Synthesis of protected group-free carbohydrates using laboratory-stable heteroarylglycosyl sulfide donors.

Abstract

A method for synthesizing compounds selected from the group consisting of C-alkyl glycosides, C-alkenyl glycosides, C-heteroaryl glycosides, Se-glycosides, and S-glycosides is disclosed, comprising: a. reacting a natural unprotected sugar with a mixture of 2-chloro-1,3-dimethylimidazolinium chloride (DMC), heteroarylthiol, and trimethylamine (Et3N) in a mixture of water and dioxane to produce a heteroarylglycosyl sulfide; and b. photo-induced cross-coupling of the heteroarylglycosyl sulfide with reagents under blue LED irradiation in the presence of hantchu ester (HE), 1,4-diazabicyclo[2.2.2]octane (DABCO), and DMSO to produce the compound.

Description

Technical Field

[0001] The present invention generally relates to methods of chemical glycosylation. In particular, the present invention relates to methods of chemical glycosylation without using protecting groups.

Background Art

[0002] Carbohydrates are an essential class of organic compounds that play extremely important roles in countless biological processes. Due to their importance, significant efforts have been made to access these saccharides in order to better understand the properties, functions, and potential disease-related effects of these saccharides, which are indispensable for the development of sugar-based therapeutic agents. Since it is difficult to extract meaningful amounts of pure samples from nature, chemists obtain most saccharides by synthetic means. For this purpose, non-enzymatic chemical glycosylation forms the basis of carbohydrate chemistry as a highly reliable and versatile method for constructing a vast variety of natural and non-natural glycoside structures.

[0003] However, unlike enzymatic systems that can mediate the glycosylation of polyhydroxylated glycosyl donors with precise site control, established non-enzymatic or chemical glycosylation methodologies are less precise and typically require challenging protecting strategies to overcome site selectivity problems. These shortcomings are particularly evident in the chemical synthesis of C-glycosides, which are gaining importance as robust and often more biologically active alternatives to O-glycosides [1]. Advances in C-glycosylation over the past few decades (Figure 1a) have required multi-step reaction sequences (hydroxyl group protection, functionalization, deprotection) with delicate or harsh reaction conditions to convert completely unprotected natural sugars into engineered glycosyl precursors containing anomeric leaving groups such as halides, esters, sulfoxides, and sulfones, thereby laying the groundwork for subsequent carbon-carbon bond formation reactions to produce the desired unprotected C-glycosides. Current multi-step strategies in the chemical synthesis of unprotected C-glycosylation involve long sequences, the generation of excess waste, strong oxidizing agents, and the complexity associated with deprotection in later stages. Given the practical drawbacks and inefficiencies of these approaches, the development of protecting group-free methods for a wide range of chemical glycosylations has remained a long-standing goal in carbohydrate science.

[0004] Therefore, there is a need for a novel chemical glycosylation method that does not require a multi-step reaction sequence (hydroxyl group protection, functionalization, deprotection) involving delicate or harsh reaction conditions. In this invention, we have developed a protecting group-free method for a wide range of chemical glycosylation. This method achieves direct chemical glycosylation of natural sugars via a transient thioglycosyl donor and achieves site-selective and diastereoselective anomeric functionalization of natural sugars without protecting groups.

[0005] In one embodiment, the present disclosure is a method for synthesizing compounds selected from the group consisting of C-alkyl glycosides, C-alkenyl glycosides, C-heteroaryl glycosides, Se-glycosides, and S-glycosides, a. Reacting natural unprotected sugars with a mixture of 2-chloro-1,3-dimethylimidazolinium chloride (DMC), heteroarylthiol, and trimethylamine (Et3N) in a mixture of water and dioxane to produce heteroarylglycosyl sulfides; and b. The heteroaryl glycosyl sulfide is photo-induced cross-coupled with a reagent under blue LED irradiation in the presence of Hantchu ester (HE), 1,4-diazabicyclo[2.2.2]octane (DABCO), and DMSO to produce the compound. This includes methods.

[0006] This disclosure has the advantage of solving a long-standing challenge in carbohydrate chemistry by providing a general strategy for achieving site-selective and stereoselective chemical glycosylation from completely unprotected natural sugar units, while avoiding unnecessary masking and manipulation of hydroxyl groups. As a result, it provides a more environmentally friendly and sustainable carbohydrate synthesis solution that significantly reduces costs and waste generation.

[0007] The present invention will be better understood by referring to the detailed description, which is considered in conjunction with non-limiting embodiments and the accompanying drawings. [Brief explanation of the drawing]

