Synthesis and Transformation of (-)-Isopulegol-Based Chiral ß-Aminolactones and ß-Aminoamides.

ABSTRACT

A library of isopulegol-based ß-amino acid derivatives has been developed from commercially-available (-)-isopulegol. Michael addition of primary and secondary amines towards α,ß-unsaturated γ-lactones was accomplished resulting in ß-aminolactones in highly-stereoselective reactions. Ring-opening of ß-aminolactones with different amines furnished excellent yields of ß-aminoamides. Moreover, the applicability of aminolactones in peptide synthesis was examined by opening the lactone ring with α- and ß-aminoesters, providing dipeptides as promising chiral substrates for the synthesis of foldamers. The antiproliferative activities of ß-aminolactones and ß-aminoamides were explored, and the structure-activity relationships were studied from the aspects of the stereochemistry of the monoterpene ring and the substituent effects on the ß-aminoamide ring system. The N-unsubstituted (-)-isopulegol-based ß-aminoamides exhibited considerable antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF7 and MDA-MB-231).