Carotenoids

Carotenoids Volume 2: Synthesis

Edited by G. Britton S. Liaaen-Jensen H. Pfander

Birkhauser Verlag Basel· Boston· Berlin

Editors:

Dr. George Britton Reader In Blochemistry Department 01 Biochemistry

The University 01 Liverpool P.O Box 147

Liverpool L69 3 BX England

Prolessor Dr. Dr. h. c. Hanspeter Plander Institut lür organische Chemie Universität Bern Freiestrasse 3 CH-3012 Bern Switzerland

Prolessor Dr. Dr. h. c. Synn0ve Liaaen-Jensen Prolessor 01 Organic Chemlstry Organic Chemistry Laboratories Norwegian University 01 Science and Technology The Norwegian Institute 01 Technology N-7034 T rondhelm Norway

A CIP catalogue record lor th,s book is available from the Library 01 Congress, Washington D.c.. USA.

Deutsche Bibliothek Cataloging-in-Publication Data

Carotenoids / ed. by G. Britton. - Basel; Boston; Berlin: Birkhäuser. NE: Bntton, George IHrsg.1 Vol. 2. Synthesls. - 1996

ISBN-13: 978-3-0348-9325-1 e-ISBN-13: 978-3-0348-9323-7 001: 10,1007/978-3-0348-9323-7

The publisher and editors cannot assume any legal responslbility lor inlormation on the use 01 chemicals, equipment and patents, drug dosage and administration contained in this publication. The respective user must check its accuracy by consultlng other sources of reference in each Individual case.

The use of registered names, trademarks, etc. In this publication, even il not identilied as such, does not Imply that they are exempt from the relevant protective laws and regulations or Iree lor general use.

This work IS subject to copyright. All rights are reserved, whether the whole or part 01 the material is concerned, specifically the rights 01 translation, repnnting, re-use 01 illustrations, recitation, broadcasting, reproduction on

microlilms or in other ways, and storage in data banks. For any kind 01 use the perm iss ion of the copyright holder

must be obtained.

© 1996 Birkhäuser Verlag, P.O. Box 133, CH-4010 Basel, SWltzerland Ca me ra-ready copy prepared by D. Kuli and Ch. Bircher,

Cover design: Markus Ettench, Basel

987654321

v

Contents

International Advisory Board and List of Contributors ...... . .... XIII

Preface ... . ... XVII

Editors' Notes ..... . ....................................................................... XIX

Chapter 1: General Aspects

Part I: Synthesis in Perspective Hanspeter Pfander, Synn¢ve Liaaen-Jensen and George Britton ..

Part II: Strategies for Building the Carbon Skeleton Milan Soukup, Paul Spurr and Erich Widmer

A. Introduction 7 B. General Strategies.. . ... 7 C. Examples . . .... II

1. Wittig reaction: Astaxanthin and zeaxanthin........................... . ........... II 2. Julia sulphone coupling: Zeaxanthin 12 3. Wittig reaction with unsymmetrical carotenoids: (S)-Trisanhydrobacterioruberin ...... 12 4. Dimerization: ~,~-Carotene ......... 13

References ..... 14

Part III: Characterization of Products Hans Mayer and Urs Hengartner

A. Introduction B. Isomers of ~,~-carotene .. C. (7Z)-Lycopene .. D. Lutein ... E. Zeaxanthin ...

.. .................................................. 18 . ....................................................................................... 20

. ................................................. 21 F.3,4,3',4'-Tetraacetoxypirardixanthin ............ 24 References.. ........ .. .. ..... ... ... . ................................................................................. 26

VI

Chapter 2: Coupling Reactions

Part I: Enol Ether and Aldol Condensations Ludvik Labler, August Ruttimann and Alfred Giger

A. Introduction B. Enol Ether Condensations ...

I. Alkyl enol ethers .. 2. Trimethylsilyl enol ethers ....

C. Aldol Condensations ... References ... .

Part II: Organometallic Reactions Percy S. Manchand

27 . .............................. 27

. ............................................... 27 . ... 30

34 ..... 52

A. Introduction ..... . ... 55 B. General Procedures... .55 C. Metals of Groups lA, I1A and I1IB (Li, Na, Mg and Zn) .... . ........ 56

1. Metal acetylides (alkynylides}... . ..... 56 2. Metal alkeny Is ... . .59 3. Allylic alkali metal derivatives 61 4. Zinc reagents .................................................................................................................................................... 62

D. Palladium-mediated and Nickel-mediated Reactions ..... . .................................. 64 1. Palladium ... 2. Nickel ...

