The synthesis and crystal structure of alpha-keto tetrazole-based dipeptide mimics

Here we report the synthesis of a cis-dipeptide mimic N-Boc-Phe-[COCN4]-Gly-OBn, 7, containing the non-hydrolysable α-keto tetrazole isostere and an unusual 2,5-disubstituted α-keto tetrazole-based peptidomimetic, 8. The incorporation of the novel cis-amide bond isostere was achieved via direct alkylation of a precursor five-substituted (1H)-tetrazole. The assignment of the resulting 1,5- and 2,5-tetrazoyl regiomers was based on the first reported X-ray structure analysis of an α-keto tetrazole, compound 8.