Self-promoted and stereospecific formation of N-glycosides

Abstract

A stereoselective and self-promoted glycosylation for the synthesis of various N-glycosides and glycosyl sulfonamides from trichloroacetimidates is presented. No additional catalysts or promoters are needed in what is essentially a two-component reaction. When α-glucosyl trichloroacetimidates are employed, the reaction resulted in the stereospecific formation of the corresponding β-N-glucosides in high yields at ambient conditions. On the other hand, when equatorial glucosyl donors were used, the stereospecificity decreased and resulted in a mixture of anomers. By NMR-studies, it was concluded that this decrease in stereospecificity was due to an, until now, unpresented anomerization of the trichloroacetimidate under the very mildly acidic conditions. The mechanism and kinetics of the glycosylations have been studied by NMR-experiments, which gave an insight into the activation of trichloroacetimidates, suggesting an S_Ni-like mechanism involving ion pairs. The scope of glycosyl donors and sulfonamides was found to be very broad including popular N-protective groups and common glycosyl donors of various reactivity. Peracetylated GlcNAc trichloroacetimidate could be used without the need for any promotors or additives and a tyrosine side chain was glycosylated as an N-glycosyl carbamate. The N-carbamates and the N-sulfonyl groups functioned as orthogonal protective groups of the N-glycoside and hence allowed further N-functionalization without risking mutarotation of the N-glycoside. The N-glycosylation was also performed on a gram scale, without a drop in stereoselectivity nor yield.

Scheme 1. Self-promoted O- and N-glycosylations.

Chart 1. Glycosyl donors used in this study.

Chart 2. Glycosyl acceptors employed for self-promoted N-glycosylations.

Scheme 2. General reaction scheme for the preparation of tosylcarbamates and nosylcarbamates.

Fig. 1. Observed conformations of N-glycosides determined from ¹H-NMR coupling constants.

Scheme 3. Glycosylations employing 2-deoxy-glycosyl TCA donors 4α and 4β.

Scheme 4. Synthesis of carbamates 18 and 19.

Scheme 5. Glycosylations of carbamates 18 and 19 with donors 1α and 1β.

Scheme 6. Orthogonal deprotection of tosyl-protected N-glycosides. Reaction conditions: (1) K₂CO₃ (2 equiv.), 0.02 M in MeOH, reflux, 4 h. (2) Zn (8 equiv.), 0.12 M in AcOH, 70 °C, 2 h. (3) TFA (20 equiv.), 0.03 M in CH₂Cl₂, rt, 8 h. (4) PhSiH₃ (4 equiv.), Pd(PPh₃)₄ (0.05 equiv.), 0.75 M in CH₂Cl₂, rt, overnight.

Scheme 7. Orthogonal deprotection of nosyl-protected N-glycosides. Reaction conditions (1) sodium p-toluenesulfinate (1.1 equiv.), Pd(PPh₃)₄ (0.1 equiv.), 0.012 M in MeOH/THF 1 : 2, rt, 1.5 h. (2) Zn (20 equiv.), 0.025 M in AcOH, rt, 0.5 h. (3) TFA (20 equiv.), 0.4 M in CH₂Cl₂, rt, o.n. ^aResulted in reduction of the Ns nitro group to the corresponding amine. ^bGlycosylation and deprotection carried out in a single step, 70% overall yield. ^cK₂CO₃ used as base. ^dKOH used as base.

Scheme 8. Gram-scale synthesis of 1-amino-1-deoxy-glycosides.

Scheme 9. Synthesis of glycopeptide model 32.

Scheme 10. Observed difference in the glycosylation behavior of glycosyl donors 1α and 1β. Conditions: T = 300 K 0.075 M in dry, neutralized CDCl₃ (passed through basic Al₂O₃) using 3 equiv. of acceptor 7.

Fig. 2. (A) Graphical illustration of the anomerization of 1β to 1α under the reaction conditions shown in Scheme 10. (B) Graphical illustration of the formation of either 20α or 20β during the anomerization of 1β. Mesitylene was used as an internal standard for concentration determination.

Scheme 11. Proposed complex favoring an S_N2-like reaction mechanism.

Scheme 12. Trapping of glycosyl cation by using acetonitrile as the solvent.

Scheme 13. Proposed intermediates during an S_Ni-like glycosylation with both α- and β-TCA glycosyl donors.