Advances in the Chemistry of Sulfur-Linked Glycosides: Focus on Functionalized 1-Thioglycosides

Abstract

The synthesis of sulfur-linked glycosides, such as S-glycosides or S-glycoconjugates, has been extensively explored due to their roles as valuable tools in various biological studies. These compounds can act as glycosidase inhibitors, antibacterial agents, antitumor agents, and more. 1-Thioglycosides are characterized by a sulfur atom bonded to the anomeric position and are rare in nature. Besides their biological and pharmaceutical significance, thioglycosides serve as key substrates for the synthesis of other glycosides (O-, N-, and C-glycosides), glycoconjugates, glycoproteins, and polysaccharides. The growing interest in biologically active S-glycosides stems from their enhanced stability compared to O-glycosides, making them less prone to enzymatic hydrolysis and chemical degradation. This stability underpins their use as enzyme inhibitors and their presence in various drugs and bioactive natural products. Consequently, the development of efficient synthetic methodologies for functionalized 1-thioglycosides remains a critical focus in medicinal and organic chemistry research. This review focuses on recent advances in the synthetic methodologies for functionalized 1-thioglycosides, highlighting key strategies and their potential applications in medicinal chemistry.

Keywords:
S-glycosides; 1-thioglycosides; glycoconjugates; metal catalysis; thiol-ene; cross-coupling

1. Introduction

Sulfur-containing carbohydrates are of great interest in science and are gaining attention in a wide range of biological and pharmacological studies.¹ 1-Thioglycoside derivatives have been considered biologically important O-glycoside bioisosteres.² There is a growing interest in biologically active S-glycosides as structural analogs and potential substitutes for O-glycosides, since S-glycosides exhibit higher stability and are less susceptible to enzymatic hydrolysis. Moreover, they display enhanced resistance to chemical degradation compared to O-glycosides. Due to this remarkable stability, S-glycosides have been extensively investigated for their potential application as enzyme inhibitors.² In addition, the thiosugar moiety is found in several drugs, natural products, and biologically active agents, including hSGLT1 inhibitor (belonging to the class of inhibitors for type 1 diabetes), lectin A protein ligand, as well as inhibitors of the enzymes galactosidase and β-glucosidase (Figure 1).³-⁶

As thioglycosides are versatile and valuable intermediates in organic synthesis,⁷ researchers have been struggling in the synthesis and biological evaluations of these glycomimetics.⁸ However, few methods for thiosaccharide synthesis have been reported in the literature to date. Typically, thioglycoside derivatives are most commonly prepared by reacting thiophenol with per-O-acetylated glycosyl in the presence of a Lewis acid⁹-¹¹ or by replacing the halogen atom on the anomeric carbon of the sugar with a thiolate anion (Scheme 1a).¹²,¹³ Although the synthesis of thioglycosides from haloor per-O-acetylated is more straightforward and relies on more readily accessible starting materials, it presents a major drawback: the formation of both anomeric isomers, which are virtually inseparable by conventional purification methods. To overcome this synthetic limitation, researchers have developed methodologies that employ 1-thiosugars with a defined configuration as starting materials, enabling the synthesis of substrates with the anomeric center defined (Schemes 1b and 1c).²

Scheme 1
Reported synthetic approaches to 1-thioglycoside synthesis.

Figure 1
1-Thioglicosides with known biological activities.

This review provides a comprehensive overview of thioglycoside synthesis that uses the 1-thiosugars with the anomeric center defined as nucleophiles. Our work encompasses metal-catalyzed cross-coupling reactions and thiol-ene reactions, offering valuable insights into their synthetic approaches, and potential applications, thereby serving as a key resource for advancing research in medicinal and organic chemistry.

2. Metal-Catalyzed Cross-Coupling Reactions

Cross-coupling reactions are of great interest in organic synthesis, as they enable the formation of new bonds, whether C-C or C-heteroatom, that are often difficult to access by other methods.¹⁴ The general strategy of cross-coupling involves the reaction of an organometallic reagent with an electrophilic partner, typically mediated by a transition metal catalyst, most commonly palladium or nickel.¹⁵ Besides, coupling reactions involving organic halides with compounds containing inactive C-H or heteroatom-H bonds, in the presence of a base and a metal catalyst, represent a widely used methodology in cross-coupling reactions.¹⁶

Among several reactions that can be performed by the cross-coupling procedure, the C-S cross-coupling reactions hold great importance in the field of organic synthesis, as the C-S bond is present in many pharmaceuticals used to treat diseases such as cancer, human immunodeficiency virus (HIV), Alzheimer’s, among others.¹⁷ Consequently, synthetic chemists increasingly recognize the need to develop new methodologies for the formation of C-S bonds.¹⁸ The first C-S cross-coupling reaction was performed by Migita and co workers¹⁹ in 1978 using [Pd(PPh₃)₄] as the catalyst.

Recent advances in cross-coupling methodologies have enabled more efficient and selective formation of C-S bonds, offering innovative routes to access diverse thioglycoside structures. The development of catalysts and conditions that tolerate glycosyl donors and thiol functionalities has expanded the synthetic toolbox for carbohydrate chemists, paving the way for novel applications in chemical biology and drug development.²⁰

2.1. Copper-catalyzed cross-coupling for 1-thioglycosides synthesis

The first report of metal-catalyzed cross-coupling 1-thioglycoside synthesis dates of 2003, when Štícha and co workers²¹ reported a copper-mediated arylation of 1-thiosugars. In this work, they presented a cross-coupling reaction between O-haloaryl triazenes and 1-thiosugars in high yields (75 to 97%) as shown in Scheme 2.

Scheme 2
General procedure for the first report of metal-catalyzed cross-coupling 1-thioglycoside synthesis.

The reaction was carried out using 1.1 equiv. of 1-thiosugar, 1 equiv. of o-iodoaryl triazene, 1 equiv. of CuI, K₂CO₃ (2 equiv.), 3 equiv. of pyridine and MeCN as solvent. This reaction was allowed to stir at 80 °C for 24 h. This methodology was suitable for both thiosugar α and β anomers with good yields, as well as different sugar moieties like per-O-acetylated 1-thio-β-D-glucose, galactose, and N-acetyl-α-D-glucosamine. This reaction also performed well with different triazene substrates, such as acyl, ester, and methyl groups. Inspired by the results obtained, the authors synthesized bivalent linked S-glycoclusters, starting from o,o’-dihaloaryl triazenes (1 equiv.) and per-O-acetylated sugar mercaptans (2.2 equiv.) under similar conditions, providing the desired product in good yields. Although this methodology is very suitable for O-haloaryl triazene substrates, the absence of the triazene group leads to unsatisfactory results, like low yields and mixtures of α and β anomers. Some selected examples are presented in Figure 2.

Figure 2
Selected examples of metal-catalyzed cross-coupling synthesis of 1-thioglycosides reported by Štícha and co workers.²¹

Later, in 2015, Xue and co workers²² developed a new methodology to synthesize (hetero)aryl thioglycosides using 2’-cyanoethyl thioglycosides to form glycosilthiolates and CuCl as a catalyst. The authors claimed that the 2’-cyanoethyl thioglycosides are better substrates than the thioglycosides, because thioglycosides are usually prone to oxidation under air. To address this, they proposed an alternative substrate capable of generating glycosyl thioanions in situ. Therefore, they selected copper catalysis, mainly because of the economic advantages. Besides, Cu-catalyzed reactions can be performed under mild conditions, and they are very suitable for many (hetero)aryl substrates. The authors synthesized a set of 2’-cyanoethyl thioglycosides to perform the reaction as shown in Scheme 3 using 1 equiv. of the sulfuration agent, 1.2 equiv. of the (hetero)alyl halide, 10 mol% of CuCl, 10 mol% of bipyridine as ligand, 2 equiv. of Cs₂CO₃ as base in refluxing MeCN (2mL) for 24 h.

