Stereoselective synthesis of C-aryl glycosides via radical-enabled 1,4-Ni migration: glycosyl chlorides as coupling partners

Abstract

C-Aryl glycosides are important skeleton motifs in medicinal chemistry and biochemistry. However, the stereoselective and efficient construction of structurally complex C-aryl glycosides under mild conditions remains challenging. Herein, we report an efficient strategy for the alkenylation and ortho-glycosylation of aryl halides through a 1,4-nickel migration. This three-component protocol uniquely employs glycosyl chlorides to achieve high anomeric stereocontrol (α/β > 20 : 1), overcoming competing arylation via LiI modulation—distinct from prior Ni-migrations with alkyl electrophiles. The method not only exhibits broad substrate scope and exceptional functional-group compatibility but also enables controllable regioselectivity in alkyne insertion. Mechanistic studies revealed that the reaction proceeds through 1,4-nickel migration of Ni(II) species and involves a glycosyl radical process. Furthermore, a deprotection experiment efficiently produced free C-aryl glycosides in excellent yields. Overall, this work expands the toolbox of migratory catalysis by introducing glycosyl chlorides as novel radical precursors and offers a modular approach for stereocontrolled C-glycoside synthesis.

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Introduction

C-Aryl glycosides, an important class of bioactive molecules, are widely found in natural products and utilized in the development of clinical pharmaceuticals.^1–9 Representative C-aryl glycoside drugs include tiazofurin 1,¹⁰ an IMP dehydrogenase inhibitor with anticancer potential;¹¹ benzamide C-riboside 2, which shows antiproliferative activity;¹² pyrazomycin,¹³ a broad-spectrum antiviral agent; and dapagliflozin,^14–16 an SGLT2 inhibitor for type II diabetes (Scheme 1a). Their clinical importance has motivated the development of efficient synthetic methodologies for C-aryl glycosides.¹⁷

Scheme 1 Background of the current work and reaction design. (a) Selected C-aryl glycoside-containing bioactive molecules. (b) Previous C-aryl glycosylation. (c) Ru-catalysis-enabled regioselective C-aryl glycosylation. (d) Pd/NBE cooperative catalysis-enabled C-aryl glycosylation. (e) This work: Ni-catalyzed alkenylation/ortho-glycosylation via 1,4-Ni migration using glycosyl chlorides as coupling partners (distinct from alkyl halides in prior systems).

Over the past years, transition-metal catalysis has shown remarkable potential in the stereoselective construction of C-aryl glycosidic bonds (Scheme 1b).^18–28 Among these strategies, C–H activation for aryl-glycosylation exhibited high efficiency and stereoselectivity. A direct ortho-C–H bond glycosylation was reported by the Chen group, employing 8-aminoquinoline (AQ) as a directing group under Pd catalysis.²⁹ In 2022, our group³⁰ developed a ruthenium-catalysed ortho- and meta-C_Ar–H glycosylation with high stereoselectivity. Around the same time, the Ackermann group³¹ also achieved meta-C-aryl glycosides using ruthenium catalysis (Scheme 1c). On the other side, the undirected C–H glycosylation also offers notable advantages in the synthesis of glycosides. Both our group and the Cheng group independently developed ortho-C–H glycosylation of iodobenzenes via Pd/NBE cooperative catalysis (Scheme 1d).^32,33 In addition, transition-metal-catalyzed cross-coupling reactions, especially those using non-precious metals,^34–38 have been successfully used to construct C-aryl glycosides.^39–45 Although significant progress has been achieved, challenges remain in the following aspects: (a) designing and removing auxiliary groups, as many current methods rely on high temperatures and precious metals; (b) achieving regio- and stereoselective C-aryl glycosylation using simple starting materials under mild conditions; and (c) improving the atom economy of the processes.

