CN120829376A

CN120829376A - A symmetric disulfide compound containing a sulfoxide group and its application in glycosidation reaction

Info

Publication number: CN120829376A
Application number: CN202410454448.4A
Authority: CN
Inventors: 万谦; 曾静; 孟令奎; 周思成; 赵祥; 李越
Original assignee: Huazhong University of Science and Technology
Current assignee: Huazhong University of Science and Technology
Priority date: 2024-04-16
Filing date: 2024-04-16
Publication date: 2025-10-24

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a symmetrical disulfide compound containing sulfoxide groups and application thereof in glycosylation reaction, wherein the structural general formula of the compound is shown as formula (I). The compound with the structural general formula shown in the formula (I) contains sulfoxide and disulfide structures, sulfinyl groups and disulfide bond-containing groups forming the sulfoxide are positioned at the ortho position of an aromatic ring, the compound can be used as an activating reagent for glycosylation reaction, and particularly, the activating reagent of the glycosyl donor and the glycosylation reaction can be effectively promoted by only using 0.25 times of the equivalent of the glycosyl donor, so that the use of a highly toxic, expensive, unstable or metal-containing activating reagent is avoided, and the problems of unstable, difficult preparation and often required equivalent or excessive activating reagent of the glucoside donor in the conventional glycosylation reaction are solved.

Description

Sulfoxide group-containing symmetrical disulfide compound and application thereof in glycosylation reaction

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a symmetrical disulfide compound containing sulfoxide groups and application thereof in glycosylation reaction.

Background

Chemical synthesis is an effective means for obtaining sugar molecules with definite structure and uniform quality on a large scale, and the key point is effective construction of glycosidic bonds. Currently, a variety of glycosyl donors, activating reagents and glycosylation methods have been developed, with the thiol donor being favored for its stability, availability and versatility, one of the most commonly used glycosyl donors in oligosaccharide synthesis.

To date, nearly hundred sulfanyl activators have been developed, of which organic sulfur reagents represented by aryl sulfenate triflic anhydride (ArSOTf) (J.Am. Chem. Soc.1998,120, 435-436) are a class of highly potent sulfanyl activating reagents. However, the reagent is poor in stability, and is usually required to be generated in situ and used in preparation by aryl sulfenamide chloride (ArSCl) and silver triflate (AgOTf), most of the reagent ArSCl is easy to oxidize and rapidly decompose when meeting water, has strong irritant malodor, and AgOTf is a noble metal reagent, is sensitive to light and has strong hygroscopicity. The above disadvantages limit the wide application of the reagent. Sugar scientists strive to find activating reagents with similar activation capacity to ArSOTf and good stability, of which the most attractive are the activated combinations of sulfinyl derivatives with triflic anhydride (Tf ₂ O), such as p-methoxyphenyl thiobenzene sulfinate MPBT (org. Lett.2000,2, 4067-4069), 1- (phenylsulfinyl) piperidine BSP (j.am. Chem. Soc.2001,123, 9015-9020), diphenyl sulfoxide Ph ₂ SO (org. Lett.2003,5, 1519-1522), phenylsulfinyl morpholine BSM (Synlett 2006,17,2846-2850) and the like. In addition to the above-described sulfoxide group-containing activating agents, compounds having a symmetrical disulfide bond in the molecular structure can also be used as a sulfanyle activating agent, such as dimethyl disulfide Me ₂S₂ (Org. Lett.2007,9, 4647-4650), to effect activation of a sulfanyle donor under low temperature conditions and complete the glycosylation reaction.

The above reagents all play a role in high efficiency of coupling between sugar units and/or between sugar units and non-sugar units, but in order to ensure adequate activation of the sulfan donor it is generally necessary to use equivalent amounts or even excessive amounts of activating reagent. In addition, compounds containing sulfoxide groups or symmetrical disulfide bonds have been reported as activating agents for use in glycosylation reactions, but compounds containing both structures are rarely reported and used. Therefore, the development of the activating reagent which has novel structure, easy preparation, stable property and lower dosage than stoichiometric has higher research significance and value.

The inventor reports that a compound VI containing sulfoxide, asymmetric disulfide bond and thioether functional group can activate a glucoside donor with 0.5 times equivalent dosage under the action of trifluoromethanesulfonic anhydride (Tf ₂ O) so as to construct a glucoside bond, but the reagent has weaker activation capability and can only activate the glucoside donor with high activity. (J.am.chem.Soc.2020, 142, 5498-5503).

Disclosure of Invention

In view of the above-mentioned drawbacks or improvements of the prior art, an object of the present invention is to provide a symmetrical disulfide compound containing sulfoxide groups and its use in glycosylation reactions, wherein the structure of the compound is improved to obtain a compound of general structural formula (I) containing sulfoxide and disulfide structures, and sulfinyl groups and disulfide-containing groups constituting sulfoxide groups are located at ortho positions of aromatic rings, the compound is convenient to prepare and efficient, has stable chemical properties, can be used as an activating reagent in glycosylation reactions, and can efficiently promote the activation of glycosyl donors and the progress of glycosylation reactions (that is, an activating reagent of general structural formula (I) of one molecule can activate a glycosyl donor of four molecules), thereby avoiding the use of extremely toxic, expensive, unstable or metal-containing activating reagents and solving the problems of unstable, difficult preparation of the activating reagent of the thiol donor and often required equivalent or excessive amount in the existing glycosylation reactions.

In order to achieve the above object, according to one aspect of the present invention, there is provided a symmetrical disulfide compound having sulfoxide groups, which is characterized by having a general structural formula as shown in formula (I):

Wherein O is an oxygen atom, S is a sulfur atom, R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, ar is a substituted or unsubstituted aromatic ring (according to conventional understanding, the substituents on Ar refer to the presence or absence of substituents at sites other than the site of attachment to a sulfinyl group or a disulfide-containing group).

As a further preferred aspect of the present invention, the R is selected from the group consisting of substituted or unsubstituted C _1～20 alkyl, substituted or unsubstituted C _6～10 aryl, wherein the substituents are one or more, independently selected from the group consisting of C _1～20 alkyl, unsubstituted or halogen substituted C _1～20 alkoxy;

ar is substituted or unsubstituted C _6-14 aryl, wherein the substituent is selected from substituted or unsubstituted C _1～20 alkyl.

As a further preferred aspect of the invention, R is selected from substituted or unsubstituted C _1～6 alkyl, substituted or unsubstituted phenyl, wherein, the substituent is one or more, independently selected from C _1～6 alkyl, C _1～20 alkoxy which is unsubstituted or substituted by 1-20 halogens, the halogens are selected from fluorine, chlorine, bromine and iodine;

Ar is selected from substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl, wherein the substituent is C _1～6 alkyl.

