Catalytic Enantioselective Birch–Heck Sequence for the Synthesis of Phenanthridinone Derivatives with an All-Carbon Quaternary Stereocenter

Novel phenanthridinone analogues
with an all-carbon quaternary
stereocenter have been enantioselectively synthesized using the Birch–Heck
sequence. Flat phenanthridinone structures have extensive bioactivity
but consequently also suffer from poor therapeutic selectivity. The
addition of a quaternary center to the phenanthridinone skeleton has
the potential to generate more complex analogues with improved selectivity.
Unfortunately, no general synthetic pathway to such derivatives exists.
Herein we report a four-step process that transforms inexpensive benzoic
acid into 22 different quaternary carbon-containing phenanthridinone
analogues with a variety of substituents on all three rings: alkyl
groups at the quaternary center; methyl, methoxymethyl, or para-methoxybenzyl on the amide nitrogen; and halogen and
methyl substituents on the aryl ring. Good to very good enantioselectivity
was demonstrated in the key intramolecular desymmetrizing Mizoroki–Heck
reaction. Transformations of the Heck reaction products into molecules
with potentially greater therapeutic relevance were also accomplished.

采用Birch-Heck序列，成功实现了包含全碳季碳立体中心的苯并呋喃酮类似物的外消旋合成。平面结构的苯并呋喃酮显示出广泛的生物活性，但随之而来的是较差的治疗选择性。将季碳中心引入苯并呋喃酮骨架中，有望生成具有更高选择性的更复杂类似物。遗憾的是，尚无此类衍生物的通用合成途径。本研究报道了一种四步法，将廉价的苯甲酸转化为22种不同的含季碳的苯并呋喃酮类似物，这些类似物在其三个环上具有多样的取代基：季碳中心上的烷基；酰胺氮上的甲基、甲氧基甲基或对甲氧基苄基；以及芳环上的卤素和甲基取代基。关键的分子内去对称化Mizoroki-Heck反应中表现出了良好至非常良好的外消旋选择性。此外，还实现了将Heck反应产物转化为具有潜在更高治疗相关性的分子的转化。