Glycosyl triflate

P-Mannosides are difficult to introduce because the axial C-2 substituent of a mannosyl donor sterically and electronically disfavors nucleophilic attack from the P-face. P-Mannosides have been obtained by the direct substitution of a-glycosyl triflates, which are conveniently prepared by the treatment of an anomeric sulfoxide with triflic anhydride (Tf20) or thioglycosides with NIS (Scheme 4.3a)... 

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],... 

After the formation of glycosyl triflate, addition of an acceptor alcohol, still at low temperature, results in the rapid formation of the desired glycosidic bond. 

Scheme 4.35 Glycosyl triflate formation in the mannose series.

When triflic anhydride is added to a preformed mixture of glycosyl sulfoxide and acceptor alcohol, it seems apparent that the first formed oxacarbenium ion is directly trapped by the alcohol, without the need for the implication of glycosyl triflates [75,280,323],... 

Although glycosyl triflates have been demonstrated to be intermediates with a number of armed donors, and even with disarmed donors not capable of neighboring-group participation, such as the sulfonate esters, typical disarmed donors with esters in the 2-position function in the anticipated manner through anchimeric... 

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. 

Although the existence of glycosyl triflates has only been demonstrated for the triflic anhydride and benzenesulfenyl triflate promoter systems, presumably the same intermediates may be invoked on preactivation with other triflate-incorporat-ing systems such as TMSOTf (Scheme 4.42) [332] and triflic add (Scheme 4.43) [84,333]. 

Scheme 8 Glycosylation through transient glycosyl triflates.

In attempts to improve the yields of problematic glycosylation reactions, it has become clear that the mechanism is much more complex than Scheme 3.5 suggests. In essence, the oxycarbenium ion(V) is susceptible to attack by nucleophiles other than the glycosyl acceptor (Scheme 3.6). Two intermediates for which there is experimental evidence are glycosyl triflates(VII)17 and glycosyl sulfenates(IX).18... 

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. 

P selectivity. Crich and coworkers proposed that, under preactivation conditions, the oxocarbenium ion is trapped by a triflate anion to form the more stable a-triflate 65. After addition of the acceptor, the a-triflate intermediate can then be displaced in an SN2-like manner to afford a p-mannoside product (68). The formation of a-glycosyl triflates was confirmed by II, 13C, and 19F NMR analyses of the activated mannosyl donor recorded at low temperature [37], The experimentally determined KIE is approximately 1.12, which is consistent with an oxocarbenium-like TS [38], It was hypothesized that the a-triflate converts into the contact ion pair 66 in which the triflate anion remains at the a face or that an exploded TS is formed where the nucleophile is loosely associated with the oxocarbenium ion as the triflate departs [39,40], The a product 69 can be explained by the formation of the solvent-separated ion pair 67 where the counterion is solvated and facial selectivity is lost. 

IOB activated by triflic anhydride has been used to convert thioglycosides into 0-glycosides (disaccharides). The reaction probably proceeds via a glycosyl triflate intermediate [52] ... 

Crich, D, Sun, S, Direct chemical synthesis of 3-mannopyranosides and other glycosides via glycosyl triflates. Tetrahedron, 54, 8321-8348, 1998. 

Crich, D, Smith, M, 5 -(4-Methoxyphenyl) benzenethiosulfinate (MPBT)/trifluoromethanesulfonic anhydride a convenient system for the generation of glycosyl triflates from thioglycosides, Org. Lett., 2, 4067-4069, 2000. 

Crich, D, Smith, M, 1-Benzenesulfinyl piperidine/trifluoromethanesulfonic anhydride a potent combination of shelf-stable reagents for the low-temperature conversion of thioglycosides to glycosyl triflates and for the formation of diverse glycosidic hnkages, J. Am. Chem. Soc., 123, 9015-9020, 2001. 

NIS-TfOH method is thought to involve iodonation at sulfur, followed by replacement with triflic acid to give the highly reactive glycosyl triflate, which then serves as the glycosyl donor. 

Crich, D. Chemistry of glycosyl triflates Synthesis of P-mannopyranosides. J. Carbohydr. Chem. 2002, 21, 667-690. 

Kim and co-workers carried out a closely related synthesis of a /<-(l -4)-mannote-traose 300, using their method for the in situ conversion of hemiacetals to glycosyl triflates by means of reaction with phthalic anhydride ( phthalan ) followed by trifluoromethanesulfonic anhydride. In this instance cleavage of the benzylidene acetal was effected with trifluoroacetic acid, and regioselective reprotection of the diol employed benzoyl chloride (Scheme 50).145... 

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