Ir/f-Ampha complex catalyzed asymmetric sequential hydrogenation of enones: a general access to chiral alcohols with two contiguous chiral centers

A general and highly efficient method for asymmetric sequential hydrogenation of alpha,beta-unsaturated ketones has been developed by using an iridium/f-Ampha complex as the catalyst, furnishing corresponding chiral alcohols with two contiguous stereocenters in high yields with excellent diastereo- and enantioselectivities (up to 99% yield, >20 : 1 dr and >99% ee). Control experiments indicated that the C=C and C=O bonds of the enones were hydrogenated sequentially, and the final stereoselectivities were determined by the dynamic kinetic resolution of ketones. Moreover, DFT calculations revealed that an outer sphere pathway was involved in both reduction of C=C and C=O bonds of enones. The synthetic utility of this method was demonstrated by a gram-scale reaction with very low catalyst loading (S/C = 20 000) and a concise synthetic route to key chiral intermediates of the antiasthmatic drug CP-199,330.

Automated summary

A highly efficient method for asymmetric sequential hydrogenation of alpha,beta-unsaturated ketones has been developed, which enables the synthesis of chiral alcohols with two contiguous stereocenters in high yields and excellent enantioselectivity. Control experiments and DFT calculations revealed the reaction mechanism and factors affecting the stereoselectivity. The synthetic utility of this method was demonstrated by gram-scale reactions and the synthesis of key chiral intermediates for the antiasthmatic drug CP-199,330.