N° d'ordre : 4155 THÈSE Présentée à L'UNIVERSITÉ BORDEAUX I ÉCOLE DOCTORALE DES SCIENCES CHIMIQUES par Dawood Hosni DAWOOD POUR OBTENIR LE GRADE DE DOCTEUR SPÉCIALITÉ : CHIMIE ORGANIQUE ********************* TOWARDS THE SYNTHESIS OF MONOTERPENOIDS INDOLE ALKALOIDS OF THE ASPIDOSPERMATAN AND STRYCHNAN TYPE ********************* Soutenue le: 17 décembre 2010 Après avis de: MM. PIVA Olivier Professeur, Claude Bernard Lyon 1 Rapporteur PALE Patrick Professeur, Louis Pasteur Strasbourg 1 Rapporteur Devant la commission d'examen formée de : MM. PIVA Olivier Professeur, Claude Bernard Lyon 1 Rapporteur PALE Patrick Professeur, Louis Pasteur Strasbourg 1 Rapporteur POISSON Jean-François Chargé de recherche, CNRS Examinateur VINCENT Jean-Marc Directeur de recherche, CNRS Examinateur LANDAIS Yannick Professeur, Bordeaux 1 Directeur de thèse ROBERT Frédéric Chargé de recherche, CNRS Codirecteur de thèse - 2010 - Abbreviations ∆: reflux °C: celsius degrees Ac: acetyle ALB Aluminium Lithium bis(binaphthoxide) complex AIBN : azobis(isobutyronitrile) aq.: aqueous Ar : aromatic BINAP : 2,2'-bis(diphenylphosphino)-1,1'-binaphthyle BINAPO : 2-diphenylphosphino-2'-diphenylphosphinyl-1,1'-binaphthalene BINOL: 1,1’-bi-2-naphthol Boc: tert-butyloxycarbonyle BOX: Bisoxazoline Bz : benzoyle Bn: benzyle cat. : catalytic DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCM: dichloromethane DCC: dicyclohexacarbodiimide dr.: diastereomeric ratio DIBAL-H: diisobutylaluminium hydride DIPEA: diisopropyléthylamine (Hünig Base) DMAP: dimethylaminopyridine DME: dimethoxyethane DMF: dimethylformamide DMSO: dimethylsulfoxyde dppp : 1,3-bis(diphenylphosphino)propane DTBMP: di-tert-butyl-4-methylpyridine ee. : enantiomeric excess EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide equiv.: equivalent Et: ethyl Et2O: diethyl ether EtOAc: ethyl acetate EWG: electron withdrawing group h: hour HOBt: hydroxybenzotriazole i- pr : iso-propyle IR: infra red KHMDS: Potassium bis(trimethylsilyl)amide LDA : lithium diisopropylamide M : concentration (mole in littre) MW : molecular weight NBS : N-bromosuccinimide NR.: no reaction NMR : nuclear magnetic resonance Nu : nucleophile o- : ortho p- : para PCC: pyridinium chlorochromate (Corey-Suggs reagent) PDC: pyridinium dichromate p-TSA = APTS : para toluenesulfonic acid Piv : pivaloyle Pyr.: pyridine quant : quantitative Rf : fronted repport SES : trimethylsilylethanesulfonyle t- = tert- : tertio r.t. : room temperature TBAF: tetrabutylammonium fluoride TBDPS: tert-butyldiphenylsilyle TBS=TBDMS: tert-butyldimethylsilyle Tf : triflate = trifluoromethane sulfonate TFA: trifluoroacetic acid THF: tetrahydrofurane TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxy radical TMS : trimethylsilyle TMSBr: trimethyl silyl bromide TMSCl: trimethyl silyl chloride TMSTf: trimethylsilyl triflate Ts : tosyle = paratoluenesulfonyle TTMS : Tristrimethylsilane Table of contents Introduction ............................................................................................................................... 5 Chapter I: Approach and synthesis of Strychnos alkaloids ................................................... 9 I. Strychnine ............................................................................................................................ 9 I.1. General Aspects ............................................................................................................ 9 I.2. Toxicity of strychnine. ................................................................................................ 10 I.3. Biosynthesis of strychnine. ......................................................................................... 11 I.4. An overview of the previous syntheses of strychnine................................................. 13 I.4.1. Generation of C7 quaternary carbon center of strychnine. .................................. 15 I.4.1.a. From indole derivatives. ................................................................................ 16 I.4.1.b. From protected anilino derivatives................................................................ 17 I.4.2. Construction of the bridged CDE ring fragment. ................................................. 18 I.4.3. Elaboration of the hydroxyethylidene side chain at C20. .................................... 20 I.4.4. Enantioselective synthesis of (-)-strychnine. ....................................................... 21 I.4.5. Some detailed syntheses of strychnine. ................................................................ 23 I.4.5.a. Woodward‟s relay synthesis of (-)-strychnine (1954). .................................. 23 I.4.5.b. Mori‟s total synthesis of (-)-strychnine (2001). ............................................ 