E. Copper ... 1. Cadiot -Chodkiewicz coupling reaction ... 2. Cuprates ....

F. Low-valent Titanium References ...

Part III: Wittig Olefination Hansgeorg Ernst

A. Introduction ..... . B. Phosphorus Ylides ...

I. Reactivity of phosphorus ylides .. 2. Production of phosphorus ylides ...

C. Stereochemistry 1. Factors that influence stereoselectivity ... 2. Steric control ...

D. Reaction Mechanisms .... E. Horner-Wadsworth-Emmons Olefination .....

.64 . .......... 69

. .. 70 ...................... 70

. ......................... 71 .. 71

. .................................................. 76

.................................. 79 . .. 80 . .. 80

............................ 81 ... 82 ... 82 . .. 83 ...85

. .................. 87

F. Use of the Wittig Reaction in Carotenoid Synthesis ... 1. Introduction ... 2. Bond formation between C(7)/C(8), or C(7')/C(8') .... 3. Bond formation between C( II )/C(l2), or C( II ')/C( 12') 4. Bond formation between C( 15)/C( IS')

References

Part IV: Sulphone Coupling funza Otera

A. Alkylation - Elimination Method .. I. Synthesis of vitamin A derivatives ... 2. Synthesis of carotenoids

B. Double Elimination Method References

Chapter 3: Carotenoid Synthesis

Part I: Polyene Synthons Robert K. Muller

A. Introduction .. B. Symmetrical Central CIO"Components ...

VlI

.... 89 . ..................................... 89

. ...... 90 . ........ 92

98 101

......................................... 103 . ................................... 103

108 III 113

liS .. 116

1. CIO-Components of various functionality .. 116 2. Industrial routes to the C lO-dialdehyde.. . ..................................... 1 17 3. Unsymmetrically functionalized central CIO-components.... . .......... 118

C. Synthesis of Protected CJ5" and C2o-Dialdehydes. . . 120 D. CIO-Components for the Synthesis of Segments C(8) to C(1S) and

C(IS') to C(8') ........................................ 121 E. 1,4-Bifunctional Isoprenoid Cs-Building Blocks ... . . .................................. 123

1. (E)-4-Acetyloxy-2-methylbut-2-enal.... . .................... 123 2. Monoacetals of (E)-2-methylbut-2-ene-1 ,4-dial 125 3. Cs-Phosphonium ester salts and Cs-phosphonate esters.. . ............ 126 4. 5-Hydroxy-4-methyl-2(5H)-furanone.. . .................... 128

References .... 129

Part II: Acyclic Carotenoids Hanspeter Pfander and Bruno Traber

A. Introduction ... B. Carotenoids with the 'I' End Group

131 132

VIIl

C. Carotenoids with the 3,4-Didehydro-'I' End Group ................................................................... 139 D. Carotenoids with the 1,2-Dihydro-'I' End Group .............................................................. 140 E. Carotenoids with the I-Hydroxy-3,4-didehydro-l,2-dihydro-'I' End Group ....... 141 F. Carotenoids with the I-Methoxy-3,4-didehydro-l,2-dihydro-'I' End Group ..... 142 G. Carotenoids with the I-Hydroxy-l,2-dihydro-'I' End Group ................................. 144 H. Carotenoids with the 16-Hydroxy-'I' End Group ...... .. ....... 145 I. Carotenoids with the 1,2-Dihydroxy-3,4-didehydro-l,2-dihydro-'I' End Group. 147 J. Carotenoids with the 1,2-Epoxy-l,2-dihydro-'I' End Group.... . .. 148 K. Carotenoids with the I-Methoxy-2-keto-3,4-didehydro-l,2-dihydro-'I'

End Group ... ..150 L. C4S- and Cso-Carotenoids ... . ........................... 152 M. Diapocarotenoids . References ....

