Hydrogen atom transfer enabled acylsugar synthesis via cooperative copper and NHC catalysis

Abstract

In this study, we report a direct acylation method for saccharides, achieved through the combination of copper and N-heterocyclic carbene (NHC) catalysis. This modular Cu/NHC dual-catalysis system exhibits excellent tolerance toward diverse functional groups and broad substrate applicability, enabling the efficient synthesis of a series of acylsugars, including derivatives bearing structurally complex natural product scaffolds and pharmacologically relevant motifs. To further validate the practical utility of this transformation, we successfully applied it to the potent modification of β-elemene, a naturally occurring molecule with well-documented antitumor activity. Additionally, preliminary mechanistic investigations and density functional theory (DFT) calculations provide compelling support for a radical coupling pathway underlying this reaction.

---

Introduction

Acylsugars function as both intrinsic components and secondary metabolites in biological processes, where they not only play pivotal roles but also serve as valuable agents in food, drugs, and natural insecticides.^1,2 For instance, the glucose ester chaenomeloidin³ presents promising therapeutic prospects for the treatment of gastric cancer, offering a potential novel option for clinical intervention (Fig. 1a, left). Additionally, taraxiroside B⁴ is a natural compound isolated from Taraxacum officinale and exhibits potent inhibitory activity toward α-glucosidase. In agricultural and horticultural settings, herbicidin B⁵ functions as a herbicide that is primarily utilized to suppress weed growth and exhibits broad-spectrum weed-killing activity (Fig. 1a, right). In addition, chemists have reported several methods to optimize the pharmaceutical profiles of sugar-based drugs via acylation reactions.⁶ Thus, there is considerable importance in developing efficient and simple methods for the synthesis of acylsugars and their derivatives.

Fig. 1 (a) Significant acylsugars. (b) Reactive glycosyl intermediates. (c) Acylation of saccharides and carbonyl compounds. (d) HAT-enabled acylsugar synthesis.

Glycosyl compounds constitute a class of compounds where sugar moieties are covalently connected to aglycones specifically through glycosidic bonds.⁷ Beyond their intrinsic biofunctions, glycosyl compounds also serve as critical components in pharmaceutical development and food industry applications.⁸ Given their significance, glycosyl compound diversification is among the most important research topics in carbohydrate chemistry.⁹ Current studies on glycosylation reactions mainly involve four primary types of reactive intermediates: glycosyl cations, glycosyl metal complexes, glycosyl anions, and glycosyl radical species (Fig. 1b). When comparing these glycosylation strategies, glycosyl radical species have garnered significant attention owing to their high reactivity and relative stability.¹⁰ Research on the radical coupling of glycosyl precursors is currently mainly focused on C-glycosyl radical species, and important developments have been achieved by Molander,¹¹ Koh,¹² Niu,¹³ Diao,¹⁴ Shu,¹⁵ Ma,¹⁶ Chi,¹⁷ Ackermann,¹⁸ and Kong¹⁹ groups. However, reports on the diversification of glycosyl compounds via O-glycosyl radical processes remain scarce (Fig. 1b, right).

Acylation reactions²⁰ including those between carboxylic acids/derivatives and alcohols to yield esters constitute foundational transformations in both biological pathways and organic chemistry.²¹ It is noteworthy that acylsugars represent an important class of compounds, which are generally characterized by the esterification of carboxylic acids with the hydroxyl groups of saccharides. In addition, transition metal-catalyzed (TM = Cu, Fe, etc.) acylation reactions of saccharides with carbonyl compounds such as anhydrides and acyl chlorides have been well developed (Fig. 1c, left).²² In 2024, Ye²³ developed the asymmetric coupling of aryl aldehydes and alcohols to synthesize axially chiral diaryl ethers via NHC catalysis, in which only one example of sugar derivatives was explored. Recently, NHC-catalyzed chirality-controlled site-selective acylation of saccharides has been reported by Chi,²⁴ which did not involve the glycosyl radical process.

