The Chemistry ofNatural Products The Chemistry of Natural Products Second edition Edited by R.H. THOMSON Emeritus Professor of Organic Chemistry University of Aberdeen Springer-Science+Business Media, B.V. © 1993 Springer Science+Business Media Dordrecht OriginalIy published by Chapman & HalI in 1993 Softcover reprint of the hardcover 1s t edition 1993 ISBN 978-94-010-4950-4 ISBN 978-94-011-2144-6 (eBook) DOI 10.1007/978-94-011-2144-6 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the UK Copyright Designs and Patents Act, 1988, this publication may not be reproduced, stored, or transmitted, in any form or by any means, without the prior permission in writing of the publishers, or in the case of reprographic reproduction only in accordance with the terms of the Iicences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of Iicences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries conceming reproduction outside the terms stated here should be sent to the publishers at the Glasgow address printed on this page. The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or Iiability for any errors or omissions that may be made. A Catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data The Chemistry of natural production / edited by R.H. Thomson.--2nd ed. p. cm. Includes bibliographical references and index. 1. Natural products. 1. Thomson, R.H. (Ronald Hunter) QD415.C483 1993 547.7- -dc20 93-21794 CIP Preface The first edition ofthis book appeared in 1984 and covered the literature until the end of 1982 (one chapter dealt with much of 1983). The present volume is based on the literature published since then until approximately mid-1992. As before, itattempts to highlight the most important advances in all the main areas of natural products research, focusing on structure, chemistry, synthesis, and this time, where appropriate, biosynthesis. Each chapter is necessarily selective but the scope is extended by frequent citation ofrecent reviews. R.H.T. Contributors Dr C. Bladon Interprobe Chemical Services, Gallowhill House, Larch Avenue, Lenzie, Glasgow G66 4HX, UK DrM. Gill UniversityofMelbourne, SchoolofChemistry, Parkville, Victoria 3052, Australia DrK.J. Hale University College London, Chemistry Department, ChristopherIngoldLaboratories, 20 Gordon Street, London WC1H OAJ, UK DrR.A. Hill Chemistry Department, University of Glas gow, Glasgow G12800, UK DrJ.B. Hobbs UniversityofBritish Columbia, NucleicAcid Protein Service Unit, c/o Biotechnology Lab oratory, Room 237, Westbrook Building, 6174 University Boulevard, Vancouver BC, V6T 1Z3, Canada DrD.R. Kelly UniversityofWales College ofCardiff, School ofChemistry and Applied Chemistry, PO Box 912, CardiffCF1 3TB, UK DrJ. Leonard Department of Chemistry and Applied Chem istry, University of Salford, Salford M5 4WT, UK DrL.R. Milgrom Department of Chemistry, BruneI University, Uxbridge, Middlesex UB8 3PH, UK Ms F. O'Neill Department of Chemistry, Brunei University, Uxbridge, Middlesex UB8 3PH, UK DrA. Richardson Department of Chemistry, King's College, Strand, London WC2R 2LS, UK DrA.B. Turner University of Aberdeen, Department of Chemistry, Meston Walk, Old Aberdeen AB9 2UE, UK Contents 1 Carbohydrates 1 K.J. HALEand A.C. RICHARDSON 1.1 Introduction 1 1.2 RecentdevelopmentsinO-glycosidationmethodology 1 1.3 RecentdevelopmentsinC-glycosidesynthesis 20 1.4 Synthesisofantibioticsugars 26 1.5 Useofcarbohydratesaschiraltemplatesandreagentsforasymmetricsynthesis 32 1.5.1 Asymmetricreduction 32 1.5.2 Enantioselectivealkylationofcarbohydratederivednucleophiles 35 1.5.3 Enantioselectivealkylationofcarbohydratederivedelectrophiles 38 1.5.4 Monosaccharidesaschiralauxiliariesforcycloadditionreactions 