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Total Synthesis of Biologically Relevant Natural Total synthesis of biologically relevant natural products in the diketopiperazine and oxepine series : oxidative functionalizations and oxa-Cope rearrangement studies Wei Zhang To cite this version: Wei Zhang. Total synthesis of biologically relevant natural products in the diketopiperazine and oxepine series : oxidative functionalizations and oxa-Cope rearrangement studies. Organic chemistry. Sorbonne Université, 2018. English. NNT : 2018SORUS433. tel-02957219 HAL Id: tel-02957219 https://tel.archives-ouvertes.fr/tel-02957219 Submitted on 5 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Sorbonne Université Ecole doctorale 406, Chimie Moléculaire Molécules de Communication et Adaptation des Micro-organismes (UMR 7245, CNRS-MNHN) TOTAL SYNTHESIS OF BIOLOGICALLY RELEVANT NATURAL PRODUCTS IN THE DIKETOPIPERAZINE AND OXEPINE SERIES Oxidative functionalizations and oxa-Cope rearrangement studies Par Wei ZHANG Thèse de doctorat de Chimie organique Dirigée par Bastien NAY et Didier BUISSON Présentée et soutenue publiquement le 3 OCTOBRE 2018 Devant un jury composé de : Dr. GRIMAUD Laurence Directrice de Recherche Examinatrice Dr. EVANNO Laurent Maître de conférences Rapporteur Dr. DE PAOLIS Michaël Chargé de Recherche Rapporteur Dr. ROUSSI Fanny Directrice de Recherche Examinatrice Dr. NAY Bastien Directeur de Recherche Examinateur Dr. BUISSON Didier Directeur de Recherche Examinateur ACKNOWLEDGEMENTS First and foremost, I would like to express my deepest gratitude to my research supervisors Dr. Bastien Nay and Dr. Didier Buisson, for giving me this great opportunity to work with them. Thank you for your patient guidance, enthusiastic encouragement and useful advises already from my master internship. Thanks, Bastien, your broad knowledge and experience in organic chemistry brought me a lot and helped me understand the chemical research field. Thank Didier, for sharing your great knowledge in biotransformation and every interesting skill in lab with me. Your scientific rigor and passion taught me how to be a real chemist. The discussions with all of you has motivated me to keep moving forward in my project and as well in my future. I want to express my very special thanks to Dr. Gilles Frison. Thank you for investing time for guiding me to finish all the calculation work. I enjoyed immensely the project I’ve worked on, even only several months. With your help, I have learned more than I could have imagined during my thesis project. Many thanks go equally to Dr. Emmanuel Baudouin for carrying out all biological testes for radulanins. Your amazing work brought more value to my project. I would like to thank all the members of the jury committee, Dr. Laurent Evanno, Dr. Michaël De Paolis, Dr. Laurance Grimaud and Dr. Fanny Roussi for sparing your time to evaluate my Ph.D. research work and come to my defense. Secondly, I would like also to thank all the group members from MCAM and LSO for their warm welcome and generous help during my stay. Dr. Sébastien Prevost and Dr. Alexis Archambeau, thanks for giving thought-provoking chemical and technical suggestions every time when I need help, as well as for your patience to help me solve all problems. Your contributions to the lab of Muséum and LSO make the lab life much easier. I would like also to acknowledge Pr. Bernard Bodo, Dr. Stéphane Mann, Pr. Soizic Prado, Dr. Caroline Kuntz for rich conversations and useful advices during the seminars or coffee time. Dr. Benjamin Laroche and Dr. Mehdi Zaghouani, thanks for all your chemical help from my very beginning work in the lab. Your guys have set up outstanding examples for me. Even for today, I’m still learn from you and regard you as models (Some of your advices, I began to understand in the end of my thesis, such a pity). i Dr. Marine Vallet, Dr. Ambre Dezaire, Cécile Anne, Margot Barenstrauch, Anne Tourneroche, Laura Guedon and Andrea Diaz, thank you for all your help in Myco and for every pleasant chat with you. I can still remember the birthday surprise you brought me in my first year of my Ph.D. It’s always been much appreciated to go out with you girls. Lunch, drinking and of course our 10km running, such unforgettable moments. I promise that there will be for sure a big party organized in my home after my defense! Vincent Revil-Baudard and Oscar Gayraud, thanks for helping me dealing with any small or big problems (NMR, computer…). I really enjoy having coffee time with you guys and appreciate all fruitful discussions about science and life. We should go back