This page intentionally left blank Metathesis in Natural Product Synthesis Edited by Janine Cossy, Stellios Arseniyadis, and Christophe Meyer Related Titles Christmann, M., Brăase, S (eds.) Dalko, P I (ed.) Asymmetric Synthesis – The Essentials Enantioselective Organocatalysis 395 pages with 85 figures and tables Reactions and Experimental Procedures 2008 559 pages with 364 figures and 115 tables Softcover 2007 ISBN: 978-3-527-32093-6 Hardcover ISBN: 978-3-527-31522-2 Hudlicky, T., Reed, J W The Way of Synthesis Evolution of Design and Methods for Natural Products 1018 pages with 285 figures and 15 tables 2007 Softcover ISBN: 978-3-527-31444-7 Cornils, B., Herrmann, W A., Muhler, M., Wong, C.-H (eds.) 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Asymmetric Synthesis with Chemical and Biological Methods 470 pages with 84 figures and 57 tables 2007 Hardcover ISBN: 978-3-527-31473-7 2007 Hardcover ISBN: 978-3-527-31161-3 Metathesis in Natural Product Synthesis Strategies, Substrates and Catalysts Edited by Janine Cossy, Stellios Arseniyadis, and Christophe Meyer With a Foreword by Robert H Grubbs The Editors Prof Janine Cossy Laboratorie de Chimie Organique, ESPCI 10 Rue Vauquelin 75231 Paris Cedex 05 France Dr Stellios Arseniyadis Laboratoire de Chimie Organique, ESPCI 10 Rue Vauquelin 75231 Paris Cedex 05 France Dr Christophe Meyer Laboratoire de Chimie Organique, ESPCI 10 Rue Vauquelin 75231 Paris Cedex 05 France Cover The gryffon painting being part of the front cover picture has been kindly provided by Dominique Escortell All books published by Wiley-VCH are carefully produced Nevertheless, authors, editors, and publisher not warrant the information contained in these books, including this book, to be free of errors Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de © 2010 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim All rights reserved (including those of translation into other languages) No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers Registered names, trademarks, etc used in this book, even when not specifically marked as such, are not to be considered unprotected by law Cover Adam Design, Weinheim Typesetting Laserwords Private Limited, Chennai, India Printing and Binding Strauss GmbH, Moă rlenbach Printed in the Federal Republic of Germany Printed on acid-free paper ISBN: 978-3-527-32440-8 V Foreword In the last few decades, metathesis has been among the key reactions that have revolutionized the synthesis of complex molecules Many organic chemists in academic and industrial laboratories, in the field of natural products, have used this reaction as a very practical, versatile, and selective synthetic tool Olefin metathesis has helped to elevate the art and science of chemical synthesis to its present high level The examples in this book will demonstrate that organic chemists, with the metathesis reaction in hand, have a new way to consider the connections that are required for efficient access to natural products This book assembles the most important and interesting examples in the synthesis of natural products using metathesis Owing to the possibilities opened by olefin and acetylenic metathesis, a great variety of carbocyclic – nitrogen-, oxygen-, sulfur-containing heterocycles – natural products with small-, medium-, and macrocyclic size can be obtained rapidly The synthetic transformations that couple metathesis steps in cascade reactions are particularly elegant Emphasis has been put on the metathesis step showing the importance of the catalysts that are tolerant of a large variety of functional groups, very regio-, stereoselective, and even enantioselective The power of the catalysts and of the metathesis reaction can be appreciated when alternative pathways are considered Every reaction and catalyst can always be improved In the area of metathesis, the development of more active and robust catalysts, catalysts that can control the E and Z stereoselectivity of the formed olefins, particularly the stereoselectivity of trisubstituted olefins, or catalysts that can control the enantioselectivity remains a challenge As has been demonstrated in the past, improvements of the catalyts give rise to increasingly exciting applications in the field of complex molecules and particularly in the field of natural products synthesis This book will be a good source of inspiration for those planning future developments of metathesis reactions in the field of natural and non-natural products Robert H Grubbs Metathesis in Natural Product Synthesis: Strategies, Substrates and Catalysts Edited by Janine Cossy, Stellios Arseniyadis, and