. .............................................................................................................. 157

Part III: Synthesis of Cyclic Carotenoids Hanspeter Pfander and Birgit Bartels

..159

A. Introduction... . ............... 161 B. Carotenoids with the ~ End Group ..................................................................................................... 162

1. ~,~-Carotene ..... .. 162 2. Carotenoids with the 3,4-didehydro-~ end group...... .. 164 3. Retro-carotenes... . ................ 166 4. Carotenoids with the 2-hydroxy-~ end group.. 167 5. Carotenoids with the 3-hydroxy-~ end group.. ....... ... .......... ........ ... ...... 169 6. Carotenoids with the 4-hydroxy-~ end group ... . ............................................................ 172 7. Carotenoids with the 3,4-dihydroxy-~ end group ... .173 8. Carotenoids with the 5,6-dihydroxy-5,6-dihydro-~ end group ............................................. 175 9. Carotenoids with the 3,5,6-trihydroxy-5,6-dihydro-~ end group 10. Carotenoids with the 5,6-epoxy-5,6-dihydro-~ end group .. .. 11. Carotenoids with the 5,8-epoxy-5,8-dihydro-~ end group .. .

176 .176 .177

12. Carotenoids with the 3-hydroxy-5,6-epoxy-5,6-dihydro-~ end group ...................... 179 13. Carotenoids with the 2-oxo-3,4-didehydro-~ end group 180 14. Carotenoids with the 3-oxo-retro-~ end group...... . ........................................ 181 15. Carotenoids with the 4-oxo-~ end group .................... 182 16. Carotenoids with the 3-hydroxy-4-oxo-~ end group ............................................ 183

C. Carotenoids with the € End Group... . ................ 186 1. ~,€-Carotene and €,€-carotene... .. ....... 186 2. Carotenoids with the 3-hydroxy-€ end group

D. Carotenoids with the 'Y End Group ... E. Carotenoids with the l( End Group .. F. Carotenoids with Aromatic End Groups

1. Carotenoids with the <jJ end group 2. Carotenoids with the 3-hydroxy-<jJ end group .... 3. Carotenoids with the X end group

G. Cso-Carotenoids

187 . .................................................. 189

.. ....... 190 .................................... 192

192 ......... 193

193 193

IX

1. Carotenoids with a substituted ~ end group .. . ............. 193 2. Carotenoids with a substituted £. end group .... 3. Carotenoids with a substituted y end group.

H. Norcarotenoids .. References ....

Part IV: Synthesis of Acetylenic, Allenic and In-chain Substituted Carotenoids Masayoshi Ito

.. 195

.. 196

. .. 198 .. 199

A. Introduction . . 201 B. Synthesis of Acetylenic Carotenoids.. . .. 202 C. Synthesis of Allenic Carotenoids .... .. 204 D. Synthesis of Butenolide Carotenoids... ... 208

1. SuI phone method .. . .. 209 2. Synthesis of the optically active Cwepoxyformyl ester.. ... 211 3. Synthesis of the optically active C22-allenic suI phone with an abnormal

location of the in-chain methyl group.. .212 4. Synthesis of optically active peridinin ... . .. 213

E. Synthesis of ~-Diketone Carotenoids 213 1. The aldol condensation route.. . .. 213 2. The Wittig condensation route ... . .. 214 3. The Claisen condensation route .. . ................................................................ ~ ......... 214

References

Part V: Total Synthesis of (Z)·Isomers Kurt Bernhard and Synn¢ve Liaaen-Jensen

A. Introduction B. Strategy .. C. Formation of (Z)-Double Bonds by Synthesis

1. Sterically unhindered disubstituted (Z)-double bond (15Z) 2. Sterically hindered disubstituted (Z)-double bonds (7Z and lIZ) 3. Trisubstituted (Z)-double bonds (5Z, 9Z and 13Z) 4. Thermodynamically favoured cis double bonds ...

D. Direct synthesis of (Z)-isomers. 1. Carotenes 2. Xanthophylls 3. Apocarotenoids ...

References

216

.217

.218

.219 219

.. 219

... 220 220

..221 221 225 230

.231

x

Part VI: Labelled Carotenoids Frans Jos Jansen and Johan Lugtenburg

A. Introduction .. B. Synthesis ...

I. Synthesis and use of 13C-labelled synthons ... 2. Synthesis of the central CIO-unit with 13C-Iabe1s. 3. Synthesis of unlabelled synthons ... 4. Synthesis of labelled carotenoids .. 5. Deuterium-labelled spheroidenes ..

References ...

