Meissner, Andreas

Okayama University Scientific Achievement Repository

 H30：様式甲／Style Kou ２－１ 学位論文の要旨 Abstract of Thesis  研究科 School 自然科学研究科 専 攻 Division 地球生命物質科学専攻 学生番号 Student No. 51428203 氏 名 Name Andreas Meissner  学位論文題目 Title of Thesis（学位論文題目が英語の場合は和訳を付記） Study of the Convergent Synthesis of Enigmazole A, Neopeltolide and Ciguatoxin 3C  (Enigmazole A、Neopeltolide及びCiguatoxin 3Cの収束的合成についての研究)  学位論文の要旨 Abstract of Thesis This thesis consists of two parts. In the first part, synthetic studies of the two macrolides enigmazole A and neopeltolide are described. Enigmazole A was isolated from the marine sponge cinachyrella enigmatica and gained much interest due to its strong cytotoxicity and complex structure, resulting in five total syntheses to date. The synthesis presented in this thesis started from ethyl bromopyruvate I and chiral propargylic alcohol II. Following a literature procedure, dithiane III was prepared and coupled to chiral epoxide IV to give chiral alcohol V which was converted to the carboxylic acid fragment VI. Esterification of VI with alcohol fragment VII under Shiina conditions furnished ester VIII. Reductive acetylation of the ester VIII gave α-acetoxy ether IX. The cyclization precursor IX was subjected to the intramolecular allylation with MgBr2·OEt2 to provide THP derivative IX was prepared and converted to lactone X by Yamaguchi`s conditions. Selective deprotection of the MOM group delivered alcohol XI, a known synthetic intermediate of enigmazole A XII.    OHMeEtOOOBrHSSON MeOMeMe TBSOOSSON MeOMeMeTBSOHOON MeOMeMeHO2CMPMO OTBScarboxylic acid fragment (VI)OMOMMe MeOTBSalcohol fragment (VII)OOOMOMMe MeOTBSOTBSO ON MeOMeMeMPMTMSOHTMS  IIIIIIIVVVIII     H30：様式甲／Style Kou ２－２  Name Andreas Meissner  OOMe MeOOOH ON MeOMeMePHOHOOEnigmazole A (XII)LiteratureDIBALthen (ClCH2CO)2OOOHMe MeOO ON MeOMeMeMPMOIX XXIOOMOMMe MeOTBSOTBSO ON MeOMeMeMPMMgBr2⋅OEt2OOOMOMMe MeOTBSOTBSO ON MeOMeMeMPMTMSOClVIII Next, the synthesis of the macrolactone core of neopeltolide, isolated from the marine sponge of Daedalopelta is described. Since its isolation, neopeltolide became a quite famous target for synthetic chemists. To date, more than 20 formal and total syntheses are published. Using L-aspartic acid XIII as the starting material, alcohol XIV was prepared according to a literature procedure. Subjection to a reaction sequence involving chiral allylation gave lactone XV. Further transformation led to the carboxylic acid fragment XVI. The acid was coupled to alcohol fragment XVII under Shiina`s conditions to give ester XVIII. Reductive acetylation and intramolecular allylation installed the desired THP ring of derivative XIX. This compound was transformed to the macrolactone XX which is a known synthetic intermediate of neopeltolide XXI.    The second part of this thesis discusses research towards the polyether ciguatoxin 3C, isolated from the dinoflagellate Gambierdiscus toxicus. Two syntheses are published from Hirama`s group which gave fundamental insights in the reactivity of the protecting groups. The synthetic study was based on H-M ring fragment XXII. The stannane containing acetal was prepared via reductive acetylation and acetal exchange to give XXIII. Conversion to OHOOHONH2OO MeOHOO MeOTBDPSMeMeTBDPSO Me OOMeOHcarboxylic acid fragment (XVI)TMSOHTBSOMeTBDPSOMeOMe OOTBSOMeTBDPSOOMeMeOTBSOTMSreductive acetylationintramolecular allylationMeOOOOMe OMeO NONHOMeOMeOOOMe OMeOLiteraturealcohol fragment (XVII)L-aspartic acid (XIII)XIV XVXVIII XIXXXNeopeltolide (XXI)     H30：様式甲／Style Kou ２－３  Name Andreas Meissner  the carboxylic acid fragment XXIV and coupling to A-E alcohol fragment XXV under Shiina`s conditions delivered ester XXVI. Treatment with TMSI/HMDI furnished an allyl stannane which was subjected to reductive acetylation and intramolecular allylation to install the desired G-ring of compound XXVII.     OOOOOOOH H HHHMeONAPMe HMeHHHMeONAPOOOOOOO H H HH HONAPH H H H HTBDPSOMeSnBu3OO OOOOH HHHHMeMe H MeHHHMeONAPOOOOO H H HH HONAPH H H H HTBDPSOMeOONAPHOHTMSOOOOOOOH H HHHMeONAPMe HMeHHHMeONAPTBSOMeOOOOOOOH H HHHMeONAPMe HMeHHHMeONAPTBSOMeOSnBu3MeHO2COOOOOOOH H HHHMeONAPMe HMeHHHMeONAPMeOSnBu3Mecarboxylic acid fragment (XXIV)alcohol fragment (XXV)OHOOOOO H H HH HONAPH H H H HTBDPSOreductive acetylationintramolecular allylationMeOXXII XXIIIXXVIXXVII

Enigmazole A、Neopeltolide及びCiguatoxin 3Cの収束的合成についての研究

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Enigmazole A、Neopeltolide及びCiguatoxin 3Cの収束的合成についての研究

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