Asymmetric Hydrogenation Of ?-Keto Acid And Its Cyclic Derivatives

Asymmetric catalytic hydrogenation reaction is one of the most direct and effective methods for preparing chiral compounds,and the reaction is also widely used in industry.Chiral alcohols are ubiquitous in various natural products,medicines,flavors and fragrances.The asymmetric hydrogenation of carbonyl compounds is one of the most important methods for the construction of such chemicals.The asymmetric hydrogenation of simple ketones and partially functionalized ketones has been well developed.In particular,the tridentate ligands developed in recent years have pushed the Turnover Number of asymmetric hydrogenation of these compounds to millions.However,the asymmetric hydrogenation of ?-keto acid compounds,especially nitrogen-containing cyclic ?-ketoamide compounds,is still a problem.This thesis developed an efficient asymmetric hydrogenation reaction of chain ?-keto acids and cyclic ?-ketoamides,based on a series of ferrocene skeleton tridentate ligands developed by Professor Zhang Xumu's group.Using Ir/f-amphox as catalyst achieved highly efficient asymmetric hydrogenation of cyclic ?-ketoamides,in the presence of potassium hydroxide as base and tetrabutylphosphonium bromide as addition in methyl tertiary butyl ether under the mild condition(25 oC and 40 atm H2),and got excellent results(up to 99% conv.,up to 96% ee,up to 20:1 dr).For the acyclic keto acid substrate,the asymmetric hydrogenation of benzoyl formic acid is achieved at room temperature by using Ir/f-amphol as the catalyst(95% yield,93% ee).Taking this method as a key step,the blockbuster chiral drug Clopidogrel Bisulfate was successfully synthesized...