Design And Synthesis Of Chiral Lewis Basic Organocatalysts For Asymmetric Reduction Of Imines

Catalytic enantioselective reduction of imines represents one of the moststraightforward and efficient methods for the preparation of chiral amines, animportant intermediate for the synthesis of natural products and chiral drugs. However,asymmetric reduction of imines remains a big challenge and highly enantioselectivecatalysts with a satisfactorily broad substrate scope remain elusive. Factorscontributing to the difficulty of this transformation include the weakreactivity of theC=N bond and the existence of inseparable mixtures of E/Z isomers.Starting from chiral proline, pipecolinic acid, piperazine-2-carboxylic acid and1,2-diphenyl amino alcohol, a series of structurally simple and easily prepared amideswere developed as highly effective Lewis basic organocatalysts for the asymmetricreduction of imines with trichlorosilane as the reducing agent, which promoted thereduction of N-aryl imines with high yields and excellent enantioselectivities with anunprecedented substrate spectrum.In the literature, it has been believed that besides the N-formyl group, theexistence of an arylamido group in the structure of Lewis basic organocatalysts is aprerequisite for obtaining high enantioseleetivity in the catalytic reduction of imines.However, we found that the N-formyl-L-prolinamides bearing non-arylamido groups,including structurally simple C₂-symmetric tetraamides, could also work as effectiveLewis basic catalysts to promote the asymmetric reduction of ketimines with highenantioselectivities (up to 86ï¼…ee), which are even more enantioselective than theanalogues with arylamido groups. In further studies, we developed novel N-formamides with arytamido groups andnon-arylmido groups as Lewis basic catalysts using the commercially availableL-pipecolinic acid as the template. The catalysts (S)-1-formyl-piperidine-2-carboxylicacid naphthylamide 28 and (2S,1'S,2'S)-acetic acid 2-[(1-formyl-piperidine-2-carbonyl)-amino]-1,2-diphenyl-ethyl ester 30 were found to promote the reduction of a broadrange of N-aryl imines in high yields (up to 98ï¼…) and excellent ee values (up to 96ï¼…)under mild conditions. Furthermore, catalyst 30 also exhibited highenantioselectivities (up to 95ï¼…ee) for the challenging aliphatic ketimines and,-unsaturated imines despite that these imines exist as E/Z isomeric mixtures. Thebroad substrate spectrum of this catalyst is unprecedented in catalytic asymmetricimine reduction, including transition-metal-catalyzed hydrogenation processes.Many of the currently available highly enantioselective catalytic systems onlytolerate methyl ketimines, which gave poor results for bulkier non-methyl ketimines.Starting from L-piperazine-2-carboxylic acid, we developed (S)-4-(4-tert-butylbenzenesulfonyl)-1-formyl-N-phenyl-piperazine-2-carboxamide as highlyenantioselective Lewis basic catalysts for the hydrosilylation of both methyl ketiminesand steric bulky non-methyl ketimines. Moreover, higher enantioselectivities wereobtained for non-methyl ketimines than methyl ketimines under the catalysis of thiscatalyst. Thus, this catalyst system complements with 30 in terms of the substratescope.We also found that easily accessible (1R,2S)-N-formyl-1,2-diphenyl2-aminoethanol worked as an effective Lewis basic catalyst in the enantioselectivehydrosilylation of ketimines, affording high enantioselectivities (up to 82ï¼…ee) for abroad range of ketimines.To rationalize the high efficiencies of the structurally novel catalysts wedeveloped, several catalytic models have been proposed.