有機不對稱連鎖反應應用於動力學分割及去對稱反應

Abstract

本論文在探討有機不對稱連鎖反應應用於動力學分割及去對稱反應，本論文包含四個研究主題：第一部分探討有機不對稱催化應用於去對稱化 Michael 加成反應，藉由樟腦架構之L-脯胺酸衍生之有機催化劑 194 和金雞納霜辛可尼衍生之一級胺催化劑 186，使用環己酮衍生物 36 與1,1-雙(苯基磺酰基)乙烯 112 反應，進行去對稱化 Michael 加成反應。此研究利用烯胺分子的催化模式，使用有機催化劑 186 和 194 合成去對稱化產物 196 以及鏡像異構物 ent-196。利用金雞納霜辛可尼衍生之催化劑 186，得到產物的鏡像異構物 ent-196，具有高的選擇性 (產率高達 96%，93%的鏡像選擇性)。 第二部分探討有機去對稱化酸酐起始物，使用起始物環酸酐 212 和硝基苯烯丙醇 213，進行去對稱化反應。利用去對稱化反應，合成高產率以及高鏡像選擇性之半酸半酯產物 214-225 (高達90%之產率以及 99% ee的鏡像選擇性)，由於半酸半酯產物分子之架構，常見於天然物以及藥物分子之中間體，有效建立立體選擇性於合成化學極為重要，另一方面，微調反應條件，發現利用辛可尼一級胺基催化劑 186，可得到鏡像異構物 ent-214-225。 第三部分進行有機不對稱催化連鎖反應，使用醛類化合物 103、2-(苯甲基)-銦烷-1,3-二酮 233，以及偶氮化合物 99，利用α,α-L-雙苯環脯胺醇矽醚 72 (10 mol%) 為催化劑，進行連鎖反應。所得到的環酮螺形架構衍生之產物分子 237a-l 具有高產率 (55-78%) 以及高鏡像選擇性 (51-93% ee )。 第四部分為分離出 Michael 加成產物之二氫惡嗪氧化物中間體 252 (Dihydrooxazine N-oxide)，利用外消旋硝基烯丙胺 248、醛類化合物 103 為起始物，進行有機催化動力學分割連鎖反應，多官能基的硝基烯丙胺 248 進行反應。醛類化合物 103 與 (S)-硝基烯丙胺 248 (活性較好)，以及α,α-L-雙苯環脯胺醇矽醚催化劑 72，進行動力學分割 Michael 加成反應，形成高選擇性產物之二氫惡嗪氧化物中間體 252 (高達50%的產率、非鏡像選擇性20:1以及98% ee的鏡像選擇性)，並且回收高光學純度 (S)-硝基烯丙胺 248 (活性較小)。此外，利用中間體 252 進行水解反應，得到高產率以及高的選擇性的四氫吡啶 250 (高達50%的產率、非鏡像選擇性20:1以及98% ee的鏡像選擇性)。接著，由NMR的研究以及理論計算，瞭解反應機構之進行，包括酸添加劑所扮演的角色以及質子化中間體 252 的位置。提出合理的反應機構於 [4 + 2] Michael 環化加成反應、質子化/開環，以及最後的水解和脫水的過程。The dissertation entitled “Organocascade Kinetic Resolution and Desymmetrization Reactions” comprises of four chapters. The first chapter describes the organocatalytic desymmetrization of prochiral cyclohexanones 36 derivatives through Michael addition of these nucleophiles to 1,1-bis(phenylsulfonyl)ethylene 112 employing pyrrolidinyl-linker-camphor 194 and cinchonidine derived primary amine 186. The study provides both antipodal stereoisomers through chiral enamine catalysis initiated by organocatalysts 186 and 194. The enantiomeric products were obtained with high to excellent levels of stereoselectivity when the cinchonidine-derived catalyst 186 was employed (up to 96% yield、93% ee). The organocatalytic desymmetrization of cyclic meso-anhydrides 212 with functionalized nitroallylic alcohols 213 was discussed in second chapter. The alcoholysis of meso-anhydrides provides the corresponding hemiesters 214-225 in high chemical yields with high to excellent enatioselectivities (up to 90% yield and 99% ee). The hemiesters are valuable precursors in organic synthesis as theses can provide numerous naturally occurring biologically active complex motifs. On the other hand, the reversal of enantioselectivity was observed when an amine cinchonidine derived organocatalyst 186 was used under the similar reaction conditions. The third chapter deals with the synthesis the hexahydropyridazine dervatives 237a-l via a one-pot three components triple organocascade reaction of 2-arylidene-1,3–indandiones 233, aldehydes 103 and azodicarboxylates 99 by the privileged organocatalyst α,α-L-diphenylprolinol trimethylsilyl ether 72 (10 mol%). A library of substituted hexahydropyridazines 237a-l were obtained in good to high chemical yields (55-78%) with moderate to high enatioselectivities (51-93% ee). Isolation of critical dihydrooxazine N-oxide intermediary species 252 in Michael addition of aldehydes 103 to nitroolefins 248 and their hydrolysis along with organocatalytic kinetic resolution of densely functionalized nitroallylic amines 248 was demonstrated in the fourth chapter. The α,α-L-diphenylprolinol silyl ether 72 derived resting states were isolated in excellent chemical yields with high diastereo- and enantioselectivities (up to 50% yield, 20:1 d.r.; 98 ee) in Michael addition of aldehydes 103 to kinetically (R)-nitroallylic amines 248 (more reactive). The less reactive (S)-nitroallylic amines 248 were resolved with high optical purities. Further, hydrolysis of the intermediates 252 produced the enantioenriched tetrahydropyridines 250 with high chemical yields with high to excellent levels of diastereo- and enantioselectivities (up to >20:1 dr and 99:1 er). And then, detailed NMR studies and computational studies were probed to understand the mechanism which includes the role of acid additive and site of protonation in oxazine intermediate 252. A reasonable mechanism was proposed that undergo sequential Michael addition initiated [4+2] cycloaddition, protonation/ring opening, followed by hydrolysis and dehydration process.