, and J . Diamond, Biochem., 1977,16, 813; L. A. Sklar, B. S. Hudson, and R. D. Simoni, Biochem., 1977, 16, 819;E. S Tecoma, L. A. Sklar, R . D. Simoni, and B. S. Hudson, Biochem, 1977, 16, 829;W.Stoffel, K. Salm, and U . Kijrkemeier, 2. physiol. Chem., 1976, 357, 917; W. Stoffel and G. Michaelis, 2. physiol. Chem., 1976,357, 925; W. Dunges, Analyt. Chem., 1977,49, 442. S. Gronowitz, B. Herslijf, and R . Ohlson, Chem. Phys. Lipids, 1976, 1.7, 244. U. Varanasi, R . E. Apfel, and D. C. Malins, Chem. Phys. Lipids, 1977, 19, 179. A. 1. Feher, F. D. Collins, and T. W. Healy, Austral. J. Chem., 1977, 30, 5 1 1. H. W. S. Chan and G. Levett, Chem. and Ind., 1977, 692. H.W.S. Chan and G . Levett, Lipids, 1977,12, 99. H . W. S. Chan and G. Levett, Lipids, 1977, 1 2 , 837.


250

Frankel e t al. used g.c.-m.s. to study autoxidation products before and after reduction of hydroperoxide to hydroxy derivative. Methyl oleate furnished epoxy esters, 0x0 esters, allylic hydroxy esters, allylic enones, and dihydroxy 18 : 1 and 18 : 0. The yield of 8- and 1 1-hydroperoxides (26-28%) was marginally higher than the yield of 9- and 10-hydroperoxides (23-24%).Il5 With methyl linoleate, 9- and 13-hydroperoxyoctadecadienoateswere formed in equal amounts and some minor products were also identified after r e d u c t i ~ n . "Autoxi~ dation of methyl linolenate furnished triene hydroperoxides, cyclic endoperoxides (such as 25), and prostaglandin-like endoperoxides (such as 26). Among the triene hydroperoxides the 9- and 16-hydroperoxides (75---82%),are formed preferentially over the 12- and 13-hydroperoxides ( 18-25%). Catalytic hydrogenation of (25) furnishes 9,10,13- and 12,15,16-trihydro~ystearate.'~~

(25) R' = Et, R2 = (CHJ7C0,Me or R' = Me0,C(CHJ7-, R' = Et

OOH (26)

The formation of cyclic peroxides (endoperoxides) from appropriate unsaturated hydroperoxides is of interest because of their similarity t o the prostaglandin endoperoxides. Methylene-interrupted polyenes must have at least three double bonds for this reaction to happen (Scheme 12). The hydroperoxy endoperoxides are also thought to be the source of the propanedial (malondialdehyde) which is the essential component for the thiobarbituric acid test for ~xidation."'-"~ The pro-oxidant effect of inorganic chromium compounds seems to be based on their ability to abstract hydrogen from methyl linoleate and to decompose hydroperoxides. 120 Photolytic oxidation is of two types. If the alkene is activated then the products are the same as those obtained in autoxidation but if the oxygen is activated the reaction follows a different course. It gives structurally different products, is not markedly inhibited by the usual radical scavengers, and the relative reaction rates of oleate, linoleate, and linolenate ( 1.O: 1.7 :2.3) are very different from those observed in autoxidation.f21

'" R . '16

'"

F. Garwood, B. P. S. Khambay, B. C. L. Weedon, and E. N. Frankel, J.C.S. Chem. Comm., 1977, 364; E. N. Frankel, W. E. Neff, W. K. Rohwedder, B. P. S. Khambay, R . F. Garwood, and B. C. L. Weedon, Lipids, 1977, 12, 901, 908. E . N. Frankel, W. E. Neff, W. K. Rohwedder, B. P . S. Khambay, R . F. Garwood, and B . C . L. Weedon, Lipids, 1977, 1 2 , 1055. N. A. Porter, J . Nixon, and R. Isaac, Biochim. Biophys. Actu, 1976, 441, 506. N. A. Porter, M. 0. Funk, D. Gilmore, R. Isaac, and J . Nixon, J. Amer. Chem. Soc., 1976,98,6000.

W. A. Pryor, J . P. Stanley, and E. Blair, Lipids, 1976, 1 1 , 370. 120 N. Ikeda and K. Fukuzumi, J. Amer. Oil Chemists' SOC.,1977, 54, 105. 12' D. J . Carlsson, T. Suprunchuk, and D. M . Wiles, J. Amer. Oil Chemists'Soc., 1976, 53, 656; J. Terao and S. Matsushita, J. Amer. Oil Chemists'Soc., 1977, 54, 234; H . W. S. Chan, J. Amer. Oil Chemists' Soc., 1977, 54, 100. '19

25 1

Fa t ty A cid s

Alkyl hydroperoxides and dialkyl peroxides are conveniently prepared from bromides or iodides by reaction with hydrogen peroxide or alkyl hydroperoxides in the presence of silver trifluoroacetate.'22

00

1

OOH I

Scheme 12

Hydroperoxides are often prepared by enzymic oxidation and oxidation by plant lipoxygenases has been reviewed (see ref. 249). The 13-L-hydroperoxide from linoleic acid (27) is readily available using soybean lipoxygenase. The corresponding 9-D-hydroperoxide (28) is more difficult to obtain but tomato R~CH(OOH)CH-L-CHCHACHR~ (27) (28)

R' = Me(CH,),, R2 = (CH,),CO,H R' HO,C(CHJ,, R2 = (CH,),Me

fruit is reported to provide a useful enzyme preparation.'= The effect of substrate polarity on the activity of soybean lipoxygenase isoenzymes has been reported" and also the calcium activation of peanut lip~xygenase.'~'Soybean lipoxygenase promotes oxidation of 18 : 3 (n-6) t o two hydroperoxyoctadecatrienoates: 9 - 0 0 H 6cl Ot 12c and 13-00H 6c9cl I t , but arachidonic acid (20 : 4, n-6) gives only 15-00H 5c8c 1 l c 13t .126 Presented with isomeric methyleneinterrupted C 18 dienes, soybean lipoxygenase promotes the oxidation of only the 9c 12c (linoleic) and 13c 16c isomers. The latter substrate produces, after reduction, 13-hydroxy< 15%) and 17-L-hydroxystearates (85%) indicating that the enzyme can remove hydrogen attached t o the 15th (n-4) carbon as well as the 1 l t h (n-8).'*' Another study has shown that soybean lipoxygenase promotes a rapid reaction to give a monohydroperoxide and a slower reaction to give a bishydroperoxide in substrates which still contain a 1,4diene after the first reaction. Dienes and n-3 trienes thus give monohydroperoxides only but n-6 trienes and tetraenes form bishydroperoxides.128 The reaction with arachidonic acid is shown in Scheme 13.

"'P. G. Cookson, A, G. Davies, and B. P. Roberts, J.C.S. Chem. Comm., 1976, 1022. 123

lZ4

12'

lZ7

''*

J . A . Mathew, H. W. S. Chan, and T. Galliard, Lipids, 1977, 12, 324. G. S . Bild, C. S. Ramadoss, and B. Axelrod, Lipids, 1977, 12, 732. M. S. Nelson, H . E. Pattee, and J . A. Singelton, Lipids, 1977, 12, 418. M. 0. Funk, K. Isaac, and N. A. Porter, Lipids, 1976, 11, 11 3. M. R. Egmond, G. A. Veldink, J . F. G . Vliegenthart, and J . Boldingh, Biochim. Biophys. Acta, 1975,409, 399. G. S. Bild, C. S. Ramadoss, and B. Axelrod, Arch. Biochem. Biophys., 1977, 184, 3 6 .

25 2


OOH

OOH

R' = CHJCH,),, R'

OOH

R'

= (CH,),CO,H #

Scheme 13

Animalderived preparations are known t o convert arachidonic acid into 12-hydroxy, 1 1-hydroxy-, and 15-hydroxyeicosatetraenoic acid and it is now shown that rabbit peritoneal neutriphils convert the n-6 20 4 and 20: 3 acids into 5-L-OH 6t8cl lc14c and 8-L-OH 9 t l lc14c re~pectively.'~' The triyne acid 20: 3 5a8a 1 l a selectively inhibits platelet n-8 lip~xygenase.'~' When unsaturated acids are adsorbed on silica gel their oxidation takes a different course. There is little or no reaction with oleic acid and linoleic acid gives a mixture of two mono cis epoxides with little or no hydroperoxide or conjugated diene. Under the same conditions linelaidic acid gives two mono trans e ~ 0 x i d e s . lThe ~ ~ chemiluminescence which accompanies this reaction has been studied.132 Secondary Reactions of Hydroperoxides.-Once formed, hydroperoxides produce secondary products of .lower, higher, o r similar chain-length. The short-chain aldehydes which have been recognized in cucumber and contribute to its characteristic flavour are decomposition products of hydroperoxides available from linoleic, linolenic, or palmitoleic acid. The following aldehydes have been recognized 9 : 1(3c), 9 : 1(2t), 6 : 0 , 9 : 2(2t6c), 1 5 : 1(8c), along with 1243x0dodec-cis-9enoic acid.'33 Tomato fruit produces the 9- and 13-hydroperoxides (95 and 5%, respectively) but only the minor 13-hydroperoxide subsequently undergoes cleavage. 12-Oxododec-trans-1Oenoic acid is formed from linolenic acid in the chloroplast of tea leaves along with hexenal: isomerization of the 9c Hydrocarbons are released during decompoto 1Ot double bond must sition of hydroperoxides in the presence of ascorbic acid and copper or iron salts. n-6 Acids give pentane (1.3 mol%), n-3 acids give ethane and ethene (4.3 and

'29 I3O 13' 132

133

134

135

P . Borgeat, M . Hamberg, and B. Samuelsson,J. B i d . Chem., 1976, 2 5 1 , 7 8 1 6 . S. HammarstrGm, Biochim. Biophys. Acta, 1 9 7 7 , 487, 5 1 7 . Guey-Shuang Wu and. J . F. Mead, Lipids, 1977, 1 2 , 9 6 5 ; Guey-Shuang Wu, K. A. Stein, and J . I;. Mead, Lipids, 1977, 12, 9 7 1 . V . Slawson and A. W . Adamson, Lipids, 1976, 1 1 , 4 7 2 . T. Galliard and D. R. Phillips, Biochirn. Biophys. A m , 1 9 7 6 , 4 3 1 , 2 7 8 ; T. Galliard, D. R. Phillips, and J . Reynolds, Biochim. Biophys. Actu, 1976, 441, 1 8 1 ; J . Sekiya, T. Kajiwara, and A. Hatanaka, Phytochernistry, 1977, 16, 1043; T. K . Kemp, Phytochemistry, 1977, 16, 183. T. Galliard and J . A. Matthew, Phytochemistry, 1977, 16, 339. A. Hatanaka, T. Kajiwara, 1 . Sekiya, and Y . Kido, Phytochemistry, 1977, 1 6 , 1828.

25 3

Fatty Acids

10.6 rn01%).'~~char^'^^ considers that the 9 and 13 hydroperoxides are interconverted before thermal decomposition. The thermal oxidation of short-chain monoenoic acids138and of t r i - ~ l e i n ' has ~ ~ been examined. OH

SY

OZ (29) R' = Me(CH2),, RZ = (CHz),C02H Z = H o r Et, Y = CHzCH(NHz)C02H or CH,CH(NHAc)CO,H

Gardner et al. studied the reaction between linoleic acid hydroperoxide and cysteine or N-acetylcysteine to give products mainly of the type (29). In the presence of guaiacol and lipoxygenase, linoleic hydroperoxide furnishes an extensive mixture of CI8 compounds including four products (30 and 31) not

previously r e c 0 g n i ~ e d . l ~ Tocopheryl ~ ethers result from autoxidation of linoleate in the presence of tocopher01.l~~ The changes which occur in the enzyme during the interaction of linoleic acid 13-hydroperoxide with soybean lipoxygenase have been reported143 and it is apparent that a crude soy extract catalyses the conversion of the 13-hydroperoxide into (32) along with other products.14 Mangold et al. have studied the autoxidation of glycerol ethers.'45

E. E. Dumelin and A1 L. Tappel, Lipids, 1977, 12, 894. H. W . S. Chan, F. A. A. Prescott, and P. A. T. Swoboda, J. Amer. Oil Chemists' SOC., 1976, 53, 572. C. B. Whitlock and W. W. Nawar, J. Amer. Oil Chemists' Soc., 1976, 5 3 , 586, 592. 139 E. Selke, W. K. Kohwedder, and H. J . D u t t o n , J. Amer. Oil Chemists' SOC., 1977, 54, 62. I4O H . W. Gardner, D. Weisleder, and K. Kleiman, Lipids, 1976, 1 1 , 127; H . W. Gardner, R. Kleiman, D. Weisleder, and G . E. Inglett, Lipids, 1977, 1 2 , 655. I4l G. Streckert and H. J . Stan, Lipids, 1975, 10, 847. 142 G. K. Koch, R. K. W. Han, J . J. L. Hoogenboom, M. Mutter, and H. van Tilborg, Chem. Phys. Lipids, 1976, 1 7 , 8 5 . 14 3 G. J . Garssen, G. A. Veldink, J. I?. G . Vliegenthart, and 3. Boldingh, European J. Biochem., 1976, 6 2 , 3 3 ; M. R. Egmond, P. M. Fasella, G. A. Veldink, J. F. G. Vliegenthart, and J. Boldingh, European J. Biochem., 1977, 7 6 , 4 6 9 ; J . Verhagen, A. A. Bouman, 3. F. G. Vliegenthart, and J. Boldingh, Biochim. Biophys. Acra, 1977, 486, 114. 144 H. W. Gardner and R. Kleiman, Lipids, 1977, 1 2 , 9 4 1 . 14s N . Yanishlieva, H. Becker, and H. K. Mangold, Chem. Phys. Lipids, 1976, 1 7 , 393; 1977, 18, 149; N. Yanishlieva and H. K. Mangold, Chem. Phys. Lipids, 1977, 20, 21.

13'

254


Other Oxidation Reactions.-The oxidation of long-chain saturated and unsaturated (up to three double bonds) alcohols to aldehydes has been effected with dipyridine chromic anhydride complexlM and with chromic acid adsorbed o n to a celite c01urnn.l~~ The latter reaction is recommended for use at the mg o r pg scale. Peroxycarboxylic acids can be prepared from acid halides and 85% hydrogen peroxide in the presence of tetrahydrofuran and pyridine. 148 Long-chain compounds acting as phase transfer catalysts improve the oxidation of alkenes t o diols by KMn04, t o short chain products by R u 0 4 , and the cleavage of epoxides by H I 0 4 Osmium and ruthenium tetroxides can be used in catalytic amounts in conjunction with sodium hypochlorite, t-butyl hydroperoxide, or N-methylmorpholine-Nexide which continually regenerate the tetroxide. Several papers on epoxidation and epoxide reactions have appeared. Epoxidation is effected with organometallic compounds such as (Ph#)2Pt02 ,lS1 H202-tris(acetylacetonate)iron(III) (which gives mainly the trans epoxide from both cis and trans alkenes),lS2 and during Ag* chromatography with peroxidized solvent.'s3 Polymer-supportedperoxy acids have also been used for epoxidation.'% In a review on the mechanism of olefin epoxidation by peracids D r y ~ k ' ~ ~ emphasized the importance of the solvent and the ratio of acidic and basic components in bifunctional catalysis. Contrary to previous claims it is reported that peracid epoxidation of 2t esters gives the %OX0 ester and not the 2,3-epoxide.lS6 The formation and reactions of linoleate epoxides still provide surprises. A Russian reinvestigating the reaction of diepoxides with acidic reagents, Me(CH,),CH(OH)

H

YkH

CH (OH)(CH,),CO,H

(33)

find them t o include tetrahydropyrans, tetrahydrofurans, and some tetrahydroxystearates. The cyclopropane acid (33) has been identified (20% yield) among the products of reaction of linoleic acid with performic acid."* 146

A. J . Valicenti a n d R. T. Holman, Chem. Phys. Lipids, 1976, 17, 389. D. P. Schwartz a n d S. F. Osman, Analyt. Biochem., 1977, 89, 70. 14' J . Y . Nedelec, J . Sorba, a n d 1). Lefort, Synthesis, 1976, 82 1, A. Y. Krapcho, J. K. Larson, and J . M. Eldridge, J. Org. Chem., 1977, 42, 3749; T. A . Foglia, P. A. Barr, and A. J . Malloy, J. Amer. Oil ChemBts'Soc., 1977, 54, 8SdA. T. Okimoto and D. Swern, J. Amer. Oil Chemists'Soc., 1977, 54, 862A, 867A. 150 K. B. Sharpless a n d K. Akashi, J. Amer. Chem. Soc., 1976, 98, 1968; T. A. Foglia, P. A. Barr, A. J. Malloy, and M , J . Constanzo, J. Amer. Oil Chemists' SOC., 1977, 54, 870A; V. van Kheenen, R. C. Kelly, and D. Y. Cha, Tetrahedron Letters, 1976. 1973. Is' M. J. Y . Chen and J . K. Kochi, J.C.S. Chem. Comm., 1977, 204. l S 2 T. Yamamoto and M. Kimura, J.C.S. Chem. Comm., 1977, 948. S. L.Chen, R. A. Stein, and J. F. Mead, Chem. Phys. Lipids, 1976, 16, 161. C. R. Harrison and P. Hodge, J.C.S. Perkin I , 1976, 605. l S 5 V. G. Dryuk, Tetrahedron, 1976, 3 2 , 2855. l S 6 A. A. Ansari, F. Ahmad, and S. M. Osman, Fette, Seifen, Anstrichm., 1977, 79, 328. I. L. Kuranova, C. L. Gordienko, G. H. Korckaya, and E. V. Filanova, Zhur. org. Khim., 147

'"

1976,12, 1699. 158

E. S. Olson, J. Amer. Oil Chernists'Soc., 1977, 54, 5 1 .

255

Fatty Acids

Privett et all5' examined the ozonides produced from several mono- and polyenoic esters. Methanolic boron trifluoride is recommended as a reagent for converting mono-ozonide into short-chain esters'60 and the preparation and selective hydrolysis of acetal esters is reported.161 Double Bond Stereomutation and Migration.-Deoxygenation of epoxides with Me3SiK, occurring with inversion of stereochemistry, provides a method for the interconversion of cis and trans alkenes162 (Scheme 14). Olefin inversion also results from reaction of epoxides with Ph$X2 t o give, after two inversions, a dihalide which is then submitted to trans elimination with zinc.163 Halogenation is a trans addition but dehalogenation with sodium iodide is a cis elimination so that halogenation-dehalogenation leads t o an overall inversion.'@ Aromatic sulphinic acids (ArS02H) promote the establishment of the equilibrium mixture of cis trans isomers without double bond migrati~n.'~'

RICH=CHRZ cis

-

0 /\

R'CHCHR'

A [ R'CH(OK)CH(OSiMe,)R' threo

]

-

R'CH=CHR2 trans

Reagent: i, Me,SiSiMe,, KOMe

Scheme 14

Isomerization of methyl linoleate t o conjugated dienoates occurs in good yield in the presence of rhodium comp1exes.lM Palladium compounds promote the isomerization of acyl halides to a-branched corn pound^.'^^ Among acetylenic alcohols, rearrangement to the A' isomer occurs with potassium 3-aminopropylamide [ KNH(CH2)3NH2] and a safer way of making this reagent avoiding the use of potassium hydride has been suggested (Scheme 15).168

Reagent: i, KNH(CH,),NH,, NH, (CH,),NH,

Scheme 15

Analytical methods of determining double bond positions and configurations have been reviewed.'69 159

160 16'

162 163 16 4

166

167

E. C. Nickell, M . Albi, and 0. S. Privett, Chem. Phys. Lipids, 1976, 17, 378. K. G. Ackman, Lipids, 1977, 12,293. K. 0. Adlof, W. E. Neff, E. A. Emken, and E. H. Pryde, J. Amer. Oil Chemists' SOC., 1977, 54,414. P. B. Dervan and M. A. Shippey,J. Amer. Chem. SOC., 1976, 98,1265. P. E. Sonnet and J . E. Oliver,J. Org. Chem., 1976,41,3279. P. E. Sonnet and J . E. Oliver, J. Org. Chem., 1976,41,3284. T. W.Gibson and P. Strassburger, J. Org. Chem., 1976,41,791. H. Singer, R. Seibel, and U. Mees, Fette, Seifen, Anstrichm., 1977, 79, 147. T. A. Foglia, P. A. Barr, and M. J . Idacavage, J. Org. Chem., 1976,41,3452. C. A. Brown and A. Yamashita, J.C.S. Chem. Comm., 1976, 959; J. C. Lindhoudt, G . L. van Mourik and H . J . J . Pabon, Tetrahedron Letters, 1976,2565;H. Hommes and L. Brandsma, Rec. Trav. chim., 1977,96,180. H. B. S. Conacher, J. Chromatog. Sci., 1976, 14,405.

25 6


Other Reactions.-By reaction with mercuric acetate, followed by demercuration by sodium borohydride in aqueous tetrahydrofuran, appropriate diunsaturated esters furnish cyclic ethers (tetrahydrofurans, tetrahydropyrans). Further examples of this are reported by Lam and Lie Ken Jie.lm CH, =CH

(CH,) , C0,Me

(34) n = 2-8

MeO,C(CH,), CH=CH (CH,), C0,Me

(35) n = 2-8

Metathesis continues t o attract attention. The alkene (34) furnishes (35) and ethylene 17' and heterogeneous catalysts such as rhenium heptoxide on alumina promoted with a little tetramethyltin are reported t o give good result^."^ The topic has been reviewed'73 and an international symposium has been reported.'% An improved preparation of alkane thiols has been reported'75 and there has been a further study of the nucleophilic and radical addition of hydrogen sulphide t o methyl linolenate and linseed The interaction of alkenes with thiocyanogen has been examined. The addition products ( 3 6 and 37) can be converted into heterocyclic compounds with acid or base.177 R'CH(SCN)CH(SCN)R'

R1CH(SCN)CH(NCS)R2

(36)

(37)

R' = Me(CH,), R2 = (CH,),CO,Me or R' = MeO,C(CH,), R2 = (CH,),CH, During hydrogenation of methyl oleate and methyl elaidate, double bond migration is quicker with the 9 t than with the 9 c isomer but the rate of hydrogenation is independent of the configuration. It has been suggested that hydrogenation and stereomutation occur through the half-hydrogenated intermediate or o-complex but double bond migration involves the 71 ally1 mechanism.'78 The distribution of double bonds in partially hydrogenated methyl linoleate has been examined by a mathematical approach.'- Cationic rhodium complexes for the partial hydrogenation of alkynes are said t o be superior to Lindlar's catalyst.'m Alkynols are reduced to trans alkenols with lithium aluminium hydride18' and 170

172

174

17' 176

'79

I8O

C. H . Lam and M. S . F. Lie Ken Jie, J. Chromatog., 1976, 116, 425; Chem. Phys. Lipids, 1976, 16, 181;M. S. F. Lie Ken Jie and C. H. Lam, J. Chromatog., 1976, 129, 181. R. Baker and M. J. Crimrnin, Tetrahedron Lefters, 1977,441. E. Verkuijlen, F. Kapteijn, J. C. Mol, and C. Boelhouwer, J.C.S. Chem. Comm., 1977, 198. E. Verkuijlen and C. Boelhouwer, Fette, Seifen, Anstrichm., 1976,7 8 , 444;N. Calderon, E. A. Ofstead, and W. A. Judy, Angew. Chem., 1976, 15,401. International Symposium on Metathesis, Rec. Truw. chim., 1977,96,M 1 -M 141. I. Degani, R. Fochi, and M. Santi, Synthesis, 1977,873. A. W. Schwab, L. E. Gast, and W. K. Rohwedder, J. Amer. Oil Chemists' Soc., 1976, 5 3 . 762. R. J. Maxwell, L. S. Silbert, and J. R. Russell, J. Org. Chem., 1977, 42, 1510; R. J . Maxwell and L. S. Silbert, J. Org. Chem., 1977, 42, 1515; R. J. Maxwell, G . G . Moore,and L. S. Silbert,J. Urg. Chem., 1977,42, 1517;K. J . Maxwell, P. E. Pfeffer, and L. S. Silbert, J. Org. Chem., 1977,42, 1 5 2 0 . P. van der Plank and H. J . van Oosten,J. Cutdysis, 1975,38, 2 2 3 . Y. Kubota, Fette, Seifen, Anstrichm., 1976,7 8 , 1 1 8. R. R. Schrock and J. A. Osborn, J. Amer. Chem. Soc., 1976,98,2143. R. Rossi and A. Carpita, Synthesis, 1977,561.

