First Total Syntheses of Both C10 Epimers of Mycenolide A: Stereochemical Assignment and Reassessment of Its Reported Neuroprotective Activity

Abstract

Abstract Mycenolide A, a marine-derived 5-substituted butenolide, possesses a remote C10 quaternary stereocenter whose absolute configuration was previously unassigned. Herein, we report the first stereodivergent total syntheses of both C10-epimers of mycenolide A in only nine steps (longest linear sequence) from readily available chiral pool precursors. Comparative spectroscopic studies demonstrated that conventional 13C NMR analyses in multiple solvents and optical rotation data were insufficient for unambiguous assignment. However, mixed-sample 13C NMR experiments in CDCl3 enabled diagnostic differentiation between the two epimers. Through these studies, the absolute configuration at C10 of the natural product was successfully assigned. Biological reassessment in HT22 hippocampal neurons revealed that neither epimer exhibited significant neuroprotective activity under d-galactose-induced or serum-deprivation conditions. These findings contrast with previous reports in TrkB-overexpressing cell models and suggest that the reported neuroprotective effects of mycenolide A are highly dependent on cellular context and TrkB expression levels.