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

• Published in: Journal of the American Chemical Society 2013-09, Vol.135 (35), p.12984-12986
• Main Authors: Granger, Brett A, Jewett, Ivan T, Butler, Jeffrey D, Hua, Bruce, Knezevic, Claire E, Parkinson, Elizabeth I, Hergenrother, Paul J, Martin, Stephen F
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Indole Alkaloids - chemical synthesis; Indole Alkaloids - chemistry; Indole Alkaloids - pharmacology; Molecular Structure; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja4070206

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.