Part VII: Technical Syntheses Joachim Paust

A. Economic Importance ... I. Sales

.. 233 .. .................. 236

.236 . ............................... 241

.. 243 . ........... 251

..255

..257

................................... 259 259

2. Areas of application.. ... .... 259 B. Industrial Carotenoid Syntheses not involving any Wittig OIefination ..................... 261

I. Carotenoid synthons from the Roche synthesis of vitamin A.. .261 2. p,p-Carotene .. . ........... 264 3. Apo-p-carotenoids .. . ............ 266 4. Xanthophylls .. ....... 267

C. Industrial Carotenoid Syntheses by means of Wittig OIefination .. . .....269 I. Carotenoid building blocks from the BASF synthesis of vitamin A... . ..................... 269 2. p,p-Carotene 274 3. Apo-p-carotenoids .. . .......................................... 276 4. Xanthophylls ... ........ 281

D. Formulation . . ......... 287 I. Colouration of lipophilic media ... . ........... 287 2. Colouration of hydrophilic media - Production of bioavailable preparations 288

References. 290

Part VIII: Partial Synthesis of Glycosides and Glycosyl Esters Hanspeter Pfander

A. Carotenoid Glycosides ... B. Carotenoid Glycosyl Esters .. References

...................... 293 . ..................................... 294

294

Part IX: Partial Synthesis of Sulphates Synn¢ve Liaaen-Jensen

XI

A. Introduction 295 B. General Route ... . ......... 295 C. Synthesis of Stable Carotenoid Sulphates 296 D. Synthesis of Less Stable Carotenoid Sulphates.. . ..................................................... 297 E. Preparation and Solvolysis Reactions of Unstable Carotenoid Sulphates 298 F. Properties of Carotenoid Sulphates... . ..... 299 References 300

Worked Examples

Example 1: Enol Ether Condensation Kurt Bernhard and Stephan Jiiggli

A. Introduction B. Examples References

Example 2: Organometallic Reactions Percy S. Manchand

A. Introduction B. Synthesis of Ethynyl-~-ionoL C. Synthesis of Vinyl-l3-ionoL .. D. Synthesis of (Z)-I3-Ionylideneacetic Acid ... References

Example 3: Wittig and Horner-Emmons Reaction Hansgeorg Ernst and Peter Munster

A. Introduction B. Syntheses of ~-Apo-8'-carotenoic acid ethyl esters References ....

Example 4: Sulphone Coupling Junzo Otera

A. Retinoic Acid by the Alkylation-Desulphonylation Method ... B. (all-E)-Retinyl Acetate by the Double Elimination Method References ...

301 301 302

303 ................. 303

. ...... 304

. ........ 304 305

307 307

. .... 310

. ....... 311 313

. .................................. 314

XII

Example 5: Asymmetric Syntheses Hanspeter Pfander

A. Introduction .. B. Asymmetric Epoxidation ... C. Asymmetric Dihydroxylation References.

Example 6: Synthesis ex Chiral Pool Hanspeter Pfcmder

A. Introduction ..

........ 315 .. ..... 315

318 . ... 320

....... 321 321 B. Examples

References .. . ................................................................... 3M

Example 7: Optical Resolution of Racemic a-Ionone Urs HenKartner and Johann Riegl

A. Introduction .. B. Synthesis of (R)-( + )-a-Ionone

Example 8; p,p-Carotene Joachim Paust and Percy S. Manchand

A. Introduction B. Synthesis of p.p-Carotene by use of the Wittig Reaction ... C. Synthesis of p,p-Carotene by use of Low-valent Titanium ...

Appendix I: List of Synthons Hampeter

..... 325 325

327 . ................................. 327

. ..... 329

331

Appendix II: List of Naturally Occurring Carotenoids Prepared by Total Synthesis Marc Lanz and Hanspeter Pfander... . ................. 339

List of abbreviations .. ..353

Index ...... 355

International Editorial Advisory Board

K. Bernhard, F. Hoffmann-La Roche Ltd., Switzerland

C. H. Eugster, University of Zurich, Switzerland

H. A. Frank, University of Connecticut, USA

M. Ito, Kobe Pharmaceutical University, Japan

H. Mayer, F. Hoffmann-La Roche Ltd., Switzerland

J. Paust, BASF AG, Germany

K. Schiedt, Arlesheim, Switzerland

B. C. L. Weedon, University of Nottingham, England

List of Contributors

Birgit Bartels

University of Natal

Department of Chemistry

Private Bag XO I

Scottsville/Pietermaritzburg 3209, South Africa

Kurt Bernhard

F. Hoffmann-La Roche Ltd.

Vitamins and Fine Chemicals Division

CH-4070 Basel, Switzerland

George Britton

University of Liverpool

Department of Biochemistry P.O. Box 147 Liverpool L69 3BX, England

Hansgeorg Ernst

BASFAG

ZHFB-9

D-67071 Ludwigshafen, Germany

Alfred Giger

F. Hoffmann-La Roche Ltd.

Vitamins and Fine Chemicals Division

CHA070 Basel, Switzerland

XIII

XIV

Urs Hengartner F. Hoffmann-La Roche Ltd.

