Total Synthesis of (−)‐Himeradine A. Issue 45 (25th September 2019)

• Record Type: Journal Article
• Authors: Burtea, Alexander; DeForest, Jacob; Li, Xinting; Rychnovsky, Scott D.
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 45(2019)
• Page Start: 16193
• Page End: 16197
• Publication Date: 2019-09-25
• Subjects: alkaloids -- chiral resolution -- cross-coupling -- heterocycles -- total synthesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201910129
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: (−)‐Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)‐fastigiatine. A 2, 4, 6‐trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst‐controlled Overman rearrangement. The piperidine segment was coupled in a B ‐alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)‐fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one‐pot procedure. (−)‐Himeradine A was prepared in 17 steps in the longest linear sequence. Abstract : The complex alkaloid (−)‐Himeradine A was prepared from 2‐bromo‐4‐methylpyridine in 17 steps for the longest linear sequence. Key transformations include a diastereoselective piperidine hydrogenation, classical salt resolution, diastereoselective Overman rearrangement, B ‐alkyl Suzuki coupling, and a final Mannich cascade that formed 5 bonds and 4 rings in one reaction flask.