Christophe Meyer Copyright © 2010 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim ISBN: 978-3-527-32440-8 This page intentionally left blank VII Contents Foreword V Preface XV List of Catalysts XIX List of Contributors XXI Abbreviations XXV 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 2.1 2.2 2.2.1 2.2.2 2.2.2.1 2.2.2.2 2.2.2.3 2.2.3 2.2.3.1 Synthesis of Natural Products Containing Medium-size Carbocycles by Ring-closing Alkene Metathesis Nicolas Blanchard and Jacques Eustache Introduction Formation of Five-membered Carbocycles by RCM Formation of Six-membered Carbocycles by RCM 11 Formation of Seven-membered Carbocycles by RCM 22 Formation of Eight-membered Carbocycles by RCM 30 Formation of Nine-membered Carbocycles by RCM 33 Formation of 10-membered Carbocycles by RCM 34 Conclusion 39 References 40 Natural Products Containing Medium-sized Nitrogen Heterocycles Synthesized by Ring-closing Alkene Metathesis 45 Sebastiaan (Bas) A M W van den Broek, Silvie A Meeuwissen, Floris L van Delft, and Floris P J T Rutjes Introduction 45 Five-membered Nitrogen Heterocycles 47 Dihydropyrroles 47 Pyrrolidine Alkaloids 47 Pyrrolidines 47 Dipyrrolidines 49 Polyhydroxypyrrolidines 49 Indolizidine Alkaloids 52 Polycyclic Indolizidines 52 Metathesis in Natural Product Synthesis: Strategies, Substrates and Catalysts Edited by Janine Cossy, Stellios Arseniyadis, and Christophe Meyer Copyright © 2010 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim ISBN: 978-3-527-32440-8 VIII Contents 2.2.3.2 2.2.4 2.3 2.3.1 2.3.1.1 2.3.1.2 2.3.1.3 2.3.1.4 2.3.2 2.3.3 2.4 2.5 2.6 Polyhydroxyindolizidines 55 Pyrrolizidine Alkaloids 59 Six-membered Nitrogen Heterocycles 61 Piperidine Alkaloids 61 Piperidines 61 Piperidine Carboxylic Acids 66 Piperidones 68 Polyhydroxypiperidines 69 Indolizidine Alkaloids 70 Quinolizidine Alkaloids 73 Seven-membered Nitrogen Heterocycles 78 Eight-membered Nitrogen Heterocycles 81 Conclusion 82 References 83 Synthesis of Natural Products Containing Medium-size Oxygen Heterocycles by Ring-closing Alkene Metathesis 87 Jon D Rainier Introduction 87 General RCM Approaches to Medium Rings 89 Laurencin 95 Eunicellins/Eleutherobin 102 Helianane 104 Octalactin A 105 Microcarpalide and the Herbarums 106 Marine Ladder Toxins 109 Ciguatoxin 109 Brevetoxin 117 Gambierol, Gambieric Acid, Olefinic-ester Cyclizations 120 Conclusion 124 Acknowledgments 124 References 124 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.8.1 3.8.2 3.8.3 3.9 4.1 4.2 4.3 4.4 4.5 4.6 Phosphorus and Sulfur Heterocycles via 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palladium-catalyzed domino allylic 54 alkyne carboxylation, nickel-mediated 321 allo-colchicine 190 allylation 118 – N-allylation 62, 64 – asymmetric 20, 69 – coupling of hemiketal with allylsilane 101 – diastereoselective via N-acyliminium ion 65, 71 – double palladium-catalyzed decarboxylative 24 allylboration, asymmetric 65, 77 allylic amination, asymmetric 48, 66 allylic hydride addition 142 D-altritol 227 ambrettolide 211 aminopalladation 67, 74 amphidinolide 165f – (−)-amphidinolide E 197, 200 – amphidinolide V 221 – amphidinolide X 254 amphinidol 291 (−)-anaferine 333 (+)-anatoxin-a 187 angucyclinone 191 annonaceous acetogenin 237f anolignan 197f, 308 ansamycin derivative 172 anthramycin 308 anthramycin (+)-anthramycin 193 (−)-archazolid B 270, 274 arenastatin 173 asimicin 301 aspercylide C 168 asperpentyn 274, 277 (+)-aspicilin 160 (+)-astrophylline 333 attenol A 231f auxiliary-based synthesis 64, 72 aza-Diels-Alder reaction 197 azasugar 49ff, 69ff b baconipyrone C 305, 348 Bayer-Villiger reaction of ketone, regioselective 63 bicyclic acetal 113 bicyclo[4.3.1]phosphate 135f bis-alkoxysilane 227 bistramide A 303, 325 1,3-bis(2,4,6-trimethylphenyl)− 2-imidazolidinylidene 45 bitungolide E 140 (+)-brasilenyne 253 brevitoxin 88f, 117ff bryostatin, ring-expanded analog of 280 Metathesis in Natural Product Synthesis: Strategies, Substrates and Catalysts Edited by Janine Cossy, Stellios Arseniyadis, and Christophe Meyer Copyright © 2010 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim ISBN: 978-3-527-32440-8 374 Index c Cadiot-Chodkiewicz reaction 315 callipeltroside A 278 carbapenem 186 carpacephem 186 cascade metathesis 303, 313ff – asymmetric ROM/CM 304 – catalytic carbene complexes for 314 – CM/RCM 306 – ene-ene RCM/CM 314 – ene-yne-ene RCM/CM 315f, 321 – ene-yne-ene RCM/RCM 316ff – for preparation of tricyclic structures 319ff – metallotropic [1,3]-shift/CM 315 – ring-closing ene-yne metathesis/CM 307 – ROM/RCM see ring-rearrangement metathesis – ROM/CM of cyclopropene ketal 303, 322ff – ROM/CM/RCM 