含多氢键给体的氨基-硫脲类有机小分子催化剂的设计、合成及应用

Design,synthesis and application of multiple-hydrogen-bonding-donor amine-thioureas in asymmetric organocatalysis

在过去的10年里,有机小分子催化作为一门环境友好的有机合成方法学在不对称催化合成中的应用得到了重新发掘,新颖的有机小分子催化剂和新型有机小分子催化的不对称反应受到广泛的关注.含有氢键给体的手性有机小分子化合物通过分子间的氢键作用来活化反应底物中的羰基或硝基等官能团,在很多的不对称催化反应中展示了优秀的手性诱导效果,并获得了显著的进展.其中,具有双官能团氨基-硫脲类有机小分子催化剂在一系列的不对称迈克尔加成反应中获得了成功.基于对现有的文献中关于双官能团氨基-硫脲类有机小分子催化剂分子的结构分析,我们将"多氢键给体协同活化"策略成功应用于合成一类新型含多个氢键给体、具有多个手性中心、而且其空间位阻和电子效应等精细结构具有可调控性的手性氨基-硫脲类双官能团有机小分子催化剂Ⅰ和Ⅱ.这类具有多氢键给体的氨基-硫脲类催化剂在乙酰丙酮、α-取代的β-酮酯、硝基烷烃等对各种取代的硝基烯烃类化合物的不对称迈克尔加成反应,以及硝基烷烃对亚胺类化合物的不对称Nitro-Mannich反应中,展现了非常优异的催化活性与底物适用范围.

In the past decade, the importance of small organic molecules as catalysts has been rediscovered, and the design and application of organocatalysts have received much attention due to asymmetric organocatalysis emerging as a powerful and environmentally friendly methodology for the catalytic production of the valuable synthetic building blocks. Impressive progress has been made in the development of smallv chiral molecules bearing hydrogen bonding donors for a diverse range of reactions with high enantioselectivities attributed to their strong activation of carbonyl or nitro groups through efficient hydrogen-bonding interactions. Of the developed organocatalysts, bifunctional amine-thioureas have been proved to be powerful and applied successfully in asymmetric Michael addition reactions. Considering the importance of the hydrogen bonding interactions between thiourea moiety and substrates in amine-thiourea catalyzed asymmetric reactions, we designed and synthesized a novel class of amine-thiourea catalysts through application of the strategy of multiple hydrogen bonds synergistic activation for the first time. The attractive features of the fine-tunable amine-thiourea catalysts include multiple hydrogen bonding donors and stereocenters, which significantly enhance the adjustability of the electronic effect and steric hindrance effect of those organocatalysts. The novel bifunctional multiple- hydrogen-bonding- donor amine-thiourea catalysts I and II showed excellent performances in catalytic asymmetric Michael addition of acetylactone, （x-substituted β-ketoesters and nitroalkanes to various nitroolfins, and nitro-Mannich reaction, resulting in high enantioselectivity, diastereoselectivity and a broad scope.