Fatty A cids

257

trans alkenes can be generated from alk-1-ynes and alkylhalides using B 4 A1H and butyl lithium. 182 Cobalt catalysts promote the reaction of methyl oleate with carbon monoxide and hydrogen to give the formylstearates (38) or their dimethylacetals if the reaction is conducted in methanol. The aldehyde is accompanied by the hydroxymethyl ester (39) and more of this is produced if the addition reaction is followed by hydr0genati0n.l~~Rhenium catalysts, which normally give the formyl products (38) can also catalyse their oxidation t o the carboxystearates (40). These are formed directly when palladium catalysts are used.lM Both cobalt and rhenium catalysts promote the cis addition of H and CH0.18' The formylated compounds are the basis of many other products including the bishydroxymethyl derivatives (41) by reaction with fomaldehyde and base1= and the acetals (42)and (43) by reaction with glycerol and acetic R'CH2CH(CHO)R2

R1CH,CH(CH20H)R2

R1CH2CH(C02H)R2

(38)

(39)

(40)

R'CH,CHR2

R'CH2CHR2

CH,OH

I R1CH2CR2

I

I

CH

";i"

I

CH,OH

OAc

(41)

(43) R1 = Me(CH2), RZ = (CH,),CO,Me or R' = MeO,C(CH,), RZ = (CH,),CH,

In studies of the reactions of saturated chains of carboxylic acids and related compounds conformational calculations have been used t o explain the chromic acid oxidation of saturated acids.'= Oxidation of C12-C17 macrocyclic lactones results in non-random attack mainly around the central region of the saturated segment, 18' Selective chlorination of dicarboxylic acids and of longchain amides has been examined.lgO Reaction with the amides occurs mainly in the central area and the results are discussed in terms of the folded-back structure arising from hydrophobic interactions. Hydroxylation of palmitic acid with 182

185

188

S. Baba, D. E. van Horn, and E. Negishi, Tetrahedron Letters, 1976, 1927. E. N. Frankel, J. Amer. Oil Chemists'Soc., 1976, 53, 138. J . P. Friedrich,J. Amer. Oil Chemists' SOC.,1976, 5 3 , 125; E. N. Frankel and E. H . Pryde, J. Amer. Oil Chemists'Soc., 1977, 54, 873A. A. Stefani, G. Consiglia, C. Botteghi, and P. Pino, J. Amer. Chem. SOC.,1977, 99, 1058. W. K. Miller and E. H . Pryde, J. Amer. Oil Chemists'Soc., 1977,54, 882A. W. E. Neff, E. N . Frankel, E. H. Pryde, and G. R. Riser, J. Amer. Oil Chemists' SOC., 1976, 5 3 , 152. C. R. Eck, D. J . Hunter, and T. Money, J.C.S. Chem. Comm., 1974, 865; D. A. Winnik and D. S. Saunders, J.C.S. Chem. Comm., 1976, 156. G . Eigendorf, C. L. Ma, and T. Money, J.C.S. Chem. Cornm., 1976, 561. F. Kamper, H. J . Schlfer, and H. Luftmann, Angew. Chem., 1976, 15, 306; N . C. Deno and E. J. Jedziniak, Tetrahedron Letters, 1976, 1259.

258


trifluoroacetic acid gives a random mixture of 5- to 15-hydroxypalmitic acids in about 70% yield.’” Acid chlorides have been used t o prepare alka-2,4-diones (Scheme 16)’92 and diacyl peroxides’93 by reaction with potassium superoxide (KO2 ). Stearic RCOCl

RCOCH,

RCOCH,COCH,

Reagents: i, EtOMgCH(C0, Et),; ii, EtOAc, NdH

Scheme 16

acid is converted into a mixture of heptadecenes in 90% yield in the presence of RhC13 and Ph#. The composition of the product varies with the catalyst preparation.lw The. a-anions of long-chain acids and esters furnish a-amino acids’” and the sulphur-containing compounds (44) and (45).’96

6 Biological Reactions

de novo Synthesis.-In

studies of the fatty acid synthetase, Bloch et al. conclude that their M . smegmatis extracts contain two synthetase systems producing shorter (C16 and C18) and longer (C,-C,) fatty acids, respectively, in a bimodal pattern and that synthetase activity is enhanced by mycobacterial polysaccharides containing 3-0-m et h y lm anno se and 6-0 -met h y lglucose ,re spe ct ive ly . Bimodal distribution is explained in terms of the rates of elongation and terminal transacylation of the two activities. Diffusion of long-chain acyl-CoA (C14-C24) from the enzyme is considered t o be rate-limiting and t o be facilitated by the polysaccharides mentioned above.19’ A study of the stereochemistry of de n o w synthesis suggests that if the dehydration step involves syn elimination of water then condensation occurs with inversion of configuration, but if there is anti elimination in the dehydration

N . C. Deno and L. A. Messer, J.C.S. Chem. Comm., 1976, 1051. D. E. Douglas and L. E. Francis, Lipids, 1977,12,635. 193 K. A. Johnson, Tetrahedron Letters, 1976, 331. 194 T. A. Foglia and P. A. Barr, J. Amer. Oil Chemists’ Soc., 1976, 5 3 , 773. 19’ F. A. Guerri, erases Aceitas (Seville), 1975, 26, 90;(J. Amer. Oil Chemists’ SOC.,1976, 53,234A). 196 D. A. Konen, P. E. Pfeffer, and L. S. Silbert, Tetrahedron, 1976, 3 2 , 2 5 0 7 . 19’ J. M . Odriozola and K. Bloch, Biochim. Biophys. Actu, 1977,488,198;J. M. Odriozola, J . R. Ramos, and K. Bloch, Biochim. Biophys. Acta, 1977,488,207;D. 0.Peterson and K. Bloch, J. Biol. Chem., 1977, 252, 5735; K. J . Banis, D. 0. Peterson, and K. Bloch, J. Biol. Chem., 1977, 252, 5740; W. I. Wood, 11. 0. Peterson, and K. Bloch, J . BioZ. Chem., 1977,252, 5745. 192

Fatty Acids

259

then condensation occurs with retention of configuration at C-2 of malonate during formation of the new carbon carbon bond."* Little is known about the fatty acid synthetase from insects. The synthetase complex from Ceratitis capitata, which has been isolated ( 182-fold concentration) produces C -C 18 saturated acids with the C 16 member predominat ing. Elongation.-Study of the chain-extension of several saturated and unsaturated acids show that the condensation step is rate-limiting and that different enzymes may operate with saturated and unsaturated acyl-CoA compounds.200 Partial purification of the fatty acid elongation systems in the outer and inner membranes of beef liver mitochondria has been reported.m' Desaturation.-Sterculic acid (46) inhibits the A'desaturase which converts saturated into monoene acids. The corresponding 6,7-cyclopropenes (47) did not inhibit either A' or A6 desaturation and it is concluded that the inhibitor is not covalently attached to the enzyme at any point.202

/!\H,

(46)

Me (CH,) .C=C(CH,),CO,H (47) n = 4 or 10

Opposing conclusions about the existence of a Ag desaturase based on the metabolism of labelled substrates have been reported. In the developing brain the 18 : 3 and 20 : 3 n-3 acids furnish a variety of products but the authors believe there is no evidence for a A8 d e s a t ~ r a s e . ~Whilst '~ this is also true in rat liver and rat brain it does not hold for rat testes204 and for cancerous and non-cancerous human tissue2" where a A8 desaturase seems t o be required. There is further evidence to support the view that 6desaturation is the ratelimiting step in the conversion of linoleate t o arachidonate2% and two research groups have independently shown that cytochrome b 5 is a requirement for this enzyme ~ y s t e m . ~ "The acetylenic 18 : 4 acid in moss accumulates in the triacyglycerols and is virtually absent from-the phospholipids. It is probably produced via the corresponding olefinic acid: 18 : 3 ( 9 ~ 1 2 ~ 1 --+5 ~ )18 : 4 ( 6 ~ 9 ~ 1 2 ~ 1 5 ~ ) 18 : 4 (6a9c12c15c).20g __f

198

199

'O'

'03 '04 '05

'06 '07

"*

B. Sedwick, J . W. Cornforth, S. J. French, K. T. Gray, E. Kelstrup, and P. Willadsen, European J. Biochem., 1977,75,481. A. M. Municio, M . A. Lizarbe, E. RelaRo, and J. A. Ramos, Biochim. Biophys. Actu, 1977,487,175. J . T. Barnert, jun. and H . Sprecher, J. Biol. Chem., 1977, 252, 6736. L. W.Bond and T. I. Pynadath, Biochim. Biophys. Actu, 1976,450,8 . K. Jeffcoat and M . R. Pollard, Lipids, 1977, 12,480. G. A. Dhopeshwarkar and C. Subramanian, Lipids, 1976, 11, 67,689. D. H . Albert and J . G. Coniglio, Biochim. Biophys. Actu, 1977,489, 390. I. Nakazawa, J. E'. Mead, and K. H . Yonemoto, Lipids, 1976, 11, 79. 1. N. T. Gomez Dumm, M. J . T. Alaniz, and R. R. Brenner, Lipids, 1976, 11, 8 3 3 . Ten-Ching Less, K . C. Baker, N. Stephens, and E'. Snyder, Biochem. Biophys. Actu, 1977,489,25;T. Okayasu, T. Ono, K. Shinojima, and Y. Imai, Lipids, 1977, 12, 267. J. L. Gellerman, W. H . Anderson, and H. Schlenk, Biochem., 1977, 16, 1258.


260

Evidence is adduced for an enzyme in rat liver microsomes which can desaturate 2 0 : 3 (n-6) not only as a coenzyme A derivative but also as a 1-acyl-2eicosatrienylp hosp hat id y lcholine.209 Not all animals can effect the desaturation of linoleate and/or linolenate. The lion (like the cat and turbot) unable t o desaturate linoleic acid and the turbot and red sea bream cannot desaturate linolenic 20 : 4 (5a8al la14a) inhibits conversion of 18 : 2 into 20 : 4 and of 20 : 4 into 22 : 4 and 22 : 5.2'1

Metabolism of Selected Acids.-In a series of papers on the biosynthesis of cyclopentenyl fatty acids it is concluded that the longer-chain acids in this class are produced by chain extension of aleprolic acid which itself results from cyclopentenylglycine (Scheme 17).212

RCH($JH,)CO; -+ RCOCO;

--

RCOSCOA

-

R(CH,),COSCOA

R = > Scheme 17

The unsaturated fatty acids in Tetrehyrnena pyroforrnis are mainly of conventional type and arise from the (216 and C18 A9 acids. The less usual diene 18 : 2 ( 6 , l l ) is probably formed by the pathway shown in Scheme 18.213

16:O

1 6 : l (9)

-

1 8 : l (11)

Scheme 18

-

18:2(6,11)

It has been shown that in the yellow clam the following acids are metabolized t o thosegiveninparenthsis: 2 : 0 (12 : 0, 14 : 0, 15 : 0, 16 : 0, 14 : 1, 16 : 1, 18 : 1, 2 0 : 1, 1 6 : 2 , 1 8 : 2 , 2 0 : 2 , 2 0 : 3 ) , 1 6 : 0 ( 1 8 : O a n d 1 8 : l ) , 1 8 : 0 ( 1 8 : 1 , 1 8 : 2 , 20 : 1 , 20 : 2 ) , 18 : 2 n-6 (20 : 2 ) , 18 : 3 n-3 (20 : 3 and 18 : 4).2f4Study of the incorporation of labelled acetate into the marine sponge Microciona prolifera supports the proposal that 26 : 1 (5,9) is produced from 16 : 0 via 26 : 0 and 26 : 1 (9) and that 26 : 3 (5,9,19) is produced from 16 : 1 (9) in a similar way.215

'14

E. L. Pugh and M . Kates, J. Biol. Chem., 1977, 2 5 2 , 68. C. B. Cowey and J . R. Sargent, Comp. Biochem. Physiol., 1977, 57B, 269; J . P. W. Rivers, A. G . Hassam, M. A. Crawford, and M. R. Brambell, F.E.B.S. Letters, 1976, 6 7 , 269. J . G. Coniglio, D. Buch, and W. M. Grogan, jun., Lipids, 1976, 11, 143. U. Cramer and F. Spener, Biochim. Biophys. Acta, 1976, 450, 261; European J. Biochem., 1977,74,495. N. J. Koroly and R. L.Conner,J. Biol. Chem., 1976, 2 5 1 , 7588. J. E. A. de Moreno, V. J . Moreno, and R. R. Brenner, Lipids, 1976, 11, 561; Lipids,

*'*

R. W. Morales and C. Litchfield, Lipids, 1977, 1 2 , 570.

*09

'lo 211 '12

*13

1977, 1 2 , 804.

261

Fatty A cids

In continuation of their study of fat metabolism in higher plants, Stumpf et d 2 1 6 conclude that in the avocado mesocarp palmitic, stearic, and oleic acids are produced as ACP derivatives which are hydrolysed and converted into CoA derivatives before being incorporated into polar lipids or, in the case of oleyl CoA, further desaturated to Linoleyl-CoA. Triacylglycerols are produced from ACP and CoA derivatives. The possible role of dietary linolenic acid is still uncertain. On the basis of the importance of 22 : 6 it is considered that linolenic acid must be significant2” and the association of superior learning capacity with incorporation of n-3 acids by the young rat into brain glycerophosphatides is offered as support for an essential role for dietary linolenic acid in the young rat.218 The ar-hydroxylation of fatty acids in rat brain219 and the hydroxylation of palmitic acid at or near the methyl and of the chain have been investigated.220 Phleic acids (48) may arise from chain extension of myristic or palmitic acid by crotonate (49) possibly in a dibasic acid form. Crotonic acid is the vinylogue of acetic and may therefore be expected t o show similar reactivity.221 Me(CH,), (CH=CHCH,CH,), CO,M (48) m = 1 2 0 1 14, n = 4 , 5 , o r 6

MeCH=CHCO,H (49)

A study of the membrane lipids of AchoIepEasma ZaidEawii indicates how the system operates t o retain optimal or near-optimal viability over a wide fatty acid composition range.222 The effects of various unsaturated acids in microbial mutants are reported.223 Butyrivibrio fibrosolvens reduces linoleic acid to 18 : 1 ( 1 I t ) via the isomerized 9c 11t diene. This reduction occurs under strictly anaerobic conditions and both the additional hydrogen atoms are water-derived.224 The only other isomeric methylene-interupted CI8 diene t o react is the 2c5c acid which is readily isomerized t o the 3t5c isomer. This, in turn, is slowly reduced, probably t o the 3t monoene

W. E. Shine, M . Mancha, and P. K. Stumpf, Arch. Biochem. Biophys., 1976, 172, 110; 1976, 173,472. 217 B. P. Poovaiah, J. Tinoco, and R. L. Lyman, Lipids, 1976, 11, 194. 218 M. S. Lamptey and B. L. Walker, J. Nutrition, 1976, 106, 86. 2 1 9 S. Murad, R. H . K. Chen, and Y . Kishimoto,J. Biol. Chem., 1977,252, 5206. 2 2 0 P. P. Ho and A. J . Fulco, Biochim. Biophys. Acta, 1976, 431, 249. 221 C. P. Asselineau and H. L. Montrozier, European J. Biochem., 1976, 63, 509. Y. Saito, J . R. Silvius, and R. N. McElhaney, Arch. Biochem. Biophys., 1977, 182, 443; J . R . Silvius, Y . Saito, and R. N. McElhaney, Arch. Biochem. Biophys., 1977, 182, 455. 223 B. J. Holub and W. E. M. Lands, Canad. J. Biochem., 1975, 53, 1263;J. B. Ohlrogge, E. D. Barber, W. E. M. Lands,’E’. D. Gunstone, and I. A. Ismail, Canad. J. Biochem., 1976, 54, 736; W. E. M. Lands, J . B. Ohlrogge, J . R . Robinson, R. W. Sacks, J . A. Barve, and F. D. Gunstane, Biochim. Biophys. Acta, 1977, 486, 451; J. B. Ohlrogge, F. D. Gunstone, I. A. Ismail, and W. E. M. Lands, Biochim. Biophys. Acra, 1976,431, 257. 224 W. J. Hunter, F. C. Baker, I. S. Rosenfeld, J . B. Keyser, and S. B. Tove, J. Biol. Chem., 1976, 251, 2241. 2 2 5 P. T. Garcia, W. W. Christie, H. M. Jenkin, L. Anderson, and R. T. Holman, Biochim. Biophys. Acra, 1976,424, 296.

‘16

’”

262


7 Booksland Reviews During 1976 and 1977 books were published dealing with: polyunsaturated fatty acids,226 natural waxes,227 plant lipids,228 lipid metabolism in mammals;29 the modification of lipid r n e t a b o l i ~ m ? and ~ ~ the function and biosynthesis of lipid s.23 Reviews appeared on the following topics: palm oil and palm kernel olive lipids,233jojoba oil,234fish lipids,235 milk fat,236 docosenoic acid in dietary ~ ~ ~ tissue plant galactolipids,m unsaturfat ,237 ~ y a n o l i p i d s ,plant ated lactones,%’ alkene synthesis via P-functionalized organosilicon com~~ of acylglycerols pounds,x2 the synthetic utility of 2 - 0 x a z o l i n e s ~synthesis and phosphoglycerides,m synthesis and biological investigation of phosphonates,%’ the chemistry and biochemistry of unsaturated acids,% some chemical and biological properties of unsaturated C18 acids,x7 fat hydrogenation,a8 plant l i p o x y g e f i a ~ e slipid , ~ ~ c h r o r n a t ~ g r a p h y , ~mass ’ ~ spectrometry of lipids?” ruminant m e t a b ~ l i s r n , ~ plant ’~ lipid m e t a b l i ~ r n , ~and ’ ~ books and reviews in lipids.254

‘Polyunsaturated Fatty Acids’, ed. W. H. Kunau and R. T. Holman, Amer. Oil Chemists’ SOC.,Champaign, Illinois, 1977. 12’ ‘Chemistry and Biochemistry of Natural Waxes’, ed. P. E. Kolottukudy, Elsevier, Amsterdam, 1976. 2 2 8 ‘Lipids and Lipid Polymers in Higher Plants’, ed. M. Tevini and H. K. Lichtenthaler, Springer-Verlag, Berlin, 1977. 12’ ‘Lipids Metabolism in Mammals’, ed. F. Snyder, Plenum, New York, 1977, Vols. 1 a n d 2. 230 ‘Modification of Lipid Metabolism’, ed. E. G. Perkins and L. A. Witting, Academic Press, Nzw York, 1975. 23’ N. G. Bazzan, K. R. Brenner, and N. M. Giusto, ‘Function and Biosynthesis of Lipids’, Plenum, New York, 1977; ‘Function and Metabolism of Phospholipids’, ed. G. Porcellati, L. Amaducci, and C. Galli, Plenum, New York, 1976. 232 J. A. Cornelius, Progr. Chem. Fats Other Lipids, 1977, 15, 5. 233 I?. Fedeli, Progr. Chem. Fats Other Lipids, 1977, 1 5 , 57. 234 J. Wisniak, Progr. Chem. Fats Other Lipids, 1977, 15, 167. 235 I. Reichwald, Fette, Seifen, Anstnchm., 1976, 7 8 , 328. 236 S. Smith a n d S. Abraham, Advances in Lipid Research, 1975, 13, 195. 237 J. A. Beare-Rogers, Progr. Chem. Fats Other Lipids, 1977, 15, 29. 238 K. L. Mikoljczak, Progr. Chem. Fats Other Lipids, 1977, 15, 97. 2 3 9 S. S Kadwan a n d H. K. Mangold, Adv. Lipid Research, 1976, 14, 171. 240 H. C. van Hummel, Progr. Chem. Organic Natural Products, 1975, 32, 267. 14‘ Y. S. Rao, Chem. Rev., 1976, 7 6 , 625. 2 4 2 Tak-Hang Chan, Accounts Chem. Res., 1977, 10,442. 243 A. I. Meyers and E. D. Mihelich, Angew. Chem., 1976, 1 5 , 270. 244 R. G. Jensen and R. E. Pitas, Adv. Lipid Res., 1976, 14, 21 3. 14’ R. Engel, Chem. Rev., 1977, 7 7 , 349. 246 W. H. Kunau,Angew. Chem., 1976, 15, 61. 247 F. D. Gunstone, Accounts Chem. Res., 1 9 7 6 , 9 , 34; Chem. and Ind., 1976, 243. 248 Anon. Fette, Seifen, Anstrichm., 1977, 7 9 , 465. 249 G. A. Veldink, J. G. G. Vliegenthart, a n d J. Boldingh, Progr. Chem. Fats Other Lipids, 1977, 1 5 , 131. A. Kuksis, J. Chromatog., 1977, 143, 3 . N. Natale, Lipids, 1977, 12, 847. 2 5 2 G. A. Garton, in ‘International Review of Biochemistry. Biochemistry of Lipids II’, ed. T. W. Goodwin, Univ. Park Press, Baltimore, 1977, Vol. 14. 253 R. B. Park and P. K. S t u m p f , in ‘Lipid Metabolism; Plant Biochemistry’, 3rd edition, ed. J . Bonner and J . E. Varner, Academic Press, New York, 1976. 2 5 4 F. D. Gunstone, Progr. Chem. Fats Other Lipids, 1977, 15, 75. 226

8 Lipids BY A . K. LOUGH

1 Introduction

This review on lipids includes their chemical synthesis, chemical and physical properties, and structural determination of natural members. No account has been taken of physical interactions between different lipid substances or between lipids and other biological materials, moreover the influence of water on lipid substances is considered only insofar as it relates to the hydration of complex lipids and to adsorption of water on lipid molecules. The period of coverage extends from January 1976 to November 1977 except for U.K. and U.S.A. publications which extend to December 1977.

2 Occurrence and Identification of Lipids Animal Lipids.-In a study of the composition of skin lipids of the guinea pig it was'noted that the glycerol ether diesters constituted a singular feature, in comparison with species so far examined, in that the acyl groups consisted solely of saturated fatty acids.' Slices of epidermis from pig tails or ears yielded a lipid component which was shown by hydrolytic degradative procedures t o comprise a phosphatidyl-(N-acy1)-ethanolamine. The fatty acid moiety was predominantly saturated; palmitic acid was the major component. Synthesis of 1,2 -d ipalmit oy 1-sn-glyc er0-3-phospho-(N-p almit oy 1)-et h anolamine enabled a c omparison of i.r. spectra to be made, which confirmed the identity of the natural compound .2 A phospholipid isolated from the koilin-glandular layer of gizzard glands of the domestic fowl (Gallus domesticus) yielded on acid hydrolysis a Czz-saturated aldehyde, sn-glycerol-3-phosphate, ethanolamine, and D( -)-ribose. The phospho- 2 stable 4 ) toalkaliandon acid lipid(mo1. wt. = 653;C32H64N010P;[ ~ ] ~ ~ ~ was methanolysis gave a CZ2dimethyl acetal. The phospholipid exhibited spasmolytic activity and was tentatively assigned the structure 1,2-U-docosylidene-sn-glycero3 -phosphate-( 1'-rib o sy1)-et ha no lamine ( 1), Many glycolipids of intestinal origin are outwith the scope of this Report by virtue of the high content of carbohydrate but a novel sulphated glycolipid has been isolated from the lipid extract of human gastric content. Degradation D. M . Sharaf, S. J . Clark, and D. T. Downing, Lipids, 1977, 12, 786;D. T. Downing and D. M . Sharaf, Biochim. Biophys. Acta, 1976,431,378. G. M. Gray, Biochim. Biophys. Acta, 1976, 4 3 1 , 1 . B. Gruijic-Injac, M . Dimitrijevid, S. Laj&&, D. Stefanovid, and I. Micovic, Hoppe-Seylers 2. Physiol. Chem., 1977,358,499.

263

264


studies revealed the presence of glucose, sulphate, fatty acids, and glycerol monoethers; structure was determined by partial acid hydrolysis, oxidation with periodate and chromium trioxide, and by permethylation. The diacylglycerol moiety comprised a mixture of 1-0-alkyl-2-0-acyl-glycerol and 1U-acyl-2-0alkyl-glycerol in the relative proportions of 6 5 : 35, respectively. The glycolipid was assigned the structure SO3H-6-Glca-( 1-+6)-Glca-( 1-+6)Glca-l-3diacylglycerol4 CHj-0 CH-0

OH OH

Lecithin, isolated from the acetone-insoluble fraction of beef-heart lipids by successive use of aluminium oxide and silicic acid chromatography, comprised : 1,2-diacyl- (5 7%); 1-0-alkenyl-2-acyl- (39%); 14-alkyl-2-acyl- (3%), and di-0-alkyl- (0.2%) lecithins.’ Identification of the di-0-alkyl glycerol moiety was determined by comparison with reference compounds on thin-layer chromatography and i.r. spectrometry. Phosphatidylglycerol, synthesized by phospholipase D (E.C. 3.1.4.4.) from egg phosphatidylcholine and glycerol, was subjected t o stereochemical analysis by treatment, initially, with phospholipase C (E.C. 3.1.4.3.). The released a-glycerophosphate, devoid of P-glycerophosphate, was a 1 : 1 mixture of sn-1 and sn-3 glycerol phosphates as determined by the action of the stereospecific enzyme sn-glycerol-3-phosphate dehydrogenase.‘

Plant Lipids.-In epicuticular wax of the drought-resistant perennial pasturegrass, Agropyron intermedium, Pdiketones constituted some 47% of wax from flowering plants and 58% of spike wax. Prominent among this group of compounds was a novel constituent, hentriacontane-7,16,18-trione.’ Alkaline hydrolysis of the ketone yielded myristic acid and 10-oxohexadecanoic acid. The constitution of a less abundant Pdiketone, hentriacontane-l0,14,16-trione was similarly established yielding palmitic and 5-oxotetradecanoic acids. The proton nuclear magnetic resonance spectrum (’ H n.m.r.) of the trione contained

’

B. L. Slomiany, A. Slomiany, and G. B. J . Glass, European J. Biochem., 1977, 78, 3 3 . E. L. Pugh, M. Kates, and D. J . Hanahan,J. Lipid Res., 1977, 18, 710. A. Joutti and 0. Kenkonen, Chem. Phys. Lipids, 1976, 17, 264. A. P. Tulloch and L. L. Hoffman, Phytochemistry, 1976, 15, 1145.

Lipids

2 65

a quartet at 6 1.82 due t o the protons on C-12, which are p t o the carbonyls at C-10 and C-14. Another novel Pdiketone in the wax included hentriacontane-6,15,17,21tetraone; the 'H n.m.r. spectrum with a quartet a t 1.82 p.p.m. and an enolic proton at 5.33 p.p.m. was consistent with this structure. Hydroxy-oxopdiketones were also reported as comprising a mixture of three isomers: 4-hydroxy-25-oxo-, and 26-hydroxy-lO-oxo-hentriacontane-14,16-diones. 25-hydroxy- 1O-oxo-, Hydrolysis of the mixture gave two 0x0 acids (5-oxotetradecanoic and 10oxohexadecanoic) and two hydroxy acids which were separated chromatographically.' The report includes a study of the mass spectral fragmentation of oxygenated P-diketones from the wax. In a related study on epicuticular wax of Agropyron smithii leaves estimation of the relative proportions of individual components in mixtures of hydroxyqdiketones was inaccurate when mass spectrometry was employed. However, 13C n.m.r. spectroscopy of hydroxytetradecanoates obtained by hydrolysis of mixed hydroxy Pdiketones showed proportions of isomers more accurately. The investigation included I3C n.m.r. spectral analysis of synthetic 10- and 11hydroxyoctadecanoates. Maize seeds of the Moskovskaya-5 strain, harvested on the 15th day after pollination, yielded a glycolipid which on hydrolytic degradation gave ethane1,2diol, galactose, glucose, and fatty acid. Pure samples of glycolipid were obtained by partitioning between heptane and 95% methanol and by silica gel chromatography. Components resultiiig from deacylation were identified using gas-liquid chromatography of trimethylsilyl ethers and by mass spectrometry ; the structure assigned to the glycoside was that of 1-acyl-2.(O-&D-galactopyranosyl)-ethane-l,2-diol;the main fatty acyl groups were palmitoyl, stearoyl, and oleoyl.' The related, 2-acyl-1 -(O-/3-D-glycopyranosyl)-ethane-l,2diol is a component of ripening wheat seeds." Bacterial Lipids.-A series of macrocyclic diglycerol dialkyl tetraethers segregated from methanolysates or hydrolysates of the complex lipids of membranes of extreme thermoacidophile bacteria of the Caldariella series was assigned structure (2).11*12 In a study of the composition of the mixture of ethers obtained from Sulfolobus acidocaldarius and Thermoplasma acidophile spectroscopic studies indicated the presence of i.r. peaks corresponding to hydroxy, ether, carbinol, and alkyl groupings. Degradation of the ethers with HI or with BC13 gave rise to dihalides from which the corresponding diols and hydrocarbons were obtained; gas chromatography, mass spectrometry, and H n.m.r. studies

lo

A. P. Tulloch, Phytochemistry, 1976, 15, 11 53. V. A. Vaver, K. G . Todriza, N. V. Prakazova, B. V. Rozynov, and L. D. Bergelson, Biochim. Biophys. A c t a , 1977,486, 60. V. A. Vaver, V. G. Stoyanova, N . S. Geiko, A. P. Nechaev, K. G. Todriya, and L. D. Bergelson, Bioorg. Khim., 1976, 2, 5 3 0 . T. A. Langworthy, Biochim. Biophys. A c t a , 1977, 487, 37; T. A. Langworthy and W. R. Mayberry, Proc. Soc. Gen. Microbiol., 1976, 3 , 165. M. de-Kosa, S. de-Rosa, A, Gambacorta, L. Minale, and J . D. Bu'Lock, Phytochemistry, 1977,16, 1961.

266


indicated the structure of the three biphytanyl diols (3), (4), and (5) corresponding t o the hydrocarbons C d S 2 (acyclic), C4,-,Hm (monocyclic), and C4&178 (bicyclic) and pointed towards a ‘head to head’ linkage of the diterpenes. Confirmation of structures (2)-(4) was afforded by molecular weight determination of the mixed ethers ( M = 1290), n.m.r. studies of the tetraether diacetates, and ‘H n.m.r. of the hydrocarbons, the Ca diols, and of and C32 diols derived by chain-shortening reactions. 12,13

The structure of the cyclic diglycerol di-(acyclic)-alkyl tetraether (2) was established independently. It was shown that glycerol and the CW terminal alkyl diols were present in equimolar proportion, the isolation of monoacetate and monomethoxy derivatives established the presence of two hydroxy groups while i.r. spectra indicated the presence of two carbinol bands; n.m.r. confirmed the presence of four ether linkages, two hydroxy groups, and two isoprenoid branched Ca hydrocarbon chains. Vapour phase osmometry and gel permeation 11 chromatography gave mol. wt. = 1300 as required for C8&117206. The structures (3), (4), and (5) were confirmed by 13C n.m.r. analysis which also established the trans stereochemistry of each cyclopentane ring. l4 Hydrocarbons corresponding t o ( S ) , the tetracyclic diol ( 6 ) , and the pentacyclic diol ( 7 ) were found t o be constituents of the ether lipids of the MT-4 strain of Caldariella and were components of the macrocyclic compounds (8). Cleavage of one of these ethers with BC13 gave a 1 : 2 : 1 mixture of glycerol,

13 14

M . de-Rosa, A. Gambacorta, and J . D. Bu’Lock, Phytochemistry, 1976, 1 5 , 143. M . de-Rosa, S. de-Rosa, and A. Gambacorta, Phytochemistry, 1977, 16, 1909.

Lipids

267

C40 dichloride, and a nonitol C g H 2 0 0 9 . The nonitol has [ a ]g-8.7’ (in H,O), and o n mass spectrometry gave a base peak at m/e 25 5 ( M t -OH).” Structure (2) constitutes a revision of the cyclic glycerol alkyl diether13 and the dialkyl glycerol diether16 structures proposed earlier. A glucosylated diphosphatidylglycerol was found to be a component of the polar lipids in Group B Streptococci. Following deacylation by alkaline hydrolysis degradative studies on the products indicated the structure 2’-0-aD-glucopyranosyl-l’,3’-bis-(1,2diacyl-sn-glycero-3-phospho)-glycerol(9). The

l5 16

17

M . de-Rosa, S. de-Kosa, A. Gambacorta, and J . L). Bu’Lock, J.C.S. Chem. Comm., 1977, 5 14. K. J. Mayberry-Carson, T. A. Langworthy, W. K. Mayberry, and P. F. Smith, Biochim. Biophys. A c t a , 1 9 7 4 , 3 6 0 , 2 17. W. Fischer, Biochim. Biophys. A c t a , 1977,487, 89. W. Fischer, Biochim. Biophys. A c t a , 1977, 487, 74.


268

fatty acid constituents mainly comprised hexadecanoic, hexadecenoic, octadecanoic, and octadecenoic distributed in non-random fashion with the saturated components preferentially in the l - p ~ s i t i o n . ' ~

4 CH,OH

I R%O,-CH

I

H,CO,C R4

HO

H,CO,CR' 0

I II H$-O-P-O-CH,-C I 0

Ho 0

I -CH2I H

H

RTO,-CH

8 0-P-0-CH,

I

I

0 H

(9 1

Other lipid components of B. Streptococci included: 1(3),2-diacyl-3( 1)-Oa-Dglucopyranosyl-sn-glycerol, 1( 3),2-diacyl-3( 1)O-[a-D-glucopyranosyl(1,2)-0a-D1'-sn-glycerol, lysylglucopyranosyl] -sn -glycerol, 1,2-diacyl-sn-glycero-3-phosphophospha tidylglycerol, and 1',3'-bis( 1,2diacyl-sn-glycero-3-phospho)-glycerol.17 The complex lipids present in three obligately anaerobic bacteria Butyrovibrio spp. were isolated on thin layers of silica gel and the resultant fractions were deacylated by alkaline hydrolysis. The water-soluble products of hydrolysis were separated either by paper chromatography or by paper ionophoresis. The three species contained only small proportions of N-containing lipids; all contained N-acyl phosphatidylethanolamine and a novel lipid which was probably a galactosylphosphorylethanolamine (plasmalogen). All contained phosphatidylglycerol as the butyryl ester. Two organisms contained glycerylphosphorylgalactosyldiacylglycerol. All three .contained monogalactosylfuranosyldiacylgljcerol. In all of the lipids examined the 'diglyceride' moiety mainly comprised alk- l'-enyl-a~yl-glycerol.~~ Enzymic degradation was used t o establish the structure of a novel lipid 1,2diacylan-glycero-D-4'-p hosphoryloxy-3'-hydroxybutyl-1-phosphonate (the phosphonate analogue of phosphatidylglycerophosphate) which was formed as a metabolic product when rac-3,4dihydroxybutyl-l-phosphonatewas added t o cells of E. coli strain 8 in c u 1 t ~ r e . l ~ Tahara and co-workers isolated, from Gluconobacter cerinus, two derivatives of Nu-3-hydroxypalmitoylornithine.The structures assigned are [ 10; X = OH, R=Me(CH2)5CH(CH2)CH(CH2)s]20 and [ 11 , X X = N H ( C H ~ ) ~ S R=Me(CH2I1 O~H, CHOH] .2 A fipoamino acid from Agrobacterium turnefaciens2 was tentatively

19

2o

22

N. G. Clarke, G. P. Hazlewood, a n d K. M. C. Dawson, Chem. Phys. Lipids, 1976, 17, 222. R. J . Tyhach, R. Engel, and B. E. T r o p p , J. Biol. Chem., 1976, 251, 6717. Y. Tahara, M. Kameda, Y. Yamada, and K. Kondo, Biochim. Biophys. A c t a , 1976, 450, 225. Y. Tahara, M . Kameda, Y. Yamada, and K. Kondo, Agric. Biol. Chem., 1976, 40, 2 4 3 . Y. Tahara, Y. Yamada, a n d K. Kondo, Agric. Biol. Chern., 1976,40, 1449.

Lipids

269

assigned the structure (1 2); hydrolysis gave the acid R C 0 2 H (lactobacillic, vaccenic, palmitic.

(CH2)4 CHJCH

I

CHCH,CONHCHCO,H 121

0

RCO (1 2)

A lipoamino acid from the mycelium of Actinomyces aureoverticillus was 3-L-acylo~y)-acyl-L-ornithine,~~ while reported t o have the constitution 2-N-( Actinomyces divaceus was found t o include phosphatidylbutane-2,3-diolas well as a phosphatidyl m a n n ~ s i d e . ~ ~ An acidic glycolipid from Mycobacterium paraffinium was characterized using high-resolution mass spectrometry, i.r. and ‘H n.m.r. spectrometry, and by degradation of its per-@methyl derivatives. The glycolipid was assigned structure 2 - 0 0 2 tanoyl-2’, 3 4i-Ode canoy 1-6-0s u ccinoy l a ,a-D-trehalo se .25

Fungal Lipids.-An examination was made of the long-chain bases of sphingomyelin from Entomorphthora coronata, a fungus pathogenic for humans; dinitrophenylation of the bases followed by periodate oxidation led t o the aldehydes comprising branched-chain comformation of twelve C14 -CI7 pounds as well as saturated and unsaturated components. The most abundant parent base was a 1,3-dihydro~y-2-aminohexadecene.~~ A polar lipid from the lower fungus Pythium profatum gave sphingosine and 2-aminoethylphosphonate on acid hydrolysis; t h e structure assigned was that of ceramide a m i n o e t h y l p h ~ s p h o n a t e .The ~ ~ complement of fatty acid comprised palmitic, oleic, linoleic, and an unidentified component. From gas --liquid chromatography and mass spectrometry, evidence has been presented that cerebroside isolated from Aspergillus oryzae (Japanese yellow mold) was mainly N-2’-hydroxystearoyl-1-O-glucosyl-methyl sphingadienine and h’-2’-hydroxy-trans-octadecenoyl-O-glucosylrnethyl sphingadienine; it is suggested that the bases had the is0 (branched) structure.28 23

24

25

26

27

S. G. Batrakov, N . N. Pridachina, E. B. Kruglyak, A. V. Martyakova, and L . I>. Bergelson, Bioorg. Khim., 1977, 3 , 9 2 0 . S. G. Batrakov, A . G. Panayosan, I. V . Konova, and L. D. Bergelson, 1zwest.Akud. Nuuk. S.S.S.R. Ser. Biol., 1 9 7 6 , 678. S. G. Batrakov, B. V. Rosynov, T. V. Koronelli, R . A. Kozhukhova, and L . 1). Bergelson, Bioorg. Khim., 1 9 7 7 , 3, 5 5 . C. de Bievre and F. Mariat, Biochim. Biophys. Acta, 1977, 486, 179. M. K. Wassef and J . W. Hendrix, Biochim. Biophys. Acta, 1 9 7 7 , 4 8 6 , 172. Y . Fujino and M. Ohnishi, Biochim. Biophys. Acta, 1977, 4 8 6 , 16 1.

*’

270


Pythium sylvaticum grown in a medium containing [ H] cholesterol yielded a metabolite which was isolated by chromatography on silica gel. Synthesis of chole st erol~-D-glucoside-6’-O-p alm it at e allowed comparison of spectra and allocation of structure (1 3) t o the metabolite. Similar structures were obtained when fl-sitosterol or campesterol were included in the culture medium.29

HO

HO

Marine Lipids.-Lipids extracted from the marine algae, P. canniculata, F. vesiculosus and F. serratus yielded fractions from column chromatography on silica gel/magnesium silicate treated with sodium borate, which o n subsequent thin-layer separation gave the pure sulphated aliphatic alcohols: triacontane1,l$-diol, triacontan-1-01, octadecane-l,6diol, and eicos-lOene-l,18di01.~ The products of hydrolytic and methanolytic degradation of a phosphonosphingoglycolipid from the viscera of Turbo cornutus included galactose, N-methylaminoethylphosphonic acid, hexadecanoate and 2-hydroxyhexadecanoate, and dienic dihydroxy long-chain bases. From this and other evidence the structure of the lipid was given as 1-0-[6’-O-(N-methylarninoethylphosphonyl)galactopyranosyl] ceramide ( 14).31 Included in the report are mass spectra of galact ose-N-met hylaminoethy lphosphonate and gly cerol-N-methylaminoe thy1 p hosp honate .31 Among the bases identified from sphingolipids from the fresh-water bivalve C. sandai were the hexadeca-, heptadeca-, iso-octadeca-, octadeca-, and anteisononadeca-4-sphingenines; apparently neither the is0 nor the anteiso compound has been previously reported in shellfish.32 3 Chemical Synthesis

Glycerol Esters.-New procedures for synthesizing racemic 1,3diacylglycerols (and therefore triacylglycerols) take advantage of the isomerization of 1,2- t o 29 30 31

32

T. C . McMorris and R. H. White, Biochim. Biophys. Acra, 1977, 4 8 6 , 308. P. Q. Liem and M.-H. Laur, Biochimie, 1976, 58, 1 3 8 1 . E‘. Matsuura, Chem. Phys. Lipids, 1 9 7 7 , 19, 2 2 3 ; A. Hayashi, F. Matsuura, and T. Matsubara, Yukaguku, 1976, 25, 5 0 1 . M. Sugita, 0. Itasaka, and T. Hori, Chem. Phys. Lipids, 1976, 16, 1.

Lipids

27 1

H

0

ll

O-CH2-CH-CH-R2

I

NH

OH

I

I

OH

CO

I

R'

1,3-diacylglycerols in the solid state at elevated temperature^.^^ In Scheme 1 glycerol esters ( 16) and (1 7), prepared from epichlorhydrin ( 15) and fatty acid sodium salt in the presence of tetraethylammonium bromide, were heated with the catalyst and with one another or with the same fatty acid at 100°C. The product was a mixture of the 1,3-isomer and the 1,2-isomer in varying proportions; isomerization 5-lOoC below the melting point for 3-10 days gave pure 1,3-diglyceride (18) and (19) in 70-75% overall yield. Acylation of 1,3-diglyceride gave (20). The products in Scheme 1 were characterized by i.r. spectroscopy, X-ray, differential thermal, g.l.c., t .l.c. and lipase analysis and included the novel compounds 2-heptadecanoyl- 1,3-dipentadecanoylglycerol (m.p. 66OC); 2(trans-9-hexadecenoy1)-1,3-dipalmitoylglycerol (m.p. 54 "C); 2-elaidoyl-3-oleoyl1-palmitoylglycerol (m.p. 26 "C); 3-elaidoyl-2-oleoyl-1 -palmitoylglycerol (m.p.

