The catalytic asymmetric polyene cyclization of homofarnesol to ambrox

• 成果类型: Article
• 署名作者: Luo, Na; Turberg, Mathias; Leutzsch, Markus; Mitschke, Benjamin; Brunen, Sebastian; Wakchaure, Vijay N.; Noethling, Nils; Schelwies, Mathias; Pelzer, Ralf; List, Benjamin
• 署名单位: Max Planck Society; BASF; BASF
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5339
• DOI: 10.1038/s41586-024-07757-7
• 发表日期: 2024-08-22
• 页码: 795-+
• 关键词: squalene; (-)-ambrox; triterpene; ambergris; chemistry; biology; olefins

摘要

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon-carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors(1-3). Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (-)-ambrox is recognized as a longstanding challenge in chemical synthesis(1,4-7). Here we report a diastereoselective and enantioselective synthesis of (-)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly BrOnsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork-Eschenmoser hypothesis(8-10). Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations.