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Helicoselective Synthesis of Dioxa[6]Helicenes and Design of Orginal P-Stereogenic Brønsted Acid Organocatalystsx

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Helicoselective Synthesis of Dioxa[6]Helicenes and Design of Orginal P-Stereogenic Brønsted Acid Organocatalystsx Helicoselective Synthesis of Dioxa[6]helicenes and Design of Orginal P-Stereogenic Brønsted Acid Organocatalystsx. Peng Liu To cite this version: Peng Liu. Helicoselective Synthesis of Dioxa[6]helicenes and Design of Orginal P-Stereogenic Brøn- sted Acid Organocatalystsx.. Organic chemistry. Ecole Centrale Marseille, 2020. English. NNT : 2020ECDM0004. tel-03127048 HAL Id: tel-03127048 https://tel.archives-ouvertes.fr/tel-03127048 Submitted on 1 Feb 2021 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. N° BU: ……………….. THÈSE Helicoselective Synthesis of Dioxa[6]helicenes and Design of Original P-Stereogenic Brønsted Acid Organocatalysts Présentée par Peng LIU Pour obtenir le grade de Docteur en Sciences de l'Université Aix-Marseille Spécialité : Chimie Organique École Doctorale des Sciences Chimiques - ED 250 Institut des Sciences Moléculaires de Marseille (iSm2)-UMR 7313 Équipe Synthèse Totale et Réactivité Organique (STeRéO) Soutenue publiquement le 21 septembre 2020 devant la commission d’examen composée de : Dr Angela MARINETTI, Institut de Chimie des Substances Naturelles (ICSN) Rapporteur Pr Jieping ZHU, École Polytechnique Fédérale de Lausanne (EPFL) Rapporteur Pr José Luis VICARIO, University of the Basque Country Examinateur Pr. Alexandre MARTINEZ, Aix Marseille Université Examinateur Pr. Jean RODRIGUEZ, Aix Marseille Université Invité Dr. Laurent GIORDANO, Aix Marseille Université Co-encadrant Dr. Damien BONNE, Aix Marseille Université Directeur 1 Index Acknowledgements ....................................................................................................... 6 Abbreviations ................................................................................................................. 8 General introduction ...................................................................................................... 9 Chapter 1: Background of chirality in science ............................................................ 12 1.1) Research and definition of chirality .................................................................. 12 1.2) Different types of chirality ............................................................................... 14 1.3) The importance of controlling chirality ............................................................ 15 1.4) Different strategies to control chirality ............................................................. 17 1.5) The different activation modes of organocatalysis ........................................... 18 1.5.1) Covalent activation .................................................................................... 19 1.5.1.1) Enamine activation .............................................................................. 19 1.5.1.2 Iminium activation ................................................................................ 21 1.5.2) Non-covalent activation ............................................................................. 22 1.5.2.1) Hydrogen-Bond catalysis .................................................................... 22 a) Urea/thiourea ............................................................................................ 22 b) Squaramides .............................................................................................. 24 1.5.2.2 Brønsted acid ........................................................................................ 30 Chapter 2: Simultaneous Control of Central and Helical Chiralities: Expedient Helicoselective Synthesis of Dioxa[6]helicenes .......................................................... 33 2.1) Introduction ...................................................................................................... 33 2.2) State of the art on the enantioselective synthesis of heterohelicenes ............... 34 2.3) Importance of the heteroatom in the heterohelicene structures ........................ 38 2 2.4) Presentation of our strategy for the enantioselective synthesis of heterohelicenes .................................................................................................................................. 40 2.4.1) Previous work of the laboratory: atroposelective synthesis of 3-arylfurans .............................................................................................................................. 40 2.4.2) Strategy for the enantioselective synthesis of heterohelicenes .................. 43 2.5) Simultaneous control of multiple stereogenic elements ................................... 45 2.5.1) Installation of central and axial chiralities ................................................. 45 2.5.1.1) [2+2+2] cycloaddition ......................................................................... 45 2.5.1.2) Dynamic kinetic resolution (DKR) ..................................................... 46 2.5.1.3) Desymmetrization ............................................................................... 50 2.5.1.4) Other organocatalyzed reaction ........................................................... 53 2.5.2) Installation of planar and axial chiralities .................................................. 56 2.5.3) Installation of helical and axial chiralities ................................................. 57 2.6) Configurational stability of the target ............................................................... 58 2.7) Enantioselective synthesis of dihydrofurans bearing central and helical chiralities .................................................................................................................. 61 2.7.1) Synthesis of the starting materials ............................................................. 61 2.7.2) Preliminary results and reaction optimization ........................................... 64 2.7.3) Reaction scope ........................................................................................... 68 2.7.4) Determination of the absolute configuration ............................................. 75 2.8) Aromatization to dioxa[6]helicenes .................................................................. 78 2.8.1) Primary investigations ............................................................................... 78 2.8.2) Reaction scope for the elimination reaction ............................................... 80 2.8.3) Absolute configuration ............................................................................... 82 3 2.8.4) Barriers to enantiomerization barriers ....................................................... 84 2.8.5) Reaction mechanism .................................................................................. 85 2.9) Conclusion ........................................................................................................ 87 Chapter 3: Design, synthesis and evaluation of original P-stereogenic organocatalysts ..................................................................................................................................... 89 3.1) Brønsted acid catalysis, with traditional CPA catalysts ................................... 89 3.2) Design of original P-stereogenic Brønsted acid organocatalysts ..................... 93 3.3) State of the art ................................................................................................... 95 3.4) Synthesis of original P-Stereogenic organocatalysts ........................................ 96 3.5) Application of new P-Stereogenic organocatalysts ........................................ 100 3.5.1) Application in enantioselective organocatalyzed transfer hydrogenation of quinolines ........................................................................................................... 100 3.5.2 Application in enantioselective Pictet-Spengler Reaction ........................ 101 3.5.3 Application in atroposelective annulation reaction ................................... 104 3.6) Summary and perspective ............................................................................... 108 General conclusion .................................................................................................... 109 Chapter 4: Experimental procedures and characterization of compounds ................ 111 4.1) General information ........................................................................................ 111 4.2) Experimental procedure for chapter 2 ............................................................ 113 4.2.1) Synthesis of dinaphtho[2,1-b:1',2'-d]furan-2-ol 1 .................................... 113 4.2.2)Experimental procedures for the synthesis and characterization of chloronitroalkene 2 ............................................................................................. 114 4.2.3) Experimental procedures for the enantioselective synthesis and characterization of dihydrofurans 3 .................................................................... 119 4 4.2.4) Experimental procedures of elimination and characterization of helicenes 4 ...........................................................................................................................
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