Springer Theses Recognizing Outstanding Ph.D. Research Jianxian Gong Total Synthesis of (±)-Maoecrystal V Springer Theses Recognizing Outstanding Ph.D. Research For furthervolumes: http://www.springer.com/series/8790 Aims and Scope The series ‘‘Springer Theses’’ brings together a selection of the very best Ph.D. theses from around the world and across the physical sciences. Nominated and endorsed by two recognized specialists, each published volume has been selected for its scientific excellence and the high impact of its contents for the pertinent fieldofresearch.Forgreateraccessibilitytonon-specialists,thepublishedversions includeanextendedintroduction,aswellasaforewordbythestudent’ssupervisor explaining the special relevance of the work for the field. 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Jianxian Gong Total Synthesis of (±)-Maoecrystal V Doctoral Thesis accepted by Peking University, Beijing, China 123 Author Supervisor Dr. JianxianGong Prof.Zhen Yang School ofChemical Biologyand College ofChemistry andMolecular Biotechnology Engineering Peking UniversityShenzhen Graduate Peking University School Beijing Shenzhen,Guangdong People’s Republic ofChina People’s Republic ofChina ISSN 2190-5053 ISSN 2190-5061 (electronic) ISBN 978-3-642-54303-6 ISBN 978-3-642-54304-3 (eBook) DOI 10.1007/978-3-642-54304-3 Springer Heidelberg NewYork Dordrecht London LibraryofCongressControlNumber:2014931688 (cid:2)Springer-VerlagBerlinHeidelberg2014 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionor informationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar methodology now known or hereafter developed. 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While the advice and information in this book are believed to be true and accurate at the date of publication,neithertheauthorsnortheeditorsnorthepublishercanacceptanylegalresponsibilityfor anyerrorsoromissionsthatmaybemade.Thepublishermakesnowarranty,expressorimplied,with respecttothematerialcontainedherein. Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) Parts of this thesis have been published in the following journal articles: Gong J, Lin G, Li C-C et al. (2009) Synthetic study toward the total synthesis of maoecrystal V. Org Lett 11:4770–4773 (Reprinted with permission. Copyright (2010) American Chemical Society.) Gong J, Lin G, Sun W-B et al. (2010) Total Synthesis of (±) Maoecrystal V. J. Am. Chem. Soc. 132:16745–16746 (Reprinted with permission. Copyright (2009) American Chemical Society.) Supervisor’s Foreword Thefieldoftotalsynthesisofnaturalproductsispracticedinascientificandartistic way. The strategy should be balanced based on the dimensions, geometries, and symmetriesofthemolecules.Duringthepursuitoftotalsynthesis,theartistictaste wasexercisedinthewaycombiningchemicalreactionstoarriveatastrategythat will lead to the target molecule. The powerful methodology and sophisticated instrumentationavailabletodayhaveprofoundlyaffectedthewayinwhichorganic moleculesaresynthesizedandcharacterized.Inspiteofthegreatadvancesthathave enormously facilitated our operations, the synthesis of organic molecules even of mediumlevelsofcomplexitystillfacespractical,theoretical,andlogicalchallenges. This thesis focuses on the total synthesis of Maoecrystal V. Maoecrystal V, anaturalproductwithpotentbiologicalactivity,isanovelditerpenoidwhichwas isolated from the leaves of Chinese medicinal herb, Isodon eriocalyx, by Prof. Handong Sun and co-workers. The synthesis challenge exists in the novel pentacyclic ring system and six chiral centers, including four continuous chiral centers, three all quaternary carbon centers. Manydistinguishedsyntheticgroupshavecarriedoutthetotalsynthesistoward Maoecrystal V due to the complexity of the structure and the importance of its bioactivity. The thesis mainly focuses on two aspects: the first part is the stereo- selective construction of the tetracyclic model system and the second part is the first total synthesis of natural product Maoecrystal V. Based on the model study, the total synthesis of Maoecrystal V is accomplished in 17 steps, 1.2 % yield. In such an exciting field, only a tip of the iceberg in terms of molecular diversityfromnaturehasbeenjusttouchedbythesynthesis.Withthedevelopment of organic synthesis, I strongly believe that we are going to see a lot of creative and efficient strategies for the synthesis of complex molecules. As Prof. K. C. Nicolaousaid‘‘It’srathercomplicatedtoevendefineart,science,andtechnology. Thereisatriangleofart,whichisthepursuitofsomethingnew,usuallyassociated withesthetics;science,thepursuitofsomethingnew,perhapstheunderstandingof nature; and technology, the application of science.’’ Keeping ourselves busy inventinganddiscoveringnewgenerationsofmedicineusedinthepharmaceutical and biotechnology industries will always be our unremitting pursuit. Beijing, March 2013 Zhen Yang vii Contents 1 Research Background of Total Synthesis of Natural Product Maoecrystal V and Its Family. . . . . . . . . . . . . . . . . . . . . 1 1.1 Introduction to the Research Background of Total Synthesis of Natural Products. . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Terpenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1.3 Ent-Kaurane Diterpene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1.4 Isolation and Structure Identification of Diterpenoid Natural Product Maoecrystal V. . . . . . . . . . . . . . . . . . . . . . . . 7 1.5 Biosynthetic Hypothesis for Maoecrystal V . . . . . . . . . . . . . . . 8 1.6 Bioactivity of Maoecrystal V . . . . . . . . . . . . . . . . . . . . . . . . . 8 1.7 A Brief Review on Synthesis Works of Maoecrystal V . . . . . . . 9 1.7.1 The Synthetic Strategy of Our Group . . . . . . . . . . . . . . 9 1.7.2 The Synthesis Research of Baran’s Group . . . . . . . . . . . 17 1.7.3 The Synthesis Research of Danishefsky’s Group. . . . . . . 18 1.7.4 The Synthesis Research of Nicolaou’s Group. . . . . . . . . 21 1.7.5 The Synthesis Research of Singh’s Group . . . . . . . . . . . 22 1.7.6 The Synthesis Research of Thomson’s Group. . . . . . . . . 23 1.7.7 The Synthesis Research of Trauner’s Group. . . . . . . . . . 25 1.7.8 The Synthesis Research of Zakarian’s Group. . . . . . . . . 25 1.8 Brief Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 2 Model Study of Maoecrystal V. . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.1 Model Study of Maoecrystal V: Synthesis Strategy. . . . . . . . . . 29 2.2 The Model Synthesis of Maoecrystal V . . . . . . . . . . . . . . . . . . 29 2.2.1 Pinhey Arylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 2.2.2 The Development and Synthetic Application of Diels–Alder Reaction. . . . . . . . . . . . . . . . . . . . . . . . 31 2.2.3 Construction of [2.2.2] System via Sequential Oxidative Dearomatization/IMDA Reaction. . . . . . . . . . 35 2.2.4 The Model Study of Maoecrystal V . . . . . . . . . . . . . . . 38 ix x Contents 2.3 Experimental Section. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 2.3.1 Experimental Materials and Equipment . . . . . . . . . . . . . 48 2.3.2 Experimental Process and NMR Data of Model Study. . . 49 2.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 3 Total Synthesis of Maoecrystal V . . . . . . . . . . . . . . . . . . . . . . . . . 73 3.1 Retro-synthetic Analysis of Maoecrystal V. . . . . . . . . . . . . . . . 73 3.2 Strategy 1 of Total Synthesis: DA/Oxa-bridge Formation. . . . . . 73 3.2.1 Retro-synthetic Analysis . . . . . . . . . . . . . . . . . . . . . . . 73 3.2.2 The Preparation of 1,3-Keto Ester. . . . . . . . . . . . . . . . . 74 3.2.3 Diastereoselective Reduction of Ketone Carbonyl Group of 1,3-Keto Ester . . . . . . . . . . . . . . . . . . . . . . . 76 3.2.4 Intramolecular Diels–Alder/Oxa-bridge Strategy. . . . . . . 79 3.3 Oxa-bridge/IMDA: Intramolecular S 2 to Form Oxa-bridge. . . . 84 N 3.4 Oxa-bridge/IMDA Strategy: Intramolecular Oxa-Michael Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 3.5 Oxa-bridge/IMDA Strategy: Rh(II)-catalyzed Intramolecular O–H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . 89 3.6 The Experimental Process and NMR Data of Total Synthesis. . . 96 3.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 4 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Abbreviations Ac Acetyl AVMA Asymmetric vinylogous Mukaiyama aldol Bn Benzyl Boc t-butoxycarbonyl BOM Benzyloxymethyl i-Bu i-butyl n-Bu n-butyl t-Bu t-butyl Bu Butyl CAN Cerium(IV) ammonium nitrate Cp Cyclopentadienyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DEAD Diethyl azodicarboxylate DIBAL-H Diisobutylaluminum hydride DIPEA N,N-diisopropylethylamine DMAP N,N-4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMP Dess–Martin Periodinane DMSO Dimethylsulfoxide dr Diastereoselective ratio EA Ethyl Acetate EE 2-ethoxyethyl Et Ethyl eq. Equivalent HMPA Hexamethylphosphoramide i-Pr i-propyl LDA Lithium Diisopropylamide LiHMDS Lithium Hexamethyldisilazide NaHMDS Sodium Hexamethyldisilazide Me Methyl MEM (2-methoxyethoxy) Methyl MES Mesityl MOM Methoxymethyl xi