Dimethylformamide: an unusual glycosylation modulator.

The key steps in oligosaccharide synthesis are protectinggroup manipulation and stereoselective glycosylation. Various strategies have emerged to expedite glycosylation, and some of these strategies have been elaborated for automated solid-phase synthesis and one-pot cascade glycosylation. Most glycosylation strategies rely on traditional methods for stereochemical control over glycosidic-bond formation. Although such tactics work well for the formation of 1,2trans b-glycosidic bonds, there is no straightforward solution for the formation of a 1,2-cis a-glycosidic bond. Existing methods often require extensive optimization of the reaction conditions, including the selection of an ethereal solvent, a transition-metal-complex promoting system, a remote participating group, a silylidene protecting group, and a chiral or achiral accessory group at the C2 position, or the installation of a fluoride substituent at the C2 position. However, most of these methods require additional steps for the installation of a specific functionality and are therefore less convenient for routine synthesis. Herein, we report a simple and general a-glycosylation method in which N,Ndimethylformamide (DMF) is used as a modulating molecule to direct the stereochemical course of glycosylation. Further elaboration of this approach led to a practical a-selective procedure based on preactivation that is useful for the glycosylaton of both O-glycoside and thioglycoside acceptors. In a previous study of the chlorination of glycosyl hemiacetals, we observed that residual DMF in the glycosylation mixture promoted the formation of 1,2-cis a-glycosidic bonds. A search of the literature revealed that DMF has been utilized as a glycosylation solvent and as a component in the Vilsmeier–Haack reaction for glycosylations. Koto et al. reported the use of DMFas an additive to effect a-glycosylation; however, this protocol suffered from undesired glycosyl formate formation. Lemieux and Driguez employed DMF (20–30 vol%) as one component of a mixed solvent system in particular glycosylations; however, such reactions required 4 days to reach completion, and the role of DMF was not stated. We hypothesized that the activation of a thioglycoside generates an oxocarbenium ion pair, which upon trapping by nucleophilic DMF gives rise to an equilibriummixture of a-/b-glycosyl imidates. Assuming that the b imidate is more reactive than its a counterpart; subsequent coupling of the b imidate with an acceptor produces the desired a anomer as the major product (Scheme 1). Since DMF has a modulating function in the reaction, we coined the term DMF-modulated glycosylation strategy for this approach.