非鏡像氰醇化反應之探討
Abstract
摘要
不對稱氰醇化反應在有機合成上是一重要的反應，此反應所產生之官能基-氰醇基(cyanohydrins)亦為一重要之官能基，它可以應用於許多雙官能基(1,2-bifunction)分子的合成上；除此之外，氰醇基是許多天然物、農用化學藥劑及具有藥物活性化合物結構中所共有的官能基；因此，發展有效率合成方法製備具光學活性的氰醇化合物是相當重要的。許多氰基試劑均被應用於氰醇化合物的合成，而由於TMSCN (trimethylsilyl cyanide)活性穩定，為商品化試劑，故以TMSCN當作氰基來源較為常見。
本研究以對掌輔助劑N-phenyl camphorpyrazolidinone 60為架構，利用所衍生之-酮醯胺衍生物75-78為起始物，與TMSCN進行不對稱氰醇化反應，可得到不錯的結果。我們成功篩選出以等當量數之路易士酸TiF4及Sn(OTf)2催化不對稱氰基加成反應，可得到不錯的產率(91 %)及非鏡像選擇性(92 % de)，亦探討溶劑及溫度對反應結果之影響，以二氯甲烷為反應之最佳溶劑，而反應溫度的降低亦對於起始物為脂肪族取代基77、78有顯著的影響，非鏡像選擇性隨著溫度降低，有明顯的提高。主產物的絕對立體組態亦由X-ray結構分析得之為S-form，而由400 MHz核磁共振儀所測得之13C NMR提供可能之反應機構。
Cyanohydrins are important synthetic targets due to their application industrially as pesticides and their utility as precursors to many useful classes of organic compounds. The preparation of non-racemic cyanohydrins are considerable utility in organic synthesis due to enantiomerically pure cyanohydrins are important blocks for the synthesis of several 1,2-bifunctional products. For this purpose, several useful cyanating reagents were introduced. Among them, TMSCN (trimethylsilyl cyanide) seems to be one of the most effective and safe cyano anion sources for nucleophilic addition to carbonyl compounds. As part of a research program in organic processes, we report herein a convenient, mild, and efficient method for generating acylated cyanohydrins. Diastereoselective cyanation of N-phenyl camphorpyrazolidinone 60 derived -keto amides 75-78 was examined by using trimethylsilyl cyanide in the presence of various Lewis acids. Among these Lewis acids, TiF4 and Sn(OTf)2 are more effective, and we use acetyl chloride as protecting reagent to afford acylated cyanohydrins. The corresponding -carbonyl-O-acetylated cyanohydrins are obtained in good to high level of stereoselectivities(up to 92 % de). 13C NMR studies suggest that a prefered s-cis conformation was formed by the chelation of Lewis acid to the dicarbonyl oxygen atoms.
Cyanohydrins are important synthetic targets due to their application industrially as pesticides and their utility as precursors to many useful classes of organic compounds. The preparation of non-racemic cyanohydrins are considerable utility in organic synthesis due to enantiomerically pure cyanohydrins are important blocks for the synthesis of several 1,2-bifunctional products. For this purpose, several useful cyanating reagents were introduced. Among them, TMSCN (trimethylsilyl cyanide) seems to be one of the most effective and safe cyano anion sources for nucleophilic addition to carbonyl compounds. As part of a research program in organic processes, we report herein a convenient, mild, and efficient method for generating acylated cyanohydrins. Diastereoselective cyanation of N-phenyl camphorpyrazolidinone 60 derived -keto amides 75-78 was examined by using trimethylsilyl cyanide in the presence of various Lewis acids. Among these Lewis acids, TiF4 and Sn(OTf)2 are more effective, and we use acetyl chloride as protecting reagent to afford acylated cyanohydrins. The corresponding -carbonyl-O-acetylated cyanohydrins are obtained in good to high level of stereoselectivities(up to 92 % de). 13C NMR studies suggest that a prefered s-cis conformation was formed by the chelation of Lewis acid to the dicarbonyl oxygen atoms.
Description
Keywords
氰醇化反應, 氰醇基, Cyanation, Cyanohydrin