Abstract
Partially modified retro‐ (PMR) and retro‐inverso (PMRI) ψ[NHCH(CF~3~)]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 α‐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‐ψ[NHCH(CF~3~)]Gly tripeptides have been studied in solution by ^1^H 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 retropeptides, was evidenced, as a likely consequence of two main factors: 1) severe torsional restrictions about sp^3^ bonds in the [CO‐CH~2~‐CH(CF~3~)‐NH‐CH(R)‐CO] module, which is biased by the stereoelectronically demanding CF~3~ group and the R side chain; 2) formation of nine‐membered intramolecularly hydrogen‐bonded rings, which have been clearly detected both in CHCl~3~ 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(CF~3~)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(CF~3~)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(CF~3~)‐NH‐CH backbone angle close to 120°, CCF~3~ bond substantially isopolar with the CO) 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 CF~3~ group, tetrahedral backbone carbon).