[0008] [Figure 1] This is a schematic diagram illustrating conventional techniques and developments in protecting group-free approaches to the chemical glycosylation of natural sugars. (a) Challenges in multi-step chemical synthesis of protecting group-free sugars, using C-glycosides as an example. (b) Design of traceless activation strategies to achieve site-selective and diastereoselective anomeric functionalization of protecting group-free natural sugars. [Figure 2]This is a schematic diagram illustrating the reaction development. a) Selection of appropriate activators for site-selective nucleophilic substitution reactions. b) Identification of the most effective thioglycosyl donors in photo-induced cross-coupling reactions. Yields were determined by 1H NMR analysis of the crude reaction mixture; yields in parentheses indicate isolation yields. The α:β anomeric ratio was determined by 1H NMR and LC-MS analysis. DMC, 2-chloro-1,3-dimethylimidazolinium chloride; CDMT, 2-chloro-4,6-dimethoxy-1,3,5-triazine; NMM, N-methylmorpholine; HE, hantchu ester (diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid); DABCO, 1,4-diazabicyclo[2.2.2]octane; DMSO, dimethyl sulfoxide; LED, light-emitting diode; RT, room temperature; C6F4, 2,3,5,6-tetrafluorophenyl. [Figure 3] This is a schematic diagram illustrating the mechanism study. a. Different anomers of the thioglycoside intermediate ultimately converge as stereoisomers to the pure C-glycosyl product. b. Radical trapping experiments support the existence of glycosyl radical species as intermediates. c. UV / Visible absorption spectra of the reactants in DMSO. d. A plausible mechanism of activation of the natural sugar and photo-induced cross-coupling. Yields were determined by 1H NMR analysis of the crude reaction mixture; yields in parentheses indicate isolation yields. The α:β anomer ratio was determined by 1H NMR and LC-MS analysis. TEMPO, 2,2,6,6-tetramethyl-1-piperidinyloxy; DMI, 1,3-dimethylimidazolidinion-2-one; PET, photo-induced electron transfer; HRMS, high-resolution mass spectrometry; ESI, electrospray ionization; E, electrophile; calcd, calculated value. [Figure 4] This is a schematic diagram illustrating the range of reactions using various natural sugars. It shows cross-coupling reactions of monosaccharides and oligosaccharides with unprotected glycosyl donors to directly obtain unprotected C-alkylglycosyl compounds. Yields were determined by 1H NMR analysis of the crude reaction mixture; yields in parentheses indicate isolation yields. The α:β anomeric ratio was determined by 1H NMR and LC-MS analysis. Bn represents benzyl. [Figure 5]This is a schematic diagram illustrating the synthesis of diverse classes of potent glycosides and glycoconjugates. a. C-alkylglycosyl compounds by reaction with I. b. C-alkenyl and C-heteroarylglycosyl compounds by reaction with II (for 44) and III (for 45-47). c. Se-glycosides by reaction with IV. d. S-glycosides by reaction with V. Yields were determined by 1H NMR analysis of the crude reaction mixture; yields in parentheses indicate isolation yields. α:β anomeric ratio, diastereomeric ratio (dr), and E:Z ratio were determined by 1H NMR and LC-MS analysis. *Obtained as a mixture with E:Z = 77:23. †D-galactose was used. Ar: aryl; X: halide; Ac: acetyl; Boc: tert-butoxycarbonyl.

[0009] This disclosure describes a method for synthesizing protected group-free carbohydrates using laboratory-stable heteroarylglycosyl sulfides as donors.

[0010] In one embodiment, the present disclosure is a method for synthesizing compounds selected from the group consisting of C-alkyl glycosides, C-alkenyl glycosides, C-heteroaryl glycosides, Se-glycosides, and S-glycosides, a. Reacting natural unprotected sugars with a mixture of 2-chloro-1,3-dimethylimidazolinium chloride (DMC), heteroarylthiol, and trimethylamine (Et3N) in a mixture of water and dioxane to produce heteroarylglycosyl sulfides; and b. The heteroaryl glycosyl sulfide is photo-induced cross-coupled with a reagent under blue LED irradiation in the presence of Hantchu ester (HE), 1,4-diazabicyclo[2.2.2]octane (DABCO), and DMSO to produce the compound. This includes methods.

[0011] Inspired by reports of biological S-glycosylation [2] in which S-glycosyltransferases catalyze the formation of metabolically stable S-glycosidic bonds with unprotected nucleotide sugars (generated from natural variants by site-selective phosphorylation of hemiacetals), the present invention aims to provide a reactive thioglycoside intermediate that has sufficient lifespan and can undergo desulfurization cross-coupling with appropriate reagents in a single operation, employing a biomimetic approach that preferentially activates and substitutes anomeric hydroxyl groups (hemiacetals) in natural sugars. In this process, the transiently introduced S-glycosyl donor (heteroarylglycosyl sulfide) disappears without leaving a trace. In the present invention, 2,3,5,6-tetrafluoro-4-pyridiylglycosyl sulfide, a heteroarylglycosyl sulfide, is disclosed as an air and moisture-stable glycosyl donor for a wide range of carbohydrate units (Figure 1b). These compounds can be easily obtained in one step from naturally occurring (completely unprotected) sugars and can be isolated in their pure form, or directly subjected to photo-induced cross-coupling (without isolation) to construct C-alkyl glycosides. This invention solves a long-standing challenge in carbohydrate chemistry by providing a general strategy for achieving site-selective and stereoselective chemical glycosylation from completely unprotected natural sugar units, avoiding the masking and manipulation of unwanted hydroxyl groups. As a result, it significantly reduces costs, minimizes waste generation, and enables more environmentally friendly and sustainable carbohydrate synthesis solutions. This invention paves the way for the future development of protecting group-free strategies, which will facilitate broad applications in carbohydrate science.

[0012] The aforementioned natural unprotected sugar may be any type of sugar. In one example, the natural unprotected sugar is a monosaccharide. In another example, the monosaccharide is selected from the group consisting of triose, tetrose, pentose, hexose, heptose, octose, and nonose. In yet another example, the triose is selected from the group consisting of glyceraldehyde and dihydroxyacetone. In yet another example, the tetrose is selected from the group consisting of erythrose, threose, and erythrulose. In yet another example, the pentose is selected from the group consisting of arabinose, lyxose, ribose, xylose, ribulose, xylulose, and deoxyribose. In yet another example, the hexose is selected from the group consisting of allose, altrose, galactose, glucose, growth, idose, mannose, talose, fructose, psicose, sorbose, tagatose, fucose, and rhamnose. In another example, the heptose is selected from the group consisting of mannoheptulose and sedoheptulose. In yet another example, the octose is selected from the group consisting of octolose and 2-keto-3-deoxy-manno-ocnate. In yet another example, the nonose is sialose.

[0013] In another example, the natural unprotected sugar is a disaccharide. In another example, the disaccharide is sucrose. In another example, the disaccharide is lactose. In another example, the disaccharide is trehalose. In another example, the disaccharide is maltose. In another example, the disaccharide is cellobiose. In another example, the disaccharide is genthiobiose. In another example, the disaccharide is isomaltose. In another example, the disaccharide is kojibiose. In another example, the disaccharide is laminaribiose. In another example, the disaccharide is mannobiose. In another example, the disaccharide is melibiose. In another example, the disaccharide is nigerose. In another example, the disaccharide is rutinose. In another example, the disaccharide is xylobiose.