Scheme 3
General procedure for 1-thioglycoside synthesis using CuCl as catalyst.

The yields obtained were very satisfactory (83 to 98%), and it was possible to synthesize 28 different compounds, and some of them are shown in Figure 3. The reaction conditions were sufficiently mild to be compatible with a wide range of functional groups, including esters, olefins, acetals, ethers, halides, amides, and ketals, as well as pyranosides and furanosides for the sugar moiety. Moreover, the absolute configurations of the anomeric centers were retained, and no epimerization was observed. Furthermore, since most of the yields were close, no group effect was observed, neither from steric hindrance, nor from electron-donating or withdrawing groups, providing an efficient method with high group tolerance.

Figure 3
Selected examples of 1-thioglycoside synthesis using CuCl as catalyst.

Messaoudi and co-workers,²³ in 2016, reported a copper-catalyzed C-H activation with thioglycosides as nucleophiles. This was the first report of a thioglycosylation performed through a C(sp²)-H activation. The reaction was carried out using as coupling partners 1-thiosugars and several arenes containing the 8-aminoquinoline as directing group and Cu(OAc)₂.H₂O as catalyst. The reaction proceeded as described in Scheme 4, using 1 equiv. of the aryl partner, 1.5 a 2 equiv. of the thiosugar moiety, 20 mol% of Cu(OAc)₂.H₂O and 2 equiv. of Ag₂CO₃ in DMSO at 110 °C for 2 h. It was found that the aminoquinoline group is a sine qua non condition to this reaction.

Scheme 4
General procedure for the first copper-catalyzed C-H activation using 1-thiosugars.

When the authors used ortho-substituted aryl partners, only one product was obtained, the monosubstituted. Besides, when they used substrates with both ortho position free, the authors obtained both the monoand the disubstituted products.

The authors explored mono-, di-, and trisaccharides, as well as several (hetero)aryl and one vinyl partner. When comparing the yields obtained for the monosubstituted thiosugars, a noticeable decrease was observed when the protecting group was changed from acetyl (OAc) to benzyl (OBz), which is likely attributable to increased steric hindrance. A similar trend is evident when comparing the mono-, di-, and trisaccharide derivatives, whose yields progressively decline as the carbohydrate chain length increases. Some of the examples synthesized and their yields are shown in Figure 4.

Figure 4
Selected examples for the first copper-catalyzed C-H activation using 1-thiosugars.

Concerning the suitability of this methodology, the authors successfully used 16 substrates with yields from 25 to 98% and all the products obtained had the β-anomer configuration retained. The main limitation of this methodology lies in its narrow substrate scope, as the aryl coupling partner must necessarily be a quinoline derivative, and substitution at the ortho position is required to avoid the formation of mixtures of monoand disubstituted products, which can be difficult to separate. However, the aminoquinoline group can be hydrolyzed under basic conditions to furnish the benzoic acid. It can also be removed by acid-promoted hydrolysis to give the corresponding ester. Moreover, it can be converted into aldehydes through a reaction with the Schwartz reagent. In their work, the authors used a protocol to convert the aminoquinoline group into an ester group, and remove the acetyl (OAc) protection group, and the ester obtained undergoes a lactonization reaction to afford a benzoxathiepinone (58% yield).

Inspired by this work, the same group performed the functionalization of 1-thiosugars with perbenzylated C2 amido-glycals, as shown in Scheme 5.

Scheme 5
General procedure for copper-catalyzed C-H thiolation in the pseudo-anomeric position of glycals.

In this work,²⁴ the authors reported a C-H activation to functionalize several glycals in the pseudo-anomeric position. The reaction was carried out using 1 equiv. of the C2-amidoglycal, 2 equiv. of the 1-thiosugar, 40 mol% of Cu(OAc)₂, 40 mol% of neocuproine, 3 equiv. of Ag₂CO₃, in MeCN, at 90 °C for 24 h. The scope of this work presents 5 different thiosugars, and the highest yields were obtained with the acetyl (Ac) protecting groups at the thiosugar moiety (67% for peracetylated thio-D-glucose, 52% for peracetylated thio-D-galactose, and 40% for peracetylated disaccharide thio-cellobiose). Replacing the acetyl protecting groups by benzoyl or benzyl groups in thio-D-glucose afforded the desired products, although only in moderate yields of 25 and 21%, respectively. This reduced reactivity can likely be attributed to the diminished accessibility of the thiol group, owing to the steric hindrance imposed by the bulky benzoyl or benzyl substituents. Regarding the glycal partners, 5 different glycals were applied to this methodology. The benzylated substrate showed a 67% yield. The reaction of the per-PMB (p-methoxybenzyl)-protected analog with the thiosugar exhibited a reactivity profile comparable to the benzylated model substrate, delivering the desired compound in 51% yield. Notably, the use of peracetylated D-glucal as a coupling partner was unsuccessful, likely due to deactivation of the glycal double bond by the electron-withdrawing nature of the acetyl groups.

Furthermore, in this same work, the authors also performed the reactions with alkyl and aryl thiols, obtaining 8 different compounds with yields from 16 to 76%. Overall, 17 different compounds were obtained with this methodology. Some compounds synthesized by the authors, as well as their yields are shown in Figure 5. Although some of the yields can be considered low, the methodology is innovative and can be used as the basis for further synthetic studies that encompass the C-H activation reaction.

Figure 5
Selected examples of copper-catalyzed C-H thiolation in the pseudo-anomeric position of glycals.

More recently, in 2022, Venkatesh et al.²⁵ reported a copper(I)-catalyzed Sandemeyer-type S-arylation of 1-thiosugars using aryldiazonium salts (Scheme 6).

Scheme 6
General procedure for copper(I)-catalyzed Sandemeyer-type S-arylation of 1-thiosugars.

The optimized conditions involved 0.25 mmol of 1-thiosugars, 0.275 mmol of aryldiazonium salts, 0.25 mmol 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), 5 mol% of CuI in CH₃CN, at 0 to 5 °C, stirring for less than 5 min, to obtain the 1-thioglycosides. These conditions were then applied to aryldiazonium salts with electron-donating and withdrawing groups, to verify the effects of substitutions on the reaction progress. Surprisingly, the authors found no difference between the yields for electron-donating and withdrawing groups in para positions, and all the yields were obtained in a range of 78 to 87%. For aryldiazonium salts bearing meta- and ortho substituents, the yields range from 55 85%. Furthermore, heretoaryldiazonum salts led to good yields from 74 to 80%. It appears that neither the position of the substituent nor the electronic effects (donating or withdrawing) have a direct influence over the yields. Some selected examples and their yields are shown in Figure 6. The S-arylation of amino sugars was also investigated, and it was found that aryldiazonium salts bearing electron-donating and electron-withdrawing groups underwent a chemoselective S-arylation, affording thioglycosides in 84-88% yields. Further, the S-arylation of different monoand disaccharides, furanose sugar, and monosaccharides with different protecting groups, leading to yields from 75 to 87%.

