Synthesis of C-glycosides enabled by palladium-catalyzed glycosylation reactions

Abstract

C-Glycosides are a privileged class of carbohydrates that exhibit remarkable biological and pharmaceutical activities. Transition metal-catalyzed cross-coupling reactions are powerful tools for the efficient and rapid construction of C–C bonds. Among various transition-metal catalyzed methods, palladium-catalyzed C-glycosylation is an effective and reliable approach to synthesize C-glycosides and involves the reaction of glycosyl donors and various reaction partners via C–C glycosidic bond formation under mild conditions with high regio/stereo-selectivities. In this review, palladium-catalyzed C-glycosylation reactions from 2020 to 2024 are summarized and discussed in detail, with focus on the synthesis of C-aryl glycosides, C-alkyl glycosides, C-alkenyl glycosides, and other functionalized C-glycosides. Some representative synthetic strategies and their transformation application along with reaction mechanisms are also highlighted.

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Wenli Tong

Wenli Tong obtained her Bachelor's degree from the XinZhou Normal University in 2023. Currently, she is doing research toward her Master's degree at Jiangxi Normal University. Her research interests currently focus on metal-catalyzed organic synthesis and sustainable catalysis and synthesis.

Jie-Ping Wan

Prof. Dr Jie-Ping Wan studied chemistry from 2000–2004 in the Department of Chemistry, Nanchang University. After obtaining a BSc degree in 2004, he moved to the Department of Chemistry, Zhejiang University in 2005 for his postgraduate studies under the guidance of Prof. Yuanjiang Pan. After receiving his PhD degree there in 2010, he joined the College of Chemistry and Chemical Engineering, Jiangxi Normal University as an assistant professor in the same year, and was promoted to full professor in 2017. He conducted postdoctoral research at RWTH Aachen University with Prof. Dieter Enders from Sep. 2011 to Aug. 2012. His current research interests focus on diversity-oriented synthesis, the discovery and application of platform synthons and sustainable catalysis and synthesis.

Jianchao Liu

Jianchao Liu received his PhD from South China University of Technology (SCUT) under the supervision of Prof. Biaolin Yin (2012–2017). Since 2017, he has been with the National Engineering Research Center for Carbohydrate Synthesis at Jiangxi Normal University. His current research interests mainly focus on the development and applications of new synthetic methods.

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1. Introduction

C-Glycosides, which possess a C–C bond between a carbohydrate moiety and an aglycone unit, are widely present in various bioactive natural products and drug candidates.¹ These cores often exhibit higher chemical and metabolic stability compared with their O- and N-linked glycoside congeners.² In this context, many C-glycosides can be valuable as important mimics of biologically active natural O-glycosides and thus can be employed as potential therapeutic agents,³ including antibiotics, and antitumor and antidiabetic treatments.⁴ Given their tremendous structural and functional diversity, much effort has been dedicated toward the development of efficient and practical methods for synthesizing C-glycosides.⁵ Traditional methods mainly involve acid-promoted Ferrier rearrangements,⁶ Friedel–Crafts-type C-glycosylation of arenes,⁷ and nucleophilic reactions of organo-metallic reagents with glycosyl donors.⁸ However, these methods often required stoichiometric amounts of activators and prefunctionalized organometallic partners and have a narrow substrate scope with poor functional group compatibility. Moreover, the stereoselective formation of the C-glycosidic bond is still challenging due to the absence of the anomeric effect. Consequently, the development of highly efficient catalytic synthetic routes to stereoselectively obtain structurally diverse C-glycosides is desirable.

Transition-metal catalyzed reactions have advanced organic chemistry by enabling the construction of new bonds for the creation of novel organic molecules.⁹ In this regard, the application of transition metal catalysis for constructing glycosyl linkages has significantly increased in recent years.^10–17 Unlike many metal catalysts, palladium catalysts are resilient to oxygen, moisture, and even acid, with no serious toxicity problems. Moreover, palladium catalysis has been revolutionized by its ability to accommodate and tolerate a wide variety of functional groups, making it an essential tool for constructing various C–C bonds in synthetic chemistry.¹⁸ Within this realm, palladium-catalyzed glycosylation reactions have displayed tremendous versatility for the synthesis of C-glycosides via C–C glycosidic bond formation with high regio/stereo-selectivities.

In general, four effective strategies have been developed for palladium-catalyzed C-glycosylation. The first one involves using themigratory insertion of glycals into organopalladium species to form alkyl palladium intermediates, which can undergo β-elimination to provide a reliable route to obtain α-C-glycosides as major products (Fig. 1a). On the other hand, the second strategy would begin with the stereoselective formation of a π-allyl palladium complex. Further functionalization of the π-allyl palladium complex produces the final β-selective product (Fig. 1b). Another powerful strategy involves the coupling reactions of pre-functionalized glycosyl donors (such as tin, boron, and halide reagents) with the corresponding electrophilic reagents in a stereoselective manner (Fig. 1c). In addition, palladium-catalyzed C–H functionalization, including C–H carbofunctionalization of glycosyl donors and glycosylation of C–H bonds enabled by directing groups or the Catellani reaction, has emerged as a powerful strategy for the synthesis of predominantly α-C-glycosides (Fig. 1d).

Fig. 1 Strategies for palladium-catalyzed C-glycosylation.

Despite the growing interest in palladium-catalyzed synthesis,^19,36,54 and the recently published reviews focusing on transition-metal catalyzed glycosylations,^20,21 we believe it is still necessary to systematically summarize the recent progress made in the development of palladium-catalyzed C-glycosylations to access C-glycosides. Notably, to the best of our knowledge, only the Pd-catalyzed C–C bond formation in carbohydrates and their applications have been summarized in 2021 by Hussain and co-workers.^20f Therefore, in this review, we will summarize the most recent achievements in palladium-catalyzed C-glycosylation reactions, including C-aryl glycosylation, C-alkyl glycosylation, and C-alkenyl glycosylation, as well as other glycosylation reactions from 2020 to 2024. Both classical catalytic systems and reaction mechanisms are briefly discussed in this article.

