Synthesis, structure and conformation of partially-modified retro- and retro-inverso psi[NHCH(CF3)]Gly peptides

Partially modified retro-(PMR) and retro-inverso (PMRI) psi[NHCH(CF3)]Gly peptides, a conceptually new class of peptidomimetics, have been synthesized in wide structural diversity and variable length by aza-Michael reaction of enantiomerically pure alpha-amino esters and peptides with enantiomerically and geometrically pure N-4,4,4-trifluorocrotonoyl-oxazolidin-2-ones. The factors underlying the observed moderate to good diastereocontrol have been investigated. The conformations of model PMR-psi[NHCH(CF3)]Gly tripeptides have been studied in solution by H-1 NMR spectroscopy supported by MD calculations, as well as in the solid-state by X-ray diffraction. Remarkable stability of turn-like conformations, comparable to that of parent malonyl-based retro- peptides, was evidenced, as a likely consequence of two main factors: 1) severe torsional restrictions about sp(3) bonds in the [CO-CH2-CH(CF3)-NH-CH(R)-CO] module, which is biased by the stereoelectronically demanding CF3 group and the R side chain; 2) formation of nine-membered intramolecularly hydrogen-bonded rings, which have been clearly detected both in CHCl3 solution and in some crystal structures. The former factor seems to be more important, as turn-like conformations were found in the solid-state even in the absence of intramolecular hydrogen bonding. The relative configuration of the -C*H(CF3)NHC*H(R)- stereogenic centers has a major effect on the stability of the turn-like conformation, which seems to require a syn stereochemistry. X-ray diffraction and ab initio computational studies showed that the [-CH(CF3)NH-] group can be seen as a sort of hybrid between a peptide bond mimic and a proteolytic transition state analogue, as it combines some of the properties of a peptidyl -CONH- group (low NH basicity, CH(CF3)-NH-CH backbone angle close to 120degrees, C-CF3 bond substantially isopolar with the C=O) with some others of the tetrahedral intermediate [-C(OX)(O-)NH-] involved in the protease-mediated hydrolysis reaction of a peptide bond (high electron density on the CF3 group, tetrahedral backbone carbon).