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. 2019 Oct 23;141(42):16743-16754.
doi: 10.1021/jacs.9b07022. Epub 2019 Oct 9.

Matching Glycosyl Donor Reactivity to Sulfonate Leaving Group Ability Permits SN2 Glycosylations

Ming-Hua Zhuo  1 , David J Wilbur  1 , Eugene E Kwan  2 , Clay S Bennett  1
Affiliations

Matching Glycosyl Donor Reactivity to Sulfonate Leaving Group Ability Permits SN2 Glycosylations

Ming-Hua Zhuo et al. J Am Chem Soc. .

Abstract

Here we demonstrate that highly β-selective glycosylation reactions can be achieved when the electronics of a sulfonyl chloride activator and the reactivity of a glycosyl donor hemiacetal are matched. While these reactions are compatible with the acid- and base-sensitive protecting groups that are commonly used in oligosaccharide synthesis, these protecting groups are not relied upon to control selectivity. Instead, β-selectivity arises from the stereoinversion of an α-glycosyl arylsulfonate in an SN2-like mechanism. Our mechanistic proposal is supported by NMR studies, kinetic isotope effect (KIE) measurements, and DFT calculations.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(A) Classical approaches to Lewis acid-mediated glycosylation. (B) This work. LA = Lewis acid.
Figure 2
Figure 2
SN1–SN2 continuum in glycosylations. The KIE at C1 measures how early or late the transition state is, while the KIEs at C2 and C5 measure how much positive charge is present.
Figure 3
Figure 3
Computed glycosylation transition states (B3LYP-D3(BJ)/6-31G*/PCM(THF) at −60 °C). Lowest-energy transition structures with the sodium ion: (a) bound to the alkoxide (red), (b) bridging the alkoxide and the sulfonate (green), and (c) bound to the sulfonate (blue). The sodium ion is purple. A dimethyl ether is bound to the sodium. (d) The 106 transition states found spanned a wide range of energies and geometries. (The lowest-energy transition states depicted in parts a–c are circled.) (e) Most bridging (type b) transition states gave KIE predictions at C1 that were within experimental error (highlighted), while all type a and c structures were inconsistent with experiment.
Figure 4
Figure 4
More reactive donors require more electron-rich sulfonyl chloride activators. RRV = relative reactivity value.,
See this image and copyright information in PMC

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