Kruegel Andrew C, Rakshit Souvik, Li Xiaoguang, Sames Dalibor
Department of Chemistry, Columbia University , New York, New York 10027, United States.
J Org Chem. 2015 Feb 20;80(4):2062-71. doi: 10.1021/jo5018102. Epub 2015 Jan 29.
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.
由于依波加生物碱据报道具有逆转或显著减少对主要滥用药物的渴望及自我给药的能力，它们在科学界和大众媒体中都引起了相当大的关注。我们开发了三种新的分子内C-H官能化方法，可生成依波加骨架的核心七元环，事实证明这种环化极具挑战性。亲电钯盐Pd(CH3CN)4(BF4)2对多种N-(2-芳基乙基)异喹啉的环化有效，产率为10-35%。两步法溴化-还原Heck反应方案对合成依波加明也有效，产率为42%。最后，直接的Ni(0)催化C-H官能化提供了依波加明（74%）和表依波加明（38%）的苯并呋喃类似物。尽管每种方法都有明显的缺点，但综合起来，所描述的方法为合成多种依波加明类似物提供了实用途径。
