Asymmetric Transfer Hydrogenation And Its Application

This thesis is concerned with the exploration of novel conditions for the asymmetric transfer hydrogenation of ketones or imines,the design and synthesis of novel catalysts and their use in the synthesis of chiral drugs.It mainly contains the following four parts.1.Asymmetric transfer hydrogenation of aqueous phase and preparation of new polymer-supported catalystsAsymmetric transfer hydrogenation in aqueous phase is a new stage in the development of asymmetric reduction.Starting from studying the reaction conditions,we initially achieved a high conversion and good stereoselectivity in ATH of ketone 96 through the aqueous phase.We got partial success of trying to synthesize benzimidazole ligand and the design of new polymer-supported catalysts.Taking catalyst of compound 100 as an example,the reduction of acetophenone can reach 100% conversion and 95% ee.2.Application of asymmetric transfer hydrogenation in synthesis of antimalarial drug mefloquine hydrochloride and determination of its absolute configurationMefloquine hydrochloride is an important antimalarial agent and currently used clinically as a racemic mixture,and the distinct effects of the two enantiomers to the human body are known.We envisaged the transformation by ATH from ketone 96 to the single configuration of mefloquine hydrochloride which is none toxic and side-effects.The absolute configuration of the enantiomer of mefloquine hydrochloride has been controversial for near 40 years.We have determined unambiguously the absolute configuration of(+)-erythro-mefloquine by chemical methods.Moreover,it was found that the stereochemical outcome of the enantioselective transfer hydrogenation of 2-pyridyl ketone 96 is contrary to the well-established chemistry.We proposed a reasonable model to explain the exception of 2-pyridyl ketone 96,and obtained some excellent results in the ATH of other 2-pyridyl ketones.3.Design and synthesis of novel Iridacycle catalysts and their application in asymmetric transfer hydrogenation of IminesIridacycle catalysts showed high activity in the reaction of getting racemic alcohols and amines,but their chiral versions have not been reported.Based on the dominant chiral backbone of TsDPEN and the BINOL axial chirality,we tried to develop it into a new ligand for the Iridacycle catalysts and obtained some experimental results.After the kinetic resolution of ketone(±)-136 by ATH,an optically pure planar chiral ferrocene(R)-(+)-136 was obtained.We synthesized the corresponding planar chiral ferrocene Iridacycle catalyst by using this as material.By using ferrocene Iridacycle catalyst 146 as an example in imine ATH,it can give excellent conversion and up to 68% ee.4.Discovery and application of novel N,O-Ir CatalystIn the process of studying novel Iridacycle catalysts,we discovered a new type of Ir complex.Using ligand 162 as material,after simply changing the reaction condition,either N,C-or N,O-Ir complex could be selectively obtained.For the first time,it was found that the difference in the coordination modes has a dramatic effect on the catalytic activity and enantioselectivity in the ATH.The N,O-Ir complex can achieve high efficiency and stereoselective reduction of various aromatic ketones as high as 99% ee,while the N,C-Ir complex catalyzed ATH is far inferior to the former in both conversion and stereoselectivity under the same conditions.We also demonstrated that the both the nature of the amine and its ratio with HCOOH affect considerably the enantioselectivity of the N,O-Ir complex catalyzed ATH,which is a hitherto little-noticed finding.