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

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 α-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 β-turn, while the scaffold with the 3‘S,6‘S,7‘aR stereochemistry mimicked a
right-handed poly-d-proline II helix.