铜催化α-取代α,β-不饱和底物不对称硼共轭加成反应及其产物转化研究

Asymmetric catalytic conjugate addition reaction has been developed fast during the last two decades, as it could produce a very useful chiral synthon bearing a β-stereogenic center from the very simply available α,β-unsaturated compounds. However, reports about asymmetric catalytic conjugate addition on α-substituted α,β-unsaturated compounds were quite rare, probably due to: 1) the reactivity of trisubstituted alkene substrates has been substantially diminished with known catalytic systems; (2) nonstereospecific protonation complicates its diastereoselective control; and (3) it lacks mild, neutral conditions to avoid or minimize epimerization and the formation of side products. Recently, our group has successfully achieved the first highly enantio- and diastereoselective asymmetric catalytic boron conjugate addition onto α-functionalized α,β-unsaturated compounds, by a chiral Cu(I) catalysts with weak Lewis base counterion under non-alkaline conditions. The reaction was featured by highly functional group tolerance, controllable diastereoselectivity, high catalytic reactivity, clean reaction et al. In this research, we will mainly focus on expanding the substrate scope and the application of the chiral products, target the synthesis of highly complex natural products and active compounds that bear multiply stereogenic centers, and develop a simple, general and practical synthetic strategy for highly valuable compounds.

对具有α-取代基的α,β-不饱和底物的不对称催化共轭加成反应可以在α位和β位产生两个相邻手性中心，对合成多手性中心化合物极具意义，然而这类报道却很少。不对称催化硼共轭加成反应近年来发展很快，所得β-手性硼化合物具有较大潜力成为重要合成中间体，然而该反应仍面临较多问题：1）对α-取代α,β-不饱和底物非对映选择性很低且底物适用范围窄；2）产物的立体专一性转化范围窄。.在申请人的前期工作中，采用弱路易斯碱阴离子配对的手性铜催化剂，实现了对α-官能团化的α,β-不饱和酮的高对映和非对映选择性硼共轭加成反应，其具有官能团适应性广、产物构型可调控、催化反应活性较高、反应干净等特点。本研究将通过设计合成新的手性配体及催化剂，优化反应条件，将该反应拓展到反应活性较低的底物，并研究β-手性硼化合物通过形成手性五元烯丙基硼杂环中间体的立体专一性转化，开发利用β-手性硼化合物为关键中间体的简捷通用合成方法。

硼化合物是极其重要的合成中间体，被广泛应用于偶联及其他转化，同时含硼官能团也是重要的药物结构单元。高效构筑含硼手性化合物并研究其立体专一性转化具有特别重要的意义。本项目基于铜催化α,β-不饱和化合物的不对称硼共轭加成反应，发展出了在不添加碱就可促进反应进行的铜催化体系，可用于α-取代α,β-不饱和化合物的对映选择性和非对映选择性硼共轭加成反应。从简单易得的底物出发，一次性构筑含相邻官能团化手性中心的化合物，为复杂手性化合物的合成提供了潜在的便捷途径。由于α-取代α,β-不饱和化合物中不饱和键上的取代基数目较多，空间位阻较大，通常在铜催化不对称硼共轭加成反应中广泛使用的双膦配体等不再适用于此类底物。本项目通过对二茂铁骨架的手性胺基膦配体进行结构改造，并对添加剂和铜催化剂前体等进行了深入系统地研究，成功实现了相对活性较低的α-取代α,β-不饱和酯的高对映选择性和非对映选择性硼共轭加成反应，收率最高可达90%以上，ee值最高可达99%以上。由于酯作为官能团具有更高的转化潜力，所以本项目对α-取代α,β-不饱和化合物的对映选择性和非对映选择性硼共轭加成反应具有较好的推动作用。