Amphidinolide N was isolated from the dinoflagellate Amphidinium and bears a unique carbon frameworkof which the relative and absolute stereochemistry have not been determined. Initial biological screensrevealed that it is one of the most cytotoxic compounds ever tested against cancer cell lines; however, its lownatural abundance precludes further biological studies. Proposed herein is a first total synthesis of thisnatural product. A stereodivergent route has been designed to access all conceivable stereoisomers,however by using NMR shift analysis as a guide the structural elucidation of amphidinolide N will beachievable without having to synthesize every possibility. In many cases, asymmetric induction at chiralcenters will be controlled by transition metal-catalyzed reactions to offer flexibility in obtaining either absoluteconfiguration. The feasibility of synthesizing the correct stereoisomer of this natural product will also requirea concise and convergent route. Hence, the 26-membered macrolide will be simplified to five key fragmentsof equal complexity and the central step for macrocyclization will feature a novel intramolecular Ru-catalyzedalkene-alkyne coupling between an internal alkyne and an allylic alcohol. This synthesis will enable furtherevaluation of this molecule as a potential anticancer drug and finally resolve its unknown relative andabsolute stereochemistry.
| Trost, Barry M; Stivala, Craig E; Fandrick, Daniel R et al. (2016) Total Synthesis of (-)-Lasonolide A. J Am Chem Soc 138:11690-701 |
| Trost, Barry M; Stivala, Craig E; Hull, Kami L et al. (2014) A concise synthesis of (-)-lasonolide A. J Am Chem Soc 136:88-91 |
