Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions

Abstract

Controlling the chemical glycosylation reaction remains the major challenge in the synthesis of oligosaccharides. Though 1,2-trans glycosidic linkages can be installed using neighboring group participation, the construction of 1,2-cis linkages is difficult and has no general solution. Long-range participation (LRP) by distal acyl groups may steer the stereoselectivity, but contradictory results have been reported on the role and strength of this stereoelectronic effect. It has been exceedingly difficult to study the bridging dioxolenium ion intermediates because of their high reactivity and fleeting nature. Here we report an integrated approach, using infrared ion spectroscopy, DFT computations, and a systematic series of glycosylation reactions to probe these ions in detail. Our study reveals how distal acyl groups can play a decisive role in shaping the stereochemical outcome of a glycosylation reaction, and opens new avenues to exploit these species in the assembly of oligosaccharides and glycoconjugates to fuel biological research.

Fig. 1. NGP and LRP in glycosylation reactions offers an opportunity to control the stereoselectivity of glycosylations.

Schematic representation of possible reactive intermediates in NGP (a) and LRP (b). P protection group, E–X promoter system, Nu nucleophile.

Fig. 2. S-phenyl donors equipped with ester protection groups on systematically varied positions on the ring.

a Glycosyl donors used for IRIS experiments and DFT computations. Donors 3–9 and 13–15 were converted into their corresponding sulfoxides prior for the IRIS experiments to improve the yield of the glycosyl cation generation. b Glycosyl donors used for chemical glycosylation reaction in solution.

Fig. 3. Infrared ion spectroscopy of glycosyl cations.

a Oxocarbenium ions and dioxolenium ions give different diagnostic peaks (in blue). Overview of a comparison of the computed IR-ion spectra (filled blue) and the measured IR-ion spectra (black line) of the glycosyl cations derived from glucosyl (b–d), mannosyl (e–g) and galactosyl (h–j) donors 1–9. Ring-opening of donors 3, 5, 6, and 9 have been presented as accessible structures, their exact conformation is presented in Supplementary Figs. 3, 5, 6, and 9 and coordinates presented in the Supplementary Data file.

Fig. 4. Overview of the workflow to map the relative stability of glycosyl dioxolenium- and oxocarbenium ions.

(1) Two rotamers are used to probe long-range participation: R1 makes it geometrically feasible to form dioxolenium ions, where R2 generates the free oxocarbenium ion. (2) The complete conformational space of the 6-membered rings was scanned by computing 729 prefixed structures per rotamer; A few canonical conformations (chair, half-chair, envelope, and boat) are depicted. (3) The associated energies were graphed on slices dividing the Cremer–Pople sphere; the CEL map of the R1 rotamer and CEL map of the R2 rotamer. (4) Based on the CEL maps of R1 and R2 the relative stability of both intermediates can be evaluated.

Fig. 5. CEL maps of selected glycosyl cations in which the local minima identified are shown with their respective energy.

Two acetyl ester rotamers (R1 and R2) were considered for all computed glycosyl cations generating two sperate CEL maps. All energies are as computed at PCM(CH₂Cl₂)-B3LYP/6-311G(d,p) at 213.15 K and expressed as solution-phase Gibbs free energy. CEL maps for C3-acetyl pyranosyl ions (a–c), C4-acetyl pyranosyl ions (d–f), C6-acetyl pyranosyl ions (g–i). j Table summarizing the relative energy of the dioxolenium and oxocarbenium ion conformers in the gas- and solution-phase.