R'C0,Na)

p

0,CR2

-

RTO,HbHo{

-0,CR'

CH,O,CR'

0,CR' (1 8)

(16)

-O,CR~ -0,CR2 (20)

R'C0,Na

CH202CRZ (19)

(17)

Scheme 1 33

A. P. J. Mank, J . P. Ward, and D. A. van Dorp, Chem. Phys. Lipids, 1976, 16, 107.


272

22-23 "C), 3-eicosenoyl-2-oleoyl-1-stearoylglycero1(m.p. 41 -42 "C), and 2-(cis- 13-docosenoy1)-1,3-distearoyl glycerol (m.p. 47 "C). Chiral acyl glycerols were preparedM by stereospecific transformation of L-serine via L-glyceric acid and 2,3-O-isopropylidene-sn-glycerol which was obtained in 45% yield. Treatment of the latter compound with triphenylphosphine in tetrachloroethane gave 2,2dimethyl-4-chloromethyl- 1,3-dioxolane (2 1) in 85% yield. Hydrolysis of ( 2 1) and subsequent dehydrohalogenation gave (-)-D-glycidol (22) [ a ] - 14.3' (neat). Acylation of (22) gave (-)-D-glycidol ester; thereafter the route is as in Scheme 1, yielding the following opticallym.p. 49 'C; 3-propionylactive triacylglycerols: 3-acetyl-l,2distearoyl-sn-glycerol 1,2-distearoyl-sn-glycerol m.p. 48'C; 3-butyryl-l,2-distearoyl-sn-glycerol m.p. 4 9 'C;

h2

CH,C1

I

I

CH,OH

3-palmitoyl-1,2-distearoyl-sn-glycerolm.p, 6 1 "C; 2,3-dipalmitoyl-l-stearoyl-snglycerol m.p. 58 'C; 1-oleoyl-2,3-dipalmitoyl-sn-glycerol m.p. 37 'C; 2,3diacetyl-1stear0y 1-sn-glycerol m .p . 47 'C ; 2-b ut y ry l-3-palmitoy 1- 1-stear0y 1-sn-glycerol m.p. 49 'C; 3-butyryl-2-palmitoyl-1-stearoyl-sn-glycerol m.p. 49 'C. Optical purity of the triacylglycerols and their precursors was determined by 'H .n.m.r. using chiral shift reagents. Intermediates affording protection at the 2-hydroxy group of glycerol such as 2-O-dimethyl-butylsilylglycerol and 2-0-(2',2',2'-trichloroethoxycarbinol)-glycerol were prepared for the synthesis of glycerolipids and of ~ardiolipin.~'The protecting group was readily removed by acid hydrolysis in cardiolipin synthesis.36

Glycosidic Lipids.-In relation to studies of the lipid components of membranes of Streptococci 3-O-ja-D-glucopyranosy1)- 1,2di-O-stearoyl-L-glycerol (23; R = C17H35 ) was ~ y n t h e s i z e d .2-O-Allyl-3,4-di-O-benzyl-l,6di-O-p-nitro~~ benzoyl-D-glucopyranosylchloride (25 ; R' = O C O C & N O 2 - p ; R2 = Cl)38 derived from (24; R' = R2 = OCOC&4N02-p)39 was condensed with 1,2dic)(but-2-enyl)-sn-glycerol to give (26; R' = 0COC&4N02-p), R2 = CH2CHCH2, R3 = CH2CHCHMe). The pure a-epimer (26) was obtained by recrystallization. A series of transformations involving the blocking groups of (26) afforded the 34

35

36

3a

39

C. M . Lok, J . P. Ward, and D. A. van Dorp, Chem. Phys. Lipids, 1976, 16, 1 1 5 . G. H . Dodd, B. T. Golding, and P. V. Ioannou, J.C.S. Perkin I, 1976, 2273. F. Ramirez, P. V. Ioannou, J . F. Maracek, G. H. Dodd, and T. Golding, Tetrahedron, 1977, 33, 599. R. Gigg, A. A. E. Penglis, and R . Conant, J.C.S. Perkin I , 1977, 2014; P. A. Gent, R. Gigg, and A. A. E. Penglis, J.C.S. Perkin I, 1976, 1'395. P. A. Gent and R. Gigg, Chem. Phys. Lipids, 1976, 17, 1 1 1 . P. A. Gent and R. Gigg, Carbohydrate R e x , 1 9 7 6 , 4 9 , 325.

273

Lipids

derivative 3-0-( 2,3,4,6-tetra-0-benzyl-a-D-glucopyranosy1)- 1,2-0-isop ropylid enesn-glycerol (27). Acid hydrolysis, acylation with octadecanoyl chloride, and hydrogenolysis gave (23).37

CH20H

CH2R1

HOQ/H[-02cR

phcHzo@R2

OH

CH20,CR

(23)

OCH,CH=CH,

(24) R' = R2 = OCOC,H,NO,-p (25) R' = OCOC,H,N02-~, R2 = C1

The compound (23) was available by an alternative route. 1,6-Anhydro2,3,4-tri-O-benzyl-&D-glucopyranose (28; R = CH2Ph) treated with acetylchloride gave 6-0-acetyl-2,3,4-tri-O-benzyl-D-glucopyranosyl chloride (29; R = CH2 Ph), which condensed with 1,2di-O-(but-2-enyl)-L-glycerolto give (30; R1 = Ac, R2 = CH2CHCHMe). Removal of the but-2-enyl group and subsequent acylation followed by deblocking afforded (23). CH20R2 R~O+H

CH2-0

OR (28)

(29)

OCH2Ph (30)

The usefulness of the compound 3-0-(2,3,4-tri-O-benzyl+~-D-glucopyranosyl)1,2-di-~-stearoyl-L-glycerolas an intermediate for the synthesis of three other naturally -occurring com ple x lip ids is mentioned .36 A series of monoglycosyl derivatives was prepared by glycosylation of dibenzylglycerol using 2,3,4,6-tetra-O-acetyl derivatives of ID-glucopyranosyl bromide , D-galactopyranosyl bromide, and D-mannopyranosyl bromide. Acylation with tetradecanoyl, hexadecanoyl, octadecanoyl, or octadec-6-enoyl

274


chlorides in the presence of base, and de-acetylation with hydrazine solution yielded 3-UCMe,

ro CH,OPOCH,CHCO,E t

I

x ( 5 5 ) X = NEt,, Y = : (56) X = OCH,Ph, Y = : (57) X = OCH,Ph, Y = 0

r

r"')->CMe,

CH,OP /NEtz R'

&1 HO

CH,O,CR

I

TH0,CR

0-P-OCH,

I

0 H (59)

Preparation of compounds related to phosphatidylserine were described; these are non-isosteric L-serine-rac-2,3-di(hexadecyloxy)propyl-phosphonateand its die st er analogue di( he xade can0y lo xy )propyl-p hosphonat e and isost eric L-serine-rac-3,4-di(hexadecyloxy)butyl-phosphonate and the corresponding di(hexadecanoyloxy) compound ." 1-O-(Hexadec-1-enyl)-2-octadecanoylan-glycerolwas used as starting material in a synthesis of phosphatidial ~ e r i n e . ~ ~ Phosphatidyl 1nositols.-Phosphatidyl muco-inositol (5 9) was prepared in 50% yield by treatment of rac- 1-0-acetyl-2,3: 5,6-di-isopropylidene muco-inositol with phosphorus oxychloride prior to condensation with rac-l,2-distearoyl-glycerol and removal of the protecting groups.80 Oxidation of myo-inositol with chromium trioxide and reduction of the product with sodium borohydride gave the scyllo-isomer, which on treatment with 1,2-distearoylglycerophosphate and removal of protecting groups gave phosphat idyl-scy ZZo -inosit 01.81

78

79

8o

''

I. L. Doerr, J.-C. Tang, A. R. Rosenthal, R. Engel, and B. E. Tropp, Chern. Phys. Lipids, 1977, 19, 185. I. A. Vasilenko, I. A. Lobenova, G. A. Serebrennikova, and R. P. Evstigneeva, Bioorg. Khim., 1976, 2, 1138. V. P. Shevchenko, T. Yu. Lazurkina, Yu. G. Molotkovskii, and L. D. Bergel'son, Bioorg. Khim., 1976, 2 , 923. V. P. Shevchenko, T. Yu. Lazurkina, Yu. G. Molotkovskii, and L. D. Bergel'son, Bioorg. Khim., 1977, 3, 252.

283

Lipids

In studies of derivatives of asymmetrically-substituted myo-inositol the synthesis is described of 1-0’4 1U-palmitoyl-2-O-oleoyl-3-glycero-phosphoryl)-myoinositol-4-phosphate (60; R’ = C15H31, R2 = C17H33) and of 1U‘-( 1,2di-Opalmitoyl-sn -glycero -3-0-phosphoryl)-2-O’-u-D-mannopyranolsyl-sn-rnyo -inositol (61; R = C15H31).g2

CH,OCR

1 II 1 .P- OCH, 1 0-

CH,OCR’

0 OHOH

)I

0

I CH02CR2 I

CH0,CR

0OH

HO

A series of intermediates in the synthesis of a-linked D-glucopyranosyl- and D-galactopyranosyl-diacylglycerols were prepared.83 Treatment of benzyl citronellyl hydrogen phosphate with 1,2-isopropylidene3,4,6-tri-O-acetyl-glucopyranoseand subsequent hydrolysis yielded 0-D-glycopyranosyl-1-citronellyl phosphate.M The lY2-orthoester of a-D-glucopyranoside tetra-acetate treated with the barium salt of 1,3-di-O-acetylglycero-3di-O-benzylphosphite followed by removal of the benzyl blocking groups with sodium iodide gave, after hydrolysis, the intermediate compound P-D-glucopyranosyl-1 -glycerophosphate in 80% yie Id. 85 The chemical synthesis of glycerophosphatide analogues containing steroid groups has been described; these are 1,2-dipalmitoyl-rac-gllyceryl-3-phosphoryl3’0-cholesterol and 1,2-dipalmitoyl-rac-glyceryl-3-phosphoryl-20’~ 3'0-hy droxy norpregn-s-ene). 86 Phosphatidylglycerol and Analogues.-A versatile approach to the synthesis of phosphorus mono-, di- and tri-ester structures has been based on the reactions of gly c e r ~ a m i d o p h o s p h i t e s . ~ ~ 82

83 84

85

86

87

A. E. Stepanov, V . I . Shvets, and K. P. Evstigneeva, Zhur. obshchei Khim., 1977, 4 7 , 165 3. A. P. Kaplun, V. I. Shvets, and K. P. Evstigneeva, Bioorg. Khim., 1977, 3 , 2 2 2 . L. L. Danilov, L. V. Volkova, and R. P. Evstigneeva, Zhur. obshchei Khim., 1977, 4 7 , 2137. I. A. Vasilenko, I. A. Lobanova, G. A. Serebrennikova, and R. P. Evstigneeva, Bioorg. Khim., 1976, 2 , 1138. T. Muramatsu, I. Hara, and M . Hayashi, Chem. Phys. Lipids, 1977, 2 0 , 131; F. Kamirez, P.V. Ioannou, and J . F. Maracek, Synthesis. 1977, 673. D. A. Predvoditelev, T. G. Chukbar, and E. E. Nifant’ev, Zhur. obshchei Khim., 1976, 4 6 , 291; E. E. Nifant’ev, D. A. Predvoditelev, and V. A. Shin, Zhur. obshchei Khim., 1976,46,2369.

284


Glyceroamidophosphites have been used to obtain bis(&-phosphatidic acid) and bis(0-phosphatidic acid). The &-isomer was prepared by two routes? one involving NO oxidation of (RO)2POCH2PIi where R = isopropylidene glycerol; the other route was via the acid phosphite ( R 0 ) 2 P ( 0 ) H with PhCH20H in CCI4 containing E t a . The fl-isomer preparation followed from the phosphorylation of 173-benzylidene glycerol by tris-(diethy1amino)phosphine. Hydrolysis of the resulting bis-( 1,3-benzylidene glycero1)amidophosphite with acetic acid gave the acid phosphite and this was converted into the benzyl phosphate triester derivative. Deprotection of the glycerol and subsequent acylation (by octadecanoyl chloride) followed by hydrogenolysis of the benzyl group produced the bisphosphatidic acid isomer.88 A synthesis of cardiolipin has been described.36 (172-Dimethyl ethylene)pyrophosphate ( 6 2 ) in the presence of triethylamine phosphorylated 1,2diacylsn-glycerol with retention of the enediol ring t o give (63); further addition of 2-0-dimethyl-t-butyl silyl glycerol gave (64; X = CH(Me)COMe, Y = U-Si(Me)2 B u t ) . The acetoinyl, but not the acyl groups, were removed from (64) by hydrolysis in water/triethylamine. Removal of the silyl group by acid hydrolysis and subsequent treatment with ammonia yielded the dianimonium salt of cardiolipin (65; X = NH4+, Y = O H ) ; the product was purified on DEAEcellulose in acid media. Overall yields of cardiolipins were, myristoyl, 25%; palmitoyl, 23%; stearoyl, 29%. Synthesis was achieved with conservation of stereochemistry with no isomerization and virtually no hydrolysis of acyl esters.” As part of a study of the chemical and physical proflerties of phytanyl ethers the synthesis is described of 3-0-phytanyl-sn-glycero-1 -phosphoryl- 1I-sn-glycerol [(mono K+ salt [ a ] + 4.1” ( c 2.9 in CHC13)] ;the i.r. spectrum was reported.” Application of an unsymmetrical monofunctional phosphorylating reagent to the synthesis of phosphatidylglycerol was described.72 Condensation of 2,2,5,5-tetrarnethylpyrroline-N-oxide-3-carbonyl chloride with cardiolipin yielded spin-labelled diphosphatidyl glycerol 2-(2’,2‘,5’,5’-tetrame thylp yrroline -IV-oxide)carb o xy lat e .9o The identity of a naturally-occurring ceramide-1 deoxy-1-sulphonic acid was confirmed by synthesis. CISH31CH(OCH2Ph)CH(NHCOC17H35)CH20H treated with P2S5 in xylene gave the thiazoline derivative which at pH 3.5 cleaved t o the thiol. The latter was oxidized by H 2 0 2 in acetic acid to the sulphonic acid, which, after methylation with diazomethane, was debenzylated with sodium methoxide in methanol. The racemic product was finally obtained .91 in the preparation of cerebroside analogues DL-threo-3-phenylserine was esterified to the ethyl ester hydrochloride, N-acylated, reduced with sodium

89

90 91

D. A. Predvoditelev, T C. Chukbar, and E. E. Nifant’ev, Bioorg, Khim., 1977,3 , 76. F. Kamirez, N. Nowakowski, and J . 1;. Maracek, J. Amer. Chem. SOC., 1977,99, 4515; F. Karnirez, J. F. Maracek, and H . Okazaki, J. Amer. Chem. Soc., 1976, 98, 5310; F. Kamirez, P. V. Ioannou, J . F. Maracek, B. T. Golding, and G. H. Dodd, Synthesis, 1976, 769; 1;. Kamirez, H . Okazaki, J . F. Maracek, and H. ‘I‘suboi, Synthesis, 1976,819. C. Landriscinon, F. M. Megli, and E. Quagliariella, Analyt. Biochem., 1976, 7 6 , 292. N. N. Karpyshev, A. S . Bushnev, E. N. Zvonkova, and K. P. Evstigneeva, Bioorg. Khim., 1977, 3, 1374.

Lipids

285

yL
PO2-; groups, the >C=O group and the choline group when modulated-excitation i.r. spectroscopy and total reflection i.r. spectroscopy were applied to multilayers of the phospholipid in a relative humidity of 75% at 30°C."9 Hydration of the headgroup of dipalmitoylglycerophosphorylcholine was measured by proton n.m.r. and 31 Prelaxation time. Experimental findings confirmed predictions from quantum mechanics calculations t o the effect that stepwise hydration of the headgroup occurs in the order phosphate followed by trimethylammonium group, and leads to about eight molecules H 2 0 bound t o phosphate and another ten molecules H 2 0 more tenuously associated with the trimethylammonium group.'** Quantum chemical calculations of water binding to the dimethylphosphate anion are reported.12' Solubility measurements were made of the Na+ and Ca2+salts and of the free acid forms of phosphorylcholine, phosphorylethanolamine, and DL-phosphoserine. 22 Capacitance measurements of thin films of diacylglycerophosphorylcholines were made under differing conditions of hydration of the lipid layer and over a range of temperatures, which included the transition temperature^.'^^ 115

M . Ozaki, I. Hara, and T. F. Fujiyama, Chem. Phys. Lipids, 1976, 17, 2 8 . G. Klose and G. Hempel, Chem. Phys. Lipids, 1977, 18,274. Y. Koyama, S. Tode, and Y . Kyogoku, Chem. Phys. Lipids, 1977, 19, 74. 11* G. L. Jendrasiak and J . C. Mendible, Biochim. Biophys. Acta, 1976,424, 133 and 149. U . P. E'ringeli and H. H. Giinthard, Biochim. Biophys. Acta, 1976,450, 101. G . Peinel, W. Gruender, G. Kabisch, and K. Arnold, Stud. Biophys., 59, 37. H. Frischleder, S. Gleichmann, and K. Krahl, Chem. Phys. Lipids, 1977, 19, 144. l Z 2 G . Schumacher and H. Sandermann, jun., Biochim. Biophys. Acta, 1976,448,642. 123 W. L. Procarione and J. W. Kauffman, Chem. Phys. Lipids, 1977, 18, 49. '16

'''

291

Lipids

Ultrasonic velocity, adiabatic compressibility, and acoustic impedence of lipids were measured using quantities of material in the range 4 x to 4x cm3 .124 5 Aspects of Lipid Chemistry

Autoxidation Studies.-In a study of autoxidation of alkoxylipids the influence of the type and position of functional groups in the kinetics of peroxide formation was examined using model compounds. These comprised 1-0-alkylglycerol, 2-0-alkylglycerol, 1,2-0-dialkylglycerol, 1,3-Odialkylglycerol, the corresponding fully acylated analogues, 1,2,3-0-trialkylglycerol,triacylgly cerol, propyl alkyl ether, isopropyl alkyl ether, propyl ester, and isopropyl ester. Ether compounds were oxidized more rapidly than ether-esters and esters. The presence of hydroxy-groups enhanced the rate of autoxidation in 1-0-alkylglycerol; autoxidation of 2-0-alkylglycerol was lower than the corresponding bisdeoxy compound (i.e. an isopropyl-alkyl ether) presumably because negative inductive effects of the vicinal hydroxy-groups lead t o a decrease in electron density of the C-H bond at C-2. The kinetics of autoxidation of ethers was in accordance with a radical chain process.'25 An autoxidation study involving tritetradecyl glyceryl ether, trimyristoyl glycerol, and coconut oil was reported.'26 Autoxidation of methyl linoleate in the presence of a-tocopherol and tetrabutyl ammonium hydroxide for 2 h at 95 "C in air led to the formation of three ether compounds all of which contained tocopherol and methyl octadecadienoate in l : l ratio, and from which unchanged tocopherol could be regenerated by acid hydrolysis.'2' Hydrolysis of Sphingo1ipids.-Use of HF as a reagent for the cleavage of phosphodiester linkages has been extended t o hydrolysis of sphingomyelin t o ceramide. The yield of ceramide was about 95% when sphingomyelin was treated with 40% HF at 4OoC for 72 h; the treatment neither altered the fatty acid composition nor the stereochemical configuration of the sphingosine moiety of ceramide formed.128 3-Ketosphingolipids derived from cerebroside and sphingomyelin were converted by treatment with 0.0005M-Na2C03 in chloroform-methanol (2 : 1 , v/v) t o 2-acylamido-3-keto-14-octadecadienes as judged by several spectroscopic procedures. The reaction which can be used to obtain oligosaccharides, phosphorylcholine, and other hydrophilic moieties from sphingolipids, is considered to effect cleavage of 3-ketocerebrosides and 3-ketosphingomyelins by way of o-e~imination.'~~ lZ4

126

127

128

U . Varanasi, R . E. Apfel, and D. C. Malins, Chem. Phys. Lipids, 1977, 19, 179. N. Yanishlieva and H. K. Mangold, Chem. Phys. Lipids, 1977, 2 0 , 2 1 ; N. Yanishlieva, H. Becker, and H . K. Mangold, Chem. Phys. Lipids, 1977, 18, 149; N . Yanishlieva, H . Becker, and H . K. Mangold, Chem. Phys. Lipids, 1976, 17, 393. V. Mueller, Fette, Seifen, Amstrichm., 1976, 78, 4 1 2 . G. K. Koch, R. K. W. Han, J . J . L. Hoogenbrom, M. Mutter, and H. Tilborg, Chem. Phys. Lipids, 1976, 17, 8 5 . P. V . Reddy, V. Natarajan, and P. S. Sastry, Chem. Phys. Lipids, 1976, 17, 373. M. Iwamori and Y . Nagai, Chem. Phys. Lipids, 1 9 7 7 , 2 0 , 193.

292

A 1ip ha tic and R e la te d Nu tu ra l Pro du c t Ch e m ist ry

Sphingomyelinase activity was assayed by liberation of N-acylaminonitrophenol from 2-N-hexadecanoylamino-4-nitrophenylphospho~lcholine hydroxide. '30 Analysis of Long-chain Diols and Related Compounds.- -Resolution of DLhexadecane-l,2-diol and DL-octadecane-l,3-diol into their respective enantiomers was accomplished when their bis-L-acetylrnandelate esters were subjected t o chromatography on thin layers of silicic acid. In this manner, lY2-alkanediols prepared from diester waxes of rat skin were assigned the D-configuration as were the 2-hydroxy acids from the same s o ~ r c e . ' ~High ' resolution n.m.r. was employed in identification of naturally-occurring diesters of 1,2- and 2,3-alkanediols and for discriminating between the erythro- and threo-forms of the latter group of corn pound^.'^^ The preparation and some chemical and physical properties of a number of long-chain aliphatic diketones was r e ~ 0 r t e d . l ~ ~ Chemical Approach to Lipid-Protein Interactions.-l8-Azido[ 9,10,12,1 3-3H41linoleic acid was incorporated into phosphatidylcholine and sphingomyelin and these were recombined with apolipoprotein A-I of human serum high density lipoprotein. Irradiation of the lipoprotein led to the formation of nitrenes; the resulting lipoprotein preparation appeared as a single radioactive band on gel electrophoresis and contained fatty acid residues covalently linked t o polypeptide chains.lM The considerable assistance given by Mr. C . R. A. Earl and Mrs D. Maxwell is gratefully acknowledged.

130 13' 13* 133 134

A. E. Gal and F. J . Fash, Chem. Phys. Lipids, 1976, 16, 71. P. C. Bandi and H . H . 0. Schmid, Chem. Phys. Lipids, 1976, 17, 267. M . K. Logani, D. B. Nhari, and R. E. Davies, Chem. Phys. Lipids, 1976, 16, 8 0 . D. E. Douglas and L . E. Francis, Lipids, 1 9 7 7 , 1 2 , 6 3 5 . W. Stoffel, W. Darr, and K-P. Salm, Hoppe-Seyler's Z . Physiol. Chem., 1977, 3 5 8 , 1 , 4 5 3 .