[0014] In another example, the aforementioned natural unprotected sugar is an oligosaccharide. Oligosaccharides are sugar polymers containing a small number (usually 3 to 10) monosaccharides. In one example, the oligosaccharide is a trisaccharide consisting of three monosaccharides. The trisaccharide is selected from the group consisting of nigerotriose (three glucose units linked by α(1-3) glycosidic bonds), maltotriose (three glucose units linked by (1-4) glycosidic bonds), melegitose (glucose-fructose-glucose), maltotriulose (glucose-glucose-fructose), raffinose (galactose-glucose-fructose), and kestose (glucose-fructose-fructose). In yet another example, the oligosaccharide is a tetrasaccharide consisting of four monosaccharides. The tetrasaccharide is selected from the group consisting of nigerotetraose (four glucose units linked by α(1-3) glycosidic bonds), maltotetraose (four glucose units linked by (1-4) glycosidic bonds), licnose (galactose-glucose-fructose-galactose), nystose (glucose-fructose-fructose-fructose), sesamos (galactose-galactose-fructose-glucose), and stachyose (galactose-galactose-glucose-fructose). In another example, the oligosaccharide is a pentasaccharide consisting of five sugar units. Most N-linked oligosaccharides are pentasaccharides. In another example, the oligosaccharide is a hexasaccharide consisting of six sugar units. α-cyclodextrin is one example, consisting of six glucose units linked by α-1,4 bonds. In yet another example, the oligosaccharide is a heptasaccharide containing seven sugar units. In another example, the oligosaccharide is an octase containing eight sugar units. In yet another example, the oligosaccharide is a xunasose containing nine sugar units. In yet another example, the oligosaccharide is a decasose containing ten sugar units.

[0015] In another example, naturally occurring unprotected sugars are polysaccharides, which are sugar polymers containing more than 10 monosaccharide units. In yet another example, the polysaccharide is a linear polysaccharide. In yet another example, the polysaccharide is a branched polysaccharide.

[0016] In another example, the natural unprotected sugar is selected from the group consisting of glucose, mannose, melibiose, lactose, and cellobiose. In another example, the natural unprotected sugar is glucose. In another example, the natural unprotected sugar is mannose. In another example, the natural unprotected sugar is melibiose. In another example, the natural unprotected sugar is lactose. In another example, the natural unprotected sugar is cellobiose.

[0017] The natural, unprotected sugars disclosed herein may be either L-isomers or D-isomers.

[0018] The heteroarylglycosyl sulfide is synthesized by reacting a naturally occurring unprotected sugar with a mixture of 2-chloro-1,3-dimethylimidazolinium chloride (DMC), a heteroarylthiol, and trimethylamine (Et3N) in a mixture of water and dioxane (step a of the method disclosed herein). In one example, the molar ratio of DMC to heteroarylthiol and Et3N is in the range of 1 to 20:1 to 20:1 to 20. In another example, the molar ratio of DMC to heteroarylthiol and Et3N is 4:5:17. In yet another example, the synthesis of the heteroarylglycosyl sulfide is carried out in a solvent in which the volume ratio of H2O to dioxane is 1 to 20:1 to 20. In yet another example, the synthesis of the heteroarylglycosyl sulfide is carried out in a solvent in which the volume ratio of H2O to dioxane is 1 to 20:20 to 1. In another example, the synthesis of the heteroarylglycosyl sulfide is carried out in a solvent with a volume ratio of H2O to dioxane of 1:1. In yet another example, the synthesis of the heteroarylglycosyl sulfide is carried out at 0 to 100°C. In yet another example, the synthesis of the heteroarylglycosyl sulfide is carried out for 1 to 24 hours. In yet another example, the synthesis of the heteroarylglycosyl sulfide is carried out at 0°C for 2 hours.

[0019] In one example, the heteroarylthiol is 2,3,5,6-tetrafluoro-4-pyridinethiol (C5F4N-SH), and the heteroarylglycosyl sulfide is 2,3,5,6-tetrafluoro-4-pyridylyl glycosyl sulfide.

[0020] Compared with existing technologies that require multiple steps and stringent reaction conditions for the synthesis of glycosyl donors, in step a of the method disclosed herein, a wide variety of 2,3,5,6-tetrafluoro-4-pyridylyl glycosyl sulfides (not fully protected) that are stable to air and moisture can be synthesized and isolated from natural sugars in one step under mild conditions.

[0021] In one example, the heteroarylglycosyl sulfide, such as 2,3,5,6-tetrafluoro-4-pyridylyl glycosyl sulfide, is isolated prior to step b.

[0022] In another example, the heteroarylglycosyl sulfide, such as 2,3,5,6-tetrafluoro-4-pyridylyl glycosyl sulfide, is not isolated prior to step b. The heteroarylglycosyl sulfide, such as 2,3,5,6-tetrafluoro-4-pyridylyl glycosyl sulfide, can be generated in situ from natural sugars and used as a temporary donor (without isolation) to form glycosides by photoinduced cross-coupling with an electrophile. Thus, there is no need to isolate the glycosyl donor, and the glycoside product can be directly obtained from natural sugars in one operation, resulting in significant cost and time savings.

[0023] The heteroarylglycosyl sulfide synthesized in step (a) of the method disclosed herein is then subjected to photoinduced cross-coupling with a reagent under blue LED irradiation in the presence of Hunig's ester (HE), 1,4-diazabicyclo[2.2.2]octane (DABCO) and DMSO to produce the compounds disclosed herein (step b of the method disclosed herein).

[0024] In one example, the reagent is an alkene and the resulting compound is a C-alkyl glycoside. The alkene is any monosubstituted alkene CH2=CH-R or 1,1-disubstituted alkene CH2=CR-R'. R and R' can be any organic substituent including, but not limited to, alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group. In another example, -R or R' is selected from the group consisting of aryl, alkyl, SO2R, P(O)(OR)2, SiR3 and BR2. In another example, -R is -CO2tBu. In another example, -R is -NHPh. In another example, -R is -CO2Bn. In another example, -R is -CO-NMePh.