Figure 6
Selected examples of copper(I)-catalyzed Sandemeyer-type S-arylation of 1-thiosugars.

Besides, the authors also performed the reaction with unprotected thiosugars. To perform this reaction, MeOH was used as the solvent and CuCl as the catalyst. Overall, 50 different compounds were synthesized with protected 1-thiosugars, and four compounds were obtained using unprotected thiosugars.

After proving the efficiency of this methodology, the authors demonstrated a synthesis of the biologically relevant antidiabetic dapagliflozin S-analogue and arbutin S-analogues (tyrosinase inhibitors).

2.2. Palladium-catalyzed cross-coupling for 1-thioglycosides synthesis

Alami and co-workers² reported in 2013 the first palladium-catalyzed C-S cross-coupling using 1-thiosugars and (hetero)aryl halides. After studying several conditions, the authors found the best condition to perform this coupling reaction as follows: 0.375 mmol of the 1-thiosugar, 0.25 mmol of the (hetero)aryl halide, in dioxane (1.5 mL) in the presence of 5 mol% of Pd(OAc)₂, 2.5 mol% of xantphos and 0.25 mmol of Et₃N at 100 °C for 1 h (Scheme 7a). The author performed the reaction with several substrates, including αand β-thiosugars, different protection groups in thiosugars such as acetyl and benzyl, and one example of an unprotected thiosugar. For the aryl coupling partners, the authors have used aryl bromides and iodides with para- and meta- electron-donating or electron-withdrawing substituents to give thioglycosylated products in good to excellent yields (61 to 99%) with complete β-selectivity. In addition, sterically hindered ortho-substituted coupling partners were tolerated toward the coupling reaction, leading to β-thioglycosylated derivatives in excellent yields. The extension of the coupling partners to heteroaromatic halides was also successful (88 to 95% yield). Concerning the changing of the protection group, there was no great impact on the reactivity, and the unprotected sugar had a slight decrease in the yield, leading to the β-thioglycoside in 66% yield. Overall, 29 different compounds were synthesized with good to excellent yields (61 to 99%). Furthermore, the methodology was successfully applied to the synthesis of a biologically active molecule MUS-CB (4-methyl-7-thioumbelliferyl-β-d-cellobioside, Figure 7a) with 75% yield.

Scheme 7
General procedure for palladium-catalyzed functionalization of 1-thiosugars via C-S cross-coupling.

Figure 7
Biologically active compounds synthesized with palladium-catalyzed functionalization of 1-thiosugars via C-S cross-coupling.

Later, in the same year, Messaoudi and co workers²⁶ used very similar conditions (Scheme 7b) to perform the C-S cross-coupling between 1-thiosugars and alkenyl, alkynyl, and alkyl halides. For alkenyl coupling partners, the stereochemistry of the reaction was investigated. It was found that, for β-bromostyrenes, the reaction was selective to a single E-isomer, even when stating from a mixture of isomers (E/Z 85:15), suggesting that the Z partner does not react. However, when β-iodostyrenes were used, both E and Z partners reacted, so when the authors used mixtures E/Z in any ratio, the products were obtained as a mixture of E/Z in the same initial ratio. Also, this methodology worked well for both α and β-styrenes, cyclic alkenyl halides, and alkynyl halides as well. For the scope of 1-thiosugars, the authors have applied the optimized conditions to monoand disaccharide substrates. The coupling reactions proceeded cleanly with high yields without any significant side reaction, such as anomerization of the resulting alkenyl thioglycosides. Also, it was not observed significant impact of protecting groups on the reactivity of the thiosugar derivatives since the benzyl-protected carbohydrate reacted similarly to the O-acetylated derivative. The reaction with α-thiosugar did not proceed. In addition, alkynylated thioglycoside products were obtained diastereoselectively in good to excellent yields.

Overall, the authors synthesized 28 different compounds, including the synthesis of a biological compound which acts as a leaf-movement inhibitor (Figure 7b).

A very similar protocol was published by Messaoudi and co workers²⁷ in 2015, for the synthesis of fused thioglycosyl benzo[e][1,4]oxathiepin-5-ones and benzo[f][1,4]thiazepin-5(2H)-ones.

In this study, the authors performed the sequential coupling/cyclizations between substituted 2-iodobenzoates and thioglycosides. Initially, the cross-coupling reaction was performed as described in Scheme 8, using 1 equiv. of 1-thiosugar, 1.2 equiv. of 2-iodobenzoate, 5 mol% of Pd(OAc)₂, 2.5 mol% of xantphos, 1.5 equiv. of Et₃N, in dioxane (0.05 M) at 100 °C for 1-2 h. It was possible to synthesize 15 compounds with yields from 31 to 100%. The scope of the reaction included methyl 2-iodobenzoate having para- and meta-electron-donating or electron-withdrawing substituents to give thioglycosylated products in good to excellent yields with complete β-selectivity. When Z-methyl-3-iodo-acrylate reacted with thioglycoside, the product was stereoselectively obtained as the β-thioglycosidated Z-alkene without any thermal isomerization. Concerning the nature of the thiosugar, peracetylated-1-thio-β-D-glycosides, the products were obtained with the β configuration retained. For some substrates, as the disaccharides and the N-acetyl-1-thio-β-D-aminogluco-pyranose, mixtures of isomers were obtained, but they were separated by flash chromatography column to afford the isolated products.

Scheme 8
General procedure for palladium-catalyzed C-S cross-coupling between 1-thiosugars and 2-iodobenzoates, and posterior lactonization or lactamization.

Subsequently, the authors performed the deprotection followed by cyclization of the substrates, as shown in Scheme 8. For O-acetyl groups in the C2 position, the reaction was performed using 0.1 mmol of the coupling product, 0.3 equiv. of K₂CO₃, in 1 mL of MeOH, under argon atmosphere, stirring from 30 min to 1 h. On the other hand, for N-acetyl function at the C2 position, it was necessary 1 equiv. of K₂CO₃ and a higher time, from 12 h (for α-thioglycoside) to 3 days (for β-thioglycoside).

In 2015, in the light of the success of the Buchwald palladacycle precatalysts, which proved to be very effective for C-N and C-O cross-coupling reactions, Messaoudi and co workers²⁸ decided to apply these catalysts to the C-S cross-coupling of 1-thioglycosides. As shown in Scheme 9, the reaction was carried out using 1 mol% of the Pd-G3 xantphos precatalyst, 1 mmol of 1-thiossacharide, 1 mmol of an aglycone, and 1 equiv. of Et₃N, in tetrahydrofuran (THF) (0.25 M) as the solvent, at room temperature for 1 h.

Scheme 9
General procedure for Pd-G3-xantphos-catalyzed C-S cross-coupling for 1-thiosugars functionalization.

The scope of this reaction included several aryl halides, and this methodology showed a great tolerance group. Aryl iodides containing para- and meta-electron-donating or electron-withdrawing groups afforded good to excellent yields (67 to 99%). The sterically hindered ortho substituents influenced the outcome of the coupling reaction, furnishing the expected coupling product with a modest 38% yield. No significant impact of protecting groups on the reactivity of the thiosugar derivatives was observed, since acetateor benzoyl-protected carbohydrate reacted similarly to the unprotected derivative, leading to the thioglycoside products in 99, 99, and 75% yields, respectively. For alkenyl, the desired alkenyl thioglycoside derivatives were obtained stereoselectively in good to excellent yields (54 to 87%), and the alkynylated thioglycoside product was obtained diastereoselectively in a 79% yield.