2. C1-Aryl glycosylation

Taking advantage of the pioneering studies by Liu and co-workers, 3,4-O-carbonate glycals have been frequently employed as coupling partners for palladium-catalyzed glycosylations.²² In 2020, Zou, Huang and Yao et al. reported a stereoselective C-glycosylation of 3,4-O-carbonate glycals with arylboronic acids by using 1,2-bis(phenylsulfinyl)ethane palladium(II) acetate (white catalyst) as the palladium precursor (Scheme 1).²³ This transformation was conducted in open air without using ligands or additives. Furthermore, it demonstrates excellent efficiency and functional group tolerance for the construction of C-aryl glycosides with high 1,4-trans-selectivity due to steric effects. The decarboxylation of 3,4-O-carbonate glycals provided the driving force for this reaction. Under standard conditions, the white catalyst firstly reacts with boronic acid to generate intermediate A.²⁴ Subsequently, the coordination and migratory insertion of A with glycal from the trans-face of the C-4 group affords intermediate Cvia the four-membered-ring transition state B. Finally, the β-elimination of C affords the C-glycosylation product.

Scheme 1 C-Glycosylation of 3,4-O-carbonate glycals with arylboronic acids.

In the same year, Liu and co-workers disclosed a palladium-catalyzed C-glycosylation of glycals with diaryliodonium salts as aryl precursors by employing Et₃N as the ligand and TBAC as the additive (Scheme 2).²⁵ A range of glycals, including D-glucal, D-galactal, D-allal, L-rhamnal, L-fucal, L-arabinal, D-maltal, and D-lactal, were well tolerated and smoothly converted to the desired 2,3-dideoxy C-aryl glycosides with good α-stereoselectivities. The authors proposed a mechanism involving a Pd(II)/Pd(IV) palladacycle. First, palladium(II) undergoes oxidative addition with an aryl triflate to give the Ar–Pd(IV)-OTf complex A, which coordinates with the double bond on glycal and then undergoes migratory insertion to afford intermediate C from the α-face. Intermediate C undergoes further anti-β-OAc elimination and reductive elimination of Pd(IV), leading to the formation of α-C-aryl glycosides. Of note, the glycosylation proceeded smoothly to give products in high yields with absolute α-selectivity, except for 3,4,6-tri-O-acetyl-D-allal, where both α- and β-glycosides were obtained in a 1 : 1 ratio. This was likely due to the steric hindrance induced by the axial C3 acetate of D-allal, which distorted the π-Pd(IV) species, resulting in poor α-selectivity.

Scheme 2 C-Glycosylation of glycals with diaryliodonium salts.

The Achmatowicz rearrangement plays an important role in synthetic chemistry.²⁶ In 2020, Tong and colleagues demonstrated a Pd-catalyzed arylation of Achmatowicz rearrangement products with arylboronic acids via Tsuji–Trost-type C-glycosylation under phosphine-free conditions (Scheme 3).²⁷ The palladium precatalyst and the use of an inorganic base were critical to the allylic arylation. The 4-keto group of pyranulose acetate is essential for the formation of the Pd π-allyl complex or for increasing the reactivity of the Pd-π-allyl complex. What's more, they found that pyranulose acetate exhibited reverse reactivity under different palladium catalysis and Lewis acid activation conditions.

Scheme 3 Tsuji–Trost-type anomeric arylative C-glycosylation.

In the past decade, the development of direct C–H activation/C–C coupling reactions provided a new avenue for synthesizing C-glycosides.²⁸ In 2020, Chen and co-workers elegantly applied this strategy to realize Pd-catalyzed auxiliary-directed remote C–H glycosylation of tryptophan with an α-mannosyl chloride donor, using Ac-Ile-OH as the additive (Scheme 4).²⁹ Isoquinoline-1-carboxylic acid (i₁QA) was chosen as the optimal directing group, affording biologically valuable C2-α-mannosyl-tryptophan amino acid in high efficiency. The amide-linked i₁QA auxiliary group of the product could be removed by treatment with zinc powder, giving the amine product without racemization. What's more, the ester and benzyl groups were easily removed under saponification and hydrogenolysis conditions, respectively. Notably, this work also achieved the first total synthesis of the insect adipokinetic hormone Cam-HrTH-I.³⁰ Based on density functional theory (DFT), the authors proposed a concerted oxidative addition mechanism for the stereospecific functionalization of the palladacycle intermediate with the mannosyl chloride donor.

Scheme 4 Pd-catalyzed C–H glycosylation of tryptophan with an α-mannosyl chloride donor.

The Catellani reaction, originally discovered by Catellani et al., has become an increasingly useful method for synthesizing polysubstituted arenes and benzofused compounds by simultaneous functionalization of both ortho and ipso positions of aryl halides.³¹ In 2020, Cheng et al. described a Catellani-type C–H glycosylation of (hetero)aryl iodides with glycosyl halides through an S_N1 pathway (Scheme 5).³² The termination step, which involves ipso-Heck reaction, hydrogenation, Suzuki coupling, and Sonogashira coupling, enables straightforward access to various highly decorated α-C-aryl glycosides and glycoside–pharmacophore conjugates in a modular and stereoselective manner. Notably, a catalytic amount of Pd(OAc)₂ could efficiently promote the formation of the oxocarbenium ion intermediate B, and the stereochemistry of this reaction was driven by the stereochemical interaction between the arylnorbornyl palladacycle A and the oxocarbenium ion B.

Scheme 5 Catellani-type C–H glycosylation of (hetero)aryl iodides with glycosyl halides.

Almost at the same time, Liang et al. described a similar palladium/norbornene-catalyzed ortho-C–H glycosylation/ipso-alkenylation of aryl iodides and glycosyl chlorides for the synthesis of α-C-aryl glycosides in good to excellent yields and with excellent diastereoselectivities (Scheme 6).³³ In addition, ipso-arylation and cyanation were also realized by using 5-norbornene-2-carbonitrile as a transient mediator. A possible mechanism was proposed, as shown in Scheme 6. Oxidative addition of Pd(0) with aryl iodine gives intermediate A. Then migratory insertion of norbornene and the subsequent ortho-C–H activation generates the five-membered palladacycle C. Meanwhile, the glycosyl chloride donor converts to the oxocarbenium ion intermediate D by palladium catalysis. Intermediate C undergoes oxidative addition with intermediate D to generate intermediate E, which undergoes reductive elimination to give intermediate F. Intermediate G is then generated via the extrusion of norbornene. Finally, intermediate G undergoes a palladium-catalyzed Heck reaction with alkene to afford C-aryl glycosides.