1,n-Metal migratory catalysis,^46–50 which allows the construction of complex molecules from readily available starting materials through the efficient reactive site transportation, has emerged as a powerful strategy for remote C–H bond transformation.^51–58 However, the development of the 1,4-Ni migration process remains limited. The original work was reported by the Martin group, which claimed the first 1,4-Ni migration from alkenyl to aryl and realized the carboxylation of a remote aryl C–H bond.⁵⁹ Building on this, the Zhu⁶⁰ and Martin⁶¹ groups separately developed a three-component 1,4-Ni migration strategy, achieving ortho- and ipso-difunctionalization of aryl bromides. In 2023, our group first established a ligand-enabled strategy which allowed aryl-to-alkenyl type 1,4-Ni migration to deliver trisubstituted alkene compounds.⁶² The Zhu group also reported a bromobenzene-enabled 1,4-Ni migration via an aryl-to-alkenyl pathway in the same year.⁶³ However, these well-developed transformations did not allow glycosides as potential substrates. Driven by our group's ongoing interest⁶⁴ in catalytic glycosylation chemistry,⁶⁵ we envisioned that glycosyl chlorides could be the radical precursors in a mild three-component strategy which realizes the alkenylation and ortho-glycosylation of aryl halides with high stereoselectivity. However, this approach encounters two main difficulties: (a) site-selectivity issues due to competing glycosylation at C(sp²)–X sites or at the immediate vinylation position and (b) the difficulty in achieving stereoselective synthesis of complex C-aryl glycosides. To address these challenges unique to carbohydrate chemistry, we present here a catalytic methodology that uses glycosyl chlorides to allow the stereoselective synthesis of C-aryl glycosides via an alkenyl-to-aryl 1,4-Ni migration (Scheme 1e). Notably, glycosyl bromides and secondary alkyl chlorides didn't provide any positive outcomes under optimized conditions, highlighting the good substrate selectivity of this methodology.

Results and discussion

This transformation was carried out using methyl 4-bromobenzoate (1a), 1-phenyl-1-propyne (2a), and D-mannofuranosyl chloride (3a) as the starting materials (details are provided in the SI, Tables S1–S8). The initial attempt using ligand L1 did not give a detectable product. Ligand screening revealed that 2,2′-bipyridine^66,67 derivatives bearing substituents at the C6-position delivered a positive result (L2, 44% yield). Further optimization revealed that introducing a bulky electron-donating group at the C4-position of the ligand dramatically improved the reaction efficiency (L8, 82%).

The optimization of reaction conditions indicated that changing the nickel catalyst or solvent was negative for this reaction (Table 1, entries 2–5). Different manganese (Mn) powder and zinc (Zn) powder were used as the reductants, and both decreased the reaction efficiency (entries 6 and 7). Control experiments demonstrated that the addition of sodium iodide (NaI) and lithium iodide (LiI) is important for this reaction. Unlike previous reports using general alkyl halides, glycosyl chlorides exhibit different reactivities in this reaction. The additional LiI could inhibit competitive arylation at the C(sp²)–X position of the glycosyl donor, enabling the insertion of alkynes and the following 1,4-Ni migration to produce the desired three-component product (entries 8–10, details are shown in the SI, section 1.2, Table S7). The optimal reaction conditions were determined: NiCl₂·glyme as the catalyst, L8 as the ligand, NaI and LiI as additives, Mn powder as the reducing agent, THF as the solvent, and a reaction temperature of 30 °C, with the addition of 4 Å molecular sieves. Under these conditions, the target product 4a was obtained in a yield of 82% with excellent α-selectivity.

Table 1 Optimization and control reactions^a

Entry	Variations in conditions	Yield (%)
a Reaction conditions: 1a (0.20 mmol, 1.0 equiv.), 2a (0.40 mmol, 2.0 equiv.), 3a (0.30 mmol, 1.5 equiv.), NiCl2·glyme (5.0 mol%), L8 (10.0 mol%), NaI (0.20 mmol), LiI (0.10 mmol), 4 Å MS (40 mg), Mn (0.40 mmol). THF (1.0 mL) at 30 °C for 24 h, isolated yields.
1	None	82
2	DMAc instead of THF	57
3	Ni(COD)2 instead of NiCl2·glyme	74
4	NiBr2 instead of NiCl2·glyme	75
5	NiBr2·diglyme instead of NiCl2·glyme	71
6	Mn (−325 mesh) instead of Mn (−140 + 325 mesh)	69
7	Zn instead of Mn	74
8	No NaI	62
9	No LiI	68
10	No NaI and LiI	ND

