手性单齿亚膦酸二酯-非手性单膦混合配体与铑催化的四取代烯烃和环状烯烃的不对称氢化

During the last fifty years, transition-metal catalyzed asymmetric hydrogenations have become a powerful synthetic tool in pharmaceutical industry and life sciences, increasingly being used in large scale to introduce stereogenic centers to chiral APIs, drug candidates for clinical trials, agrochemicals, fragrance ingredients, and their key synthetic precursors. The asymmetric hydrogenations of nonsymmetrically tetrasubstituted alkenes and cyclic olefin derives can provide valuable chiral intermediates for a diverse range of biologically active compounds. However, these reactions are notoriously much more challenging and remain less explored so far. This project aims to develop highly efficient chiral catalyst systems for asymmetric hydrogenation of these challenging alkenes, based on the screening of metal catalysts generated in-situ by self-assembly of a cost effective chiral secondary phosphine oxide (SPO) ligand, a readily available triaryl-substituted achiral monophosphine ligand, and a Rh(I) precursor. The coordination flexibility and the hydrogen-bonding of the chiral/achiral monophosphine ligand components might prove helpful in circumventing the difficulties of loose ligation and hence weak activation of the substrate, caused by its steric bulkiness and structural rigidness. The catalyst libraries will be examined in the asymmetric hydrogenation of some tetrasubstituted alkenes, specifically α- or β-(acylamino)acrylates, enamides, enolacylates, itaconates, as well as their cyclic analogues. Mechanistic studies will be performed on some selected reaction systems, using a combination of spectroscopic, kinetic, and computational techniques, to shed light on the detailed pathways and the substrate-metal-ligand interaction mode that may provide a rational basis for further catalyst design. To demonstrate the synthetic utility of the methodologies, the best catalysts will be tested in the asymmetric hydrogenation of some industrially relevant substrates. The outcomes from this project are expected to substantially broaden the range of valuable chiral chemicals accessible from catalytic asymmetric hydrogenation, and hence contributing significantly to the efficient and green stereochemically well-controlled synthesis via a sustainable chirotechnology.

经近五十年的发展，过渡金属催化不对称氢化已成为制药工业和生命科学领域的高效合成方法，在手性医药、农药、香精及食品添加剂等工业生产中得到了广泛应用。对非对称的四取代烯烃和环状烯烃进行不对称催化氢化，可以得到种类繁多的生物活性化合物和关键手性合成中间体, 然而到目前为止，这些底物的反应仍然富于挑战性，且研究较滞后。本项目拟结合组合催化原理，探索带有氢键结构单元的手性单齿亚磷酸二酯、廉价的非手性膦混合配体与Rh(I) 原位自组装形成的催化体系在一些四取代烯烃及环状烯烃的不对称氢化中的应用，发展催化活性和立体选择性优越的混合配体催化体系。拟在一些四取代或环状的α-或β-脱氢氨基酸、烯酰胺、烯醇酯等不对称氢化中筛选催化剂库，研究相关机理，揭示底物-金属-配体之间的配位等对选择性控制规律；拓展氢化底物类型，并用所建立的方法学合成具有重要生物活性的化合物，为不对称催化氢化在更大范围的应用提供技术支持。

在过去数十年里，过渡金属催化不对称氢化反应在基础研究领域和精细化学品工业合成方面取得了重要进展和成功应用，但至今仍有很多底物的不对称催化氢化反应存在活性不高、选择性低或底物适用范围有限等问题。另一方面，传统方法中新型手性配体和催化剂的合成通常路线繁琐且费时费力，研发经济上不合算。本项目通过两种不同配体与催化中心金属进行组合在反应体系中现场形成催化剂库的混合配体策略，提供了一条方便快捷的催化剂研发路径。项目成功发展了手性单齿亚磷酸二酯和非手性单膦混合配体与金属铑(I)组成的催化体系，并将其成功应用于一些挑战性的烯烃底物不对称催化氢化反应中，均表现出了较高的催化活性和优秀的对映选择性。对多种类型的取代烯烃进行了不对称催化氢化，实现了包括多种双芳基取代丙烯酸、(Z)-α-氟-β-芳基-β-烷基丙烯酸、环状不饱和羧酸α-色烯-3-甲酸类化合物、(E)-2-烷基-3-芳甲酰基丙烯酸、exo型环状羧酸化合物、α烷基-β-芳基砜不饱和羧酸等高对映选择性不对称催化氢化，并应用于生物活性化合物(-)-8'-epi-aristotetralone和(-)-8’-epi-aristoligone、鬼臼毒素、失眠药物ramelteon等生物活性分子的合成中。本项目创新发展的催化体系，为一些手性高值分子的合成提供了高效的路径，充分展示了混合配体不对称催化氢化策略在复杂手性分子构建中的效能。

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