Novel Glycosylation Methodologies Propelled by Ring-Strain Release

Novel Glycosylation Methodologies Propelled by Ring-Strain Release

The development of stereoselective chemical glycosylation reactions is pivotal in glycochemistry, enabling the preparation of biologically and pharmaceutically significant oligosaccharides and glycoconjugates as pure materials in adequate quantities with precise structures. Prof. Xue-Wei Liu’s research group at Nanyang Technological University is devoted to glycochemistry and glycobiology. And we have developed a series of glycosylation reactions inspired by original concepts, including the acceptor-controlled stereoselective glycosylation reaction and protection-less glycosylation reaction (key references: Acc. Chem. Res. 2018, 51, 628; Chem. Soc. Rev. 2019, 48, 4006.).

Organic molecules with strained ring structures serve as important synthons extensively employed in diverse chemical transformations. We recently developed a novel glycosylation reaction of armed thioglycoside donors promoted by a readily accessible thiophilic strained structure, i.e., donor-acceptor cyclopropane (DAC) (CCS Chem. 2023, 10.31635/ccschem.023.202202671.). A limitation of the reaction is that it proceeds with disarmed glycosyl donors only at elevated temperatures. Our attempts to apply this methodology to the synthesis of chitooligosaccharides employing disarmed thioglycoside donors derived from glucosamine, driven by our long-standing interest in amino sugars as potential antibacterial agents (Chem. Sci. 2020, 11, 3171.), suffered from paltry conversion rate. To extend the substrate scope of glycosylation reactions driven by ring-strain release, we envisioned that the reactivity of the donor could be enhanced by incorporating the DAC into the anomeric leaving group, rendering the nucleophilic ring-opening an intramolecular process. And we identified the ester-type donors, widely employed in chemical glycosylation reactions, as ideal targets for further methodology development.

Inspired and guided by the rational reaction design, we successfully synthesized a menagerie of DAC-bound glycosyl ester donors (glycosyl ortho−2,2-dimethoxycarbonylcyclopropylbenzoate, glycosyl CCBz), and accomplished the development of a new generation of strain-release glycosylation with these donors. The new generation glycosylation reaction shows multiple notable merits: 1. Excellent donor stability under ambient conditions, enduring storage for several months without decomposition or hydrolysis; 2. Facile activation under mild conditions, consuming a catalytic amount of Sc(OTf)3 to proceed and afford high product yields even for disarmed glycosyl donors; 3. Compatibility with a wide array of glycosyl donors, including imidate-type donors, glycosyl ortho-alkynylbenzoate donors, and thioglycoside donors, offering opportunities for one-pot orthogonal glycosylation; 4. Broad substrate scope and excellent functional group tolerance, particularly to acid-labile groups, due to the mild activating conditions. To our delight, the strain-release driven glycosylation reaction with glycosyl CCBz donors proved highly efficient for synthesizing complex oligosaccharides or glycoconjugates, as demonstrated by the smooth assembly of the chito-tetrasaccharide scaffold of Lipid IV on gram-scale.

More details of this work can be found here: “Efficient and versatile formation of glycosidic bonds via catalytic strain-release glycosylation with Glycosyl ortho−2,2-Dimethoxycarbonylcyclopropylbenzoate donors” in Nature Communications.

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