Steric and electronic effects in enantioselective hydrogenation of ketones on platinum modified by cinchonidine: Directing effect of the trifluoromethyl group

Abstract

The directing effect of the CF 3 group on Pt/alumina modified by cinchonidine in the enantioselective hydrogenation of activated ketones was studied experimentally and theoretically using aliphatic α , α , α -trifluoromethyl ketones as model compounds. α , α , α -Trifluoromethyl ketones with varying steric hindrances of the groups on the two sides of the keto group (methyl-trifluoromethyl ketone 1a, adamantyl-trifluoromethyl ketone 2a, and tert-butyl-trifluoromethyl ketone 3a) were examined. The catalytic results show that in weakly polar solvents, in which the interaction of the solvent with the substrate, modifier, and Pt is less important, the three alcohols 1b, 2b, and 3b have the same absolute configuration ( R). This indicates that enantioselectivity is guided by the trifluoromethyl substitution rather than by the relative bulkiness of the substituents at the two sides of the carbonyl group. The fluorinated substrate has a preferential interaction on the side of the α , α , α -trifluoromethyl group, as corroborated by the calculation of hydrogen–bonding interactions. When this interaction mode is calculated for the system alkaloid–trifluoroacetone, an energy difference between the Pro( R) and the Pro( S) configurations is found. Our findings suggest that electronic effects give a bias toward the formation of the ( R)-enantiomer.