Author Index

Aarsman, A. J., 279 Abatjoglou, A. G., 221, 222 Abdel-Halim, M. S., 232 Abe, K., 116 Abraham, N. A., 192 Abraham, S., 262 Abraham, W. R., 7 Abrahamsson, S., 248 Abramovitch, A., 1 1 9 Achenbach, H., 144 Achiwa, K., 87, 95 Achunova, W. R. 70 Ackman, R. G., 236, 237, 255 Adam, W., 222 Adams, R. P., 81 Adamson, A. W.,252 Addae-Mensah, I., 17, 237 Adinolfi, M.,45 Adlof, R. O., 255 Agulld , C,, 239 Ahmad, E., 238 Ahmad, F., 254 Ahmad, I., 238 Ahmed, M., 1 3 Ahrens, E. H., jun., 97 Aihara, Y., 106 Aizawa, Y., 226 Aizenshtat, Z., 198 Akahori, Y., 233 Akasaka, K., 149 Akashi, K., 254 Akiyama, S., 1 4 3 Akiyama, T., 163 Akutagawa, S., 68, 7 7 Alam, M., 60 AIaniz, M. J. T., 259 Alarkon, K. K., 278 Alberino, S. P., 225 Albert, D. H., 259 Albi, M., 255 Alder, V. E., 103 Aldrich, C. D., 165 Allen, M. S., 40, 137 Alster, K., 244 Ameel, J. J., 167 Amico, V., 4 7 , 4 8 , 50,52 Anchel, M., 12, 144 Andersen, A. B., 9 Andersen, N. H., 174 Anderson, L., 261

Anderson, M. E., 103 Anderson, R. J., 124 Anderson, W. H., 259 Andrewes, A. G., 145 Andrews, D. A., 84 Aneshansley, D. J., 114 h g g i r d , E., 232 Ansari, A. A., 237, 254 Ansell, J. M., 13, 118, 125 Antosz, F. J., 166 Aoki, K., 178 Apfel, R. E., 249, 291 Apon, J. M. B., 237 Aquiar, J. M., 42 Araki, E., 247 Arbuzov, Y. A., 69 Argyle, J. C., 7 3 Ariga, T., 247 Arison, B. H., 131 Arn, H., 103, 116 Arndt, H. C., 213 Arnd, A., 242 Arnold, K., 290 Asai, M., 143 Ashes, J. R., 246 Asselineau, C. P., 261 Astin, K. B., 9 1 Atal, C. K., 17 Aul'chenko, I. S., 8 4 Au-Yeung, B. -W.,174 Axelrod, B., 251 Axen, U., 183,217, 234 Ayer, W. A., 114 Baba, S., 119, 257 Babich, S. A., 68 Babler, J. H., 121 Baczynskyj, L., 2 1 9 Badar, Y., 137 Baer, E., 278 Baer, T. A., 241 Baggiolini, M., 103 Bagli, J. F., 192 Bailey, A. V., 248 Bailey, J. M., 231 Bailey, W. J., 157 Baillie, T. A., 225 Baker, A. D., 75 Baker, F. C., 261 Baker, J. T., 20, 49, 58 Baker, R., 77, 102, 114, 116,256

293

Baker, R. C., 259 Baker, T. C., 103, 106 Bakuzis, M. L. F., 19 1 Bakuzis, P., 191 Ballantine, J. A., 61 Ban, Y., 149 Bandi, P. C., 292 Bandoni, R. J., 15 Banis, R. J., 258 Banno, K., 126 Banthorpe, D. V., 77 Barak, A. V., 110 Baraldi, P. G., 194 Baran, J. S., 94, 277 Barber, E. D., 261 Barbier, M., 47 Barcelos, F., 200 Barco, A,, 194 Bari, S. S., 84, 93, 9 7 Baridty, J., 235 Barlow, L., 8 6 Barnert, J. T., jun., 259 Barnette, W. E., 183, 185, 186 Barr, P. A., 254, 255, 2 58 Barreiro, E., 170, 194 Bartlett, P. A., 171 Bartley, D. A., 246 Bartmann, W., 193, 197 Bartolotto, M., 61 Barton, D. H. R., 99, 145 Barton, J., 184 Barve, J. A., 248, 261 Bates, G. S., 148 Batrakov, S. G., 269, 274, 286 Battersby, A. R., 97 Baudouy, R., 161 Baxter, I., 17, 237 Bazzan, N. G., 262 Beard, B., 115 Beare-Rogers, J. A,, 262 Beck, G., 193, 197 Beck, T. G., 148 Becker, A. M., 137 Becker, H., 2S3, 291 Beddell, C. R., 233 Bedford, C. T., 3 Bedoukian, R. H., 82 Beechan, C. M., 4 3 Begley, M. J., 115, 134 Behr, D., 92 '

Author Index

294 Bell, A. A., 115 Bell, W. J., 125 Benetti, S., 194 Benjamin, D. M., 1 15 Benn, M., 245 Benn, M. H., 114 Bennett, G. B., 2 0 1 Bennett, M. J., 114 Beno, M. A., 162 Benson, A. A., 277 Beppu, K., 70 Bergelson, L. D., 265, 269, 275, 282

BergstrClm, S., 226 Bernady, K. F., 193 Bernhard, K., 65 Bernhardt, J. C., 241 Bernstein, H. J., 248 Berreur-Bonnenfant, J., 47

Bestmann, H. J., 108, 117, 119

Beuving, D. C., 235 Bhattacharjee, D., 3 Bicking, J. B., 222, 223 Biddlesom, W. G., 2 13 Bienkowski, M. J., 229 Bierl, B. A., 114 Biermacher, J. J., 224 Bild, G. S., 251 Billings, R. F., 1 11 Billmann, W., 1 19 Binder, R. G., 15 Bindra, J. S., 170 Bindra, R., 170 Birch, A. J., 77 Birch, E. J., 237 Birch, M. C., 1 11 Birnbaum, J. E., 139,213 Bishop, D. G., 247 Bittman, R., 279 Blackman, A. J., 48 Blair, B., 128 Blair, E., 250 Blake, W., 4 0 Blank, M. L., 286 Blasio, B. D., 44 Blight, M. M., 111 Bloch, K., 258 Bloch, P., 136 Bloomer, J. L., 133 Blum, M. S., 112, 1 13, 114,239

Boar, R. B., 99 Bocker, H., 152 Body, D. R., 236 Boeckman, R. K., jun., 141,242

Boelhouwer, C., 256 Boerth, R., 234 Bohannon, M. B., 248 Bohlmann, F., 2, 4, 5, 6, 7, 9, 10, 13, 84, 9 7

Bohn, E., 212 Boland, W., 24

Boldingh, J., 251, 253, 262

Boll, P. M., 130, 133 Bollinger, P., 136 Bonafide, J. D., 17, 239 Bond, L. W., 259 Boon, J. I., 247 Boot, J. R., 225, 228, 2 30

Boppre, M., 108 Borch, G., 65 Borgeat, P., 252 Bornatsch, W., 2 13 Borowski, E., 155, 156 Boscher, J., 115 Botteghi, C., 257 Boullier, P. A., 77 Bouman, A. A., 253 Bowden, B. F., 53 Bowen, L., 144 Bowers,W. S., 111, 112 Boyd, J., 7 2 Bradley, D. G., 198 Bradshaw, J. W. S., 1 1 6 Braekman, J. C., 46, 47, 61, 102, 112, 114

Brain, F. H., 279 Braksmayer, D., 278 Brambell, M. R., 260 Brambilla, R., 155 Branchaud, B., 198 Brand, J. M., 112 Brandsma, L., 255 Brash, A. R., 225 Bregvadze, U. D., 85 Breitenstein, W., 158 Brems, D. N., 9 0 Brenner, R. R., 259, 260, 262

Brettle, R., 164 Bright, W., 158 Brittle, J. A., 53 Brody, E. P., 9 6 Bronson, G. E., 234 Brooks, C. J. W., 234, 2 87

Brown, A. G., 147 Brown, C. A., 255 Brown, C. H., 195 Brown, J. M., 9 8 Brown, W. V., 1 1 1 Browne, L. E., 111 Browne, L. M., 114 Bruggemann-Rotgans, 1. E. M., 113 Bruhn, M. S., 195 Brunelle, D. J., 148, 149, 24 5

Bryan, R. F., 158 Bryant, R. W., 231 Buch, D., 260 Buchecker, R., 65 Buckler, R. T., 2 10 Buehring, M., 1 12 Buendia, J., 192

Bu’Lock, J. D., 265, 266, 267

Bundy, G. L., 29, 195, 224

Bunting, S., 229, 230, 231, 232

Buren, W. F., 114 Burgstahler, A. W., 125 Burke, B. A., 6 1 Burke, G., 229 Burke, S. D., 207 Burkhatdt, T., 2 Burkholder, W. E., 110, 116

Burreson, B. J., 22 Burton, T. S., 190 Bus, J., 247, 289 Bushnev, A. S., 284 Butler, S. S., 2 3 4 Buytenhek, M., 228 Bycroft, B. W., 169 Bygdeman, M., 226 Byler, R. C., 110, 1 16 Byrne, K., 116 Caccamese, S., 43 Cafieri, F., 56, 57 Calas, R., 7 1 Calderon, N., 256 Callaghan, P. T., 288 Callipotitis, A., 7 7 Cammaerts-Tricot, M.C., 112

Campbell, D. C., 40, 62 Carde, A. M., 106, 127 Carde, R. T., 102, 103, 106, 127

Cardillo, G., 84 Carhart, R. E., 7 0 Carlson, E. C., 1 15 Carlson, R. M. K., 58, 59

Carlsson, D. J., 250 Carman, F. R., jun., 232 Carney, R. L., 241 Carpenter, M. P., 229 Carpio, H., 2 14 Carpita, A., 127, 256 Carr, K., 234 Carrara, M. C., 225 Cassidy, R. F., jun., 110, 116

Caton, M. P. L., 190 Cavill, G. W. K., 114 Ceder, O., 155 Cernigliaro, G. J., 124 Ceserani, R., 216 Cha, D. Y., 176, 254 Chain, Sir E. B., 128, 238

Chakravarti, D., 239 Chakravarti, R. N., 239 Chamberlain, J. W., 169 Chan, B. G., 115 Chan, G . F. Q., 15

Author Index Chan, H. W. S., 249, 250, 251 , 2 5 3 Chan, M. F., 2 3 7 Chan, T. H., 1 1 7 , 2 6 2 Chan. W. IL,1 4 8 , 1 5 3 Chang, C., 1 4 0 Chang, W. C., 2 3 0 Chapya, A., 11 5 Charmillot, P. J., 1 0 3 Chaudhury, M. F. B., 1 1 4 Chebyshev, A. V., 274, 280 Cheer, C. J., 4 6 Chen, C. -W., 1 6 5 Chen, J. C., 2 4 3 Chen, M. J. Y., 254 Chen, R. H. K., 2 6 1 Chen, S., 1 6 9 Chen, S. L., 254 Chiang, C. C., 1 6 2 Chiang, J., 1 9 9 Cho, M. J., 2 2 4 Chong, A. O., 8 8 Chopra, A. K., 1 3 7 Christensen, P., 2 3 5 Christian, S. T., 2 8 0 Christie, W. H., 286 Christie, W. W., 261 Chukbar, T. C., 283, 2 8 4 Ciereszko, L. S., 40, 50 Cimino, G., 10, 21, 27, 56 Cirillo, V. J., 2 3 3 Clague, A. D. H., 5 8 Clancey, C. J., 235 Clardy, J., 31, 4 1 , 4 3 , 4 9 , 51, 52, 5 3 , 5 5 , 60, 114, 163 Clare, R. A., 225 Clark, B. C., jun., 80 Clark, S. J., 2 6 3 Clarke, N. G., 2 6 8 Clearwater, J. R., 1 0 9 Clifford, K. H., 144 Cobbs, M. R., 81 Cockerill, A. F., 225, 226, 228,230 Coen, R., 1 8 0 Coffee, E. C. J., 1 9 0 Cole, R. J., 162, 1 6 3 Colin, M., 5 4 Coll, J. C., 37, 53, 54 Collins, F. D., 2 4 9 Collins, P. W., 1 9 5 Colvin, E. W., 1 5 9 Conacher, H. B. S., 2 5 5 Conant, R., 272 Condon, R., 1 5 5 Coniglio, J. G., 259, 2 6 0 Connor, D. T., 1 2 8 Conner, R. L., 2 6 0 Consiglia, G., 2 5 7 Constanzo, M. J., 2 5 4 Conti, C., 1 2 7 Cook, H. W., 2 2 8

2 95 Cookson, P. G., 2 5 1 Cookson, R. C., 7 7 Cooper, G. K., 1 7 7 Coppel, H. C., 110 Corcoran, J. W., 148 Cordbella, A,, 9 7 Corey, E. J., 78, 141, 1 48, 149, 160, 161, 183, 184, 188, 189, 219, 222, 2 4 5 Cornelius, J. A, 262 Cornette, J. C., 2 3 5 Cornforth, J. W., 2 5 9 Cornwell, D. G., 2 2 8 Corvol, P., 2 3 5 Cottee, F., 2 3 0 Cowdrey, S. E., 2 2 6 Cowey, C. B., 2 6 0 Cox, R. E., 1 6 8 Cox, R. H., 1 6 2 Coxon, D. T., 8, 11, 15, 2 39 Cozzini, B. O., 2 2 5 CrabbB, P., 161, 170, 1 9 4 , 199, 2 0 3 Cragoe, E. J., jun., 199, 222, 2 2 3 Cramer, U., 2 6 0 Crammer, B., 1 9 8 Craven, B. M., 2 4 8 Crawford, M. A., 2 6 0 Crawford, T. C., 2 1 9 Crewe, R, M., 114 Crews, P., 32, 33, 3 5 Crimmin, M. J., 2 5 6 Cristoph, G. G., 1 6 2 Crombie, L., 18, 1 15 Cross, J. H., 110, 1 1 6 Crossland, N. M., 1 9 0 Crossley, N. S., 1 7 0 Crumrine, A. L., 9 4 Cruz, A., 170, 1 9 4 Csendes, I., 1 6 4 Culvenor, C. C. J., 108 Cummings, D. P., 164 Curat, J. L., 2 4 8 Curran, D. P., 1 6 1 Curtis-Prior, P. B., 1 7 0 Cuvigny, Th., 7 4 Czerson, H., 7, 9, 10 Czira, G., 1 5 6 Dahlbn, B., 2 4 8 Dailey, R. G., 1 5 8 Dajani, E. Z., 1 9 5 , 2 1 2 Daloze, D., 46, 47, 6 2 , 63, 102, 1 1 4 Daly, J. J., 4 4 Daly, J. W., 12 Damodaran, N. Y., 7 8 Damon, R. E., 8 6 , 1 3 2 , 136 Dampier, M. F., 1 6 5 Damps, K., 9 9 Daniels, E. G., 29, 2 2 4

Danilov, L. L., 2 8 3 Danise, B., 5 0 Darias, J., 20, 41, 4 2 Darr, W., 292 Das, N., 1 4 0 Data, J. L., 232 d’Atri, G., 2 1 1 Davidson, A. H., 2 4 0 Davies, A. G., 2 5 1 Davies, R. E., 2 9 2 Davis, J. B., 8 3 Davison, A. N., 279 Dawson, C. A., 225 Dawson, M., 242 Dawson, R. M. C., 2 6 8 Dawson, W., 2 2 5 , 2 2 8 , 230 d e Bievre, C., 2 6 9 De Camargo, J. M. F., 113,239 Dechavanne, M., 2 3 5 De Clercq, P., 180, 2 3 3 De Deckere, E. A. M., 2 30 Degani, I., 2 5 6 Dejarlais, W. J., 2 4 3 d e Koning, H., 1 9 9 , 2 0 3 d e Lange, F., 2 4 7 de Leeuw, J . W., 2 4 7 Della Vecchia, L., 202 Delley, B., 103 Deloze, D., 6 1 Demailly, G., 7 9 Demarco, P. V., 1 6 2 Dembinska-Kiec, A., 2 3 2 De Montellano, P. R. O., 95 de Moreno, J . E. A., 2 6 0 De Napoli, L., 45, 5 6 , 57 Deno, N. C., 257, 2 5 8 Deprgs, J . P., 170, 194, 199,203 Derguini-Boumechal, F., 84 Deroo, P. W., 2 7 9 de-Rosa, M., 6 0 , 247, 265,266,267 de-Rosa, S., 37, 2 4 7 , 265,266,267 Dervan, P. B., 255 Descoins, D., 1 2 0 Deshmukh, P. V., 1 6 6 , 167 Desiderio, D. M., 229, 234 Desmet, M., 1 8 0 Desmyter, E. A., 275 D’Esposito, L., 2 8 7 Dessy, F., 193, 2 1 3 De Stefano, S., 10, 21, 27, 5 6 De Titta, G. T., 233, 2 4 8 Dev, S., 7 8 , 1 6 2 Devilbiss, E. D., 1 1 4

A utho r Index

296 De Waard, E. R., 82, 202 Dhar, K. L., 1 7 Dhopeshwarkar, G. A., 259 Diamond, J., 249 Dias, H. W., 1 3 7 Diaz, A., 4 1 Di Blasio, B., 4 5 Diczfaluzy, U., 232 Dimitrijevi; , M., 2 6 3 Dimsdale, M. J., 1 7 5 Dinizo, S. E., 241 Disselkoetter, H., 11 6 Ditschuneit, H., 2 4 6 Dittmar, K., 2 4 6 Djemilev, U. M., 7 0 Djerassi, C., 43, 46, 4 7 , 58, 59, 60, 64, 2 8 7 Do, U. H., 229, 242 Dodd, G. H., 272, 2 8 4 Doerr, I. L., 282 Dolby, L. J., 1 7 7 Dolezal, S., 1 9 7 Domazet, Z., 2 2 5 Dommes, V., 2 3 6 Dooley, C. J., 2 4 7 Doolittle, R. E., 1 1 0 Doria, G., 2 1 6 Dornberger, K., 155 Dorset, D. L., 287 Douglas, D. E., 258, 292 Douglas, S. L., 2 3 4 Downing, D. T., 2 6 3 Dradi, E., 2 1 8 Draffan, G. H., 225 Dray, F., 2 2 5 Drexler, H. - J., 2 8 6 Driskill, D. R., 1 9 5 Dryuk, V. G., 2 5 4 Ducruix, A., 1 5 1 Duffield, R. M., 112 Duggan, A. J., 2 6 Duhl-Emswiler, B., 1 2 7 Dulova, V. G., 8 4 Dumelin, E. E., 2 5 3 Dumont, W., 2 4 0 Danges, W., 249 Dunham, E. W., 222 Dunogues, J., 71 Dupont, J., 2 3 5 Duran, I., 2 4 0 Dutton, H. J., 2 5 3 Dyadchenko, A. I., 9 7 Dzhemilev, U. M., 75 Eakins, JS. E., 2 3 3 Eaton, C. A., 237 Eck, C. R., 2 5 7 Edgar, J. A., 108 Edmonds, C. G., 287 Edwards, R. G., 2 8 0 Edwards, R. L., 1 3 5 Egan, R. W., 2 2 9 Egge, H., 237

Eggelte, H. J., 222 Eggelte, T. A., 2 0 3 Egger, E., 277 Eggert, H., 4 7 Egmond, G. J. N., 2 4 2 Egmond, M. R., 251, 253 Ehlers, D., 4, 7, 1 0 Eigendorf, G., 257 Eisfelder, W., 7 5 Eisner, T,, 26, 1 1 4 Eiter, K., 1 1 6 Ekstrand, J. D., 4 0 , 5 0 Elder, M., 2 8 8 Elder, M. G., 2 2 5 Eldridge, J. M., 2 5 4 Eliasson, B., 2 3 9 Ellestad, G. A., 1 4 7 Elliger, C. A., 1 15 Ellis, D. H., 2 2 7 Ellis, J. E., 1 3 6 Ellison, R. A., 161 Elvidge, J. A., 1 3 2 Emken, E. A., 240, 243, 255 Engel, R., 262, 268, 276, 278, 282 Engelhardt, G., 155 Ensley, H. E., 7 8 Enzell, C. R., 9 2 Epple, G., 2 3 7 Eppley, R. M., 1 5 7 Epstein, W., 7 2 Epstein, W. W., 7 3 Eremenko, L. E., 2 8 0 Eremenko, L. T., 2 7 4 Erickson, K. L., 26, 40, 4 1 , 52 Erman, M., 2 3 3 Erman, M. B., 84 Ernest, I., 1 7 0 Ertle, A. R., 277 Eurosawa, E., 4 3 Evans, D. A., 102, 114, 116, 219 Evans, G. E., 1 3 1 Evans, S. L., 113, 2 3 9 Evstigneeva, R. P., 274, 280, 282, 283, 284, 286 Fairbrother, J. R. F., 3 Falardeau, P., 232 Fales, H. M., 1 1 4 Falkowski, L., 155, 1 5 6 Fallis, A. G., 6 1 Farley, D. B., 2 3 5 Farnum, D. G., 1 2 7 Farrell, I. W., 1 0 Fasella, P. M., 2 5 3 Fash, F. J., 2 9 2 Fattorusso, E., 44, 47, 48, 50, 5 2 , 55, 56, 57, 5 8

Faulkner, D. J., 20, 21, 26, 32, 37, 39, 40, 5 1 , 53, 55, 61, 93 Fauscher, S., 116 Favara, D., 1 7 1 Fedeli, E., 262 Feher, A. I., 2 4 9 Feinmark, S. J., 2 3 1 Feldstein, G., 1 2 4 Feline, T. C., 128, 2 3 8 Fenical, W., 2 2 , 23, 29, 38, 3 9 , 4 1 , 4 4 , 49, 50, 5 1 , 5 5 Ferezou, J. P., 4 7 Ferguson, G., 1 2 8 Ferrell, W. J., 2 7 5 Feuge, R. O., 2 4 9 , 2 8 9 Fields, E. K., 2 8 6 Filanova, E. V., 254 Finer, J . , 4 1 , 4 3 , 4 9 , 51, 52,53, 55,60 Finlay, W. H., 2 8 0 Finn, W. E., 1 0 6 Fischer, W., 2 6 7 Fitzpatrick, F. A., 1 9 5 , 234, 235 Fitzpatrick, J. M., 161, 24 5 Fitzgerald, T. D., 1 0 9 Fleming, I., 1 7 4 Fleming, R., 6 4 Fletcher, D. G., 2 1 3 Flint, A. P. F., 2 2 5 Floss, H. G., 1 4 0 Flower, R. J., 229, 2 3 9 Fochi, R., 2 5 6 Fogerty, A. C., 2 4 6 Foglia, T. A., 247, 254, 255,258 Folwell, R., 1 1 4 Fontaliran, F., 235 Ford, C. L., 2 4 6 Ford, M. E., 241 Forgione, A., 2 1 8 Fortier, S., 2 3 3 Fourneron, J. D., 41 Franca, N. C., 1 1 , 2 3 9 Franceschini, J., 2 1 6 Francis, L. E., 258, 2 9 2 Francke, W., 1 1 1 , 1 1 2 Frankel, E. N., 2 5 0 , 257 Frdter, G., 72 Frazee, W. J., 9 2 Frede, E., 248, 2 8 7 Fredholm, B. B., 2 3 2 , 2 3 3 Freerksen, R. W., 241 French, S. J., 2 5 9 Fretz, T. A., 81 Fried, J. H., 136, 184, 214 Friedman, Y., 229 Friedrich, J . P., 2 5 7 Fringeli, U. P., 2 9 0 Frischleder, H., 2 9 0 Fritz, H., 1 4 5

297

Author Index Frohlich, J. C., 225, 2 3 0 234 Fronckowiak, M., 2 3 3 Froyen, P., 127 Fuhrer, H., 1 4 4 Fujimoto, K., 152 Fujino, Y., 269 Fujiyama, T. F., 2 9 0 Fukami, H., 1 1 0 Fukamiya, N., 2 0 7 Fukui, H,. 1 1 0 Fukumoto, K., 88 Fukuyama, K., 1 4 7 Fukuyama, Y., 1 6 0 Fukuzumi, K., 2 5 0 Fulco, A. J., 261 Fumagatli, A., 2 1 6 Funk, M. O., 2 2 8 , 2 5 0 , 25 1 Furuhata, K., 1 5 1 Furumai, T., 1 5 1 Furusaki, A., 3 9 , 4 1 Fyles, T. M., 1 17,118 Gaffney, J., 6 4 Gager, A. H., 21 5 Gagnaire, G., 1 9 4 Gairola, C., 1 4 0 Gal, A. E., 2 9 2 Galambos, G., 1 8 3 Galavage, M., 229 Gallagher, E. M., 1 0 9 Galliard, T., 251, 2 5 2 Gallo, A. A., 2 8 9 Gallois, M., 1 2 0 Gambacorta, A., 2 4 7 , 265,266,267 Gandolfi, C., 2 16, 2 1 8 Ganguly, A. K., 155, 165 Garbers, C . F., 74, 1 2 2 Garces, A., 275 Garcia, P. T., 261 Gardner, H. W., 2 3 9 , 2 5 3 Gariboldi, P., 9 7 Garlaschelli, L., 1 6 1 Garrett, V. H., 1 15 Garson, M. J., 1 4 5 Cisrssen, G. J.. 2 5 3 Garton, G. A., 2 6 2 Garwood, R. F., 2 5 0 Gasic, G. P., 183, 1 8 6 Gaskell, S. J., 2 8 7 Gast, L. E., 2 5 6 Geer, J. C., 2 2 8 Geiko, N. S., 2 6 5 Gelin, S., 1 3 2 Gellerman, J. L., 2 5 9 Gelpi, E., 2 3 4 Gensler, W. J., 237, 243, 248 Gent, P. A., 272 Georget, P., 4 6 Gerken, B., 1 1 1 Gerlach, H., 159, 1 6 2 Gerrard, J. M., 222