Concerning the scope of the 1-thiosugar, the methodology was suitable for protected and unprotected N-acetylated thiosugars (97 and 67% yields, respectively), several different protected and unprotected monosaccharides, an unprotected disaccharide example (80% yield), and a protected and an unprotected trisaccharide example (69 and 51% yields, respectively). The general mechanism for Pd G3-xantphos-catalyzed C-S cross-coupling is presented in Figure 8.

Figure 8
General mechanism for Pd-G3-xantphos-catalyzed C-S cross-coupling.

Overall, 33 different compounds were produced with this methodology, including an example using cysteine as a thiol source. Besides, the authors performed a multigram-scale reaction, using 50 mmol of thioglycoside, 50 mmol of p-iodotoluene, 1 mol% of the G3-xantphos precatalyst, and 1 equiv. of Et₃N, in THF. The reaction was allowed to stir at room temperature, and after 9 min, it was observed by thin layer chromatography (TLC) that all the starting materials were consumed. All yields obtained were satisfactory (38 to 99%), under mild conditions, including the multigram-scale experiment which afforded a 98% yield. Moreover, this methodology proved to have a great functional group tolerance for aryl partners bearing electron-donating or electron-withdrawing, for alkenyl and alkynyl partners, for mono-, di-, and trisaccharides, and protected and unprotected sugars. Scope of this reaction is shown in Figure 9.

Figure 9
Scope for Pd-G3-xantphos-catalyzed C-S cross-coupling for the functionalization of 1-thiosugars.

Given the success and the efficiency shown by the Buchwald palladacycles precatalysts for the functionalized thioglycosides synthesis, the Messaoudi group extended the methodology for more complex substrates. In 2017, Messaoudi and co workers⁸ reported the palladium-catalyzed Buchwald-Hartwig-Migita cross-coupling between 1-thioglicosides and 2-iodoglycals under mild conditions to form (1→2)-S-linked saccharides. This synthesis was carried out using 1.2 equiv. of thioglycoside, 1 equiv. of 2-iodoglycal, 4 mol% of Pd-G3-xantphos, and 1.5 equiv. of Et₃N, in 1.1 mL of 1,4 dioxane at 60 °C for 2-3 h (Scheme 10).

Scheme 10
General procedure for the Pd-G3-xantphos-catalyzed synthesis of (1→2)-S-linked saccharides.

This protocol proved to be very effective for several nucleophiles, including mono-, di-, and polythiosaccharides, as well as αand β-thiosaccharides. All the substrates were obtained with the retention of the anomeric configuration. Cysteine and alyphatic thiols were also applied in this synthesis with success. Overall, 17 different compounds were achieved with yields from 55 to 86% for the saccharide moiety. Some selected examples are presented in Figure 10. Also, the deprotection of 2 substrates was performed with success, with yields of 98% for a monosaccharide substrate and 95% for a trisaccharide substrate. Thus, this methodology proved to be useful to construct complex molecules (1→2)-S-linked saccharides.

Figure 10
Selected examples of the Pd-G3-xantphos-catalyzed synthesis of (1→2)-S-linked saccharides.

To continue the study of the efficiency of the Buchwald palladacylcles precatalysts applied in thyogliconjugate synthesis, Messaoudi and co workers²⁹ reported in 2018 a Buchwald-Hartwig-Migita cross-coupling reaction for deoxyribonucleic acid (DNA) thioglycoconjugation. At first, to establish appropriate conditions for the reaction, the authors carried out the coupling using unprotected 5-iodouridine (1 equiv.), a thioglycoside (1.2 equiv.) in THF (0.7 mL), Pd-G3 xantphos (10 mol%) and Et₃N (1.3 equiv.), at 60 °C for 2 h (Scheme 11a). All the coupling reactions proceeded in good yields and without epimerisation at the anomeric position. Per-O-acetylated 1-thiosugars, N-Ac 1 thiosugars, and unprotected 1-thiosugars were efficiently coupled with the 5-iodouridine to give corresponding thioglycoconjugates (46 to 98% yield). Moreover, the reaction was not limited to monosaccharides, and it was applied to more complex diand trisaccharide derivatives (55 and 35% yield, respectively). Then, encouraged by these results, the authors proceeded with the insertion of thiosugars in oligonucleotides. The optimization of this reaction was performed with 1-hexanethiol, and it was found that, for this reaction, it was necessary to use 10 equiv. of the thiol moiety, 20 equiv. of Pd-G3-xantphos and 40 equiv. of the Et₃N, in H₂O/THF at 60 °C for 20 min. The reactions performed by the authors are shown in Scheme 11b, and it was possible to synthesize 8 different oligonucleotides functionalized with 1-hexanethiol. Overall, the authors synthesized 14 thioglicoconjugated oligonucleotides with excellent yields (73 to 98%). Some examples are shown in Figure 11.

Scheme 11
General procedure for Pd-G3-xantphos-catalyzed thyogliconjugate synthesis.

Figure 11
Selected examples for Pd-G3-xantphos-catalyzed thyogliconjugate synthesis.

This methodology is a great advance in the organic synthesis area, and it opens several possibilities for researchers to apply this protocol to other syntheses for new glycoconjugate oligonucleotides of interest.

Another great application founded using Pd G3 xantphos in Buchwald-Hartwig-Migita cross-coupling reaction is the thioglycoconjugation of iodoaryl peptides and amino acids. Messaoudi and co workers³⁰ reported this procedure in 2018, in which the reaction was carried out in a semi-aqueous media under mild conditions. As shown in Scheme 12, thioglycosylation was performed using 0.27 mmol (1 equiv.) of thiosugar, 1 equiv. of iodoaminoacids, 3 mol% of Pd-G3-xantphos, and 1 equiv. of Et₃N, in H₂O/THF (2:1), at room temperature for 30 min.

Scheme 12
General procedure for Pd-G3-xantphos-catalyzed thioglycoconjugation of iodoaryl peptides and amino acids.

After standardization, the authors expanded the scope of the reaction to structurally diverse αand β-thiol derivatives of mono-, di-, and trisaccharides with various amino acids. All the coupling reactions proceeded in good yields and without epimerization at the anomeric position. The reaction also worked well with unprotected thiosugars. Using this procedure, 18 different compounds were achieved by coupling thiosugars and amino acids with yields ranging from 55 to 96% (Figure 12). Furthermore, the authors performed the coupling between β-thioglucose and various diand tripeptides using the same protocol, and it was possible to synthesize 6 compounds in yields of 56-96%.

Figure 12
Scope of the Pd-G3-xantphos-catalyzed thioglycoconjugation of iodoaryl peptides and amino acids.

Encouraged by the success of these syntheses, the authors wanted to assess the efficiency of this protocol for the synthesis of very long thioglycopeptides. They investigated the reactivity of analogues of the human Mucin MUC1. The reaction was carried out between tri-O-acetylated β-thio-GlcNAc, its unprotected congener, and α-thioGalNAc with two fully-unprotected modified 60-amino-acid sequences of MUC1 (MUC1-derived mono-iodo peptide and tri-iodo peptide), as shown in Scheme 13.

