Letort, Aurelien (2015) Ring-Closing Metathesis Cascade toward a Formal Synthesis of Taxol. PhD thesis. http://theses.gla.ac.uk/6677/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study This thesis 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 Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] Ring-Closing Metathesis Cascade toward a Formal Synthesis of Taxol Aurélien Letort Master Sciences - Chimie Organique 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 July 2015 Ring-Closing Metathesis Cascade toward a Formal Synthesis of Taxol July 2015 Abstract TaxolTM and its derivatives are the largest selling anticancer drugs of all time. Numerous synthetic works and total syntheses have been published since its discovery, but to date no high yielding synthesis with less than 37 steps has been achieved. In this thesis is presented our synthetic efforts toward such a robust and efficient synthesis of Taxol. The optimisation of the Shapiro coupling fragments syntheses were investigated to enhance the robustness of our strategy. Then the C7-deoxy model ABC tricycle ring-system of Taxol, which lacks the oxygenated substituent at C7, has been efficiently synthesised by a dienyne ring-closing metathesis cascade (RCDEYM). This cascade closed the AB 6/8 membered ring system in a single operation. Other dienyne ring-closing metathesis cascades with similar substrates were also performed, assessing the influence of ruthenium catalysts, C1-C2 diol protecting groups (R1, R2), and substitution of the alkene at C13. Synthetic efforts were also devoted to apply such a powerful method toward a formal synthesis of Taxol from an intermediate Holton and co-workers synthesised. During our studies, the C7-oxy group was found to be critical to access the ABC tricyclic core of Taxol by metathesis cascade. Understanding of the importance of this C7-oxy group was undertaken and led to the conception of a metathesis cascade prediction model. Once the metathesis cascade was optimised, differentiation of the three trisubstituted alkenes present on the ABC tricyclic ring system was studied and elaboration of a formal synthesis was endeavoured. I Ring-Closing Metathesis Cascade toward a Formal Synthesis of Taxol July 2015 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. “Highly Efficient Synthesis of the Tricyclic Core of Taxol by Cascade Metathesis” Letort, A.; Aouzal, R.; Ma C.; Long D.-L.; Prunet, J. Org. Lett. 2014, 16, 3300-3303. ___________________ Aurelien Letort ___________________ Dr. Joëlle Prunet II Ring-Closing Metathesis Cascade toward a Formal Synthesis of Taxol July 2015 Acknowledgements First and foremost, I would like to give my deepest gratitude to my supervisor Dr. Joëlle Prunet for giving me the opportunity to undertake my PhD in her group on such interesting and challenging projects. I also would like to thank her for her support, guidance, accessibility and patience regarding my endless questions over the years (Joëlle !? une dernière question ?). A special thanks goes to David “Dj. F” France, for his guidance and inspiration during our joint Frunet group meetings and synthetic challenges through the years. I would like to thank Dr. Coralie De Schutter for her courage and bravery when she volunteered to proofread my thesis. She supported and encouraged me for these last few difficult months. Thank you for being who you are my Sweet Coralie… I would like to thank all the people who shared with me this incredible journey. A gigantic thank goes to my precious Alex “Philibert”, “Mighty stallion”, “You are such a crook, Philicrook!!”, “Fifi j’ai besoin de toi…” for being here when I needed him, in the bright as well as the dark times of this journey, you are a great friend and I hope you will stay one for the years to come (Don’t forget, I still want to be the bartender of the “Phili-bar”!). Stéphane “the beast” who supported (and traumatised) me for the last 4 years!! (pingouin ou manchot? Would you stop making that stupid noise!?). Stephen “Momo”, “Sweet sweet Momo” Morrison, you were and still are my sweet and greatest padawan. A big thank goes to my flatmate, THE ONLY ONE, sweet sweet (way too sweet) Filo! There is no word to describe this Italian “phenomenon”, it was a pleasure to spend these years with you!! Masha “Mish-Mash”, biggest fan of the “баранина”. I will never forget that you stole Philibert from me… He was mine!! Craig “Dragon slayer” Smith for being a true, loyal, and crazy friend, you are my handsome chap! Lewis “Tiny lewiwi” Williams, France Boys