Stereoselective Synthesis of Tertiary Ethers through Geometric Control of Highly Substituted Oxocarbenium Ions

Abstract

Oxocarbenium ions are intermediates in a number of synthetic processes including Prins cyclizations, [1] acid-mediated additions to acetals, [2] allyl group transfers, [3] and additions of carbonyls to electrophiles. [4] Stereocontrol in these transformations can be quite high as a result of the strong preference, calculated at approximately 2 kcalmol −1 , [5] for monosubstituted oxocarbenium ions to exist in E configurations. However, reports of geometric control for 1,1-disubstituted oxocarbenium ions are rare [6] because the steric difference between the alkyl groups is generally smaller than the steric difference between an alkyl group and a hydrogen atom. General models that predict the geometry of disubstituted oxocarbenium ions would be valuable for designing syntheses of natural products or natural-product-like libraries [7] that contain tertiary ether groups. Recently, our research group reported [8] that intramolecular nucleophilic additions to alkynyl-substituted oxocarbenium ions proceed with minimal stereocontrol to provide cis-and trans-2,6-disubstituted tetrahydropyrans. This unusual lack of stereo-control results from the approximate energetic equivalence of the E and Z oxocarbenium ions, which is a result of the small steric difference between an alkynyl group and a hydrogen atom (Scheme 1). Herein, we describe a rare application of carbon-hydrogen bond functionalization for stereoselective syntheses of molecules that contain fully substituted carbon atoms. The approach is based on the development of a model that is able to predict the geometries of 1,1-disubstituted oxocarbenium ions involved in nucleophilic additions that form tertiary ethers with high stereocontrol. We also report a model that illustrates stereocontrol in intramolecular additions to monosubstituted oxocarbenium ions relative to a tertiary ether.We postulated that 1,1-disubstituted oxocarbenium ions containing an alkyl group and an alkynyl group should exist in a conformation in which the two alkyl groups have a trans relationship in consideration of the minimal steric demands of alkynyl groups. We chose to employ a DDQ-mediated ether oxidation [9] protocol for carbocation formation to test this hypothesis because these conditions eliminate the potential for acid-induced solvolytic product decomposition [10] The synthesis of the ether linkage between the two branched carbon atoms in 2 (Scheme 2) was readily constructed by applying Yamamoto's Me 3 Almediated acetal opening protocol [11] to alkynyl acetal 1. Functional group manipulations provided the cyclization substrate 3, which was exposed to DDQ at room temperature and ** We thank the National Institutes of Health and the Institute of General Medicine (GM062924) for their generous support of this work. We thank Prof. Paul Wender for valuable discussions.