Synthesis of pure stereoisomers of benzo[ b]thienyl dehydrophenylalanines by Suzuki cross-coupling. Preliminary studies of antimicrobial activity

Abstract

Several benzo[ b]thienyldehydrophenylalanines were synthesized from pure stereoisomers of the methyl ester of N-( tert-butoxycarbonyl)-β-bromodehydrophenylalanine as an extension of our previously reported method for the synthesis of dehydrotryptophan analogues to dehydrophenylalanine derivatives. The latter were obtained in high yields by N-deprotection and bromination of N, N-bis-( tert-butoxycarbonyl)-( Z)-dehydrophenylalanine using TFA and NBS. This was carried out in two steps or in a one pot procedure resulting in different E/ Z ratios. These compounds were coupled under Suzuki cross-coupling conditions [Pd(PPh 3) 4, Na 2CO 3, DME/H 2O] with several boronic benzo[ b]thienyl acids in good to high yields maintaining the stereochemistry of the starting materials. The best yields were obtained when the boronic acid was in position 7 of the benzo[ b]thiophene and with the E isomer of the brominated dehydrophenylalanine. In some cases it was possible to increase the lower yields by changing the Pd source to PdCl 2(PPh 3) 2. A model dipeptide was prepared coupling a benzo[ b]thienyldehydrophenylalanine with the methyl ester of alanine. Preliminary antimicrobial studies were performed with both isomers of one of the β, β-diaryldehydroalanines obtained. The results show that the compounds are selective and very active (very low MICs) against Gram positive bacteria ( B. cereus and B. subtilis) the Z-isomer being more active. The compounds are also active against Candida albicans presenting similar MICs.