A short synthetic route to nordihydroguaiaretic acid (NDGA) and its stereoisomer using Ti-induced carbonyl-coupling reaction

A rapid synthetic approach to natural meso-nordihydroguaiaretic acid (NDGA) and its non-meso isomer is described from (3,4-dimethoxyphenyl)acetone using as a key step the low-valent Ti-induced carbonyl-coupling reaction of the ketone. The method involves a simple separation of the E- and Z-isomers that result from the dehydroxylation of the diol product of the coupling. The present approach allows the preparation of various analogs of NDGA.