Scheme 6 Palladium/norbornene-catalyzed ortho-C–H glycosylation/ipso-alkenylation.

In the same year, Kandasamy and co-workers reported a palladium-catalyzed Heck-type reaction of glycal-enone with arylboronic acids by using 1,10-phenanthroline as the ligand (Scheme 7).³⁴ Various enones derived from D-glucal, D-galactal, L-rhamnal, D-rhamnal, and L-arabinal smoothly underwent the coupling with electron-donating- or electron-withdrawing-functionalized arylboronic acids, giving C-1 aryl enones in good to excellent yields. Moreover, a stereoselective reduction of C-1 arylated enones under Pd–C/H₂ conditions provides 2-deoxy-β-aryl-C-glycosides in excellent yields. The C-1 aryl enones are also useful precursors for the preparation of 2-hydroxy-β-aryl-C-glycosides via a NaBH₄–CeCl₃ reduction, benzyl protection and hydroboration cascade reaction. A plausible mechanism of this reaction is shown in Scheme 7. Firstly, palladium acetate coordinates with 1,10-phenanthroline to give the palladium(II) complex A, which undergoes transmetalation with arylboronic acid to form complex B. Then, the migratory insertion of complex B and enone from the α-face generates intermediate C, which undergoes a palladotropic shift to form enolate D and then rearranges to E. Finally, the syn-β-H elimination of E and subsequent reductive elimination leads to the formation of product H, which participates in an α-face reduction process to give 2-deoxy-β-aryl-C-glycosides.³⁵

Scheme 7 Palladium-catalyzed Heck-type reaction of glycal-enone with arylboronic acids.

In 2020, Liu and co-workers described a palladium-catalyzed heterocyclization and C-glycosylation cascade reaction of o-alkynylanilines with 1-iodoglycals using P(p-MeOPh)₃ as the ligand to access polyheterocycle 3-indolyl-C-glycosides in good to excellent yields with high step economy (Scheme 8).³⁶ This protocol featured a broad substrate scope and good functional group tolerance. Furthermore, derivatizations of the products were also conducted to verify the synthetic potential of this method. Of note is that the N-protecting group has a great impact on this reaction. A plausible mechanism of the process is proposed in Scheme 8. The oxidative addition of Pd(0) to 1-iodoglycal produces the palladium species A, which coordinates with the triple bond of o-alkynylanilines to give intermediate B. Subsequently, intramolecular aminopalladation of B generates intermediate C. Finally, the desired product is obtained via reductive elimination of C.

Scheme 8 Palladium-catalyzed cascade heterocyclization and C-glycosylation of o-alkynylanilines with 1-iodoglycals.

In 2021, Chen and co-workers reported a Pd-catalyzed ortho-directed C–H glycosylation reaction with glycosyl chloride using various urea- and amide-linked bidentate auxiliaries for the synthesis of C-aryl glycosides (Scheme 9).³⁷ A broad range of pyranose and furanose moieties can be installed at the ortho position of arylamine, benzylamine and N-heteroarene substrates to achieve high yields and α-diastereoselectivities. These N-linked auxiliaries can be readily installed and removed under relatively mild conditions.

Scheme 9 Pd-catalyzed ortho-directed C–H glycosylation reactions.

Compared with the C(sp²)–H activation of aromatic bonds or glycals, the functionalization of less activated C(sp³)–H bonds is more challenging, especially for the anomeric C–H bond activation of sugar partners. In 2021, Messaoudi successfully developed a Pd-catalyzed anomeric C(sp³)–H (hetero)arylation reaction by employing picolinic amide as the directing group to access elusive C-(hetero)aryl glycosides with exclusive α-selectivity (Scheme 10).³⁸ A range of sterically and electronically diverse aryl bromides and iodides, including reactive functional groups, were well tolerated in this transformation using tAmOH as the solvent. The anomeric σ-organopalladium complex was isolated in which the C–Pd bond was formed in the α-configuration, demonstrating that the C(sp³)–H activation step occurs stereoselectively at the axial anomeric C–H bond. The authors proposed that a Pd-catalyzed concerted metalation–deprotonation gives the five membered palladacycle B, which then undergoes oxidative addition with aryl iodide to generate the Pd(IV) complex C. Finally, C undergoes reductive elimination, affording the corresponding C-aryl glycoside. The authors also noted that the more stable ¹C₄ conformation of α-arylated glycoside would be controlled by the anomeric α-stereochemistry, and the switch from ⁴C₁ conformation to ¹C₄ probably occurs during oxidative addition/reductive elimination steps.

Scheme 10 Pd-catalyzed anomeric C(sp³)–H (hetero)arylation reaction.

In 2021, Liang and co-workers successfully developed a palladium-catalyzed C–H glycosylation and retro Diels–Alder tandem reaction approach for the synthesis of highly functionalized 4-glycosylindoles from o-iodoaniline, glycosyl chloride and structurally modified norbornadiene (smNBDs) (Scheme 11).³⁹ Mannosyl chlorides with different functional groups afforded the desired products in high yields with exclusive α-selectivity. Interestingly, α-ribofuranosyl chlorides delivered the corresponding products with β-selectivity, probably due to the steric hindrance caused by the C2 and C3 substituent groups. Notably, the smNBDs likely play an important role in regulating the reactivity of the key aryl-norbornadiene-palladacycle (ANP) intermediates. The ANP intermediate A was characterized by single-crystal X-ray diffraction. Control experiments further proved that the migration–insertion of smNBDs with phenylpalladium intermediate took place in a high chemo- and regioselectivity manner. Finally, density functional theory (DFT) calculations were also conducted to elucidate the formation of the five-membered aryl-norbornadiene-palladacycle intermediate.