24 I.4.5.c. Bodwell‟s formal synthesis of strychnine (2002).......................................... 27 I.4.5.d. Padwa‟s total synthesis of strychnine (2007). ............................................... 28 I.4.5.e. Andrade‟s total synthesis of (±)-strychnine (2010). ...................................... 30 I.5. Conclusion .................................................................................................................. 32 II. Mossambine ...................................................................................................................... 33 II.1. General comments ..................................................................................................... 33 II.2. Kuehne‟s Synthesis of Strychnos alkaloids. .............................................................. 35 II.2.1. Intramolecular Diels-Alder reactions. ................................................................ 36 II.2.1.a. Construction of the C, D and E rings in (±)-echitamidine. .......................... 36 II.2.1.b. Reductive cleavage of the C/E ring. ............................................................ 37 II.2.1.c. Complete synthesis of (±)-echitamidine. ..................................................... 38 II.2.2. Condensation-sigmatropic rearrangement sequence. ......................................... 39 II.2.2.a. Construction of the C and E rings in (±)-echitamidine. ............................... 39 II.2.2.b. Closure of the D ring. .................................................................................. 39 II.2.3. Selective total synthesis of mossambine and epi-mossambine. .......................... 40 II.2.3.a. Construction of the pentacyclic ketone motif. ............................................. 40 II.2.3.b. Alkylation and synthesis of the key cyclization precursor. ......................... 41 II.2.3.c. Radical cyclization reaction. ........................................................................ 43 II.2.4. Enantioselective approach to (-)-mossambine. ................................................... 45 III. Conclusion ....................................................................................................................... 46 1 Chapter II: Double Michael approach applied to arylcyclohexa-2,5-diene derivatives, and a new route to the synthesis of Büchi’s ketone. ............................................................. 47 I. Synthesis of Büchi‟s ketone ............................................................................................... 47 I.1. Bibliography ............................................................................................................... 47 II. Our strategy ...................................................................................................................... 50 II.1. Retrosynthetic analysis .............................................................................................. 50 III. Synthesis of arylcyclohexa-2,5-dienes. ........................................................................... 51 III.1. Overview on the Birch reaction. .............................................................................. 51 III.2. Achievements of our laboratory. .............................................................................. 53 III.3. Synthesis of biaryls. ................................................................................................. 56 III.4. Mechanistic considerations. ..................................................................................... 58 III.5. The nature of the electrophile. ................................................................................. 61 III.6. Proposed mechanism for the alkylation step. ........................................................... 63 IV. Desymmetrization processes. .......................................................................................... 66 IV.1. Principles and advantages. ....................................................................................... 66 IV.2. Desymmetrization of cyclohexa-2,5-dienes. ........................................................... 67 V. Michael reaction. .............................................................................................................. 68 V.1. Bibliography. ............................................................................................................. 68 V.2. Results. ...................................................................................................................... 72 V.2.1. Preparation of dienone. ...................................................................................... 72 V.2.2. Double Michael addition. ................................................................................... 76 V.2.3. Enantioselective