Hetero-2,5-diketopiperazines containing proline and hydroxy-proline residues represent a unique class with important characteristics in both structural detail and biological activity. Since the first reported isolation of a diketopiperazine (DKP) from the sponge Dysidea herbacea, there have been several reports describing the isolation of this class of compound from other marine sponges. DKPs are also reported from marine microbial sources, including the proteobacteria Alcaligenes faecalis, isolated from the sponge Stelletta tenuis. The metabolites reported in these investigations are mostly the products of 4-hydroxy-proline or proline reacting with phenylalanine, arginine , leucine, isoleucine, norvaline or alanine. Because of their important biological uniqueness, it is prime important to develop an efficient flexible, and cost-effective synthetic strategy for synthesis of these proline-based marine microbial metabolites. Our longstanding involvement in benzotriazole (Bt)-mediated oligopeptide chemistry prompted us to design a new, versatile, and flexible strategy able to provide either cis- or trans-configured DKPs starting from the same inexpensive dipeptidoyl benzotriazoles. Herein, we report a tandem deprotection/cyclization methodology which leads to the formation of marine-derived DKPs.

Benzotriazole-mediated route to marine-derived hetero-2,5-diketopiperazines containing proline

248th National Meeting (2014)

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