Scheme 11 Palladium-catalyzed C–H glycosylation and retro Diels–Alder tandem reaction.

In 2022, Kandasamy and co-workers accomplished a palladium-catalyzed cross-coupling reaction of aryl iodides and glycal enones to prepare C-1 aryl enones under ligand-free conditions (Scheme 12).⁴⁰ Notably, the synthetic potential of the methodology was demonstrated by the preparation of dapagliflozin analogues (SGLT-2 inhibitors) and C-2 nitro aryl enones.

Scheme 12 Palladium-catalyzed cross-coupling reaction of aryl iodides and glycal enones.

In 2022, Yao and co-workers reported an extension of the palladium-catalyzed decarboxylative allylation reaction of 3,4-O-carbonate glycals and arylboronic acids for the preparation of α-C-aryl fucosides and β-C-aryl arabinosides with high 1,4-trans-selectivity (Scheme 13).⁴¹ This protocol featured good compatibility with amino and alcoholic/phenolic hydroxyl groups, mild conditions and simple operation.

Scheme 13 Preparation of C-aryl fucosides and arabinosides.

In 2022, Liang and co-workers explored a palladium-catalyzed C–H glycosylation of indoles or tryptophan with glycosyl chloride donors (Scheme 14).⁴² This transformation provided an efficient method to synthesize a broad range of 2,3-diglycosylindoles (β : α > 20 : 1) and tryptophan-C-glycosides (α : β > 20 : 1)²⁹ under mild and simple conditions. The authors suggested that the S_N1 nucleophilic reaction of α-mannofuranosyl chloride with indole C3 Pd species leads to the formation of 3-indolyl-C-glycoside in an α/β mixture, due to the isomerization of 3-indolyl-α-C-glycoside to 3-indolyl-β-C-glycoside. The β-selectivity of the C2 glycosylation may be influenced by the β substitution at the C3 position. Mechanistic studies on the indole 2,3-diglycosylation sequence indicated that glycosylation occurred first at the C3 position of the indole, followed by glycosylation at C2. On the basis of control experiment results, a possible mechanism is proposed. Initially, directed C–H bond activation of the indole gives palladacycle A. Palladacycle A undergoes 1,2-palladium migration and generates species B.⁴³ The subsequent S_N1 reaction gives the 3-indolyl-C-glycoside C. Then, D undergoes a palladium-catalyzed C–H activation to form palladacycle E. Finally, the target product is obtained through oxidation addition of glycosyl chloride and the subsequent reduction elimination.

Scheme 14 Synthesis of 2,3-diglycosylindoles and tryptophan-C-glycosides.

After Liang's work, Mandal and co-workers accomplished a palladium-catalyzed direct C–H glycosylation of free N–H indole or tryptophan for the stereoselective synthesis of 2-glycosylindoles and tryptophan-C-glycosides by using norbornene as the ortho-directing transient mediator with high α-stereoselectivity (Scheme 15).⁴⁴ The synthetic potential of the methodology was demonstrated by various product derivatizations. A catalytic pathway was proposed. Initially, N-palladation of the indole gives A, which through aminopalladation of norbornene forms the Pd(II) species B. After that, regioselective C–H activation of indole or tryptophan affords the palladacycle C. Then α-stereoselective oxidative addition of the sugar chloride donor to the palladacycle gives D. Finally, D undergoes reductive elimination and subsequent norbornene extrusion to deliver the 2-glycosylindole or tryptophan-C-glycoside.

Scheme 15 Direct C–H glycosylation of free N-H indole or tryptophan.

In 2023, Chen and co-workers reported a coupling of glycosyl stannanes and sulfonium salts enabled by synergistic Pd/Cu catalysis under mild conditions (Scheme 16).⁴⁵ A series of sulfonium salts bearing different functional groups could take part in the reaction, leading to the desired C-aryl/alkenyl glycals in good yields. In addition, the reaction could be conducted on a gram scale and the product could be converted into tetracyclic terpene-like glycoside via a Diels–Alder cycloaddition.

Scheme 16 Coupling of glycosyl stannanes and sulfonium salts.

Later, Messaoudi and co-workers realized a Pd-catalyzed intermolecular anomeric C(sp³)–H arylation of 3-aminosugars and aryliodides by using a transient imine directing group (Scheme 17).⁴⁶ In comparison with their previous study,³⁸ this protocol obviates installation and removal of the directing group. The released free amine C-glycoside products with excellent α-selectivity smoothly undergo Cu-catalyzed azidation to deliver azide C-glycosides,⁴⁷ which could be further converted into C3-triazolo C-glycosides via a copper-catalyzed azide–alkyne cycloaddition.⁴⁸ The α-configuration of the aryl group and the ¹C₄ conformation of the product were confirmed by X-ray crystal structure analysis, demonstrating the high diastereoselectivity of this process. In the proposed mechanism, firstly, the axial imine intermediate A is generated from 3-aminosugars and the transient directing group. Then, intermediate A undergoes CMD-type C–H activation of the anomeric C(sp³)–H bond to give intermediate B, which through cascade oxidative addition with aryliodides, reductive elimination, and a hydrolytic process affords the 3-amino C-glycosides.

Scheme 17 Anomeric C(sp³)–H arylation of 3-aminosugars and aryliodides.

Higashibayashi and co-workers demonstrated a Pd-catalyzed stereospecific Suzuki–Miyaura-type cross-coupling of glycosyl borates with aryl bromides (Scheme 18).⁴⁹ A library of aryl bromides bearing substituents with different electronic and steric properties, as well as heteroaryl bromides were also tolerated, giving the desired β-C-glycosides in moderate to good yields. Moreover, canagliflozin, a therapeutic agent for type 2 diabetes mellitus, could be accessed by this method in good yield.

Scheme 18 Pd-catalyzed Suzuki–Miyaura-type cross-coupling of glycosyl borates with aryl bromides.

Ferrocene and glycoside-containing hybrids play a significant role in biologically active molecules.⁵⁰ In 2023, Zhang and co-workers successfully developed a palladium-catalyzed stereoselective dual C–H bond glycosylation of ferrocenyl amides and glycosyl chlorides (Scheme 19).⁵¹ A wide range of ferrocene amides and diverse sugar derivatives, including D-mannose, D-glucose, L-xylose, L-rhamnose, D-mannofuranose, were competent reaction partners, delivering the diglycosylated ferrocenyl amides in good to excellent yields with high α-selectivity. Notably, the protected D-ribofuranose chloride donor reacts smoothly to give the desired product with β-selectivity. Preliminary mechanistic studies indicated that a mononuclear Pd^II intermediate might be involved in the C–H palladation step.

Scheme 19 Palladium-catalyzed dual C–H bond glycosylation of ferrocenyl amides and glycosyl chlorides.

In the same year, Lei, Yu and co-workers achieved a ligand-enabled Pd-catalyzed C–H glycosylation reaction of native carboxylic acids with sugar-boron reagents to install various glycals onto the aglycon parts (Scheme 20).⁵² This protocol features advantages including direct C–H glycosylation without external directing groups, a broad substrate scope, scalable synthesis, and diverse synthetic utility. The C–H glycosylation methodology allows for late-stage glycosylation of complex drug or natural product molecules. Ac-Ala-OH, as the ligand, plays a significant role in this weakly coordinated C–H glycosylation. Mechanistic investigations indicated that the reaction proceeds via a radical pathway. This work also led to the discovery of a new potent small-molecule inhibitor of SGLT-2 that could serve as a lead drug for type 2 diabetes treatment. Moreover, the C–H glycosylation of drug molecules also provides a tool for medicinal chemists to alter the PK/PD profiles.⁵³

Scheme 20 Pd-catalyzed C–H glycosylation of carboxylic acids with sugar-boron reagents.

In 2023, Liu and co-workers reported a cascade aminopalladation and Heck-type glycosylation of 2-alkynylanilines and simple glycals under mild conditions (Scheme 21).⁵⁴ This transformation efficiently provided a range of indolyl-C-glycosides in good yields with high stereoselectivities. C2/C3-branched indolyl glycosides were successfully obtained when 2,3-pseudoglycals were used as the substrates. The synthetic utility of this protocol was demonstrated by a large-scale reaction and synthetic derivatization of the C-glycoside products. Control experiments indicated that O₂ is credited with protecting the Pd species from aggregating into Pd black. Firstly, the active Pd catalyst A is generated from the reaction of Pd(OAc)₂ with KI. Then, A coordinates with the carbon–carbon triple bond of 2-alkynylaniline to give B, which undergoes intramolecular nucleopalladation to generate the indolylpalladium intermediate C. Intermediate C through an α-face migratory insertion across the double bond of glycal followed by trans-elimination affords the target product.

Scheme 21 Cascade aminopalladation and Heck-type glycosylation of 2-alkynylanilines and glycals.

Chromone C-glycosides are privileged scaffolds found in bioactive natural products.⁵⁵ In 2024, Hussain et al. explored a palladium-catalyzed cross-coupling of glycals with 3-halo chromone derivatives (Scheme 22).⁵⁶ This methodology has good functional group tolerance and affords various C-glycosides of chromones in good yields with high α-selectivities. Moreover, late-stage modifications of pharmaceutical and natural products, gram-scale synthesis, and the synthesis of 2-deoxy-chromone C-glycosides were also carried out to reinforce the synthetic utility of this method.

Scheme 22 Synthesis of chromone C-glycosides.

The proton sponge 1,8-bis(dimethylamino)naphthalene is an important reagent in synthetic chemistry.⁵⁷ Recently, Kancharla disclosed a palladium-catalyzed Heck-type coupling reaction of glycals with aryl iodides by using 1,8-bis(dimethylamino)naphthalene (proton sponge) as a reductant, a ligand precursor, and an organic base, providing a convenient synthetic tool for the stereoselective synthesis of 2′,3′-unsaturated α-C-aryl glycosides (Scheme 23).⁵⁸ Moreover, C-aryl glycosides were also converted to 3-keto-β-C-glycosides via ring-opening and ring-closing reactions. First, Pd(OAc)₂ reacts with the proton sponge and forms the Pd(0) complex A, which is stabilized by the cationic proton sponge. Then, complex A undergoes oxidative addition with the aryl iodide to afford intermediate B, which subsequently undergoes 1,2-migratory insertion with glycal from the α-face to give C. Finally, C undergoes β-hydride elimination to provide the desired C-aryl glycosides.

Scheme 23 Proton sponge-enabled palladium-catalyzed Heck-type coupling reaction of glycals with aryl iodides.

The use of readily available aryl thianthrenium salts as highly effective arylation reagents has attracted continuous interest in synthetic chemistry.⁵⁹ In this context, a palladium-catalyzed Heck coupling reaction of nonactivated glycals and aryl thianthrenium salts for the construction of α-C-aryl glycosides has been developed by Liu, Wang and co-workers (Scheme 24).⁶⁰ A plausible mechanism for this glycosyl arylation is proposed. First, palladium acetate undergoes ligand exchange and eliminates acetic acid, and is reduced to Pd(0) to enter the catalytic cycle. Ar-TT⁺BF₄⁻ undergoes oxidative addition with Pd(0) to form the Pd(II) complex intermediate A, which undergoes carbopalladation with glycals from the α-face to generate complex B. Finally, complex B undergoes β-elimination to produce the target product aryl glycoside.

Scheme 24 Palladium-catalyzed Heck coupling reaction of nonactivated glycals and aryl thianthrenium salts.

In 2024, Wang and co-workers reported a palladium-catalyzed Catellani reaction for the direct preparation of 1,2-disubstituted C-aryl glycosides from 2-iodoglycals, bromoaryl, and alkene/alkyne substrates (Scheme 25).⁶¹ This transformation features operational simplicity and scalability, exhibiting a wide substrate scope and accommodating diverse functional groups. However, 2-iodoglycals protected with electron-withdrawing groups were not compatible with this approach.

Scheme 25 Synthesis of 1,2-disubstituted C-aryl glycosides.

