Ligand-enabled next-generation glycosyl Stille cross-coupling for the stereospecific synthesis of sterically hindered aryl C-glycosides

Domain: chemistry
Published: 2026-02-21
Editorial outcome: major_revision

Abstract
Sterically hindered aryl C-glycosides are biologically important, yet their stereoselective synthesis remains challenging due to severe anomeric congestion. Here we report an next-generation, ligand-enabled, stereospecific Pd-catalyzed glycosyl cross-coupling that efficiently delivers sterically hindered aryl C-glycosides with exclusive anomeric control. Two underexplored biaryl monophosphine ligands, featuring P-bound 3,5-bis(trifluoromethyl)phenyl groups and methoxy or isopropoxy substituents at the 2’- and 6’-positions of the lower aryl ring, are uniquely effective for this challenging C-glycosylation. The scope and practicality of this next-generation Stille glycosylation are demonstrated in over 65 examples, including (un)protected sugars, deoxy sugars, and oligosaccharides. Crystallography reveals that bromide-bridged dimeric Pd(II) complexes as intrinsic features of diaryl biaryl monophosphine ligands, while natural bond orbital (NBO) analysis shows that subtle ligand electronics control the selectivity between β-methoxy elimination and C–C reductive elimination. This predictable, highly chemo- and stereoselective protocol expands the glycosylation toolbox, enables glycomimetic drug discovery, and informs rational ligand design.

Introduction
Carbohydrates play indispensable roles as natural building blocks and in therapeutics, diagnostics, and functional foods1–3. Glycomimetics, including C-, N-, and S-glycosides, often retain the biological functions of their natural O-glycoside counterparts while exhibiting distinct chemical properties, making them valuable tools for probing glycan function and facilitating drug discovery4. Among these, C-glycosides have attracted sustained interest across chemical, biological, and medical disciplines owing to their characteristic C–C glycosidic bonds, which impart hydrolytic and metabolic stability compared to traditional C–O linkages5–7. Within this subclass, aryl C-glycosides are distinguished by the direct attachment of aryl groups at the anomeric C-1 position of sugar rings. This structural motif has attracted significant attention due to its unique chemical properties, druggability, and diverse biological activities, including applications in cancer agents8, antibiotics9, and antidiabetic drugs10. Of particular note are sterically hindered aryl C-glycosides1, which feature bulky aryl aglycones and are prevalent in numerous bioactive natural products and clinically relevant glycomimetics (Fig. 1a)5. Representative examples include Saptomycin B2, isolated from Streptomyces sp. HP530, which exhibits potent in vitro and in vivo antitumor activities11. Another notable case is the α-C-mannosylation of tryptophan moiety 3 in glycoproteins, a rare and sterically demanding C-glycosylation occurring as a post-translational modification in TSR family proteins12. Additionally, spiro C-arylated glycopyranosides such as Papulacandin D 4 demonstrate antibiotic and antifungal properties13. Fused cyclic aryl C-glycosides, including Bergenin 5, widely distributed in medicinal plants, possess broad biological profiles encompassing antitumor, antiviral, and antifungal properties14. The glycosylated angucycline Gilvocarcin M 6 displays activity against Gram-positive bacteria15. More recently, Enavogliflozin 7, a sterically hindered aryl C-glycoside, was identified as an important sodium-glucose cotransporter 2 (SGLT-2) inhibitor for treating type 2 diabetes patients with impaired renal function16. Sterically hindered C-glycosidic linkages are also a characteristic structural feature within the angucycline family. For example, Marmycin A 8 exhibit potent anticancer activity, attributed in part to its sterically congested C-glycosidic linkages17.

Given their broad significance as key glycomimetics, aryl C-glycosides have attracted sustained interest as synthetic targets for stereoselective anomeric arylation6,7,18–23. Established chemical methods for C-glycosylation can be broadly classified into three principal strategies based on the nature of the reactive glycosyl intermediates involved (Fig. 1b): (i) Friedel−Crafts-type reactions of electron-rich arenes with glycosyl electrophiles, or direct phenol O-glycosylation followed by stereoselective O→C rearrangement, both proceeding via glycosyl oxocarbenium ions24–27 (pathway I); (ii) radical glycosyl cross-coupling reactions, with or without transition metal catalysis, involving glycosyl radicals (pathway II)28–34; and (iii) transition-metal-catalyzed glycosyl cross-coupling (GCC) via stereospecific transmetalation of glycosyl anions (pathway III)35,36. Despite significant advancements, achieving highly controllable, chemoselective, and stereoselective aryl C-glycosylation—particularly for sterically hindered aryl C-glycosides—remains a considerable and ongoing challenge. Classical substitution methods involving glycosyl oxocarbenium ions encounter notable obstacles, including reliance on stoichiometric Lewis acid promoters, preference for electron-rich arenes, and difficulties in managing chemoselectivity between C- and O-glycosylation pathways. Controlling anomeric stereochemistry for sterically hindered aryl C-glycosides is especially demanding due to the combined effects of the saccharide framework, C2 substituents on sugar rings, and the electronic and steric profiles of bulky aryl groups—all of which exacerbate stereoselectivity issues at the highly congested anomeric center (Fig. 1b, pathway I)6,24,25. Recently, radical C-glycosylation has gained prominence as a powerful strategy for the synthesis of aryl C-glycosides30,37–58, offering broad functional group tolerance, good anomeric selectivity, and compatibility with unprotected sugar substrates. In radical-mediated C-glycosylation, the saccharide backbone strongly governs anomeric control, with substrate-dictated stereoselectivity often observed, typically favoring α-stereoselectivity. However, the stereodivergent synthesis of both optically pure α- and β-glycosides remains a formidable challenge in carbohydrate chemistry, yet is essential for the systematic investigation of glycan structure–function relationships38,52,59–61. Moreover, the electronic and steric properties of the aryl coupling partners can markedly impact the α/β selectivity62,63, rendering the stereoselective construction of sterically hindered aryl C-glycosides particularly challenging (Fig. 1b, pathway II). Transition metal-catalyzed glycosyl cross-coupling (GCC) reactions, which unite glycosyl nucleophiles with aryl electrophiles, have emerged as a powerful strategy for constructing aryl C-glycosides (Fig. 1b, pathway III)35. In this context, we have successfully developed highly stereospecific Pd-catalyzed cross-coupling reactions between both α- and β-anomers of glycosyl stannanes and aryl halides, enabling the modular and predictable synthesis of stereochemically pure α- and β-aryl C-glycosides59,60,64. This strategy showcases broad substrate scope, excellent functional group tolerance—including compatibility with fully unprotected sugars—and consistently high stereospecificity. A key to this success lies in the stereoretentive transmetalation step that preserves the anomeric configuration regardless of the steric or electronic properties of both the glycosyl donors and aryl electrophiles. This principle has been elegantly demonstrated in palladium-catalyzed stereoretentive intramolecular glycosylations, enabling efficient access to both cis- and trans-fused cyclic C-glycosides without erosion of optical purity61. However, while the stereoretentive nature of these transformations ensures precise anomeric control, the application of sterically hindered aryl electrophiles in intermolecular glycosyl cross-coupling remains highly challenging, with such substrates frequently exhibiting severely diminished reactivity or complete inertness under established conditions (Fig. 1b, pathway III)60,61.

Motivated by unresolved synthetic challenges and the notable bioactivity of sterically hindered aryl C-glycosides, and guided by the high selectivity and reliability achieved in our preliminary work59,60, we aimed to develop a next-generation stereospecific glycosyl cross-coupling platform using glycosyl stannanes to access these sterically demanding structures. The rapid evolution of transition metal-catalyzed cross-coupling reactions has been intimately linked to a deeper understanding of ligand steric and electronic effects and their influence on metal reactivity65–69. In particular, the successful of Csp2-Csp3 Stille glycosylation reaction has relied on electron-deficient phosphine ligands, which enhance reactivity by generating more electrophilic palladium(II) species, compensating for the low nucleophilicity of glycosyl stannanes, and facilitating efficient transmetalation59,60,70. The key to achieving efficient synthesis of sterically hindered aryl C-glycosides lies in the rational design of ligands tailored for these challenging aryl electrophiles. Such an effective ligand should possess: (i) electron-withdrawing properties to create more electrophilic Pd(II) species, thereby facilitating transmetalation in the presence of bulky aryl electrophiles; and (ii) suitable steric effects, where bulkiness aids reductive elimination but excessive steric hindrance may hinder oxidative addition with bulky electrophiles and the subsequent transmetalation of Pd(II) species bearing hindered aryl groups.