39 1.6 Useofcarbohydratesaschiralstartingmaterialsforthesynthesisof enantiomericallypurenaturalproducts 45 References 53 2 Aromaticcompounds 60 M. GILL 2.1 Introduction 60 2.2 Benzenoids 60 2.3 Coumarins 65 2.4 Isocoumarins,chromanones,chromonesandcannabinoids 68 2.5 Macrocycliclactones 72 2.6 Pyrones,butenolides,lignansandbenzofurans 74 2.7 Terphenyls 77 2.8 Flavonoids 78 2.9 Xanthonesandbenzophenones 80 2.10 Naphthalenesandnaphthoquinones 82 2.11 Anthraquinones 85 2.12 Anthracyclines 92 2.13 Someotherpolycyclicantibiotics 96 2.14 Ansamycins 98 References 99 3 Terpenoids 106 R.A. HILL 3.1 Introduction 106 3.2 Monoterpenoids 107 3.3 Sesquiterpenoids 117 3.4 Diterpenoids 124 3.5 Sesterterpenoids 129 3.6 Triterpenoids 131 3.7 Carotenoids 134 References 135 viii THECHEMISTRYOFNATURALPRODUCTS 4 Steroids 140 A.B. TURNER 4.1 Introduction 140 4.2 Molecularrearrangement 140 4.3 Remotefunctionalisation 147 4.4 Photochemicalreactions 154 4.5 Partialsynthesis 160 4.5.1 Oestranes 160 4.5.2 Androstanes 162 4.5.3 Pregnanes 164 4.5.4 Cholanes 165 4.5.5 Cardenolidesandbufadienolides 167 4.5.6 VitaminsD 169 4.5.7 Cholestanesandderivatives 172 References 176 5 Aminoacids, peptidesand proteins 183 C. BLADON 5.1 Introduction 183 5.2 Aminoacids 183 5.2.1 Synthesis 183 5.2.2 Newnaturallyoccurringaminoacids 186 5.3 Peptides 188 5.3.1 Synthesis 188 5.3.2 Synthesisofglycopeptides 191 5.3.3 Synthesisofphosphorylatedpeptides 193 5.3.4 Post-translationalmodifications 193 5.3.5 Designofpeptide-basedpharmaceuticals 195 5.3.6 Newpeptidesfromnaturalsources 198 5.4 Techniquesforstructuralelucidation 200 5.4.1 X-raycrystallography 200 5.4.2 N.m.r. spectroscopy 202 5.4.3 Molecularmodelling 208 5.5 Proteins 208 5.5.1 Incorporationofunnaturalaminoacids 208 5.5.2 Purificationandanalysis 209 5.5.3 Sequences,databasesandproteinfolding 209 5.6 Appendix 211 5.6.1 Usefulbooks 211 5.6.2 Databases 211 References 211 6 Alkaloids 218 J. LEONARD 6.1 Introduction 218 6.2 Biomimeticstudies 218 6.2.1 Biomimeticsynthesisof/bogaandAspidospermaalkaloids 219 6.2.2 BiomimeticroutestoDaphniphyllumalkaloids 222 6.3 Synthesis 231 6.3.1 Reserpine 232 6.3.2 Otheryohimbineandheteroyohimbinealkaloids 239 6.4 Marinealkaloids 243 6.4.1 Themanzamines 245 6.4.2 Biosyntheticoriginofmanzamines 247 CONTENTS IX 6.4.3 TotalsynthesisofmanzamineC 249 6.4.4 SyntheticapproachestomanzamineA 249 References 257 7 Nucleosides, nucleotidesand nucleicacids 259 1.B. HOBBS 7.1 Introduction 259 7.2 Nucleosides 260 7.2.1 Nucleosidesynthesis:generalmethods 260 7.2.2 Nucleosidescontainingmodifiedsugars 264 7.2.3 Othernucleosidesofinterest 280 7.2.4 Someusefulandnovelreactions 283 7.3 Nucleotides 285 7.3.1 Nucleosidemonophosphatesandtheiranalogues 285 7.3.2 Cyclicnucleotides 289 7.3.3 Nucleosidepolyphosphatesandtheiranalogues 290 7.4 Nucleicacids 301 7.4.1 Oligodeoxyribonucleotidesynthesis 301 7.4.2 Oligoribonucleotidesynthesis 311 7.4.3 Oligonucleotidescontainingmodifiedinternucleotidiclinks 313 7.4.4 Nucleicacidsequencing 317 7.5 Supplementaryreading 319 References 320 8 Porphyrins 329 L.R. MILGRaMand F.O'NEILL 8.1 Generalintroduction 329 8.2 Macrocyclebiosynthesis 329 8.2.1 Introduction 329 8.2.2 SubstitutionpatternofuroporphyrinogenIII 331 8.2.3 BiosynthesisofvitaminB12 334 8.3 Haemoproteinmodelcompounds 336 8.3.1 Introduction 336 8.3.2 Supramoleculareffectsinhaemoproteinmodelcompounds 337 8.3.3 CytochromeP-450models 344 8.4 Porphyrinswitheasilyoxidisablesubstituents 347 8.4.1 Introduction 347 8.4.2 Mesotetrakis(3,5-di-t-butyl-4-hydroxyphenyl)porphyrin 347 8.4.3 Mesotetrakis(pyrogallyl)porphyrin 351 8.5 Utilisationofporphyrinexcitedstates 351 8.5.1 Introduction 351 8.5.2 