Analogs of cyclosporin A modified at the D-Ala8 position.

Abstract

The conversion of [2-deutero-3-fluoro-D-Ala8]cyclosporin A (1) to a dehydroalanine analog [delta-Ala8]cyclosporin A (2) was achieved with lithium diisopropylamide in THF at low temperature. This dehydro compound is a useful intermediate for the preparation of position 8 analogs of cyclosporin A formed from it by the conjugate addition of thiol compounds. NMR conformational studies have provided evidence for the restoration of D-stereochemistry in the modified Ala8 residues. The preparation of several of these cyclosporin analogs and their bioactivities are described.