Synthesis of (±)-Actinophyllic Acid and Analogs: Applications of Cascade Reactions and Diverted Total Synthesis

Actinophyllic acid
is a biologically active indole alkaloid with
a unique structural framework that incorporates five contiguous stereocenters.
A total synthesis of (±)-actinophyllic acid has been completed
that proceeds in only 10 steps from readily available, known compounds
and with the isolation of nine intermediates. The synthesis features
a novel cascade of reactions of N-stabilized carbocations
with π-nucleophiles to create the tetracyclic core of actinophyllic
acid in a single chemical operation. This pivotal cascade sequence
generates substructures of the actinophyllic acid core that are not
otherwise accessible, and one key intermediate was modified to furnish
several novel compounds having potentially promising anticancer activity,
one of which induces cell death in a wide range of cancer cell lines.

放线叶素酸（Actinophyllic acid）是一类具有生物活性的吲哚生物碱（indole alkaloid），其拥有独特的结构骨架，分子内包含五个连续的手性中心（stereocenters）。目前研究人员已完成外消旋(±)-放线叶素酸的全合成（total synthesis）：该路线以易得的已知化合物为起始原料，仅需10步反应即可完成，且共分离得到9种中间体。该合成策略的核心亮点在于开发了一种全新的N-稳定碳正离子（N-stabilized carbocations）与π-亲核试剂（π-nucleophiles）级联反应（cascade reactions）体系，可通过单步化学操作直接构建放线叶素酸的四环核心骨架（tetracyclic core）。这一关键级联序列能够生成常规方法难以获取的放线叶素酸核心亚结构；此外，研究人员对其中一种关键中间体进行结构修饰，获得了多款具有潜在优异抗癌活性的全新化合物，其中一款化合物可在多种癌细胞系（cancer cell lines）中诱导细胞死亡。