Studies on polypeptide antibiotics: I. 2,5-Diketopiperazines as models of cyclic polypeptide antibiotics

Abstract

The d-d, l-l, d-l, and l-d stereomers of valyllysine anhydride hydrochloride and phenylalanyllysine anhydride hydrochloride were synthesized for purposes of comparison with the cyclic polypeptide antibiotics. Synthesis was achieved via the dicyclohexylcarbodiimide-mediated condensation of formyl- l(or d)-valine or formyl- l (or d)-phenylalanine with N ϵ-carbobenzoxy- l(or d)-lysine methyl ester, deformylation with methanolic hydrochloric acid of the N ϵ-formyl- N ϵ carbobenzoxydipeptide methyl ester so secured, cyclization of the resulting product with methanolic ammonia to the corresponding N ϵ-carbobenzoxylated 2,5-diketopiperazine, and decarbobenzoxylation of the latter to the desired product by palladium catalyzed hydrogenolysis. All four stereomers of each of the synthetic 2,5-diketopiperazines were insusceptible to the hydrolytic action of proteolytic enzymes, a behavior reminiscent of that of the natural cyclic polypeptide antibiotics; however, none exhibited the antibacterial propensities of the latter. The relationship between the chemical structure of polypeptide antibiotics and their antibacterial properties is discussed.