Here, we report a next-generation, ligand-enabled, stereospecific glycosyl cross-coupling for glycosyl stannanes with sterically bulky aryl electrophiles14, providing efficient and robust access to structurally demanding aryl C-glycosides (Fig. 1c). This efficient approach allows for precise stereocontrol over the anomeric configuration of both α- and β-anomers derived from various saccharides. Through systematic modification of the first-generation ligand JackiePhos L1, we identified two uniquely effective variations of Jackiephos biaryl phosphine ligands, L10 and L11, bearing methoxy and isopropoxy substituents at the 2’- and 6’-positions of the “lower” aryl ring, respectively, specifically designed to facilitate C–C reductive elimination. These ligands outperform the original JackiePhos system, particularly in promoting the coupling of ortho-monosubstituted and ortho-disubstituted sterically hindered aryl halides. The versatility and robustness of this refined glycosyl Stille cross-coupling protocol were demonstrated across more than 65 examples, featuring both protected and unprotected mono- and oligosaccharides, and a diverse range of bulky aryl electrophiles, including bioactive natural products and pharmaceutical agents. Computational analysis reveals that the underexplored ligand L11 favors reductive elimination to forge sterically hindered C–C bonds over β-methoxy elimination, opposite to the first-generation ligand L1, consistent with experimental observations. Natural bond orbital (NBO) analysis further revealed that Pd in Int3 (L11) carries a slightly higher NBO charge (+0.18) than in Int3′ (L1, +0.16). The more electron-rich Pd center in Int3′ better stabilizes the β-methoxy elimination transition state, favoring this pathway, whereas the electron-deficient Pd in Int3 facilitates C–C bond formation, promoting reductive elimination.

Results
Progress in transition metal-catalyzed cross-couplings has been largely propelled by the development of increasingly effective ligands. To identify a suitable ligand for glycosyl C(sp3)−C(sp2) cross-coupling involving sterically hindered aryl electrophiles, we integrated insights from established ligand effects and mechanistic studies of Stille-type couplings71,72. As a model, we tested the reaction of (2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)tributylstannane 16 and the sterically hindered methyl 2-bromobenzoate 14a under previously reported Stille glycosyl cross-coupling reactions (Fig. 2)59–61. JackiePhos L1, a biaryl monophosphine ligand featuring strongly electron-withdrawing P-bound 3,5-bis(trifluoromethyl)phenyl groups, has been widely used as an optimal ligand for stereospecific Stille glycosyl C(sp3)−C(sp2) couplings of aryl electrophiles59–61,64,70,73. However, it proved less effective for the title reaction, affording only 15% of coupling product 17. As anticipated, substituting the P-bound electron-withdrawing (3,5-bis(trifluoromethyl)phenyl) groups in L1 with electron-donating cyclohexyl substituents, as in BrettPhos L2, completely abolished reactivity. This result is consistent with prior findings that electron-deficient phosphine ligands are crucial for enabling Stille C-C couplings59,60,70, thereby ruling out the use of electron-rich phosphines for promoting the oxidative addition of sterically hindered electrophiles. Tris(3,5-bis(trifluoromethyl)phenyl)phosphine L3 delivered product 17 in 21% yield but with extensive formation of by-products via β-O elimination (17-1, 79%) and β-H elimination (17-2, 49%). Recognizing that transmetalation is the rate-limiting step in Stille glycosyl C(sp³)−C(sp²) cross-coupling reactions59, particularly for bulky aryl electrophiles, we hypothesized that more electrophilic and less sterically demanding Pd(II) intermediates would facilitate critical transmetalation step. Maintaining electron-withdrawing substituents on the phosphorus atom while removing the two methoxy groups on the “upper” aryl ring A of the biaryl backbone, we systematically modified the “lower” aryl ring B by varying substituents at the 2′, 4′, and 6′ positions (see Fig. 2 for numbering). Ligands L4-L8 showed progressively improved yields (24% to 70%) alongside suppression of by-product 17-1 formation. This finding indicates that, contrary to prior reports59,74, the methoxy groups on the “upper” aryl ring, particularly at the C3 position, are not indispensable for sterically hindered cross-coupling reactions. Earlier studies suggested that the methoxy group located in the ortho position to phosphorus is critical for maintaining catalyst stability through coordination with the O-bound Pd(II) center, which is challenging to form due to the increasing steric interference from the bulky aryl ring. Compared to JackiePhos L1, its analogue L4 (lacking the two methoxy groups on the “upper” aryl ring A) provided only a modest yield improvement (15% vs. 24%). To advance this objective, we designed a ligand, L5, bearing hydrogen atoms at the 2’, 4’, and 6’ positions of the “lower” aryl ring B to reduce the steric hindrance. This modification led to a notable increase in the yield of 17 to 62%, compare to 24% obtained with L4. When 2’ and 6’ substituent groups were replaced with alkoxy groups, such as methoxy L6, cyclohexyloxy L7, and isopropoxy L8, the yields improved to 70%, 39%, and 46%, respectively, compared to L4. These results suggest that an electron-rich “lower” aryl ring might benefits the reaction by strengthening coordination to the Pd(II) center via the C-bound Pd(II)75. However, excessive steric demand of electron-donating groups like cyclohexyloxy (L7) and isopropoxy (L8) may partially offset these benefits. This conclusion also extends to ligands L9-L12, which feature an “upper” aryl ring A and ring C identical to JackiePhos L1. These ligands showed improved yields ranging from 66% to 82%, along with a significant reduction in β-H elimination. Comparing ligand pairs L5 vs. L9, L6 vs. L10, and L7 vs. L11 further established that while methoxy groups on ring A are not strictly necessary, their presence consistently enhances catalytic performance. This effect is particularly pronounced when R1 is i-Pr, with the yield increasing significantly from 46% to 73%, likely due to the C3 methoxy substituent acting as a flexible coordination site that stabilizes the electrophilic and the sterically hindered aryl-Pd(II) center B, even when O-bound Pd(II) intermediates are disfavored sterically. Interestingly, relocating the methoxy group from the C6 to the C5 position on the “upper” aryl ring enhanced the performance of L13 over L1, though this positional adjustment slightly decreased the efficiency of L14 relative to L10. Further modification of the “lower” aryl ring yielded ligands L15 (fused cyclic alkoxy groups) and L17 (carbazolyl group). Despite their differing steric demands, both ligands furnished comparable yields (64% and 71%, respectively), indicating no further advantage beyond the trends already observed. Finally, we investigated variations in the “upper” ring of the biaryl moiety. Four ligands (L16, L18, L19, and L20), each bearing the optimized “lower” aryl ring, were synthesized, incorporating different groups in the upper ring: indenyl L16, indole L18, imidazole L19, and pyrazole L20. These variations afforded the desired product 17 in yields of 39%, 48%, 0%, and 52%, respectively. These results underscore the critical role of the upper aryl ring in modulating catalytic performance. Notably, all reactions across this ligand set consistently furnished the β-anomer exclusively, even with sterically hindered aryl electrophiles, highlighting the high stereocontrol, robustness, and reliability of the glycosyl cross-coupling protocol. Based on these evaluations, ligands L10 and L11 were identified as optimal for further applications and mechanistic investigations.

A detailed understanding of oxidative addition palladium (II) complexes is central to elucidating how ligands influence metal coordination and catalytic reactivity in cross-coupling reactions76,77. Biaryl monophosphine ligands, in particular, have proven indispensable in enabling C–C bond formation65. Accordingly, the synthesis and structural characterization of these Pd(II) intermediates remain key to advancing ligand design and mechanistic insight. For dialkylbiaryl monophosphine ligands, extensive studies have established both C-bound OA1 and O-bound OA2 isomers, supported by crystallographic data75,78–83. In contrast, although C-bound OA3 and O-bound OA4 species derived from diarylbiaryl monophosphine ligands have been frequently proposed74, their structures remain poorly defined due to the lack of crystallographic evidence. This structural ambiguity may have contributed to the relatively limited development and application of diarylbiaryl ligands in catalysis. Motivated by this, we investigated the structures of diarylbiaryl monophosphine ligand-based Pd(II) complexes, aiming to explore whether unconventional binding modes might be accessible beyond the established paradigms (Fig. 3a).

