Efficient and versatile formation of glycosidic bonds via catalytic strain-release glycosylation with glycosyl *ortho*-2,2-dimethoxycarbonylcyclopropylbenzoate donors

Carbohydrates play crucial roles in various biological processes, leading to a high demand for glycans and glycoconjugates with defined structures. Catalytic glycosylation is a desirable approach for large-scale synthesis, minimizing promoter consumption and reducing side reactions and environmental concerns. While catalytic activation methods exist for various glycosyl donors (fluorides, imidates, epoxides, phosphates), many are highly reactive and moisture-sensitive. Glycosyl esters offer good stability but typically require superstoichiometric promoters. This research aims to design a stable glycosyl donor activated by a catalyst via a novel, non-covalent interaction mode, inspired by the success of gold-catalyzed glycosylation with glycosyl ortho-alkynylbenzoates. The strategy utilizes the inherent reactivity of donor-acceptor cyclopropanes (DACs), which readily undergo conjugate additions due to ring strain release. By incorporating a DAC structure into a glycosyl ester, the authors propose a dual-functional anchor: a metallophilic 1,3-dicarbonyl group for activation and an ensuing enolate to scavenge protons. This approach promises mild conditions, broad substrate scope, and the ability to form challenging glycosidic bonds.

The authors review existing catalytic glycosylation methods, highlighting their advantages and limitations. They discuss the use of different glycosyl donors, including glycosyl fluorides, imidates, epoxides, and phosphates, noting their reactivity and stability issues. They also examine existing catalytic activation methodologies for glycosyl esters, such as those employing superacids and gold catalysts. The limitations of these methods, including harsh reaction conditions, narrow acceptor scopes, and the use of expensive or toxic catalysts, are discussed. The authors then introduce the concept of using strained rings, specifically DACs, for enhanced reactivity in organic synthesis and their potential application in glycosylation. They note the lack of effective catalytic strain-release-driven glycosylation for obtaining natural sugar derivatives.

The researchers designed a glycosyl ortho-2,2-dimethoxycarbonylcyclopropylbenzoate (CCBz) donor. Synthesis of the CCBz donor involved coupling anomeric hemiacetals with ortho-2,2-dimethoxycarbonylcyclopropylbenzoic acid (CCBzOH) using EDC-HCl, DIPEA, and DMAP. The reaction conditions were optimized using glucosyl CCBz 1a and cholesterol 2a. Various Lewis acids were screened, with Sc(OTf)3 showing superior performance (96% yield of 3a and 99% yield of 4). The reaction was found to be highly selective for Sc(OTf)3 compared to other Lewis acids, demonstrating the orthogonality of the glycosyl CCBz donor with other glycosyl donor types. The molecular sieve (MS) type significantly impacted the yield, with 5 Å MS providing the best results. The optimal conditions were identified as: 1.2 equiv of donor, 1.0 equiv of acceptor, 0.1 equiv of Sc(OTf)3, 5 Å MS, and CH2Cl2 as the solvent. A control experiment with glucose pentabenzoate showed minimal product formation, confirming the unique activation mode of the CCBz donor. The scope of the reaction was then examined using diverse acceptors (aliphatic alcohols, sugar alcohols, carboxylic acids, phenols, and heteroatom nucleophiles) with glucosyl CCBz 1a, demonstrating high yields and β-selectivity. The synthesis of chitooligosaccharides was achieved through iterative glycosylation. Gram-scale synthesis of a Lipid IV tetrasaccharide was performed using a similar approach, highlighting the scalability of the method.

The study successfully developed a novel catalytic glycosylation method using glycosyl *ortho*-2,2-dimethoxycarbonylcyclopropylbenzoate (CCBz) donors. Sc(OTf)3 was identified as an efficient catalyst, activating the donor through a ring-strain release mechanism mediated by non-covalent interactions with the DAC moiety. The method showed high efficiency and versatility, enabling the formation of O-, S-, and N-glycosidic bonds with various acceptors under mild conditions. The method exhibited high β-selectivity. Importantly, the reaction showed minimal aglycone transfer, a common side reaction in glycosylation reactions with thioglycoside acceptors, making this an orthogonal method. The method's utility was demonstrated by the synthesis of structurally diverse chitooligosaccharide derivatives and the gram-scale synthesis of a Lipid IV tetrasaccharide, a potential target for antibiotic development. The findings demonstrate the potential of the CCBz glycosyl donor as a new generation of catalytically activable glycosyl donors for complex oligosaccharide synthesis.

The successful development of this catalytic glycosylation method addresses the limitations of existing approaches by offering a highly efficient and versatile method with broad substrate scope and mild reaction conditions. The use of a readily accessible and non-toxic Sc(III) catalyst is advantageous over other methods that use expensive or toxic catalysts. The minimal aglycone transfer observed with thioglycoside acceptors opens up opportunities for orthogonal glycosylation reactions, allowing for more complex oligosaccharide synthesis. The gram-scale synthesis of the Lipid IV tetrasaccharide highlights the practical applications of this method for large-scale synthesis of biologically important molecules. This contributes significantly to the field of carbohydrate chemistry, providing a powerful tool for the synthesis of complex glycans and glycoconjugates.

This research successfully developed a highly efficient and versatile catalytic glycosylation method using glycosyl CCBz donors. The method features mild reaction conditions, broad substrate scope, and minimal aglycone transfer, making it a valuable tool for the synthesis of complex oligosaccharides. The gram-scale synthesis of a Lipid IV tetrasaccharide demonstrates the scalability of this method. Future research could focus on exploring the scope of the reaction with even more diverse substrates and exploring the potential of this method in the synthesis of other biologically important molecules.

While the method demonstrates high efficiency and versatility, some limitations exist. The reaction's success may be substrate-dependent. Although various acceptors were explored, further testing is needed to fully define its scope and limitations. While the gram-scale synthesis of Lipid IV is a significant accomplishment, optimizing yields for certain substrates may be necessary for broader applicability.