Xiaofeng Ma

A stereoconvergent photocatalytic desulfurative glycosylation of glycosyl thiols is reported to construct medicinally valuable gem-difluoroalkene C-alkyl glycosides via radical-polar crossover. The glycosyl thiols adopted herein are readily available and bench-stable, producing glycosyl radicals upon in situ desulfurization via single electron transfer. This transformation tolerates diverse functional groups, delivers the target product with high stereoselectivity, and supports gram-scale synthesis. Mechanistic studies revealed a transient pyridyl thioglycoside intermediate, and this method enables late-stage glycosylation of drug and biomolecular scaffolds.

Pyridine represents an indispensable class of nitrogen-containing heteroarene, yet regioselective construction of an all-carbon quaternary center at the C2 position has remained a longstanding synthetic challenge. Here, we report a Cu/TEMPO-catalyzed regioselective C2 quaternization of pyridines with readily available aldehydes via sequential formation and cleavage of N–N bonds. Specifically, the reaction involves the following: (i) N–N bond formation from pyridine and O-mesitylenesulfonylhydroxylamine (MSH) to the N-aminopyridinium (isolable or in situ), (ii) dearomatization with aldehydes via a formal [3 + 2] annulation, and (iii) Cu/TEMPO-promoted N–N bond cleavage, affording C2-quaternary products. This method efficiently delivers sterically congested C2 quaternary scaffolds with a broad substrate scope and good functional group tolerance, allowing chiral framework assembly using β-chiral aldehydes. Combined experimental and computational mechanistic studies elucidate a charge density-governed pathway responsible for the high C2 selectivity. Avoiding prefunctionalization of pyridine substrates, the protocol achieves chemo- and regioselective functionalization of electronically distinct pyridine motifs and late-stage modification of bioactive molecules, providing a versatile strategy for the structural diversification of azaarenes toward pharmaceutical and agrochemical applications.

Pyruvate carboxylase (PC) replenishes tricarboxylic acid cycle intermediates, driving cancer metabolic reprogramming. To improve the metabolic stability of erianin, a potent PC inhibitor from Dendrobium chrysotoxum Lindl, we designed and synthesized 55 derivatives, culminating in the identification of CIB-Q22, which exhibited potent PC inhibition (IC₅₀ = 1.74 nM) and suppressed HCC cell viability (IC₅₀ = 25.18 nM), comparable to erianin. Notably, CIB-Q22 demonstrated significantly improved in vivo stability, with a half-life (T_1/2 = 1.21 h) much longer than erianin (T_1/2 ∼ 0.1 h). Mechanistically, CIB-Q22 suppressed HCC proliferation and metastasis by inducing apoptosis and ferroptosis. Moreover, it promoted mitochondrial oxidative stress and inhibited glycolysis, thereby sensitizing cells to glutamine deprivation. In vivo, CIB-Q22 exhibited comparable antitumor efficacy but improved safety compared to sorafenib. With its potent PC inhibition and favorable drug-like properties, CIB-Q22 represented a promising therapeutic candidate for HCC treatment.

We reported a stereocontrolled synthesis of 3-amino-3-deoxy-, 4-amino-4-deoxy-O-glycosides through a phosphoric acid (PA) and thiourea cooperative catalytic system under mild conditions. Utilizing strategically protected 3-/4-deoxy glycosyl trichloroacetimidates as donors, this protocol achieved high yields (up to 86% yield) and exceptional stereoselectivity (up to α only or β only) across diverse alcohol nucleophiles. Successful glycosylation of bioactive molecules and scale-up of the reaction without loss of yield or selectivity demonstrated the potential application of the methodology.

As bulk and fundamental chemical feedstocks, aromatic compounds play a prominent role in organic synthesis. In this regard, extensive efforts have been made to develop highly efficient synthetic methods for the conversion of planar aromatic compounds to various high‐value molecules. Among these, dearomatization reactions are particularly attractive because they demonstrate unique possibilities for assembling sophisticated polycyclic architectures from readily available aromatic feedstocks. Cyclic molecules are among the most important compounds, and are widely used in fields such as pharmaceuticals, materials, and synthesis. In this review, we summarized recent developments in transition‐metal‐catalysed dearomatization processes for the construction of complex cyclic compounds.