Gersch, D., 1 5 2 Gharib, A., 235 Ghooi, R. B., 2 1 2 Gibson, H. W., 2 8 9 Gibson, K. H., 213, 2 3 2 Gibson, T. W., 255 Gigg, R., 2 7 2 Gilboa, H., 2 8 8 Gill, G. B., 69 Gilman, N. W., 2 4 7 Gilman, S., 8 7 Gilmore, D., 222, 228, 250 Gil-Quintero, M., 9 7 Girdaukas, G., 1 8 6 Giusto, N. M., 262 Glass, G. B. J., 2 6 4 Glass, R. L., 2 3 9 Gleichmann, S., 2 9 0 Gmelin, R., 21 Goad, L. J., 58, 6 4 Gohbara, M., 1 3 2 Gokhale, P. D., 7 8 Golding, B. T., 272, 2 8 4 Golik, J., 155, 1 5 6 Gomez Dumm, I. N. T., 259 Gonzalez, A. G., 39, 41, 42,97 Goodfellow, R. J., 7 3 Goodford, P. J., 2 3 3 Gopinath, K. W., 2 Gordienko, C. L., 2 5 4 Gordon, D., 225 Gordon-Wright, A., 2 2 5 Gormon, J. E., 1 1 0 Gorman, R. R., 195, 219, 229, 2 3 0 , 2 3 5 Goto, T., 1 3 0 Gottlieb, 0. R., 11, 2 3 9 Gould, N. P., 1 9 9 , 2 2 2 Grachev, M. K., 2 8 0 Graham, E. A., 1 5 Grandi, R., 71 Granstrlim, E., 225, 226, 227,235 Gray, G. M., 2 6 3 Gray, J. R., 1 1 5 Gray, M. S., 249, 2 8 9 Gray, R. T., 2 5 9 Green, F. R., 1 7 1 Grhen, K., 210, 225, 226, 234 Greenberg, A. J., 2 3 7 Greenberg, R., 192 Greenblatt, R. E., 1 1 0 , 116 Greene, A. E., 161, 170, 194,199,203 Greenough, R. C., 1 2 8 Greensley, M. K., 1 6 2 Greenwald, S. M., 2 8 7 Greev-s, D., 1 5 6 Greger, H., 4 Gregory, B., 6 1

Gregson, R. P., 2 9 Grenz, M., 5, 6, 7, 9, 10 Grieco, P. A., 85, 8 7 , 207, 2 1 0 , 2 1 7 Grieder, A., 1 8 Griffin, L. P., 232 Grigorev, A. E., 1 9 1 Groenewegen, A., 2 8 9 Grogan, W. M., jun., 2 6 0 Gronowitz, S., 249, 2 8 8 Groweiss, A., 5 3 Gruber, L., 1 7 3 Gruber, V. F., 225 Grudzinskas, C. V., 2 1 3 Gruijic-Injac, B., 2 6 3 Gruner, J., 1 4 4 Gruender, W., 290 Gryglewski, R. J., 229, 232 Guarneri, M., 1 9 4 Gudkova, S. F., 2 8 0 Gueriguian, J. L., 2 3 3 Guerri, F. A., 2 5 8 Gunthard, H. H., 2 9 0 Gund, P., 229 Gunstone, F. D., 239, 247,248,261,262 Guntz-Dubini, R., 80 Gupta, K. C., 74 Gupta, 0. P., 1 7 Gupta, S. C., 1 7 Gutsche, C. D., 9 6 Gutt, A. L., 1 2 8 Gutteridge, N. J. A., 2 2 6 Gutwillinger, H., 201 Guziec, F. S., jun., 141, 242 Haber, A., 1 6 7 Hager, L. P., 28, 2 4 0 Hagerman, A., 8 1 Haibara, K., 1 4 3 Haken, J. K., 246 Haleeva, R. I., 70 Hallett, W. A., 2 1 3 Ham, P. J., 1 1 5 Hamaguchi, H., 1 7 8 Hamasaki, T., 147 Hamberg, M., 231, 232, 2 52 Hammarstrom, S., 2 3 2 , 233, 2 5 2 Hamon, A., 2 0 6 Han, H. B., 1 0 Han, R. K. W., 253, 291 Hanahan, D. J., 2 6 4 Hancock, A. J., 276, 287, 289 Handa, V. K., 9 7 Hands, A. R., 2 8 0 Hanessian, S., 1 8 9 Haning, R. V., jun., 2 2 5 Hanson, C. A,, 1 3 1 Hanson, J., 2 2 5 Hansson, B., 15 5

Author Index

298 Hansson, G., 227 Hanyu, T., 225 Hanzlik, R. P., 93 Hara, I., 283, 290 Harada, K., 151, 155 Harada, S., 154 Harada, Y., 1 5 1 Harata, Y., 168 Hargreaves, J. A., 8, 15 Harring, C. M., 111 Harris, E. J., 115 Harris, R. L., 109 Harrison, C. R., 254 Harrison, I. T., 136, 203 Hart, M., 224, 229 Hartmann, D., 132 Hartzler,.H. E., 210 Hasenkamp, R., 147 Hashiba, N., 39, 4 1 Hashimoto, Y., 86, 91, 150,211,212

Haslouin, J., 123 Hassam, A. G., 260 Hassid, A., 229 Hata, G., 7 4 Hata, M., 226 Hatanaka, A,, 19, 252 Hatanaka, Sh. I., 12, 2 1 Hatsuda, Y., 147 Hawes, G. B., 49, 54 Haxo, F. T., 65 Hayaishi, O., 205, 228, 232

Hayase, Y., 148, 153 Hayashi, A., 270 Hayashi, M., 174, 205, 212,283

Hayashi, S., 77 Hazlewood, G. P., 268 Healy, T. W., 249 Hearn, J. P., 229 Hearn, M. T. W., 13 Heath, R. R., 116 Heckers, H., 246 Hedin, P., 103 Hedin, P. A., 109 Heeman, V., 111, 112 Heikkila, R. E., 228 Heimbach, P., 68 Heller, P., 247 Hemler, M. E., 228, 232, 242

Hempel, G., 290 Hendry, L. B., 103 Henrick, C. A., 116, 124 Henrix, J. W., 269 Hensby, C., 233 Henson, B. E., 224 Herald, C. L., 40, 53,63 Herald, D. L., 63 Herin, M.,53, 54 Herslof, B., 249, 288 Herz, W., 228, 230 Hicks, K., 114 Hidai, M., 68, 77

Higgs, E. A., 229 Higgs, M. D., 32, 61, 116 Highet, R. J., 157 Hill, A. S., 106 Hill, R. A, 145 Hindenlang, D. M., 103 Hindley, N. C., 84 Hirao, N., 7 0 Hirata, F., 225 Hirata, Y., 130 Hiro, E., 192 Hiroi, K., 118 Hirose, Y., 36 Hirotsu, K., 31, 49, 55, 60

Hirsch, A. F., 275 Hitchcock, P., 288 Ho, J. T., 289 Ho, P. P., 261 Hodge, P., 254 Hoffman, L. L., 264 Hoffman, N. E., 247 Hofheinz, W., 31, 57 Hofle, G., 21 Hogberg, H. -E., 36 Holker, J. S. E., 168 Holland, B. C., 247 Holland, G. W., 227 Holland, J. F., 249 Hollenbeak, K., 40 Holliday, J. A, 239 Holman, R. T., 254,261 Holmbom, B., 246 Holton, R. A., 180 Holtz, W. J., 222, 223 Holub, B. J., 261 Hommes, H., 255 Hong, E., 213 Honma, K., 103 Hood, R. L., 246 Hoogenbrom, J. J. L., 253,291

Hootele, C., 6 1 Hope, H., 145 Hopf, H., 25 Hori, T., 270 Hornych, A,, 235 Horton, E. W., 170, 232 Horton, R., 235 Horvith, G., 234 Hosagai, T., 83 Hossain, M . B., 53 Houghton, E., 114 Houlihan, W. J., 201 Howard, B. M., 38, 39, 44,49

Huang, F. -C., 186 Hubbard, W. C., 225, 234 Hudson, B. S., 249, 277 Hughes, J. M., 73 Hughes, P. R., 111 Huhn, C., 13 Huisman, H. O., 82, 199, 202,203

Hull, P., 79

Hulshof, L. A., 145 Humes, J. L., 229 Hunter, D. J., 257 Hunter, W. J., 261 Hurley, L. H., 139, 140 Hursthouse, M. B., 137 Hutchins, R. F. N., 114 Hutchinson, C. R., 1 6 1 Huynh, C., 7 1 Ichihara, A., 141, 142, 144,146

Ichikawa, N., 36 Ichinose, I., 39, 83 Idacavage, M. J., 255 Ide, J., 208 Iemura, S., 86, 9 1 Iengo, A., 45 Iguchi, K., 88 Iguchi, S., 205, 212 Ihn, W., 155 Iitaka, Y., 30, 15 1 Ikan, R., 198 Ike, N., 74 Ikeda, N., 250 Ikeda, T., 115 Ikegami, S., 186 Il’ina, E. F., 274 Imai, H., 154 Imai, Y., 259 Imaki, K., 225 Imamoto, S., 174 Imperato, F., 32 Ingerman, C. M., 183 Inglett, G. E., 253 Inoue, K., 173, 193 Inoue, S., 1 3 1 Inouye, K., 2 1 8 Inukai, N., 171, 2 1 5 Ioannou, P. V., 272, 283, 2 84

Ireland, C., 32, 53, 196 Isaac, R., 228, 250, 251 Isaacson, Y. A,, 279 Isagawa, K., 7 6 Ishida, A, 136 Ishida, T., 161 Ishihara, Y., 225 Ishii, S., 110 Ishii, Y., 171, 215 Ishimoto, S., 178, 194, 211

Ishiwatari, H., 68 Ismail, 1. A., 261 Isobe, T., 115 Isogai, K., 193 Itasaka, O., 270 Ito, M., 137 Ito, S., 168 Itoh, H., 205 Ivanov, G. E., 75 Iwamori, M., 291 Iwamoto, H., 171,215 Iwamura, J., 7 0 Iwasaki, K., 151

299

A u tho r Index Iyengar, R., 1 9 3 Izawa, M., 152 Jackson, R. w.,187, 2 1 4 Jacobs, J., 237 Jacobsen, J. P., 1 3 3 Jacobson, M., 103, 1 1 5 Jaeger, J., 2 4 6 Jaenicke, L., 2 1 , 2 4 Jaffe, E. A., 230 Jaiswal, D. K., 132 Jakubowski, A. A., 141, 151,242 Jakupovic, J., 9 James, D. R., 9 9 , 100 Jamieson, G. R., 246 Janick, M. J., 289 Jaouni, J., 1 1 4 Jarman, T. R., 99 Jarvis, B. B., 1 5 8 Jedziniak, E. J., 257 Jeffcoat, R., 259 Jendrasiak, G. L., 2 9 0 Jenkin, H. M., 261 Jenkins, C. L., 145 Jensen, R. G., 262 Jente, R., 1 3 Jernberg, K. M., 7 0 Jewett, D. M., 110 Johansen, J. E., 65, 101 Johns, S. R., 2 4 7 Johnson, A. R., 246 Johnson, C. B., 237 Johnson, F., 171 Johnson, H. T., jun., 229 Johnson, R. A., 1 8 3 , 2 1 9 , 229,230,258 Johnson, R. D., 167 Johnson, W. S., 9 8 Jommi, G., 9 7 Jones, Sir Ewart R. H., 3, 13, 1 5 Jones, J. H., 2 2 2 , 2 2 3 Jones, J. R., 1 3 2 Jones, R. B., 1 2 8 Jones, T. H., 1 1 4 Joshi, A. P., 7 8 Joutti, A., 264 Judy, W. A., 2 5 6 Julia, M., 77, 82 Julia, S., 7 1 Jung, C. J., 195 Jung, Ed, 2 7 7 Jurd, L., 8 4 Kabanov, S. P., 2 8 6 Kabasakalian, P., 1 6 5 Kabisch, G., 290 Kabuto, C., 1 6 3 Kaib, M., 1 1 4 Kaiser, R., 70, 239 Kaisin, M., 47, 61 Kaji, K., 151 Kajiwara, T., 19, 252

Kakinuma, JS., 131, 166, 167 Kalinowski, H. -O.,160, 246 Kalliney, S., 1 6 5 Kamata, K., 241 Kameda, M., 268 Kameo, Icy180 Kameoka, H., 4 Kametani, T., 88 Kamikawa, T., 115 Kamoshida, A, 3 9 G m p e r , F., 257 Kaneda, T., 246 Kanter, G., 1 2 8 Kantrowitz, F., 232 Kao, J. P. Y., 4 0 Kaplun, A. P., 274, 2 8 3 Kappler, F. E., 1 3 3 Kapteijn, F., 2 5 6 Karim, S. M. M., 2 3 3 Karl, W., 1 1 6 Karle, I. L., 1 2 Karlsen, S., 1 2 7 Karlsson, R., 47, 61 Karpyshev, N. N., 2 8 4 Kashiwagi, M., 31 Kashman, Y., 53, 57 Katagiri, T., 74, 8 4 Katayama, M., 9 9 Kates, M., 260, 264, 2 7 6 Kato, T., 39, 48, 8 3 Kato, Y., 2 0 Katsube, J., 210, 2 2 0 Katsube, Y., 1 4 7 Katzenellenbogen, J. A., 94, 1 1 6 Kauffman, J. W., 290 Kaul, P., 40 Kawasaki, Ic, 1 0 3 Kazlauskas, R., 23, 29, 31, 3 5 , 4 2 , 4 4 , 54, 57, 58, 62 Keane, J. W., 277 Keck, G. E., 1 8 3 Keirse, M. J. N. C., 2 2 6 Keiser, I., 115 Kelbch, G., 2 4 6 Kelecom, A., 62, 6 3 Kelly, R. C., 176, 187, 235,254 Kelly, R. W., 229, 2 3 4 Kelstrup, E., 2 5 9 Kemp, T. R., 16, 252 Kenig-Wakshal, R., 2 2 9 Keogh, M. F., 2 4 0 Keyser, J. B., 261 Khambay, B, P. S., 2 5 0 Kheifits, L. A., 8 4 Khokhar, A. R., 1 3 7 Kho-Wiseman, E., 33, 35 Kido, Y., 252 Kieczykowski, G. R., 1 7 7 Kieliszek, F. X., 2 2 5

Kikuchi, Ic, 149 Kimball, F. A, 2 1 4 Kimura, M., 2 5 4 Kimura, R., 142, 1 4 6 Kimura, Y., 76, 132 Kindahl, H., 225, 227, 235 King, H. L., jun., 91 King, R. M., 9 King, T. J., 147, 169 Kingston, J. F., 6 1 Kinnel, R., 26 Kinner, J. H., 230 Kinoshita, M., 152 Kinumaki, A., 151, 1 5 5 Kiriyama, N., 135 Kirkemo, C. L., 160 Kirksey, J. W., 162, 1 6 3 Kirton, K. T., 2 3 5 Kishaba, A. N., 1 0 3 Kishi, T., 152, 1 5 4 Kishimoto, Y., 261 Kitagawa, I., 6 3 Kitagawa, Y., 86, 91, 150 Kitahara, T., 30 Uitahara, Y., 39, 48, 83 Kitamoto, M., 180 Kitamura, S., 2 2 5 Kjdsen, H., 6 5 Kleijn, H., 74 Kleiman, R., 236, 238, 239,248,253 Klein, E., 68, 7 9 Klein, M. G., 1 1 0 Kleveland, K., 8 2 Klimetzek, D., 103, 1 0 6 Klimova, E. I., 6 9 Klisiewicz, J. M., 1 5 Klor, H. U., 246 Klose, G., 2 9 0 Kluender, H. C., 2 1 0 Knapp, H. R., 232 Knaus, G., 241 Knight, D. W., 134, 1 3 5 Knoll, K. H., 7 Knolle, J., 188, 1 8 9 Kobayashi, A., 8, 60, 63, 91, 95, 132, 142, 143, 178, 194, 2 1 1 , 2 1 2 Koch, G. K., 253, 291 Kochi, J. K., 254 Kocienski, P. J., 1 3 , 118, 124,125 Koenig, J. L., 287 Korkemeier, U., 2 4 9 Kogiso, S., 9 Kohl, W., 1 4 4 Koizumi, K.,142 Kojirna, K., 2 0 8 Kolodziejczyk, P., 1 5 6 Kondo, E., 1 5 6 Kondo, K., 75, 182, 192, 268 Konen, D. A., 2 5 8

Author Index

300 Konova, I. V., 2 6 9 Konya, S., 8 Kopp, H. G., 2 3 5 Korckaya, G. H., 2 5 4 Kori, S., 174, 2 12 Korolev, A. M., 2 7 4 Koroly, N. J., 2 6 0 Koronelli, T. V., 2 6 9 Kosaka, K., 2 2 5 Koschatsky, K. H., 1 1 9 Kovacs, G., 173, 1 8 3 Kow, R., 9 8 Koyama, Y., 2 9 0 Kozhukhova, R. A,, 2 6 9 Kozuharov, S., 2 4 6 Krahl, R., 2 9 0 Krammer, R., 9 7 Krapcho, A. P., 254 Kraus, G., 1 8 0 Krecioch, E., 2 3 2 Krick, T. P., 2 3 9 Krief, A., 2 4 0 Krolikiewicz, K., 1 4 9 Krueger, W. C., 224 Kruglyak, E. B., 2 6 9 Kubo, I., 62, 1 1 5 Kubodera, N., 1 7 1 Kubota, T., 1 15 Kubota, Y., 2 5 6 Kuehl, F. A., jun., 199, 222,223,229,233 Kuhlein, K., 200, 2 0 4 Kuehne, M. E., 8 6 Kuepper, F. W., 117 Kuhn, E. S., 2 8 6 Kuksis, A., 247, 2 6 2 Kulkarni, S., 4 0 Kumar, S. D., 84,9 3 Kummerow, F. A., 2 4 6 Kunau, W. H., 2 3 6 , 2 6 2 Kunstmann, M. P., 1 4 7 Kunstmann, R., 193, 1 9 7 Kunze, D., 2 7 7 Kunze, H. B., 2 12 Kupchan, S. M., 1 5 8 Kupriyanov, S. E., 2 8 6 Kuranova, I. L., 2 5 4 Kurbanov, M., 9 7 Kurchacova, E., 2 1 0 Kurihara, H., 1 4 3 Kurihara, T., 2 4 5 Kurono, M., 2 14, 22 5 Kurosawa, E., 39, 4 1 Kurozumi, S., 178, 194, 211,212 Kuwahara, Y., 110, 1 2 5 Kuwano, H., 1 6 3 Kvantrishvili, V. B., 281 Kyogoku, Y., 2 9 0 Lacoume, B., 2 0 6 Ladd, T. L., 1 1 0 Lagarde, M., 235 La&, S., 2 6 3 Lakwikj, A. C., 1 1 6

Lalanne-Cassou, B., 1 2 0 Lam, C. H., 243, 246, 248,256 Lam, J., 9, 1 5 Lammers, J. G., 2 8 0 Lamparsky, D., 70, 2 3 9 Lamptey, M. S., 2 6 1 Lancini, G., 1 6 5 Landriscinon, C., 2 8 4 Lands, W. E. M., 228, 232, 2 3 3 , 2 4 2 , 261 Langford, D. D., 2 7 7 Langone, J. J., 2 4 3 Langs, D. A., 2 3 3 Langworthy, T. A., 265, 267 h n z i l o t t a , R. P., 1 9 8 Laos, I., 277 Lapierre Armande, J. C., 201 Larcheveque, M., 7 4 Larkin, J. P., 9 6 Larock, K. C., 241 Larson, D. L., 222 Larson, J. R., 2 5 4 Lau, P. -Y., 2 8 6 Lauderdale, J. W., 2 1 4 Laur, M. -H., 2 7 0 Lavallee, P., 1 8 9 Lazurkina, T. Yu., 2 8 2 Leach, M., 1 3 8 Le Borgne, J. F., 7 4 Le Drian, C., 1 6 1 Lee, A. D., 2 0 2 Lee, B. K, 1 5 5 Lee, T. -J., 199, 2 2 2 Lee, T. V., 1 7 5 Lee, Y. W., 115 Leeney, T. J., 2 2 0 Lefort, D., 2 5 4 Legein, K., 1 8 0 Le-Kim, D., 2 1 2 Lentz, C. M., 9 3 Lerch, U., 193, 1 9 7 Leslie, D. R., 2 4 7 Less, T. -C., 2 5 9 Levai, A, 1 5 6 Le Van, N., 7 , 9, 10 Levasseur, S., 2 2 9 Levett, G., 2 4 9 Levine, L., 225, 229, 2 3 2 Levinson, A. R., 110, 1 1 6 Levinson, H. Z., 110, 115, 116 Levkoeva, E. I., 202 Leysacc, P. P., 2 3 5 Leznoff, C. C., 1 17, 1 18 Li, E., 100 Li, L. -H., 166, 1 6 7 Liaaen-Jensen, S., 65, 101 Liao, J. C., 2 4 7 Lidgard, R. O., 3 1 Lie Ken Jie, M. S. F., 237, 243, 246, 247, 248, 256 Liem, Y. Q., 2 7 0

