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Spirotenuipesine A (1) is a trichothecane sesquiterpene which has recently been isolated from Paecilomyces tenuipes (also called Isaria japonica). It possesses an activity in neurotrophic factor biosynthesis, so it can be a lead compound in drug development for neuronal disorders such as Alzheimer's disease. Despite the fascinating activity and structure, total synthesis has not been reported yet. Toward the total synthesis, we planned to construct the carbon skeletal structure of Spirotenuipesine A (1) in short steps, and designed a synthetic approach without using any protecting groups. Starting from the known compound 8, we constructed racemic bicyclic lactone 6 through the reaction of the Ni(0) catalyzed cyclization. To get the spirocompound 4, we designed regioselective and stereoselective 2 steps' coupling reaction with (Z)-dibromide 5. On epoxidation of spirocompound 4, the product was a good crystal, so we analyzed the stereochemistry of three new stereocenters by X-ray crystallographic analysis. By the stereoselective bromohydroxylation and subsequent base treatment, we got epoxide 18 with a correct stereochemistry. Since we could not get next thiocompound 19, we changed the synthetic plan. Epoxidation of bromohydrin 17 gave us a precursor of the key step. In the key DIBAL reduction, lactone 20 was converted to a lactol 21, which was then converted to alcohol 22 by the acid treatment. Fortunately we found that alcohol 22 could be obtained in one step by DIBAL reduction in the presence of diethylalminium chloride. Treatment of 22 with KHMDS gave epoxide 23. Final step with n-BuLi gave racemic Spirotenuipesine A (1). In summary, we could synthesize Spirotenuipesine A (1) in 10 steps from the known compound 8 without using any protecting groups.