Recently, Zhu and co-workers described an elegant palladium-catalyzed Suzuki–Miyaura cross-coupling reaction of glycal boronates with (hetero)aryl electrophiles (Scheme 26).^62a This methodology enables the efficient assembly of C1-aryl glycals in good to excellent yields under mild reaction conditions. Remarkably, alkenyl, alkynyl and alkyl electrophiles were well-tolerated, yielding the corresponding C1-vinyl glycals, C1-alkynyl glycals, and C1-alkyl glycals in moderate to excellent yields. In addition, late-stage modifications of pharmaceutical molecules and synthesis of glycal–DNA conjugates were carried out to demonstrate the synthetic utility of this method. At the same time, Wang and Zhang et al. explored the possibility of extending the palladium-catalyzed Suzuki–Miyaura cross-coupling strategy to glycosyl chlorides and (hetero)aryl boronic esters for the synthesis of C-aryl glycosides.^62b The authors speculated that the stereoselectivity of the reaction was controlled by the steric effects of the protecting groups and the conformation of the glycosyl radical intermediate. The utility of this reaction was demonstrated by scaled-up preparation, late-stage modification of drug molecules and diverse transformations of the products. Radical trapping reactions and electron paramagnetic resonance (EPR) experiments indicated that the transformation might involve a radical pathway.

Scheme 26 Suzuki–Miyaura cross-coupling reaction of glycal boronates.

Later, a Pd-catalyzed stereoretentive glycosylation of reversed anomeric stannanes with aryl halides was realized by Zhu and co-workers (Scheme 27).⁶³ This cross-coupling provides an efficient method for the modular synthesis of nonclassical aryl C-glycosides in good to excellent yields. This protocol featured a broad substrate scope and high levels of chemoselectivity and stereospecificity. Various protected and unprotected saccharides, deoxy sugars, oligopeptides, and complex aryl halides were all amenable to this reaction. Moreover, biological evaluation indicates that the late-stage glycodiversification of drug molecules can positively impact their biological activity.

Scheme 27 Glycosylation of anomeric stannanes with aryl halides.

3. C1-Alkyl glycosylation

In 2020, Liu et al. successfully demonstrated a palladium-catalyzed trifluoroacetate-promoted C(sp³)–H glycosylation of N-phthaloyl α-amino acids with glycals by using N-quinolylcarboxamide as the directing group (Scheme 28).⁶⁴ Taking advantage of this method, the authors completed the synthesis of C-alkyl glycosides under mild conditions. The transformations are compatible with sensitive functional groups, tolerant of air and water, and suitable for gram scale synthesis. Notably, the C-alkyl glycosides could be easily converted to β-substituted C-alkyl glycoamino acids by a hydroboration–oxidation reaction. What's more, the palladacycle has been successfully prepared to elucidate the mechanism of this glycosylation process. As shown in Scheme 28, the stable palladacycle A was first generated via cyclometallation with high regioselectivity. Then, the oxidative addition of A with 1-iodoglycal gives intermediate B, which undergoes reductive elimination to afford intermediate C. Finally, the desired product was obtained by the release of the Pd catalyst. The authors suggested that the trifluoroacetate may serve as a ligand to stabilize the palladacycle intermediate A or promote the oxidative addition step.

Scheme 28 Palladium-catalyzed C(sp³)–H glycosylation of N-phthaloyl α-amino acids with glycals.

Later, Ackermann et al. independently reported a palladium-catalyzed C(sp³)–H glycosylation of structurally complex amino acids and peptides enabled by the assistance of triazole peptide-isosteres (Scheme 29).⁶⁵ This approach provided a facile route to access structurally complex C-alkyl glycoamino acids and glycopeptides with excellent regio-, chemo- and diastereoselectivities. Moreover, the synthetic utility of this strategy was demonstrated by the assembly of BODIPY-equipped fluorescent glycoamino acids.⁶⁶

Scheme 29 C(sp³)–H glycosylations of amino acids and peptides.

The de novo synthesis of saccharides using Achmatowicz rearrangement products as glycosyl donors has emerged as a powerful tool with regio- and stereospecific control via a Pd-π-allyl intermediate.⁶⁷ Compared with C-aryl glycoside synthesis, the formation of C-alkyl glycosides from Achmatowicz rearrangement products is more challenging. In 2020, Song et al. described a stereoretentive Pd-catalyzed C-glycosylation using Achmatowicz rearrangement products as glycosyl donors and methylcoumarins as acceptors via an allyl–allyl coupling process under mild conditions (Scheme 30).⁶⁸ Mechanistically, the authors found that the strong electron-withdrawing “cyano” group in the coumarin was necessary for the transformation. The γ-position of methylcoumarin is more nucleophilic than the α-position due to the electronic and steric effect of the cyano group at the C3 position.⁶⁹ Further investigations revealed that the coumarin-glycosides showed excellent fluorescence quantum yields with redshifted emission wavelengths.

Scheme 30 Pd-catalyzed C-glycosylation using Achmatowicz rearrangement products.

In the same year, Shinozuka et al. reported a palladium-catalyzed benzyl C-glycosylation of TIPS-protected 1-tributylstannyl glycals with benzyl bromides (Scheme 31).⁷⁰ The reaction was accelerated by the addition of Na₂CO₃. Of note, 2-substituted benzyl bromide failed to generate the expected products under the standard conditions.

Scheme 31 C-Glycosylation of 1-tributylstannyl glycals with benzyl bromides.

C-Glycosamino acids, which have been shown to have similar biological activities as their naturally occurring analogs, have been successfully employed in specific therapeutics.⁷¹ In 2021, Wang et al. described an elegant Pd/Cu dual catalyzed α-glycosylation of aldimine esters (Scheme 32).⁷² This reaction provided a facile synthetic tool to access unnatural C-glycosamino acid skeletons bearing two contiguous stereogenic centers in good yields with excellent diastereoselectivities. From the products, various C-glycosamino acid derivatives have been achieved.

Scheme 32 Synthesis of C-glycosamino acid skeletons.

