Glycosylation Methods Using Thioglycosides and Related Derivatives as Glycosyl Donors

Various forms of thioglycosides are probably the most extensively studied glycosyl donors. As shown in Scheme 2, the functional group R' can vary to have a significant influence on the reactivity of the resultant thioglycosides as donors.

(A) Activation of thioglycosides

Activation of n-pentenyl glycosides .I

(C) Activation of glyca|s 8 I (D) Activation of glycosyl hemiacetals

OH X = thiophile; Ph = phenyl; Tf = trifluoromethylsulfonyl ro ^ Zncl ^ V<or-- r and r- = protecting group; R-'OH = glycosyl acceptor;

Scheme 2 Glycosylation method using thioglycosides, n-pentenyl glycosides, glycals, and glycosyl hemiacetals as glycosyl donors.

Therefore, through the modification of R', one can easily tune the reactivity of thioglycosides (39,40) to meet specific demands from a glycosylation or a synthetic design. Moreover, like glycosyl donors, thioglycosides are exceptionally stable, but they can be easily activated under special conditions. These properties make thio-glycosides very attractive in the synthesis of complex oligosaccharides and in the design of convergent synthetic strategies.

For the activation of thioglycosides, many thiophilic promoters have been developed (41), among which the most commonly used are methyl triflate (MeOTf), dimethyl-methylthiosulfonium triflate (DMTST) (42), N-iodosuccini-mide/triflic acid (NIS/TfOH) (43), iodonium dicollidine perchlorate (IDCP), and sulfenyl triflate or halides (44). Recently, Crich et al (45) have developed another useful promoter, 1-benzenesulfinyl piperidine and applied it to stereoselective formation of p-mannosides, which is difficult to achieve. Methyl, ethyl, phenyl, and p-methylphenyl thioglycosides are most commonly used glycosyl donors. Recently, p-methylphenyl thioglycosides have received significant attention in the development of innovative synthetic strategies (8,46). Heterocyclic aryl thio-glycosides have also been extensively explored. The 2-pyridyl thioglycosides introduced by Hanessian and coworkers (47) can be activated by "remote activation" with methyl iodide as the promoter. Demchenko and coworkers (48,49) have recently introduced benzoxazolyl and thiazolinyl thioglycosides that can be selectively activated by MeOTf or silver triflate (AgOTf) in the presence of alkyl thio-glycosides for stereoselective 1,2-cis-glycosylation and one-pot oligosaccharide synthesis (49).

After oxidation, thioglycosides were converted into glycosyl sulfoxides that can be activated by triflic anhydride (Tf2O) at low temperature, hence, offering another powerful glycosylation method by Kahne et al. (50). This method has been employed to synthesize complex oligosaccharides both in solution (51) and by solid-phase strategy (52). Its application has been further expanded by Crich et al. (53) in the synthesis of p-mannosides. The seleno analogues of thioglycosides are more reactive than thioglycosides, so they can be selectively activated under specific conditions (54).

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