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

[摘要] Several benzo[b]thienyldehydrophenylalanines were synthesized from pure stereoisomers of the methyl ester of N-(tert-butoxycarbonyl)-beta-bromodehydrophenylalanine as an extension of our previously reported method for the synthesis of dehydrotryptophan analogues to dehydrophenylalamne derivatives. The latter were obtained in high yields by N-deprotection and bromination of N,N-bis-(tertbutoxycarbonyl)-(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(PPh3)(4), Na2CO3, DME/H2O] 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 PdCl2(PPh3)(2). A model dipeptide was prepared coupling a benzo[b]thienyldehydrophenylaianine with the methyl ester of alanine. Preliminary antimicrobial studies were performed with both isomers of one of the beta, beta-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. (C) 2004 Elsevier Ltd. All rights reserved.

[发布日期] 2004-12-13

[关键词] amino acids;dehydrophenylalanines;benzo[b]thiophenes;Suzuki coupling;palladium;antimicrobial