Han Ding

Quaternary stereocenters on densely functionalized furanoside frameworks are challenging to construct with high chemo-, regio-, and stereocontrol, especially in the presence of nitrogen-containing motifs and multiple downstream diversification handles. Here, we disclose a sequence-programmed three-component radical carboamination of reverse exo-glycals that provides modular access to C4-quaternary furanosides through a distinct radical retrosynthetic logic. In this photoredox process, an N-centered radical adds to an electron-rich reverse exo-glycal to form a pseudo-anomeric radical, which is then intercepted by a Giese acceptor, enabling concomitant C–N and C–C bond formation in a single step. The protocol accommodates diverse N-radical precursors and electron-deficient alkenes, is further extendable to distinct pyranose- and furanose-derived reverse exo-glycals, supports late-stage glyco-functionalization of structurally complex molecules, and furnishes a spiro-glycosyl donor on preparative scale. Subsequent Vorbrüggen glycosylation enables divergent entry to structurally distinct spironucleosides. Preliminary biological profiling of these compounds reveals a modest antiviral signal against influenza A (PR8) at 50 μM, supporting the utility of this platform for probing underexplored spironucleoside chemical space. Mechanistic experiments support the proposed photoredox-mediated radical relay, while DFT studies provide a plausible basis for the contrasting reactivity of representative N-radical precursors. Collectively, this work offers a concise and programmable strategy for the synthesis of quaternary-center furanosides and their downstream spirocyclic derivatives from readily available carbohydrate feedstocks.

Antimicrobial resistance threatens both human health and economic stability, urgently demanding antibiotic-free infection strategies. This global crisis brings to the fore a central challenge in antimicrobial material design lying in reconciling potency with biocompatibility, a dilemma acutely epitomized by cationic amphiphilic materials, despite their longstanding therapeutic significance. To address this, we present a glyco-cloaked charge-masking strategy that converts an intrinsically toxic cationic scaffold into a biocompatible and multifunctional platform. By employing a deep-red aggregation-induced emission-active pyridinium scaffold, systematic glycosylation affords eight derivatives in acetyl-protected and deprotected forms. Glycosylation attenuates cationic charge exposure on nanoaggregates, dramatically reducing mammalian cell internalization, cytotoxicity, and hemolysis, while fully preserving robust photodynamic activity with efficient dual-type reactive oxygen species generation, alongside bacterial-targeting capability. Strikingly, the lead compound Man-PEBT enables precise intracellular bacterial imaging and on-demand photodynamic bacterial elimination in vitro and in vivo, concurrently demonstrating negligible myoblast toxicity and exceptional myogenesis compatibility, which redefines the functional scope of cationic materials. This work unites infection control with tissue support in a single platform and establishes glyco-cloaking as a transformative design strategy to bridge the critical efficacy–biocompatibility divide, offering a step toward a more sustainable bioeconomy and safer biomedicine.

Thioglycoside preactivation enables one-pot oligosaccharide assembly but relies on unstable sulfenyl chloride activators. We report a user-friendly manifold that forms sulfenyl chlorides in seconds from common thiols and N-chlorosuccinimide, with succinimide precipitating and the clear supernatant serving as a drop-in activator solution. The protocol tolerates the substrate scope, accommodating special stereoselective glycosylation reactions and iterative one-pot sequences. A concise synthesis of a human milk tetrasaccharide demonstrates rapid one-pot access to a biologically relevant motif.

We report the design, synthesis, and immunological evaluation of an Antrodia cinnamomea galactomannan library consisting of 11 oligosaccharides, with chain lengths ranging from 4 to 24 sugars. These oligosaccharides maintain a consistent composition of 75% mannose and 25% galactose, mirroring the key structural features of natural galactomannan. Notably, the library includes five tetrasaccharides and four octasaccharides, exhibiting all possible frameshift patterns of A. cinnamomea galactomannan, offering valuable materials for structure-activity relationship studies to explore the role of linking modes and domain effect. The synthesis of this library was achieved through a highly effective stereoselective α-galactosylation approach. Immunological evaluations revealed that octasaccharide 4 and its two subunit tetrasaccharides 7 and 10 exhibited potent immunoregulatory activities, demonstrating a notable domain effect. Preliminary mechanistic studies unveiled that these oligosaccharides exert their effects by suppressing mitogen-activated protein kinase signaling pathway. In addition, octasaccharide 4 uniquely attenuated nuclear factor κB pathway, highlighting its compound-specific mechanism and demonstrating a 1 + 1 > 2 effect.