Given our long-standing focus on transition metal-catalyzed radical reactions,²⁵ including previous work on C–H bond functionalization via the hydrogen atom transfer (HAT) process,²⁶ we report here a direct intermolecular cross-dehydrogenative coupling of aldehydes with sugars via C–H/O–H bond activation under Cu/NHC radical catalysis (Fig. 1d). The key reaction step commences via single electron transfer (SET) from a Cu(I) species to deprotonated di-tert-butyl peroxide (DTBP), generating the tert-butoxy radical intermediate and a Cu(II) species. This tert-butoxy radical then abstracts a hydrogen atom from the OH group of sugar-derived substrates via the intermolecular HAT pathway, which results in the formation of an O-glycosyl radical intermediate. The reaction between the NHC-bound ketyl radical Int2 and the O-glycosyl radical ultimately affords the cross-coupling product, accompanied by the regeneration of the NHC catalyst to close the catalytic cycle. The solution-phase process is rather complex due to the presence of multiple radical intermediates and several potential radical reactions; however, we were fortunate to achieve the acylation coupling products in appreciable yields. These findings may serve as a stimulus for future investigations into direct intermolecular radical coupling reactions of sugars.

Results and discussion

Optimization of the reaction conditions

We initially investigated the cross-coupling between ((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol 1a and benzaldehyde 1b. Extensive optimization of the reaction conditions enabled us to validate a combination of CuPO₂Ph₂ (10 mol%), N3 (15 mol%), and DTBP (H1, 400 mol%), with 1,4-diazabicyclo[2.2.2]octane (DABCO) (350 mol%) in cyclohexane (1 mL) at 90 °C with stirring for 12 h, affording the acylsugar 1 in 74% isolated yield (Table 1, entry 1). Direct control experiments unequivocally demonstrated that both the copper-based catalyst and the HAT reagent functioned as obligate components in the reaction pathway (entries 2 and 3). Moreover, the yields were significantly reduced even without adding the NHC catalyst and base, respectively (entries 4 and 5). Other copper catalysts such as Cu(acac)₂ proved ineffective (entry 6 and Table S1). By contrast, nickel, iron, and cobalt sources were incompetent (entries 7–10). Several types of NHC catalysts and HAT reagents were also screened (Table 1, left). The replacement of the NHC catalyst with pyridine-containing ligands L1–L6 failed to improve the reaction outcomes (Table 1, right). Other tested bases such as Et₄NBr and pyridine led to inferior yields (entries 11 and 12 and Table S3). Increasing or decreasing the reaction temperature will affect the efficiency of the reaction (entries 13 and 14). However, extending or shortening the reaction time did not improve reaction efficiency (entries 15 and 16). In contrast, alternative solvents including DMA and CH₃CN were found to be unsuitable for this reaction (and Table S5).

Table 1 Optimization of the reaction conditions

Entry	Variation from standard conditions	Yield^a [%]
a Isolated yields are shown (average of 2 independent runs). Reaction conditions: 1a (0.2 mmol), 1b (0.4 mmol), catalyst (10 mol%), NHC (15 mol%), HAT reagent (400 mol%), and base (350 mol%) in cyclohexane (1.0 mL) at 90 °C for 12 h.
1	None	74
2	w/o CuPO2Ph2	No reaction
3	w/o DTBP	Trace
4	w/o N3	31
5	w/o DABCO	11
6	Cu(acac)2 instead of CuPO2Ph2	No reaction
7	Ni(COD)2 instead of CuPO2Ph2	No reaction
8	Fe(acac)3 instead of CuPO2Ph2	25
9	Ni(acac)2 instead of CuPO2Ph2	No reaction
10	Co(acac)2 instead of CuPO2Ph2	No reaction
11	Et4NBr instead of DABCO	Trace
12	Pyridine instead of DABCO	58
13	70 °C	Trace
14	110 °C	24
15	10 h	32
16	16 h	22

