Amphidinolide N was isolated from the dinoflagellate Amphidinium and bears a unique carbon framework of which the relative and absolute stereochemistry have not been determined. Initial biological screens revealed that it is one of the most cytotoxic compounds ever tested against cancer cell lines; however, its low natural abundance precludes further biological studies. Proposed herein is a first total synthesis of this natural 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 be achievable without having to synthesize every possibility. In many cases, asymmetric induction at chiral centers will be controlled by transition metal-catalyzed reactions to offer flexibility in obtaining either absolute configuration. The feasibility of synthesizing the correct stereoisomer of this natural product will also require a concise and convergent route. Hence, the 26-membered macrolide will be simplified to five key fragments of equal complexity and the central step for macrocyclization will feature a novel intramolecular Ru-catalyzed alkene-alkyne coupling between an internal alkyne and an allylic alcohol. This synthesis will enable further evaluation of this molecule as a potential anticancer drug and finally resolve its unknown relative and absolute 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 |
