Stereocontrolled Synthesis of Prostaglandin via Multicomponent Anion-Relay Strategy

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研究生：	黃冠勳 Huang, Kuan Hsun
論文名稱：	Stereocontrolled Synthesis of Prostaglandin via Multicomponent Anion-Relay Strategy Stereocontrolled Synthesis of Prostaglandin via Multicomponent Anion-Relay Strategy
指導教授：	磯部稔 Isobe, Minoru 汪炳鈞 Uang, Biing Jiun
口試委員:	廖俊臣 Liao, Chun Chen 謝興邦 Hsieh, Hsing Pang 陳建添 Chen, Chien Tien
學位類別：	博士 Doctor
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2015
畢業學年度：	103
語文別：	英文
論文頁數：	314
中文關鍵詞：	異原子誘導共軛加成、前列腺素、有機鋅化合物、不對稱醛醇反應、Brook重排反應、一鍋化反應
外文關鍵詞：	Heteroatom-directed conjugate addition, Prostaglandin, Organozincate, Symmetric aldol reaction, Brook rearrangement, One-pot reaction
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本研究主題為合成 (±)-15-deoxy-Prostaglandin E2 以及 (-)-Prostaglandin E2 methyl ester。此合成之主要策略為: (i) 利用雷福馬斯基之不對稱醛醇反應建立C11之立體中心; (ii) 利用異原子誘導共軛加成(HADCA)反應建立高立體選擇性之產物; iii) Brook重排反應; (iv) 分子內環化反應。其中(ii)-(iv) 可藉由一鍋化反應而得到具多官能基之五圓環產物。此五圓環產物可再與前列腺素的支鏈進行烷基化反應，之後再藉由去磺酸酯化反應以及去矽烷基反應可合成天然物(±)-15-deoxy-Prostaglandin E2以及 (-)-Prostaglandin E2 methyl ester。此反應總產率分別為34%和24%。本研究同時也探討利用苯硫基作為在不對稱炔類之引導官能基用於進行高位向選擇性的矽氫化反應。

Two total syntheses of (±)-15-deoxy-Prostaglandin E2 and (-)-Prostaglandin E2 methyl ester are completed through heteroatom-directed conjugate addition (HADCA). The key steps in this strategy are (i) Samarium-Reformatsky asymmetric aldol reaction; (ii) substrate control HADCA reaction in highly stereoselective manner; (iii) 1,4-Brook rearrangement; (iv) intramolecular cyclization to produce cyclopentanone, especially, (ii)-(iv) were achieved in one-pot reaction. Alkylation of the α-side chain with ketosulfone then followed by desulfonylation and desilylation afforded the (±)-15-deoxy-PGE2 and (-)-PGE2 methyl ester in 34% and 24% yield respectively. Highly regioselective hydrosilylation of unsymmetric alkynes using phenylthio moiety as directing group and also discussed in this dissertation.

Index
Abstract     i
Abstract (中文摘要)    ii
Acknowledgments    iii
Abbreviations    iv
Table Index    vii
Figure Index    viii
Chapter I    Introduction    1
1.1    Introduction of Prostaglandins    1
1.1.1    Historical Background    1
1.1.2    Corey’s Typical Prostaglandin Syntheses    2
1.1.3    Alternative Routes to Prostaglandins    4
1.2    Introduction of Hetero-Atom-Directed Conjugate Addition    10
1.2.1    Conjugate Addition of Carbon Nucleophile to The Vinyl Silylsulfone System (HADCA)    11
1.2.2    Multifunctionalized Cyclobutane Synthesis by Exploiting HADCA    14
1.2.3    Conjugate Addition by Organozincate    17
Chapter II    Research Motif    20
Chapter III    Results and Discussion    22
3.1    Synthesis of Prostaglandin Precursors    22
3.2    Improvement of Cobalt-Assisted Hydrosilylation on Acetylene Moiety for Synthesis of Prostaglandin    24
3.2.1    Hydrosilylation of Phenylthio Propargyloxy Substrates with Primary Alcohol 115, 129a-f and Its Derivatives    26
3.2.2    Hydrosilylation of Phenylthio Propargyloxy Substrates with Secondary Alcohols and Its Derivatives.    27
3.2.3    Hydrosilylation of Phenylthio Acetylene Derivatives    29
3.2.4    Hydrosilylation on Sulfinyl- and Sulfonyl Acetylenes    30
3.2.5    Plausible Reaction Mechanism for Cobalt-Catalyzed Hydrosilylation    31
3.2.6    Improvement of Regioselectivity for Prostaglandin Precursor    35
3.3    Functionalized Cyclopentanones Synthesis via HADCA 
and Anion Relay Chemistry    35
3.4    Four-Component Strategy for Total synthesis of (±)-15-deoxyl Prostaglandin E2    40
3.5    Mechanism of HADCA    42
3.6    Functionalized Cyclopentanones Synthesis via Zincate HADCA    45
3.7    Some Unexpected Results in the Model Study of HADCA with tert-Butyl Ester Vinylsilylsulfone 106 and Weinreb Amide Vinylsulfone 151    50
3.8    Synthesis of (-) Prostaglandin E2 Methyl Ester    59
3.8.1    Asymmetric Samarium-Reformatsky Reaction for Establishing Stereocenter of 11-(R)-Hydroxy of Prostaglandin Subunit    59
3.8.2    The Synthesis of Chiral 15-(S)-Hydroxy Vinyl iodide for PG chain    61
3.8.3    (-) Prostaglandin E2 Methyl Ester Synthesis via HADCA    63
Chapter IV    Conclusion    67
Chapter V    General Experimental Details    69
References and Notes    135
Appendix I. Spectra Data Section    139
Appendix II. X-ray Crystallographic Data    294
 

                                

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