钴催化不饱和羧酸的不对称氢化

COBALT-CATALYZED ASYMMETRIC HYDROGENATION OF UNSATURATED CARBOXYLIC ACIDS

肖烨

11849231

硕士

化学

张绪穆

2020-06-02

2020-07-19

哈尔滨工业大学

深圳

不对称氢化是一类在氢气氛围下利用手性催化剂高效还原潜手性不饱和化合物的方法，可以应用于种类众多的手性碳碳、碳杂原子键的不对称构建。不对称氢化反应在手性有机合成子、药物中间体的不对称合成中扮演十分重要的角色。α,β-不饱和羧酸经不对称氢化后得到的手性羧酸，广泛应用于药物、农药、调料、香水等精细化工品的制备。因此，高效、经济地不对称还原不饱和羧酸受到合成化学家的关注。近年来，不饱和羧酸不对称氢化的研究主要集中在使用钌、铑、铱等贵金属/手性膦配体的催化体系，目前尚未有铁、钴、镍等廉价金属催化氢化不饱和羧酸反应的报道。在廉价金属/手性膦配体的催化体系中，目前仅有对酮类化合物完成了高效的不对称氢化。针对这些研究现状，本论文开展了基于廉价金属的催化体系用于α,β-不饱和羧酸不对称氢化的研究。张绪穆课题组长期致力于手性配体的设计和合成，并将其应用于有机中间体、药物中间体的高效不对称合成中。本研究也尝试了本课题组发展的一些手性双膦配体，考察其在廉价金属催化下在α,β-不饱和羧酸的不对称氢化中的效果。本文对钴催化的多种α,β-不饱和羧酸不对称氢化进行了深入的研究，前期考察了一系列商业可得的手性双膦配体以及课题组发展的手性膦配体，经过配体筛选，最终确定两个合适的催化体系。在Co(acac)2、(S,S)-Ph-BPE的体系中，在温和条件下实现α-取代肉桂酸ee值达到97%的不对称氢化；在模版底物α-苯基肉桂酸反应中，可以取得高达1860的TON。在CoCl2、(S,S)-Ph-BPE的体系中，在较为苛刻的条件下较好的解决α-取代丁烯酸的不对称氢化；同时，对于α-取代丙烯酸，取得了>99%的手性控制效果。在此基础上，本文也利用此方法完成了六种药物或生物活性分子手性中间体的高效合成，从而展示该方法的潜在应用价值。

Asymmetric hydrogenation is a type of efficient catalytic reduction of prochiral unsaturated compounds catalyzed by a chiral catalyst under hydrogen atmosphere, which has been widely applied in an asymmetric construction of carbon-carbon and carbon-heteroatom bonds. Asymmetric hydrogenation plays an important role in the asymmetric synthesis of organic and pharmaceutical intermediates. The chiral carboxylic acids, obtained through asymmetric hydrogenation of α,β-unsaturated carboxylic acids, are widely used in the synthesis of refine chemicals including drugs, pesticides, spices, perfumes. Therefore, the efficient and economical asymmetric reduction of unsaturated carboxylic acids has received broad attention. In recent years, research on the asymmetric hydrogenation of unsaturated carboxylic acids has mainly focused on noble-metal-based catalysts such as Ru, Rh and Ir complexs, and there are no reports of asymmetric hydrogenation of unsaturated carboxylic acids catalyzed by inexpensive metals such as Fe, Co and Ni. Using inexpensive base-metal catalysts in combination with chiral phosphine ligands, only efficient asymmetric hydrogenation of ketones has been reported. Considering the current status of these studies, this dissertation was focused on the study of base-metal-catalyzed asymmetric hydrogenation of α,β-unsaturated carboxylic acids.Zhang’s group has long-standing interest on the design and synthesis of chiral ligands as well as their applications in asymmetric hydrogenation to synthesize key organic and pharmaceutical intermediates. This dissertation has also evaluated several types of chiral bisphosphine ligands developed by our group on the asymmetric hydrogenation reaction of α,β-unsaturated carboxylic acids.In this thesis, cobalt-catalyzed asymmetric hydrogenation of different α,β-unsaturated carboxylic acids has been studied, and two efficient catalytic systems were finally identified after extensive investigation of various commercially available chiral phosphine ligands and those developed by our group. Using Co(acac)2/(S,S)-Ph-BPE catalyst, asymmetric hydrogenation of α-substituted cinnamic acid could be achieved under mild conditions with up to 97% ee. For α-phenylcinnamic acid, TON up to 1860 was obtained. Using CoCl2/(S, S)-Ph-BPE catalytic system, the asymmetric hydrogenation of α-substituted butenoic acid was accomplished under more harsh conditions. Notably, >99% ee was obtained for the eantioselective hydrogenation of α-substituted acrylic acid. Futhermore, we applied the highly efficient asymmetric hydrogenation transformation for the asymmetric construction of chiral intermediates of six drug or biologically active molecules, thus showing the potential application value of this method.

不对称氢化 手性双膦配体 α,β-不饱和羧酸 廉价金属催化剂 钴

asymmetric hydrogenation chiral bisphosphine ligand α β-unsaturated carboxylic acids base-metal catalyst cobalt

中文

联合培养

南方科技大学

肖烨. 钴催化不饱和羧酸的不对称氢化[D]. 深圳. 哈尔滨工业大学,2020.