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. Although 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. Herein, we show the first direct 2‐deoxyglycosylation of amide groups using a newly designed Brønsted acid catalyst under mild conditions. Through mechanistic investigations, we discovered that the amide group can inhibit acid catalysts, and the inhibition has made the 2‐deoxyglycosylation reaction difficult. Diffusion‐ordered two‐dimensional NMR spectroscopy analysis 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 π‐scaffold of the catalyst played a crucial role for this phenomenon. This relative insusceptibility to inhibition by amides is more responsible for the catalytic activity than the strength of the acidity.

Azolium/Hydroquinone Organo‐Radical Co‐Catalysis: Aerobic C−C‐Bond Cleavage in Ketones

“…As a starting point, we examined the oxidative C−C‐bond cleavage [17] of 2‐phenylcyclohexanone ( 1 a ) at ambient temperature in air (Table 1). Various phenol and naphthol derivatives were employed as electron donors to reduce the azolium‐based electron acceptor ( 4 a⋅TfOH ) [14b] (entries 1–5). To our delight, when 2‐naphthol ( 3 a ) was used as an electron donor, the C−C cleavage product 2 a was obtained as a single product, albeit in low yield (entry 1).…”

“…Moreover, the azolium salts 4 d⋅TfOH – 4 f⋅TfOH , which bear other substituents at the C2 position, furnished 2 a in 75–76 % yield (entries 8–10). Among the electron acceptors screened, we selected 4 c⋅TfOH as the optimal co‐catalyst based on its synthetic advantages, given that it can be readily synthesized in two steps from inexpensive commercial reagents [14b] . The expanded π‐scaffold of the azolium salts seems to be important, as the use of benzimidazolium salt 4 g⋅TfOH furnished 2 a in lower yield, while imidazolium salt 4 h⋅TfOH did not afford the desired product at all (entries 11 and 12).…”

Organocatalysis applied to carbohydrates: from roots to current developments

“…Recently, the organocatalysed N-glycosylation of amides, carbamates and ureas using glycals as glycosyl donors was reported. 52 The catalyst used was the haloazolium cation 147 that furnished the β-N-2-deoxygalacto-(148-151) and glucosides (152-155) in high yields and complete stereoselectivities for the galactoside series. In the case of glucals as donors, the…”

Reactions Catalyzed by 2-Halogenated Azolium Salts: From Halogen-Bond Donors to Brønsted-Acidic Salts

“…We also became interested in the further development and application of Brønsted-acidic salt catalysts and the origin of their good catalytic performance. Therefore, we subsequently focused on the 2-deoxyglycosylation of amides, 33 as the 2-deoxyglycosylation of asparagine residues could stabilize the peptide chain against enzymatic hydrolysis, which would result in enhanced biological activity and selectivity. 34 In addition, there have been no reports on the direct 2-deoxyglycosylation of simple amides, although the direct 2-deoxyglycosylation of hydroxy and sulfonamide groups has been extensively developed using various transition-metal catalysts and organocatalysts.…”