[0025] In another example, the reagent is an alkenyl halide (X-CH=CH-R) and the resulting compound is a C-alkenyl glycoside. The halide group X of the alkenyl halide (X-CH=CH-R) is selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In one example, X is F. In another example, X is Cl. In another example, X is Br. In another example, X is I.

[0026] R of the alkenyl halide (X-CH=CH-R) can be any organic substituent including, but not limited to, hydrogen, alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group.

[0027] In another example, the reagent is a heteroarene (Ar-H), and the resulting compound is a C-heteroaryl glycoside. A heteroarene (Ar-H) is an aromatic molecule that contains at least one heteroatom (an atom other than carbon or hydrogen) as part of an aromatic ring. Heteroarenes include, but are not limited to, pyridine, furan, thiophene, cytosine, indole, pyrrole, imidazole, oxazole, isoxazole, thiazole, purine, adenine, guanine, thymine, uracil, tetrahydrofuran, pyrrolidine, pyrran, pyrimidine, oxiran, and epoxides.

[0028] In another example, the reagent is diserenide (R-Se-Se-R), and the compound produced is a Se-glycoside. R in diserenide (R-Se-Se-R) can be any organic substituent, including but not limited to alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group.

[0029] In another example, the reagent is a disulfide (RSSR), and the resulting compound is an S-glycoside. The R in disulfide (RSSR) can be any organic substituent, including but not limited to alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group.

[0030] In this specification, an alkyl group refers to a linear (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl") and has a single bond site to the rest of the molecule. An acyclic alkyl group is -C nH 2n+1 It has the general formula. Cycloalkyl groups are produced by removing one hydrogen atom from the ring of a cycloalkane, and -C n H 2n-1 It has the general formula . Unless otherwise specified, an aliphatic group contains 1 to 20 aliphatic carbon atoms. In some cases, an aliphatic group contains 8 to 20 aliphatic carbon atoms. In other cases, an aliphatic group contains 1 to 10 aliphatic carbon atoms. In other cases, an aliphatic group contains 1 to 8 aliphatic carbon atoms. In other cases, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In other cases, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other cases, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another case, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another case, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some cases, "alicyclic" (or "carbocyclic" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is either fully saturated or contains one or more unsaturated units but is not aromatic and has one bond with the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl groups, (cycloalkenyl)alkyl groups, or (cycloalkyl)alkenyl groups). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0031] In this specification, an aryl group is any functional group or substituent derived from an aromatic ring, typically an aromatic hydrocarbon such as a phenyl or naphthyl group. The term "aryl" refers to monocyclic and bicyclic ring systems with a total of 5 to 14 ring members, wherein at least one ring in the ring system is aromatic, and each ring in the ring system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain examples of the present invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthracyl, etc., which may have one or more substituents. The scope of the term "aryl" as used herein includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantridinyl, tetrahydronaphthyl, etc. In one example, an aryl group is a tolyl, xylyl, phenyl, or naphthyl group. In another example, the aryl group is an optionally substituted group selected from: a phenyl group; a saturated or partially unsaturated carbon ring of 3 to 7 members; a bicyclic saturated, partially unsaturated, or aryl ring of 8 to 10 members; a monocyclic heteroaryl ring of 5 to 6 members having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a saturated or partially unsaturated heterocycle of 4 to 7 members having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a bicyclic saturated or partially unsaturated heterocycle of 7 to 10 members having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a bicyclic heteroaryl ring of 8 to 10 members having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0032] In this specification, halides are selected from the group consisting of F, Cl, Br, and I.

[0033] In this specification, alkyl halides (also called haloalkanes) consist of alkyl groups disclosed herein bonded to halogens selected from the group consisting of F, Cl, Br, and I.

[0034] In this specification, an alcohol group contains one hydrogen atom and one carbon atom bonded to an oxygen atom. The carbon atom is part of a larger organic structure. One common way to represent an alcohol is to use the formula R-OH, where R represents any organic fragment in which a carbon atom is directly bonded to an explicitly indicated functional group (in this case, OH). The R group is usually a chain of carbon atoms. For example, an alcohol is a primary alcohol having an -OH functional group bonded to an R-CH2- group and is written as RCH2OH. In another example, an alcohol is a secondary alcohol having an -OH functional group bonded to an R2CH- group and is written as R2CHOH. In yet another example, an alcohol is a tertiary alcohol having an -OH functional group bonded to an R3C- group and is written as R3COH.

[0035] In this specification, an aldehyde group has a hydrogen atom bonded to a carbonyl functional group and an alkyl group (or aromatic group). Aldehydes are denoted as RCHO.

[0036] In this specification, a ketone group has a pair of alkyl or aromatic groups bonded to a carbonyl functional group. Ketones are denoted as RCOR.

[0037] In this specification, a carboxylic acid group has an alkyl group or aromatic group bonded to a hydroxycarbonyl functional group. A carboxylic acid is denoted as RCOOH.

[0038] In this specification, an ester group has a pair of alkyl or aromatic groups bonded to a carbonyl + linked oxygen functional group. Esters are denoted as RCOOR.

[0039] In this specification, an amide group is a carbonyl group in which a carbon atom is bonded to one nitrogen atom and one carbon or hydrogen atom. Primary amides have an alkyl or aromatic group bonded to an amino-carbonyl functional group. Primary amides are denoted as RCONH2. Secondary amides (RCONHR) have an alkyl or aryl group bonded to a nitrogen atom. Tertiary amides (RCONR2) have two alkyl or aryl groups bonded to a nitrogen atom.

[0040] In this specification, an amine group consists of a nitrogen atom bonded to one of several combinations of carbon and hydrogen. In one example, the amine is a primary amine having an alkyl or aromatic group bonded to the nitrogen atom and two hydrogen atoms. Primary amines are denoted as RNH2. In another example, the amine is a secondary amine having a pair of alkyl or aromatic groups bonded to the nitrogen atom and one hydrogen atom. Secondary amines are denoted as R2NH. In yet another example, the amine is a tertiary amine having three alkyl or aromatic groups bonded to the nitrogen atom. Tertiary amines are denoted as R3N.