As a further preferred aspect of the present invention, the R is selected from the group consisting of a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, and a substituted or unsubstituted isopropyl group, wherein the substituent is one or more, independently selected from the group consisting of methyl group, ethyl group, and octyloxy group which is unsubstituted or substituted with 1 to 20 halogens, and the octyloxy group which is substituted with 1 to 20 halogens is preferably

The Ar is selected from substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl, wherein the substituent is methyl or ethyl, and preferably the Ar is phenylOr naphthyl radical

As a further preferred aspect of the present invention, the symmetrical disulfide compound having a sulfoxide group has a structure represented by any one of the following structural formulas I-1 to I-6:

According to another aspect of the present invention there is provided the use of a symmetrical disulfide compound as described above containing sulfoxide groups as an activating reagent in a glycosylation reaction;

Preferably, the molar ratio of the amount of the activating reagent to the glycosyl donor is (0.25-0.5): 1.

According to a further aspect of the present invention, there is provided a process for producing a glycosylation product, characterized in that the process comprises using the symmetrical disulfide compound containing a sulfoxide group as an activating agent, activating a glycosyl donor represented by the general structural formula (II) in the presence of trifluoromethanesulfonic anhydride, and reacting with an acceptor represented by the general formula (III) to obtain a glycosylation product represented by the general formula (IV);

The reaction equation is as follows:

wherein Gly is glycosyl with one or more hydroxyl groups on the sugar ring protected by protecting groups in the glycosyl donor shown in the general structural formula (II), X is sulfur or selenium atom, R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and preferably R ¹ is independently selected from ethyl (Et), isopropyl (ⁱ Pr), cyclohexyl (Cy), 1-adamantyl (Adm), benzyl (Bn), phenyl (Ph), p-methylphenyl (Tol), 2-ethylphenyl (^o EP) or 2, 6-dimethylphenyl;

the receptor shown in the formula (III) is selected from saccharides, alcohols and purine nucleophiles containing one or more nucleophilic groups.

According to a further aspect of the present invention, there is provided a process for preparing a glycosylation product, characterized in that the process comprises using a symmetrical disulfide compound containing sulfoxide groups as an activating agent, in the presence of trifluoromethanesulfonic anhydride to activate a glycosyl donor and react with an acceptor, and the resulting glycosylation product can be further activated to initiate continuous glycosylation;

The structural general formula of the glycosyl donor is specifically as follows

Wherein Gly is glycosyl with one or more hydroxyl groups on the sugar ring protected by protecting groups, X is sulfur or selenium atom, R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl;

The structural general formula of the receptor is specifically as follows

Wherein Gly 'is glycosyl with one or more hydroxyl groups on the glycosyl ring protected by protecting groups, X' is sulfur or selenium atom, R ² is substituted or unsubstituted alkyl, substituted or unsubstituted aryl;

Preferably, R ¹、R² is independently selected from ethyl (Et), isopropyl (ⁱ Pr), cyclohexyl (Cy), 1-adamantyl (Adm), benzyl (Bn), phenyl (Ph), p-methylphenyl (Tol), 2-ethylphenyl (^o EP), or 2, 6-dimethylphenyl.

With respect to continuous glycosylation (i.e., the activating reagent is involved in the continuous activation of multiple glycosyl donors), reference may be made, for example, to the following steps:

(S1) using the symmetrical disulfide compound containing sulfoxide groups as an activating reagent, activating a glycosyl donor shown in a structural formula (II) in the presence of trifluoromethanesulfonic anhydride and performing a coupling reaction with an acceptor shown in a structural formula (III ') to obtain a glycosylation product shown in the structural formula (II '), wherein the glycosyl donor shown in the structural formula (II) is a first glycosyl unit, and the acceptor shown in the structural formula (III ') is a second glycosyl unit containing an aglycone capable of being activated on an anomeric carbon and a naked hydroxyl group, and is a glycosyl donor and a glycosyl acceptor;

(S2) the glycosylation product shown in the general structural formula (II ') can be used as a glycosyl donor, is continuously activated in a reaction system without separation, and is coupled with an acceptor shown in the general structural formula (III) or the general structural formula (III ') to obtain a continuous glycosylation product shown in the general structural formula (V), wherein the acceptor shown in the general structural formula (III) or another acceptor shown in the general structural formula (III ') is a third glycosyl unit, or the general structural formula (III) can also be a non-sugar unit;

the reaction equation of the method is as follows:

as a further preferred aspect of the present invention, the structural formula of Gly, gly' is independently selected from the structural formula (II-a) or the structural formula (II-b):

wherein, P ¹、P²、P³、P⁴ is independently selected from hydrogen, alkyl, alkoxy, acyloxy and substituted amino;

Preferably, the structural general formula (II-a) has a structure represented by any one of the following structural formulas II-01 to II-16:

the general structural formula (II-b) has a structure shown in the following structural formula II-17:

The acceptor shown in the formula (III) is glycosyl acceptor containing one or more free hydroxyl groups, and has a structure shown in any one of the following structural formulas III-01 to III-11:

Or the receptor shown in the formula (III) is an alcohol receptor, and has a structure shown in any one of the following structural formulas III-12 to III-17:

or the receptor shown in the formula (III) is a purine receptor, and has a structure shown in the following structural formula III-18:

Or the acceptor shown in the formula (III) is a glycosyl acceptor containing an aglycone capable of being activated on the anomeric carbon, and has a structure shown in any one of the following structural formulas III-19 to III-20:

The acceptor shown in the formula (III') is a glycosyl acceptor containing an aglycone capable of being activated on the anomeric carbon, and has a structure shown in any one of the following structural formulas III-19 to III-20:

as a further preferred aspect of the present invention, the molar ratio of the activating reagent to the trifluoromethanesulfonic anhydride is 1 (1-2), preferably 1:2;

the molar ratio of the activating reagent to the glycosyl donor shown in the structural general formula (II) is 1 (1-6), preferably 1 (1-4);

The reaction temperature of the glycosylation reaction is-40 ℃ to 30 ℃;

The glycosylation reaction is carried out in an organic solvent, wherein the organic solvent is one of toluene, dichloromethane and acetonitrile, and preferably dichloromethane.

