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Total Synthesis of Members of the Amphidinolide Family of Natural Products Filippo Romiti

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Total Synthesis of Members of the Amphidinolide Family of Natural Products Filippo Romiti Romiti, Filippo (2015) Total synthesis of members of the amphidinolide family of natural products. PhD thesis. https://theses.gla.ac.uk/6445/ Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten: Theses https://theses.gla.ac.uk/ [email protected] Total Synthesis of Members of the Amphidinolide Family of Natural Products Filippo Romiti Dottore Magistrale in Farmacia (cum laude) Thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy School of Chemistry College of Science and Engineering University of Glasgow May 2015 Abstract The amphidinolides are macrolide natural products isolated from marine dinoflagellates of the genus Amphidinium and most of them display potent cytotoxic activities in vitro. Amphidinolides C-C3, F and T1-5 represent attractive synthetic targets due to a combination of potent bioactivity and complex molecular architecture. This thesis describes the total syntheses of amphidinolides T1, T3 and T4, and the preparation of the C1-C17 fragment of amphidinolides C and F. Concise and high-yielding total syntheses of amphidinolides T1, T3, and T4 have been completed using an alkynyl macrolactone as a common late-stage intermediate. The α-hydroxy ketone motif was installed by sequential alkyne hydrosilylation, epoxidation, and Fleming–Tamao oxidation. A tandem oxonium ylide formation [2,3]-sigmatropic rearrangement reaction was used to construct the trisubstituted tetrahydrofuran core found within the natural products. The C1-C17 fragment of amphidinolides C, C2, C3 and F was synthesised employing [2,3]-sigmatropic rearrangement of an oxonium ylide generated by decomposition of 1-sulfonyl-triazole to construct the trisubstituted tetrahydrofuran ring found in the natural products. The two main segments were conjoined using a Stille cross-coupling reaction that allowed simultaneous installation of the isomerization-prone 1,3-diene unit. I Declaration I declare that, except where explicit reference is made to the contribution of others, the substance of this thesis is the result of my own work and has not been submitted for any other degree at the University of Glasgow or any other institution. A portion of the work described herein has been published elsewhere as listed below. “Total Syntheses of Amphidinolides T1, T3, and T4” J. Stephen Clark, Filippo Romiti Angew. Chem. Int. Ed., 2013, 52, 10072-10075. Filippo Romiti Prof. J. Stephen Clark II Acknowledgements Firstly, I would like to thank my supervisor Prof. J. Stephen Clark for allowing me the opportunity to work in his group on such exciting and challenging projects, for his help and support during the course of my PhD, and for giving me the freedom to try my own ideas. I would like to thank all the people who shared with me this long and beautiful journey. A particular note of thanks is due to Dr. Alistair Boyer for his precious help with the chemistry and the numerous coffee and beer breaks we spent talking about random stuff. I would like to say a special thank you to Lewis and Mikey P, two great friends (I could have used different words, but I think they would be inappropriate in a PhD thesis), for the time that we spent chatting, making jokes, drinking and watching football together; I will never forget those moments. An enormous thank you goes to Aurelien Sr. for being an amazing flatmate and friend; I would have never survived in the flat without him. Many thanks to Ewen (always available for a chat), Aurelien Jr. (always ready to join me in the pub when I thought it was time for a pint… often more than one!), Sam (a thief of lab glassware, but also very generous in giving me loads of wine, beer and bread), Michael “The German” Sparenberg (with me throughout this journey, in the lab and in pubs), Craig Smith (a real “gentleman”) and Ludo (who worked with me in the intriguing amphidinolides C and F project). I would like to thank all the other “chemists” that worked with me in the lab and/or drink with me in the pub: Andy, Paloma, Tony, Guang, Ralphy, Kirsten, Gregor, Verena, Helen, Laetitia, Ian, Chao, Dr. David “Walter” Lindsay, Ondrej, Davey P, Natalia, Raik, Ariadna, Tom, Riccardo, Liam, Sean, Stephane “The Beast” Wittmann, Alex “Philibert” Audic, Stephen Morrison, Luis, Nikki, Helmi, Justyna and Carlos. I would like to thank everybody who offered me a beer, poured me a glass of wine, played football with