Regioselective total synthesis of (±)-berberastine

Abstract

The title compound has been synthesized in 37% overall yield from methyl 6-chloromethyl-2,3-dimethoxybenzoate (8) through the following six steps: Reformatsky-type condensation of (8) with 3,4-methylenedioxybenzaldehyde gave 3,4-dihydro-7,8-dimethoxy-3-(3,4-methylenedioxyphenyl)isocoumarin (10), which was transformed into 2,3-dimethoxy-6-(3,4-methylenedioxyphenacyl)benzaldehyde (6) by reduction with lithium aluminium hydride followed by Swern oxidation; reductive amination of compound (6) with aminoacetaldehyde dimethyl acetal afforded 2-(2,2-dimethoxyethyl)1,2,3,4-tetrahydro-7,8-dimethoxy-3-(3,4-methylenedioxyphenyl)isoquinoline (3); acid-.catalysed cyclization of the acetal (3) gave 5-hydroxytetrahydroberberines (2), from which berberastine iodide (1) was obtained by iodine oxidation. All attempts to oxidize compounds (2) to the corresponding ketone have so far failed.