Stereoselectivity in Glycosylation with Deoxofluorinated Glucosazide and Galactosazide Thiodonors

Abstract

Control of anomeric stereoselectivity in glycosylation with deoxofluorinated glycosyl donors is critical for assembly of fluorinated oligosaccharides. Here, we report the synthesis of benzylated 3-fluoro and 4fluoro analogues of phenyl 1-thioglucosazide and galactosazide donors and evaluation of their stereoselectivity in glycosylation of a series of model carbohydrate acceptors using the Tf 2 O/Ph 2 SO promoter system. Lowtemperature NMR revealed formation of covalent α-triflate and both anomers of oxosulfonium triflates under selected glycosylation conditions. This study demonstrates how the stereoselectivity depends on acceptor reactivity and glycosyl donor configuration. Reactive acceptors favor formation of 1,2-transβ-glycosides with both D-gluco and D-galacto donors, whereas poorly reactive acceptors favor formation of 1,2-cis-α-glycosides with D-galacto donors but are unselective with D-gluco donors.

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

“…This instability of amino sugar hemiacetals underscores the requirement to both protect the anomeric position with a robust protecting group and to conduct final deprotection under neutral conditions. After initial experimentation with benzyl glycosides (Scheme 1, PG = OBn), phenyl thioglycosides (Scheme 1, PG = SPh), readily available from 1,6-anhydropyranoses [39] as we described earlier [40] were found to fulfill this requirement satisfactorily. Accordingly, the synthesis started from known fluorinated 1,6anhydro-2-azidohexopyranoses 7-13 (Scheme 2) [26,40].…”

“…After initial experimentation with benzyl glycosides (Scheme 1, PG = OBn), phenyl thioglycosides (Scheme 1, PG = SPh), readily available from 1,6-anhydropyranoses [39] as we described earlier [40] were found to fulfill this requirement satisfactorily. Accordingly, the synthesis started from known fluorinated 1,6anhydro-2-azidohexopyranoses 7-13 (Scheme 2) [26,40]. Reac-Scheme 2: Conversion of 1,6-anhydro derivatives into thioglycosides, and a possible mechanism for the formation of C-furanosides by ring contraction.…”

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide thiodonors

“…This instability of amino sugar hemiacetals underscores the requirement to both protect the anomeric position with a robust protecting group and to conduct final deprotection under neutral conditions. After initial experimentation with benzyl glycosides (Scheme 1, Pg = OBn), phenyl thioglycosides (Scheme 1, Pg = SPh), readily available from 1,6anhydropyranoses [39] as we described earlier [40] were found to fulfill this requirement satisfactorily. together with main C6-fluoro product 34, suggesting that starting fluorinated 2-azido-thioglucosides were significantly less prone to thiophenyl migration than 2-azido-thiogalactosides were.…”

“…This was convenient because thioglucosides 15 and 18 (vide infra) were available for deoxyfluorination only as enriched anomeric mixtures α/β ≥ 3.3:1 and any traces of the migration products were removed in the subsequent thioaglycone hydrolysis. Thioglycosides 14-17 and 19 were also O6-benzylated [40] and then hydrolyzed to hemiacetals 27-31 (Scheme 3).…”

“…Retrosynthetic analysis of the target fluoro analogs Accordingly, the synthesis started from known fluorinated 1,6-anhydro-2-azido-hexopyranoses 7-Scheme 2)[26,40]. Reaction of compounds 7-10 with phenyl trimethylsilyl sulfide (PhSTMS) and ZnI2 delivered phenyl thioglycosides 14-17[40]. 1,6-Anhydropyranoses 11 and 12 under these conditions produced the expected thioglycosides 18 and 19, respectively.…”