Activation of Glycosyl Sulfoxides

Various promoters for the activation of glycosyl sulfoxides have been introduced and are summarized in Table 4.4. 

Activation of glycosyl sulfoxides by heterogeneous acid catalysis using Nafion-H or sulfated zirconia has also been described [256],... 

Kahne glycosidation Preparation of 0-, S- or A/-glycosides via the activation of glycosyl sulfoxides. 234... 

The combination of dicyclopentadienylzirconium dichloride and silver perchlorate activates armed glycosyl sulfoxides in dichloromethane between -20 °C and room temperature, but only very simple acceptors were studied [335]. Other Lewis and Bronsted acids studied include the environmentally benign europium, lanthanum and ytterbium triflates [336], certain polyoxometallates [337], sulfated zirconia [338] and Nafion H [338]. 

Crich and Sun propose that path b predominates when the glycosyl acceptor is present during activation of the sulfoxide. However, they have evidence to suggest that when the sulfoxide is activated, prior to addition of the acceptor, the glycosyl triflate forms within minutes.17 This has important consequences in terms of the stereochemistry of the glycosidic linkage. 

Wipf, P, Reeves, J T, Glycosylation via Cp2ZrCl2/AgC104-mediated activation of anomeric sulfoxides, J. Org. Chem., 66, 7910-7914, 2001. 

An additional version of the two-stage activation used glycosyl sulfoxides to glycosylate thioglycoside acceptors [25-28]. The thioglycosides are then readily activated as sulfoxides using oxidation with m-chloroperbenzoic acid. 

Kahne has disclosed a rapid, one-pot approach for assembling the trisaccharide 133 found in the antibiotic ciclamycin 0 (134, Scheme 6.21) [68]. The strategy owes its success to a nuanced mechanistic understanding of the reactivity of glycosyl sulfoxides when activated by catalytic amounts of... 

The most common activator for the glycosyl sulfoxides is trifluoromethanesulfonic anhydride (triflic anhydride), which, in the absence of nucleophiles, rapidly and cleanly converts most sulfoxides into the corresponding glycosyl triflates in a matter of minutes at —78 °C in dichloromethane solution [86,280,315,316]. In the more extensively studied mannopyranose series, only the a-mannosyl triflate is observed by low-temperature NMR spectroscopy (Scheme 4.35) [280]. In the glucopyranose series, mixtures of a- and (1-triflates are observed, in which the a-anomer nevertheless predominates (Scheme 4.36) [280],... 

The presence of strongly nucleophilic groups in either the donor or the acceptor can be problematic in sulfoxide-type glycosylations when activation is conducted with triflic anhydride. The most common culprit is the amide group [340,341], which is illustrated by the formation of a dihydrooxazine when a 3-acetamido alcohol was employed as acceptor (Scheme 4.47) [342]. Self-evidently, acceptor-based problems of this type could be avoided by the preactivation of the sulfoxide with triflic anhydride. 

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],... 

The mild conditions employed for the activation of sulfoxides, and the high reactivity of the glycosyl donor, suggested that the method might translate well to the solid phase. Moreover, the nonpolar nature of the sulfoxide, triflic anhydride, and DTBMP (solution-based reagents) should enable them to partition effectively into a non-polar, polystyrene-based resin. 

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