[0041] In this specification, a nitrile (or organocyanide) group has an alkyl group (or aromatic group) bonded to a carbon-triple bond-nitrogen functional group. Nitrile is denoted as RCN.

[0042] In this specification, a carboxylate group is a conjugate base of a carboxylic acid, and is a carbonyl-containing functional group in which a carbon atom is bonded to an OH group on one side and to a carbon atom or hydrogen atom on the other side.

[0043] In this specification, an amino acid may be any natural amino acid (encoded in the genome of an organism) or a non-natural amino acid (also called a non-proteinogenic amino acid or non-standard amino acid (ncAA), which is not genetically encoded by an organism and does not exist in natural polypeptide chains, such as those that are chemically synthesized). In one example, the amino acid is a group I: nonpolar amino acids, selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, and tryptophan. In another example, the amino acid is a group II: polar, uncharged amino acids, selected from the group consisting of serine, cysteine, threonine, tyrosine, asparagine, and glutamine. In yet another example, the amino acid is a group III: acidic amino acid, selected from the group consisting of aspartic acid and glutamic acid. In yet another example, the amino acid is a group IV basic amino acid, selected from the group consisting of arginine, histidine, and lysine. In yet another example, the amino acid is selenocysteine. In another example, amino acids are unnatural amino acids synthesized from natural analogs through modifications such as amine alkylation, side chain substitution, structural bond extension cyclization, and isosteric replacements within the amino acid backbone.

[0044] In this specification, the thiol group is any organosulfur compound of the form R-SH, where R represents an alkyl group or other organic substituent.

[0045] The heteroarylglycosyl sulfide synthesized in step (a) of the method disclosed herein is then subjected to photo-induced cross-coupling with reagents under blue LED irradiation in the presence of Hantchu ester (HE), 1,4-diazabicyclo[2.2.2]octane (DABCO), and DMSO to produce the compound disclosed herein (step b of the method disclosed herein).

[0046] In one example, in step b of the method disclosed herein, the molar ratio of alkene, HE, and DASCO is 1-20:1-20:1-20. In another example, in step b of the method disclosed herein, the molar ratio of alkene, HE, and DASCO is 1.5:2:2.5.

[0047] In another example, step b of the method disclosed herein is carried out at 0 to 100°C. In yet another example, step b of the method disclosed herein is carried out for 1 to 24 hours. In yet another example, step b of the method disclosed herein is carried out at room temperature for 24 hours.

[0048] In another example, step b of the method disclosed herein uses a blue LED with a wavelength of 400–450 nm. In yet another example, step b of the method disclosed herein uses a blue LED with a wavelength of 400–500 nm.

[0049] In another example, the resulting C-alkyl glycoside has an alkyl group, which may be a linear or branched saturated or unsaturated alkyl group having 8 to 20 carbon atoms. In yet another example, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, sec-butyl, isobutyl, and tert-butyl groups. In yet another example, the C-alkyl glycoside has a functional group which may be any organic substituent, including but not limited to alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group.

[0050] In another example, the resulting C-alkenyl glycoside may contain an R group which can be any organic substituent, including but not limited to hydrogen, alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group.

[0051] In another example, the resulting C-heteroaryl glycosides contain heteroarene groups including, but not limited to, pyridine, furan, thiophene, cytosine, indole, pyrrole, imidazole, oxazole, isoxazole, thiazole, purine, adenine, guanine, thymine, uracil, tetrahydrofuran, pyrrolidine, pyran, pyrimidine, oxirane, and epoxides.

[0052] In another example, the resulting Se-glycoside may contain R, which can be any organic substituent including, but not limited to, alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group.

[0053] In another example, the resulting S-glycoside may contain R, which can be any organic substituent including, but not limited to, alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group.

[0054] This invention allows a redox-active 2,3,5,6-tetrafluoro-4-pyridiylglycosyl sulfide to form a glycoside via a photo-induced cross-coupling reaction with an electrophile at room temperature under visible light irradiation, in the presence of a mild organoelectron donor (e.g., a Hantchu ester) and an organic base. 2,3,5,6-tetrafluoro-4-pyridiylglycosyl sulfide is a novel donor that has not been reported to undergo radical-based cross-coupling reactions. The direct conversion of natural sugars to fully unprotected C-glycosides via these transiently generated glycosyl sulfide intermediates has not been demonstrated until now.

[0055] In this application, the singular forms "a," "an," and "the" include the plural form unless otherwise explicitly stated in the context. For example, the term "a metal" includes multiple metals (including mixtures and combinations thereof).

[0056] In this specification, the term "comprising" means "including." Variations of the word "comprising," such as "comprise" and "comprises," each have different meanings. Therefore, for example, a composition "comprising" X may consist only of X, or it may contain one or more additional components not listed.

[0057] In this specification, the term “about” in the context of the concentration of a substance, the size of a substance, the length of time, or other stated values ​​means + / - 5%, + / - 4%, + / - 3%, + / - 2%, + / - 1%, or + / - 0.5% of the stated value.

[0058] Throughout this disclosure, certain embodiments may be disclosed in range form. It should be understood that range form is for convenience and conciseness only and should not be interpreted as a strict limitation on the scope of the disclosed range. Therefore, a range description should be considered to specifically disclose all possible sub-ranges and individual numerical values ​​within that range. For example, a range description of 1–6 should be considered to specifically disclose sub-ranges such as 1–3, 1–4, 1–5, 2–4, 2–6, 3–6, and individual numerical values ​​within those ranges, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0059] The disclosures described herein as examples can be adequately implemented even without any elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted broadly and without limitation. Furthermore, the terms and expressions used herein are for illustrative purposes only, not for limitation. The use of these terms and expressions is not intended to exclude equivalents of any or any of the illustrated and described features, but it should be recognized that various modifications are possible within the scope of the claimed invention. Therefore, while the invention is specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the invention disclosed herein are possible by those skilled in the art, and such modifications and variations are considered to be within the scope of the invention.

