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研究生:金志龍
研究生(外文):Chih-Lung Chin
論文名稱:(±)-PygmaeocinC之全合成研究及新有機合成方法:1,3-環己二烯及烯環戊烷之製備
論文名稱(外文):The Total Synthesis of (±)-Pygmaeocin C and New Synthetic Methods:Formation of 1,3-Cyclohexadienes and Methylenecyclopentane Ring
指導教授:劉行讓
指導教授(外文):Prof. Hsing-Jang Liu
學位類別:博士
校院名稱:國立清華大學
系所名稱:化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:220
中文關鍵詞:多重烯環化反應還原烷化反應Diels-Alder反應雙萜類天然物
外文關鍵詞:polyene cyclizationreductive-alkylationDiels-Alder reactionDiterpenoids
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本論文共分為三部分,分別為 (1) (±)-pygmaeocin C之全合成研究;(2) γ-氰基-α,β-不飽和酮化合物之合成應用:1,3-環己二烯之製備;(3) ω-矽炔α-氰酮分子內環化反應之研究。
第一部分是利用多重烯環化反應來進行 (±)-pygmaeocin C (3) 之全合成。以市售之dimedone (72) 為起始物,經過10個合成步驟可成功地合成出交叉共軛系統的β-酮酯關鍵中間物81,即使化合物81存有一反式雙鍵,我們仍然可使用三氟醋酸進行關鍵之環化反應,可得高產率之三環化合物86,化合物86再經由脫羧、氧化及去保護反應即可完成 (±)-pygmaeocin C (3) 的全合成。從dimedone (72) 至 (±)-pygmaeocin C (3)總共用了14步,總產率為4.6%。
第二部分主要探討以萘化鋰為還原試劑進行γ-氰基-α,β-不飽和酮化合物138及140之還原烷化反應,並應用於1,3-環己二烯化合物145、146、147及149之製備。利用共軛二烯醇化合物131與acrylnonitrile進行Diels-Alder反應,再經水解和氧化反應可製備所需的α’-氰環烯酮125,然後進行Michael加成反應,接著在酸催化下進行醛酮縮合反應,即可成功合成具有獨特的六、六之γ-氰基-雙烯酮化合物138、140。最後將所得之γ-氰基-雙烯酮化合物138及140以萘化鋰為還原試劑進行還原烷化反應,可合成出在有機合成上不易製備之1,3-環己二烯化合物145、146、147及149。
第三部分主要探討ω-矽炔α-氰酮之分子內環化反應。我們利用不同的ω-矽炔α-氰酮化合物173和174經碘化鋅作用下,可進行分子內環化反應,分別得到環化產物191和197;即使運用在有立體障礙的化合物175上,亦可得環化產物198。此反應有著高產率、高立體及幾何選擇性之優點。
The first chapter of this thesis describes the first total synthesis, in racemic form, of the natural product pygmaeocin C (3) utilizing a polyene cyclization reaction as the key step to construct the B ring. Starting with commercially available dimedone (72), highly functionalized cross congjugated β-keto ester 81 was achieved in 10 steps. The pivotal cyclization step was accomplished by treating enone (81) with trifluoroacetic acid to give tricyclic keto ester 86. This cyclization step was found to be highly chemo- and facial selective as well as highly reproducible and high yielding. Following this, the total synthesis endeavor was achieved from ketone 86 by 3 steps including decarboxylation, oxidation, and removal of the methyl protecting groups. In all, the total synthesis of naturally occurring pygmaeocin C (3) in racemic form was achieved from dimedone (72) in 14 steps via the longest sequential with an overall yield of 4.6%.
Chapter 2 of this thesis details a novel methodological development towards structural motifs which are difficult to attain using precedent processes. This newly established protocol calls for the employment of a γ-cyano-α,β-unsaturated ketone (i.e. 138 and 140) as a starting point for the generation of a β,γ- unsaturated ketone in a reductive process. As such, model compound 138 and 140 were readily synthesized starting with a Diels-Alder cycloaddition reaction between diene 131 and acrylonitrile followed by hydrolysis and oxidation. The thus obtained enone 125 was then treated with a suitably functionalized Michael acceptor to furnish the desired bicyclic enones 138 and 140 in a Robinson annulation process. The central theme of this methodology was then accomplished by treatment of enone 140 with lithium naphthalenide as the reducing agent which furnished ketone 147 in a high yielding fashion. The ensuing enolate in the reduction process could, alternatively, be trapped with an alkylating agent (i.e. allyl bromide) to give reductive products alkylated in highly regioselective manner (i.e. 138à149). As well, by the use of excess lithium naphthalenide and excess alkylating agent, symmetrical gem-alkylations was achieved (i.e. 140à145 or 146). This newly developed methodology not only allows simple access to it also provides for a one-pot procedure to functionalized said motif.
The third chapter of this thesis delineated a newly developed process towards highly functionalized methylene cyclopentanes. Starting with α-cyano ketones 173 and 174, readily obtained using established synthetic procedures, treatment with zinc iodide allowed for the formation of bicyclic products 191 and 197 respectively in a high yielding and stereoselective fashion. This exo-dig cyclization process was found to not be affected by steric congestion of the starting carbocycle as highly congested ketone 175 readily yielded compound 198. The details of the development of this and above mentioned methodology as well as the total synthesis of 3 constitutes the contents of this thesis.
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