Scheme 13
Coupling between 1-thiosugars and mono-, di-, and tri-iodopeptides.

For these syntheses, the authors used 1 equiv. of the iodopeptide, 5 to 15 equiv. of Pd-G3-xantphos, 15 to 25 equiv. of Et₃N, 3 equiv. of the thiosugar, in a mixture of H₂O/THF (2:1). The reaction was stirred at 40 °C for 1 h, affording 6 different thioglycoconjugates in yields ranging from 50 to 80%.

This protocol represents a great advance in the synthesis of thioglycoaminoacids, and it was compatible with nearly all natural amino acids. Besides, this methodology was successful with more complex substrates, as diand tripeptides and the analogues of the glycoprotein MUC1. This kind of procedure is quite important for the development of new tools to explore and modulate biological systems.

Among other important approaches of Buchwald-Hartwig-Migita cross-coupling using thioglycosides as nucleophiles developed by Messaoudi and coworker³¹ is the one-pot synthesis of unsymmetrical birayl thioglycosides. The one-pot multicomponent reaction was carried out using 0.6 mmol of thiosugar, 0.5 mmol of bromo-iodo-benzene, 2 equiv. of boronic acid, 5 mol% of Pd-G3-xantphos, and 4 equiv. of K₂CO₃, in THF, at room temperature for 15 min, then for 5 h at 100 °C. The reaction presented in Scheme 14 consists in two steps: the first step is a C-S cross-coupling between the thiosugar and the dihalogenated arenes, and the second step is a Suzuki-Myiaura cross-coupling between the boronic acid and the monohalogenated thioglycoside intermediate.

Scheme 14
General procedure for Pd-G3-xantphos-catalyzed three-component tandem reaction.

First, the authors extended the substrate scope for this catalytic process by varying the boronic acids, iodobromoarenes, and the thiosugar substrates. A variety of electron-rich and electron-deficient, para- and meta substituted arylboronic acids effectively underwent reaction with meta-iodo-bromobenzene and per-O acetylated 1-thiosugars, affording yields ranging from 53-80%. The reaction of para-iodo-bromobenzene with thiosugar and boronic acids resulted in the selective formation of biphenyl para-β-thioglycoside in a good yield (60%), while the ortho-dihalogenated substrate gave only a moderate yield (32%), probably due to steric hindrance. Regarding the thiosugar partners, this procedure tolerated a large variety of glycosylthiols: O-acetylated β-1-thiosugars, O-acetylated N-Ac-β-1-thiosugar, with respectable yields (45-62%). Importantly, this procedure is not limited to only protected β-glycosyl thiols, but it also worked successfully with unprotected 1-thioglucose without any loss of reactivity (63 to 50% yield). Moreover, the reaction scope was not limited to monosaccharides, and was also applied to diand trisaccharide derivatives, obtaining yields of 41 and 35%, respectively.

This protocol proved to be highly selective, with no side products observed. The methodology showed great functional group tolerance, and it was possible to synthesize 29 different compounds with yields ranging from 35 to 80%. Some selected examples of the substrates synthesized in this methodology are presented in Figure 13.

Figure 13
Selected examples for Pd-G3-xantphos-catalyzed three-component tandem reaction.

In their continuous pursuit for new thioglicomimetics with medicinal and pharmaceutical value, Messaoudi and co workers³² reported in 2020 the synthesis of S-aryl S-trifluoromethylsulfoximine thioglycosides. Sulfoximines have recently emerged as active pharmaceutical ingredients, and they are an important building block for the synthesis of new potential drugs. Thus, the authors decided to combine both moieties, performing a C-S cross-coupling reaction between o-iodo S-trifluoromethyl S-phenylsulfoximines and 1-thioglycosides as described in Scheme 15. The reaction was performed using 1 equiv. of racemic iodo-sulfoximine, 1.2 to 2 equiv. of thiosugar, 10 mol% of Pd-G3-xantphos, and 1.5 equiv. of Et₃N, in dioxane at 60 °C for 15 to 30 min. The reaction afforded a diastereoisomer mixture of 1:1, which could be easily separated by crystallization or high-performance liquid chromatography (HPLC). All the products were isolated as single β-anomers.

Scheme 15
General procedure for Pd-G3-xantphos-catalyzed synthesis of S-aryl S-trifluoromethylsulfoximine thioglycosides.

The scope of this reaction (Figure 14) includes a variety of different O-acetylated β-1-thiosugars (galactose, glycose and fucose, affording 79, 70 and 78% yields, respectively), unprotected thiosugars (glycose and galactose, affording 47 and 40% yields, respectively), different protection groups, such as -Bz, -Me and -TBS, affording 45, 66 and 56% yields, respectively, and more complex saccharides like disaccharide thio-β-D-cellobiose (60% yield) and trisaccharide thio-β-D-maltotriose (49% yield).

Figure 14
Selected examples for Pd-G3-xantphos-catalyzed synthesis of S-aryl S-trifluoromethylsulfoximine thioglycosides.

Recently, Liang and co workers³³ reported the synthesis of aryl thio/selenoglycosides via the Catellani strategy. The authors used β-thio and selenosugars with acetyl or benzoyl groups attached to the chalcogen atom. In this sense, for thioglycosides, the reaction was performed with 0.2 mmol of iodoarene, 0.1 mmol of the thiosugar, 10 mol% of Pd(TFA)₂, 20 mol% of P(p-ClC₆H₄)₃, 3 equiv. of K₃PO₄, and 4 equiv. of norbonene, in dioxane at 100 °C for 17 h under argon atmosphere (Scheme 16).

Scheme 16
General procedure for palladium-catalyzed synthesis of aryl thio/selenoglycosides via Catellani strategy.

A variety of substituted β-thiosugars with aryl iodides could successfully give the corresponding aryl S-glycosides in moderate to good yields with exclusive β-selectivity under standard conditions. 1-Thiosugars bearing protection groups such as acetyl (Ac), pivaloyl (Piv), benzyl (Bn), and benzoyl (Bz) were also well tolerated (51 to 82% yield). Concerning the protection group, the lower yields were observed for the benzyl and benzoyl groups, and this can be attributed to the steric hindrance of these groups. This reaction also showed good compatibility for dithiosaccharides, affording the target products in excellent yields, showing no loss of reactivity when compared with the monosaccharides. The effect of the aryl iodine was also carried out, and showed that monoand dimethyl-substituted aryl iodides provided the aryl thioglycosides in good yields (58 to 70%), and the lower yields can be justified by the steric hindrance of the methyl groups.

Overall, the authors synthesized 17 different functionalized thioglycosides with yields ranging from 51 to 89%. Some examples and their yields are presented in Figure 15. Also, it was performed a successful gram-scale reaction with 79% yield. This reaction was a new approach to synthesizing aryl thio/selenoglycosides by cleaving the C(O)-S/C(O)-Se bond of glycosyl sulfate/selenolate.

Figure 15
Selected examples for palladium-catalyzed synthesis of aryl thio/selenoglycosides via Catellani strategy.

The contribution of our group to the functionalization of thioglycosides catalyzed by palladium is the work reported by Santos et al.³⁴ In this work, the authors described the functionalization of thiosugars with the 5-bromobenzothiadiazole (BTD), which is known for its luminescent properties (Scheme 17).

