A convergent route to phthalideisoquinoline alkaloids via directed metalation of tertiary benzamides

Diastereomeric phthalideisoquinolines 8 and 9 have been synthesized by a route involving an amine-induced bromohomophthalic anhydride – phthalide-α-carboxamide rearrangement, 3 + 4 → 6, as the key step. This rearrangement has been applied to the synthesis of the methoxylated phthalide-α-carboxamide 18 which has been converted into the dehydrophthalide 19 thereby achieving a formal synthesis of the phthalideisoquinoline alkaloids cordrastine I (1a) and cordrastine II (1b). The key intermediate in this sequence, 3,4-dimethoxyhomophthalic acid (15), has been efficiently prepared in two steps via directed lithiation of 2,3-dimethoxy-N,N-diethylbenzamide (13).