To investigate the structural behavior of diarylbiaryl monophosphine ligands, we synthesized oxidative addition Pd(II) complexes using hindered ortho-methylbromobenzene 14b as the electrophile and analogues of JackiePhos L11 and Jackiephos L1 as ligands. Crystallization from the mixture of pentane and DCM afforded the desired oxidative addition complexes (OAC) OA5 and OA6 in 78% and 82% yields, respectively (Fig. 3b, c). Unexpectedly, X-ray analysis revealed dimeric Pd(II) species bridged by two bromide atoms, rather than the anticipated monomeric C-bound OA3 or O-bound OA4 structures. We initially hypothesized that the unusual dimeric geometry observed might arise from the use of a sterically hindered electrophile. However, performing the reaction with a non-hindered substrate, ethyl 4-bromobenzoate 14c, yielded the same dimeric Pd(II) species OA6, indicating that electrophile sterics alone do not dictate dimer formation (Fig. 3d). During the course of this work, the Buchwald group reported the synthesis and NMR characterization of a Pd(II) complex bearing a 2-naphthyl group and supported by a JackiePhos/CPhos hybrid ligand81. Although no crystal structure was provided, the authors proposed a C-bound OA3-type monomer, inconsistent with the bromide-bridged dimeric species we consistently observed. This was particularly intriguing, as the hybrid ligand shares the same A and C aryl rings as JackiePhos L1 and L11, suggesting that L1- and L11-based Pd(II) complexes might also form well-defined species amenable to crystallization. To examine this, we repeated the synthesis using the hybrid ligand. Remarkably, single crystals suitable for X-ray diffraction were obtained, which revealed the same dimeric Pd(II) species bridged by two bromide rather than the proposed OA3 monomer (Fig. 3e). Notably, dissolution of OA5 in CD₂Cl₂ gave a mixture of bromide-bridged dimeric Pd(II)–OA complexes and O-bound OA2 isomers, as revealed by NMR, indicating that the bromide-bridged dimers are the more stable species, coexisting in dynamic equilibrium with the less stable O-bound OA2 isomers in solution. In contrast, dissolution of OA6, OA7, and OA8 in solvent exclusively yielded the bromide-bridged dimeric Pd(II)–OA complexes (see Supplementary Note 3.1 for experimental details). With well-defined oxidative addition palladium(II) complexes OA5 and OA6 in hand, we evaluated their catalytic performance in the reaction between glucosyl stannane 16 and methyl 2-bromobenzene 14b under standard conditions (see Supplementary Note 3.2 for experimental details), affording the desired product in 99%, and 32% yield, respectively. Together, these findings indicate that the formation of dimeric Pd(II) species is an inherent structural feature of diarylbiaryl monophosphine ligands, largely independent of the steric or electronic nature of the aryl electrophile or the P-bound substituents. More importantly, this challenges a prevailing assumption and clarifies a key structural ambiguity, informing future ligand design and expanding the scope of diarylbiaryl monophosphine ligands in catalysis.

To gain deeper insight into and accurately predict the impact of different ligands on reaction yield and chemoselectivity (β-H and β-O elimination), we developed multivariate linear regression models that correlate ligand properties with the yields of various products and byproducts (Fig. 4). Initially, experimental data were collected for 20 different ligands. Ligand characteristics were then quantified using a (PdL) reaction model, based on the above crystal structures obtained from our own experiments (Fig. 3). These descriptors included electronic parameters such as NBO parameters (natural charges on Pd, P, C1, C2, and C3), the Wiberg bond index (WBI_Pd_P), and frontier orbital energies (HOMO, LUMO). Steric parameters included percent buried volume (%Vbur) for Pd and P, sterimol parameters (bmin, bmax, L along Pd to P), as well as bond lengths (Pd–P, P–C) and bond angles (Pd–P–C). To construct and validate the models, the dataset was randomly divided into training and test sets at an 80:20 ratio. All three models showed strong linear correlations, with R² values of 0.85, 0.89, and 0.90, respectively. Although based on a modest dataset of 20 ligands, the MLR model shows strong correlations (R² = 0.85–0.90) and good agreement with test set predictions. Cross-validation (80:20 split) confirms its robustness, and undoubtedly, a larger dataset could further improve generality. The predicted yields for the four ligands in the test set were in close agreement with the experimental results, with the exception of the 17-2 product from ligand L4, which exhibited a noticeable deviation. The resulting models revealed distinct structure–property relationships for each product. For product 17, the yield was positively correlated with higher HOMO energy and C3_NBO charge, and negatively correlated with higher C1_NBO, bmin_Pd_P, and bmax_Pd_P values. For product 17-1, increased C1_NBO and bmin_Pd_P values were associated with higher yields, whereas increased C3_NBO and longer P–C3 bond length had a negative effect. In the case of product 17-2, higher values of HOMO energy, C1_NBO and C2_NBO, and longer P–C1 bond length were associated with lower yield. These findings demonstrate that by fine-tuning ligand electronic and steric properties—such as electron density distribution, frontier orbital energies, and Pd–P coordination characteristics—it is possible to simultaneously optimize reaction efficiency and selectivity, thereby enabling the targeted enhancement of desired product yields.

Kinetic studies revealed a first-order dependence on 16, the palladium catalyst, and KF, indicating that all three components participate directly in, or precede, the rate-determining step (Fig. 5a). In contrast, a zero-order dependence was observed for the aryl iodide, suggesting that the oxidative addition is rapid and not rate-limiting. To gain further mechanistic insight, detailed DFT calculations were performed (Fig. 5b). To optimize computational efficiency, the OBn group was replaced with OMe, and Bu₃Sn was replaced with Me₃Sn. The computed Gibbs free energy profile for the reaction catalyzed by JackiePhos-derived biaryl phosphine ligand L11 is presented. The iodine-bridged dimeric Pd(II) species int1, formed upon oxidative addition, was identified as the resting state of the catalytic cycle and taken as the reference point (0.0 kcal/mol). The catalytic cycle proceeds through transmetalation and reductive elimination steps to deliver the major product. Oxidative addition of the aryl iodide regenerates the dimeric Pd(II) complex, thereby completing the cycle. Dissociation of the dimeric Pd(II) species requires an energy input of 10.2 kcal/mol. In the presence of KF, int2 undergoes stereoretentive transmetalation with stannane 16 via a six-membered cyclic transition state ts-164, forming intermediate int3 and significantly lowering the activation barrier to 26.7 kcal/mol. This transmetalation step is identified as turnover-limiting, consistent with the kinetic data. An alternative stereoretentive transmetalation pathway proceeding through a four-membered cyclic transition state (ts-1′) was calculated to require a significantly higher barrier of 37.8 kcal/mol, rendering it unfavorable. From int3, the reaction can proceed via C–C reductive elimination to afford the major product. Alternatively, in the presence of CuCl and F⁻, an E2-type β-methoxy elimination pathway can generate a side product59. Reductive elimination via ts-2 from int3 occurs with a modest activation barrier of 7.8 kcal/mol, yielding the desired aryl C-product and regenerating the active Pd(0) catalyst. Subsequently, oxidative addition of the aryl iodide onto the Pd(0) species proceeds via transition state ts-3, with a low energetic span of 2.2 kcal/mol, forming an intermediate analogous to int2. Notably, the β-methoxy elimination pathway via ts-2a (in the presence of CuCl F⁻) has an overall energy barrier of 10.0 kcal/mol, which is 2.2 kcal/mol higher than that for C–C bond-forming reductive elimination from Int3. These computational results suggest that the indentifed phosphine ligand L11 promotes the C–C reductive elimination pathway, thereby favoring formation of the desired aryl C-product over side-product formation. In contrast, when the ligand L11 is replaced with the first-generation JackiePhos L1, the computational results show the opposite trend. From intermediate int3′, the C–C bond-forming reductive elimination proceeds via transition state ts-2’ with an activation barrier of 9.8 kcal/mol, whereas the competing β-methoxy elimination pathway via ts-2a′ requires only 7.8 kcal/mol, rendering it more favorable. This trend aligns well with experimental observations, where β-methoxy elimination is the dominant pathway with ligand L1. Structurally, no significant geometric differences were observed between intermediates int3 and int3′ that could clearly account for this reversal in selectivity. To further probe the electronic factors underlying this divergence, we compared the natural bond orbital (NBO) charges on the palladium center in both intermediates. The calculated NBO charge on Pd in int3 is +0.18, while it is slightly lower at +0.16 in int3′. This subtle difference in electron density may influence the relative activation barriers for the two competing pathways. The slightly more electron-rich Pd center in int3′ (L1) may better stabilize the developing negative charge in the β-elimination transition state, thus lowering its energy relative to C–C reductive elimination. Conversely, the more electron-deficient Pd in int3 (L11) may favor the reductive elimination step by facilitating bond formation with the aryl group. While these electronic effects are modest, they are consistent with the observed reactivity trends and may contribute to the distinct selectivity observed with the two ligands.

Having identified optimal ligand structures, we next evaluated their performance in the cross-coupling of sterically hindered aryl electrophiles. Each bulky (hetero)aryl halide was tested with the first-generation ligand JackiePhos L1 and the underexplored second-generation ligands L10 and L11 to benchmark their efficacy in aryl C-glycosylation. As shown in Fig. 6 a broad array of sterically hindered aryl bromides and iodides, including ortho-substituted arenes and heterocycles, underwent smooth coupling with L10 or L11, delivering the desired C-glycosides in good to excellent yields with exclusive anomeric control. In stark contrast, L1 afforded low yields or failed to promote product formation altogether. We systematically probed the impact of steric and electronic substituents using ortho-substituted aryl halides as a representative platform. ortho-Substituents such as ester 18, methyl 21-27, 2-ethoxy-2-oxoethyl 28, hydroxymethyl 29, isopropyl 30, benzo 31, phenyl 32, phenoxy 33, benzyloxy 34, acetoxy 35, hydroxy 36, acetylamino 37, benzoyl 38, formyl 39, cyano 40, and nitro groups 41 were all well tolerated, affording the corresponding C-glycosides in moderate to excellent yields. Notably, several substrates that were unreactive or less reactive using L1 as ligand, including those bearing hydroxymethyl, isopropyl, phenyl, benzyloxy, acetylamino, benzoyl, cyano, and nitro groups, exhibiting markedly enhanced reactivity with L10 and L11. The transformation demonstrates broad functional group compatibility, including tolerance toward acidic phenolic hydroxyl, hydroxymethyl, acetamido, and formyl groups. Even in the context of more sterically congested 1,5-disubstituted aryl halides, fully unprotected glycosyl stannanes could be efficiently coupled to deliver products 42–44 in 60–79% yield using L10 or L11, while L1 gave only 12–21% yield under otherwise identical conditions.

Encouraged by these promising results, we next explored the substrate scope of glycosyl stannanes using sterically demanding electrophiles such as ethyl 2-bromobenzoate 14a and ethyl 4-bromo-3-methylbenzoate 14e as representative models. As shown in Fig. 7, a broad range of (un)protected glycosyl stannanes efficiently participated in the cross-coupling, delivering the corresponding sterically hindered aryl C-glycosides in moderate to excellent yields while consistently maintaining exclusive anomeric selectivity for either the β- or α-isomer. Glucosyl stannanes bearing common groups (OBn, OPiv, OLev, OBz, and OTIPS) exhibited excellent compatibility under the standard conditions with ligand L10, affording products 20 and 47-48 in isolated yields of 63%-93%. Fully disarmed peracetylated and perbenzoylated 2-deoxy-D-glucosyl stannanes smoothly reacted to afford the corresponding products 49 and 50 in 79% and 72% yield, respectively. Moreover, structurally diverse glycosyl stannanes derived from a series of monosaccharides, including D-galactose 51, 2-deoxy-D-glucose (52, 53), D-mannose 54, reversed D-galactose 5564, reversed D-mannose 56, L-rhamnose 57, underwent efficient cross-coupling to furnish the desired hindered aryl C-glycoside. Notably, achieving both optically pure α- and β-isomers under a single set of conditions remains rare in C-glycosylation38,59,60,64. The second-generation glycosyl cross-coupling platform reliably yielded both α- and β-isomers (for example, 52 and 53) with complete stereocontrol even in the presence of sterically hindered aryl electrophiles. The ability to access both optically pure α- and β−2-deoxy aryl C-glycosides (52 and 53) highlights the advantage of this method in overcoming the longstanding reliance on C2-neighbouring group participation for stereocontrol in C-glycosylation reactions. Furthermore, unprotected or partially unprotected aryl C-glycosylation has historically posed a formidable challenge due to difficulties in achieving both high chemo- and stereoselectivity42,53,59,60. Encouragingly, the indentified ligands, in combination with hindered aryl electrophiles, enabled efficient coupling of unprotected glycosyl stannanes to deliver partially and fully unprotected aryl C-glycosides (59–62) in good yields and with high stereoselectivity. The successful synthesis of fully unprotected, sterically hindered aryl C-glycosides 61 and 62 provides compelling evidence that transition metal-catalyzed glycosyl cross-coupling via glycosyl nucleophiles remains the most robust and arguably the only general strategy for accessing both optically pure anomers, irrespective of the sugar structure or the steric and electronic properties of the aryl coupling partner. Significantly, oligosaccharide stannanes 63 and 64 were also viable coupling partners without modification of the standard conditions, delivering aryl C-disaccharides in 67% and 60% yields, respectively. Anomeric configurations were assigned by analysis of 1H NMR spectra of the crude reaction mixtures, based on the characteristic 3J(HH) coupling constants of the H1 proton. These signals typically appeared at 3.81−5.25 ppm range (CDCl3), with J values of 8.80−9.40 Hz for 1,2-trans isomers and 4.20−6.20 Hz for 1,2-cis isomers.

Late-stage glycodiversification of drug molecules offers a direct and promising strategy for modulating pharmaceutical properties, including solubility, metabolic stability, and target specificity4. However, this process poses significant challenges, as it requires a delicate balance between chemoselectivity and stereoselectivity, all while accounting for the electronic properties and steric hindrance of the drug molecules84. Motivated by the high chemo- and stereoselectivity of our developed glycosyl cross-coupling platform and its compatibility with sterically hindered substrates, we sought to apply this strategy to the late-stage glycodiversification of bioactive molecules and approved drugs using fully unprotected D-glucosyl stannanes (Fig. 8). Using this method, a series of aryl C-glycosylated pharmaceutical derivatives, including Gemfibrozil 67, Clofibrate 68, Fenofibrate 69, Isoxepac 70, Flurbiprofen (71 and 72), Naproxen 73, and Xanthotoxin 74, were synthesized via a concise and highly selective sequence. Key to this process was the regioselective C–H halogenation (bromination or iodination) of aryl scaffolds85–87, followed by palladium-catalyzed glycosyl cross-coupling with full unproteced glycosyl stannane 18. The reaction displayed remarkable chemoselectivity in halogenated substrates (e.g., 68, 69, 71, 72), with no erosion of stereochemical integrity even in structurally complex molecules such as Naproxen 73. Notably, electron-rich and sterically hindered substrates (e.g., 68–70, 74) typically challenging for cross-coupling reactions underwent efficient glycosylation under standard conditions. As anticipated, by tuning the site of halogenation, glycosylation patterns could be precisely modulated, enabling programmable, site-selective late-stage glycodiversification. This precise late-stage C-glycosylation protocol provides a reliable, general, and robust strategy for directly introducing glycan motifs into complex drug-like molecules and natural products, expanding access to various glycosylated analogues for biological evaluation and pharmaceutical optimization.

1,2-Annulated sugars have attracted considerable attention owing to their diverse structures and potent biological activities88. Among them, fused cyclic aryl C-glycosides represent a valuable yet under-explored subclass, largely due to the pronounced steric congestion surrounding the anomeric center. While established cross-coupling strategies are well-suited for acyclic aryl C-glycosides6, their direct application to the synthesis of fused cyclic aryl C-glycosides has been severely hampered by steric constraints, often compromising stereoselectivity89. Previously, we reported the stereospecific intramolecular glycosyl cross-coupling strategy for the construction of both cis- and trans-fused cyclic C-glycosides61. However, this approach required additional manipulations, including the pre-installation of a 2-iodobenzyl group at the C2-OH position of the glycosyl donor, thereby limiting its overall synthetic efficiency. To facilitate the sterically demanding coupling, the method relied on an intramolecular design, high palladium catalyst loading (10 mol%) and prolonged reaction times (72 h). To address these longstanding challenges and demonstrate the practical utility of our sterically hindered glycosyl cross-coupling platform, we devised a direct and highly stereospecific strategy for the one-step synthesis of fused cyclic aryl C-glycosides. This approach capitalizes on the efficient Stille glycosylation of glycosyl stannanes 77 bearing a free C2-OH group and bulky aryl halides 14-1 containing an ortho-ester substituent, enabling simultaneous formation of C–C glycosidic and C–O bonds in a single operation. As shown in Fig. 9a, a variety of common glycosyl stannanes coupled smoothly with methyl 2-bromobenzoate 14a, affording the desired fused cyclic aryl C-glycosides 79–83 in isolated yields of 29–57%. Moreover, other sterically hindered aryl halides 14–1, featuring substituents such as chloro 84, aldehyde 85, naphthyl 86, ester 87, and methyl 88, were also well tolerated under the optimized conditions, delivering the corresponding products in moderate yields. Notably, the anomeric selectivity of all annulated C-glycosides is governed by stereoretentive transmetalation, with α-anomeric stannanes affording exclusively the α-product and β-anomeric stannanes yielding the β-product.

Navogliflozin, a next-generation SGLT2 inhibitor for type 2 diabetes, features a highly sterically hindered aryl C-glycosidic bond, a structural element critical to its pharmacological efficacy and safety90. A previously reported synthesis of compound 7 began with the reaction between an aryl lithium reagent and lactone 76. Following this key C–C bond-forming step, four additional transformations were required to reconstruct the anomeric configuration and adjust protecting groups88. Notably, the method relied heavily on reactive and flammable reagents, posing operational challenges and yielding exclusively the β-anomer. In contrast, our approach enables the direct coupling of sterically hindered aryl bromides with fully unprotected glycosyl stannane 18 and its α-anomer 18-α in a single step, delivering the corresponding β- and α-anomers in 96% and 68% yield, respectively, with excellent stereoselectivity (Fig. 9b). This streamlined route not only simplifies the synthetic sequence but, crucially, provides access to both anomers, facilitating more comprehensive structure activity relationship studies.

Chrysin 8-C-β-D-glucosides are natural flavone aryl C-glycosides isolated from the herbs of Psidium guajava, featuring a sterically congested β-C-glycosidic linkage and exhibiting broad biological activities, including anti-diabetic, antibacterial, antiviral, antioxidant, anti-inflammatory, and anti-tumor effects89. Given its pronounced steric hindrance and electron-rich aromatic core, chrysin 8-C-β-D-glucoside was chosen as a model to further showcase the robustness of our next generation of glycosyl Stille cross-coupling conditions (Fig. 9c). The synthesis began with methylation of hydroxyl groups of Apigenin 89 to afford 90 in 86% yield, followed by regioselective bromination at C-8 to give 91 in 82% yield. Subsequent intermolecular Stille coupling of 91 with C2-OH unprotected β-D-glucosyl stannane 45n proceeded under standard conditions, furnishing 92 in 13% yield but with exclusive anomeric control. The low yield observed for the cross-coupling of substrate 91 arises from its combined steric hindrance and electron-rich character, which hinders both oxidative addition and transmetalation. Increasing the palladium loading does not improve the yield and instead leads to significant β-OBn elimination from glycosyl copper intermediates, indicating that these intermediates cannot efficiently undergo transmetalation and that steric hindrance in transmetalation likely represents the rate-limiting factor. Final global debenzylation with BCl₃ provided chrysin 8-C-β-D-glucoside 93 in 81% yield.