---

Substrate scope

The reactivity of various aldehydes was systematically evaluated under the optimized reaction conditions (Fig. 2). Aldehyde substrates bearing halogen substituents on the arene underwent smooth conversion, affording compounds 2–7 in moderate to good yields. The predominant isomeric configurations of compound 7 were unambiguously determined via X-ray crystallography. A broad range of aryl aldehydes with electron-deficient substituents including CF₃, OCF₃, phenyl, and ester groups on the arene efficiently yielded the target products (8–11). Furthermore, substrates featuring various alkyl moieties at the para-positions such as methyl, ethyl, tert-butyl, isopropyl, and cyclopropyl, as well as OMe and OPh groups were further investigated, yielding the corresponding products 12–22 in 58–81% yields. Overall, the electron-donating properties of substrates appear to have an obvious impact on the efficiency of this transformation. Notably, aryl aldehydes featuring multiple substituents on the aromatic ring (23–27) underwent this coupling reaction smoothly. Favorable coupling results were observed for heteroaromatic-substituted aldehydes with diverse functional groups or moieties, including thiophene (28–29), benzofuran (30), benzodioxan (31), and dihydrobenzofuran (32). Furthermore, naphthyl-, acenaphthenyl-, pyrenyl-, and biphenyl-substituted aldehydes (33–37) were also found to be compatible. Additionally, the dialdehyde underwent successful simultaneous glycosidation, with compound 38b serving as a representative example. However, alkyl aldehydes were not suitable for this reaction system.

Fig. 2 Scope of aldehydes. Isolated yields are provided (average of 2 independent runs). Reaction conditions: 1a (0.2 mmol), aldehyde (0.4 mmol), CuPO₂Ph₂ (10 mol%), N3 (15 mol%), H1 (400 mol%) and DABCO (350 mol%) in cyclohexane (1.0 mL) at 90 °C for 12 h.

Subsequent efforts focused on exploring the scope of saccharide partners. As shown in Fig. 3, all the tested saccharides afforded acylation products that retained the original stereoselectivity and were isolated as single anomers. First, α-D-xylofuranose-derived substrates bearing a variety of protecting groups such as silane, Bn, Bz, and Tr underwent this acylation smoothly (39–42). Here, we demonstrate that both diacetone-D-glucose and diacetone-D-alose undergo radical acylation, yielding α-selective products (43–45) in moderate to good yields. When diacetone-D-mannofuranose was subjected to this reaction, the acylated mannofuranose product 46 was obtained with high selectivity. Then, protected pyranosides were studied to evaluate the reactivity and selectivity. Benzyl-protected D-glucopyranoside yielded product 47 with 27% yield. The D-fructopyranose-derived product (48) could also be prepared via this method with good efficiency. Moreover, the D-galactopyranose derivative (49) was also found to be compatible with this reaction, enabling the efficient synthesis of stereo-controlled acylation products. Carbohydrates and derivatives such as diacetone D-fructose (50) and diacetone L-sorbose (51) proved to be viable coupling partners. Notably, the disaccharide (52) was also found to be a suitable substrate, albeit with a slightly lower yield.

Fig. 3 Scope of sugars and modification of structural compounds. Isolated yields are reported. All products observed and isolated occur as single anomers. Reaction conditions: sugar (0.2 mmol), aldehyde (0.4 mmol), CuPO₂Ph₂ (10 mol%), N3 (15 mol%), H1 (400 mol%) and DABCO (350 mol%) in cyclohexane (1.0 mL) at 90 °C for 12 h.

Next, we further employed benzaldehyde as a “bridge” to mediate the linkage between alkyl alcohols and glycosides via this methodology, thereby enabling the post-modification of natural products and pharmaceuticals (Fig. 3, bottom). Notably, all the substrates investigated in this study successfully underwent the target transformation, affording the corresponding products in moderate to good yields (53–62). For instance, naturally occurring alkyl alcohols such as carveol (53), menthol (54), perillol (56), farnesol (60), geraniol (61), and phytol (62) were validated as competent substrates, yielding the target adducts with synthetically useful efficiency. Moreover, medicinal raw materials and synthetic fragrances including majantol (55), ribofuranoside (57), crotyl alcohol (58), and cholesterol (59) were confirmed to be viable substrates. These substrates enabled the synthesis of the desired adducts with yields that are synthetically useful, further verifying the method's compatibility with structurally diverse molecules.

