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

• Record Type: Journal Article
• Authors: Burtea, Alexander; DeForest, Jacob; Li, Xinting; Rychnovsky, Scott D.
• Is Part Of: Angewandte Chemie. Volume 131:Number 45(2019)
• Page Start: 16339
• Page End: 16343
• Publication Date: 2019-09-25
• Subjects: Alkaloide -- Heterocyclen -- Kreuzkupplung -- Racematspaltung -- Totalsynthese; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201910129
• Languages: English
• ISSNs: 0044-8249

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 : Das komplexe Alkaloid (−)‐Himeradin A wurde aus 2‐Brom‐4‐methylpyridin in 17 Stufen in der längsten linearen Sequenz hergestellt. Schlüsselschritte sind eine diastereoselektive Piperidin‐Hydrierung, eine klassische Racematspaltung, eine Overman‐Umlagerung, die B ‐Alkyl‐Suzuki‐Kupplung und eine finale Mannich‐Kaskade, mit der 5 Bindungen und 4 Ringe in einem Reaktionsgefäß aufgebaut werden.