Vitamins and Fine Chemicals Division CH-4070 Basel, Switzerland

Masayoshi Ito Kobe Pharmaceutical University Dept. Instrumental Analytics 4-19-1 Motoyamakita-machi Higashinada-ku, Kobe 658, Japan

Stephan JaggJi F. Hoffmann-La Roche Ltd. Vitamins and Fine Chemicals Division CH-4070 Basel, Switzerland

Frans 1. Jansen University of Leiden Department of Organic Chemistry P.O. Box 9502 NL-2300 RA Leiden, Netherlands

Ludvik Labler Talweg 9 CH-4125 Riehen, Switzerland

Marc Lanz University of Berne Institute of Organic Chemistry Freiestr. 3 CH-3012 Berne, Switzerland

Synn¢ve Liaaen-Jensen Norwegian Institute of Science and Technology Department of Chemistry and Biology

Organic Chemistry Laboratories N-7045 Trondheim, Norway

Johan Lugtenburg University of Leiden

Department of Organic Chemistry

P.O. Box 9502

NL-2300 RA Leiden, Netherlands

Percy S. Manchand Hoffmann-La Roche Inc.

340 Kingsland Street Nutley, NJ 07110-1199, USA

Hans 1. Mayer

Obere Hofackerstrasse 5

CH-4414 Fullinsdorf, Switzerland

Robert K. MUlIer

F. Hoffmann-La Roche Ltd.

Vitamins and Fine Chemicals Division

CH-4070 Basel, Switzerland

Peter Munster

BASFAG

ZHFB-9 D-67071 Ludwigshafen, Germany

Junzo Otera Okayama University of Science Department of Applied Chemistry Redai-cho Okayama 700, Japan

Joachim Paust ZHF B-9

BASFAG

D-67071 Ludwigshafen, Germany

xv

XVI

Hanspeter Pfander University of Berne Institute of Organic Chemistry Freiestr. 3 CH-3012 Berne, Switzerland

Johann Riegl F. Hoffmann-La Roche Ltd. Vitamins and Fine Chemicals Division CH-4070 Basel, Switzerland

August Riittimann F. Hoffmann-La Roche Ltd. Vitamins and Fine Chemicals Division CHA070 Basel, Switzerland

Milan Soukup F. Hoffmann-La Roche Ltd. Pharmaceuticals Division CHA070 Basel, Switzerland

Paul Spurr F. Hoffmann-La Roche Ltd. Pharmaceuticals Division CHA070 Basel, Switzerland

Bruno Traber University of Berne Institute of Organic Chemistry Freiestr. 3 CH-3012 Berne, Switzerland

Erich Widmer Mittelweg 47 CH-4142 Miinchenstein, Switzerland

XVII

Preface

George Britton, Synnl/Jve Liaaen-Jensen and Hanspeter Pfander

This book, Volume 2 in the series Carotenoids, is the first book to be published that is devoted entirely to the total synthesis of carotenoids, but it is timely in view of the rapid development and the growing diversification of the carotenoid field.

The 1971 Carotenoids book contained a major chapter of 250 pages on total synthesis by H. Mayer and O. Isler. That comprehensive and authoritative review described systematically the construction of many synthons and the synthesis of many natural and unnatural carotenoids and related compounds. Twenty five years on, that chapter remains an essential reference work and source of information, with its extensive collection of tabulated data and lists of references to the original literature. Surveys of progress since 1971 have been presented at the IUPAC International Symposia on Carotenoids and are included in the published proceedings of these symposia.

The history of major publications in the carotenoid field, leading to the development of this series, was outlined in the preface to the series published in Vol. IA. The general philo­sophy outlined in that preface, with emphasis on practical guidance and the inclusion of worked examples of some of the most useful procedures, is maintained in Vol. 2. In kceping with this philosophy, Vol. 2 is not intended to be an exhaustive review of the literature, but is planned as a practical book, as well as a source of information.

The main text consists of four sections (Chapters) each dealing with a major theme and divided into a number of parts, each written by a specialist on that particular topic.