To illustrate the advantages of our second-generation glycosyl Stille cross-coupling reaction in constructing sterically hindered aryl C-glycosides, we chose electron-rich, sterically demanding 2-bromo-4-methoxyphenol 94, which bears multiple potential reactive sites, along with 4-methoxyphenol 98, as model substrates to systematically investigate three different approaches involving glycosyl anions, glycosyl cations, and glycoside radicals (Fig. 10). As expected, both optically pure α- and β-isomers of glucosyl stannanes coupled smoothly with 2-bromo-4-methoxyphenol 94, affording the corresponding β-aryl C-glycosides 95 and α-aryl C-glycosides 96 in yields of 58% and 15%, respectively, with exclusive anomeric control and no detectable O-glycoside 99 formation (Fig. 10a). This outcome highlights the excellent chemo- and stereoselectivity of our method. In contrast, classical Friedel–Crafts-type glycosylations of electron-rich arenes with glycosyl electrophiles via glycosyl cations, typically Lewis acid-catalyzed, often lack chem- and stereoselectivity24,25. For example, anomerically pure α- or β-O-glucosyl trichloroacetimidate 97 reacted with 4-methoxyphenol 98 under catalytic TMSOTf conditions furnished only O-glycosides 99 with similar α/β ratios (1:1.26 and 1:1.30), rather than the desired α-hydroxy aryl C-glycosides 95 or 96 (Fig. 10b). This result reflects the oxocarbenium-ion-mediated mechanism of Schmidt glycosylation, in which the initial anomeric configuration is largely erased (Fig. 10b).[15a] More recently, nickel-catalysed reductive coupling of glycosyl halides with aryl halides via glycoside radicals have emerged as an alternative route to aryl C-glycosides63. To assess this approach for sterically hindered C-glycosides, the Ni/tBu-Terpy/Zn system was tested with glucosyl bromide 100 and 2-bromo-4-methoxyphenol 94, but no desired products 95 or 96 were obtained (Fig. 10c). These comparisons further emphasize the robustness, broad compatibility, and high selectivity of our Pd-catalyzed strategy. Furthermore, although the distinct advantages of second-generation ligands (L10 and L11) over first-generation ligands L1 with sterically hindered electrophiles were firmly established in the substrate scope, it was necessary to confirm their performance with non-hindered substrates. As shown in Fig. 10d, coupling of model substrate 16 with bromobenzene under identical conditions afforded the product in 80%, 76%, and 80% yields with L1, L10, and L11, respectively. These results demonstrate that the second-generation ligands are broadly effective for both sterically hindered and unhindered systems, thereby justifying their replacement of the first-generation Stille glycosyl cross-coupling reactions35,36.

In summary, we developed a highly efficient and stereospecific Pd-catalyzed glycosyl cross-coupling protocol for the synthesis of sterically hindered aryl C-glycosides, enabled by two underexplored biaryl monophosphine ligands (L10 and L11). Featuring electron-withdrawing P-bound 3,5-bis(trifluoromethyl)phenyl groups and 2′,6′-methoxy (L10) or isopropoxy (L11) substituents, these ligands outperform first-generation JackiePhos (L1), showing enhanced reactivity with bulky aryl electrophiles and overcoming long-standing limitations in hindered aryl C-glycosylation. Computational analysis shows that the underexplored ligand L11 favors reductive elimination to form sterically hindered C–C bonds over β-methoxy elimination, opposite to the first-generation ligand L1, consistent with experimental results. NBO analysis further reveals that Pd in Int3 (L11) carries a slightly higher charge than in Int3′ (L1); the more electron-rich Pd in Int3′ stabilizes the β-methoxy elimination transition state, whereas the electron-deficient Pd in Int3 promotes C–C bond formation via reductive elimination. Crystal structure analysis revealed that bromide-bridged dimeric Pd(II) species are intrinsic to diarylbiaryl monophosphine ligands—challenging a longstanding assumption and resolving a structural ambiguity relevant to ligand design. The developed method shows broad applicability, accommodating diverse (un)protected sugars and sterically demanding aryl partners with consistently high chemo- and stereoselectivity. Overall, this work provides a timely solution to a long-standing challenge in the stereoselective synthesis of sterically hindered aryl C-glycosides, advances glycomimetic drug discovery, and offers deeper insights into biaryl monophosphine ligand design, thereby expanding the scope of Pd-catalyzed cross-couplings.

