Stereoselective Synthesis of Freidinger Lactams Using Oxaziridines Derived from Amino Acids

Article abstract of DOI:10.1021/jo961670j

Conformationally restrained dipeptidyl lactams are building blocks for the synthesis of peptidomimetics, including Freidinger lactams (Figure 1). Few synthetic methodologies toward such moieties allow for incorporation of a stereodefined substituent on the ring nitrogen (i.e., corresponding to an amino acid side chain). Enantiopure Freidinger lactams were obtained by (1) condensation of (S)-tert-butoxycarbonyl (Boc)-protected 2-aminocycloalkanones with commercially available α-amino esters, (2) oxidation of the resulting imines with m-CPBA to give spirocyclic oxaziridines, and (3) photorearrangement. Conformational analyses of seven- and eight-membered dipeptidyl lactams by NMR and by X-ray crystallography are described. The utility of this chemistry was illustrated by the synthesis of potential inhibitors of angiotensin converting enzyme (ACE).