[0060] The present invention is described in a broad and general form herein. The narrower species and subgenera taxa included in this general disclosure also constitute part of the present invention. This includes general descriptions of the invention with conditional or negative limitations that exclude certain matters from a genus, whether or not the excluded matters are specifically described herein.

[0061] Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this invention pertains.

[0062] Other embodiments are within the scope of the following claims and non-limiting embodiments. [Examples]

[0063] Non-limiting examples of this disclosure are described in more detail by reference to specific embodiments, but this should not be construed as limiting the scope of this disclosure in any way.

[0064] As shown in Figure 1(a), advances in C-glycosylation over the past few decades have required multi-step reaction sequences (hydroxyl group protection, functionalization, deprotection) with delicate or harsh reaction conditions to convert completely unprotected natural sugars into engineered glycosyl precursors containing anomeric leaving groups such as halides, esters, sulfoxides, and sulfones, thereby laying the groundwork for subsequent carbon-carbon bond formation reactions to produce the desired unprotected C-glycosides. Challenges in the multi-step chemical synthesis of unprotected sugars include long sequences, the generation of excess waste, the complexity associated with deprotection in later stages, and the need for strong oxidizing agents.

[0065] As shown in Figure 2, reaction parameters that promote regioselective nucleophilic substitution (capping) were first evaluated using D-glucose 1 as a model substrate. Taking advantage of the higher acidity of the anomeric OH group compared to other hydroxyl units, we investigated the conversion of 1 to the laboratory-stable 2,3,5,6-tetrafluoro-4-pyridinethioglycoside derivative 2 under weakly basic conditions using various activators (R-LG) (Figure 2a). Using commercially available 2-chloro-1,3-dimethylimidazolinium chloride (DMC) as the activator and triethylamine as the base, 2 was obtained at 0°C within 2 hours in 85% yield (isolation yield 72%) with a β:α ratio >95:5. 2 (white solid) could be stored in the laboratory in air for several months without significant degradation. While yields were significantly reduced with other analogues of DMC (3 and 4), other commonly used reagents such as chlorophosphonium salt 5 and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) / N-methylmorpholine (NMM) failed to accelerate the reaction.

[0066] Since DMC was confirmed to be the most effective activator, various unprotected (hetero)arylthioglucosides (6-9) were synthesized for comparison, in addition to 2, using nucleophilic substitution reaction conditions. To promote glycosylation, the thioglucosides were subjected to reaction with acrylate 10 under visible light irradiation. After investigating a wide range of conditions, it was found that when hantchu ester (HE) was used as a reducing agent and 1,4-diazabicyclo[2.2.2]octane (DABCO) and dimethyl sulfoxide (DMSO) were used as solvents, 2 underwent desulfurization CC coupling at room temperature under blue LED irradiation, producing unprotected C-alkylglucoside 11 in 96% yield (isolation yield 82%) with α-selectivity exceeding 95% (Figure 2b).

[0067] In contrast, conversion rates were reduced for S-glucosides with low redox activity derived from other (hetero)arylthiols (6-9) with low electron-withdrawing properties, highlighting the importance of the fluorinated heteroaromatic moiety in photo-induced cross-coupling. On the other hand, removing the light source resulted in HE or DABCO being detrimental to the reaction, and changing the base or solvent reduced the yield. To demonstrate the power of the "cap-and-glycosylation" approach via traceless activation, we showed that α-11 can be generated from 1 in a single sequence without the need to isolate S-glycosyl intermediate 2 (Figure 2, inset). The overall step efficiency and yield (64% yield, 52% isolation yield) offer significant advantages over conventional chemical C-glycosylation approaches requiring multiple steps.

[0068] Experiments were conducted to elucidate the individual processes of activation and cross-coupling of natural sugars. As shown in Figure 3a, 2,3,5,6-tetrafluoro-4-pyridinethioglycoside 2 was obtained by nucleophilic substitution of D-glucose 1 in 85% yield (isolation yield 72%) with a β:α ratio > 95:5. On the other hand, it was found that the corresponding thioglycoside 13 could be obtained from D-maltose 12 under the same conditions in 44% yield (isolation yield 30%) with an α:β ratio > 95:5 (Figure 3a). In solution, the α-anomers and β-anomers of the natural sugars (1,12) are thought to interconvert and be in equilibrium. Each anomeric reacts individually with DMC before undergoing stereoinversion nucleophilic substitution by thiols. Alternatively, the 2-OH group of the DMC-activated β-anomer intermediate generates a 1,2-anhydride species through intramolecular nucleophilic attack involving neighboring groups, and this anhydride species is susceptible to site-selective ring cleavage by thiol nucleophiles. This pathway is considered unimportant in the reaction leading to β-13, as only trace amounts of β-13 were detected. For other sugars (see Figure 4), various nucleophilic substitution pathways may be preferred to varying degrees in the reaction system.

[0069] When 2 and 13 were subjected separately to standard cross-coupling conditions with acrylates, 11 and 15 were obtained, respectively, both exhibiting anomeric selectivity in the same direction (Figure 3a). This particularly suggests that, unlike heterolytic glycosylation, the C1 stereochemistry of the S-glycosyl donor is irrelevant, highlighting the remarkable advantage of this strategy in converting a mixture of unprotected natural sugar isomers into stereoisomerically pure glycosides in a streamlined manner via its thioglycoside derivative. In another study, the addition of exogenous 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) inhibited the photo-induced conversion of 2 to 11 (Figure 3b). HRMS analysis revealed the formation of a complex resulting from the TEMPO glycoside adduct 16, providing evidence that this reaction process generates a sufficiently long-lived glycosyl (anomeric) radical species. These processes are in contrast to heterolytic glycosylation, which essentially lacks the formation of distinct intermediate species (e.g., glycosyl cations). The properties of the photo-induced reaction (using 2 as a model substrate) were further investigated by ultraviolet / visible absorption (UV / vis) spectroscopy (Figure 3c). The independent absorption spectra of 2 and DABCO showed bands mainly in the ultraviolet region, and a mixture of these two components resulted in only a slight redshift extending to the visible region (>400 nm). On the other hand, a DMSO solution of HE showed strong absorption in the visible region, but no significant change was observed in the HE and DABCO mixture. Interestingly, the mixture of 2 and HE showed a slight bathochromic shift, and this shift was significantly amplified when 2, HE, and DABCO were mixed in solution. These results suggest the formation of a presumed ternary complex between 2, HE, and DABCO, which is proposed to absorb visible light and undergo fragmentation to glycosyl radicals.