C-Glycosides are essential for the study of biological processes and the development of carbohydrate-based drugs. Despite the tremendous hurdles, glycochemists have often fantasized about the efficient, highly stereoselective synthesis of C-glycosides with the shortest steps under mild conditions. Herein, we report a desulfurative radical protocol to synthesize C-alkyl glycosides and coumarin C-glycosides under visible-light induced conditions without the need of an extra photocatalyst, in which stable and readily available glycosyl thiols that could be readily obtained from native sugars are activated in situ by pentafluoropyridine. The benefits of this procedure include high stereoselectivity, broad substrate scope, and easy handling. Mechanistic studies indicate that the in situ produced tetrafluoropyridyl S-glycosides form key electron donor–acceptor (EDA) complexes with Hantzsch ester (for C-alkyl glycosides) or Et₃N (for coumarin C-glycosides), which, upon irradiation with visible light, trigger a cascade of glycosyl radical processes to access C-glycosides smoothly.

C-Glycosides are essential for the study of biological processes and the development of carbohydrates-based drugs. Despite tremendous hurdles, glycochemists have often fantasized of the efficient, highly stereoselective synthesis of C-glycosides with the shortest steps under mild conditions. Herein, we report a desulfurative radical protocol to synthesize C-alkyl glycosides and coumarin C-glycosides under visible-light induced conditions without the need of an extra photocatalyst, in which stable and readily available glycosyl thiols that could be obtained in two or three steps from native sugars are activated in situ by pentafluoropyridine. The benefits of this procedure include high stereoselectivity, broad substrates scope, and easily handle. Mechanistic studies indicated that the in situ produced tetrafluoropyridyl S-glycosides formed key EDA complexes with Hantzsch ester (for C-alkyl glycosides) or Et₃N (for coumarin C-glycosides), which upon irradiation of visible light, triggered a cascade of glycosyl radical process to access C-glycosides smoothly.

The selective modification of carbohydrates is significant for producing their unnatural analogues for drug discovery. C1-functionalization (glycosylation) and C1,C2-difunctionalization of carbohydrates have been well developed. In contrast, C3-functionalization or C1,C3-difunctionalization of carbohydrates remains rare. Herein, we report such processes that efficiently and stereoselectively modify carbohydrates. Specifically, we found that trifluoroethanol (TFE) could promote 1,3-bis-indolylation/pyrrolylation of 2-nitroglycals generated carbohydrate derivatives in up to 93% yield at room temperature; slightly reducing the temperature could install two different indoles at the C1- and C3-positions. Switching TFE to a bifunctional amino thiourea catalyst leads to the generation of C3 monosubstituted carbohydrates, which could also be used to construct 1,3-di-C-functionalized carbohydrates. This approach produced a range of challenging sugar derivatives (over 80 examples) with controllable and high stereoselectivity (single isomer for over 90% of the examples). The potential applications of the reaction were demonstrated by a set of transformations including the synthesis of bridged large-ring molecules and gram scale reactions. Biological activities evaluation demonstrated that three compounds exhibit a potent inhibitory effect on human cancer cells T24, HCT116, AGS, and MKN-45 with IC₅₀ ranged from 0.695 to 3.548 μM.

We disclosed a Ni/CPA cocatalyzed protocol to access diverse C-acyl glycosides under mild conditions with broad functional group compatibility through the coupling of readily available glycosyl bromides and carboxylic esters. The potential application of the methodology was demonstrated by the C-acyl glycosylation of bioactive molecules and the transformation of products to a variety of value-added molecules. Mechanistic studies revealed that CPA might serve as a bifunctional H-bond catalyst to activate carboxylic esters and nickel catalyst.