Synthetic applications

β-Elemene is a sesquiterpene isolated from the rhizome of Curcuma wenyujin.²⁷ Commercially available anti-cancer drugs have been well developed from β-elemene (Fig. 4a).²⁸ Notably, β-elemene exhibits poor water solubility, necessitating formulation as liposomes, while its antitumor activity remains moderate. Consequently, targeted structural modifications are warranted to improve its physicochemical properties and enhance its antitumor efficacy. As depicted in Fig. 4b, our glycosidation approach exhibited excellent compatibility with a diverse range of fructoses and pyranoses (64–74) during their coupling with the β-elemene-derived aldehyde (63). Specifically, the disaccharide substrate generally afforded a moderate coupling yield (71). Furthermore, the coupling of 63 with various sugar-conjugated pharmaceutical intermediates or natural products proceeded efficiently, as exemplified by compounds 65 and 68.

Fig. 4 Synthesis of glycoside derivatives containing β-elemene. Isolated yields are reported. Standard conditions: sugar (0.2 mmol), 63 (0.4 mmol), CuPO₂Ph₂ (10 mol%), N3 (15 mol%), H1 (400 mol%) and DABCO (350 mol%) in cyclohexane (1.0 mL) at 90 °C for 12 h.

Having successfully synthesized the β-elemene glycoside compounds (64–74), we proceeded to evaluate their in vitro antitumor activities against two tumor cell lines: HCT116 (colon cancer cells) and A549 (lung cancer cells), as shown in Table 2.²⁹ Compounds 68 and 73 (entries 5 and 10, respectively) both showed lower half-maximal inhibitory concentration (IC₅₀) values against these two tumor cell lines than the positive controls β-elemene and its aldehyde intermediate 63 (entries 12 and 13). Notably, compound 73 exhibited over 2-fold higher activity than β-elemene in the HCT116 cell line, with IC₅₀ values of 107.0 µM and 218.1 µM, respectively. Similarly, in the A549 cell line, compound 73 showed approximately 6.5-fold greater activity compared to β-elemene, with corresponding IC₅₀ values of 58.1 µM and 378.0 µM, respectively. The above findings demonstrate that compound 73 exhibits significantly stronger antiproliferative activity than the positive controls. This not only confirms that the introduction of the glycosyl moiety has effectively enhanced the antitumor efficacy of β-elemene but also validates the feasibility of our cross-coupling strategy for the structural modification of β-elemene in subsequent studies.

Table 2 Antiproliferative activities of compounds against two cancer cell lines^a

Entry	Compound	IC50 (μM) S549	IC50 (μM) HCT116
a The in vitro antiproliferative activity of the synthesized compounds was tested against two cancer cell lines including A549 and HCT116 using CellTiter-Glo. Data are presented as mean ± standard deviation of n = 5 independent experiments.
1	64	>1500	>1500
2	65	>1500	>1500
3	66	401.4 ± 8.1	304.3 ± 29.0
4	67	>1500	>1500
5	68	198.5 ± 27.2	217.8 ± 41.5
6	69	463.6 ± 23.5	336.7 ± 21.6
7	70	>1500	>1500
8	71	320.6 ± 18.4	290.7 ± 57.5
9	72	473.9 ± 12.2	282.6 ± 43.7
10	73	107.0 ± 3.3	58.1 ± 3.9
11	74	>1500	>1500
12	63	213.5 ± 14.3	294.4 ± 41.1
13	β-Elemene	218.1 ± 9.2	378.0 ± 24.4

---

Mechanistic consideration

To highlight the potential utility of this strategy for scalable applications, a gram-scale reaction was carried out, which led to the synthesis of coupling product 1 with a yield of 41% (Fig. 5-1). Next, a series of control experiments were performed to gain deeper insights into the specific details of the reaction. To verify the possible radical mechanism, radical scavengers were incorporated into the acylation reaction under standard conditions (Fig. 5-2). Consequently, the yield of 1 was directly affected by 2,2,6,6-tetramethyl-1-oxylpiperidine (TEMPO) in both the presence and absence of 1b (eqn (1)), and the TEMPO-trapped species 75 was detected by NMR and LC-MS.³⁰ Similar results could be observed in the reaction using 2,6-di-tert-butyl-4-methylphenol (BHT) (eqn (2)). Furthermore, the TEMPO-trapped compound 77 and the Giese reaction product 78 were detected via LC-MS analysis when TEMPO and ethene-1,1-diyldibenzene were added, respectively (eqn (3)), in which 1b was separately present in the reaction. The above results collectively support the inference that a radical–radical coupling mechanism is likely involved in this reaction. Moreover, no coupling product was observed from the reaction of 1a and 1b under aerobic conditions (eqn (4)), which directly confirms that the reaction is sensitive to oxygen. Finally, comparative experiments show that epoxy heterocyclic compounds with simple structures were applicable to this reaction.³⁰