Modellingphotosynthesis 352 8.5.3 Solarenergyconversion 354 8.6 Porphyrinsinphotodynamictherapy 357 8.6.1 Introduction 357 8.6.2 Haematoporphyrinderivative, HpD 357 8.6.3 Secondgenerationporphyrins 359 8.6.4 Newapproachestophotosensitiserdelivery 364 8.6.5 Mechanismofphotodynamicaction 364 8.6.6 Photosensitisingporphyrinsasherbicides 366 8.7 DNA-porphyrininteractions 366 8.7.1 Introduction 366 8.7.2 DNAcleavage 367 8.7.3 DNAbinding 368 8.8 Porphyrinsasnovelmaterials 368 x THECHEMISTRYOFNATURALPRODUCTS 8.8.1 Introduction:solidstateandliquidcrystallinephenomena 368 8.8.2 Porphyrinsinmolecularelectronics 370 8.9 Porphyrinswithliquidcrystallineproperties 373 8.9.1 Introduction 373 8.9.2 Porphyrinswithdiscoticphases 375 References 376 9 Aliphaticcompounds 382 D.R. KELLY 9.1 Introduction 382 9.2 Semiochemicals 382 9.2.1 Lepidopteranpheromones 383 9.2.2 Methylsubstitutedaliphaticpheromones 387 9.2.3 Unbridgedspiroketals 391 9.3 Developmentofsynthetictechnology 392 9.3.1 Bridgedspiroketalsemiochemicalsofbarkbeetles 393 9.3.2 Organosulphursemiochemicals 397 9.4 Marinenaturalproducts 400 9.4.1 Palytoxin 400 9.4.2 Okadaicacid,dinophysistoxinsandacanthifolicin 402 9.4.3 Fusedringpolyethers 406 9.5 Enyne-alleneandenediyneantibiotics 417 9.5.1 Neocarzinostatin 418 9.5.2 Trisulphidetriggeredenediyneantibiotics: theesperamicinsand calicheamicins 421 9.5.3 Dynemicins 421 References 428 Chemicalabbreviationsandacronyms 442 Index 445 1 Carbohydrates K.J. HALE and A.C. RICHARDSON 1.1 Introduction Synthetic carbohydrate chemistry has undergone a renaissance in the last decade, and the purpose of this chapter is to highlight some of the more significant advances that have taken place in the area. All aspects of the subject are reviewed annually in the Royal Society of Chemistry publica tion SpecialistPeriodicalReports: Carbohydrate Chemistry. 1.2 Recentdevelopments in O-glycosidation methodology 112 Thehistorical methods - usedfor O-glycosidationhave beendiscussedin some detail in a series of monographs,13 and in the following sections we will emphasise some of the more significant developments that have occurred in glycosidation technology since 1982. Thioglycosides have now emerged as one of the most important classes of glycosyl donor for complex glycoside synthesis. They are conveniently prepared by a number of routes that include reaction of peracetylated sugars with a thiol and a Lewis acid catalyst; 14 reaction of a methyl glycoside with a thioalkylsilane and a Lewis acid;15-16 treatment of a suitably protected sugar hemiacetal with a phosphine and an alkyl disul phide,17 or by Mitsunobu reaction of a lactol with a thiol nucleophileY Themainadvantageofthioglycosidesas glycosyldonors lies in theirability to withstand a wide variety ofchemical transformations, and subsequently to undergo glycosylation with an acceptor alcohol, after having been converted into a reactive sulphonium intermediate bycomplexation with a softthiophilic reagent. A wide variety ofthiophilicelectrophiles and metal ions are available for this purpose, all of which operate under mild conditions that do not disrupt acid- and base-sensitive functionality that may be present in the reactants. By judicious choice of reagent, reaction solvent, and substituent at C(2), thioglycoside donors can be conveniently convertedintoeither 1,2-cis-or1,2-trans-glycosideswithfair to good levels ofstereocontrol. A powerful activator of thiomethylglycosides is the combination of benzeneselenyl triflate and 4A molecular sieves in dry toluene. It permits rapid glycosidation even at -40°C,18 and leads to almost exclusive forma tion of 1,2-trans-glycosides when an acyl oramido group is located at C(2)