A regiospecific synthesis of protoberberine alkaloids

The protoberberine skeleton has been prepared in two steps from N-benzyl-3,4-dihydroisoquinolinium salts. Treatment of the salts with the anion of methyl methylthiomethylsulfoxide yields mixtures of diastereomeric adducts that cyclize on heating with concentrated hydrochloric acid to dihydroprotoberberines. The latter compounds may be reduced to their tetrahydro analogues with sodium borohydride, oxidized to protoberberinium salts with iodine, or converted to 13-methyltetrahydroprotoberberines by treatment with formaldehyde according to an established procedure. The method has been applied successfully to the synthesis of (±)-tetrahydropalmatine, palmatine iodide, (±)-xylopinine, (±)-sinactine, and (±)-corydaline. N-Benzylisoquinolinium salts may be used in place of their dihydro analogues as starting materials in this synthesis, thereby extending the range of substitution patterns potentially available.