Fig. 5 (1) Gram-scale reaction. (2) Control experiments. (3) DFT calculations. Calculated at the M06/2X-PBE0-D3/Def2SVP4-PCM(DME)//B3LYP-D3/6-31+g(d,p)-SDD-PCM(DME) level of theory, kcal mol⁻¹.

Density functional theory (DFT) calculations were conducted to gain deeper insights into the underlying reaction mechanism.³⁰ The energy barrier for the hydroxyl group of furanose 1a to undergo HAT (TSb, ΔG^‡ = 12.8 kcal mol⁻¹) is significantly lower than that for the α-C–H bond of 1a (TSa, ΔG^‡ = 15.0 kcal mol⁻¹) in the presence of a tert-butoxy radical, indicating that OH is more susceptible to attack by the tert-butoxy radical and thus undergoes HAT (Fig. 5-3a). The obtained O-glycosyl radical 1aa could undergo further 1,5-HAT (TSc) to generate the α-C-glycosyl radical 1aa′, with an energy barrier of only 10.1 kcal mol⁻¹. This indicates that the α-C–H bond of 1a could serve as a potential radical coupling site; however, we did not find the relevant evidence in this reaction system. In addition, DFT results showed that the energy barrier for the generation of TS4 from benzaldehyde 1bvia a HAT process is only 9.8 kcal mol⁻¹, and the exothermic generation of the aldehyde radical 1ba is −13.1 kcal mol⁻¹ (Fig. 5-3b).

It is worth noting that these two generated radicals (1aa and 1ba) may rapidly couple to create product 1, which is consistent with the results of control experiments (Table 1, entry 4). The relaxation scan along the C–O bond in product 1 shows a monotonic increase in energy (Fig. 5-3c), indicating that the coupling process between 1aa and 1ba is barrier-free. This is mainly because both generated radicals are highly reactive.

Consequently, the coupling reaction primarily follows the NHC catalytic pathway. The potential energy surface (PES) of the reaction is depicted in Fig. 5-3d. First, NHC and benzaldehyde 1b undergo nucleophilic addition to generate carbene intermediates (TS1, ΔG^‡ = 23.3 kcal mol⁻¹). The occurrence of this process under the current reaction conditions indicates the feasibility of its kinetics. The in situ generated Breslow intermediate TS1 undergoes deprotonation in the presence of a base, yielding carbene species Int 1. Next, Cu(II)-mediated SET occurs on Int 1, resulting in the formation of Int2 and Cu(I). The generated carbene species Int2 exhibits a Gibbs free energy of 0.6 kcal mol⁻¹. Thereafter, the coupling of Int2 with radical 1aa is characterized by an activation energy barrier of 15.9 kcal mol⁻¹, which validates that the radical coupling process is kinetically accessible. The transformation of TS2 (ΔG^‡ = 16.5 kcal mol⁻¹) into Int3 (ΔG^‡ = −37.2 kcal mol⁻¹) is accompanied by significant heat release. Then, NHC is removed from Int3 to afford the glycoside intermediate (TS3, ΔG^‡ = −35.8 kcal mol⁻¹) with an energy barrier of 1.4 kcal mol⁻¹, which is indicative of a notably fast NHC release kinetics. Ultimately, the formation of product 1 (ΔG^‡ = −61.4 kcal mol⁻¹) is accompanied by significant heat release. Notably, computational results demonstrate that the generation of tert-butoxy radicals from DTBP and Cu(I) via SET is thermodynamically feasible (ΔG^‡ = −13.8 kcal mol⁻¹). Then, the Cu(II) species was reduced by the Breslow intermediate Int1 to produce Cu(I) and the NHC-bound ketyl radical Int2 in the presence of DABCO, closing the cycle (ΔG^‡ = −2.7 kcal mol⁻¹).

