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Conventional methods for thioglycoside activation often rely on precious and toxic platinum group metals. Here, we report a catalytic glycosylation strategy employing diazo-thioglycoside donors activated by earth-abundant iron or photosensitizer-free blue light conditions. It confers orthogonal reactivity relative to most glycosyl donors, including widely used thioglycosides and alkyne-based donors, thereby enabling one-pot orthogonal synthesis of glycans.The Thorpe-Ingold-like effect drives the proximity of iron- or blue-light-generated carbenes to the sulfur atom of thioglycosides. This approach accommodates diverse protecting groups and nucleophiles. It applies to various glycosyl donors derived from glucose, mannose, galactose, rhamnose, xylose, lactose, 2-deoxyamino glucose, and furanose derivatives such as ribose and arabinose. Moreover, we demonstrate the robustness of this methodology through challenging 1,2-cis furanosides, late-stage modifications of biomolecules like cholesterol, and the drug simvastatin on a gram scale, along with the iterative synthesis of challenging hexasaccharides. 

ABSTRACT The stereocontrolled construction of 1,2‐cisfuranosidic linkages remains a challenge in carbohydrate chemistry, as existing approaches often require multistep donor synthesis, anomerically pure precursors, and harsh activation conditions that compromise generality. Conventional thioglycosides are bench‐stable donors; however, their activation typically requires strong acids and cryogenic conditions, resulting in poor chemoselectivity, diminished stereocontrol, and epimerization to thermodynamically controlled 1,2‐transisomers. Here, we disclose a metal‐ and photosensitizer‐free photochemical strategy in which blue light promotes the chemoselective photolysis of an S─N bond in a sulfenylnitrene precursor, generating sulfenylnitrene that chemoselectively activates conventional thioglycosides. Sulfenylnitrene shows unique reactivity towards thioglycosides and remains unreactive with non‐glycosyl thioethers. This neutral process circumvents classical S_N2‐type pathways, enabling Lewis‐acid‐free and highly stereoselective furanosylations across ribose, arabinose, xylose, and the particularly challenging 2‐deoxyribose systems. Mechanistic investigations reveal that the steric and electronic effects of the C5‐protecting group induce the stereoselectivity. The synthetic utility of this platform is demonstrated by the efficient construction of glycosylated bioactive molecules and a 1,2‐cisribopentasaccharide. Overall, this work introduces sulfenylnitrene‐mediated activation as a sustainable and broadly applicable strategy for stereocontrolled furanosylation, expanding the conceptual scope of sulfur‐based nitrene chemistry in selective bond construction. 

In this study, we investigate the reactivity of nitrous oxide (N₂O) with lithiated diarylmethylhydrazines, leading to the formation of diarylethanesviadinitrogen extrusion. 

Traditional glycosylation methods using thioglycosides often require harsh conditions or expensive metal catalysts. This study presents a more sustainable alternative by employing copper, an earth-abundant catalyst. We developed diazo-based thioglycoside donors that, through copper catalysis, undergo intramolecular activation to form glycosyl sulfonium ions, leading to the generation of oxocarbenium ions. This versatile approach efficiently accommodates a variety of O-nucleophiles, including primary, secondary, and tertiary, as well as complex bioactive molecules. It is compatible with various glycosyl donors and protecting groups, including superarmed, armed, and disarmed systems. Notably, the methodology operates orthogonally to traditional thioglycoside and alkyne donors and has been successfully applied to the orthogonal iterative synthesis of trisaccharides. Mechanistic insights were gained by studying the electronic effects of electron-donating (OMe) and electron-withdrawing (NO2) groups on the donors, offering a valuable understanding of the intramolecular reaction pathway. 

Given the prevalence of nitrogen-containing heterocycles in commercial drugs, selectively incorporating a single nitrogen atom is a promising scaffold hopping approach to enhance chemical diversity in drug discovery libraries. We harness the distinct reactivity of sulfenylnitrenes, which insert a single nitrogen atom to transform readily available pyrroles, indoles, and imidazoles into synthetically challenging pyrimidines, quinazolines, and triazines, respectively. Our additive-free method for skeletal editing employs easily accessible, benchtop-stable sulfenylnitrene precursors over a broad temperature range (−30 to 150°C). This approach is compatible with diverse functional groups, including oxidation-sensitive functionalities such as phenols and thioethers, and has been applied to various natural products, amino acids, and pharmaceuticals. Furthermore, we have conducted mechanistic studies and explored regioselectivity outcomes through density functional theory calculations. 

Abstract Herein, we present an approach for catalytic orthogonal glycosylation utilizing earth‐abundant copper carbenes. This method operates under mild conditions and employs readily accessible starting materials, including benchtop stable enynal‐derived glycosyl donors, synthesized at the gram scale. The reaction accommodates a variety of glycosyl acceptors, including primary, secondary, and tertiary alcohols. The enynal‐derived copper carbenes exhibit remarkable reactivity and selectivity, allowing for the formation of glycosidic linkages with different protecting groups and stereochemical patterns. This approach provides access to both 1,2‐cis‐ and ‐trans‐glycosidic linkages. The product stereoselectivity is independent of the anomeric configuration of the glycosyl donor, which also has orthogonal reactivity to widely used alkynes and thioglycoside donors. An iterative synthesis of a trisaccharide further demonstrates the application of this orthogonal reactivity. 

This study introduces a cascade approach that proceeds with an N–H insertion into an enynal-derived zinc–carbenoid, followed by an intramolecular aldol reaction to provide (2-furyl)-2-pyrrolidines with high diastereoselectivity (dr ≥ 98:2).