Applications of samarium(II) iodide-promoted 8-membered ring cyclization reactions in natural product total synthesis: I. The total synthesis of (+)-isoschizandrin. II. Progress toward the total synthesis of variecolin

Over the last 25 years, samarium(II) iodide has been employed as a versatile reagent to effect a wide array of functional group transformations. Consequently, SmI2 has been applied in a large number of total synthetic efforts with great success. The construction of a variety of different ring systems can be achieved by exploiting the mild and selective nature of SmI2. Specifically, SmI2 is capable of effecting medium-membered ring cyclizations, which have posed a significant challenge to chemists in the past. The results reported herein highlight the power of samarium(II) iodide to assemble the eight-membered rings present in the natural products (+)-isoschizandrin and variecolin.; (+)-Isoschizandrin is one of nearly forty dibenzocyclooctadiene lignans isolated from the fruit of Schizandra chinensis. The extract from this lignan-rich plant finds use in traditional medicine as an antitussive and also displays anti-ulcer activity in rats. Synthesis of the eight-membered ring of (+)-isoschizandrin, possessing the attendant functionality and stereochemistry, provides a significant synthetic challenge. The 13-step synthesis of (+)-isoschizandrin reported herein features a novel samarium(II) iodide-promoted 8-endo ketyl-olefin coupling to assemble the eight-membered ring present in the target concomitantly with the required functionality and stereochemistry.; The sesterterpenoid variecolin was first isolated by Hensens in 1991 from the fermentation of the fungus Aspergillus variecolor. Variecolin is an antagonist of the angiotensin-II AT1 receptor and has been shown to be a potent immunosuppressant. Despite such interesting properties, variecolin has received little synthetic attention, and so it is an active target for total synthesis in our laboratories.; The goal of our research is to utilize a samarium(II) iodide-promoted annulation procedure for the construction of the cyclooctanyl core. Synthesis of the key hemiketal has been obtained in a model system. The success of this key reaction further demonstrates the utility of samarium(II) iodide to generate medium-sized rings in complex systems.