Synthesis and solid-state conformations of 6S,8aR/S-6-alkyl-3,3-dimethyltetrahydrooxazolo[3,4-a]pyrazine-5,8-diones (pseudoproline DKPs).

Peptide-like self-immolative molecular clips are required for release of active drugs from prodrugs by endopeptidases, generating diketopiperazines (DKPs) as by-products. Two diastereomeric series of cyclo-L-aminoacyl-R/S-dimethyloxazolidinecarboxylate DKPs, derived from L-Ala, L-Leu and L Val, were synthesised. The oxazolidines were constructed by acid-catalysed condensation of N-protected L-Aaa-L/D-SerOMe dipeptides with Me2C(OMe)2, providing the protected Dmo dipeptides. Deprotection exposed the primary amines, which cyclised rapidly to give the desired DKPs. The conformations were studied by NMR in CDCl3 solution and, for the L,R series, by X-ray crystallography. The L,S series had the DKP in a boat conformation with the oxazolidine in a half-chair; the L,R series had the DKP in a flattened conformation with the oxazolidine in an alternative half-chair. Early kinetic studies have shown that L,R-Dmo dipeptide amides cyclised more rapidly than L,S-diastereoisomers and that the rate of cyclisation in the L,R series depends inversely on steric bulk at the alpha-carbon. Cyclo-L-Leu-R-Dmo was non-toxic towards human HT29 cells.