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We then turned to exploring the reaction scope. As shown in Scheme 2, we first tested a variety of bromobenzenes and successfully obtained the corresponding products (4a–4t) with excellent α-selectivity (α/β > 20 : 1). Substrates containing electron-withdrawing groups produced the desired glycosides in good yields (4a–4f, 4l–4o). Notably, the structure of product 4e, featuring a difunctionalized arene with E-configured olefin moieties, was confirmed by single-crystal X-ray diffraction analysis. However, substrates with electron-donating groups exhibited lower reactivities (4j–4k). para-Substituted (4a–4d) and meta-substituted (4l–4o) bromobenzene compounds provided comparable outcomes. Additionally, substrates containing halogen atoms (4g, 4h, 4p) were also tolerated, and they delivered products in moderate yields, which indicated the good selectivity of this reaction. Naphthyl and heteroaromatic rings were also employed, yielding the corresponding products 4q and 4r in acceptable yields, while products 4s and 4t were achieved in good yields of 73% and 66%. Importantly, the reaction results of 4l–4t further proved that migratory insertion reactions preferentially occur at the less sterically hindered ortho positions. Furthermore, aryl iodides derived from natural products or pharmaceuticals were found to participate effectively in the reaction and delivered the products 4u–4w in good yields.

Scheme 2 Scope of Ni-catalyzed 1,4-Ni migration for stereoselective C-aryl glycosylation with glycosyl chlorides. Reaction conditions: 1 (0.20 mmol, 1.0 equiv.), 2 (0.40 mmol, 2.0 equiv.), 3 (0.30 mmol, 1.5 equiv.), NiCl₂·glyme (5.0 mol%), L8 (10.0 mol%), NaI (0.20 mmol, 1.0 equiv.), LiI (0.10 mmol, 0.5 equiv.), 4 Å MS (40 mg), Mn (0.40 mmol, 2.0 equiv.). THF (1.0 mL) at 30 °C for 24 h, isolated yields. α/β ratios were determined from ¹H NMR spectra.

We next evaluated the generality of alkynes. Notably, alkynes bearing either electron-donating or electron-withdrawing groups at the C4-position of the phenyl ring were well tolerated, affording the corresponding products in good yields (5a–5e). meta-Chloro-1-phenylpropyne also delivered the desired glycoside in 62% yield (5f). Furthermore, ortho-methyl-substituted 1-phenylpropyne produced the target compound in 77% yield (5g). Additionally, alkynes bearing heterocyclic structures (5h, 5j, 5k) reacted well, but the yield of 5l was only 20%. The use of 1-phenylbutyne and 1-phenylhexyne successfully afforded the corresponding C-aryl glycosides in good yields (5m, 5n). Internal symmetrical alkynes, which typically exhibit low reactivity,⁶⁸ also formed the corresponding glycosides in acceptable yields (5o, 5p).

The scope of glycosyl chlorides was also explored. A series of tetrabenzyl-, tetramethyl-, tetraacetyl-, and TBDPS- and benzyl-protected α-mannosyl chlorides serve as suitable coupling partners, exhibiting excellent α-selectivity (6a–6d). Tetrabenzyl-protected α-galactosyl chloride, α-glucosyl chloride, benzyl-protected α-rhamnosyl chloride, as well as benzyl- or TBDPS-protected β-ribosyl chlorides all demonstrated good reactivity and resulted in satisfactory outcomes with excellent stereoselectivity(6e–6i). Notably, the benzyl-protected α-rhamnosyl chloride was successfully converted with a yield of 90% (6g), while tetrabenzyl-protected α-galactosyl chloride and α-glucosyl chloride yielded β-configuration products in moderate yields (6e and 6f). In contrast, the TBDPS-protected β-ribosyl chloride afforded the α-configuration product as the major product in 49% yield (6i).

To further demonstrate the utility of this strategy, we performed a gram-scale synthesis, and 4a was successfully obtained in a 62% yield (Scheme 3a). Subsequently, compound 4a was subjected to a one-pot deprotection experiment,⁶⁹ yielding the multi-hydroxyl compound 7 with a yield of 92% (Scheme 3b).