Glycals and their [2,3]-dehydrosugar derivatives have commonly been used as electrophiles under Lewis acid⁷³ or metal catalyzed conditions.⁷⁴ In 2022, Rhee et al. reported a Pd-catalyzed umpolung allylation of glycal acetates and their [2,3]-dehydrosugar isomers, where the glycals and isomers were used as nucleophiles (Scheme 33).⁷⁵ Both aromatic and enolizable aliphatic aldehydes worked well under the reaction conditions, giving the desired C-alkyl glycosides in good to excellent yields with high C1 regioselectivity and stereoselectivity. The synthetic utility of this reaction was demonstrated by a short synthesis of the anticancer natural product mucocin.⁷⁶

Scheme 33 Pd-catalyzed umpolung allylation of glycal acetates.

In 2022, a palladium-catalyzed decarboxylative reaction of bicyclic galactals with 2-oxindoles was developed by Xiang, Lu and co-workers (Scheme 34a).⁷⁷ The target β-type C-glycosides were obtained in more than 90% yields with high efficiency and stereoselectivity. The decarboxylation intermediate of galactal may serve as a base to deprotonate the enol tautomer of 2-oxindole and enhance its nucleophilicity.⁷⁸ The β-stereoselectivity of the products is probably due to the steric hindrance of palladium and the bulky ligand. Later, Xiang, Yao and co-workers demonstrated a similar palladium-catalyzed decarboxylative β-C-glycosylation of glycals with oxazol-5-(4H)-ones as the amino acid precursors, delivering various β-C-glycosyl amino acids in good yields (Scheme 34b).⁷⁹ In 2023, a Pd-catalyzed decarboxylative reaction of 3,4-O-carbonate-D-galactal and nitroalkane under mild conditions was realized by Yao and Huang et al. (Scheme 34c).⁸⁰ This annulation protocol provided an efficient method to synthesize various β-C-glycosides in good to excellent yields with satisfactory functional group compatibility for both electron-withdrawing and electron-donating nitroalkanes.

Scheme 34 Palladium-catalyzed decarboxylative C-glycosylation.

Ngai and Liu et al. reported an elegant excited-state palladium-catalyzed α-selective C-ketonylation strategy to prepare C-alkyl glycosides from readily available 1-bromosugars and silyl enol ethers (Scheme 35).⁸¹ The reaction featured excellent α-selectivity and mild conditions and tolerated a wide range of functional groups and complex molecular architectures. The resulting α-ketonylsugars could serve as versatile precursors for their β-isomers and other C-glycosides. Preliminary experimental and computational studies of the mechanism suggested that this reaction probably proceeded via a radical pathway, involving the formation of a palladoradical and glycosyl radical that undergo polarity-mismatched coupling with silyl enol ether, followed by H–Br elimination and hydrolysis reaction to deliver the desired α-ketonylsugars.

Scheme 35 Excited state palladium-catalyzed α-selective C-ketonylation.

Recently, para-quinone methides (p-QMs) have emerged as important synthetic building blocks for the synthesis of analogues containing diarylmethane units via the reaction of carbon and heteroatom-centered nucleophiles.⁸² Kumar Mandal and co-workers reported a Pd-catalyzed directed C(sp²)–H functionalization of C2-amido glycals with p-QMs with the assistance of the bidentate amidoquinoline-type directing group (Scheme 36).⁸³ Substrates bearing diversely substituted aryl rings in p-QMs and possessing different types of glycal configurations were all amenable to this reaction, giving the unsymmetrical gem-diarylmethyl C-glycoside products in good yields. The derivatizations of the products and removal of the directing group further showcases the utility of this protocol.

Scheme 36 Synthesis of unsymmetrical gem-diarylmethyl C-glycoside.

C-Oligosaccharides are privileged scaffolds found in natural products and pharmaceuticals;⁸⁴ however, modular and stereoselective synthesis of C-oligosaccharides remains a challenge due to the fact that connecting two sugar units at the C1–C1 position requires anomer carbon polarity reversal. Very recently, Liang and co-workers reported a palladium-catalyzed Catellani-type C1–H glycosylation/C2-alkenylation, cyanation, and alkynylation of 2-iodoglycals with glycosyl chloride donors (Scheme 37).⁸⁵ This protocol provides a stereoselective and efficient access to C-oligosaccharides via the difunctionalization of 2-iodoglycals, offering advantages such as high diastereoselectivity, broad applicability, and operational simplicity. They disclosed that the oxidative addition mechanism of the alkenyl-norbornyl-palladacycle (ANP) intermediate with α-mannofuranose chloride favours the α-selective pathway due to steric hindrance.

Scheme 37 Access to C-oligosaccharides.

4. C1-Alkenyl glycosylation

Although synthetic methods for obtaining C-aryl/alkyl glycosides have been widely explored, the synthesis of C-alkenyl glycosides, which are found in many natural products and frequently used as mimics of O-glycosides in glycomimetic design,⁸⁶ is more challenging and remains under-developed. In 2020, Liang et al. demonstrated a visible-light-induced palladium-catalyzed Heck reaction of simple and readily available bromine sugars with aryl olefins (Scheme 38).⁸⁷ This methodology exhibits good functional group tolerance and leads to various C-glycosyl styrenes in one pot with high regio- and stereoselectivities. β-C-Glycosides are formed as the major products in this work. While triacetyl-protected D-xylose gives a 1 : 1 β/α stereoselectivity, D-mannose and D-mannofuranose give only α stereoselectivity, probably due to steric hindrance. The results of control experiments implied that the reaction involved a radical pathway. Initially, the active Pd (0) complex A is generated from the in situ-generated Pd (0) via visible-light irradiation. Then, the active complex A undergoes a SET with bromide pyranose and gives the Pd–Br radical species B, which via radical addition to styrene generates the radical intermediate C. Finally, the desired pyranose styrene product was obtained by β-H elimination of C.

Scheme 38 Visible-light-induced palladium-catalyzed Heck reaction of bromine sugars with aryl olefins.

In 2021, Chen and He et al. successfully employed an easily removable bidentate auxiliary as the directing group to achieve the Pd-catalyzed C–H glycosylation of unfunctionalized alkenes with glycosyl chloride donors for the stereoselective synthesis of predominantly C-α-vinyl glycosides except C-β-vinyl ribosides (Scheme 39).⁸⁸ The authors suggested that the stereochemical outcome of the reaction is probably controlled by both steric and stereoelectronic effects. Notably, use of other structural analogues of isoquinolic acid gave lower yield, and the carboxylic acid additive is also important to the reaction.⁸⁹ Both the γ C–H bond of allylamines and the δ C–H bond of homoallyl amine substrates were suitable and gave the desired products in high yields with excellent regio- and stereoselectivities. What's more, the synthesized products could undergo further derivatization to give a variety of C-alkyl glycosides with high stereospecificities.

