Synthesis of beta-benzo[b]thienyldehydrophenylalanine derivatives by one pot palladium-catalyzed borylation and Suzuki coupling (BSC) and metal-assisted intramolecular cyclization: studies of fluorescence and antimicrobial activity

Abstract

Palladium-catalyzed borylation and Suzuki coupling (BSC) in a one pot procedure was successfully applied to the synthesis of several beta-substituted dehydrophenylalanines in the benzo[b]thiophene series maintaining the stereochemistry of the starting materials. Bromobenzo[b]thiophenes bearing an ortho EDG (OMe or Me) were used as the components to be borylated with pinacolborane. Pure stereoisomers of beta-bromodehydrophenylalanines were used as the other Suzuki coupling component. Treatment of the methyl ester of N-(tert-butoxycarbonyl)-(Z)-beta-(2,3,5-trimethylbenzo[b]thien-6-yl)dehydrophenylalanine thus obtained, with Pd(OAc)2 and Cu(OAc)2 in DMF at 160 oC gave two indole derivatives (1:3). The major product resulting from isomerization and cyclization and the minor product resulting from direct cyclization (thienoindole). Reaction at 100 oC gave the same products in similar amounts. Using as starting material the methyl ester of N-(tert-butoxycarbonyl)-(Z)-beta-(2,3,7-trimethylbenzo[b]thien-6-yl)dehydrophenylalanine gave only one product, resulting from isomerization and cyclization at 100 oC. Two of the cyclized compounds were submitted to fluorescence studies; the thienoindole could be used as a fluorescent probe. Preliminary studies of antimicrobial activity were performed on the precursors and on the cyclized products.Fundação para a Ciência e Tecnologia - POCTI/99/QUI/32689, SFRH/BD/4709/2001