催化不对称 aza-Claisen 重排反应研究

Claisen重排及其变体是有机合成中生成新的碳-碳键并同时建立新的连续的手性中心，特别是全碳取代的手性中心的最高效方法之一。因此类方法为复杂分子的合成提供了强大的工具，常被应用于重要的天然产物和药物分子中极具挑战性的结构单元的构筑。但是催化的对映选择性Claisen重排难于实现，鲜有文献报道。本项目拟发展一种新的催化策略，即采用手性胺与两种反应底物反应生成季铵离子中间体并随后发生[3,3]σ迁移的有机催化对映选择性aza-Claisen重排（3-aza-Cope重排），以期通过这一新策略拓展Claisen重排在有机合成中解决复杂化合物合成的实用性问题。本项目的实现将是有机催化研究中的一个重要突破。

The Claisen rearrangement and its variants proceed via highly ordered cyclic transition states resulting in excellent chirality transfer from starting material to product. By forming a new carbon-carbon bond, these transformations concomitantly generate up to two new stereocenters, especially the all-carbon quaternary stereocenters. Therefore, Claisen rearrangement and its variants are extremely valuable for the construction of intricate molecular structures, and have been directly applied to the synthesis of complex structural motifs found within important natural products and pharmaceutical targets. Although several approaches using chiral auxiliaries and stoichiometric promoters have been successful, the development of catalytic asymmetric Claisen rearrangement has been a challenge and yet powerful. This research proposal describes a conceptually novel approach to harness the full synthetic utility of the Claisen rearrangement by developing the organocatalytic asymmetric aza-Claisen rearrangement. Chiral amines could be used to directly combined two starting materials via N-ally-enammonium formation and subsequent [3,3] sigmatropic rearrangement to afford the formal Claisen rearrangement product. The investigation of this aza-Claisen rearrangement shall examine its scope, limitation and extendibility including accessing all-carbon quaternary stereocenters with complete control of diastereoselectivity and enantioselectivity, which represents a major breakthrough in the field of asymmetric catalysis.