Methods
General procedure for cross-Coupling of glycosyl stannanes with hindered aryl halides. Inside an argon-filled glovebox, an oven-dried 3 mL vial was charged with anomeric stannane (1.5–2.0 equiv), aryl halide (1.0 equiv), Pd2(dba)3 (2.5–5 mol%), L10/L11/L1 (10–20 mol%), CuCl (300 mol%), KF (200%) and anhydrous 1,4-dioxane (1.5 mL). The vial was capped and taken outside of the glovebox. The resulting mixture was placed into a pre-heated (110 °C or 140 °C) aluminium block and stirred for the indicated period of time, cooled to rt, filtered through a pad of Celite, and concentrated. 1H NMR spectra was recorded using this mixture to evaluate diastereoselectivity. The crude material was purified by column chromatography on SiO2.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "Feng Zhu and coworkers disclose a modified version of the glycosyl cross-coupling reaction utilizing glycosyl stannanes and aryl halides. The authors claim that the use of less hindered ligand systems enables the glycosylation of sterically hindered aryl halides with glycosyl stannanes. While the Stille coupling utilizing the glycosyl stannanes is well studied by Walczak’s group, the current work provides more refined conditions to access the ortho-substituted aryl glycosides in a stereoretentive fashion. Crystallographic and theoretical studies have been conducted to provide an in-depth understanding of the mechanistic differences in using the ligands L1, L10, and L11, which exhibit superior reactivity.\n\nThe reactivity of glycosyl stannanes is poor and utilizing the electon-deficient ligand systems to enhance the electrophilicity on palladium to improve the reactivity of glycosyl stannes is all studied and published earlier by the Feng Zhu in Walczak’s group. While the current method by Feng Zhu with new slightly more electron-deficient and less hindered ligands, is showcased on a good number of substrates, most of the substrates that the authors have chosen are mono-ortho substituted and with not-so-bulky substituents, and do not really count as sterically hindered substrates. Also, most of the aryl partners chosen are relatively electron-deficient aryls (with ortho ester, nitro, cyano etc) that are suited to undergo the coupling easily. Indeed, the synthesis of Chrysin glycoside with relatively more hindered and electron-rich substrate provided the product in a paltry 13% yield (Fig. 9).\n\nWithout a doubt, the method significantly enhances the utility of glycosyl stannanes, providing access to aryl glycosides with increased complexity and in a stereoselective fashion. However, since major developments in this direction have already been published in a couple of JACS papers earlier, this reviewer does not believe that the improvements presented in this manuscript are significant enough to warrant a publication in Nature Communications.", "reviewer_2": "This manuscript describes the development of a next generation Stille-Cross Coupling type C-aryl-glycosylation, improving upon the Walczak method in Refs 57-58. A wide series of sterically hindered aryl halides, in particular the ortho-substituted variants can be tolerated. The reaction is highly stereospecific and retentive, generating the anomer that is the same configuration as the initial glycosyl stannane. A range of protecting group schemes are tolerated, and even unprotected glycosyl stannanes can be assimilated.\n\nAn extensive study of the catalyst structure was conducted (Fig 2). The authors also crystallized oxidative addition complexes to gain insights into the active Pd species (Fig 3). Multivariate modelling offered insights into the relationship between ligand structure and product distribution (Fig 4).\n\nComputations in synergy with kinetics were conducted, which supported first order dependence on Pd, KF and glycosyl stannane in the rate limiting step (Fig 5). The applicability of the strategy was further extended to construction of fused cyclic C-glycosides through a Stille/lactonization sequence (Fig 9). Several expedient total syntheses including Enavogliflozin and Chrysin 8-beta-C-glucoside were demonstrated with the Stille method.\n\nThis is a robust strategy that gains access into difficult C-glycosidic structures, tolerating even unprotected glycosyl stannanes (derivative 62 and Fig 8). I am hence supportive of\n- Lately appearing aryl-C-glycosylation strategies and relevant reviews in catalytic glycosylations reviews has to be additionally cited:\nAngew. Chem. Int. Ed. 2025, 64, e202514167.\nAngew. Chem. Int. Ed. 2025, DOI: 10.1002/anie.202517553\n- Is there a reason why disarming groups (OPiv, OLev, OBz) are only installed on the O6 position (in 47, 48, 49)? Do fully disarmed perbenzoylated/peracetylated substrates work in this method?\n- Fig 10 b: While comparisons were made with the Schmidt glycosylation, this is not a balanced analysis because the authors have used anomerically pure alpha or beta glycosyl stannanes in panel A for their stereospecific result, while the anomeric mixture of the trichloroacetimidate 97 was used for the less selective result.\nIf the anomerically pure alpha or beta anomers of the 97 were used with TMSOTf as promoter, would the authors then get a stereospecific result?", "reviewer_3": "Zhu and co-workers report a next-generation glycosyl cross-coupling approach for the synthesis of sterically hindered C-aryl glycosides. The manuscript is technically sound, supported by extensive ligand-optimization studies, DFT calculations, and a broad substrate scope featuring more than 65 examples. C-Glycosides are important structural motifs with significant relevance to drug discovery, and the authors aim to address longstanding challenges associated with anomeric congestion by using newly identified ligands that engage bulky aryl halides for stereoselective C-glycoside formation.\n\nHowever, I note that closely related strategies have been previously explored by the corresponding author in earlier work conducted with Prof. Maciej Walczak (J. Am. Chem. Soc. 2016, 138, 12049; J. Am. Chem. Soc. 2017, 139, 17908). In particular, the 2017 JACS paper (J. Am. Chem. Soc. 2017, 139, 17908–17922) successfully employed sterically demanding aryl halides in the total synthesis of Dapagliflozin and Salmochelin TGE—both featuring highly hindered aglycone units. Some sterically demanding aryl halides in J. Am. Chem. Soc. 2016, 138, 12049−12052 has also explored substituted aryl halide derivatives. In the present manuscript, the primary difference appears to be the use of modified ligands, while the overall reaction design and catalytic system remain largely unchanged.\n\nGiven these concerns regarding novelty and considering the high threshold for conceptual advance expected for Nature Communications, the present work represents an incremental extension of the authors’ previous contributions. Therefore, I do not recommend publication in Nature Communications.\n\nMajor concerns:\n1. Much of the introduction focuses on conventional C-aryl glycosides, whereas the most compelling and novel aspect of this manuscript, in my view, is the annulated C-glycoside chemistry. The authors are advised to revise the introduction to more clearly highlight the significance and novelty of the annulated C-aryl glycosides. Alternatively, they may consider removing this section from the current manuscript and preparing a separate article dedicated exclusively to the annulated scaffolds. If retained, the introduction and the title should be rewritten to ensure clarity and better alignment with the core contribution before submitting to another journal.\n2. DFT calculations were carried out using glycosyl stannanes that were not included in the experimental substrate scope. Is there any specific reason for selecting these unstated substrates for the computational studies?\n3. For the annulated C-glycosides section, the authors should provide a clearer rationale for the observed variations in selectivity when different glycosyl donors are employed. Additionally, several recent and relevant reports have not been cited, such as the work published in Organic Letters 2025, 27, 12, 2924–2929.\n4. During the cross-coupling of substrate 91 with glycosyl stannanes, the yield dropped significantly. Is there any specific reason for this decrease? The authors should provide a clear explanation. At present, they only attribute the outcome to the novelty of incorporating sterically demanding aryl halides, which is insufficient. A mechanistic or experimental rationale is needed to justify the observed low yield.\n\nIn conclusion, considering the substantial work the authors have carried out, I believe this manuscript has the potential to be submitted to other high-impact journals such as Angewandte Chemie or ACS Catalysis, but not Nature Communications.", "reviewer_4": "This manuscript reports a ligand-enabled, next-generation glycosyl Stille cross-coupling strategy for the stereospecific synthesis of sterically hindered aryl C-glycosides, addressing a long-standing challenge in carbohydrate chemistry. The study is thoughtfully designed, featuring comprehensive experimental evaluation, mechanistic investigations, and valuable demonstrations in late-stage glycodiversification and the total synthesis of bioactive molecules. The identification of novel biarylmonophosphine ligands (L10 and L11), together with structural and computational insights, represents a meaningful advance in glycosyl cross-coupling chemistry. Overall, the manuscript is scientifically rigorous, clearly written, and of broad interest to researchers in synthetic chemistry, glycobiology, and drug discovery. Given the robustness of the work and the timely significance of catalytic carbohydrate synthesis, the reviewer supports publication in Nature Communications pending revision to address the following points.\n1. The DFT calculations attribute the selectivity difference between L1 and L11 to subtle changes in Pd electron density. Could the authors provide additional mechanistic evidence or further analysis to clarify how such a small electronic difference leads to a reversal of the preferred reaction pathway?\n2. The MLR model is constructed using only 20 ligands. Could the authors comment on the reliability and predictive power of the model given this relatively small dataset?\n3. In the DFT studies, why was a methoxy-protected sugar chosen as the model substrate instead of the more commonly used BnO-protected analogue?\n4. Reference 50 requires the inclusion of volume and page numbers."}, "author_response": "We sincerely thank the reviewers for their time and thoughtful comments on our manuscript. Their constructive feedback has been invaluable in improving the quality and clarity of our work. We have carefully addressed all the reviewers’ suggestions in the revised manuscript. Please find the revised version of the manuscript and Supporting Information, with all changes clearly highlighted.\nPoint-by-point responses to the reviewers' comments is as follows：\nReviewer 1:\nFeng Zhu and coworkers disclose a modified version of the glycosyl cross-coupling reaction utilizing glycosyl stannanes and aryl halides. The authors claim that the use of less hindered ligand systems enables the glycosylation of sterically hindered aryl halides with glycosyl stannanes. While the Stille coupling utilizing the glycosyl stannanes is well studied by Walczak’s group, the current work provides more refined conditions to access the ortho-substituted aryl glycosides in a stereoretentive fashion. Crystallographic and theoretical studies have been conducted to provide an in-depth understanding of the mechanistic differences in using the ligands L1, L10, and L11, which exhibit superior reactivity.\nThe reactivity of glycosyl stannanes is poor and utilizing the electon-deficient ligand systems to enhance the electrophilicity on palladium to improve the reactivity of glycosyl stannes is all studied and published earlier by the Feng Zhu in Walczak’s group. While the current method by Feng Zhu with new slightly more electron-deficient and less hindered ligands, is showcased on a good number of substrates, most of the substrates that the authors have chosen are mono-ortho substituted and with not-so-bulky substituents, and do not really count as sterically hindered substrates.