Total Syntheses and Biological Evaluation of Lamellolactones A and B via Direct Butenolide Functionalization

Abstract

Lamellolactones A and B are pseudoregioisomeric natural products bearing oxidized butenolide frameworks and have attracted interest in the context of fibrodysplasia ossificans progressiva (FOP). We achieved their first total syntheses via Ni-catalyzed reductive coupling of a common alkyl iodide with α- and β-bromobutenolides. A preliminary examination of alkyl electrophiles indicated that the coupling could be applied to simple primary and secondary alkyl iodides. The route also furnished analogues for comparison of γ-substitution effects on bone morphogenetic protein (BMP)-induced alkaline phosphatase inhibition and cytotoxicity.