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Catalytic asymmetric synthesis of cyclic ethers containing an α-tetrasubstituted stereocenter.

Cyclic ethers are an important class of heterocycles present in a variety of biologically active molecules. For example, tetrahydrofurans (THFs) and tetrahydropyrans (THPs) are found in several classes of natural products, including macrodiolides, acetogenins, ionophores, lignans, and macrolides, while arene-fused THPs are the major structural motif of chromans. The importance of cyclic ethers as structural elements of organic molecules has led to continued interest in the development of new catalytic and stereoselective methods for their synthesis. However, despite significant progress in the field, the asymmetric synthesis of cyclic ethers containing tetrasubstituted stereocenters is still a major synthetic challenge. Herein we describe the development of a method for the catalytic, asymmetric synthesis of THFs, THPs, and chromans containing a tetrasubstituted stereocenter. Our approach is based on a catalytic method for the synthesis of cyclic ethers developed in 2006 by Widenhoefer and co-workers, who reported a gold-catalyzed exo-selective cyclization of allenols as an efficient method for the synthesis of THFs and THPs. This method has been applied to the asymmetric synthesis of compounds containing trisubstituted, but not tetrasubstituted stereocenters. 11] We reasoned that cyclic ethers containing a tetrasubstituted stereocenter could be prepared by cyclization of enantioenriched trisubstituted allenols, as outlined in Scheme 1a. The key aspect of this transformation is transfer of chirality from the chiral axis of an allene to the tetrasubstituted stereocenter of the cyclic ether. Chirality transfer to a trisubstituted stereocenter in exo cyclizations of allenols is known to be compromised by the formation of a mixture of diastereoisomers with the opposite sense of chirality (Scheme 1b). However, chirality transfer to a tetrasubstituted stereocenter has so far not been explored in the context of this transformation. Furthermore, chirality transfer from enantioenriched trisubstituted allenes has, in general, rarely been used in gold-catalyzed hydrofunctionalization reactions, despite its enormous potential in the asymmetric synthesis of tetrasubstituted stereocenters, because of the lack of a general method for the synthesis of enantioenriched trisubstituted allenes. With the exception of the synthesis of dihydrofurans by endo-selective hydroalkoxylation of allenes pioneered by Marshall and Pinney, and further developed by Krause and co-workers, there are only few isolated examples of such transformations. Our group has recently reported the synthesis of enantioenriched trisubstituted allenes by copper-catalyzed substitution of propargylic phosphates using alkyl boranes as nucleophiles. 18] As Scheme 2 illustrates, we were able to