Scheme 17
General procedure for Pd-G3-xantphos-catalyzed functionalization of 1-thiosugars with BTD moiety.

Thus, it was used 1 equiv. of the BTD moiety and 1.2 equiv. of the 1-thiosugar, 1.5 equiv. of triethylamine (TEA), 4 mol% of Pd-G3-xantphos, 1 mL of dioxan, under nitrogen atmosphere, at 90 °C for 2 h. Overall, 8 different BTD derivate compounds were synthesized in yields ranging from 10 to > 99%, and all of them were obtained as single β-anomers (Figure 16). In this way, the authors explored the reactivity of monosaccharides (14 to 99% yield), and the methodology proved to be effective for disaccharides as well, leading to 95 and 99% yields.

Figure 16
Selected examples for Pd-G3-xantphos-catalyzed functionalization of 1-thiosugars with BTD moiety.

After this study, the authors performed deprotection reaction to afford the BTD-derivative unprotected thioglycosides in excellent yields (76 to 99%). In addition, this methodology was applied to other important substrates, which are precursors of biologically active compounds, affording yields in the range of 52 to 88%.

Furthermore, the authors performed the ultraviolet visible (UV-Vis) study for all the synthesized substrates, and they observed a hypercromic effect when compared to the starting materials.

2.3. Nickel-catalyzed cross-coupling for 1-thioglycosides synthesis

The first report of nickel catalyzed synthesis of functionalized 1-thioglycosides was accomplished by Messaoudi and co workers² in 2013. After their frustrating attempts to perform C-S cross-coupling with unprotected thioglycosides using palladium as catalyst, the authors came up with the idea of using nickel to perform this coupling.³⁵ It was found that unprotected thioglycosides have limited stability under high temperatures and/or basic conditions. In this sense, it was developed a methodology performed at room temperature. Thus, the authors successfully performed the nickel catalyzed cross-coupling reaction between unprotected thioglycosides and (hetero)aryl halides, as well as alkenyl and alkynyl halides. Initially, the authors synthesized a nickel(0) catalyst using a mixture of 1 equiv. of Zn, 30 mol% of NiCl₂.DME and 300 mL pyridine. This mixture was heated at 55 °C to generate the nickel(0) species [Ni⁰(DME)₂(Py)]. Then, a solution containing 0.25 mmol of the respective unprotected thiosugar, 0.5 mmol of the aryl, alkenyl, or alkynyl partner in 1 mL of MeOH was added dropwise to the mixture containing the nickel(0) complex. The reactions are summarized in Scheme 18, and they were allowed to stir at 20 °C for 1-4 h (for aryl partners) and 2 h for alkenyl and alkynyl partners.

Scheme 18
General procedure for nickel-catalyzed functionalization of unprotected 1-thiosugars.

The authors reacted 1-thio-β-D-glucopyranose with aryl iodides that contained para- and meta-electron-donating or electron-withdrawing substituents to afford thioglycosylated products in good to excellent yields with complete β selectivity (68 to 99% yield). In addition, the ortho-substituted aryl iodides were tolerated in the coupling reaction, leading to β-thioglycosides in good yields (70 to 86%), regardless of the electronic nature of the substituents. Reactive electrophilic functional groups, such as aldehyde, ester, hydrazone, and bromo substituents, were well-tolerated, which could be used for further derivatization of the β-arylthioglycosides. Heteroaryl coupling partners also worked well in this methodology, leading to moderate or good yields (49 to 65%).

As the scope of the saccharides, the reaction was performed with several unprotected monosaccharides, αand β-anomers, and disaccharides as well. There were no significant differences in reactivity between the αand β-anomers; good yields were obtained from the coupling reactions of 4-iodoanisole with 1-thio-α-D-glucopyranose and 1-thio-β-D-glucopyranose (80 and 99% yields, respectively). In addition, the coupling procedure was not only limited to monothioglycosides, but it also worked successfully with 1-thiodisaccharides, leading to yields of 65 to 69%.

Besides, the authors performed the coupling reactions of unprotected αor β-thioglycosides with alkenyl iodides and alkynyl bromides as aglycone partners. The scope of this methodology is presented in Figure 17. All the products were obtained with good to excellent yields, with a single anomer, and no thermal isomerization was observed.

Figure 17
Scope for the nickel-catalyzed functionalization of unprotected 1-thiosugars.

Overall, the authors synthesized 41 different compounds containing the unprotected thiosugar moiety, being two of them, biologically interesting thioglycosylated compounds, the 4-methyl-7-thioumbelliferyl-β D cellobioside (MUS CB), which is a fluorescent non-hydrolyzable analogue of cellulases, and the analogues of phenstatin and isocombretastatin A-4 (isoCA-4), two highly promising cytotoxic and antitubulin agents. This methodology showed good tolerance to functional groups, and the yields varied between 45 and 99%. Besides, nickel catalysts have lower costs compared to palladium catalysts. Therefore, this methodology is beyond practicality to be used in other syntheses.

Nickel catalysts are desirable because their properties are similar to palladium, but they have a lower cost. Several authors have devoted to developing new protocols suitable for nickel catalysts. In this sense, it raises the nickel photoredox catalysis, which is a green protocol that uses visible light as a source of energy. In this way, Messaoudi and co workers³⁵ reported in 2019 a Ni/Ru photoredox catalysis protocol for 1-thiosugars functionalization with (hetero)aryl, alkenyl, and alkynyl halides. This methodology is performed as described in Scheme 19, using 0.2 mmol of the thiosugar, 1.5 equiv. of the halide, 5 mol% of the Ru(bpy)₃ as the photocatalyst, and 2 mol% of the HAT (hydrogen atom transfer) agent in dry dimethylformamide (DMF), under blue light emitting diode (LED) irradiation in a 24 h period.

Scheme 19
General procedure for 1-thioglycoside synthesis via dual-photoredox catalysis.

The authors used an ammonium bis(catechol)alkylsilicate as a HAT agent to abstract an H atom from the 1-thiosugar moiety, generating a thyil glycosyl radical. On the other hand, the halide undergoes oxidative addition to a nickel species, which comes from nickel(0) and becomes nickel(II). The thiyl glycosyl radical adds to the nickel(II) species, generating a nickel(III) species, which undergoes reductive elimination and forms a nickel(I) species and affords the functionalized thioglicoside. A single-electron transfer (SET) promoted by the photocatalyst reduces the nickel(I) to nickel(0) species. This protocol lays out the use of any base, and it was suitable for several substrates, including aryl iodides and bromides. All the couplings proceeded selectively in good yields. Various electron-deficient and electron-rich aryl iodides having para- and meta-substitution effectively underwent reaction with tetra-O-acetylated 1-thio-β-D-glucopyranose in yields up to 96%. It was found that electron-withdrawing groups in para position afforded high yields (76 to 96%), except for para-nitro group (35% yield). Electron-donating groups in para position also led to good yields (62 to 88%). The presence of a group in ortho position (donating or withdrawing) did not affect the coupling process, leading to yields of 88, 73, and 85%. Heteroaryl halides derived from quinolinone, pyridine, and indole have also been successful, leading to excellent yields (87-95%). The coupling of 1-thiosugar with halogenated alkenes and alkynes proceeded successfully, and afforded the alkenyl derivative stereoselectively in 87% yield and the alkynyl derivative in 58% yield. Besides, the scope of different glycosyl thiols was verified, and the methodology was suitable for monoand disaccharides, as well as tolerated benzyl and acetyl protecting groups.