Substituent functionalization of unprotected and partially protected carbohydrates with controlled regioselectivity remains challenging due to the difficulty in differentiating hydroxyl groups with similar reactivities. This study presents an efficient protocol for site-specific modification through a “two-stage,” regiodivergent polyol tagging and functionalization strategy. To achieve effective tagging, we developed two complementary Ag₂CO₃-ligand-based regimes that enable the regioselective sulfonylation of cis-diol and trans-diol in carbohydrates, controlled by simply toggling the presence of a [Pd] catalyst. Competition experiments and DFT simulations elucidated the underlying dual mechanisms accounting for the regioselectivity. [Pd] catalyst complexes to cis-diol as a bidentate ligand, enhancing the differentiated electrophilicities through stereoelectronic effects and preferentially activating the equatorial C3-OH groups. Conversely, without [Pd], the Ag­(I) complex switches the reaction position, directing sulfonylation to the axial hydroxyl within 1,2-cis-diol, a position that is typically kinetically inert under conventional conditions. And the Ag­(I) complex preferentially coordinates to cis-1,2-substituents on the sugar ring and selectively activates the C2-OH group. The sulfonylated products serve as versatile synthons for the following structural derivations and chemical glycosylations, facilitating efficient access to structurally unique rare sugars, deoxy- and aminosugar analogues, and complex oligosaccharides. This dual-catalytic approach provides a robust platform for precision carbohydrate engineering, advancing the synthesis of biologically relevant oligosaccharides and glycoconjugates.

Rare sugar-based thio(seleno)glycosides are synthetically and biologically important yet challenging-to-prepare synthons. We here present a novel approach to such constructs from readily available C-glycosides with photocatalyzed decarboxylative thio(seleno)etherification of redox-active uronates as the key transformation following a C1-to-C5 switch strategy. This protocol tolerates diverse substrates and various protecting groups, stereoselectively affording the desirable thio(seleno)glycosides in moderate-to-high yields. The power of this method is demonstrated by the successful assembly of a 1,7-S-linked trisaccharide composed of α-d-ido-heptopyranosyl units.

Four main classes of glyco-nanoplatforms that exploit multivalent carbohydrate–lectin interactions to enable targeted cancer therapy, biosensing, immunomodulation, and antimicrobial treatment.

2-Deoxy-β-glycosides are essential components of natural products and pharmaceuticals; however, the corresponding 2-deoxy-β-glycosidic bonds are challenging to chemically construct. Herein, we describe an efficient catalytic protocol for synthesizing 2-deoxy-β-glycosides via either IPrAuNTf₂-catalyzed activation of a unique 1,2-trans-positioned C2-S-propargyl xanthate (OSPX) leaving group or (PhO)₃PAuNTf₂-catalyzed activation of a 1,2-trans-C2-ortho-alkynylbenzoate (OABz) substituent of the corresponding thioglycosides. These activation processes trigger 1,2-alkyl/arylthio-migration glycosylation, enabling the synthesis of structurally diverse 2-deoxy-β-glycosides under mild reaction conditions. The power of this strategy is demonstrated by the first synthesis of the pentasaccharide chain corresponding to velutinoside A, which features gold(I)-catalyzed construction of four successive β-l-oleandrosidic bonds in both a convergent and a one-pot glycosylation manner. Mechanistic studies, including control experiments and deuterium-labeling experiments, emphasize the crucial role of the OSPX and the involvement of the gold(I)-activated C≡C triple bond during the glycosylation process. The low-temperature NMR experiments unveiled a unique dual-coordination pattern of the gold(I) catalyst to the thiocarbonyl group and the alkynyl group of the OSPX, initiating a 5-exo-dig cyclization process. Furthermore, density functional theory (DFT) simulations reveal the ligand-induced match-mismatch effect between leaving groups OSPX and OABz and gold catalysts IPrAuNTf₂ and (PhO)₃PAuNTf₂. The DFT simulations also suggest that the formation of 2-deoxy-β-glycosidic bonds occurs via the bottom-face attack of the acceptor to the oxocarbenium intermediate, which adopts a ⁴H₃ half-chair conformation, leading to an energetically favored, ⁴C₁-conformed intermediate Dβ that is stabilized by a hydrogen bonding interaction.

GlcNAc-1,6-anhydro-MurNAc is a key peptidoglycan elongation terminator of biological and medicinal importance. Herein, we present a concise approach to this molecule in 12 steps with an overall 25% yield using d-glucosamine as the sole starting material. Our synthesis features the formation of a 1,6-anhydro-MurNAc building block by an intramolecular glycosylation and the selective conversion of the phthalimido group of the MurNPhth moiety, paving the way for antibiotics with a new killing mechanism by targeting bacterial transglycosylase.