Synthesis of chlorinated isocoumarin derivatives

Abstract

Syntheses of 5-chloro-, 7-chloro-, and 5,7-dichloro-Isocoumarin derivatives, including the fungal metabolites 5-chloro-3,4-dihydro-8-hydroxy-6-methoxy-3-methylisocoumarin (3), 7-chloro-3,4-dihydro-8-hydroxy-6-methoxy-3-methylisocoumarin (2), and 5,7-dichloro-3,4-dihydro-8-hydroxy-6-methoxy-3-methylisocoumarin (1), are described. This is the first total synthesis of compounds (1) and (2) to be reported. The synthetic route involves carboxylation of chlorinated 2,4-dimethoxy-6-methylbenzoic acids, yielding homophthalic acids. The corresponding homophthalic anhydrides were acetylated and decarboxylated to produce isocoumarins. The naturally occurring 7-chloro-8-hydroxy-6-methoxy-3-methylisocoumarin (7) has been synthesised for the first time.