Inc., I need you to investigate! David “DP” Phillips, my master student who became a man, a real one! Aurélien “Jr.” Jacquin-Labarre who wanted to become senior way to soon… and failed! You will always be our junior, you know it! Ludovic “Belle coiffe” “Décul-tôt” Stop writing random things on the SPS door! Someone will notice it one day… maybe. Michael “PP”, “Popacheck”, “Papanovich” Popadynec who inherited our Throne in Castle Street. Clément “Eh bim!!” Morrisse, (Mec nan, t’as encore mangé tous les choco-suisses?) You warmly welcomed me in a wet and freezing Glasgow, I will never forget what you have done for me… Sean “The III Ring-Closing Metathesis Cascade toward a Formal Synthesis of Taxol July 2015 LepreSean”, craziest Irish boy, my second padawan (remove your hands please…) You are my favourite (I told you to remove your hands from my bottom!). -Chao, did you know that you are a weird Chinese girl? -Me? No! You are the weirdo! Weirdo! Weirdo! Weirdo!! Alejandro “tocayo!” the nicest Mexican on the planet. Yehezkiel the friendliest Mexican on the planet. Carlos the strongest Mexican on the planet. Michael “le bordélique” Mathieson, the first Prunet in my heart! Toni, Amaïa, Andres, Jo, Anna, Mhairi, Faustine, Alan (tall guy n°1), Liam (tall guy n°2), Tomicat “Cogsy” (You are a champion), Riccardo “Bambino gelato”, Ewen, German Michael, Aliboy and the boyer-boys, Colin “I am sure that this guy is a son of a pear!”. Thanks to all my students who made me learnt what patience truly meant. Quentin Llopis (chapeau l’artiste, you are a real Prunet!), David, Alice and of course “The calamity”. Thanks to my friends in France; Alex “Barzi”, Vince “Beri” and Jerem “La brute” and my brother “Jo” who fell in love with the Isle of Skye and the Scottish whisky, but more importantly who cheered me up when I needed it the most. Thanks to all of you. I would like to give a special thanks to my parents, for their support, kindness, and more importantly for putting a roof above my head, two trestles and a wooden board to write this thesis… Thanks to all of you! « Aurélien? Tu sais qu’il y a une panne de micro dans la pièce du fond qui te brouille l’écoute ? » Dr. Joëlle Prunet. IV Ring-Closing Metathesis Cascade toward a Formal Synthesis of Taxol July 2015 À ma famille, sans qui rien de tout ça n’aurait été possible… V Ring-Closing Metathesis Cascade toward a Formal Synthesis of Taxol July 2015 Abbreviations ADmix Asymmetric dihydroxylation mixture Ac Acetyl AQN Anthraquinone Bn Benzyl BOM Benzyloxymethyl Bu Butyl Bz Benzoyl CM Cross metathesis Cp Cyclopentadienyl CSA Camphor sulfonic acid DABCO 1,4-Diazabicyclo[2.2.2]octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCC N,N'-Dicyclohexylcarbodiimide dba Dibenzylideneacetone DHQ Dihydroquinine DHQD Dihydroquinidine DIBALH Diisobutylaluminium hydride DIPA Diisopropylamine DIPEA N,N-Diisopropylethylamine DMAO N,N-Dimethyl aniline oxide DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMP Dess-Martin periodinane DMSO Dimethyl sulfoxide DNA Deoxyribonucleic acid DPC Di-2-pyridyl carbonate EDCi 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EE Ethoxyethyl ee Enantiomeric excess Et Ethyl HMPA Hexamethylphosphoramide VI Ring-Closing Metathesis Cascade toward a Formal Synthesis of Taxol July 2015 Hz Hertz IBX 2-Iodoxybenzoic acid LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide m meta Me Methyl mCPBA m-Chloroperoxybenzoic acid MEM Methoxyethoxymethyl Mes Mesityl MOM Methoxymethyl MOP Methoxypropyl MS Molecular sieves nbd Norbornadiene NMO N-Methylmorpholine N-oxide NMR Nuclear magnetic resonance p para PCC Pyridinium chlorochromate Ph Phenyl Pin Pinacolato Piv Pivaloyl PMB p-Methoxybenzyl PHAL Phthalazine PHN Phenanthrene ppm Parts per million pTSA pToluenesulfonic acid PYR Pyrimidinediyl R Generalised group RCDEYM Ring-closing dialkene alkyne metathesis RCEYM Ring-closing alkene alkyne metathesis RCM Ring-closing metathesis RT Room temperature t tert TBAF Tetrabutylammonium fluoride TBAI Tetrabutylammonium iodide VII Ring-Closing Metathesis Cascade toward a Formal Synthesis of Taxol July 2015 TBDPS tert-Butyldiphenylsilyl TBS tert-Butyldimethylsilyl TES Triethylsilyl THF Tetrahydrofuran Tf Trifluoromethanesulfonyl (triflyl) TIPS Triisopropylsilyl TMS Trimethylsilyl Tris 2,4,6-Triisopropylbenzenesulfonyl Troc Trichloroethylcarbamate Ts Tosyl (p-toluenesulfonyl) VIII Ring-Closing Metathesis Cascade toward a Formal Synthesis of Taxol July 2015 Table of Catalysts Here is presented a non-exhaustive list of metathesis catalysts.