Compared with the prior art, the compound shown in the structural general formula (I) contains sulfoxide and disulfide structures, sulfinyl groups forming the sulfoxide and groups containing disulfide bonds are positioned at the ortho positions of aromatic rings and have a special relative position relationship, and the compound can be particularly used as an activating reagent for glycosylation reaction, so that the dosage of the activating reagent is greatly reduced. The compound containing sulfoxide groups and symmetrical disulfide structures as shown in the general structural formula (I) is used as an activating reagent, and a plurality of groups of thioposide or selenoside donors (II) are released simultaneously under the action of trifluoromethanesulfonic anhydride, so that the compound can continuously participate in activating the thioposide or selenoside donors. In other words, one molecule of the activating reagent (I) activates four molecules of the glycosyl donor. Therefore, based on the compound with the general structural formula (I) obtained by the invention, only 0.25 times of equivalent of the glycosyl donor (namely, the molar ratio of the using amount of the activating reagent to the glycosyl donor is 0.25:1) is needed, so that the activation of the glycosyl donor and the glycosylation reaction can be effectively promoted, and the problems that the activating reagent of the glucoside donor is unstable, is difficult to prepare and often needs equivalent or excessive in the existing glycosylation reaction can be solved.

As shown in examples below, when the compound of the formula (I) of the present invention is used as an activating reagent, only 0.25-fold equivalent is required for activating a donor having high activity (as compared with the compound of the formula VI described in the "background art" section, which is used as a compound of the formula VI in the prior art, 0.5-fold equivalent is required), and when a donor having low activity (as a decommissioned glycosyl donor) is used as an activating donor, the compound of the formula (I) of the present invention has a remarkable effect, and an excellent yield can be obtained at 0.5-fold equivalent (as compared with the compound of the formula VI of the prior art, which is used as a compound of the formula VI in the prior art, which is used as a compound of the comparative example 2 in the following).

The preparation method of the compound with the structural general formula (I) is simple, and for example, the following synthetic route can be adopted:

Namely, chlorinated hydrocarbon is used as a reaction raw material, thioacetyl is introduced into a benzyl position, acetyl is removed through hydrolysis to obtain benzyl mercaptan derivatives, symmetrical disulfide is prepared through metal catalytic oxidative coupling, and then the symmetrical disulfide compound containing sulfoxide groups is obtained through selective oxidation of sulfide.

The compound of the general structural formula (I) obtained by the invention can especially comprise the following 2 cases when being used as an activating reagent for glycosylation reaction:

i) The compound shown in the structural general formula (I) is used as an activating reagent to promote the glycosyl donor to react with the acceptor under the coordination effect of trifluoro methanesulfonic anhydride (Tf ₂ O) to obtain a glycosylation product, for example,

Or alternatively

Ii) the compound shown in the formula (I) is used as an activating reagent, a glycosyl donor is activated in advance under the coordination effect of trifluoro methanesulfonic anhydride (Tf ₂ O), and is coupled with a glycosyl acceptor (shown as a structural formula (III ') containing an aglycone capable of being activated on the anomeric carbon to generate a glycosylation product, the glycosylation product can be used as the glycosyl donor to be activated continuously, and then the glycosylation product is coupled with another acceptor (for example, the acceptor can be shown as the formula (III) or the structural formula (III') continuously, so that the continuous glycosylation product is obtained, thereby realizing one-pot connection of a plurality of glycosyl units or one-pot connection of a plurality of glycosyl units and a non-glycosyl unit, for example,

Overall, the invention can achieve the following beneficial effects:

1) The compound shown in the structural general formula (I) has novel structure, contains sulfoxide groups and symmetrical disulfide bond structures meeting specific relative position relation, has stable chemical properties (can be stably stored in room temperature air atmosphere), has no pungent smell, and is convenient and efficient to prepare, and raw materials are cheap and easy to obtain.

2) The compound shown in the structural general formula (I) can be used as an activating reagent for glycosylation reaction, and can be used in combination with trifluoromethanesulfonic anhydride (Tf ₂ O), so that the dosage of the activating reagent can be reduced to 0.25 times equivalent of a thioglycoside donor (namely, only 0.25 times equivalent of the activating reagent of the thioglycoside donor is needed when one glycosidic bond is constructed, and 0.5 times equivalent of the activating reagent of the thioglycoside donor is needed when two glycosidic bonds are constructed, and the like), thereby effectively solving the problems that the activating reagent of thioglycoside needs equivalent and excessive activating agent in glycosylation reaction;

3) The activating reagent shown in the structural general formula (I) can realize activation of multiple sulfur/selenoside donors, is widely applied to various glycosylation reactions, avoids the use of the conventional extremely toxic, expensive, unstable or metal-containing activating reagent in the glycosyl donor activation process, and realizes safe and efficient glycosylation reaction.

4) The invention also provides a method for realizing continuous one-kettle glycosylation based on the activating reagent shown in the structural general formula (I). Specifically, the reagent shown in the general structural formula (I) is activated and coupled with an acceptor while in-situ generating a plurality of groups of thiophilic intermediates by using a thioglycoside or selenoside donor (II) auxiliary structure, and the generated thiophilic intermediates can continuously participate in activating the thioglycoside or selenoside donor, so that one-time activator combination feeding can be realized, the sequential activation of different glycosyl donors can be accurately controlled, and the sequential construction of a plurality of glycosidic bonds and one-kettle connection among a plurality of glycosyl units (or between glycosyl units and non-glycosyl units) are realized.

Drawings

FIG. 1 is a graph showing the comparison of nuclear magnetic resonance hydrogen spectra of Compound I-1 in example 7 before and after one month of the same time period at room temperature (30 to 35 ℃ C.) without light and in an air atmosphere.

FIG. 2 is a graph showing the comparison of nuclear magnetic resonance hydrogen spectra of Compound I-2 in example 7 before and after one month of the same exposure to air at room temperature (30-35 ℃ C.) without light.

Detailed Description

The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.

In the present invention, a "substituted or unsubstituted" group means that the group can be substituted with a substituent defined later, or can be a group not substituted with a substituent, and if substituted with a substituent, the substituent may be located at any position which can be substituted.

Unless otherwise indicated, the starting materials or reagents used in the present invention are commercially available. All reagents were commercial grade and used according to the received standards. All moisture sensitive reactions were carried out under an argon atmosphere. The reaction was monitored by Thin Layer Chromatography (TLC), detected by UV absorption (254 nm), sprayed if necessary with 10% by volume of ethanol solution of sulfuric acid, and carbonized at 80-150 ℃. Flash column chromatography adopts silica gel H. ¹ H and ¹³ C nuclear magnetic resonance spectra were recorded on Bruker AV 400, bruker AV 600 using deuterated chloroform (CDCl ₃) as deuterating agent. Chemical shift (δ) is expressed in ppm with tetramethylsilane as an internal standard. Coupling constants (J) are expressed in Hz.