305 – ROM/RCM/CM 305 – RRM/CM 337 – RRM/RCM 332ff (+)-castanospermine 326 (−)-centrolobine 328 characiol 279 chlorotonil A 293f ciguatoxin 109ff citreofuran 218 civetone 162, 211 clavirolide 169 cleavage reaction – of α-hydroxy ketone 15 – of silyl ether 55 clusianone 297 CM see cross-metathesis (−)-cochleamycin A 244 coleophomone 169 colletol 289 conformation constraint 31 (R)-coniine 346 cornexistin 250 cross-metathesis (CM) 25, 45, 74, 138ff, 193, 239 – alkyne CM 309f – control of double bond configuration 226 – cross-coupling of side chains 300f – for appending functionalized side chains 299f – for appending unfunctionalized side chains 296ff – for partly removing a side chain 298f – of ene-yne systems 184f, 195ff, 308f – on solid phase 362ff – promoted by microwave heating 288, 361 – relay cross-metathesis (relay CM) 264, 271, 274 – two-directional 287 – with 1,1-disubstituted alkenes in 2-methyl-2-butene 297 – with acrolein 291 – with acrylate 290 – with acrylic acid 288 – with acrylimide 289 – with acryonitrile yielding (Z)-alkene 287 – with allyl phosphonate 294 – with allyl silane 294 – with allylic alcohol derivative 294f, 299 – with thioacrylate 288 – with vinyl boronate 292 – with vinyl ketone 292 – with vinyl silane 293 cruentaren A 215 cuprate addition 136, 139f cuscohygrine 333 (+)-cyanthiwigin U 336 cyclization – by electrochemical oxidation – Pictet-Spengler 54, 77 cyclization see also macrocyclization – Bischler-Napieralski 38, 52 – boron trifluoride-mediated 23 – cationic, of allylic O, N-acetals 73 – electrophilic selenocyclization 240 – fused heterocycle system via 1,4prototropic shift/[3 + 2] cycloaddtion 288 – intramolecular allylstannane/acetal 117 – Mitsunobu 59, 247 – of 1,6-dienes via RRCM 263 – of allylidene via RRCM 266, 274 – of electron-deficient β-ketoalkylidene via RRCM 266f – of hindered substrates via RRCM 268ff – of hydroxy-epoxide to furan ring system 98 – of olefinic esters using Tebbe reagent 123 – of trienes 99 – of triene-yne precursor 116f – one-pot sequential 72 – radical 25 – stereoselective 5-exo trig – to lactams 66 – via intramolecular allylation 117 – via reductive amination 55 – zirconium-mediated 10 cyclodepsipeptides 173f cyclopeptide 150 Index cyclophanes 168 cycloproparadiciol 153 cyclorelease reaction 350f – of dysidiolide analogs 352 – of epothilone 351 – of lactams 351 – of O-alkenyl glycosides 352 – of polymer-bound oligosaccharides 352 – of tetrapeptide macrocycle 351 – of β-turn mimetics 352 cylindramide A (+)-cylindramide A 338 cylindramide A 289, 305 cylindrocyclophane 306 d Dauben oxidation 28 decarboxylative oxygen-to-carbon migration 19 dehydrohomoancepsenolide 309 10-deoxymethynolide 158 (+)-14-deoxy-9-oxygigantecin 238 desymmetrization – lipase-mediated 49 – of C2 -symmetric diol using phosphate tether 135 – palladium-catalyzed, of meso-bis-carbamate 57 – via ROM 304 – via RRCM 275 diallylamine formation 47, 52, 62f – diastereoselective 65 – enantioselective 51, 54, 59, 67 diallylation, regioselective 77 diazoester cyclopropanation, intramolecular 10 (2S, 7S)-dibutyroxynonane 235f dictyostatin 132, 140 (+)-didemniserinolipid B 271, 275 Diels-Alder cycloaddition 26f, 102f, 189, 289 – transannular, biomimetic 243 1,6-diene dienolide 150 (±)-differolide 187 (+)-dihydrocuscohygrine 335 dihydro-epi-deoxyarteannuin B 270, 273 dihydrooxasiline 272 dihydroxylation 26, 49, 56, 58f, 77 – diastereoselective syn-dihydroxylation 57 – face-selective, of cyclic olefin 69 – side chain-directed syn-dihydroxylation 50 discodermolide – (+)-discodermolide 132, 140 272, 276 diterpenoides 150, 169f dolabelide C 139ff, 292 double enantioselective allyltitanation 62 double-bond preorganization in cyclic systems 15f (+)-dumetorine 333 dynamic kinetic asymmetric transformation (DYKAT) 51 e enantioselective synthesis 49, 54f, 58, 61 – enantioselective olefin metathesis 343ff – of functionalized piperidine 77 – of oxazolidinone derivative 57 ene reaction, asymmetric ene-yne metathesis 45, 92 – on solid phase 369ff ene-yne precursor 52 enzymatic resolution 69 epilacnene 211 epothilone 163ff, 213, 239f, 351 epoxidation – hydroxyl-directed of homoallylic alcohol 29 – selective 28, 60, 69 – Sharpless 62, 67, 80 epoxide hydrolysis, selective 70 ergorgiane 307 eromophilane 189 erythocarine 322 erythravine 322 erythroidine 323 24,24-ethanovitamine D3 lactones 197 exaltolide 163 f faranal 289 (+)-ferruginine 187 Fischer tungsten-carbene complex 183 floresolide B 170 fluvirucin B1 172 FR901464 302 fumagillin Făurstner catalyst see metathesis catalyst, [Ru-V] g (−)-galanthamine 191 gambieric acid 122 gambierol 120f, 307 gauche-effect in