[0070] The research presented here supports the mechanism proposed in Figure 3d. Site-selective capping of the more acidic anomeric hydroxyl group by DMC forms an activated leaving group, which is readily attacked nucleophilically by 2,3,5,6-tetrafluoro-4-pyridinethiol under basic conditions, simultaneously generating 1,3-dimethylimidazolidined-2-one (DMI) as a byproduct. The formation of a 1,2-anhydride species before the nucleophilic substitution reaction cannot be completely ruled out. The resulting thioglycoside intermediate is presumed to bind with HE and DABCO in solution, forming a ternary complex that absorbs visible light and induces photo-induced electron transfer (PET). Consistent with previously reported reactions, the thioglycoside exhibits sufficient redox activity for PET due to the high electrophilicity of the fluorinated heteroaryl group. This generates a dihydropyridine radical 17 and a radical anion 18, which are susceptible to desulfurization fragmentation, producing a glycosyl radical species and 2,3,5,6-tetrafluoro-4-pyridinethiolate (the conjugate acid was detected in the reaction mixture). The subsequent reaction of the glycosyl radical, facilitated by 17, with its electrophilic cross-coupling partner proceeds stereoselectively under kinetic control to yield the desired unprotected glycoside.

[0071] As a proof of concept, it was demonstrated that natural sugars can be directly converted to C-alkyl glycosides without isolating glycosyl sulfide intermediates. This procedure completely eliminates the transiently introduced S-glycosyl donor. The desired C-glycoside product is obtained in a single purification step with good total yield and diastereoselectivity, comparable to a two-step method. This approach significantly simplifies chemical glycosylation, providing a more efficient and sustainable solution for carbohydrate synthesis.

[0072] The versatility of the disclosed protecting group-free protocol was highlighted by the broad spectrum of natural monosaccharides and oligosaccharides that can be reliably converted to complete unprotected C-alkyl glycosides via 2,3,5,6-tetrafluoro-4-pyridinethioglycoside precursors (Figure 4). These precursors were either isolated or generated in situ (without purification) and used for cross-coupling. Representative examples include pyranoside products constructed from biomass-derived monosaccharides (19-21, 24), rare sugars (22, 23), and non-natural L-glucose (25). More complex natural glycans also served as effective substrates for generating corresponding C-alkyl glycosides (15, 26-29) with good efficiency. Overall, good to excellent stereoselectivity was observed.

[0073] In Figure 5a, in addition to α,β-unsaturated carbonyl compounds, other alkenes were also investigated as cross-coupling partners. Highly functionalized acrylates and acrylamides bound to bioactive compounds (30, 31), aminosalicylic acids (32), amino sugars (33), and oligopeptides (34-36) were suitable substrates, providing access to highly polar C-glycosylation conjugates with multiple acidic and basic sites. This provides a convenient method for glycosylation of complex molecules with natural sugars in a variety of applications, such as the design of sugar-based peptide mimes. Other Michael acceptors, such as vinyl sulfones (37), vinyl phosphonates (38), vinyl boronates (40), and less electrophilic vinyl silanes (39) and allyl acetates (41), also reacted efficiently, providing desired C-alkyl glycoside adducts with functional groups that can be used as useful synthetic handles for further manipulation. Of particular note is the confirmation that cross-coupling proceeds even in the presence of a less active alkyl-substituted alkene (42). Importantly, metabolically stable pseudo-oligosaccharide units such as the newly formed C-glycoside disaccharide 43, which has two stereocenters, could be rapidly assembled with complete stereocontrol through reaction with exoglucar as a radical acceptor.

[0074] To demonstrate the applicability of this "capping and glycosylation" approach to other categories of unprotected sugars, the alkene coupling partner was substituted with other electrophiles capable of acting as radical acceptors. Using a haloalkene reagent (Figure 5b), we successfully obtained a C-alkenylglycosyl compound (44) with high anomeric selectivity. This process is presumed to proceed via a glycosyl radical addition-reduction-β-halide elimination pathway. C-heteroarylglycosylation can also be achieved by direct coupling with heteroarenes under acid-free conditions, selectively generating unprotected 45-47 at the most electron-deficient site. This is consistent with previous reports regarding fully protected glycosyl radicals.

[0075] Beyond C-glycosylation, protecting group-free reactions have been diversified to the preparation of other sugar mimetic compounds such as selenoglycosides (Figure 5c) and thioglycosides (Figure 5d). Along with C-glycosyl compounds, these compounds have found many applications as robust substitutes for naturally occurring O-saccharides, and there is a strong demand for efficient synthesis methods with high stereochemical purity. Fortunately, unprotected Se-glycosides (48,49) and S-glycosides (50-54) can be obtained by reaction with diselenide or disulfide reagents, respectively, which is superior to conventional protocols that relied on the cumbersome preparation of glycosyl precursors. [Industrial applicability]

[0076] The laboratory-stable heteroarylglycosyl sulfides disclosed herein do not require protecting groups and provide an easy method for obtaining a variety of unprotected glycosides. These sulfide donors can also be generated from natural sugars (completely unprotected) and can be used in situ (without isolation) in photo-induced cross-coupling to obtain unprotected glycosides. For commercial purposes, these sulfides will serve as benchmark glycosyl donors for use in all applications related to carbohydrate synthesis. The resulting glycosides are important basic building blocks used in the preparation of high-value chemicals such as sugar-based natural products, pharmaceuticals, and therapeutic candidates.