\nResponse: We thank the reviewer for the insightful and thoughtful comments. The present study builds upon these foundations but is not a simple reiteration. Instead, it aims to address a distinct and long-standing challenge associated with steric effects in glycosyl cross-coupling reactions, particularly within the context of structurally complex carbohydrate substrates.\nIt is important to emphasize that carbohydrates are inherently different from typical small-molecule coupling partners. Owing to their multiple stereocenters, dense functionalization, and rigid three-dimensional frameworks, steric effects in glycosylation reactions arise not only from the electrophile itself, but also from the cooperative and often non-intuitive steric interactions between the electrophile and the glycosyl fragment. As a result, steric hindrance in glycosyl cross-couplings cannot be evaluated solely based on conventional definitions used for simple aryl substrates.\nIn this context, mono-ortho-substituted electrophiles do represent sterically hindered substrates for glycosyl stannanes, even if they may not be considered highly congested in a general cross-coupling sense. This distinction is well recognized in carbohydrate chemistry, where such substrates often show dramatically diminished reactivity or are entirely overlooked in classical chemical glycosylation reactions. The pronounced sensitivity of glycosyl donors to ortho-substitution is precisely one of the reasons why these substrates have historically been underexplored.\nMoreover, we would like to highlight that the current method is not limited to mono-ortho-substituted electrophiles. The manuscript also demonstrates several examples involving ortho-disubstituted electrophiles (42, 43, 44, 73, and 74), which further underscores the capability of the newly developed, less hindered and more electron-deficient ligand system to overcome steric constraints unique to glycosyl cross-coupling chemistry.\nTaken together, while we acknowledge the reviewer’s point regarding the conventional classification of steric hindrance, we believe that within the specific and highly constrained chemical space of carbohydrate-derived nucleophiles, the substrates investigated in this work do constitute sterically demanding cases. The successful coupling of these substrates therefore represents a meaningful advance beyond prior reports.\nAlso, most of the aryl partners chosen are relatively electron-deficient aryls (with ortho ester, nitro, cyano etc) that are suited to undergo the coupling easily. Indeed, the synthesis of Chrysin glycoside with relatively more hindered and electron-rich substrate provided the product in a paltry 13% yield (Fig. 9).\nResponse: We thank the reviewer for this comment. The developed method does not show an inherent preference for electron-deficient aryl partners. Both electron-deficient and electron-rich aryl electrophiles are competent coupling partners, as demonstrated by the broad substrate scope in the manuscript. The use of ortho-ester-substituted aryl electrophiles as standard substrates during glycoside scope evaluation was primarily for practical reasons, namely to facilitate product purification, rather than to favor more reactive partners.\nNotably, the substrate scope includes more than 20 examples bearing electron-donating substituents, including several pharmaceutically relevant aryl motifs, clearly indicating good compatibility with electron-rich substrates.\nRegarding the chrysin glycoside, although the yield is 13%, chrysin is a particularly challenging, electron-rich and sterically congested substrate for C-glycosylation. To the best of our knowledge, this represents the first successful TM-catalyzed stereospecific cross-coupling at this position, and thus constitutes a meaningful proof of concept that could be further improved through systematic optimization, for example, by further ligand development.\nWithout a doubt, the method significantly enhances the utility of glycosyl stannanes, providing access to aryl glycosides with increased complexity and in a stereoselective fashion. However, since major developments in this direction have already been published in a couple of JACS papers earlier, this reviewer does not believe that the improvements presented in this manuscript are significant enough to warrant a publication in Nature Communications.\nReviewer 2:\nThis manuscript describes the development of a next generation Stille-Cross Coupling type C-aryl-glycosylation, improving upon the Walczak method in Refs 57-58. A wide series of sterically hindered aryl halides, in particular the ortho-substituted variants can be tolerated. The reaction is highly stereospecific and retentive, generating the anomer that is the same configuration as the initial glycosyl stannane. A range of protecting group schemes are tolerated, and even unprotected glycosyl stannanes can be assimilated.\nAn extensive study of the catalyst structure was conducted (Fig 2). The authors also crystallized oxidative addition complexes to gain insights into the active Pd species (Fig 3). Multivariate modelling offered insights into the relationship between ligand structure and product distribution (Fig 4).\nComputations in synergy with kinetics were conducted, which supported first order dependence on Pd, KF and glycosyl stannane in the rate limiting step (Fig 5). The applicability of the strategy was further extended to construction of fused cyclic C-glycosides through a Stille/lactonization sequence (Fig 9). Several expedient total syntheses including Enavogliflozin and Chrysin 8-beta-C-glucoside were demonstrated with the Stille method.\nThis is a robust strategy that gains access into difficult C-glycosidic structures, tolerating even unprotected glycosyl stannanes (derivative 62 and Fig 8). I am hence supportive of publication.\nResponse: We sincerely thank the Reviewer for the thorough evaluation and the highly positive assessment of our work. We are grateful for the recognition of the methodological advances, mechanistic investigations, and synthetic applications presented in this manuscript. The Reviewer’s supportive comments strongly encourage us and reinforce the significance of this study. We appreciate the recommendation for publication.\n1. Lately appearing aryl-C-glycosylation strategies and relevant reviews in catalytic glycosylations reviews has to be additionally cited: Angew. Chem. Int. Ed. 2025, 64, e202514167. Angew. Chem. Int. Ed. 2025, DOI: 10.1002/anie.202517553\nResponse: We thank the Reviewer for this helpful suggestion. These two significant publications have now been appropriately cited in the revised manuscript as Refs. 22 and 23.\n2. Is there a reason why disarming groups (OPiv, OLev, OBz) are only installed on the O6 position (in 47, 48, 49)? Do fully disarmed perbenzoylated/peracetylated substrates work in this method?\nResponse: We thank the Reviewer for this helpful suggestion. Initially, disarming groups were introduced only at the O6 position to systematically evaluate the compatibility of disarming protecting groups with the cross-coupling reaction, while also considering the ready availability of the corresponding starting materials.\nAs suggested by the Reviewer, we further examined fully disarmed substrates. It should be noted that when disarming groups such as OAc or OBz are installed at the C2 position, the corresponding glycosyl stannanes are stable under the reaction conditions but undergo complete decomposition to glycals during silica gel chromatography, which limited their initial inclusion in the substrate scope.\nNevertheless, we have now investigated two fully disarmed, perbenzoylated and peracetylated 2-deoxyglucose-derived glycosyl stannanes. Under the standard reaction conditions, both substrates underwent smooth cross-coupling to afford the desired C-glycosides 49 and 50 in good yields with complete stereospecificity, as shown in the uppted Fig. 7.\nAccordingly, Fig. 7 has been updated, and the relevant discussion has been revised in the manuscript. The revised text now reads:\n“Fully disarmed peracetylated and perbenzoylated 2-deoxy-D-glucosyl stannanes smoothly reacted to afford the corresponding products 49 and 50 in 79% and 72% yield, respectively.”\n3. Fig 10 b: While comparisons were made with the Schmidt glycosylation, this is not a balanced analysis because the authors have used anomerically pure alpha or beta glycosyl stannanes in panel A for their stereospecific result, while the anomeric mixture of the trichloroacetimidate 97 was used for the less selective result. If the anomerically pure alpha or beta anomers of the 97 were used with TMSOTf as promoter, would the authors then get a stereospecific result?\nResponse: We thank the Reviewer for this insightful comment and constructive suggestion. Following the Reviewer’s recommendation, we examined the use of anomerically pure α- or β-trichloroacetimidate donors analogous under standard TMSOTf-promoted Schmidt glycosylation conditions. In these experiments, the desired C-glycosides were not formed; instead, only O-glycosides were obtained, and no stereospecificity was observed, even when anomerically pure donors were employed.\nThis outcome reflects the intrinsic ionic nature of Schmidt glycosylation, which proceeds through an oxocarbenium-ion-like intermediate. As a result, the initial anomeric configuration of the donor is largely lost, and stereochemical outcomes are governed by neighboring group participation and substrate-dependent effects rather than anomeric memory.\nIn contrast, the glycosyl Stille cross-coupling described in this work operates via stereoretentive transmetalation from well-defined α- or β-anomeric stannanes, enabling faithful transfer of the anomeric configuration and complete stereospecificity, even for sterically hindered substrates.\nAccordingly, Fig. 10b has been updated, and the relevant discussion has been revised in the manuscript. The revised text now reads:\n“For example, anomerically pure α- or β-O-glucosyl trichloroacetimidate 97 reacted with 4-methoxyphenol 98 under catalytic TMSOTf conditions furnished only O-glycosides 99 with similar α/β ratios (1:1.26 and 1:1.30), rather than the desired α-hydroxyaryl C-glycosides 95 or 96 (Fig. 10b). This result reflects the oxocarbenium-ion-mediated mechanism of Schmidt glycosylation, in which the initial anomeric configuration is largely erased (Fig. 10b).”\nReviewer 3:\nZhu and co-workers report a next-generation glycosyl cross-coupling approach for the synthesis of sterically hindered C-aryl glycosides. The manuscript is technically sound, supported by extensive ligand-optimization studies, DFT calculations, and a broad substrate scope featuring more than 65 examples. C-Glycosides are important structural motifs with significant relevance to drug discovery, and the authors aim to address longstanding challenges associated with anomeric congestion by using newly identified ligands that engage bulky aryl halides for stereoselective C-glycoside formation.\nHowever, I note that closely related strategies have been previously explored by the corresponding author in earlier work conducted with Prof. Maciej Walczak (J. Am. Chem. Soc. 2016, 138, 12049; J. Am. Chem. Soc. 2017, 139, 17908). In particular, the 2017 JACS paper (J. Am. Chem. Soc. 2017, 139, 17908–17922) successfully employed sterically demanding aryl halides in the total synthesis of Dapagliflozin and Salmochelin TGE—both featuring highly hindered aglycone units. Some sterically demanding aryl halides in J. Am. Chem. Soc. 2016, 138, 12049−12052 has also explored substituted aryl halide derivatives. In the present manuscript, the primary difference appears to be the use of modified ligands, while the overall reaction design and catalytic system remain largely unchanged.\nResponse: We thank the Reviewer for these comments. We would like to clarify that in the 2017 JACS paper (J. Am. Chem. Soc. 2017, 139, 17908), the aryl halides used in the total syntheses of Dapagliflozin and Salmochelin TGE did not have substituents near the reaction site and thus are not sterically hindered. In the 2016 JACS paper (J. Am. Chem. Soc. 2016, 138, 12049−12052), only three ortho-substituted aryl halides were examined; one contained an ortho-fluoro substituent (which has minimal or no steric effect), and the other two gave relatively low yields. These results indicate that the first-generation glycosyl cross-coupling of anomeric stannanes does not reliably enable the synthesis of sterically hindered C-glycosides.