Unless otherwise defined, scientific and technical terms and acronyms used in the present invention have the meanings commonly understood by one of ordinary skill in the art. For example, "equivalent" in the present invention means a ratio of amounts of substances of respective substances participating in the reaction, and as another example, a meaning of a partial abbreviation is as shown in Table 1:

TABLE 1

Abbreviations	Chinese meaning	Abbreviations	Chinese meaning
				Me	Methyl group	Ph	Phenyl group
Et	Ethyl group	Tol	P-tolyl radical
				ⁱPr	Isopropyl group	Adm	1-Adamantyl group
Phth	Phthaloyl group	TBS	Tertiary butyl dimethylsilyl group
				Ac	Acetyl group	Fmoc	Fluorene methoxycarbonyl group
Bn	Benzyl group	Cbz	Benzyloxycarbonyl group
				Bz	Benzoyl group	Toluene	Toluene (toluene)
Tf	Trifluoromethanesulfonyl group	DCM	Dichloromethane (dichloromethane)
				MeCN	Acetonitrile	DTBMP	2, 6-Di-tert-butyl-4-methylpyridine

The symmetrical disulfide reagent containing sulfoxide groups shown in the structural general formula (I) in the invention is shown in the table 2, and can be, for example:

TABLE 2 activating reagent of the general structural formula (I) of the present invention

The activating reagent shown in the structural general formula (I) can be prepared according to the following method:

the method comprises two stages of symmetrical disulfide bond construction and selective oxidation, wherein the general step A is as follows:

1) The corresponding chlorinated hydrocarbon (1.0 eq) was dissolved in acetone (concentration c=0.5M), potassium carbonate (1.1 eq) was added, thioacetic acid (1.1 eq) was slowly added with stirring at 0 ℃, followed by warming to room temperature for reaction until the chlorinated hydrocarbon consumption was complete. The reaction system was diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate and saturated sodium chloride solution. The organic phase is dried by anhydrous sodium sulfate, filtered and concentrated, and the crude product is purified by silica gel column chromatography to obtain the thioacetylated derivative.

2) The thioacetylated derivative (1.0 eq) was dissolved in methanol (concentration c=0.4M), potassium carbonate (0.2 eq) was added and reacted at 60 ℃ until the consumption of the starting material was complete. The reaction solution is filtered by diatomite and concentrated to obtain the crude product of the acetyl-removed mercaptan derivative, which is directly used in the next step.

3) The above mixture was dissolved in acetonitrile (concentration c=0.4M), sodium iodide (0.2 equivalent) and ferric trichloride (0.1 equivalent) were added in this order, and the mixture was stirred at room temperature under an air atmosphere to react for 1 hour. Acetonitrile was removed by concentration. The reaction system was diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate and saturated sodium chloride solution. The organic phase is dried by anhydrous sodium sulfate, filtered and concentrated, and the crude product is purified by silica gel column chromatography to obtain a non-oxidized precursor of the symmetrical disulfide reagent containing sulfoxide groups.

4) The non-oxidizing reagent precursor (1.0 eq) was dissolved in dichloromethane (concentration c=0.1M), cooled to 0 ℃, and a solution of the oxidizing agent M-chloroperoxybenzoic acid (2.0 eq) in dichloromethane (concentration c=0.3M) was slowly added and the temperature was maintained for 0.5 hours. The reaction was terminated by adding a saturated sodium thiosulfate solution to the reaction flask. The reaction system was diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate and saturated sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product is purified by silica gel column chromatography to obtain the symmetrical disulfide reagent (I) containing sulfoxide groups.

The following are specific examples (yields appearing hereinafter "..+ -. For 4steps", all refer to the total yield of the four steps of general step a above) unless otherwise specified:

EXAMPLE 1 Synthesis of Compound I-1

Referring to general procedure A starting from 2- (2-propylsulfanyl) benzyl chloride, pale yellow oily liquid I-1 (5.82 g, yield) 74％for 4steps).¹H NMR(400MHz,CDCl₃)δ7.88-7.82(2H,m,Ar-H),7.51-7.41(4H,m),7.35-7.28(2H,m),3.90(1H,d,J＝12.8Hz,Bn-H),3.84(1H,d,J＝12.8Hz,Bn-H),3.76(2H,d,J＝12.8Hz,Bn-H),3.00-2.85(2H,m,-CH(CH₃)₂),1.25(3H,d,J＝6.8Hz,-CH(CH₃)₂),1.23(3H,d,J＝7.2Hz),1.16(3H,d,J＝6.18Hz,-CH(CH₃)₂),1.16(3H,d,J＝6.8Hz,CH(CH₃)₂).¹³C NMR(100MHz,CDCl₃)δ141.7,141.6,135.2,131.3,131.3,131.2,131.2,128.9,128.9,125.9,125.9,54.5,54.5,39.3,39.2,17.4,17.3,13.8,13.7.HRMS(ESI-TOF)m/z:[M+Na]⁺calc.for C₂₀H₂₆O₂S₄Na 449.0708;Found 449.0732.

EXAMPLE 2 Synthesis of Compound I-2

Referring to general procedure A starting from 2-methylthiobenzyl chloride, yield I-2 (0.5 g, yield) as a white solid 65％for4steps).¹H NMR(600MHz,CDCl₃)δ8.02(2H,dd,J＝7.8,2.4Hz,Ar-H),7.54(2H,t,J＝7.8Hz,Ar-H),7.48-7.44(2H,m,Ar-H),7.25-7.24(2H,m,Ar-H),3.94(2H,d,J＝12.8Hz,-CH₂Ph),3.82(1H,d,J＝12.8Hz,-CH₂Ph),3.72(1H,d,J＝12.8Hz,-CH₂Ph),2.77(1H,s,-CH₃),2.75(1H,s,-CH₃).¹³C NMR(150MHz,CDCl₃)δ145.2,134.2,134.2,131.5,131.2,131.1,129.9,129.8,124.5,124.5,44.1,44.0,39.2,39.2.HRMS(ESI-TOF)m/z:[M+Na]⁺calc.for C₁₆H₁₈O₂S₄Na 393.0082;Found 393.0075.

