Synthetic Approaches to cularines. III. Nucleophilic addition and substitution

Attempts to induce the formation of the dibenzoxepine ring of cularine compounds by generating an electron-deficient system in ring C of an 8-hydroxybenzylisoquinoline met with failure. Attack by C-8 phenol on a “p-quinone methide” intermediate afforded benzofurans 16 , which it has been suggested are intermediates in the biogenesis of quettamines. Among the nucleophilic substitution reactions tried, only that based on a phenoxide attack on a benzyne intermediate (generated by dimsyl sodium treatment of a 2′-bromo-8-hydroxybenzylisoquinoline) afforded the dibenzoxepine nucleus of tetradehydrocularines 25 and 27. Competing N-attack afforded the indolizine skeleton present in 24 and 26. From compounds 25 and 27 , the corresponding cularines, cularimines and oxocularines were obtained.