Lin, C. H., 206, 217, 226, 232 Lincoln, F. H., 29, 183, 224, 2 3 4 Lindhoudt, J. C., 2 5 5 Lindstedt, S., 2 3 9 Linkies, A., 200, 2 0 4 Linstrumelle, G., 71, 84, 124 Liotta, D. C., 7 5 Lippmaa, E., 81 Litchfield, C., 237, 2 6 0 Liu, C., 1 3 8 Liu, M., 1 3 8 Liu, Y. T., 1 6 5 Liyanage, N., 53, 54 Lizarbe, M. A., 2 5 9 Lloyd, H. A., 1 12 Lobanova, I. A., 282, 283 Lofgren, H., 2 4 8 Lofquist, J., 1 1 2 , 1 13 Logan, D. M., 103 Logani, M. K., 2 9 2 Lok, C. M., 272, 2 8 9 Lonitz, M., 9 Lorne, R., 84 Loskant, G., 103, 1 0 6 Losman, D., 6 1 Love, R. M., 2 3 9 Lovegren, N. V., 249, 2 89 Lubosch, W., 1 6 0 Luddy, F. E., 2 4 7 Luftmann, H., 2 5 7 Lukacs, G., 150, 151 Lukefahr, M. J., 1 1 5 Lundberg, B., 2 4 8 L u n d h , B. M., 2 4 8 Lunnon, M. W., 161 Luo, T., 132 Lusby, W. R., 109 Lustgarten, R. K., 2 3 4 Luxa, H. -H., 21 Lyman, R. L., 261 Ma, C. L., 2 5 7 Mabry, T. J., 1 1 5 Mabuni, C!. T., 1 6 1 McCandless, L. L., jun., 116 McCarthy, 3. R., 1 6 5 McCarthy, T. P., 2 4 6 MacConnell, J. G., 1 1 4 McConnell, 0. J., 22, 2 3 McCosh, E. J., 2 3 5 McDonald, F. J., 1 1 4 McDonald, K. M., 1 9 8 MacDonald, L. M., 1 1 6 McDowell, P., 1 1 4 McElhaney, R. N., 2 6 1 McEnroe, F. J., 50 McEwen, F. L., 1 1 5 MacFarlane, R. D., 1 6 3 McGahren, W. J., 1 4 7

301

Author Index McGiff, J. C., 229 McGovern, W. L., 1 0 9 .McGuire, J. C., 230, 235 Machida, M., 154 McInnes, A. G., 138 McKellar, F. A., 139 McKibben, G. H., 1 0 9 MacLouf, J., 225 MacMillan, J. A., 43, 161, 162 McMorris, T. C., 270 McQuillin, F. J., 82 Madrigal, R. V., 240 Maehr, H., 138 Magerlein, B. J., 2 10 Magno, S., 4 4 , 4 7 , 4 8 , 50, 52, 58 Magnusson, G., 126 Magolda, R. L., 183, 186 Mahadevan, V., 246 Mahanta, P. K., 2, 7, 9 Mahato, S. B., 239 Mahendran, M., 36 Maiese, W., 139 Majetich, G., 207 Makin, S. M., 98 Maldonado, L. A., 197 Malins, D. C., 249, 291 Mallams, A. K.,156 Mallen, D. N. B., 225, 226,228,230 Malloy, A. J., 254 Malmsten, C. L., 219 Mancha, M., 261 Mandel, L. R., 222, 223 Mangold, H. K., 253, 262, 29 1 Mank, A. P. J., 271 Mansfield, J. W., 8 , 1 5 Mao, D. T., 70 Maracek, J. F., 272, 283, 284 Marai, L., 247 Marcus, A. J., 230 Mariat, F., 269 Marner, F. -J., 31 Marnett, L. J., 229 Marosfalvi, J., 191 Marsh, L. L., 7 3 Marsh, W. C., 128 Marshall, J. P., 237, 243, 248 Marsham, P. R., 220 Marston, J. H., 229 Martens, D. R. M., 9 8 Martin, D. E., 229 Martin, J. D., 20, 39, 41, 42,97 Martin, M. J., 121 Martin, P. Ic, 166 Martinez, E., 216 Martyakova, A. V., 269 Marumo, S., 99, 128 Maruoka, K., 150 Marx, J. L., 232

Masaki, Y., 207 Masamune, S., 148, 1 5 3 Masamune, T., 2 5 Masaoka, K., 118, 24 1 Mahsiko, T., 87 Mashkovskii, M. D., 202 Mashraqui, S. H., 80 Mason, R. B., 201, 288 Masui, T., 149 Matson, J. A., 5 3 Matsubara, S., 21 1 Matsubara, T., 270 Matsue, H., 25 Matsui, M., 124, 127, 130 Matsumoto, K., 1 5 6 Matsumoto, M., 75, 138, 156, 157 Matsumoto, T., 141 Matsumura, F., 110, 11 5 Matsuo, M., 143 Matsushita, S., 250 Matsuura, F., 270 Matthew, J, A., 251, 252 Maurer, B., 18, 9 3 Maxwell, R. J., 256 Mayberry, W. R., 265. 267 Mayberry- Carson, K. J., 267 Mayol, L., 44, 45, 47, 48, 50, 52, 5 8 Mayzaud, P., 237 Mazurek, M., 247 Mazzola, E. P., 157 Mead, J , F., 252, 254, 259 Meana, M, C., 170, 194, 203 Mees, U., 2 55 Megli, F. M., 284 Mehrotra, M. M., 243 Meijer, J., 74 Meinwald, J., 26, 108, 114 Melcher, F. W., 246 Melian, M. A, 42 Mellon, F. A., 11 1 Mellows, G o , 128, 2 3 8 Melnikova, V. I.,., 19 1 Menard, J., 235 Mendelsohn, R., 248 Mendible, J. C., 290 Menon, N. Ic, 231 Menzer, R. E., 109 Merritt, M. V., 234 Messer, L. A, 258 Messerotti, W., 71 Meusy, J. J., 47 Meyers, A. I., 241, 262 Meyer,D. L., 235 Meyerson, S., 286 Michaelis, G., 243, 249 Michaelson, R. C., 87 Michel, C., 5 3 Michel, K. H., 162 Michelot, D., 71, 124 Midovid, I., 263

Middleditch, B. S., 229 Mihelich, E. D., 262 Mikoljczak, K. L., 262 Miiavetz, B. I., 166 Miller, J. R., 103 Miller, 0. V., 195, 229 Miller, P. A., 138 Miller, R. W., 109, 238, 239 Miller, W. R., 257 Milliez, P., 235 Minale, L., 20, 21, 32, 37, 50, 5 1 , 56, 5 8 , 6 0 , 2 6 5 Minato, H., 138, 156, 157 Minkes, M., 232 Mishima, H., 143 Mitcham, D., 248 Mitchell, E. B., 109 Mitchell, J. C., 1 5 Mitchell, M. D., 225 Mitchell, S. J., 37 , 5 3 Mitsunobu, O., 245 Mitzlaff, M., 200 Miura, I., 26, 115 Miura, S., 194, 21 1 Miura, Z., 114, 115 Miyake, A., 154 Miyake, H., 205, 212 Miyamoto, T., 228 Miyano, M., 21 2 Miyashita, D. H., 1 I 5 Miyashita, M., 85, 207 Miyazawa, J., 15 1 Miyazawa. M., 4 Miyazawa, S., 143 Mizsak, S . A., 1 8 3 Mizuno, K., 143 Moesinger, S. M., 7 3 Moinat, T. J. H., 199 Mol, J. C.. 256 Molotkovskii, Yu. G., 282 Molotkovsky, J. G., 275 Moncada, S., 229, 230, 231,232 Money, T., 257 Monroe, R. E., 106 Montgomery, M. E., 11 1, 112 Monti, J. A., 280 Montrozier, H. L., 261 Moolenaar, M. J., 82 Moon, C. K., 10 Moore, B. P., 11 1 Moore, G. G., 256 Moore, J. L., 165 Moore, R. E., 20, 21 , 22, 31, 36 Morales, R. W., 237, 260 Moreno, V. J., 260 Morgan, E. D., 112, 1 16 Morgan, J. L., 227 Morge, R. A,, 187, 224

Author Index

3 02 Mori, K., 103, 1 0 6 , 116, 1 2 4 , 126, 1 2 7 , 1 3 0 Moriyasu, K., 142 Morrisett, J, D., 241 Morrow, G., 2 8 6 Morton, D. R., 230 Morton, G. O., 1 4 7 Moss, G. P., 65 Moss, H. R., 2 1 3 Moss, R. A., 1 4 3 Muchowski, J. M., 2 1 4 , 216 Mueller, R. H., 1 9 6 Mueller, V., 274, 29 1 Mukaiyama, T., 9 1 , 95, 126, 136, 148, 1 4 9 , 161 Mulheirn, L. J., 58 Mullane, K., 232 Muller, J. M., 1 4 4 Mumma, R. O., 1 0 3 Munakata, K., 9 Municio, A. M., 259 Munk, M. E., 8 1 Murad, S., 261 Murahashi, S. I., 2 4 0 Murai, A., 25 Murakami, A,, 2 3 3 Murakami, M., 171, 215 Muramatsu, T., 2 8 3 Murase, H., 25 Murata, T., 247, 2 4 8 Murawski, U., 237 Muroi, M., 1 5 2 Murota, S. I., 2 3 0 Murphy, P. T., 23, 29, 35, 42, 44, 54, 57, 58, 6 2 Murphy, R., 8 6 Murphy, V., 5 8 Mutter, M., 253, 291 Myatt, L., 225 Mychajlowskij, W., 117 Myers, C., 2 1 3 Myher, J. J., 2 4 7 Mynderse, J. S., 31

.

Nlf, F., 18, 122 Nagai, K., 77 Nagai, Y., 291 Nagano, H., 1 9 9 Nagano, N., 171 Nagarajan, R., 1 6 2 Nagashima, K., 1 4 2 Naik, V. G., 7 8 Nair, K. S. S., 1 15 Nair, M. S. R., 1 2 , 1 4 4 Naito, T., 1 6 6 Nakagawa, A., 1 5 1 , 1 5 4 Nakai, T., 1 9 1 Nakajima, Y., 2 4 5 Nakamura, H., 30 Nakamura, M., 2 1 8 Nakamura, N., 1 16,207

Nakanishi, K., 9 3 , 114, 115 Nakayama, M., 77 Nakazawa, I., 2 5 9 Nakazawa, N., 2 2 5 Naples, J. O., 1 4 9 Nara, M., 1 7 4 Narasaka, K., 149, 161, 222 Narayanaswami, A., 239 Nash, S. A., 2 2 7 Nashat, M., 230, 231 Natale, N., 262, 285 Natarajan, V., 279, 291 Natori, S., 142, 1 6 3 Natu, A. A., 7, 1 0 Nault, L. R., 111, 1 1 2 Nawar, W. W.,2 5 3 Naya, Y., 3 6 Nayak, U. R., 7 8 Nechaer, A. P., 265 Nedelec, J. Y., 254 Nedenskov, P., 2 4 4 Nederlof, Y. J. R., 82 Needleman, P., 231, 232 Neff, W. E., 250, 255, 257 Negishi, E., 1 1 9 , 257 Nelson, M. S., 2 5 1 Nelson, N. A., 186, 187, 214 Nemoto, H., 8 8 Neszmelyi, A., 1 5 0 Newton, J. R., 1 0 3 Newton, R. F., 175, 1 9 0 Ng, P., 35 N’Galamulume-Treves, M., 21 Nhari, D. B., 292 Niccoli, A., 1 2 7 Nickell, E. C., 255 Nieolaides, N., 237 Nicolau, K. C., 148, 149, 183, 185, 186, 219 Nidy, E. G., 183, 2 1 9 Nielson, M. W., 1 1 1 Nies, A. S., 232 Nifant ’ev, E. E., 278, 280,281, 283,284 Niimura, Y., 12 Nikulina, L. F., 275 Nishida, R., 1 1 0 , 125 Nishida, T., 9 2 Nishigaki, Y., 225 Nishikawa, T., 12 Nishikawa, Y.,8 Nishino, C., 1 1 1, 1 12 Nishiyama, K., 141, 142 Nishizawa, M., 87, 2 0 7 Nitta, K., 135 Niwa, H., 2 1 4 Nixon, J., 228, 250 Noble, D., 1 4 3 Noble, M., 1 4 3 Noble, T. A., 7 3 Noguez, J. A., 197

Nonhebel, D. C., 9 6 Nooijen, P. J. F., 1 1 0 Nooijen, W. J., 1 1 0 Norcross, B. E., 1 3 Nordgard, S., 65 Normant, H., 74 Norton, R. S., 34 Norton, T. R., 31 Noto, G., 237 Novdk, L., 1 9 1 Novikov, Yu. N., 8 4 Nowakowski, N., 2 8 4 Nozaki, H., 86, 8 8 , 91, 122, 150, 162 Nugteren, D. H., 228, 2 30 Nukina, M., 1 2 8 Oates, J. A., 225, 230, 227,232,234 Obayashi, M., 1 2 2 OberhBnsli, W. E., 31, 44,49, 54 O’Brien, D. H., 11 5 O’Brien, M. A., 2 4 6 O’Brien, P. J., 2 2 8 Oda, K., 1 4 6 Oda, M., 1 3 0 Ode, R. H., 5 2 Odinokov, V. N., 7 0 Odriozola, J. M., 258 Oelz, O., 232 Oelz, R., 2 3 2 Oertle, K., 1 5 9 , 1 6 2 Oesterling, T. O., 224 Ofstead, E. A., 256 Ogasawara, K., 1 7 1 , 1 7 3 Ogino, N., 205, 2 2 8 Ogino, T., 1 9 3 Ogura, H., 1 5 1 Ogura, K., 1 3 4 Oh-Hashi, N., 87, 95 Ohki, S., 205, 225 Ohloff, G., 1 8 , 83, 9 3 , 122 Ohlrogge, J. B., 261 Ohlson, R., 249 Ohlsson, H., 2 3 4 Ohnishi, M., 269 Ohta, K., 2 2 , 24 Oien, H. G., 1 9 9 , 2 3 3 Ojima, N., 1 3 4 Okami, Y ., 30 Okawara, M.,191 Okayasu, T., 259 Okazaki, H., 284 Okazaki, T., 30 Okimoto. T., 254 Okuda, T., 15 5 Okuhara, K., 241 Okuma, M., 232 Okuniewicz, F. J., 210, 217 Oliver, J. E., 255 Olivson, A., 8 1

A uthor Index Olson, D. L., 239 Olson, E. S., 254 Omura, S., 131, 150, 151, 154

Ono, T., 259 Onodera, K., 166 Oppong, I. V., 17,237 Ord, M. R., 11 Orena, M., 84 Oriente, G., 47,48, 50, 52 Orr, A. F., 1 6 1 Osborn, J. A., 256 Osborne, D. J., 225, 226, 228,230

Osman, S. F., 254 Osman, S . M., 237, 238, 2 54

Ostrow, R. W., 118 Otsuji, Y., 7 6 Otsuka, S., 68, 7 7 Ottenheijm, H. C. J., 139 Ottenstein, D. M., 246 Ottinger, R., 4 6 Overman, L. E., 89 Overton, K. H., 9 5 Ozaki, M., 290 Pabon, H. J. J., 242, 255

Pabst, W. E., 241 Pace, C., 35 Pace-Asciak, C. R., 225, 230,231,232, 234 Padilla, A., 194 Pagnoni, U. M., 7 1 Pailer, M., 201 Palermo, R. E., 87 Palmer, J. R., 195 Paltauf, F., 274, 281 Panayosan, A. G., 269 Pancoast, T. A., 127 Pandey, R. C., 15 5 Pandit, U. JL, 201 Panganamala, R. V., 228 Panosyan, A. G., 274 Pappo, R., 195 Paquette, L. A., 75 Paradis, M., 236 Park, D. S., 10 Park, N. S., 10 Park, R. B., 262 Parker, C. W., 233 Parker, R. B., 234 Parker, T., 190 Partridge, L. G., 287 Partridge, R., 213 Pascard, C., 15 1 Pascher, I., 248, 287 Pasquet, G., 206 Pastura, A., 246 Patel, K. M., 241 Pattee, H. E., 251 Pattenden, G., 18, 86, 134,135 Patwardhan, S. A., 162

303 Paul, I. C., 43, 162, 1 6 6 Paul, K. G., 171 Pauling, H., 84 Paulus, H., 119 Pawlak, J., 156 Pawlak, M., 18, 122 Paxton, J., 229 Payne, N. A., 227 Payne, T. L., 106 Pearce, G. T., 116 Pearce, R. E., 236, 237 Pearson, A. J., 76, 7 7 Pedder, D. J., 114 Pedler, A. D., 100 Pedone, C., 44,45 Pedro Llinares, J. R., 242

Peinel, G., 290 Pelick, N., 246 Pella, E., 218 Pellegata, R., 216, 218 Pelz, K., 192 Penglis, A. A. E., 272 Percy, J., 102 Percy, J. E., 109 Perez, C., 39,41, 97 Perkins, E. G., 246 Perron, R., 248 Perry, D. L., 234 Persoons, C. J., 110, 113

Peruzotti, G. P., 210, 213

Peskar, B. A., 225 Peskar, B. M., 225 Petcher, T. J., 136 Peter, M. G., 95 Petersen, M., 249 Peterson, D. C., 195 Peterson, D. O., 258 Pettei, M. J., 93, 115 Pettit, G. R., 40, 53, 6 3 Pettus, J. A., jun., 23, 24, 47

Petty, R. L., 108 Pfeffer, P. E., 247, 256, 258

PflUger, M., 237 Phillips, D. R., 252 Phillips, G. T., 144 Phillips, L., 128, 238 Piancatelli, G., 177 Piantadosi, C., 286 Piattelli, M., 47,48, 50, 52 Pickardt, J., 9 Picken, D. J., 95 Picker, D. H., 156, 174 Piggin, C. M., 11, 15 Pike, J. E., 29, 217, 224, 232

Pilgrim, W. R., 206 Pilkiewicz, F. G., 93, 114, 115

Pillot, J.-P., 7 1 Pindak, R., 289

Pino, P., 2 5 7 Pirillo, D., 195, 196 Pisareva, I. V., 68 Pitas, R. E., 262 Pitman, G. B., 1 11 Pitzele, B. S., 9 4 Pivnitskii, K. K., 191 Plattner, J. J., 215 Plattner, R. D., 236, 238, 239,240

Platz, H., 108 Pliske, T. E., 108 Plummer, E. L., 1 16 Pogonowski, C. S., 177, 207

Poletto, J. F., 193 Poling, M., 53 Pollard, M. R., 247, 259 Pollini, G. P., 194 Pong, S. S., 232 Poovaiah, B. P., 261 Popov, S., 58, 59 Porter, N. A., 222, 228, 250,251

Portoghese, P. S., 221, 222 Posner, G. H., 93 Potgieter, D. J. J., 12 Potgieter, H. C., 12 Poulter, C. D., 73 Powell, C. C., 80 Pownall, H. J., 241 Pozsgay, V., 156 Pradelles, P., 225 Prager, R. H., 86 Prakazova, N. V., 265 Precht, D., 248, 287 Predvoditelev, D. A., 278, 280,281, 283,284

Prescott, F. A. A., 253 Prestwich, G. D., 114 Price, K. R., 8 Pridachina, N. N., 269 Priesner, E., 103 Priestap, H. A., 17, 239 Privett, 0. S., 255 Procarione, W. L., 290 Prodan, K. A., 237 F'roveaux, A. T., 110 Proverbs, M. D., 103 Pryde, E. H., 255, 257 Pryor, W. A, 250 Pugh, E. L., 260, 264 Purcell, T. A., 1 5 9 Purchas, R. W., 237 Purdham, J. T., 114 Puskas, I., 286 Pynadath, T. I., 259 Quagliariella, E., 2 84 Quinn, R. J., 23, 35, 42, 57, 58, 62

Raaijmakers, J. G. A. M., 2 34

Rackman, D. M., 226

Author Index

304 Radford, T., 80 Radwan, S. S., 262 Rahimtula, A., 228 Rainey, D. K., 175 Rainey, W. T., jun., 286 Rakoff, H., 240 Ramadoss, C. S., 251 Ramirez, F., 272, 283, 28 4 Ramirez, M. A., 39, 97 Ramos, J. A., 259 Ramos, J. R., 258 Ranganathan, D., 193, 243 Ranganathan, S., 193, 243 Rao, A. S. C. P., 37 Rao, C. V., 232, 233 Rao, G. N. S., 286 Rao, Y. S., 132, 262 Raphael, R. A., 159 Rapoport, H., 65, 137 Rapp, E., 136 Rapp, u., 155 Raucher, S., 181 Ravi, B. N., 51 Raz, A., 229, 232 Reddy, P. V., 291 Reffstrup, T., 130, 133 Reichenbach, H., 144 Reichwald, I., 262 Reid, E. H., 246 Reifz, T. J., 127 Relano, E., 259 Kernion, J., 240 R->n,W.-Y., 136 Renger, B., 160 Renkonen, O., 264 Renwick, J. A. A., 111 Restivo, R. J., 128 Reuschling, D., 200, 204 Reusser, F., 166 Reynolds, J., 252 Riccio, R., 32, 37, 50, 51 Rickards, R. W., 137 Kichman, J. E., 177 Richter, E., 13 Richter, W. J., 145 Rietschel, E. T., 238 Rilling, H. C., 90, 9 1 Rinehart, K. L., 43, 131, 155, 166, 167 Ringel, S. M., 128 Riser, G. R., 257 Ritchie, G. A. F., 220 Ritter, F. J., 110, 113 Rivers, J. P. W., 260 Ro, H. S., 10 Roach, J . B., jun., 201 Robacker, D. C., 113 Robb, C. M., 222 Roberts, B. P., 251 Roberts, L. J., 227 Roberts, S. M., 175, 190 Robertson, K. J., 5 0 , 51

Robinson, D., 232 Robinson, H., 9 Robinson, J. R., 261 Robinson, R., 278 Rodriguez, M. L., 42 Roelofs, W. L., 102, 103, 106 Roemer, S., 128 Rohwedder, W. K., 250, 253,256 Rojahn, W., 79 Rojas, M., 47 Roller, P. P., 22 Rome, L. H., 232 Ronald, R. C., 4 3 Rose, A. F., 23, 4 4 Rosegay, A., 226 Rosello, J., 234 Roseman, T. J., 234 Rosenblum, L. D., 124 Rosenfeld, I. S., 261 Rosenthal, A. F., 276, 279,282 Ross, C. H., 136 Ross, D., 239 Ross, M. S. F., 247 Rossall, S., 15 Rossi, R., 116, 127, 256 Rosynov, B. V., 269 Rouessac, F., 123, 218 Rozek, L. F., 212 Rozin, A. E., 280, 286 Rozing, G. P., 199 Rozynov, B. V., 265 Rubinstein, I., 58 Rudi, A., 57 Russell, J. R., 256 RLveda, E. A., 17, 239 Sable, H. Z,, 276, 287, 289 Sacks, R. W., 261 Safe, S., 3 Safer, M., 235 Sahni, R., 78 Sahu, W. P., 239 Saigo, K., 148 St. Pyrek, J., 97 Saito, Y., 261 Sakabe, N., 130 Sakaguchi, Y., 135 Sakai, K., 173, 193, 207, 208. 218 Sakai, R., 141, 142 Sakamura, S., 141, 142, 144, 146 Sakan, T., 116 Salm, K. - P., 249, 292 Salmon, J. A., 230, 233 Salomon, M. F., 222 Salomon, R. G., 222 Salzmann, T. N., 11 8 Samain. D., 120 Sarnpugma, J., 247 Samson, M., 233

