Asymmetric total synthesis of norzoanthamine and formal synthesis of zoanthenol

Abstract

Zoanthamine alkaloids are structurally unique and complex natural products from marine zoanthids that exhibit a broad range of biological activities and have potential in drug discovery. Among them, norzoanthamine has attracted considerable attention as a promising anti-osteoporotic drug candidate. Due to its low abundance in marine sources and its challenging heptacyclic framework, the biological profile of norzoanthamine has not yet been elucidated. Zoanthamine alkaloids commonly contain a highly functionalized and stereochemically dense heptacyclic skeleton, bearing a trans–anti–trans-fused perhydrophenanthrene ring and several challenging adjacent stereocenters. Here, we report the asymmetric total synthesis of norzoanthamine and the formal synthesis of zoanthenol, and detailed synthetic studies of the precise construction of the core structure using radical reactions as the key steps: (1) the Ueno–Stork radical cyclization was utilized to install the contiguous all-carbon quaternary centers at the C-9 and C-22 positions; (2) the Co-catalyzed HAT radical reaction was applied to construct the A–B–C ring with an all-carbon quaternary center at the C-12 position via Csp³–Csp² bond formation; (3) the Fe-catalyzed HAT radical cyclization was attempted to construct the core structure bearing two adjacent stereocenters via Csp³–Csp³ bond formation; and (4) the Mn-catalyzed HAT radical reaction was developed to stereospecifically reduce the challenging tetra-substituted olefin (C13C18) and install the contiguous stereocenters.