EXAMPLE 3 Synthesis of Compound I-3

Reference to general procedure A starting from 2- ((4-methylphenyl) thio) benzyl chloride, yield I-3 (0.4 g, yield) as a white solid 60％for 4steps).¹H NMR(600MHz,CDCl₃)δ7.82(2H,t,J＝7.2Hz,Ar-H),7.49-7.46(4H,m,Ar-H),7.44-7.38(4H,m,Ar-H),7.28(1H,d,J＝7.2Hz,Ar-H),7.25(1H,d,J＝7.8Hz,Ar-H),7.23-7.21(4H,m,Ar-H),3.94-3.87(3H,m,-CH₂Ph),3.83(1H,d,J＝12.6Hz,-CH₂Ph),2.34(6H,s,-CH₃).¹³C NMR(150MHz,CDCl₃)δ144.4,144.3,141.9,141.9,141.5,135.7,135.6,131.5,131.3,131.3,130.3,129.4,129.4,126.3,126.2,125.9,39.6,39.6,21.6.HRMS(ESI-TOF)m/z:[M+Na]⁺calc.for C₂₈H₂₆O₂S₄Na 545.0708;Found 504.0704.

EXAMPLE 4 Synthesis of Compound I-4

The known compound S1 was synthesized according to the literature (Chin. Chem. Lett.,2017,28,1693-1700, chem. Sci.,2022,13,8759-8765). S1 (1.0 eq) was weighed into a reaction flask, dissolved in methylene chloride (concentration c=0.2M), and a methylene chloride solution (1.5 eq) of thionyl chloride (SOCl ₂) was slowly added dropwise under ice bath, and after the addition was completed, the reaction was allowed to proceed to room temperature for 0.5h. After the reaction was completed, the reaction system was diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate, and saturated sodium chloride solution in this order. The organic phase is then dried over anhydrous sodium sulfate, concentrated by filtration and the crude product is purified by silica gel column chromatography to give colorless liquid S2 (yield) 64％).¹H NMR(600MHz,CDCl₃)δ7.53-7.51(1H,m,Ar-H),7.46-7.45(1H,m,Ar-H),7.29-7.27(2H,m,Ar-H),4.84(2H,s,-CH₂Ph),3.71(4H,t,J＝6.6Hz),3.69-3.64(4H,m),3.38-3.35(1H,m,SCH),2.40-2.32(4H,m,-CH₂CH₂C₆F₁₃).¹³CNMR(150MHz,CDCl₃)δ139.9,134.5,134.1,130.8,129.4,128.6,70.4,63.3(t,J＝4.0Hz,-CH₂CH₂C₆F₁₃),49.1,44.8,31.5(t,J＝21.6Hz,-CH₂CH₂C₆F₁₃).HRMS(ESI-TOF)m/z:[M+Na]⁺calc.for C₂₆H₁₉ClF₂₆O₂SNa 947.0271;Found 947.0276.

Referring to general procedure A starting from compound S2, there was obtained colorless oily liquid I-4 (30 mg, yield) 50％for 4steps).¹H NMR(400MHz,CDCl₃)δ7.89(2H,d,J＝7.2Hz,Ar-H),7.51-7.44(4H,m,Ar-H),7.32-7.28(2H,m,Ar-H),3.94(1H,d,J＝13.2Hz,-CH₂Ph),3.84(1H,d,J＝13.2Hz,-CH₂Ph),3,76(4H,d,J＝5.2Hz,-CH(CH₂)₂)),3.71(1H,d,J＝13.2Hz,-CH₂Ph),3.70-3.58(13H,m),3.25-3.18(2H,m,-CH(CH₂)₂)),2.36-2.18(8H,m).¹³C NMR(150MHz,CDCl₃)δ141.2,141.2,135.4,133.7,131.6,131.6,131.5,131.4,130.4,130.0,129.1,129.0,128.4,125.6,125.6,66.8,64.4,64.3,64.3,63.5,63.3,38.6,38.5,31.4,31.4,29.9.HRMS(ESI-TOF)m/z:[M+Na]⁺calc.for C₅₂H₃₈F₅₂O₆S₄Na 1897.0613;Found 1897.0637.

EXAMPLE 5 Synthesis of Compound I-5

The known compound S3 is synthesized according to the literature (Tetrahedron Lett.1980,21,4203-4206, J.Am.chem.Soc.2020,142, 5498-5503). S3 (1.0 eq) and 4-Dimethylaminopyridine (DMAP) were weighed into a reaction flask, dissolved in methylene chloride (c=0.2M), and triethylamine (2.0 eq) and p-toluenesulfonyl chloride (2.0 eq) were added in this order under ice bath. After the addition was completed, the reaction mixture was allowed to react at room temperature for 24 hours. After the reaction was completed, the reaction system was diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate, and saturated sodium chloride solution in this order. The organic phase is then dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product is purified by silica gel column chromatography to give oily liquid S4 (yield) 78％).¹H NMR(400MHz,CDCl₃)δ7.34(1H,dd,J＝7.6,1.2Hz,Ar-H),7.21(1H,t,J＝7.6Hz,Ar-H),7.12(1H,d,J＝7.6Hz,Ar-H),4.96(2H,s,-CH₂Ph),3.41(1H,hept,J＝6.8Hz,-CH(CH₃)₂),2.79(2H,q,J＝7.6Hz,-CH₂CH₃),1.29(6H,d,J＝7.2Hz,-CH(CH₃)₂),1.27(3H,t,J＝7.2Hz,-CH₂CH₃).¹³C NMR(150MHz,CDCl₃)δ144.4,139.2,133.7,129.5,127.8,127.1,41.7,40.3,29.9,25.9,22.6,15.6.HRMS(ESI-TOF)m/z:[M+O+Na]⁺calc.for C₁₂H₁₇ClSONa 267.0581;Found267.0582.

Referring to general procedure A starting from S4, oily liquid I-5 (0.1 g, yield 51％for 4steps).¹H NMR(400MHz,CDCl₃)δ7.73(2H,d,J＝8.0Hz,Ar-H),7.44(2H,td,J＝7.6,2.4Hz,Ar-H),7.35-7.32(2H,m,Ar-H),4.16-4.08(3H,m,-CH₂Ph),3.95(1H,d,J＝12.4Hz,-CH₂Ph),3.00-2.93(2H,m,-CH(CH₃)₂)),2.82-2.72(4H,m,-CH₂CH₃),1.29-2.23(12H,m,-CH₂CH₃,-CH(CH₃)₂)),1.17(6H,d,J＝6.8Hz,-CH(CH₃)₂)).¹³C NMR(150MHz,CDCl₃)δ144.6,144.5,142.8,142.7,132.0,131.7,131.7,129.0,129.0,123.7,123.5,54.7,54.6,37.2,36.7,25.5,25.5,17.7,17.7,15.5,13.6,13.6.HRMS(ESI-TOF)m/z:[M+Na]⁺calc.for C₂₄H₃₄O₂S₄Na 505.1334;Found 505.1328.

