First total synthesis and evaluation of the α-glucosidase inhibitory activity of (±)-methyl dihydromarmesinate, an anti-inflammatory phenylpropanoid from Ficushirta Vahl., and related benzofurans

Abstract

The first total synthesis of (±)-methyl dihydromarmesinate (6 steps, 52% yield), an anti-inflammatory phenylpropanoid from the hairy fig, is reported from 2,4-dihydroxybenzaldehyde. The concise reaction sequence involved minimal use of protecting groups, proceeding through selective phenol benzylation and ortho-halogenation, followed by a one-pot Oacetonylation and intramolecular cyclization of the resulting 1,6-dicarbonyl framework, to yield a 2-acetyl benzofuran intermediate. A Heck cross-coupling installed the three-carbon atom side chain, whereas a methyl Grignard addition to the methyl ketone carbonyl built the gem-dimethyl motif, and a catalytic hydrogenation completed the synthesis. While the natural product was inactive in the assay, some of its synthetic intermediates were promising inhibitors of α-glucosidase.