me, gave me shelter, listened to my blabbering without asking my name. All these people have contributed to make these years in Glasgow enjoyable. Thanks to my parents for their support of the choices I have made with my life and for being always there whenever I need them. A special thank you goes to my friends in Italy, my second family: Francesco “Pine” “Francé il Pazzo” Marconi, Marco “Bomber” “Filrouge” Rossi, Alberto “Charlie” “Trabant” III Travagli, Stefano “Lombardino” “Dinho” Lombardi, Francesca “Fra” “Francelli” Bedogni, Riccardo “Riky” Colle, Giacomo “Bego” “Begozzi” Beghini and Davide “Tinto” “Tenorio” Tintori. I would also like to thank my friends Gian Paolo “Paul” “GABA” Vallerini, Andrea “Greeends” Grandi and Eddi “Fabrizio” “Bidello Pazzo” Lazzarin for coming in Scotland several times to visit me. The list would be too long if I would name all of them: an enormous thank you to all the musicians I have been listening to during these years… you made me smile and cry, you brought the sunshine in the saddest days, you kept me company when I was lonely, you celebrated with me the happy moments and you opened my mind. A special thank you is due to Led Zeppelin, the greatest rock band of all time. Thanks to rock’n’roll, which made me the man I am and is the only lifestyle I share. In this section dedicated to rock’n’roll, I would like to thank Vicky, a true rocker. Finally, thanks to myself… “I’m happy when life’s good and when it’s bad I cry, I’ve got values but I don’t know how or why. They call me the seeker, I’ve been searching low and high, I won’t get to get what I’m after till the day I die” IV Abbreviations Ac acetyl acac acetylacetonate AIBN 2,2'-azobisisobutyronitrile Ar aryl BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Bn benzyl BOM benzyloxymethyl bp boiling point brsm based on recovered starting material Bu butyl c cyclo CBS Corey-Bakshi-Shibata cod 1,5-cyclooctadiene Cp* 1,2,3,4,5-pentamethylcyclopentadienyl CSA camphorsulfonic acid CuTc copper(I) thiophene-2-carboxylate Cy cyclohexyl dba dibenzylideneacetone DCC dicyclohexylcarbodiimide DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DHQD)2PHAL bis(dihydroquinidino)phthalazine DIBAL-H diisobutylaluminium hydride DIPEA diisopropylethylamine DMA N,N-dimethylacetamide DMAP N,N-4-dimethylaminopyridine DMF N,N-dimethylformamide DMP Dess-Martin periodinane DMPM 3,4-dimethoxybenzyl DMPU N,N-dimethyl propylene urea DMSO dimethylsulfoxide dppb 1,4-bis(diphenylphosphino)butane dr diastereomeric ratio V EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ee enantiomeric excess EE ethoxyethyl Et ethyl GI Grubbs first generation catalyst GII Grubbs second generation catalyst hfacac hexafluoroacetylacetonate HGII Hoveyda-Grubbs second generation catalyst HMDS 1,1,1,3,3,3-hexamethyldisilazane HMPA hexamethylphosphoramide i iso IC50 half maximal inhibitory concentration Ipc isopinocampheyl LDA lithium diisopropylamide m meta m-CPBA meta-chloroperbenzoic acid Me methyl Mes mesityl (2,4,6-trimethylphenyl) MOM methoxymethyl mp melting point Ms mesyl (methanesulfonyl) n normal (e.g. unbranched alkyl chain) NBS N-bromosuccinimide NIS N-iodosuccinimide NMO N-methylmorpholine-N-oxide nmp 5,5-dimethyl-1-(4-methylpiperazin-1-yl)hexane-1,2,4-trione NMR nuclear magnetic resonance o ortho PCC pyridinium chlorochromate PDC pyridinium dichromate pfm heptafluoro butanamide p para PG generalised protecting group Ph phenyl VI PHT pyrrolidone hydrotribromide Piv pivaloyl PMB p-methoxybenzyl PMBTCA p-methoxybenzyl-2,2,2-trichloroacetimidate PPTS pyridinium p-toluenesulfonate Pr propyl Py (pyr) pyridine quant. quantitative R generalised group RCAM ring-closing alkyne metathesis RCM ring-closing metathesis Rf retention factor in chromatography rt room temperature t tert TBAF tetra-n-butylammonium fluoride TBDPS t-butyldiphenylsilyl TBS t-butyldimethylsilyl TCBC 2,4,6-trichlorobenzoyl chloride temp. temperature TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy free radical TES triethylsilyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid tfacac trifluoroacetylacetonate THF tetrahydrofuran TIPS triisopropylsilyl TLC thin layer chromatography TMS trimethylsilyl Tol p-tolyl tpa triphenylacetate TPAP tetra-n-propylammonium perruthenate Tr trityl (triphenylmethyl) Ts tosyl (p-toluenesulfonyl) VAZO 1,1’-azobis(cyclohexanecarbonitrile) Xc chiral auxiliary VII Table of Contents Abstract I Declaration II Acknowledgements III Abbreviations V Table of Contents VIII 1 Introduction and Background 1 1.1 The Amphidinolide Family of Natural Products 1 1.2 Amphidinolides
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