again to the best falafel with Eloi Astier! Gabriela Siemiaszko, thank you for sharing your research experiences at lunch break and especially thanks for shifting your schedule to night-work mode at last period of our Ph.D., so that I could finish a lot of work even after Pjotr Roest left. My thanks also go to Dr. Qi Huang for taking time to read this manuscript and giving helpful and constructive criticism. PhD made all of us great friends. I really love to spend every joyful moment with you. We’ll for sure play the card game together! I would like to give a big hug for Aimilia Meichanetzoglou. Thank you for your constant companion from our M2 internships. I’ll never forget your support whenever I feel joyful or upset. Best wishes for your Ph.D. journey (καλή τύχη). It should be as great as you! I would like to thank cordially Alain Blond, Alexandre Deville, Arul Marie, Lionel Dubost and Vincent Jactel. Thank you for dealing with equipments and affording great NMR and HRMS analytic work. Big thanks to Séverine Amand, Christine Bailly, Brice Mollinelli, Zhilai Hong, Djéna Mokhtari, Cethaise Hyacinathe, Samir Zard, Yvan Six, Laurent El Kaïm, Béatrice Sire, Kieu Dung Ly, Xuan Chen, Julien Morain and any other group members in MCAM and LSO that I haven’t mentioned. You’ve all helped me in some way over these years, thank you for setting a great and funny work environment. I really enjoy working with you and will definitely miss all the moments that we spent together. Last but not least, I would like to express especially my love and gratitude to my Mum and Dad, who worked so hard to help me get here, and who always let me do things my own way and in my own time. Thank you for your unconditional support, both financially and ii emotionally for all my decision through these years abroad. Your love and encouragement keep me strong. I need also to give my grateful acknowledgment to all my friends, who have been always so encouraging and supportive during this journey, and so understanding of my hobbit-like social reclusiveness while I’ve been writing up this thesis. Thanks to you, I’m living a wonderful and colorful life. iii iv LIST OF ABBREVIATIONS A: adenylation domain aa: amino acids Ac: acetyl Ac2O: acetic anhydride AIBN: 2,2’-azobis(2-methylpropionitrile) Ar/ar: aryl Bn: benzyl Boc: tert-butoxycarbonyl BSTFA: N,O-bis(trimethylsilyl)trifluoroacetamide C: condensation domain CAN: ceric ammonium nitrate cat.: catalytic quantity CoA: coenzyme-A Cbz: benzyloxycarbonyl CDI: 1,1’-carbonyldiimidazole CSA: camphor sulfonic acid CDPS: cyclodipeptide synthase COD: 1,5-cyclooctadiene DKP: diketopiperazine DCM: dichloromethane DMAP: 4-N, N-dimethylaminopyridine DMF: dimethylformamide DMSO: dimethylsulfoxide DIPEA: N,N-diisopropylethylamine d.r.: diastereomeric ratio DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-dichloroethane DMDO: dimethyldioxirane DMBn: dimethoxybenzoin DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DFT: density functional theory DEAD: diethyl azodicarboxylate DIAD: diisopropyl azodicarboxylate equiv.: equivalent E+: electrophile EWG: electron withdrawing group EDG: electron donating group Fmoc: fluorenylmethyloxycarbonyl HMDS: hexamethyldisilazane HTIB: hydroxy(tosyloxy)iodobenzene (Koser’s reagent) IEFPCM: integral equation formalism polarizable continuum model IBX: 2-iodoxybenzoic acid IC50: half maximal inhibitory concentration LA: Lewis acid L: liter or neutral ligand v LDA: lithium diisopropylamide LAH: lithium aluminium hydride LSF: late-stage functionalization mCPBA: m-chloroperoxybenzoic acid Ms: mesylate MIC: minimum inhibitory concentration MoOPH: oxodiperoxymolybdenum(pyridine)-(hexamethylphosphoric triamide) MPO: 4-methoxypyridine N-oxide MS: molecular seive NRPS: non-ribosomal peptide synthase NBS: N-Bromosuccinamide NMO: N-methylmorpholine-N-oxide Nu: nucleophile NR: no reaction [O]: oxidation pH: hydrogen ion concentration in aqueous solution pKa: acid dissociation constant p-TSA: p-toluenesulfonic acid p-ABSA: para-acetamidobenzenesulfonyl azide PCC: pyridinium chlorochromate py: pyridine PG: protecting group PE: petroleum ether ph: phenyl piv: pivalate PCP (or T): peptide carrier protein PHBP: pyridinium bromide perbromide RCM: ring-closing metathesis Rf: retention factor rt: room temperature (~25 °C) sat.: saturated TBAF: tetrabutyl ammonium fluoride TBDPS: tert-butyldiphenylsilyl TBS: tert-butyl silyl TFA: trifluoroacetic acid Tf: triflate (trifluoromethanesulfonyl) TfO2: triflic anhydride TMS: trimethylsilyl THF: tetrahydrofuran TFDO: methyl(trifluoromethyl)dioxirane
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