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Development of New Methodologies in Organic Synthesis for the Preparation of Bioactive Molecules Marwa Hussein

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Development of New Methodologies in Organic Synthesis for the Preparation of Bioactive Molecules Marwa Hussein Development of new methodologies in organic synthesis for the preparation of bioactive molecules Marwa Hussein To cite this version: Marwa Hussein. Development of new methodologies in organic synthesis for the preparation of bioac- tive molecules. Organic chemistry. Université Rennes 1; Université Libanaise, 2017. English. NNT : 2017REN1S046. tel-01682268 HAL Id: tel-01682268 https://tel.archives-ouvertes.fr/tel-01682268 Submitted on 12 Jan 2018 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. ANNÉE 2017 THÈSE / UNIVERSITÉ DE RENNES 1 sous le sceau de l’Université Bretagne Loire avec Université Libanaise pour le grade de DOCTEUR DE L’UNIVERSITÉ DE RENNES 1 Mention : Chimie Ecole doctorale Sciences de la Matière, Rennes présentée par Marwa Hussein préparée à l’unité de recherche UMR 6226 CNRS / Institut des Sciences Chimiques de Rennes / Equipe PNSCM Composante universitaire : S. P. M. Thèse soutenue à Beyrouth Development of new le 20 Mars 2017 devant le jury composé de : methodologies in Thierry DURAND Directeur de Recherche CNRS, Université de organic synthesis to Montpellier /rapporteur Kamal H. BOUHADIR prepare bioactive Professeur, Université Américaine Beyrouth / rapporteur compounds Jean-Pierre BAZUREAU Professeur, Université de Rennes1 /examinateur Fares FARES Professeur, Université Libanaise Beyrouth / examinateur Ali HACHEM Professeur, Université Libanaise Beyrouth / co- directeur de thèse René GREE Directeur de Recherche CNRS (Em.), Université de Rennes 1 / co-directeur de thèse i i Table of Schemes Scheme I. 1: Main strategies for the synthesis of 2-Azetidinone ring .........................10 Scheme I. 2: The Kinugasa reaction ............................................................................11 Scheme I. 3: Original β-lactam synthesis through Kinugasa reaction [31] .................11 Scheme I. 4: Synthesis of β-lactam by Ding and Irwin [32]........................................12 Scheme I. 5: Mechanism for the Kinugasa reaction as proposed by Ding and Irwin..12 Scheme I. 6: Thermal non-catalyzed alkyne- nitrone cycloaddition reaction .............13 Scheme I. 7: Catalytic intermolecular Kinugasa reaction developed by Miura ..........13 Scheme I. 8: Catalytic asymmetric synthesis of β-lactams by using chiral ligands ....15 Scheme I. 9: Enantioselective Kinugasa reaction catalyzed by Cu(II)/TOX 13 chiral complex........................................................................................................................15 Scheme I. 10: Highly stereoselective ynamide Kinugasa reaction ..............................16 Scheme I. 11: Diastereoselective synthesis of Carbapenems via a Kinugasa reaction 17 Scheme I. 12: Synthesis of the cholesterol absorption inhibitor Ezetimibe 25 ...........17 Scheme I. 13: Asymmetric Kinugasa reaction on water..............................................18 Scheme I. 14: Synthesis of α-methylene β-lactams via ester enolate imine condensation reaction...................................................................................................20 Scheme I. 15: synthesis of α-ethylidene β-lactams via ester enolate imine condensation reaction...................................................................................................20 Scheme I. 16: Kinugasa reaction in the presence of L-proline....................................21 Scheme I. 17: The way of formation of 30 proposed by Basak...................................21 Scheme I. 18: General method for the preparation of 6-methylidene penems 40 .......22 Scheme I. 19: Synthesis of α-methylene β-lactams via PPh3-catalyzed umpolung cyclization of propiolamides........................................................................................22 Scheme I. 20: Proposed mechanism for the synthesis of α-methylene β-lactam via PPh3 catalyst.................................................................................................................23 Scheme I. 21: Synthesis of α-alkylidene-β-lactam using Kinugasa reaction with alkynes bearing a gem-diflouro group at propargylic position ....................................23 Scheme I. 22: Mechanism of the Kinugasa reaction proposed by Tang and coworkers ......................................................................................................................................27 Scheme I. 23: Our working hypothesis towards a new synthesis of α-methylene- and α-alkylidene-β-lactams.................................................................................................28 ii ii Scheme I. 24: Grignard reaction for the preparation of 47a ........................................32 Scheme I. 25: Kinugasa reaction between alkynes 47 and nitrone 2a.........................33 Scheme I. 26: Kinugasa reaction between nitrone 2a and alkynes 49 and 51 .............39 Scheme I. 27: Kinugasa reaction between nitrone 2a and alkyne 53 ..........................40 Scheme I. 28: Kinugasa reaction between alkyne 47d and nitrone 55 ........................41 Scheme I. 29: Kinugasa reaction between alkyne 47d and nitrone 57 ........................41 Scheme I. 30: Kinugasa reaction between alkyne 47d and nitrone 59 ........................41 Scheme I. 31: Kinugasa reaction between alkyne 47d and cyclic nitrone 61..............42 Scheme I. 32: Kinugasa reaction between nitrone 2a and alkynes 63.........................42 Scheme I. 33: Kinugasa reaction between simple alkyne 63d and nitrones 57, 59 and 61..................................................................................................................................44 Scheme I. 34: Direct synthesis of α-methylene and α-alkylidene β-lactams via Kinugasa reaction.........................................................................................................48 Scheme II. 1: Brook rearrangement of aroylsilanes………………………………... 93 Scheme II. 2: Proposed mechanism by Brook for the formation of aldehydes from acylsilanes ....................................................................................................................93 Scheme II. 3: Reaction of alkoxides with acylsilane 15 ..............................................94 Scheme II. 4: Reverse Brook rearrangement ...............................................................94 Scheme II. 5: First acylsilane compound synthesized by Brook .................................95 Scheme II. 6: Different methods for the synthesis of acylsilanes................................95 Scheme II. 7: Acylsilane 25 from α-silylalcohols 24...................................................96 Scheme II. 8: Acylsilanes 31 from silylalcohols 30 using mild oxidation conditions.96 Scheme II. 9: Acylsilanes 34 from silylalcohols 33 using Dess-Martin oxidant.........97 Scheme II. 10: Acylsilanes 38 from masked aldehydes 36 .........................................97 Scheme II. 11: Acylsilanes 41 from esters 39..............................................................98 Scheme II. 12: Acylsilanes 44 from esters 43 and silyllithium derivative 42 .............98 Scheme II. 13: oxidation of disilylalcohols 46' to afford acylsilanes 48.....................99 Scheme II. 14: Acylsilanes 50 from amides 49 ...........................................................99 Scheme II. 15: Synthesis of acylsilanes 50 from morpholine amides 51 ..................100 Scheme II. 16: Rearrangement observed starting from aryl morpholine amides 53 .100 Scheme II. 17: Acylsilane using aromatic/heteroaromatic morpholine amide precursors...................................................................................................................101 Scheme II. 18: Acylsilanes 62 from S-2-pyridyl esters 61 ........................................101 Scheme II. 19: Acylsilanes 50 and 65 from acyl chlorides 63...................................102 iii iii Scheme II. 20: Acylsilanes 69 from acyl chlorides 67 using palladium catalyst ......102 Scheme II. 21: Nucleophilic addition on acylsilane 70 bearing achiral center on the α- carbon.........................................................................................................................103 Scheme II. 22: Nucleophilic addition on acylsilane 73 bearing achiral center on the β- carbon.........................................................................................................................104 Scheme II. 23: Grignard additions on acylsilanes 76 ................................................104 Scheme II. 24: Addition reaction of lithium enolate on acylsilane 78.......................105 Scheme II. 25: Diastereoselective aldolizations of acylsilane 84 ..............................105 Scheme II. 26: Radical reactions of acylsilanes 89, 91 and 93..................................106 Scheme II. 27: Mechanism proposed for the radical reactions of acylsilanes. ..........106 Scheme II. 28: Synthesis of bicyclic alcohol 97 from acylsilane 96 through a radical reaction.......................................................................................................................107 Scheme II. 29:
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