Conclusions

In conclusion, we report an efficient Cu/NHC catalytic system for the synthesis of acylsugars through a HAT/radical–radical coupling process. This reaction exhibits excellent functional group tolerance and a broad substrate scope and is applicable to diverse substituted substrates, including a range of aryl aldehyde-derived natural products and pharmaceutical molecules. Notably, this work offers a practical tool for the modification of the antitumor natural medicine β-elemene via the facile introduction of glycoside moieties. Preliminary biological activity experiments support the notion that the developed synthetic method may serve as a robust driving force for investigations in medicinal chemistry and chemical biology. Results from mechanistic experiments and DFT calculations indicate that saccharides generate O-glycosyl radicals in situ, which subsequently engage in the NHC-catalyzed cycle. Current efforts in our laboratory focus on the further application of this reaction, alongside in-depth mechanistic investigations and extended biological evaluations of the synthesized products.

Author contributions

Y. T. performed the experiments. Y. X. synthesized the substrates. Y. Y. supervised the project and composed the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

All experimental data and detailed procedures are available in the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d6qo00128a.

CCDC 2434524 contains the supplementary crystallographic data for this paper.³¹

Acknowledgements

This work was supported by the funding of NSFC (22401068) and the Medical Health Science and Technology Project of the Zhejiang Provincial Health Commission (2024KY237).