Samuelsson, B., 210, 219, 225, 231, 234, 235, 2 52 Sanchez Pararedo, J., 242 Sandermann, H., jun., 290 Sanders, J. K., M., 17, 237 Sanders, M. E., 125 Sandri, S., 84 Sanjoh, H., 8 8 Sanner, J. H., 212, 233 Santacroce, C., 44, 45, 48, 50, 56, 57, 5 8 Santi, M., 256 Sargent, J. R., 260 Sarnstrand, C., 147 Sarre, O., 155, 165 Sartori, G., 165 Sasaki, K., 166 Sasaki, T., 143 Sastry, P S., 279, 291 Sato, H., 141 Sato, R., 106 Sato, T., 110, 125, 132 Satomi, T., 166 Satterwhite, D. M., 7 3 Saunders, A. D., 77, 257 Scarborough, R. M. 146 Scettri, A., 177 Schaaf, T. K., 170, 232 Schaefer, C. G., 125 Schafer, H. J., 257 Schalber, J., 192 Schalk, D. E., 9 3 Schaub, R. E., 193, 213 Schenkluhn, H., 6 8 Scherling, D., 164 Scheuer, P. J., 20, 21 Schexnayder, M. A., 229 Schildknecht, H., 113 Schiller, H., 286 Schilling, W., 148 Schlenk, H., 259 Schlessinger, R. H., 132, 136, 177 Schloeder, U., 246 Schletter, I., 187 Schmid, H., 95 Schmid, H. H. O., 292 Schmidt, D. E., jun., 286 Schmidt, S. P., 1 0 6 Schmidtchen, F. B., 137 Schmitz, B., 237 Schmitz, F. J., 20, 26, (10, 50, 62 Schneider, D., 1 0 8 Schneider, W. P., 29, 170, 187,224 Schlineweiss, S., 9 Schonholzer, P., 54, 57, 62 Scholz, D., 161 Schrock, R. R., 256 Schroeder. F.. 249 Schulze, G., 277

Author Index Schumacher, G., 290 Schuyl, P. J. W., 247 Schwab, A. W., 256 Schwartz, D. P., 247, 254 Schwartz, J. L., 131 Schwartzman, M., 229 Scolastico, C., 21 1 Scott, F., 74, 122 Scott, L. T., 149 Scribner, R. M., 201 Scrimgeour, C. M., 239, 247 Sedwick, B., 259 Seebach, D., 160 Seher, A., 286 Seibel, R., 255 Sekita, S., 142, 163 Sekiya, J., 19, 252 Selke, E., 253 Semenovskii, A. V., 97 Senior, M. W., 220 Seoane, E., 239, 242 Serebrennikova, G. A., 274, 280, 282, 283, 286 Serra, M. C., 239 Sessa, D. J., 239 Seto, H., 132, 143 Seto, S., 134 Seto, T., 8 Seuring, B., 160 Seyberth, H. E., 225 Shafer, H. M., 131 Sharaf, D. M., 263 Sharma, H. M., 228 Sharma. M. L... 74 Sharma, S. D., 74, 8 4 , 9 7 Sharpless, K. B., 85, 87, 88,254 Shaw, S. R., 225 Shaw, W. A,, 280 Sheikh, Y. M., 47, 64 Sheldon, D. R., 213 Shen, T. Y., 229 Shepherd, J., 145 Shevchenko, V. P., 282 Shibasaki, M., 186, 188, 189,219,222 Shibuya, T., 106 Shimizu, Y., 20, 60 Shimomura, H., 210,220 Shin, V. A., 283 Shine, W. E., 261 Shiner, C. S., 184 Shinojima, K., 259 Shipley, G. G., 288, 289 Shippey, M. A., 255 Shirado, M., 77 Shiraishi, K., 141, 142 Shizuri, Y., 158 Shono, T., 178 Shoolery, J. N., 247 Shorey, H. H., 102 Short, R. V., 229 Shvarts, G. Y., 202

305 Shvets, V. I., 274, 283 Sica, D., 44, 48, 5 0 , 56, 57,58 Siegelrnan, H. W., 65 Siegenthaler, W., 235 Sies, I., 247 Sih, J. C., 183, 186, 227 Silberglied, R. E., 114 Silbert, L. S., 256, 258 Silva, M., 10 Silver, M. J., 183 Silverstein, R. M., 103, 111,110,116 Silverton, J. V., 1 6 3 Silvius, J. R., 261 Simoni, R. D., 249, 277 Simonidesz, V., 173, 183 Sims, J. J., 2 3 , 2 4 , 35,44, 47 Singelton, J. A., 251 Singer, H., 255 Singh, P., 136 Singy, G., 47 Sinha, N. D., 198 Sinha, S., 237 Sinnige, M. J., 139 Sipio, W. J., 183 Siuta, G. J., 193 Sivapalan, A., 36 Sjbrquist, B., 232 Skattebqjl, L., 82, 1 2 7 Sklar, L. A., 249, 277 Skotnicki, J. S., 193, 2 13 Slawson, V., 252 Sleeper, H. L., 29 Slomiany, A., 264 Smale, T. C., 147 Small, D. M., 289 Smigel, M., 230 Smit, V. A., 97 Smith, A. B., 146, 237 Smith, A. G., 234 Smith, C. R., jun., 238, 240 Smith, D. G., 138 Smith, D. H., 46, 70 Smith, J. B., 183 Smith, P. F., 267 Smith, R. L., 199, 222 Smith, R. W., 224 Smith, S., 262 Snedden, W., 234 Sneden, A. T., 15 8 Snyder, F., 259, 286 Snydor, T. D., 81 Sobczak, R. L., 153 Sodano, G., 21, 37, 5 8 , 60 Solheim, B. A., 114 Solladie, G., 79 Song, B. J., 10 Sonnet, P. E., 109, 255 Sonoda, A., 240 Sook Choi, H., 194 Sorba, J., 254 Sors, H., 225

Sparrow, J. T., 241 Speckart, P., 235 Spek, A. L., 233 Spencer, G. F., 236, 239, 240 Spener, F., 260 Speroff, L., 225 Sprecher, H., 229, 242, 259 Springer, J. P., 114, 163 Staedler, E., 116 Stalhandske, C., 147 Stallard, M. O., 32 Stan, PI. J., 253 Stanacev, N. Z., 247,276 Stanley, J. P., 250 Starr, M. P. 145 Starratt, A. N., 242 Staunton, J., 131, 145 Steen, G., 239 Stefani, A., 257 StefanoviC, D., 263 Steffenrud, S., 234 Stehle, R. G., 224 Stein, R. A., 247, 252, 2 54 Stein, S. J., 187, 217 Steiner, E., 58 Steinman, D. H., 94 Stemp, G., 18 Stepanov, A. E., 283 Stephens, N., 259 Steudler, P. A., 40, 50 Stevens, K. L., 8 4 Stewart, T. E., 116 Stierle, D. B., 35 Stillway, L. W., 236, 237 Stipanovic, R. D., 115 Stoffel, W., 243, 249, 292 Stokes, M. A., 276 Stokie, G. J., 37, 53 Stone, K. J., 224, 229 Stork, G., 179, 180, 181 Stork, P. J., 148, 245 Stoyanova, V. G., 265 Strain, H. H., 65 Stransky, W., 117, 119 Strassburger, P., 255 Strauss, H. F., 12 Streck, R., 117 Streckert, G., 253 Streelman, D. R., 158 Strickler, H., 8 3 Stromquist, P., 89 Strunz, G. M., 136 Struwe, H., 68 Stuhne-Sekalec, L., 276, 247 Stumpf, P. K., 261 , 262 Stuttle, K. A. J., 190 Subramanian, C., 2 59 Suchy, M., 47 Sugahara, T., 188 Suggs, J. W., 78 Sugie, A., 210, 220

Author Index

306 Sugita, M., 270 Sumino, Y., 1 4 3 Sumrell, G., 248 Sun, F. F., 195,229,230, 231,235 Sun, H. H., 2 6 , 4 0 , 5 2 Sundell, S., 287 Sunder, S., 248 Sufiol, C., 234 Supina., W. R., 246 Suprunchuk, T., 250 Surmatis, J. D., 85 Suwita, A., 7, 9,lO Suzuki, A., 132 Suzuki, E., 13 1 Suzuki, K., 151 Suzuki, M., 43, 151, 155 Suzuki, T., 39, 41, 155 Svec, W. A., 65 Svensson, C., 147 Sweetman, B. J., 225, 227, 232,234 Swern, D., 254 Swoboda, P. A. T., 253 Sydnes, L. K.,82 Sykes, R. B., 143 Szintay, C., 191 Szkkely, I., 173, 183, 184 Szumlewicz, S., 165 Taber, D. F., 182 Taguchi, Y., 1 3 5 Tahara, Y., 268 Tai, H. - H., 235,224 Takabe, K., 74, 84 Takagi, M., 22 Takagi, T., 21 5 Takahashi, C., 142 Takahashi, I., 134 Takahashi, S., 248 Takahashi, T., 118, 179, 24 1 Takahatake, Y., 182 Takano, S., 171, 173 Takayanagi, H.,4 8 Takegame, Y., 274 Takeshima, H., 15 1 Taketomi, T., 68 Takigawa, T., 127 Talman, E., 110, 113, 116 Tamaki, Y., 103, 106 Tamas, J., 156 Tamm, C., 136, 158, 164 Tamura, T., 171, 215 Tamura, Y., 171 Tanaka, A., 152 Tanaka, E., 6 8 Tanaka, J., 74, 84 Tanaka, M., 74 Tanaka, T., 194, 2 11 Tang, C. - T., 276 Tang, J. -C., 276,282 Tanigawa, K., 17 3 Tanis, S. P., 114, 115

Tanouchi, T., 174 Tappel, A. L., 2 5 3 Tateson, J. E., 229 Tatsuta, IS., 152 Taub, D., 226 Tavernier, D., 2 3 3 Taylor, P. L., 229, 234 Taylor, R. J. K., 203 Tecoma, E. S., 249 Tekitek, A., 4 7 Ten Hoor, F., 230 Terada, Y., 4 9 Terao, J., 250 Terahara, A., 143 Terashima, S., 87, 174, 180 Terragno, D. A., 229 Terragno, N. A., 229 Teshima, S. I., 64 Teufel, H., 193, 197 Thaller, V., 3, 10, 11, 13, 15 Thalmann, A,, 159, 162 Tham, K. T., 234 Thgmel, F., 68 Thomas, A. F., 8 0 Thomas E. W.. 141.242 Thomas, R., 132 Thomas, R. C., 2 19 Thompson, J. L., 183 Thompson, R. H., 147 Thomson, R. H., 36 Thorogood, P., 232 Thorson, R. L., 239 Thrum, H., 152, 155 Thuy, L. P., 229 Tilborg, H., 291 Tilden, P. E., 111 Ting, J. - S., 9 3 Tinoco, J., 261 Tishler, M.,131, 141, 151,242 Tode, S., 290 Todriza, K. G., 265 Tokhs, L., 198 Tomoskozi, I., 173, 183 Tokuyama, T., 12 Tolstikov, G. A., 70, 75 Tomioka, K., 215 Torgerson, D. F., 163 Tori, K., 157 Torto, F. G., 17, 237 Toru, T., 178, 194, 211, 212 Toth,,G., 65 Toube, T. P. 1 3 7 Tove, S. B., 261 Towers, G. H. N., 1 5 Traverso, S., 195, 196 Traxler, P. 145 Treschova, E. G., 69 Tringali, C., 4 7 , 4 8 , 50, 52 Tripp, V. W., 248 Trivedi, G. K., 80 Trivellone, E., 56

Trofast, J., 146 Tronconi, G., 2 11 Tropp, B. E., 268, 276, 278,282 Trost, B. M., 8 5 , 9 2 , 118 , 150, 171 Tschinkel, W. R., 114 Tsuboi, H., 284 Tsuboi, S.,89 Tsuji, J., 1 18, 24 1 Tsuji, N., 142 Tsukihara, T., 147 Tsutsui, M., 91. 95 Tuebner, J., 286 Tulloch, A. P., 243, 247, 264,265 Tumlinson, J. H., 110, 116 Tunemoto, D., 182, 192 Turnbull, A. C., 225, 226 Turner, J. A., 228, 230 Turner, J. L., 10, 15 Tursch, B., 2 0 , 4 6 , 4 7 , 53, 54,61, 62,63, 102, 114 Tusell, J. M., 234 Tyhach, R. J., 268 Tyler, R. C., 112, 116 Tyman, J. H. P., 243 Ubatuba, F., 229 Ubukata, M., 144 Uchida, K., 162 Uchida, M., 124 Uchida, Y., 68, 77 Uebel, E. C., 109 Ueyama, M., 157 Uguen, D., 77, 82 Ui, T. 132 Utrich, P., 161, 245 Umbreit. M. A., 85 Umekawa, H., 30 Umemoto, T., 182 Umezawa, S., 152 Unruh, J., 247 Untch, K. G., 213 Uotani, N., 156 Urano, S., 132 Urry, D. W., 233 Usui, M., 148 Utimoto, K., 122, 162 Uyehara, T., 4 8 Uzawa, J., 132 Vagelos, P. R., 249 Valicenti, A. J., 254 Van-Boom, J. H., 280 Van Deenen, L. L. M., 279 Van de Graaf, B., 247 Van Den Bosch, H., 279 Vandenheuvel, W. J. A., 225 Vanderah, D. J., 26, 32, 40, 50, 60

Author Index Van Der Helm, D., 40, 50,53 Van Der Ouderaa, F. J., 228 Van Der Plank, P., 2 5 6 Van Der Wolf, L., 2 4 2 Vandewalle, M., 180, 233 Van Dorp, D. A., 228, 242,271,272 Vane, F. M., 2 2 7 Vane, J. R., 229, 230, 231,232 Vanelle, L. D., 40 Vanhaelen, M., 6 2 Van Haver, D., 2 3 3 Van H o o f , E., 1 8 0 Van Horn, D. E., 2 5 7 Vanhulle, F., 180 Van Hummel, H. C., 2 6 2 Van Mourik, G. L., 2 5 5 Van Nipsen, S. P. J. M., 139 Van Oosten, H. J., 2 5 6 Van Orden, D. E., 2 3 5 Van Rheenen.. V., 1 7 6 , 2 5 4 Van Tamelen, E. E., 99,100 Van Tilborg, H., 2 5 3 Varanasi, U., 2 4 9 , 2 9 1 Vargas, L. A., 2 7 9 Varkony, T. H., 5 8 Vasilenko, I. A., 2 8 0 , 2 8 2 , 283,286 Vaver, V. A., 2 6 5 Vedanayagam, H. S., 2 4 7 Vederas, C. J., 164 Velarde, E., 2 1 6 Veldink, G. A., 2 5 1 , 253, 262 Velthius, H. H., V., 1 13, 239 Verhagen, J., 2 5 3 Verhoeven, T. R., 85, 1 5 0 Verkuijlen, E., 2 5 6 Verma, S. P. 2 4 8 Vermeer, P., 7 4 Vermeulen, N. M. J., 1 2 Verwiel, P. E. J., 110, 113, 1 1 6 Vetter, W., 31, 2 3 5 Veysoglu, T., 1 2 7 Vial, C., 18, 1 2 2 Vicentini, C. B., 1 9 4 Vig, A. K , 93 Vig, 0. P., 7 4 , 8 4 , 9 3 , 97 Vining, L. C., 1 3 8 Vinson, W. A., 9 5 Visky, Z., 1 9 1 Vite, J. P., 103, 1 0 6 , 111 Vlattas, I., 2 0 2 Vliegenthart, J. F. G., 2 5 1, 253,262

307 Vloon, W. J., 2 0 2 Vohra, K. N., 2 4 5 Voigt, D., 1 5 5 Vokoun, J., 1 5 5 Volkova, L. V., 2 8 3 Vol’pin, M. E., 84 Von Dreele, R. B., 40, 5 3 Von Imhoff, V., 2 4 6 Von S t r a n d t m a n n , M., 1 2 8 Vorbruggen, H., 1 4 9 Voser, W., 1 4 4 Vostrowsky, O., 1 1 9 , 1 17, 108 Vuturo, S. B., 1 2 5 Wada, E., 1 9 1 Wada, K., 9, 1 6 1 Wadhams, L. J., 1 1 1, 11 6 Wagner, E., 2 7 4 Wahlberg, I., 9 2 Waiss, A. C., jun., 1 5 , 11 5 Wakamatsu, T., 1 4 9 Wakisaka, Y., 1 4 2 Walker, B. L., 2 6 1 Walker, E. R. H., 2 13 Walker, G., 2 4 6 Walker, J. A., 2 1 9 Walker, R. W., 2 2 5 Wallace, B., 6 9 Wallach, D. F. G., 2 4 8 Wang, A. H. - J., 166 Wang, C . - L. I., 2 0 7 , 210,217 Waraszkiewicz, S. M., 26, 40,41, 5 2 Ward, F. E., 2 1 0 Ward, J. P., 2 7 1 , 2 7 2 Warnaar, F., 2 3 7 Warner, T. C., 2 7 7 Warren, R. G., 3 4 Warren, S., 2 4 0 Washburn, W. N., 9 8 Wassef, M. K., 2 6 9 Wat, C. - K., 1 5 , 1 3 8 Watanabe, Y., 8 Watkins, C. L., 1 9 0 Watson, J. T., 2 2 5 , 2 3 4 Watson, K. C., 9 9 Watt, D. S., 2 4 1 Wax, R., 1 3 9 Weatherston, J., 1 0 2 , 1 1 6 , 118 Webb, C. F., 1 7 5 Webb, T. R., 1 7 1 Weber, D. J., 2 3 4 Weber, H.P., 1 3 6 Weedon, B. C. L., 6 5 , 137,250 Wegfahrt, P., 6 5 Wegmann, A. - M., 58, 59 Weigel, L. O., 1 2 5 Weil, J. - B., 2 1 8 Weinreb, S. M., 1 3 6 Weinheimer, A. J., 5 3

Weisleder, D., 2 3 8 , 239, 253 Weiss, B., 2 8 5 Weiss, M. J., 1 9 3 , 2 1 3 Weiss, Y., 2 3 5 Wekell, J. C., 5 5 Weksler, B. B., 2 3 0 Welch, SI C., 3 7 Wells, J. M., 1 6 2 , 163 Wells, M. A., 2 7 7 Wells, R. J., 2 3 , 28, 2 9 , 31, 34, 35, 4 2 , 4 4 , 4 8 , 4 9 , 54, 57, 5 8 , 6 2 Wendisch, D., 1 16 Wenham, M. J., 1 1 1 West, J. R., 1 1 6 Westcott, A. 1 6 5 Westmijze, H., 7 4 Weston, R., 1 3 9 Weyerstahl, P., 7 5 Whalley, W. B., 1 2 8 Wheller, J. W., 102, 112, 113,239 White, D. F., 2 2 4 White, D. R., 1 7 6 White, E. M., 79 White, J. D., 1 6 0 White, J. G., 2 2 2 White, J. L., 2 4 9 White, R. H., 2 8 , 2 4 0 , 270 Whiting, D. A., 1 1 5 Whiting, M. C., 9 1 Whitlock, C. B., 2 5 3 Whitlock, H. W., 1 6 5 Whittaker, N., 183, 2 3 0 Whorton, A. R., 2 3 0 Wichmann, J. K., 1 0 3 Wickberg, B., 1 4 6 Wickrema Sinha, A. J., 2 2 5 Widdowson, D. A., 9 9 Wiedenmann, B., 2 5 Wuesundera, R. C., 2 3 9 Wiles, D. M., 2 5 0 Wiley. P. F., 1 3 9 . 1 6 7 Willadsen, P., 2 5 9 Willard, A. K., 1 9 6 Williams, D. C., 9 7 Williams, D. R., 1 4 1 , 1 6 0 Williams, K, 61 Williams, L., 1 9 4 Williams, R. N., 1 1 4 Williams, P. J., 1 1 4 Willing, R. I., 2 4 7 Willoughby, D. A., 2 3 4 Wilson, B. W., 2 3 4 Wilson, N. M., 1 0 9 Wilson, S. R., 70, 93, 2 3 7 Wing, R. M., 23, 24, 3 5 Winnik, D. A., 2 5 7 Wipf, H. K., 4 7 Wiqvist, N., 2 2 6 Wirthlin, T., 1 5 6 Wirtz-Peitz, F., 2 3 6 Wisniak, J., 2 6 2

Author Index

3 08 Wissner, A.,197, 2 1 3 Witkop, B., 1 2 Wittings, L. A., 2 4 6 Witty, T. R., 1 6 6 Witzke, J., 1 4 4 Woessner, W. D., 2 1 3 Woggan, W. - D., 9 5 Wolf, F. J., 2 2 5 Wolfe, L. S., 232 Wolinsky, J., 79, 8 2 Wolinsky, L. E., 39, 9 3 Wollenberg, R. H., 1 6 0 Wong, D. H., 2 3 7 Wong, E., 2 3 7 Wong, P. Y. - K., 2 2 9 Wood, D. L., 111 Wood, G. W., 2 8 6 Wood, H. C. S., 96 Wood, M., 8 2 Wood, W. F., 1 1 4 Wood, W. I., 2 5 8 Woodruff, H. B., 8 1 Woolard, F. X . , 22, 3 6 Wrang, P., 9 Wratten, S. J., 21, 26, 37, 55 Wright, J. J., 1 5 6 Wright, J. L. C., 1 3 8 WU, G. - S., 252 Wynalda, M. A., 2 3 5

Wysong, D.

V., 1 6 5

Yabusaki, K. Y., 2 7 7 Yagi. H.. 68. 7 7 Yakhontov, L. N., 2 0 2 Yamada, K., 1 9 3 , 2 2 6 Yamada, S., 1 7 4 , 180 Yamada, S. - I., 8 7 , 9 5 Yamada, Y., 8 8 , 2 6 8 Yamaguchi, M., 161 Yamamoto, H., 86, 88, 91, 1 5 0 , 205, 210, 220 Yamamoto, S., 2 0 5 , 2 2 8 , 2 32 Yamamoto, T., 2 5 4 Yamamoto, Y., 135, 2 4 0 Yamamura, S., 4 9 Yamana, H., 1 5 4 Yamasaki, T., 116 Yamashita, A., 2 5 5 Yamashita, K., 8 Yamashita, M., 2 7 4 Yamaya, M., 1 6 2 Yanagisawa, I., 1 7 1 , 2 1 5 Yanishlieva, N., 291, 2 5 3 Yano, K., 1 6 Yarbrough, C. M., Tert., 233 Yarger, R. G., 237

Yasuda, A., 88 Yasuda, H., 118 Yasuda, I., 8 Yatagai, H., 2 4 0 Yeh, C. L., 2 4 2 Yokoyama, Y., 8 7 Yonehara, H., 1 3 2 , 1 4 3 Yonemoto, R. H., 259 Yoshihira, K., 1 4 2 , 1 6 3 Yoshikoshi, A., 85 Yoshimoto, T., 2 3 2 Young, J. C., 103, 1 1 1 Yuan, B., 2 3 5

Zakharkin, L. I., 68 Zarins, A., 2 4 9 Zdero, C., 2 , 4 , 5, 6, 7, 9, 1 0 , 8 4 Zelenova, L. M., 7 5 Zia, P., 2 3 5 Ziegler, F. E., 98 Zielinski, J., 155, 156 Zipser, R., 2 3 5 Zmijewski, M., 1 4 0 , 1 8 6 Zmuda, A., 2 3 2 Zoretic, P. A., 1 9 8 , 1 9 9 , 200 Zurita, M. E., 2 4 0 Zvonkova, E. N., 2 8 4

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