Amino−Zinc−Enolate Carbometalation Reactions: Application to Ring Closure of Terminally Substituted Olefin for the Asymmetric Synthesis of cis- and trans-3-Prolinoleucine

Abstract

The amino-zinc-enolate cyclization reaction is a straightforward route for the synthesis of 3-substituted prolines. As classical intramolecular carbometalation reactions, the applicability of the addition of zinc to a double bond was limited to a substrate in which the terminal alkene carbon was unsubstituted. Being interested in the synthesis of cis- and trans-3-prolinoleucine derivatives for our structure-activity relation (SAR) studies, we focused our effort on the preparation of these compounds by amino-zinc-enolate cyclization of terminally substituted double bonds. Herein we report that the attachment of an activating group such as cyclopropyl to the terminal olefin carbon allows the amino-zinc-enolate cyclization of a terminally substituted alkene. The reaction is stereospecific, leading to a trans-3-substituted proline derivative, whereas a cis stereochemistry was observed with the amino-zinc-enolate cyclization of terminally nonsubstituted olefins. Absolute configurations obtained for the 3-prolinoleucine were established by X-ray analysis, NMR, and optical activity comparison of the cis and trans derivatives obtained by an unambiguous pathway.