vicinal diol 95 geldanamycin 272 geodin A 340 (+)-gigantecin 238 375 376 Index gloeosporone 159 glycopyranosyl cation 69 d,l-glucosylceramide 252 Grignard reaction 77, 104, 218 – of alkyl bromide and Weinreb amide 51 griseoviridin 172 Grubbs catalyst see metathesis catalyst, [Ru-I] and [Ru-II] 45 Grubbs-Hoveyda catalyst see metathesis catalyst, [Ru-III] (±)-guanacastepene A 319 – acid-catalyzed 23 – of double bonds 31, 74 isooncinotine 175 h l halichondrin B 334 (−)-halosaline 335 harveynone 274, 277 heliannuol 300 hemibrevitoxin B 307 heterocyclic carbene 45 heterolytic fragmentation of bicyclic systems 14 histrionicotoxin 288 homoallyl alcohol 252 – with conjugated diene moiety 131 homologation 255 – diastereoselective 107 Horner-Wadsworth-Emmons coupling to enones 105 hydrogenation 55, 79, 115 – of olefin bond 60, 62 – regioselective, of bicyclic phosphate 141f – selective 176 hydrosilylation 254 14-hydroxycornexistin 250 (10S, 12R)-10-hydroxy-12-methyl-1oxacyclododecan-2,5-dione 159 1α-hydroxy-5,6-trans vitamin D2 248 hypoestoxide 272, 275 lancifodilactone G 194 (R)-lasiodiplodin 155f lasonolide A 295f (−)-lasubine II 339 latrunculin 216 lejimalide 163 lemonomycin 294 lepadine alkaloids 318 (+)-ent-lepadin B 331 Linchpin coupling, three-component longithorone – (−)-longithorone 187 – longithorone C 271 i illudin 256 indolizdine – (−)-indolizidine 167B 335 – indolizidine 251F 330 intramolecular displacement of allylic benzoate ester 60 iodoboration, chemoselective 81 iododesilylation 254 iodolactonization 10 ipomoeassin E 176 (−)-irofulvene 256 isoaltholactone 290 isomerization j Julia-Kocienski coupling 295 k kinetic resolution, hydrolytic 63 Knoevenagel condensation 8, 77 (±)-trans-kumausyne 330 72 m macrocyclic glycolipids 175 macrocyclic lipids 171 macrocyclic musk 162, 211f macrocyclic natural products – biogenetic classification of 151 – structural classification of 150 macrocyclic polyketide see also macrolide 152ff, 167f macrocyclization – stereoselectivity of double-bond formation 150 – using Otera’s catalyst 291 – via relay ring-closing metathesis 265ff – via Yamaguchi reaction 288 macrolactams 172f macrolide 140f, 150, 265ff – antibiotic 158 – resorcinylic 152ff – salicylate 155ff macrosphelide 161 Mannich reaction, intramolecular 55 manzamine A 175 marine ladder toxins 109ff marine peptide 47 medium size carbocycle melithiazole C 300 Index metacycloprodigiosin 199 metal-alkylidene complex 46 metallatropic [1,3]-shift 274 metathesis catalyst – [Mo]-I 46, 80, 89f, 121, 183, 227, 252, 306 – [Ru]-I 1f, 4ff, 46, 305, 308, 321 – [Ru]-II 1f, 6ff, 30ff, 46, 166, 231f, 241, 280, 293, 308 – [Ru]-III 46, 92, 138f, 141, 195, 239, 280, 288, 291, 299, 308, 316 – [Ru]-IV 46, 183 – [Ru]-IX 46, 74 – [Ru]-V 46, 88, 106f, 155 – [Ru]-VI 27, 46 – [Ru]-VII 302, 319, 369 – [Ru]-VIII 183, 271 – [Ru]-XI 46 – [Ru]-XII 271 – [Ru]-XIII – bearing a C2 -symmetric diolate ligand 345ff – chiral [Mo]-II 344 – chiral [Mo]-III 344f – chiral [Ru]-XV 304, 346 – comparison of, for oxepine synthesis 91 – fluorous-tagged f -[Ru]-III 351 – for cascade metathesis reaction 314 – for RCAM 206f – imidazolin-2-iminato tungsten alkylidene catalyst 208 – polymer-bound ruthenium carbene complex 256 – removal of, from target molecules 351 – stereogenic-at [Mo]-IV complex 346 – triaryl amido molybdenum complex for alkyne CM 310 metathesis reaction type 45 migrastatine 160 MM-47755 192 molybdenum hexacarbonyl 206 monoterpenoid indole alkaloid 72 Mortreux-type reaction 208 motuporamine C 211 (−)-mucocin 237f, 270 muricatacin 303 muscone 162 muscopyridine 163 mycoepoxydiene 305 – (+)-mycoepoxydiene 338 mycothiazole 309 – structure of (±)-mycothiazole 132 – total synthesis of (±)-mycothiazole, via sulfonylation-RCM sequence 132f n nakadomanine 175 narbonolide 158 Negishi coupling 254 neodihydrohistrionicotoxin nephrosteranic acid 297 nonylprodigiosyn 175 17-norcharaciol 281 nupharamine 292 132 o (+)-ochoromycinone 192 okadaic acid 230f okilactomycin 167 olefin isomerization inhibitor 37 oocydin A 266, 294, 296 oxazolidinone preparation 65, 66 oxecin skeleton 88 oxepine skeleton 88, 92, 96, 100, 109 oxidation – of metathesis catalyst 351 – oxidative cleavage of diol 110 – Pinnick 67 – Swern 61, 68 – Tamao-Fleming 22, 245, 249 oximidine 157 oximidine III 265 oxocine skeleton 88, 92, 97f, 101, 104f oxonene ring system skeleton 88, 97f, 102ff oxyallyltitanation of aldehyde, diastereoselective 37 p Paal-Knorr reaction 174 palmerolide 162 palytoxin 132 (3R, 9R, 10R)-panaxytriol 314f peloruside A 236, 265 peptide coupling 47 perhydropyrrolo[2,1-j]quinolone 72 Petasis reaction 56 Peterson elimiation 22 (−)-PF1163B 