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 (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 alpha-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).
Wolfe
Michael S.
MS
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045-2506.
Dutta
Dinah
D
Aubé
Jeffrey
J