Scheme 3 Synthetic applications. (a) Gram-scale synthesis. (b) Deprotection reaction of C-aryl furanoside.

After scope evaluation, we conducted a series of control experiments to gain more mechanistic insights (details are provided in the SI, section 1.6). The addition of the radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) completely inhibited the reaction, which suggests that the reaction might involve a radical pathway. EPR analysis of the reaction mixture after 4.5 hours revealed clear radical signals, offering evidence for a radical-based mechanism. Notably, the involvement of a glycosyl radical (inferred from TEMPO inhibition) distinguishes our mechanism from Martin/Zhu's carboxylate pathway and our group's prior work on alkyl radical addition. The synergistic Ni(II)-migration/radical capture sequence is unprecedented for C-glycoside construction. Isotopic labelling experiments revealed that when 1i-d (98%, D) was reacted with 3a and 2a under standard conditions, deuterium incorporation occurred exclusively at the alkenyl position (97% D), being consistent with the occurrence of a 1,4-Ni migration. An intermolecular kinetic isotope effect experiment (k_H/k_D = 1.06) implies that the 1,4-Ni migration step may not be involved in the rate-determining step of the reaction. Moreover, in the absence of an external metal reductant, the reaction still afforded product 4a in a 57% yield, strongly suggesting that the 1,4-Ni migration occurs at Ni(II) centers. Finally, under standard conditions, the formation of 4c was observed regardless of whether (Z)-8a or (E)-8a was employed as the counterpart. This outcome indicates that the E/Z isomerization of the alkenyl Ni(II) species is both rapid and reversible prior to the 1,4-Ni migration.

A plausible reaction mechanism was proposed based on mechanistic experiments and previous reports (Scheme 4).^70–72 Initial oxidative addition of Ar–Br to Ni(0) forms intermediate A. Subsequent migratory insertion of alkyne into the Ni–C(sp²) bond generates a reversible mixture of E/Z isomers of the alkenyl Ni(II) species (B and B′). These intermediates undergo reversible 1,4-Ni migration to form intermediate C. Intermediate C reacts with a glycosyl radical to form intermediate D, which undergoes reductive elimination to yield the target product and Ni(I)–X. The glycosyl radical is generated via single-electron transfer (SET) from a Ni(I) species to glycosyl chloride. The resulting Ni(II) species is reduced by Mn powder, thereby reinitiating the catalytic cycle.

Scheme 4 Proposed mechanism.

Conclusions

In summary, we developed a stereoselective alkene to arene type 1,4-Ni(II) migration-enabled ortho-C_Ar–H glycosylation. A key to success was the use of LiI as an additive for modulating the reactivity of the glycosyl chloride, which diverted the pathway from direct arylation to the desired migratory process. This method employs glycosyl chlorides as glycosyl radical precursors to achieve exceptional regio- and stereoselectivity without requiring directing groups, while also demonstrating good functional group compatibility. Mechanistic studies reveal a synergistic pathway involving Ni(II)-mediated reversible alkene isomerization followed by 1,4-migration. The high efficiency in the deprotection of the product highlights the practical utility of this approach in drug development. We anticipate that this strategy will inspire new paradigms in radical glycosylation and migratory catalysis for the synthesis of complex bioactive molecules.

Author contributions

Y.-M. L. conceived the project. H.-Y. L. discovered and developed the initiative. H.-Y. L. and Q. L. performed the experiments and collected the data. Y.-M. L., X.-Y. L., and J. Y. supervised the investigation. Y.-M. L., Z.-J. N., and H.-Y. L. analyzed the data and wrote the manuscript, with guidance and revisions provided by the other authors.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data underlying this study are available in the published article and its supplementary information (SI). It contains additional experimental details, synthetic procedures, compound characterization data (¹H NMR, ¹³C NMR, HRMS). See DOI: https://doi.org/10.1039/d5qo01241d.

CCDC 2402237 (4e) contains the supplementary crystallographic data for this paper.⁷³

Acknowledgements

We gratefully acknowledge the National Natural Science Foundation of China for financial support (U24A20485, NSF 22171114 and NSF 22371097).

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