Scheme 39 Pd-catalyzed C–H glycosylation of alkenes with glycosyl chloride donors.

In 2023, Chen et al. reported a synergistic Pd/Cu-catalyzed cross-coupling of glycosyl stannanes with alkenylated sulfonium salts to access C-alkenyl glycals (Scheme 40).⁴⁵ Both terminal and internal alkenyl substrates were compatible with the catalytic system, giving the products in good to excellent yields without E/Z isomerization. Moreover, different sugar substrates such as D-arabinal, D-xylal and D-rhamnal were suitable coupling partners in this reaction.

Scheme 40 Cross-coupling of glycosyl stannanes with alkenylated sulfonium salts.

5. C2-Glycosylation

A series of methods related to the synthesis of C1-functionalized glycosides have been reported. In contrast, there are still only a few reports on the preparation of C2-substituted carbohydrates, which are ubiquitous in nature and feature prominently in bioactive agents and natural products. In 2020, Messaoudi and Gandon et al. achieved a palladium-catalyzed regio- and diastereoselective arylation of 2,3-glycals with various aryl iodides in the presence of Pd(OAc)₂/AsPh₃ as the catalytic system (Scheme 41).⁹⁰ The protocol exhibits a broad substrate scope and provides the desired C2-aryl glycosides in good yields with excellent diastereoselectivities. Moreover, DFT calculations were performed to provide insights into the 2,5-cis diastereoselectivity of this reaction. The authors attribute the stereochemistry at the C2 position of the coupling product to the steric hindrance caused by the C4 substituent group of the pseudoglycal through a chirality transfer mechanism.

Scheme 41 Palladium-catalyzed regio- and diastereoselective arylation of 2,3-glycals with aryl iodides.

In the past decade, O-protected 2-iodoglycal substrates have been extensively explored to form 2-C-functionalized glycals.⁹¹ In 2020, Ferry and co-workers reported a palladium-catalyzed cyanation of unprotected 2-iodoglycals with K₄[Fe(CN)₆] in aqueous media (Scheme 42).⁹²D- or L-pyranoside-, D-furanoside-, and disaccharide-type iodoglycals are all suitable in this reaction, affording the corresponding 2-cyano-glycal scaffolds in moderate to excellent yields. Furthermore, the synthetic utility of this protocol has also been demonstrated by various derivatizations of products to access protecting group-free 2-amine, amide, tetrazole or ketone functionalized glycoanalogues.

Scheme 42 Palladium-catalyzed cyanation of unprotected 2-iodoglycals with K₄[Fe(CN)₆].

In 2022, Liang and Liu et al. discovered a palladium-catalyzed one-step synthesis of modified glycals containing stereodefined tetrasubstituted olefins from arylboronic acids, aliphatic anhydrides, and 1-iodoglycals (Scheme 43).⁹³ Control experiments and DFT calculations show that the palladium catalyst played dual roles in nucleophilic substitution and catalyzing the Suzuki coupling. This protocol, conducted under mild conditions, featured a single operation using a simple prefunctionalized glycal to access 1,2-di-C-substituted glycals, which are difficult to obtain by other methods. First, the oxidative addition of the Pd(0) complex to 1-iodoglycal gives the Pd(II) intermediate A, which undergoes ligand substitution with anhydride to generate the Pd complex B. Then, B, via a palladium-induced nucleophilic attack, gives the oxyonium Pd(II) complex C, which then reacts with a base to eliminate H atoms, along with the release of CH₃COO⁻, to form intermediate D. Finally, the Suzuki coupling reaction of D with arylboronic acid yields the desired product.

Scheme 43 Synthesis of modified glycals containing stereodefined tetrasubstituted olefins.

In 2020, Stefani et al. discovered a palladium-catalyzed carbonylative Heck reaction of activated olefins and 2-iodoglycals by employing Mo(CO)₆ as the CO source (Scheme 44).⁹⁴ The authors found that a broad range of 2-iodoglycals including D-glucal, D-galactal, D-xylal, and L-arabinal were compatible with the reaction conditions, affording the desired α,β-unsaturated 2-ketoglycosides in good yields. The authors suggested a reaction mechanism that involves oxidative addition of 2-iodoglycal with Pd(0), followed by CO insertion, migratory insertion of alkene and β-hydride elimination.

Scheme 44 Palladium-catalyzed carbonylative Heck reaction of activated olefins and 2-iodoglycals with Mo(CO)₆.

6. Conclusions

In this review, we have summarized recent advances in the field of palladium-catalyzed C-glycoside synthesis via Heck coupling reactions, C–H glycosylation, Tsuji–Trost-type C-glycosylation, and other methods. Various Pd catalysts have been successfully used in the synthesis of extremely efficient regioselectively functionalized products including C-aryl glycosides, C-alkyl glycosides, C-alkenyl glycosides, C-carbonyl glycosides, and C-cyano glycosides, as well as difunctionalized C-glycosides, with good yields and high stereoselectivities. Despite enormous efforts in the field, several challenges are yet to be addressed: firstly, as described above, the carbohydrate substrate scope is usually limited to fully or partially protected glycosyl donors. Thus, more efficient and general catalytic systems for broader substrate scopes are highly desirable. Secondly, the application of the developed reactions in the synthesis and modification of bioactive functional molecules is surely of particular interest. In addition, ligands also play a significant role in Pd-catalyzed reactions; therefore, further development of ligand-controlled stereoselective palladium-catalyzed C-glycosylation is still highly desirable. Finally, the combination of palladium-catalyzed C-glycosylation with photo/electronic reaction technologies or heterogeneous catalytic systems would be a fascinating future research direction.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21807051) and the Jiangxi Provincial Natural Science Foundation (20242BAB25124).

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