The essential foundation for work in this field is a thorough appreciation of the principles and strategies of carotenoid synthesis, and this is provided in Chapter I. Also in this chapter the editors give their own perspective of synthesis and its development over the past 45 years or so, and their prognosis for the future. The reliable characterization of intermediates and products is essential in all chemical synthesis work and this is also treated briefly in Chapter I, though for details of analytical procedures and spectroscopic methods the reader is referred to Vol. 1.

A major task in carotenoid synthesis is the construction of the polyene chain. The coupling reactions commonly used for carbon-carbon double bond formation are dealt with in the several parts of Chapter 2.

The various parts of Chapter 3 describe the preparation of polyene synthons and the synthesis of different groups of carotenoids, the partial synthesis of carotenoid glycosides, glycosyl esters and sulphates. Technical synthesis and the synthesis of isotopically labelled carotenoids are also covered. Eight Worked Examples which describe in detail reliahle and efficient experimental proce­dures for key reactions in carotenoid synthesis are presented in Chapter 4. These procedures

XVIII

are presented as recipes that can be followed by newcomers to the field and could form the basis of practical exercises for students of organic chemistry.

Finally, two appendices provide tables of useful synthons and a list of natural carotenoids that have been prepared by total synthesis.

It is the aim of the editors that this volume will serve as a useful reference source and especially as a workbook on carotenoid synthesis which, it is hoped, will encourage newco­mers to the field to consider synthesis work.

Acknowledgements

We repeat our comment from the preface to the series in Vol. IA. Although we are privileged to be the editors of these books, their production and publication would not be possible with­out the help of a great many other people.

The dedicated work of the authors, their prompt attention to requests and questions and their gracious acceptance of the drastic editing that was sometimes needed to avoid dupli­cation and to meet the stringent limitations of space, is gratefully appreciated. The job of the editors and production team is made so much easier when authors provide carefully prepared manuscripts in good time.

We cannot praise highly enough the dedicated and skilful work of Daniel Kull and Christof Bircher in the Production Office in Berne, who, despite their busy schedules as fuIl­time carotenoid researchers, somehow managed to find the time to produce the final camera­ready manuscript to a high professional standard. We also thank the members of the 'Pfander group' in Berne for their meticulous proof-reading.

The work of the chemists on the International Editorial Advisory Board in checking manuscripts and advising the editors was most useful. The guidance received from Dr. Petra Gerlach and Elizabeth Beckett and their colleagues at Birkhiluser and their efforts in finalizing publication after receipt of the camera-ready manuscripts are also much appreciated.

Finally, we again express our gratitude to Hoffmann-La Roche and BASF for the financial sponsorship without which this project would not have been possible.

George Britton Synnl1lve Liaaen-Jensen Hanspeter Pfander

XIX

Editors' Notes on the Use of this Book

As stated in the editors' notes to Vol. lA, the Carotenoids books are planned to be used with the Key to Carotenoids, Second Edition. The numbering policy that follows from this and was set out in Vol. lA is repeated here. Throughout the series, whenever a known, natural carotenoid is mentioned, its number in the Key to Carotenoids or the Appendix to this (Vol. lA Chapter 8) is given in bold print. Other compounds, which do not appear in the Key, are numbered separately, in italics, in each Chapter in order of their appearance in the text, and their formulae are shown.

Note that, when Key numbers are used, those are the ones given in the Second Edition (1987). The numbering of compounds in the original Key to Carotenoids (1976) and in the list in the 1971 Isler Carotenoids book is different. The policy on the use of trivial names, also stated in the editors' notes to Vol. lA, is again followed in Vol. 2.

As in Vol. I, authors were recommended to use selective key references and review articles whenever possible. The nature of chemical synthesis is such, however, that more references to original sources, including patent literature, are required and are therefore in­cluded. Additional references to procedures that have been used for the synthesis of individual natural carotenoids may be obtained from the Key to Carotenoids.

In this series, indexes are prepared primarily to aid the use of the books as sources of information and as practical guides, and should be used together with the lists of contents. Unlike those of Vol. lA and IB, the index to Vol. 2 includes names of compounds. The Carotenoids books form a coordinated series. Familiarity with the general procedures for handling carotenoids and for their isolation and chromatography (covered in Vol. IA) and with the spectroscopic methods dealt with in Vol. I B is an essential basis for practical work on carotenoid synthesis.