\nIn fact, the stereoselective construction of sterically hindered C-glycosides remains a major challenge in C-glycoside chemistry, and even widely studied radical glycosylation methods are unable to address it. Therefore, the impact of our work extends beyond a simple modification of reaction design or catalyst; it provides a robust and timely strategy to overcome long-standing limitations in accessing sterically congested C-glycosides, addressing a key challenge that has remained unsolved in the field.\nGiven these concerns regarding novelty and considering the high threshold for conceptual advance expected for Nature Communications, the present work represents an incremental extension of the authors’ previous contributions. Therefore, I do not recommend publication in Nature Communications.\nMajor concerns:\n1. Much of the introduction focuses on conventional C-aryl glycosides, whereas the most compelling and novel aspect of this manuscript, in my view, is the annulated C-glycoside chemistry. The authors are advised to revise the introduction to more clearly highlight the significance and novelty of the annulated C-aryl glycosides. Alternatively, they may consider removing this section from the current manuscript and preparing a separate article dedicated exclusively to the annulated scaffolds. If retained, the introduction and the title should be rewritten to ensure clarity and better alignment with the core contribution before submitting to another journal.\nResponse: We sincerely thank the Reviewer for the thoughtful comments and for recognizing the effectiveness of our method in constructing challenging annulated C-glycosides. The primary aim of our manuscript is to establish a broad and robust platform for C-glycoside synthesis, encompassing both sterically hindered and non-hindered substrates. In fact, the majority of conventional C-aryl glycosides are sterically hindered, whereas annulated C-glycosides represent a relatively rare but special subset.\nGiven that sterically hindered C-glycosides pose a long-standing synthetic challenge, they form the main focus of this study, which seeks to develop a next-generation glycosyl cross-coupling system. However, our methodology is not limited to these challenging substrates. As shown in Fig. 10b, the new-generation C-glycosylation approach is also highly effective for constructing non-hindered C-aryl glycosides, demonstrating the versatility and generality of the method.\nConsidering this, we believe that the current introduction appropriately frames the work and highlights its key contributions, in line with our research logic: starting from a significant and previously unresolved challenge in sterically congested C-glycosides, and then extending to less hindered substrates. We therefore respectfully suggest retaining the existing structure, which emphasizes both the broad applicability of the method and its ability to address previously unmet challenges in sterically congested C-glycoside synthesis.\n2. DFT calculations were carried out using glycosyl stannanes that were not included in the experimental substrate scope. Is there any specific reason for selecting these unstated substrates for the computational studies?\nResponse: We sincerely thank the Reviewer for pointing this out. The glycosyl stannane employed in the DFT calculations was intentionally chosen as the simplest and most computationally tractable model that preserves the key structural features relevant to the transmetalation step. Although this specific glycosyl stannane (OMe-protected sugar) was not included in the experimental substrate scope, our substrate studies indicate that such variations in protecting groups do not alter the stereochemical outcome of the reaction, and therefore do not affect the conclusions drawn from the computational analysis. Such simplifications are standard practice in computational studies to balance accuracy and efficiency.\nThe manuscript has been revised to clarify this point. The relevant passage now reads:\n“To optimize computational efficiency, the OBn group was replaced with OMe, and Bu₃Sn was replaced with Me₃Sn.”\n3. For the annulated C-glycosides section, the authors should provide a clearer rationale for the observed variations in selectivity when different glycosyl donors are employed. Additionally, several recent and relevant reports have not been cited, such as the work published in Organic Letters 2025, 27, 12, 2924–2929.\nResponse: We thank the Reviewer for these helpful suggestions. The structure of compound 77 has been updated in the revised manuscript to more accurately represent the molecule. The control of anomeric selectivity arises from the stereospecific transmetalation of the α- or β-anomeric stannanes, which preserves the stereochemistry of the glycosyl donor.\nWe also thank the Reviewer for pointing out the recent relevant literature. The work published in Organic Letters 2025, 27, 12, 2924–2929 has now been added in the revised manuscript as Ref. 91.\nThe relevant passage in the revised manuscript now reads:\n“Notably, the anomeric selectivity of all annulated C-glycosides is governed by stereoretentive transmetalation, with α-anomeric stannanes affording exclusively the α-product and β-anomeric stannanes yielding the β-product.”\n4. During the cross-coupling of substrate 91 with glycosyl stannanes, the yield dropped significantly. Is there any specific reason for this decrease? The authors should provide a clear explanation. At present, they only attribute the outcome to the novelty of incorporating sterically demanding aryl halides, which is insufficient. A mechanistic or experimental rationale is needed to justify the observed low yield.\nResponse: We thank the Reviewer for raising this important question. The significant drop in yield observed for the cross-coupling of substrate 91 is primarily due to its combined high steric hindrance and electron-rich character, which together hinder both oxidative addition and transmetalation, resulting in reduced reaction efficiency. Increasing the palladium loading does not improve the yield; instead, it leads to significant β-OBn elimination from glycosyl copper intermediates, which cannot efficiently undergo the subsequent transmetalation step. This observation indicates that while the electron-rich nature slows oxidative addition, steric hindrance in transmetalation likely represents the rate-limiting factor.\nThe relevant rationale has been added to the revised manuscript and now reads:\n“The low yield observed for the cross-coupling of substrate 91 arises from its combined steric hindrance and electron-rich character, which hinder both oxidative addition and transmetalation. Increasing the palladium loading does not improve the yield and instead leads to significant β-OBn elimination from glycosyl copper intermediates, indicating that these intermediates cannot efficiently undergo transmetalation and that steric hindrance in transmetalation likely represents the rate-limiting factor.”\nIn conclusion, considering the substantial work the authors have carried out, I believe this manuscript has the potential to be submitted to other high-impact journals such as Angewandte Chemie or ACS Catalysis, but not Nature Communications.\nReviewer 4 :\nThis manuscript reports a ligand-enabled, next-generation glycosyl Stille cross-coupling strategy for the stereospecific synthesis of sterically hindered aryl C-glycosides, addressing a long-standing challenge in carbohydrate chemistry. The study is thoughtfully designed, featuring comprehensive experimental evaluation, mechanistic investigations, and valuable demonstrations in late-stage glycodiversification and the total synthesis of bioactive molecules. The identification of novel biarylmonophosphine ligands (L10 and L11), together with structural and computational insights, represents a meaningful advance in glycosyl cross-coupling chemistry. Overall, the manuscript is scientifically rigorous, clearly written, and of broad interest to researchers in synthetic chemistry, glycobiology, and drug discovery. Given the robustness of the work and the timely significance of catalytic carbohydrate synthesis, the reviewer supports publication in Nature Communications pending revision to address the following points.\nResponse: We sincerely thank the Reviewer for the positive and encouraging evaluation of our work, and we greatly appreciate the Reviewer’s support for publication. We have carefully considered all comments and suggestions and have revised the manuscript accordingly to address the points raised.\n1. The DFT calculations attribute the selectivity difference between L1 and L11 to subtle changes in Pd electron density. Could the authors provide additional mechanistic evidence or further analysis to clarify how such a small electronic difference leads to a reversal of the preferred reaction pathway?\nResponse: We appreciate the Reviewer’s insightful question. The Reviewer is correct that the electronic differences between L1 and L11 are subtle and not easily discernible visually in ESP maps. However, quantitative charge analyses (NBO and Hirshfeld) reveal a consistent slight decrease in Pd electron density with L11. Importantly, the β-methoxy elimination transition state is more polarized and thus more sensitive to these small electronic changes than the C–C reductive elimination transition state. Even a modest shift (Δq ≈ 0.02) is sufficient to alter their relative energies, resulting in the observed reversal of selectivity.\n2. The MLR model is constructed using only 20 ligands. Could the authors comment on the reliability and predictive power of the model given this relatively small dataset?\nResponse: We thank the Reviewer for raising this important point. Although the dataset is relatively modest (20 ligands), the multivariate linear regression (MLR) model demonstrates strong linear correlations (R² = 0.85–0.90) and good agreement with test set predictions. Furthermore, cross-validation using an 80:20 split confirms the robustness of the model. We acknowledge that a larger dataset could further enhance its generality, and this has been noted in the revised discussion.\nThe relevant paragraph has been added to the revised manuscript and now reads:\n“Although based on a modest dataset of 20 ligands, the MLR model shows strong correlations (R² = 0.85–0.90) and good agreement with test set predictions. Cross-validation (80:20 split) confirms its robustness, and undoubtedly, a larger dataset could further improve generality.”\n3. In the DFT studies, why was a methoxy-protected sugar chosen as the model substrate instead of the more commonly used BnO-protected analogue?\nResponse: We thank the Reviewer for this thoughtful question. A methoxy-protected sugar was chosen as the DFT model substrate primarily to reduce computational cost while retaining the key steric and electronic features relevant to the transmetalation and reductive elimination steps. The methoxy group serves as a simplified yet chemically representative model of the BnO-protected analogue, avoiding the additional conformational flexibility and computational complexity introduced by the benzyl group.\nThe manuscript has been revised to clarify this point. The relevant passage now reads:\n“To optimize computational efficiency, the OBn group was replaced with OMe, and Bu₃Sn was replaced with Me₃Sn.”\n4. Reference 50 requires the inclusion of volume and page numbers.\nWe thank the Reviewer for pointing this out. Reference 50, now renumbered as 52 in the revised manuscript, has been updated to include the volume and page numbers and now reads: Org. Lett. 23, 4289–4293 (2021)."}, {"round": 2, "reviewer_comments": {"reviewer_2": "The authors have fully addressed my concerns, and those of other reviewers and I recommend publication in Nat. Commun. as it is.", "reviewer_3": "The authors have addressed all the comments and incorporated the necessary corrections suggested in the previous round of review. I am satisfied with the revisions, and the manuscript can be accepted in its current form.", "reviewer_4": "The authors have satisfactorily addressed all reviewer comments. I therefore recommend acceptance of this manuscript by Nature Communications."}, "author_response": ""}]

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