References

1. S. S. Shivatare, V. S. Shivatare and C. H. Wong, Glycoconjugates: Synthesis, Functional Studies, and Therapeutic Developments, Chem. Rev., 2022, 122, 15603–15671.
2. Y.-R. Lou, T. M. Anthony, P. D. Fiesel, R. E. Arking, E. M. Christensen, A. D. Jones and R. Last, It happened again: Convergent evolution of acyl glucose specialized metabolism in black nightshade and wild tomato, Sci. Adv., 2021, 7, eabj8726.
3. H. F. Quan, L. L. Zang, M. Ma, L. Dong and X. Y. Fu, Chemical Constituents from Populus tomentosa Leaves and Their Anti-Cancer Activity, Chem. Nat. Compd., 2023, 59, 920–925.
4. J. Choi, K. D. Yoon and J. Kim, Chemical constituents from and their α-glucosidase inhibitory activities, Bioorg. Med. Chem. Lett., 2018, 28, 476–481.
5. S. Ichikawa, S. Shuto and A. Matsuda, The First Synthesis of Herbicidin B. Stereoselective Construction of the Tricyclic Undecose Moiety by a Conformational Restriction Strategy Using Steric Repulsion between Adjacent Bulky Silyl Protecting Groups on a Pyranose Ring, J. Am. Chem. Soc., 1999, 121, 10270–10280.
6. (a) S. Ashibe, K. Ikeuchi, Y. Kume, S. Wakamori, Y. Ueno, T. Iwashita and H. Yamada, Non-Enzymatic Oxidation of a Pentagalloylglucose Analogue into Members of the Ellagitannin Family, Angew. Chem., Int. Ed., 2017, 56, 15402–15406; (b) A. Richieu, P. A. Peixoto, L. Pouységu, D. Deffieux and S. Quideau, Bioinspired Total Synthesis of (−)-Vescalin: A Nonahydroxytriphenoylated C-Glucosidic Ellagitannin, Angew. Chem., Int. Ed., 2017, 56, 13833–13837.
7. M. J. McKay and H. M. Nguyen, Recent Advances in Transition Metal-Catalyzed Glycosylation, ACS Catal., 2012, 2, 1563–1595.
8. (a) J. J. Lundquist and E. J. Toone, The Cluster Glycoside Effect, Chem. Rev., 2002, 102, 555–578; (b) E. Bokor, S. Kun, D. Goyard, M. Toth, J. P. Praly, S. Vidal and L. Somsak, C-Glycopyranosyl Arenes and Hetarenes: Synthetic Methods and Bioactivity Focused on Antidiabetic Potential, Chem. Rev., 2017, 117, 1687–1764.
9. (a) K. Kitamura, Y. Ando, T. Matsumoto and K. Suzuki, Total Synthesis of Aryl C-Glycoside Natural Products: Strategies and Tactics, Chem. Rev., 2018, 118, 1495–1598; (b) Y. Jiang, K. Yang, Y. Wei, Q. Wang, S.-J. Li, Y. Lan and M. J. Koh, Catalytic Multicomponent Synthesis of C-Acyl Glycosides by Consecutive Cross-Electrophile Couplings, Angew. Chem., Int. Ed., 2022, 61, e202211043; (c) B. Liu, D. Liu, X. Rong, X. Lu, Y. Fu and Q. Liu, Ligand-Controlled Stereoselective Synthesis of 2-Deoxy-β-C-glycosides by Cobalt Catalysis, Angew. Chem., Int. Ed., 2023, 62, e202218544.
10. Y. Jiang, Y. Zhang, B. C. Lee and M. J. Koh, Diversification of Glycosyl Compounds via Glycosyl Radicals, Angew. Chem., Int. Ed., 2023, 62, e202305138.
11. S. O. Badir, A. Dumoulin, J. K. Matsui and G. A. Molander, Synthesis of Reversed C-Acyl Glycosides through Ni/Photoredox Dual Catalysis, Angew. Chem., Int. Ed., 2018, 57, 6610–6613.
12. Q. Wang, B. C. Lee, N. Song and M. J. Koh, Stereoselective C-Aryl Glycosylation by Catalytic Cross-Coupling of Heteroaryl Glycosyl Sulfones, Angew. Chem., Int. Ed., 2023, 62, e202301081.
13. L. Q. Wan, X. Zhang, Y. Zou, R. Shi, J. G. Cao, S. Y. Xu, L. F. Deng, L. Zhou, Y. Gong, X. Shu, G. Y. Lee, H. Ren, L. Dai, S. Qi, K. N. Houk and D. Niu, Nonenzymatic Stereoselective S-Glycosylation of Polypeptides and Proteinss, J. Am. Chem. Soc., 2021, 143, 11919–11926.
14. Y. Wei, B. Ben-Zvi and T. Diao, Diastereoselective Synthesis of Aryl C-Glycosides from Glycosyl Esters via C−O Bond Homolysis, Angew. Chem., Int. Ed., 2021, 60, 9433–9438.
15. H. Xie, S. Wang and X.-Z. Shu, C−OH Bond Activation for Stereoselective Radical C-Glycosylation of Native Saccharides, J. Am. Chem. Soc., 2024, 146, 32269–32275.
16. D. Xie, W. Zeng, J. Yang and X. Ma, Visible-light-promoted direct desulfurization of glycosyl thiols to access C-glycosides, Nat. Commun., 2024, 15, 9187.