173 PGE2 methyl ester 309 (−)-phaseolinic acid 228 phenanthroindolizidine alkaloid 54 phlegmarine-type alkaloid 68 phoslactomycin B 276 phosphate – allylic displacement 134, 141f – as tether in multipodal coupling reactions 134 – cyclic phosphate from allylic alcohol and Z-dienol 134f 377 378 Index phosphate (contd.) – in organic synthesis 134 – mediation of CM 138 – multivalent activation by phosphate tether 135f – reactivity of bicyclic phosphate from RCM 136ff [2 + 2]-photocycloaddition 72 pipecolic acid see 2-piperidine carboxylic acid 2-piperidine carboxylic acid 66 pladienolide 159 pochonin 152, 154f proline homolog 66 prosophylline 367 prostaglandin 299 prostaglandin PGE2 -1, 15-lactone 212 pterocarpan 247f 2-(1H)-pyridone ring system 68 – limitations 278 resorcylide 154 ricinelaidic acid lactone 159 ring contraction – Favorskii reaction 25 – zirconium-promoted ring expansion 75 ring opening of epoxide 59 ring-closing alkyne metathesis (RCAM) 205f – complementary ene-yne metathesis 221 – mechanism of 206 – promoted by microwave heating 208 – scope and limitations 210, 212 – synthesis of stereodefined macrocyclic alkenes 211ff ring-closing metathesis (RCM) 1ff, 45 – chelation effect 106 – competing side reactions 90, 114, 157 – conformational constraint 174 q – cyclorelease reactions based on 351f quartomicin 191 – diastereoselectivity 112f quebrachamine 346 – effect of protective groups 107 – for preparation of oxygenated medium-sized r ring system 87ff radicicol 152 – formation of (E)-trisubstituted alkene 166 RCAM see ring-closing alkyne metathesis – formation of tricyclic 5,7,5-ring system 25f RCM see ring-closing metathesis – in combination with intramolecular rearrangement reaction 52 allylstannane/acetal cyclization 117f – cycloisomerization of ene-yne system 197f – in formation of (sesqui)terpenoid structures – Eschenmoser-Claisen rearrangement 23 4ff – glycolate-Claisen rearrangement 11 – in formation of carbahexofuranose 8f – Ireland-Claisen 1, 18, 72, 92, 94, 115 – in formation of carbapentofuranose 8f – Johnson-Claisen rearrangement 1f – in formation of cylcopentenes 1f – metathetic ring rearrangement 38 – in presence of Lewis-acid 160 – Overman 54, 64 – in synthesis of ciguatoxin ring system – [2,3]-rearrangement 116, 272, 335 110ff – [3,3]-sigmatropic rearrangement – of allylic acetate recifeiolide 163 – of allylic alcohol reduction – of diene-diene system to conjugated triene – N-acyliminium-mediated 67 157 – conjugate reduction of enone – of diene-ene system via cobalt complex – of ketone, stereoselective 115 153f – of lactams 61, 69 – of diene-yne systems 184f reductive amination with allyl amine 60 – of electron-rich olefins 90 Reformatsky reaction 81 – of ene-yne systems 183ff, 189 relay concept 261f relay ring-closing metathesis (RRCM) 251f, – of enol ether-olefins 121f – of epoxy-diene 99 316 – control of directionality in RRCM 267, 275 – of ether-olefins 89ff – of kinetic silyl enol ether 72 – ene-yne RRCM 269f – of olefinic sulfonates 130f – interference from premature – of phosphates 136 macrocyclization 279f, 283 – of polymer-bound dienes 355ff – interference from truncation reaction – of polymer-bound polyenes 355ff 278ff Index – of precursor with protected hydroxyl 51, 56f – of precursor with unprotected hydroxyl 9, 51, 60 – of stannyl ketals 96 – of tosyl-protected precursor 77 – of trienes to oxepines 96 – of vinyl ketone 3f, – regioselectivity 105, 166 – relay strategy 157, 261f – simultaneous multiple RCM – stereoselectivity of double-bond formation 82, 106, 226f – strategies for preparing epothilones 164, 353 – two-directional sequence 116 – two-step protocol using titanium ethylidene reagent 121 – under ethylene gas atmosphere 185, 191 – under high dilution conditions 81 – use of tetra(isopropyl) titanium as co-catalyst 106, 333 – ynolide approach to resorcinylic macrolides 153 ring-opening metathesis (ROM) 26, 346 – of ene-yne systems 184f ring-opening metathesis polymerization (ROMP) 45 ring-rearrangement metathesis (RRM) 45, 49, 54, 57, 325f – diastereoselective 328 – enantioselective 344f – mechanism of 330 – of bicyclic substrates 329f – of monocyclic substrates 326f – of norbornene derivatives 329ff – transfer of stereocenter 325 rocellaric acid 297 rollicosin 303 ROM see ring-opening metathesis ROMP see ring-opening metathesis polymerization roseophilin 173, 202 Roush reaction see allylboration, asymmetric routiennocin 304 RRCM see relay ring-closing metathesis RRM see ring-rearrangement metathesis (+)-rubiginone B2 192 ruthenacyclobutene 183ff s Sakurai reaction 246 salicylate lactone 215 salicylihalamide A 140, 