Synthetic studies on isoquinoline alkalids. I. An efficient synthesis of 9,10-substituted protoberberine alkalids.

Three synthetic routes leading to the 9, 10-disubstituted tetrahydroprotoberberine derivative (4a) were investigated. The third route involving a four-step reaction sequence starting from homoisovanillinic acid (13b) afforded 3-benzyloxy-9, 10-dimethoxy-tetrahydroprotoberberine (4a) in 65% over-all yield providing the most efficient and general synthesis of the hitherto not easily available 9, 10-disubstituted protoberberine alkaloids. The key step in this synthesis was effective conversion of 13b into the 7, 8-disubstituted isochromanone derivative (28b) which required specific introduction of hydroxymethyl into the position ortho to the phenolic function in 13b. This was nicely effected our newly discovered general method for ortho-(α-hydroxy)-alkylation of phenols using benzeneboronic acid.