Application of samarium diiodide-mediated cyclizations for the construction of polycyclic compounds. I. A general route toward the synthesis of the cladiellin skeleton and synthesis of the 3,7-diastereomer of polyanthellin A. II. Construction of bicyclic ring systems via a transannular cyclization strategy

Cladiellin diterpenes are a family of marine metabolites isolated from gorgonians and soft corals. Since the isolation of the first member of this family in 1968, more than sixty cladiellin natural products have been reported. Cladiellin diterpenes display a wide array of biological activity. In addition, they possess a unique structure: a rare oxabicyclic ring system that is composed of a hexahydroisobenzofuran moiety and an oxacyclononane unit. They contain at least six stereogenic centers. An efficient synthesis of the cladiellin skeleton is reported utilizing methods that were previously developed in this laboratory. The approach is based on a Sml2-mediated cyclization reaction for the construction of the oxacyclononane unit. A [4+3] annulation strategy was used to create the octahydroisobenzofuran moiety. This route provides the cladiellin skeleton in only fourteen steps without the use of protecting groups. The present approach also enabled the synthesis of the 3,7-diastereomer of the natural product polyanthellin A. The development of efficient methods for the construction of polycyclic compounds has been a longstanding objective of synthetic organic chemists. Traditionally, bicyclic ring systems are created via two approaches: (1) annulation of a sidechain onto an existing ring and (2) cycloaddition reactions. In addition to these strategies, a third possible approach is to form bicycles via transannular transformations. However, this strategy has not been systematically examined. Our research group has initiated a project that focuses on investigating the synthetic utility of the transannular ring formation strategy. To test the viability of this approach, the ketyl-olefin coupling, a method previously developed in this laboratory, was examined. During the course of this research, the transannular cyclization of cyclooctene, cyclodecene and cycloundecene derivatives was investigated. It was concluded that the transannular ketyl-olefin coupling proceeds with high yield, diastereoselectivity, and in the case larger ring-sized compounds, with excellent regioselectivity. These results demonstrate that the transannular cyclization strategy provides efficient access to bicyclic ring systems