Synthesis Of β-Chiral Primary Alcohols Via Asymmetric Hydrogenation

Chiral alcohols are present in numerous natural products and synthetic drugs.Among them,β-chiral primary alcohols are important intermediates for the synthesis of some non-steroidal anti-inflammatory chiral drugs.β-Chiral primary alcohols are predominantly synthesized via the asymmetric hydroboration of olefins and via the asymmetric hydrogenation of β-hydroxy terminal olefins or racemic aldehydes.These methods still suffer from the problems of inferior catalytic activity,low enantioselectivities,limited substrate scope,and require harsh reaction conditions.In order to negate these deficiencies,we envisaged that β-chiral primary alcohols could be obtained by the asymmetric hydrogenation of β,β-disubstituted enol esters.Firstly,the reaction conditions including different types of chiral transition-metal catalysts,solvents,additives,temperatures and hydrogen pressures were investigated.Optimized reaction conditions were found to be as follows: using the achiral spiro diphosphine ligand SKP as a catalyst,dichloromethane as a solvent,30 bar hydrogen pressure and performing the reaction at room temperature.Secondly,differentβ,β-disubstituted enol esters were synthesized and subjected to asymmetric hydrogenation using the above conditions.The desired products were obtained with up to 93% ee.The hydrogenated products could be applied to the synthesis of non-steroidal anti-inflammatory chiral drugs such as(+)-ibuprofen and(S)-naproxen.In conclusion,the first asymmetric hydrogenation of β,β-disubstituted enol esters with high enantioselectivities has been realized.This methodology provides a new approach to the synthesis of β-chiral primary alcohols and related chiral drugs.