Sulfoxide-based glycosylation reactions

A variety of other activating systems have been employed for the promotion of sulfoxide-based glycosylation reactions, but none have been studied to the same extent as the triflic-anhydride-mediated reaction [86]. One of the most potent activators, benzenesulfenyl triflate, a by-product of the activation with triflic anhydride, has been shown to bring about rapid conversion of sulfoxides into glycosyl triflates [280]. Unfortunately, this reagent is unstable and has to be prepared in situ from silver triflate and benzenesulfenyl chloride. 

The problem of the nucleophilicity of amides in glycosylation reactions is not limited to the sulfoxide method and has been shown to result in the formation of glycosyl imidates from intermolecular reaction with activated donors. It appears that this problem may be suppressed by the prior silylation of the amide [348,349]. Accordingly, it may be sufficient to operate the sulfoxide method with an excess of triflic anhydride when amides are present so as to convert all amides into O-triflyl imidates, which are then hydrolyzed on work-up. Despite these problems, several examples have been published of successful sulfoxide glycosylation reactions with acceptors carrying remote peptide bonds [344,345] and with donors coupled to resins via amide-based linkages [346,347], with no apparent problems reported. Sulfonamides and tertiary amides appear to be well tolerated by the sulfoxide method [340,350],... 

These direct glycosylations with non-conventional donors have so far met with only limited success. However, subtle modification of the reaction conditions might further enhance their efficiency to a generally useful level, as can be seen in the case of sulfoxide-based technology developed by Crich and coworkers. 

Sulfoxide-mediated intramolecular aglycone delivery has been conducted with a temporary linker formed in situ by the reaction of lanthanide triflates with the donor and acceptor-based alcohols (Scheme 4.66) [336], However, as the selectivities recorded were modest, it has to be assumed that intermolecular glycosylation was an important side reaction in this chemistry. 

The sulfoxide method was introduced by Kahne and coworkers,1 and was heralded as a new method for rapid glycosylation of unreactive substrates in high yield under mild conditions. The reaction involves the sulfoxide donor [sulfoxide (I)], an activating agent (usually triflic anhydride), a hindered, nonnucleophilic base (2,6-di-tert-butyl-4-mcthylpyridine, DTBMP) and a nucleophilic acceptor (most often an alcohol) (Scheme 3.1). The glycosylation of sterically hindered steroidal alcohols, phenols and the /V-glycosylation of an acetamide was reported (Table 3.1). 

Sulfoxides have also been used in the synthesis of nucleoside analogs (Scheme 3.2). Chanteloup and Beau reported the synthesis of ribofuranosyl sulfoxide 13 and its use in the glycosylation of a series of silylated pyrimidine and purine bases.7 Although 16 is not an anomeric sulfoxide, its reaction with cytosine derivative 17 is conceptually related.8... 

Based on these hndings, a mixture of the three monosaccharides (163,164 and 165) was treated with triflic acid, and the reaction resulted in the formation of a 25% yield of the trisaccharide (167) (Scheme 5.30). It was also shown that the more reactive sulfoxide (164) initially reacts with the more reactive acceptor (165) to form the disaccharide (166). In the second stage of the reaction the less reactive sUylated disaccharide (166) is glycosylated with the less reactive sulfoxide (163), giving the trisaccharide (167). 

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