156f (−)-sarain A 174 scabrosin 309 (+)-scanloenyne 271, 274 SCH 351448 279 – (+)-SCH 351448 161 Schrock catalyst see metathesis catalyst, [Mo-I] (−)-securinine 317 silicon tether – achiral silaketal tether 229 – allylsiloxane 245ff – C2 -symmetrical silaketal 227f – long-range asymmetric induction 233f – racemic silaketal tether 229 – symmetrical silaketal tether 226f – unsymmetrical bis-alkoxyalkynylsilane 242f – unsymmetrical silaketal tether 230 – vinylsiloxane 245ff, 251ff skeletal reorganization reaction 197ff, 201 solid-phase catalyst extraction 351 solid-phase metathesis reaction see also cyclorelease reaction 350ff – cross-linking of α-helices 360 – cross-metathesis 364ff – formation of 1,3-dienes via ene-yne metathesis 367ff – intraresin dimerization 358f – restricting peptide conformation through cyclization 359ff Sonogashira coupling 293 sophorose lipid lactone 213 sparteine alkaloids 77 spirastrellolide A 281 spirocyclization 27 spirofungin A 231, 304 (−)-spongidepsine 173 sporiolide B 159 squamostolide 303 stannyl ketal 96 (−)-stemoamide 185 stereoselective synthesis 56, 252 Stille cross-coupling 4, 18 (+)-streptazolin 250 streptorubin B 199 sulfoximine derivative 92 sulfur dioxide extrusion 133 sultone – leaving group ability 130f – preparation of, from olefinic sulfonyl chlorides and alkenols 130ff – synthesis of (±)-mycothiazole 132f (−)-swainsonine 328 (+)-cis-sylvaticin 237 379 380 Index synthesis – of achiral (Z)-1, 4-diols 226, 234f, 238 – of acyclic tri-/tetrasubstituted 1,3-dienes 255 – of (Z)-alkenes via CM with acrylonitrile 287ff – of (E)-alkenes via CM with electron-deficient terminal olefin 287ff – of D-altritol via TST-RCM 228 – of ansa-bridged azafulvene skeleton 174 – of aza-acenaphthylene skeleton 72f – of 1-aza[4.3.0]-bicyclic skeleton 47 – of azabicyclo[3.2.1]octene ring 187 – of azepines 80f – of benz[a]anthraquinone skeleton via ene-yne RCM 191f – of bicyclo[3,3.1]nonane skeleton 13 – of bicyclo[2.2.2]octane skeleton 13 – of bridged carbocycle – – ingenol 26 – – solanoeclepin A 27 – – vinigrol 32 – of carbacephem skeleton 187 – of carbapenem skeleton 187 – of carbon-linked disaccharides 240 – of cis-fused benzofuran-benzopyran skeleton 246f – of cis-hexahydroxy−1H-indene skeleton 197 – of conjugated Z-dienols 131f – of cyclic alkynes 207 – of cyclic ether via TST-RCM/cross-coupling sequence 254 – of cyclophane derivatives 208 – of 1,3-dienes via CM 196 – of 1,3-dienes via RCAM/hydrosilylation/dehydrosilylation 219 – of 1,3-dienes via stereoselective TST-RCM 241f – of dihydropyrroles 47 – of dihydropyrrolidines 56 – of (anti,anti)-1, 3-dihydroxy-4-methyl stereotriad 140 – of anti-1, 3-diols using phosphate tether 140ff – of dipyrrolidines 49 – of eight-membered carbocycle 14f – – fusicoccin A 30 – – (±)-mycoepoxydiene 31 – – ophiobolin M 30 – – serpendione 30 – – taxol B ring 33 – – vinigrol analog 32 – of eight-membered nitrogen heterocycle 81f – – manzamine A 81f – of eight-membered oxygen heterocycle (+)-laurencin 95f, 101 – – (+)-laurenyne 101 – – brevetoxin G-ring 121 – – ciguatoxin E-ring 110f – – heliannuol A 104f – – octalactin A 105 – of 2-ene-1,5-diols 240f – of exocyclic ethylidene moiety via TST-RCM 249f, 257 – of five-membered carbocycle 1ff – – (−) -allosamizoline – – (−) -bis(hydroxymethyl)cyclopentenyl adenine 2f – – 4a-carba-ß-D-galactofuranose – – 1,22-dihydroxynitianes – – dumsine from (R)-carvone 4f – – ecklonialactone 1f – – elisabethin A from (R)-carvone – – estrone 10 – – (+)-fomannosin – – (−)-guanacastepene E – – (−)-heptemerone B – – (±)-laurokamurene B – – nitiol 3f – – (+)-puraquinoic acid – – sequosempervirin A – – spiroepoxide structure – – spirotenuipesine – – tashironin – – tetrasubstituted cyclopentene 9f – – trisubstituted cyclopentene 6f – – via RRCM 263 – of five-membered nitrogen heterocycle 47ff – – (−)-antofine 54 – – (+)-australine 59 – – (+)-1-epi-australine 59 – – (+)-broussonetine G 51 – – (−)-bulgecinine 50 – – castanospermine 57 – – (−)-trans-dendrochrysine 49f – – 1,4-dideoxy-1,4-imino-D-ribitol (+)-DRB 49f – – 2,5-dideoxy-2,5-imino-D-mannitol (+)-DMDP 50 – – dysinosin A 48 – – (+)-β-erythroidine 52f – – erythravine 52f – – erythrocarine 52f – – (+)-hyacinthacine A2 60 Index – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – (+)-hygrine 48 – (−)-indolizidine 55 – lentiginosine 55ff, 70f, 73f – ent-lentiginosine 71 – (−)-(S)-Nicotine 47ff – oscillarin 47ff – (−)-phaseolinic acid 228 – rhynchophylline 52 – iso-rhynchophylline 52 – (−)-swainsonine 57f – (−)-trachelanthamidine 61 – using ene-yne RCM 185 of five-membered oxygen heterocycle 273 of functionalized medium-sized azacycles 355 