新型手性DMAP衍生物的制备及其在不对称催化中的应用

Nucleophilic chiral amines have been playing an important role in the field of asymmetric organocatalysis. Therefore, the development of novel amine catalysts with high nucleophilicity and further application to asymmetric synthesis has already been one of the most attractive topics in organic chemistry. Until now, a number of chiral tertiary amines have been successfully synthesized in large scale, which has also been wildly used as commercially available catalysts; however, most of them were developed based on Cinchona alkaloids and sharing quite similar core-structure. Problems such as similar catalytic reactivity and limited substrate types have been thus recognized during the application process. On the other hand, as a typical nucleophilic tertiary amine with unique catalytic property, DMAP should have a great potential in current state-of-the-art nucleophilic catalysis. Thus, in this project, we will try to synthesize a variety of new chiral DMAPs, and special emphasis will be placed upon developing a collection of C2-symmetric catalysts with higher nucleophilicity. Afterwards, the application of these catalysts to interesting and yet challenging chemical reactions, including kinetic resolutions of racemic tertiary alcohols, construction of quaternary chiral centers via cycloadditions, asymmetric MBH reactions of substituted nitroalkenes, and multicomponent cascade reactions, will be systematically studied. In summary, the implementation of this project will undoubtedly enrich the nucleophilic chiral catalyst library, provide novel synthetic tools for asymmetric catalysis and promote the development of diversity-oriented stereoselective synthesis.

亲核性手性叔胺在不对称有机小分子催化领域一直扮演着重要的角色。开发结构新颖、具有高亲核性的胺催化剂并将其应用于不对称合成，已然成为有机化学的研究热点之一。目前，许多实现批量生产且成功商品化的手性叔胺，大多都是基于金鸡纳碱骨架所开发出的结构类似物。在催化应用的过程中，这些催化剂仍然存在反应活性类似、底物范围有限等许多亟待解决的问题。DMAP作为一类具有自身特色的典型亲核性叔胺，目前仍然有着广阔的发展空间。本项目正是基于DMAP 母核，拟设计合成一系列结构新颖的叔胺催化剂，并重点发展具有高亲核性和C2对称性的新型DMAP手性催化剂。随后，将它们应用于催化外消旋叔醇的动力学拆分、环加成反应构建手性季碳中心、取代硝基烯的不对称MBH反应以及多组分串联反应等有意思且具有一定挑战性的化学转化中。本项目的成功实施，对于丰富和完善亲核催化剂体系、建立原创性的手性催化工具、发展多样性不对称合成均有重要意义。

本项目以新型手性DMAP衍生物为代表的有机小分子碱催化为研究的切入点，实现了多种底物的不对称反应以及参与的绿色合成研究。基于该领域中存在的立体选择性控制难度大、底物范围局限等问题，我们通过催化剂筛选、反应条件优化等多种方式，在保持反应高区域选择性、高立体选择性的同时，最大程度降低了反应对环境造成的影响。本项目所研究的不对称反应以及绿色合成方法多数尚未见文献报道，通过这些新的合成方法学研究，可以绿色高效地构建结构多样性的杂环骨架，主要包括：官能团富集的氧杂六元环、氮杂五元环、氮杂六元环以及一些三元环等小环结构等；除了单环、并环结构之外，还成功高效地合成了具有螺环或多环结构的类天然产物（类药物）骨架。制备这些杂环衍生物，对于研究已知药物的构效关系，或者开发具有自主知识产权的手性候选药物都具有非常重要的理论和实践意义。