EXAMPLE 6 Synthesis of Compound I-6

As shown in the synthetic route, the compound XXXV was synthesized by 4 steps of reaction using S5 as a starting material according to the method of synthesizing compound XXXV in the literature (Monatsh. Chem.1965,96, 182-207) S6(170mg,3％for 4steps).¹H NMR(400MHz,CDCl₃)δ7.99(1H,s,Ar-H),7.87(1H,s,Ar-H),7.84-7.82(1H,m,Ar-H),7.71-7.69(1H,m,Ar-H),7.51-7.45(2H,m,Ar-H),7.30-7.19(5H,m,Ar-H),4.88(2H,s,-CH₂).¹³C NMR(150MHz,CDCl₃)δ136.3,136.1,134.1,133.8,133.0,131.7,130.0,130.0,129.5,128.0,127.5,127.3,127.2,127.0,45.2.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₁₇H₁₃ClOSNa 323.0268;Found 323.0274.

According to general procedure A, starting from S6, orange-colored liquid I-6 (15 mg, yield) 50％for 4steps).¹H NMR(400MHz,CDCl₃)δ8.44(2H,d,J＝9.6Hz,Ar-H),7.91(2H,d,J＝7.6Hz,Ar-H),7.80(2H,t,J＝7.6Hz,Ar-H),7.62-7.51(10H,m,Ar-H),7.40-7.33(6H,m,Ar-H),3.84-3.72(4H,m,-CH₂Ph).¹³C NMR(150MHz,CDCl₃)δ144.7,144.6,141.3,141.2,134.3,132.7,132.7,131.6,131.6,131.2,131.1,131.0,130.9,129.7,128.9,128.8,128.6,128.0,128.0,127.6,127.4,127.2,126.5,126.4,40.1,40.0.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₃₄H₂₆O₂S₄Na 617.0708;Found 617.0709.

EXAMPLE 7 stability test of Compound I (exemplified by Compounds I-1, I-2 left at room temperature without light for 1 month)

After the compound I-1 is placed for one month at room temperature (30-35 ℃) in a non-light-proof air atmosphere, the nuclear magnetic hydrogen spectrum is unchanged (as shown in figure 1), and the compound I-1 is not sensitive to light and heat (and the compound I-1 can be stored for years under a low-temperature condition (-20 ℃).

Similarly, after the compound I-2 is placed for one month at room temperature (30-35 ℃) in an air atmosphere without light shielding, the nuclear magnetic hydrogen spectrum is unchanged (as shown in figure 2), and the compound I-2 is insensitive to light and heat.

The symmetrical disulfide compound (I) containing sulfoxide groups can be used as an activating reagent in glycosylation reaction. Based on the application, the invention provides a method for constructing glycosidic bonds by activating a donor under the coordination effect of trifluoromethanesulfonic anhydride by using an activating reagent shown in a structural general formula (I).

The method comprises the steps of:

Mixing glycosyl donor (II), acceptor (III) and activating reagent (I), and adding trifluoromethanesulfonic anhydride to carry out glycosylation reaction to obtain glycosylation product (IV), wherein the reaction formula is as follows:

or the method comprises the steps of:

Mixing glycosyl donor (II) and activating reagent (I), sequentially adding trifluoromethanesulfonic anhydride and acceptor (III ') to carry out first glycosylation reaction to obtain first glycosylation product (II '), and then adding acceptor (III) or (III ') to continue glycosylation reaction to obtain continuous glycosylation product (V), wherein the reaction formula is as follows:

For a detailed experimental procedure example, see the following examples.

Examples 8 to 10 influence of the amount of the activating reagent of the present invention on the glycosylation reaction

Taking glycosylation reaction of glycosyl donor II-01 and glycosyl acceptor III-01 under the action of activating reagent I-1 as an example, the influence of the coordination of different amounts of activating reagent and trifluoromethanesulfonic anhydride (Tf ₂ O) on glycosylation reaction is examined. The results show that the coupling of glycosyl donors and acceptors can be realized by the coordination of different amounts of activating reagent and trifluoromethanesulfonic anhydride (Tf ₂ O)

Table 3).

TABLE 3 influence of different amounts of activating reagent on glycosylation reactions

The procedure involves taking donor II-01 (0.06 mmol,1.2 eq.), activating reagent formula I-1 (with the amount equivalent shown in Table 3) and glycosyl acceptor III-01 (0.05 mmol,1.0 eq.) in a reaction flask, azeotroping toluene with water twice, followed by addition of the activating reagentMolecular sieves were combined with 2, 6-di-tert-butyl 4-methylpyridine (DTBMP) (0.06 mmol,1.2 eq.). Anhydrous dichloromethane (0.1M) was added under argon atmosphere, the reaction flask was cooled to 0 ℃ and stirred for 10 minutes, and triflic anhydride was added using a microsyringe (the amount equivalents used are shown in table 3). The reaction was continued for 1 hour at 0 ℃ followed by a temperature increase to 30 ℃ and for 5 hours until the consumption of the starting material was complete. Adding triethylamine (0.1 ml) into the reaction flask to terminate the reaction, filtering with diatomite, concentrating, and purifying the crude product by silica gel column chromatography to obtain colorless syrup compound IV-01.R_f＝0.48(PE:EA＝3:1).¹H NMR(400MHz,CDCl₃)δ7.34-7.19(28H,m,Ar-H),7.15-7.11(2H,m),4.95(1H,t,J＝8.4Hz,H-2'),4.78-4.72(3H,m),4.70(1H,d,J＝12.0Hz,Bn-H),4.65-4.58(4H,m),4.54(1H,d,J＝12.4Hz,Bn-H),4.51(1H,d,J＝11.2Hz,Bn-H),4.46(1H,d,J＝12.4Hz,Bn-H),4.43(2H,d,J＝12.0Hz,Bn-H),4.36(1H,d,J＝12.0Hz,Bn-H),4.00(1H,d,J＝1.6Hz),3.84(1H,t,J＝6.0Hz),3.80(1H,dd,J＝10.0,2.8Hz),3.78-3.72(2H,m),3.68-3.56,(5H,m),3.36-3.29(4H,m,-OMe,H-5),1.70(3H,s,-COCH₃).

