Coupling Via Glycosyl Halides

Koto and coworkers have developed a dehydrative coupling procedure employing the in situ generation of a glycosyl bromide intermediate (6, Scheme 4) [12,13]. In this procedure, a stoichiometric quantity of TMS-Br is introduced into a reaction mixture containing equimolar quantities of the 1-hydroxy glycosyl donor 1, the alcohol acceptor (R'OH), CoBr2, and tetrabutylammonium bromide. The glycosyl bromide 6, generated in situ, then proceeds to glycosylate the alcohol acceptor. Glycosyl bromides are well-established donors in the Koenigs-Knorr procedure [14], wherein these intermediates are typically isolated and activated with a halophilic promoter to

Scheme 4 Dehydrative glycosylations via glycosyl bromides [12,13,15]. * Using alternate method: MeSO3H, CoBr2, Et4NClO4.

effect glycosylation. However, the method of Koto and coworkers is distinct in that the intermediate 6 is both generated and consumed in situ under the reaction conditions, resulting in a net dehydration via a one-pot coupling process. The authors tentatively attribute the feasibility of this one-pot procedure to (1) the favorable effects of the 4 A molecular sieves acting both as a HBr scavenger and as a desiccant, and (2) the functioning of CoBr2 both as an effective desiccant and as a glycosyl bromide activator in the coupling stage with R'OH.

This procedure was used to glycosylate a number of alkyl alcohols with 2,3,4,6-tetra-O-benzyl-d-glucose, resulting in very good to moderate yields, depending on the complexity of the alcohol acceptor (e.g., 8-12). In these couplings, only trace amounts of products arising from hemiacetal self-coupling were detected, and the presence of Bu4NBr favored the formation of the a anomer of the product glycosides. It is worth noting that in an earlier related report, the reagent combination of [MeSO3H, CoBr2, Et4NClO4] was also employed by Koto to effect the desired de-hydrative glycosylation [15]. Under these reaction conditions, it is presumed that HBr is generated, leading to the formation of 6; however, this protocol generally led to diminished yields (e.g., 8 and 10) compared with the above-mentioned TMS-Br • CoBr2 procedure.

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