Stereoselectivities of nucleophilic additions to cycloheptanones. Experimental and theoretical studies and general purpose force field for the prediction of nucleophilic addition stereoselectivities

The selectivities of nucleophilic additions of ethyl, vinyl, and ethynyllithium and Grignard reagents to a 2-(3'-phenylpropyl)cycloheptanone were investigated experimentally. In all cases, cis-cycloheptanol was formed preferentially (40:1-6:1). Theoretical studies were performed on the stereoselectivities of nucleophilic additions of hydride and ethynyllithium reagents to cycloheptanones. An empirical force field for transition states of hydride and ethynyl reagents was used for transition-state geometries and conformational searches. Quantum mechanical calculations on HLi addition to cycloheptanones were compared to the corresponding cyclohexanone calculations. These results show that the formation of 2-alkyl-substituted cis-cycloheptanols is preferred for all nucleophiles studied as a result of torsional and steric effects in the transition states of these reactions.