Overall, 26 different compounds were synthesized with this methodology. Besides, this procedure was applicable in flow chemistry, leading to a yield of 79% in a short reaction time (20 min), and the authors also synthesized a bioactive compound, hSGLT1 inhibitor (Figure 18).

Figure 18
Selected examples for 1-thioglycoside synthesis via dual-photoredox catalysis.

Using a similar methodology, Anselmi and co workers³⁶ reported in 2022 a dual photoredox catalyzed coupling between 1-thiosugars and bromo/iodo-S perfluoroalkylsulfoximines. As shown in Scheme 20, the reaction was carried out under blue light emitting diode (LED) irradiation in DMF as the solvent, 1.5 equiv. of 1-thiosugar, 1 equiv. of the sulfoximine, 1.75 equiv. of the p-toluidine, which in this case works as a HAT agent, 5 mol% of the nickel catalyst Ni(4,4’-di-tert-butyl-2,2’-bipyridine)(H₂O)₄]Cl₂, and 2 mol% of the photocatalyst [Ru(bipyridine)₃](PF₆)₂. The reaction was stirred at room temperature for 3 h, leading to yields up to 95%.

Scheme 20
General procedure for nickel-catalyzed functionalization of sulfoximines with 1-thiosugars via dual photoredox catalysis.

The authors reported the synthesis of 13 different compounds, with 4 different thiosugars (40 to 73% yields), and different sulfoximines: S-trifluoromethyl sulfoximine (40 to 70% yields), S-difluoromethyl sulfoximine (19 to 70% yields), S-fluoromethyl sulfoximine (12 to 75% yields), and S-methyl sulfoximine (58% yield). Some examples are shown in Figure 19. In addition, further functionalization of some of these compounds was carried out to afford benzothiadiazole analogues. Furthermore, the reaction was performed at scale-up, and it was successful, leading to the synthesis of the desired product in 59% yield.

Figure 19
Selected examples for nickel-catalyzed functionalization of sulfoximines with 1-thiosugars via dual photoredox catalysis.

Still, in the spotlight of greener protocols, the electrosynthesis emerged as a powerful tool for organic cross-coupling reactions, because it enables the use of alternative metals that are cheaper than palladium, like nickel, besides being eco-friendly because it avoids waste. In this way, Messaoudi and co workers³⁷ reported in 2020 the Migita cross-coupling between 1-thiosugars and aryl, alkenyl, or alkynyl bromides and iodides using electrochemistry and nickel as catalysts. The reaction was carried out as shown in Scheme 21, using 0.3 mmol of the 1-thiosugar, 0.3 mmol of the halide partner, 10 mol% of NiBr₂.glyme, 10 mol% of di-t-Bubpy, 1.2 mmol of LiBr, in DMF (0.3 M), using a Mg anode and a Ni foam cathode, in an undivided cell, with a constant current of 8 mA, N₂ protection at room temperature for 3 h.

Scheme 21
General procedure for electrochemical nickel-catalyzed Migita cross-coupling.

All the S-arylation proceeded with selectivity in good yields, providing the products as a single anomer. Aryl bromides bearing various functions (-CN, -Cl, -F, -CF₃, -CHO, and -OMe) have been successfully achieved under room temperature to afford the corresponding thioglycosides in yields up to 87%. Noteworthy, the presence of an ortho substitution at the aromatic ring of the coupling partner does not affect the coupling process, as compounds were obtained in 80 and 77% yields. For some bromide substrates that afforded low yields, such as 3-bromonaphtalene (22% yield) and p-bromoanisole (15% yield), the authors performed the same reaction using the iodine substrate, and were successful in raising the yields to 73% for 3-iodonaphtalene and to 83% for p-iodoanisole. For alkenyl and alkynyl substrates, it was possible to synthesize the corresponding thioglicosides with selectivity and good yields (61 to 95%). The reaction conditions also tolerated different thiosugars, being mono-, di-, and trisaccharides, as well as different protecting groups, leading to yields ranging from 66 to 95%.

Overall, using this procedure the authors were able to synthesize 29 different compounds, including one experiment using an unprotected thiosugar and another using cysteine instead of the thiosugar. The yields ranged from 15 to 95%, and the lowest yields obtained with aryl bromides were replicated with aryl iodides, which led to higher yields. Besides, experiments using diand trisaccharides successfully achieve good to excellent yields (90 and 88%, respectively). Scope of this reaction and selected examples are shown in Figure 20.

Figure 20
Scope for electrochemical nickel-catalyzed Migita cross-coupling.

3. Functionalization of 1-Thiosugars via Thiol-ene Reaction

Sulfur radicals have been widely studied because of their many biological functions and are involved in many enzymatic processes. Due to their attractive biological functions, sulfur-centered radicals have drawn the attention of synthetic chemists.³⁸ The most useful applicability of thiol radicals is their ability to add to carbon-carbon multiple bonds. The addition can be performed under mild conditions, and this reaction has been proven to be an important tool for designing new molecules.³⁹ In carbohydrate chemistry, the thiol-ene reaction offers a particularly attractive route to thioglycosides (thio-linked glycosides). This strategy benefits from the inherent stereoselectivity, regioselectivity, and functional group tolerance observed in multiple studies. This section of the review focuses on these reactions, showing their high relevance in carbohydrate chemistry. General mechanism for thiol-ene reaction using 1-thiosugars is presented in Figure 21.

Figure 21
General mechanism for thiol-ene reaction with 1-thiosugars.

In 2009, Dondoni and co workers⁴⁰ reported the first photoinduced thiol-ene coupling between a sugar thiol and a sugar alkene in order to synthesize 1,6-linked S-dissacharides. The authors performed the reaction using 1.2 or 3 equiv. of the sugar thiol and 1 equiv. of the sugar alkene, 10 mol% of the photoiniciator DPAP (2,2-dimethoxy-2-phenylacetophenone) with CH₂Cl₂ as the solvent (0.05 M) under light irradiation of a household ultraviolet A (UVA) lamp (λ_max = 365 nm) at room temperature (Scheme 22).

Scheme 22
General procedure for the photoinduced thiol-ene coupling between 1-thiosugars and sugar alkenes.

The authors synthesized 10 compounds with different thiosugars and sugar alkenes; the methodology was suitable for αand β-thiosugars, as well as for acetyl and isopropylidene protecting groups, with yields ranging from 76 to 92%. It is important to mention that the products did not suffer any anomerization, and the synthesized compounds retained the configuration of the thiosugar. The thiosugar scope encompassed O-acetylated β-1 thiosugars, O-acetylated α-1-thiosugars, and N-acetyl-1-thio-β D aminogluco-pyranose, and it was observed no difference in rectivity between αand β-anomers. The alkenes bonded to sugar moieties encompass pyranosides and furanosides (Figure 22).

Figure 22
Selected examples for the photoinduced thiol-ene coupling between 1-thiosugars and sugar alkenes.

Later, in 2011, Dondoni and co workers⁴¹ reported the photoinduced thiol-ene coupling under similar conditions, using glycosyl thiols and allyl or vinyl glycinates to synthesize S-glycosyl amino acids. As shown in Scheme 23, the reaction was carried out using 1.2 equiv. of the thioglycoside, 1 equiv. of the alkenyl glycine, 0.1 equiv. of the photoiniciator DPAP (2,2-dimethoxy-2 phenylacetophenone) with CH₂Cl₂ as the solvent under light irradiation (λ_max = 365 nm) at room temperature for 30 min.

