Constructing Iboga alkaloids via C-H bond functionalization: examination of the direct and catalytic union of heteroarenes and isoquinuclidine alkenes.

The iboga alkaloids have attracted considerable attention in both the scientific community and popular media due to their reported ability to reverse or markedly diminish cravings for, and self-administration of, the major drugs of abuse. We have developed three new intramolecular C-H functionalization procedures leading to the core seven-membered ring of the iboga skeleton, a cyclization that proved to be highly challenging. The electrophilic palladium salt Pd(CH3CN)4(BF4)2 was effective for the cyclization of diverse N-(2-arylethyl)isoquinuclidines with yields of 10-35%. A two-step, bromination-reductive Heck reaction protocol was also effective for the synthesis of ibogamine in 42% yield. Finally, a direct Ni(0)-catalyzed C-H functionalization provided the benzofuran analogues of ibogamine (74%) and epi-ibogamine (38%). Although each approach suffers from significant shortcomings, in combination, the methods described provide practical routes to diverse ibogamine analogues.