A New Bicyclic Dipeptide Isostere with Pyrrolizidinone Skeleton

The synthesis of a new conformationally constrained Gly-(s-cis)Pro Turn Mimetic (GPTM) in both
racemic and enantiomerically pure forms and their incorporation into peptides 18, 21, and 24 are
reported. The synthetic strategy adopted to assemble the bicyclic pyrrolizidinone skeleton is based
on the 1,3-dipolar cycloaddition of the cyclic nitrone 4a derived from proline and acrylamide, followed
by a reductive cleavage/cyclization domino process. The enantiomerically pure GPTMs are obtained
by synthesis and separation of diastereomeric intermediates containing (1R)-1-phenylethylamine
as chiral auxiliary. Analysis of pseudotripeptides 18, 21, and 22 by FT-IR and NMR shows that
the amide proton of GPTM derivatives 21 is intramolecularly hydrogen bonded in CDCl3, while
DMSO was shown to disrupt this hydrogen bond.