Synthesis of Pipecolic Acid-Based Spiro Bicyclic Lactam Scaffolds as beta-Turn Mimics

摘要

A series of 6.5.5 spiro bicyclic lactam scaffolds were synthesized from pipecolic acid in a sequence of reactions that was initiated with the alpha-allylation of tert-butoxycarbonyl pipecolic acid.Oxidative cleavage of the olefin to give an aldehyde followed by condensation with D-cysteine methyl ester gave a mixture of pipecolyl thiazolidines.Cyclization of the pipecolyl thiazolidines with Mukaiyama's reagent yielded the spiro bicyclic lactams 4a-d.Epimerization of the 7'a bridgehead carbon under acidic conditions was observed for those spiro bicyclic lactam scaffolds with an S stereochemistry at this position.The 6.5.5 spiro bicyclic lactam scaffold with the 3'S,6'R,7'aR stereochemistry mimicked a type II beta-turn,while the scaffold with the 3'S,6'S,7'aR stereochemistry mimicked a right-handed poly-D-proline II helix.