基于手性醛催化的亚胺活化策略研究

The development of novel chiral catalysts and activation models is an important and lonstanding activity in asymmetric organocatalysis. During the last decade, divers of organocatalysts, such as chiral amines, chiral bronsted acids and bases, chiral carbines, chiral phase transfer catalysts and ketones have been developed. Numerous excellent works indicated that the aldehyde can activate the alfa-C-H bond of a primary amine via the formation of an imine, and an active nucleophilic intermediate alfa-imine carbanion will be generated through the subsequent deprotonation process. The imine formation between an aldehyde and an amine is reversible, which makes the usage of aldehydes as catalysts becomes realizable.Based on these, we hypothesized that the imine activation strategy initiated by chiral aldehydes can be used in the asymmetric direct alfa-functionalization of active amines. In 2014, this novel activation strategy was realized in the asymmetric direct alfa-alkylation of amino esters. The catalysts and activation model revealed in our work drew a new blueprint for the current asymmetric organocatalysis.It has good scientific values to make this strategy be a general one in the asymmetric organocatalysis. In this project, we will develop new methodologies in the catalytic asymmetric direct alfa-functionalization of amino esters and other primary amines by chiral aldehyde catalysis. Additionally, we will give a further investigation on the reaction mechanism by NMR and HRMS, as well as the application of these methodologies in organic synthesis.

新型手性有机催化剂及活化模式的发展一直是不对称有机催化领域的热门研究课题。目前报道的手性有机催化剂类型主要有：手性胺，手性酸和碱，手性卡宾，手性相转移催化剂和手性酮等。众多研究表明：醛可以通过形成亚胺的方式来活化伯胺的alfa-C-H键，进而去质子化形成具有亲核性的alfa-亚胺碳负离子。考虑到亚胺的形成是可逆的，我们认为：基于手性醛催化的亚胺活化机制可以应用到不对称有机催化当中。2014年，我们首次在氨基酸酯的不对称烷基化反应中实现了这一新催化策略。该策略所包含的催化剂类型和活化模式为当前的不对称有机催化提供了新的研究方向。将其推广到不对称有机催化领域，使之成为具有一定普适性的催化策略具有重要的学术价值。本项目将开发新型手性醛催化剂，研究手性醛催化氨基酸酯及其类似物的不对称alfa-官能化反应，并研究这系列反应的反应历程及在合成重要手性化合物上的应用。

手性醛催化自上世纪80年代开始受到了化学家们的关注，根据催化活性中间体不同大致可以分成三类。一是经由转胺化中间体进行催化活化；二是经由缩醛胺中间体进行催化活化；三是经由亚胺中间体进行催化活化。其中，经由亚胺中间体实现手性醛催化的不对称化学转化是本项目首次提出的活化策略和概念，开始了手性醛催化的一个全新研究领域。本项目重点对手性醛催化伯胺衍生物，包括氨基酸、活性苄胺等的不对称α-官能化反应进行了研究，合成了结构多样化的非天然手性氨基酸及手性胺化合物，并探讨了这些化学转化在合成商品化手性胺化合物上的应用。本项目还研究了手性醛与过渡金属以及光氧化还原的联合催化体系，将惰性键活化与手性醛催化结合，实现了纯有机催化条件下不能实现的挑战性化学反应。在本项目支持下共发表研究论文10篇，包括1篇J. Am. Chem. Soc.和6篇Org. Lett.，申请发明专利1项，获得重庆市自然科学奖三等奖1项，另有待发表研究论文2篇。关于手性醛和过渡金属联合催化氨基酸酯的不对称alpha-烯丙基化反应的论文正在修改中。本项目提出的不对称催化合成策略主要用于伯胺类化合物的不对称α-官能化反应，在手性氨基酸和手性胺合成中具有潜在的重要价值，被业内同行评为不对称有机催化中的新策略(new strategy)、新概念(new concept)以及极具前景的不对称催化概念(a highly promising concept in asymmetric catalysis)。

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