Asymmetric Synthesis Of Chiral Amino Compounds:Organocatalysis,Metal Catalysis And The Combination

Chirality is a characteristic feature of living systems. The pharmacological activity of a drug depends mainly on its interaction with drug targets such as proteins and nucleic acids, which are made of small chiral fragments. The synthesis of chiral molecules, which may interact with a drug target, attracts organic chemists' most attentions in modem drug design and development. Chiral amino compounds are important bioactive molecules and pharmaceutical intermediates. However,there are still problems in the preparation of these chiral amino compounds, such as the low activity of catalysts and limitation of substrates. We tried to resolve that in two ways:development of effcient catalysts and synthesis of novel substrates with potential application.1. The direct asymmetric vinylogous Mannich reaction of y-butenolides catalyzed by Quinine was studied. The control experiments implied that the bifunctional organocatalyst activated both substrates. The substituents of y-butenolides enhanced the y-selectivity. The sulfonated activated imines displayed high activity. Also, we studied the hydrophosphonylation of diphenyl phosphites and hydrazone, which is more stable than imines.2. Based on the combination of metal catalysis and organocatalysis, a novel bisphosphine-thiourea ligand was designed and prepared. An efficient Rh/ferrocenyl bisphosphine-thiourea catalytic system was developed.3. ?-Chiral nitroalkanes were obtained with high ee via asymmetric hydrogenation of ?, ?-disubstituted nitroalkenes catalyzed by the novel Rh/ferrocenyl bisphosphine-thiourea catalyst. The control experiments implied that the thiourea was involved in the activation of nitroalkenes via hydrogen bonding.4. a-Chiral amines were obtained with high ee via asymmetric hydrogenation of unprotected N-H iminium salts catalyzed by the novel Rh/ferrocenyl bisphosphine-thiourea catalyst. It is potentially a highly efficient and practical synthetic protocol for industrial production because it eliminates the need to protect and deprotect NH group. The research of modified ligands, different counter ions and NMR implied that catalytic chloride-bound intermediates played an important role in the mechanism. Based on the catalytic mechanism, we studied the asymmetric hydrogenation of nitrogen-containing heteroarenes.5. A high-throughput screen approach for determining the ee of chiral amines based on circular dichroism (CD) spectroscopy was tested for faster screening in the future.