Scheme 23
General procedure for the photoinduced thiol-ene coupling between 1-thiosugars and allyl or vinyl glicinates.

Overall, 8 different S-glycosyl amino acids were synthesized with this methodology, with yields ranging from 53 to 97%. The substrate scope included 3 different thiosugars, including one disaccharide, and two different alkenyl glycine (Figure 23). In addition, the reaction was successfully applied to more complex amino acids. Besides, one experiment was conducted with an unprotected thiosugar, affording a 97% yield.

Figure 23
Selected examples of the photoinduced thiol-ene coupling between 1-thiosugars and allyl or vinyl glicinates.

In 2012, Dondoni and co workers⁴² described a protocol to synthesize a new family of 1-deoxy S-disaccharides via photoinduced thiol-ene coupling between sugar thiols and glycals. Inspired by their previous works,⁴⁰,⁴¹ the authors used similar conditions to perform this reaction as described in Scheme 24, with 1 equiv. of glycal, 6 equiv. of the thiol sugar, 0.6 equiv. of the photoiniciator DPAP, with a mixture of EtOH/CH₂Cl₂ (20:1) as the solvent under light irradiation (λ_max = 365 nm) at room temperature for 1 h.

Scheme 24
General procedure for the photoinduced thiol-ene coupling between 1-thiosugars and glycals.

The authors used 4 different glycals and 4 different thiol sugars, to afford 8 different compounds, and the yields ranged from 20 to 100%. For the reactions performed using the D-glucal and the D-galactal, the products were obtained as a mixture of 2 diastereoisomers. For the reactions performed using the D-allal and the D-gullal, despite the lower yields (38 and 20%, respectively), the products were obtained as a single isomer. The reason for this is that the axial acetoxy group at C3 in these substrates leads to the exclusive formation of the 2,3-trans-diaxial substituted product, and for the other substrates, this effect is not observed.

In 2012, Borbás and co workers⁴³ reported a reaction between 2-acetoxy glycals and a 2,3-unsaturated glycoside and several thiols, including 1-thiosugars, generating S-dissacharides with full regioand stereoselectivity. In this study, the stereoselective synthesis of S-disaccharides was carried out using 1 mmol of the enose, 2 mmol of the thiosugar, 0.1 mmol of DPAP, in dry toluene (7 mL). This solution was deoxygenated and irradiated at room temperature for 15 min to afford the desired S-dissacharides (Scheme 25).

Scheme 25
General procedure for the photoinduced thiol-ene coupling between 2-acetoxy glycals or 2,3-unsaturated glycosides and 1-thiosugars.

This work demonstrated that the addition of thiols to hexose-derived 2-acetoxy glycals and a 2,3-unsaturated glycoside proceeded with total selectivity, offering an easy access to 1,2-cis-α-thioglycosides and 3-deoxy-S disaccharides. Later, in 2020, the same research group performed a study on UV-light-induced reactions of 2,3-unsaturated O-, C-, S-, and N-glycosides with thiols (including thiosugar). The authors have found that the type of the anomeric heteroatom deeply affects the reactivity, regio-, and the stereoselectivity of the thiol-ene reactions between 2,3-unsaturated sugars and thiols.

Recent advances in photoredox chemistry have allowed researchers to use visible light to perform thiol-ene reactions under mild conditions. In this way, in 2017, Wang and co workers⁴⁴ reported the thiol-ene coupling between several thiols and alkenes under blue LED irradiation using an organic photoredox catalyst as a radical initiator. After testing a broad scope of aliphatic and aromatic thiols, as well as various alkenes, the authors extended the methodology to synthesize glycoconjugates using thiosugars and amino acid derivatives. In this procedure, 0.5 mmol of the thiol and 0.6 mmol of the alkene were reacted in the presence of 1 mol% of the photocatalyst (Mes-Acr-Me⁺BF₄^-), in 1 mL of MeCN, under irradiation of blue LED for 6 h (Scheme 26).

Scheme 26
General procedure for the photoredox-catalyzed thiol-ene coupling between thiosugars and amino acid derivatives for the synthesis of glycoconjugates.

The authors synthesize 4 examples of glycoconjugates with yields ranging from 73 to 85%. Some examples are shown in Figure 24. Moreover, the authors used the same methodology to perform a thiol-ene coupling using thiosugar and a nucleoside derivative, and also a functionalized dipeptide, affording S-linked glyconucleoside and glycopeptide in yields of 78 and 79%, respectively.

Figure 24
Selected examples of the photoredox-catalyzed thiol-ene coupling between thiosugars and amino acid derivatives for the synthesis of glycoconjugates.

In 2021, Wang and co workers⁴⁵ reported the visible light-mediated thiol-ene coupling between thiosugars and alkenes in aqueous medium. The reaction was carried out by irradiating 0.137 mmol of the 1-thiosugar, 0.165 mmol of the alkene, an organic photoredox catalyst (1 mol%), 0.274 mL of the solvent with two 12 W, 450 nm LED floodlamps for 6 h (Scheme 27). The authors tested the following solvents: water, a mixture of water and MeCN, and buffer at different pH levels. They have found that pure water afforded the desired product in 72% yield. The addition of an organic solvent (H₂O/MeCN 1:1) increased the yield to 85% due to the increase in the thiosugar solubility. Additionally, the authors reported a direct relationship between buffer pH and the formation of the thiol-ene coupling or the diglycosildisulfide, and they have found that lower pH favors the thiol-ene coupling formation, as the higher pH favors the disulfide formation.

Scheme 27
General procedure for the photoredox-catalyzed thiol-ene coupling between thiosugars and alkenes.

Besides, the authors extended the methodology to perform the thiol-ene coupling between 1-thiosugars and unprotected peptides, affording the products in 50-83% yields.

4. Conclusions

This review has focused on the functionalization of 1-thiosugars, which has emerged as a powerful strategy in synthetic carbohydrate chemistry, offering access to structurally diverse and biologically relevant S-glycosylated molecules. Among the most prominent methodologies, transition metal-catalyzed cross-coupling reactions and thiol-ene chemistry have demonstrated remarkable efficiency, regioand stereoselectivity, and broad substrate compatibility.

Despite significant advances, some challenges still remain, especially regarding the development of more sustainable, metal-free, or enantioselective protocols and the translation of these methodologies to aqueous or biologically relevant environments. Nonetheless, the growing interest in thiosugars as synthetic handles and biological probes underscores the importance of continued innovation in this area.

Acknowledgments

N.L.C.D. thanks to FUNDECT/Brazil (grant No. 31/2021 - Universal 2021 - ODS) and CNPq (grant No. 09/2023 - bolsa de produtividade em pesquisa - PQ).

Data Availability Statement

The data supporting the findings of this review are available within the article and in the cited literature. All information, analyses, and discussions presented herein are based on data reported in the referenced publications.

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Edited by

• Editor handled this article:
  Giovanni Wilson Amarante (Associate)

Publication Dates

• Publication in this collection
  02 Mar 2026
• Date of issue
  2026

History

• Received
  07 Oct 2025
• Accepted
  08 Jan 2026
• Published
  04 Feb 2026