Donor‐Bound Glycosylation for Various Glycosyl Acceptors: Bidirectional Solid‐Phase Semisynthesis of Vancomycin and Its Derivatives

Abstract

The glycosidation of a polymer-supported glycosyl donor, N-phenyltrifluoroacetimidate, with various glycosyl acceptors is reported. The application of the polymer-supported N-phenyltrifluoroacetimidate is demonstrated in the synthesis of vancomycin derivatives. 2-O-[2-(azidomethyl)benzoyl]glycosyl imidate was attached to a polymer support at the 6-position by a phenylsulfonate linked with a C13 alkyl spacer. Solid-phase glycosidation with a vancomycin aglycon, selective deprotection of the 2-(azidomethyl)benzoyl group, and glycosylation of the resulting 2-hydroxy group with a vancosamine unit were performed. Nucleophilic cleavage from the polymer support with acetate, chloride, azido, and thioacetate ions provided vancomycin derivatives in pure form after simple purification. The semisynthesis of vancomycin was achieved by deprotection of the acetate derivative.

Methods for 2-Deoxyglycoside Synthesis

“… 94 Later, both this group and the Doi and Takahashi group would apply a similar strategy in the solid-phase synthesis of vancomycin. 95 , 96 …”

“…The group further demonstrated the utility of this chemistry in coupling a monoglycosylated vancomycin derivative with a vancosamine fluoride to afford the fully protected natural product in 84% yield as a 8:1 (α:β) mixture of anomers . Later, both this group and the Doi and Takahashi group would apply a similar strategy in the solid-phase synthesis of vancomycin. , …”

“…94 Later, both this group and the Doi and Takahashi group would apply a similar strategy in the solid-phase synthesis of vancomycin. 95,96 Several other Lewis acids have been shown to activate deoxysugar fluorides, many of which have been developed for specific cases. For example, Suzuki and co-workers have demonstrated that Cp 2 HfCl 2 −AgClO 4 is an excellent promoter for the reaction between fluoride donors and phenolic glycosides.…”

The behaviour of deoxyhexose trihaloacetimidates in selected glycosylations

“…Thioglycosides and trichloroacetimidates are frequently used as glycosyl donors in oligosaccharide synthesis. Recently, structural analogues of glycosyl trichloroacetimidates, namely glycosyl N-phenyl trifluoroacetimidates, 4 were successfully used as novel glycosyl donors and exploited in the synthesis of biologically relevant oligosaccharide sequences such as Lewis X, 5 a Globo H moiety, 6 saponins glycolipids, 4c,7 glycosylated antibiotics 8 and fragments of several lipopolysaccharides. 9 Interestingly, in some cases the installation of the N-phenyl trifluoroacetimidate leaving group at the anomeric position of the glycosyl donor was demonstrated to be preferable: for example, the N-glycosylation of the amide group of some asparagine building blocks was firstly performed in high yields with glycosyl N-phenyl trifluoroacetimidates, whereas analoguous trichloroacetimidate donors gave unsatisfactory yields.…”

Synthesis of Cytimidine through a One-Pot Copper-Mediated Amidation Cascade

“…The sequential N- aryl amidation of bromopyrimidine 2b with 4-iodobenzamide 3 and oxazolidine carboxamide 4 gave an overall 53% yield. Masked cytimidine 11 was then subjected to the final deprotection sequences to give cytimidine in 34% overall yield in five steps from the commercially avaiable 4 chloro-2-methylthiopyrimidine.…”