铁、钴、镍催化极性双键的不对称还原反应研究

Being totally atom-economical, scalable and robust, asymmetric catalytic reduction of polar unsaturated bonds is now universally used for the synthesis of important chiral compounds, such as alcohols and amines, and accounts for nearly half of all the industrial asymmetric catalytic processes. In both academic laboratories and industrial operations, asymmetric reduction reactions, which include asymmetric hydrogenation, asymmetric transfer hydrogenation and asymmetric hydrosilylation are catalyzed principally by metal complexes based on rhodium, ruthenium and iridium. However, the limited availability, risk in supply, high and volatile price, and toxicity of these critical metals call for their replacement with abundant, inexpensive and bio-common metals, such as iron, cobalt and nickel. As one of the most abundant metals on earth, iron is inexpensive, environmentally benign and of low toxicity, and as such, it is a fascinating alternative to the precious metals for catalysis and sustainable chemical manufacturing. Nevertheless, iron catalysts have been significantly undeveloped compared with other transition metals. Cobalt and nickel catalysts that are efficient for asymmetric reduction reactions have been even elusive. The project aims to design and synthesize novel chiral iron, cobalt and nickel complexes. Asymmetric reduction of ketones and imines catalyzed by the chiral iron, cobalt and nickel catalysts will be investigated. With these novel chiral non-precious metal catalysts, we will purpose to develop a green, effective and economic method for the synthesis of chiral antidepressant drugs, such as (R)-Fluoxetine hydrochloride. Building on the these work, we hope to map out the mechanism of the asymmetric reduction reaction via kinetic measurements and in-situ NMR probing, aiming to gain insight into the reaction and inform for developing more new active and enantioselective non-precious metal catalysts.

目前不对称催化反应研究较多的一般为手性钌、铑、铱等贵金属催化剂，价格昂贵而且有毒。铁作为地壳中含量仅次于铝的金属，因其具有来源广泛、廉价易得、安全无毒等诸多优点受到普遍关注。然而迄今为止，成功用于不对称还原的高效手性铁催化剂尚不多见，手性钴、镍催化剂用于不对称还原的例子则更加少见。本项目研究拟自行设计合成一系列新型手性铁、钴、镍络合物，表征其结构并研究其配位化学性能。进而筛选性能优秀的手性铁、钴、镍络合物催化剂，用于碳-氧及碳-氮双键的不对称还原反应，评价其催化性能，进一步将其应用至手性药物如抗抑郁药物氟西汀的合成，力图成功开发绿色、高效、廉价的手性药物合成路线。在此基础上，深入研究反应机理，总结手性络合物催化剂的结构与其催化性能之间的构效关系，为新型手性非贵金属催化剂的分子设计提供指导性原则。

手性化合物在医药、农药、食品添加剂等领域有着十分重要的应用。不对称催化是获得单一对映体化合物最经济、最有效的途径之一。目前，工业生产中的不对称催化反应大多使用手性钌、铑、铱、钯等贵金属催化剂，价格昂贵而且有毒。因此，寻找价格低廉、绿色环保的手性非贵金属催化体系用以替代目前广泛使用的贵金属催化剂具有非常重要的意义。本项目执行期间，我们成功设计合成了一系列新型手性多齿胺膦配体并进行了结构表征；将廉价易得的铁、钴、镍、锰化合物与自行设计合成的手性环状或链状胺膦配体作为起始原料，方便制备了一系列新型手性铁、钴、镍、锰络合物，并成功获得了单晶；进而，我们将这些手性铁、钴、镍、锰络合物用于催化芳香酮及亚胺的不对称还原反应中，获得了较好的结果，相应产物的对映选择性最高达99% ee。在评价其不对称催化性能的基础上，结合理论计算，较为深入地研究了手性非贵金属催化剂中不同中心金属、胺膦配体与其不对称催化性能之间的构效关系，为我们今后设计合成新型高效的手性非贵金属催化剂提供了有价值的参考。此外，研究中我们还将新型手性非贵金属催化剂用于多种杂芳酮的不对称还原反应，高对映选择性地制备了相应的手性杂芳醇。手性杂芳醇可作为许多手性药物的关键中间体，同时又是多种手性配体和活性生物分子骨架的重要组成部分，因此该研究结果为我们今后探索绿色、高效、廉价的手性药物合成新路线积累了很好的研究基础，潜在一定的应用前景。