of fused carbocycle (+)-arglabin 29 – compactin 18 – durhamycine aglycone model 20 – guanacastepene 28 – heptemerone G 28 – (−)-10α-hydroxy-4-muurolen-3-one from (R)-carvone 19 – (−)-perrotinene 18 – sphenolobane-type diterpenoids 28 – (−)-tormesol 28 – vannusal A 19f – via RCM 37f, 188, 190, 192, 198, 306, 319, 337, 344 of fused nitrogen-containing polycyclic systems via RCM 39, 51, 53f, 56f, 59f, 61, 68, 72, 74ff, 164, 172f, 175f 186f, 189, 201f, 272, 317, 339, 346, 357 of fused oxygen-containing polycyclic systems via RCM 36f, 51, 53, 57, 59f, 68, 89ff, 101, 103ff, 109ff, 121f, 135ff, 140ff, 153ff, 161f, 167ff, 173, 176f, 194, 214, 217, 306, 316f, 321, 339, 351 of fused ring system 104, 109f of heliananes 104f of heterocycle containing a N–O-bond 355ff of hindered 5,5-fused bicyclic nitrogen heterocycle 59 of hindered (Z)-trisubstituted alkene via RRCM 265 of γ -hydroxy aldehyde via TST-RCM 245 of indolizidines 52ff, 56, 70ff of isoprenyl side chain via CM 297 of lignans via TST-RCM 246f of macrolactams 351f of macrolactones 353, 359 of medium-sized carbocycles via TST-RCM/cross-coupling sequence 253f – of medium-sized cyclic ether systems 89f, 93ff – of medium-sized lactams 351, 357 – of medium-sized lactones via sulfoximines 92, 94 – of medium-sized sulfonamides 354 – of metacyclophane-macrolactams via RRCM 269f – of monohydroxypyrrolidine 61 – of nine-membered carbocycle 14 – – hydroxycornexistin 34 – – pestalotiopsin 33 – of nine-membered oxygen heterocycle 97 – – astrogorgin 103 – – benzo-fused bicyclic systems 104 – – (+)-brasilenyne 254 – – ciguatoxin F-ring 113f – – eleutherobin 102f – – eunicellin derivatives 102f – – isolaurallene 98 – – ophirin B 102 – – ribose-fused bicyclic systems 103 – of nitrogen heterocycles via ene-yne RCM 185ff – of octahydrobenzapinones via ene-yne metathesis/Diels-Alder reaction 369 – of Z-olefin by TST-RCM 226f – of oligoenynes 317 – of oxygen heterocycle via ene-yne RCM 187 – of pipecolic acid derivatives via CM 197 – of piperidine carboxylic acids 66f – of piperidines 61ff, 346 – of piperidones 68ff – of polycyclic indolizidines 52ff – of polyhydroxyindolizidines 55ff – of polyhydroxypiperidines 69f – of polyhydroxypyrrolidines 49 – of protected divinyl ketone from cyclopropene ketal 303 – of pyrrolidines 47ff, 193, 308 – of pyrrolizidines 59ff – of pyrrolo-oxazolones 57 – of quinolizidines 73 – of semicyclic 1,3-diene 307 – of seven-membered carbocycle 14 – – allo-colchicine 190 – – (−)-cyanthiwigin F 25 – – (−)-dihydroxanthatin 194 – – (±)-frondosin B 23 – – lancifodilactone G 194 – – methyllicaconitine analog 23 – – rameswaralide 24 – – (+)-sundiversifolide 24 – – thapsigargin 25 381 382 Index synthesis (contd.) – – trisubstituted cycloheptene 24 – – (+)−8-epi-xanthatin 318 – of seven-membered nitrogen heterocycle 78ff – – azepine derivative 80, 186 – – (−)-balanol 78, 80 – – (−)-stemoamide 81, 186 – – using ene-yne RCM 185 – of seven-membered oxygen heterocycle 92, 95 – – (−)-isoprelaurefucin 100 – – brevetoxin E-ring 118 – – ciguatoxin A-ring 109, 113 – – ciguatoxin D-ring 110f – – gambieric acid B-ring 122f – – gambierol H-ring 121 – of silaketals 227ff – of six-membered carbocycle – – asperpentyn 277 – – bicyclic systems 14f – – carbasugar 20f – – conduritols 21f – – cyclitol 20 – – (+)-cyclophellitol 20 – – dihydro-epi-deoxyarteannuin B 273 – – eremophilane 190 – – fumagillol 10f – – (−)-galanthamine 192 – – garsubbelin A 14 – – harveynone 277 – – ovalicin 12 – – rac-ottelione B 12 – – pancratistatin analogs 22 – – phosphatidylinositol analog 21 – – platencin 13 – – polyprenylated acylphloroglucinol 13f – – quartromicin 191 – – tricholomenyn A 277 – – (+)-valienamine 21 – of six-membered nitrogen heterocycle 61ff – – (−)-205B 72, 76 – – (−)-allosedamine 61ff – – (+)-(S)-angustureine 78, 80 – – (S)-anabasine 65, 67 – – (S)-anabatine 65, 67 – – baikiain 67f – – α-conhydrine 63 – – (−)-β-conhydrine 65f – – coniceine 70, 72 – – (S)-(+)-coniine 64f – – ent-CP-999,994 66f – – 1-deoxyallonojirimycin 69, 71 – – (−)-deoxynupharidine 75, 77 – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – (+)-epiquinamide 75, 78 – fagomine 71 – 4-hydroxy-2-pipecolic acid derivatives 66 – (±)-α-isosparteine 79 – ent-L-733,060 66f – (−)-lasubine I 76, 78 – lepadiformine 72, 74 – lycoposerramine-V 68f – (+)-meloscine 72, 75 – mitralactonine 77, 79 – (−)-pipecoline 66 – pipermethystine 69f – quinolizidine 233A 73ff – (+)-sedamine 61ff – α-sparteine 78 – (2S, 4S)-(−) -SS20846A 67f – tetrahydropyridine derivative 70 – tetraoxobispidine 77 – using ene-yne RCM 185 of six-membered oxygen heterocycle 269, 273, 347f of spiro-carbocycle – (+)-elatol 19 – (+)-laurencenone B 19 of spiroketals via TST-RCM 230ff of stereodefined macrocyclic alkenes by RCAM/semi-reduction 211ff stereoselective, of 1,n-diol via TST-RCM 234ff stereoselective, of cyclic ethers 246 stereoselective, of homoallylic alcohols 251f of 2-substituted furans via RCAM/cycloisomerization of alkyn-4one skeleton 220 tandem ene-yne RCM/metallatropic shift reaction 274ff tandem enyne-RCM process 52f tandem RCM/CM process 302 tandem ROM/RCM sequence 114 of ten-membered carbocycle 14f, 34f – bridged polycyclic systems 17 – ent-clavilactone B 36f – diversifolin 35 – eleutherobine precursor 37f – (+)-eremantholide A 36f – excentricine 38f – germacranolides 15 – (±)-periplanone C 16 – stereoselectivity of double-bond formation 38 of ten-membered lactones 106ff of ten-membered oxygen heterocycle – herbarumin I 106 Index – – – – – – – – – – – – herbarumin II 106 – herbarumin III 109 – microcarpalide 107f – pinolidoxin 107 of tetrahydrooxazepines 356 of tetrahydropyrrolizidine 59 of trans-fused oxepane polyethers 255f of tricyclic ring systems 82 of (E, E, E)-triene skeleton 172 of trihydroxyindolizidines 57 of Z-trisubstituted alkenes via TST-RCM 240, 248ff – of unsaturated cyclic phosphates 134ff – of α,β-unsaturated lactams 52, 268, 357 – of α,β-unsaturated lactones 187, 357 – of unsaturated sultones 130ff synthetic strategy – aldol/RCM sequence 97f – chirality transfer/RRCM sequence 268f – CM/reductive amination sequence 292 – combined ROM/B935RCM strategy 54 – cuprate addition/Grignard reaction/RCM sequence 12 – domino Stille/Diels-Alder reaction 82 – Evans-Tishchenko/RCM sequence 105 – glycolate alkylation-RCM sequence 99, 102 – intramolecular Mannich reaction/B886 RCM process 55 – iodolactonization/radical reduction process 23 – Ireland-Claisen rearrangement/TST-RCM strategy 228 – isomerization/CM sequence 298 – radical cyclization/skeletal rearrangement 13 – radical cyclization/RCM sequence 111f – RCAM/cycloisomerization strategy 219 – RCAM/hydrosilylation/protodesilylation strategy 219 – RCAM/Lindlar hydrogenation strategy 211 – RCM/hydrogenation sequence 11 – RCM/ring fragmentation sequence – – for preparation of anti-Bredt alkenes 17 – – for preparation of carboycle 15 – RCM-carbomagnesation process 52 – RCM/ROM/RCM cascade 38 – reductive isomerization/RCM sequence 113 – scission/recombination process 45 – [3,3]-sigmatropic rearrangement/RCM sequence 1ff, 11, 13, 18, 94, 191 – stereoselective [2,3]-Wittig rearrangement/RCM sequence 115 – sulfonylation/B959RCM sequence 131ff – thio acetal/free-radical cyclization strategy 112 – TST-RCM/CM strategy 239 – TST-RCM/organolithium ring-opening strategy 251f – TST-RCM/palladium-mediated cross-coupling strategy 253f – TST-RCM/Sakurai reaction strategy 247 t tartolon B 242 taxane analog 322 Tebbe reagent 123 temporary silicon-tethered RCM (TST-RCM) 226ff – chemoselectivity in 248 – diastereoselective reaction with alkenols 234f – enantioselective, of prochiral alkene 255f – for preparation of 2-ene-1,5-diols 240f – for preparation of Z-trisubstituted alkenes 240f – for stereoselective preparation of 1,n-diols 234ff, 245 – long-range asymmetric induction 233f – of acyclic mono-alkoxysilane 245 – of diene-yne systems 241ff – of enynesiloxane 256 – spiroketalization 232 terpenoides 169ff terpestacin 167, 309 tethered metathesis reaction see also RRCM 225ff tetrangomycin 192 tetraponerine 54, 328 thuggacin B 293 tipranavir 347 titanium alkylidene 121f tonantzilolone 169 trichloromenyn A 274, 277 tricolorin A 175 triene-yne precursor 116 trienomycin A 272 tropane alkaloid 48 TST-RCM see temporary silicon-tethered RCM tuberostemonine 298 turriane 208 u uniflorine A 55ff 383 384 Index v vinylation, diastereoselective (+)-virgatusin 247 (+)-viroallosecurinine 317 vitamin D2 249 y 64 w Weinreb amide 65 Wittig olefination 4, 13, 61, 64, 70, 110 woodrosin I 176 x xanthatin derivative – (−)-dihydroxanthatin 194 – (+)-8-epi-xanthatin 316 YM-181741 192 yuzu lactone 211 z zampanolide 161 zeralenone 152, 156 zeranol 152 ... Trt Ts TS ring-closing ene-yne metathesis ring-closing metathesis ring-opening metathesis ring-opening metathesis polymerization relay ring-closing metathesis ring-rearrangement metathesis room... impact of metathesis on the synthesis of natural products and/ or biologically active compounds, and highlight how they Metathesis in Natural Product Synthesis: Strategies, Substrates and Catalysts. .. Pyrrolidine Alkaloids 47 Pyrrolidines 47 Dipyrrolidines 49 Polyhydroxypyrrolidines 49 Indolizidine Alkaloids 52 Polycyclic Indolizidines 52 Metathesis in Natural Product Synthesis: Strategies, Substrates