Comparative example 1 influence of the amount of the activating reagent represented by the general structural formula (VI) on the glycosylation reaction

The procedure is to take donor II-01 (0.06 mmol,1.2 eq.), activating reagent formula VI (with the amount equivalent shown in Table 3) and glycosyl acceptor III-01 (0.05 mmol,1.0 eq.) in a reaction flask, azeotropically entrain toluene twice, and then add the activating reagentMolecular sieves were combined with 2, 6-di-tert-butyl 4-methylpyridine (DTBMP) (0.06 mmol,1.2 eq.). Anhydrous dichloromethane (0.1M) was added under argon atmosphere, the reaction flask was cooled to 0 ℃ and stirred for 10 minutes, and triflic anhydride was added using a microsyringe (the amount equivalents used are shown in table 3). The reaction was continued for 1 hour at 0 ℃ followed by a temperature increase to 30 ℃ and for 5 hours until the consumption of the starting material was complete. Triethylamine (0.1 ml) was added to the above reaction flask to terminate the reaction, which was filtered through celite, concentrated, and the crude product was purified by silica gel column chromatography to give colorless syrup-like compound IV-01.R _f =0.48 (PE: ea=3:1).

EXAMPLES 11-18 use of different activating reagents of the invention in glycosylation reactions

Taking glycosylation reaction of glycosyl donor II-01 and glycosyl acceptor III-02 under the action of different activating reagents (I) as an example, the application of the different activating reagents in glycosylation reaction is examined. The results show that in different reaction solvents, the glycosyl donor II-01 and the glycosyl acceptor III-02 can be successfully coupled under the action of different activating reagents (I).

TABLE 4 use of different activating reagents in glycosylation reactions

The procedure involves taking donor II-01 (0.06 mmol,1.2 eq.) and different activating reagents of formula I (0.3 eq.) and glycosyl acceptor III-02 (0.05 mmol,1.0 eq.) in a reaction flask, azeotroping toluene with water twice, followed by addition of the activated reagentMolecular sieves were combined with 2, 6-di-tert-butyl 4-methylpyridine (DTBMP) (0.06 mmol,1.2 eq.). Solvent (0.1M) was added under argon atmosphere, the reaction flask was cooled to 0 ℃ and stirred for 10 minutes, and trifluoromethanesulfonic anhydride (0.6 eq) was added using a microsyringe. The reaction was continued for 1 hour at 0 ℃ followed by a temperature increase to 30 ℃ and for 5 hours until the consumption of the starting material was complete. Adding triethylamine (0.1 ml) into the reaction bottle to terminate the reaction, filtering with diatomite, concentrating, purifying the crude product by silica gel column chromatography to obtain colorless syrup compound IV-02.¹H NMR(400MHz,CDCl₃)δ7.39-7.19(15H,m,Ar-H),4.99(1H,t,J＝9.2Hz),4.95(1H,d,J＝12.0Hz,-CH₂Ph),4.92(1H,t,J＝9.2Hz),4.86(1H,t,J＝8.8Hz,H-2'),4.72-4.69(3H,m,-CH₂Ph),4.56(1H,d,J＝11.6Hz,-CH₂Ph),4.57-4.54(2H,m,-CH₂Ph),4.46(1H,d,J＝7.6Hz,H-1'),4.39(1H,d,J＝12.0Hz,-CH₂Ph),4.11(1H,dd,J＝12.4,4.0Hz),3.87-3.78(3H,m),3.73(1H,dd,J＝10.8,2.8Hz),3.59-3.55(2H,m),3.44(1H,dd,J＝8.8,3.6Hz,H-2),3.34(1H,s,-OCH₃),3.27(1H,m,H-5),1.97(3H,s,-COCH₃),1.95(3H,s,-COCH₃),1.92(3H,s,-COCH₃),1.92(3H,s,-COCH₃).

Examples 19 to 25 activation of different glycosyl donors by the activating reagent of the invention

The activation of different glycosyl donors by the activating reagent of the invention was examined by taking the glycosylation reaction of different glycosyl donors II and glycosyl acceptors III-01 under the action of the activating reagent I-1 of the invention as an example. The results show that the glycosyl donor II and the glycosyl acceptor III-01 containing different end group protecting groups both show good glycosylation effect under the action of the activating reagent I-1, which indicates that the activating reagent (I) has good glycosyl donor activating effect.

TABLE 5 activation of different glycosyl donors by the activating reagents of the invention

The procedure comprises the steps of weighing donor II (0.06 mmol,1.2 eq.) symmetrical disulfide reagent I-1 (0.06 mmol,0.6 eq.) containing sulfoxide groups and glycosyl acceptor III-01 (0.05 mmol,1.0 eq.) in a reaction flask, azeotroping toluene with water twice, followed by addition of the activated reagentMolecular sieves. Anhydrous dichloromethane (0.1M) was added under argon, cooled to 0℃and then trifluoromethanesulfonic anhydride (0.06 mmol,1.2 eq.) was added and reacted for 1 hour. Adding triethylamine (0.1 ml) into the reaction flask to terminate the reaction, filtering with diatomite, concentrating, purifying the crude product by silica gel column chromatography to obtain colorless syrup compound IV-03.R_f＝0.39(PE:EA＝2:1).¹H NMR(400MHz,CDCl₃)δ7.39-7.21(15H,m),5.18(1H,t,J＝9.6Hz),5.03(1H,t,J＝10.0Hz),4.98(1H,dd,J＝10.0,8.0Hz,H-2'),4.83(1H,d,J＝11.6Hz),4.77(1H,d,J＝8.0Hz,H-1'),4.73(1H,d,J＝12.0Hz,-CH₂Ph),4.65(1H,d,J＝12.0Hz,-CH₂Ph),4.61(1H,d,J＝3.6Hz,H-1),4.56(1H,d,J＝12.4Hz,-CH₂Ph),4.53(1H,d,J＝12.8Hz,-CH₂Ph),4.48(1H,d,J＝12.0Hz,-CH₂Ph),4.14(1H,dd,J＝12.4,4.4Hz),4.04-3.97(2H,m),3.89-3.83(2H,m,),3.75(1H,dd,J＝10.0,3.6Hz),3.65(1H,dd,J＝10.0,5.6Hz,H-3),3.57-3.49(2H,m),3.34(3H,s),2.00(3H,s,),1.99(3H,s),1.98(3H,s),1.79(3H,s).

Comparative example 2 activation of Dearmed glycosyl donor by activating reagent of general Structure (VI)

The procedure comprises the steps of weighing donor II-08 (0.06 mmol,1.2 eq), activating reagent of formula VI (0.06 mmol,0.6 eq) and glycosyl acceptor III-01 (0.05 mmol,1.0 eq) in a reaction flask, azeotroping toluene with water twice, followed by addition of the activating reagentMolecular sieves. Anhydrous dichloromethane (0.1M) was added under argon atmosphere, cooled to 0 ℃, followed by addition of trifluoromethanesulfonic anhydride (0.06 mmol,1.2 eq.) for 1 hour, a small amount of donor was converted, then warmed to 30 ℃ and the reaction time was prolonged to 15 hours, the donor was always incompletely activated, triethylamine (0.1 ml) was added to the above reaction flask to terminate the reaction, suction filtration through celite, concentration, purification of the crude product by silica gel column chromatography gave colorless syrup compound IV-03 in 17% yield.

