Tetrahydropyrans are core units within a multitude of biologically active natural products, and methods to prepare these structures, which utilize C-H bond functionalization as a prelude to C-C bond-formation are desirable. This approach is both step and atom economical, because the substrate preparation and reactive intermediate generation employ unreactive C—H bonds, rather than conventional leaving groups. We have shown that heterocycles can be formed with high levels of diastereocontrol from benzylic and allylic ethers through the DDQ-mediated (2,3-dichloro-5,6-dicyano-l,4-benzoquinone) oxocarbenium ion formation, and subsequent intramolecular nucleophilic addition. This method is highly complementary to Prins-based methods in the preparation of tetrahydropyrans, and has been validated through its application to natural product synthesis. Additional strategic benefits of this approach include the tolerance of acid labile functional groups towards oxidative conditions, the application of facile etherification reactions to form stable linkages in segment coupling reactions, and the access to versatile unsaturated products. We have shown that this unsaturation provides a route towards a range of structurally and stereochemically diverse tetrahydropyrans through post-cyclization manipulations. Vinylsilane- and alkyne-containing products serve as useful moieties for application in target- and diversity-oriented synthesis.
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