Tetrasubstituted β-Lactams from Amino Acids

Significance

The solid-phase synthesis of (3S,4S)-tetrasubstituted β-lactam compounds from amino acids is reported. Thus, Fmoc-Xaa-Wang-resins 1 [Xaa = Ala, Phe, Lys(Boc) and Glu(t-Bu)] were converted into N-alkylated amines 2 via deprotection of the Fmoc group, imine formation with aldehydes (5 examples), and reduction of the corresponding imines. Condensation of 2 with (S)-2-chloropropionic acid was performed with Cl₃CCN/PPh₃/THF/propylene oxide to give 3 in high conversion with least epimerization at the C2 position. The key cyclization of 3 was achieved by use of tert-butylimino-tri(pyrrolidino)phosphorane (BTTP) in DMF to give the corresponding β-lactams 4. Immobilized β-lactams were detached from the resin with TFA to afford the corresponding β-lactams 5 in 11-61% yield with 41-98% ­purity (20 examples).