17. X.-Y. Ye, G. Wang, Z. Jin, B. Yu, J. Zhang, S. Ren and Y. R. Chi, Direct Formation of Amide-Linked C-Glycosyl Amino Acids and Peptides via Photoredox/Nickel Dual Catalysis, J. Am. Chem. Soc., 2024, 146, 5502–5510.
18. J. Wu, R. Purushothaman, F. Kallert, S. L. Homölle and L. Ackermann, Electrochemical Glycosylation via Halogen-Atom-Transfer for C-Glycoside Assembly, ACS Catal., 2024, 14, 11532–11544.
19. (a) S. Xu, Y. Ping, M. Xu, G. Wu, Y. Ke, R. Miao, X. Qi and W. Kong, Stereoselective and site-divergent synthesis of C-glycosides, Nat. Chem., 2024, 16, 2054–2065; (b) Z. Zhou, Y. Ai, S. Xu, X. Lin, Y. Ping and W. Kong, Stereoselective Synthesis of Glycomimetics by Photocatalytic One-Pot C(sp3)-H Acylation and Ring Contraction, Angew. Chem., Int. Ed., 2025, 64, e202510594.
20. L. L. Fang, L. Xiao, Y. W. Jun, Y. Onishi and E. T. Kool, Reversible 2′-OH acylation enhances RNA stability, Nat. Chem., 2023, 15, 1296–1305.
21. Y. Xu, H. Chen, L. Yu, X. Peng, J. Zhang, Z. Xing, Y. Bao, A. Liu, Y. Zhao, C. Tian, Y. Liang and X. Huang, A light-driven enzymatic enantioselective radical acylation, Nature, 2024, 625, 74–78.
22. (a) H. M. I. Osborn, V. Brome, L. M. Harwood and W. G. Suthers, Regioselective C-3-O-acylation and O-methylation of 4,6-O-benzylidene-beta-D-gluco- and galactopyranosides displaying a range of anomeric substituents, Carbohydr. Res., 2001, 332, 157–166; (b) J. Lv, J.-T. Ge, T. Luo and H. Dong, An inexpensive catalyst, Fe(acac)3, for regio/site-selective acylation of diols and carbohydrates containing a 1,2-cis-diol, Green Chem., 2018, 20, 1987–1991.
23. B.-A. Zhou, X.-N. Li, C.-L. Zhang, Z.-X. Wang and S. Ye, Enantioselective Synthesis of Axially Chiral Diaryl Ethers via NHC Catalyzed Desymmetrization and Following Resolution, Angew. Chem., Int. Ed., 2024, 63, e202314228.
24. Y.-G. Liu, Z. Zhong, Y. Tang, H. Wang, S. V. C. Vummaleti, X. Peng, P. Peng, X. Zhang and Y. R. Chi, Carbene-catalyzed chirality-controlled site selective acylation of saccharides, Nat. Commun., 2025, 16, 54.
25. (a) L. Deng, Y. Lin, X. Shao and Y. Ye, Nickel-Catalyzed Electroreductive Sulfuration of Alkyl Alcohols with Pyridyl Thioesters, Org. Lett., 2025, 27, 1265–1270; (b) H. Yang, N. Li, J. Jin and Y. Ye, Ni-H-Catalyzed Regioselective Hydroalkylation of Terminal Alkynes with α-Bromo Phosphonates, Org. Lett., 2025, 27, 5777–5782; (c) Y. Lin, L. Zou, R. Bai, X.-Y. Ye, T. Xie and Y. Ye, Iron-catalyzed cross-electrophile coupling of bromostyrenes and chlorosilanes, Org. Chem. Front., 2023, 10, 3052–3060; (d) Y. Ye, X. Qi, B. Xu, Y. Lin, H. Xiang, L. Zou, X.-Y. Ye and T. Xie, Nickel-catalyzed cross-electrophile allylation of vinyl bromides and the modification of anti-tumour natural medicine β-elemene, Chem. Sci., 2022, 13, 6959–6966.
26. H. Xiang and Y. Ye, Cu-Catalyzed α-Alkylation of Glycine Derivatives for C(sp³)−H/C(sp³)−H Bond Selective Functionalization, ACS Catal., 2024, 14, 522–532.
27. B. Zhai, N. Zhang, X. Han, Q. Li, M. Zhang, X. Chen, G. Li, R. Zhang, P. Chen, W. Wang, C. Li, Y. Xiang, S. Liu, T. Duan, J. Lou, T. Xie and X. Sui, Molecular targets of β-elemene, a herbal extract used in traditional Chinese medicine, and its potential role in cancer therapy: A review, Biomed. Pharmacother., 2019, 114, 108812.
28. X. Wang, Z. Liu, X. Sui, Q. Wu, J. Wang and C. Xu, Elemene injection as adjunctive treatment to platinum-based chemotherapy in patients with stage III/IV non-small cell lung cancer: A meta-analysis following the PRISMA guidelines, Phytomedicine, 2019, 59, 152787.
29. R. Bai, J. Zhu, Z. Bai, Q. Mao, Y. Zhang, Z. Hui, X. Luo, X.-Y. Ye and T. Xie, Second generation β-elemene nitric oxide derivatives with reasonable linkers: potential hybrids against malignant brain glioma, J. Enzyme Inhib. Med. Chem., 2022, 37, 379–385.
30. See the SI for details.
31. CCDC 2434524: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2mqb1r.

---