Proposed Mechanism for the Enantioselective Alkynylation of an Aryl Trifluoromethyl Ketone, the Key Step in the Synthesis of Efavirenz

Abstract

The rationalization of observations made during optimization of the zinc-mediated enantioselective addition of cyclopropylacetylene (2) to ketoaniline 8 in the presence of (1R,2S)-1-phenyl-2-(pyrrolidin-1-yl)propan-1-ol (3) to afford amino alcohol 11 has enabled us to propose a mechanism for this transformation. The proposed mechanism has been used as the basis for the development of a spreadsheet-based mass-balance simulation, which has proved useful in predicting the effects of stoichiometry changes and in process troubleshooting.