Direct Addition of Amides to Glycals Enabled by Solvation‐Insusceptible 2‐Haloazolium Salt Catalysis

Abstract

The direct 2-deoxyglycosylation of nucleophiles with glycals leads to biologically and pharmacologically important 2-deoxysugar compounds.A lthough the direct addition of hydroxyl and sulfonamide groups have been well developed, the direct 2-deoxyglycosylation of amide groups has not been reported to date.H erein, we show the first direct 2-deoxyglycosylation of amide groups using an ewly designed Brønsted acid catalyst under mild conditions.T hrough mechanistic investigations,w ed iscovered that the amide group can inhibit acid catalysts,a nd the inhibition has made the 2-deoxyglycosylation reaction difficult. Diffusion-ordered two-dimensional NMR spectroscopya nalysis implied that the 2-chloroazolium salt catalyst was less likely to form aggregates with amides in comparison to other acid catalysts.The chlorine atom and the extended p-scaffold of the catalyst played acrucial role for this phenomenon. This relative insusceptibility to inhibition by amides is more responsible for the catalytic activity than the strength of the acidity.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

A robust and tunable halogen bond organocatalyzed 2-deoxyglycosylation involving quantum tunneling

“…Specifically, we aim to harness and unravel noncovalent mechanisms unique to XB organocatalysis, so that enabling methodologies, which facilitates the preferential construction of challenging bonds over thiourea catalysis in biologically relevant molecules can be developed. In line with this aim, we have identified the biologically relevant 2-deoxyglycosylation as an ideal reaction model for the discovery for unknown XB catalytic mechanisms [46][47][48][49][50][51][52][53][54][55][56][57][58][59] . The unique poly-oxygenated nature of glycosyl substrates and products provides numerous XB acceptor moieties for the in situ catalytic establishment of dynamic noncovalent activations.…”

“…The unique poly-oxygenated nature of glycosyl substrates and products provides numerous XB acceptor moieties for the in situ catalytic establishment of dynamic noncovalent activations. Moreover, the synthetic importance of 2deoxyglycosides as a privileged and biologically useful compound class is well exemplified by the continual intense interest by many different research groups [46][47][48][49][50][51][52][53][54][55][56][57][58][59] , due to its prevalence in glycosidic natural products, such as digitoxin and saccharomicin B (ref. 46 ).…”

Urea‐catalyzed N‐Glycosylation of Amides/Azacycles with Glycosyl Halides

“…In 2018, Loh′s [60] research emphasized the use of ultra‐low thiourea catalysis for strain‐release glycosylation strategies. In parallel, Takemoto and co‐workers investigated organocatalytic techniques for N ‐glycosylation of amides, employing both glycosyl trichloroacetimidate [61] and glycals [62] . Despite these endeavors, there is a persistent demand for innovative and efficient strategies to couple glycosyl donors with N ‐nucleophiles.…”