[0077] After reading the foregoing disclosure, a person skilled in the art will see various other modifications and adaptations of the invention without departing from the spirit and scope of the invention, and all such modifications and adaptations are intended to fall within the scope of the appended claims.

[0078] References [1] Yang, Y.; Yu, B. Chem. Rev. 2017, 117, 12281-12356. [2] Xu, L.-Y.; Fan, N.-L.; Hu, X.-G. Org. Biomol. Chem. 2020, 18, 5095-5109. [3] Tanaka, T.; Matsumoto, T.; Noguchi, M.; Kobayashi, A.; Shoda, S.-i. Chem. Lett. 2009, 117, 458-459. [4] (a) Wang, Q.; Lee, B.C.; Tan, TJ; Jiang, Y.; Ser, W.H.; Koh, M.J. Nat. Synth. 2022, 1, 967-974. (b) Xu, L.-Y.; Fan, N.-L.; Hu, X.-G. Org. Biomol. Fabric. 2020, 18, 5095-5109. (c) Chen, A. et al. J. Carbohydr. Fabric. 2022, 40, 361-400. [5] Sengoku, T., Ogawa, D., Iwama, H., Inuzukab, T. & Yoda, H. Chem. Common. 2021, 57, 9858-9861.

Claims

1. A method for synthesizing compounds selected from the group consisting of C-alkyl glycosides, C-alkenyl glycosides, C-heteroaryl glycosides, Se-glycosides, and S-glycosides, a. Natural unprotected sugars are mixed with water and dioxane to form 2-chloro-1,3-dimethylimidazolinium chloride (DMC), heteroarylthiol and trimethylamine (Et ３ Reacting with a mixture of N) to produce heteroarylglycosyl sulfides; and b. The heteroaryl glycosyl sulfide is photo-induced cross-coupled with a reagent under blue LED irradiation in the presence of Hantchu ester (HE), 1,4-diazabicyclo[2.2.2]octane (DABCO), and DMSO to produce the compound. Methods that include...

2. The method according to claim 1, wherein the heteroarylglycosyl sulfide is not isolated before step b.

3. The method according to claim 1, wherein the heteroarylglycosyl sulfide is isolated before step b.

4. The method according to any one of claims 1 to 3, wherein the natural unprotected sugar is selected from the group consisting of glucose, mannose, melibiose, lactose, and cellobiose.

5. The aforementioned heteroarylthiol is 2,3,5,6-tetrafluoro-4-pyridinethiol (C ５ F ４ The method according to any one of claims 1 to 4, wherein the heteroaryl glycosyl sulfide is 2,3,5,6-tetrafluoro-4-pyridiylglycosyl sulfide.

6. The method according to claim 1, wherein the reagent is selected from the group consisting of alkenes, alkenyl halides (X-CH=CH-R), heteroarenes (Ar-H), diselenides (R-Se-Se-R), and disulfides (R-S-S-R).

7. The aforementioned alkene is a monosubstituted alkene CH ２ = CH-R or 1,1-disubstituted alkene CH ２ The method according to claim 6, wherein =CR-R', and R- or R'- is selected from the group consisting of alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group.

8. -R is -CO ２ tBu, -NHPh, -CO ２ The method according to claim 7, selected from the group consisting of Bn and -CO-NMePh.

9. The method according to claim 6, wherein X in the alkenyl halide (X-CH=CH-R) is selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I), and R- is selected from the group consisting of hydrogen, alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group.

10. The method according to claim 6, wherein the heteroarene (Ar-H) is selected from the group consisting of pyridine, furan, thiophene, cytosine, indole, pyrrole, imidazole, oxazole, isoxazole, thiazole, purine, adenine, guanine, thymine, uracil, tetrahydrofuran, pyrrolidine, pyran, pyrimidine, oxirane, and epoxide.

11. The method according to claim 6, wherein R- in the diserenide (R-Se-Se-R) is selected from the group consisting of alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group.

12. The method according to claim 6, wherein R- in the disulfide (R-S-S-R) is selected from the group consisting of alkyl, aryl, halide, alkyl halide, alcohol, aldehyde, ketone, carboxylic acid, carbonyl group, ester, amide, amine group, nitrile, carboxylate, amino acid, and thiol group.

13. The method according to claim 7, wherein the alkyl group of the C-alkyl glycoside is a linear or branched saturated or unsaturated alkyl group having 8 to 20 carbon atoms.

14. DMC, heteroarylthiol, and Et ３ The method according to any one of claims 1 to 13, wherein the molar ratio of N is 1 to 20:1 to 20:1 to 20.

15. The method according to claim 14, wherein the molar ratio of DMC, heteroarylthiol and Et ３ ３ N is 4:5:

17.

16. Step a is H ２ The method according to any one of claims 1 to 15, wherein the method is carried out at 0 to 100°C for 1 to 24 hours in a solvent in which the volume ratio of O to dioxane is 1 to 20:1 to 20.

17. Step a is H ２ The method according to claim 16, wherein the procedure is carried out at 0°C for 2 hours in a solvent in which the volume ratio of O to dioxane is 1:

1.

18. The method according to any one of claims 1 to 17, wherein the molar ratio of alkenes, HE, and DASCO is 1 to 20:1 to 20:1 to 20.

19. The method according to claim 18, wherein the molar ratio of the alkene, HE, and DASCO is 1.5:2:2.

5.

20. The method according to any one of claims 1 to 19, wherein step b is carried out at 0 to 100°C for 1 to 24 hours.

21. The method according to claim 20, wherein step b is carried out at room temperature for 24 hours.

22. The method according to any one of claims 1 to 21, wherein the blue LED has a wavelength of 400 to 500 nm.

23. The method according to claim 22, wherein the blue LED has a wavelength of 400 to 450 nm.

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