STEREOSELECTIVE SYNTHESIS OF FREIDINGER LACTAMS USING OXAZIRIDINES DERIVED FROM AMINO-ACIDS

Conformationally restrained dipeptidyl lactams are building blocks for the synthesis of peptidomimetics, including Freidinger lactams (Figur e 1). Few synthetic methodologies toward such moieties allow for incor poration of a stereodefined substituent on the ring nitrogen (i.e., co rresponding to an amino acid side chain). Enantiopure Freidinger lacta ms were obtained by (1) condensation of (S)-tert-butoxycarbonyl (Boc)- protected 2-aminocycloalkanones with commercially available alpha-amin o esters, (2) oxidation of the resulting imines with m-CPBA to give sp irocyclic oxaziridines, and (3) photorearrangement. Conformational ana lyses of seven- and eight-membered dipeptidyl lactams by NMR and by X- ray crystallography are described. The utility of this chemistry was i llustrated by the synthesis of potential inhibitors of angiotensin con verting enzyme (ACE).