| The annonaceous acetogenins, a natural product family with a long hydrocarbon chain and a terminal lactone are well-known mitochondria complex I inhibitors. Among the acetogenins, synthetic studies have been focused upon bistetrahydrofuran bearing acetogenins because of their excellent cytotoxicity toward various cancer cell lines and structural variety. The Roush [3+2]-annulation methodology provides a good way to generate a wide variety of bistetrahydrofurans with different stereochemistry. Using the [3+2]-annulation, we have developed a short and convergent synthetic route toward bistetrahydrofurans flanked by two additional hydroxyl groups, which was applied for four different diastereomers of acetogenin including 10-hydroxytrilobacin, 10-hydroxyasimicin, and 4, 10-dihydroxysquamocin-N. Still shorter synthetic routes were proposed for the synthesis of acetogenins lacking the 4- or 10-hydroxyl groups. The synthesis of tetrahydrofurans with erythro-relationship to the adjacent hydroxyl group was recently enabled by the Roush group. Combining all of these ideas, we now have all the technology available to access a considerable portion of a 64-membered diastereomer library of bistetrahydrofuran-containing acetogenins. |