Examples 26 to 43

The standard procedure for the glycosylation of examples 26-43, unless otherwise specified, is to place the glycosyl donor, activating reagent (I) and glycosyl acceptor in a reaction flask, azeotropically entrain toluene twice, and then add the activated reagentMolecular sieves (100 mg/ml in the form of CH ₂Cl₂ solution), sealed with a rubber stopper, anhydrous dichloromethane (0.1M) was added under argon atmosphere, the reaction flask was cooled to 0℃and then triflic anhydride (Tf ₂ O) was added. After the reaction was completed, triethylamine (0.1 ml) was added to the above reaction flask to terminate the reaction, which was concentrated after suction filtration through celite, and the crude product was purified by silica gel column chromatography to obtain the glycosidation product. In some embodiments, the specific details are not consistent with the standard reaction procedure.

EXAMPLE 26 Synthesis of glycosylation product IV-04

After synthesis of S7 according to literature (carbohydro.res., 1993,249,221-241), S7 (970 mg,1.81 mmol) was weighed into a round bottom bottle, toluene azeotropically brought twice with water, followed by addition of activatedMolecular sieves. Anhydrous dichloromethane (3.7 mL) and benzyl mercaptan (255 μL,2.17 mmol) were added under argon, cooled to 0deg.C, and boron trifluoride etherate (0.7 mL,5.43 mmol) was slowly added. After the reaction was completed by monitoring the reaction by TLC at 0 ℃ for 24 hours, the reaction system was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate, and saturated sodium chloride solution in this order. The organic phase is dried by anhydrous sodium sulfate, filtered and concentrated, and the crude product is purified by silica gel column chromatography to obtain colorless syrup II-02(950mg,84％).R_f＝0.45(PE:EA＝5:1).[α]_D ²⁵＝-41.3(c＝1.0,in CHCl₃).¹H NMR(400MHz,CDCl₃)δ7.42-7.22(20H,m,Ar-H),5.52(1H,t,J＝9.6Hz,H-2),4.99(1H,d,J＝11.6Hz,-CH₂Ph),4.70(1H,d,J＝12.0Hz,-CH₂Ph),4.62(1H,d,J＝11.6Hz,-CH₂Ph),4.56(1H,d,J＝12.0Hz,-CH₂Ph),4.52(1H,d,J＝11.6Hz,-CH₂Ph),4.47(1H,d,J＝11.6Hz,-CH₂Ph),4.24(1H,d,J＝9.6Hz,H-1),4.01(1H,d,J＝2.4Hz,H-4),3.97(1H,d,J＝12.8Hz,-CH₂Ph),3.85(1H,d,J＝12.8Hz,-CH₂Ph),3.67-3.61(2H,m),3.57(1H,t,J＝6.0Hz),3.53(1H,dd,J＝9.6,2.8Hz,H-3),2.05(3H,s,-COCH₃).¹³C NMR(100MHz,CDCl₃)δ169.9,138.7,138.2,138.0,1379,129.4,128.7,128.6,128.6,128.4,128.3,128.1,128.1,128.0,127.7,127.6,127.1,82.7,81.7,77.7,74.7,73.8,73.3,72.3,69.8,68.8,33.5,21.2.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₃₆H₃₈NaO₆S,621.2281;Found 621.2296.

According to the standard reaction procedure, glycosyl donor II-02 (36.7 mg,0.061 mmol), glycosyl acceptor III-03 (25 mg,0.051 mmol), activating reagent I-1 (6.5 mg,0.015 mmol), DTBMP (12.6 mg,0.061 mmol) and molecular sieve are added into a reaction bottle, after pre-cooling to 0 ℃ and adding Tf ₂ O, after the reaction is completed, colorless syrup is obtained by treatment IV-04(44.7mg,91％).R_f＝0.38(PE:EA＝5:1).¹H NMR(400MHz,CDCl₃)δ7.36-7.24(19H,m,Ar-H),7.23-7.09(6H,m,Ar-H),5.35(1H,dd,J＝10.0,8.4Hz,H-2'),5.00-4.93(2H,m,Bn-H),4.77(1H,d,J＝12.0Hz,Bn-H),4.73(1H,d,J＝10.4Hz,H-1'),4.66(1H,d,J＝12.4Hz,Bn-H),4.60(1H,d,J＝11.6Hz,Bn-H),4.59(1H,d,J＝3.2Hz,H-1),4.55-4.51(2H,m,Bn-H),4.45(1H,d,J＝12.4Hz,Bn-H),4.30(1H,d,J＝11.6Hz,Bn-H),4.20(1H,d,J＝11.6Hz,Bn-H),3.96(1H,d,J＝2.4Hz,H-4'),3.83(1H,t,J＝9.2Hz,H-3),3.79-3.67(3H,m),3.53(1H,t,J＝8.4Hz,H-4),3.50-3.44(1H,m,H-5),3.44-3.35(3H,m),3.34-3.28(4H,m,-OMe),2.00(3H,s,-OAc),0.84(9H,s,-C(CH₃)₃),0.00(6H,s,-Si(CH₃)₂).¹³C NMR(100MHz,CDCl₃)δ169.5,139.6,139.0,138.7,138.2,138.1,128.6,128.5,128.4,128.2,128.1,128.1,128.1,127.9,127.9,127.6,127.2,101.0,98.3,80.6,80.1,79.7,75.6,74.8,73.7,73.6,73.5,72.8,72.2,71.8,71.2,68.1,61.5,55.2,26.1,21.3,18.4,-4.9,-5.2.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₅₆H₇₀NaO₁₂Si⁺,985.4529;Found,985.4538.

EXAMPLE 27 Synthesis of glycosylation product IV-05

After S8 was synthesized according to the literature (Org. Lett.,2010,12,2080-2083), the reaction was monitored by TLC for completion and the reaction system was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate and saturated sodium chloride solution in this order, starting from S8 (356 mg,0.66 mmol) and benzyl mercaptan (182. Mu.L, 1.58mmol,5.0 equiv) for 1 hour. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography to give colorless syrup II-03 (369 mg, 93%). Alpha/beta mixture in a ratio of 4.5:1 (this ratio is the ratio of the amounts of alpha configuration product to beta configuration product material in the product, as described below). R _f =0.43 (PE: ea=5:1.) the main product (α)：¹H NMR(400MHz,CDCl₃)δ7.39-7.11(20H,m,Ar-H),5.38(1H,d,J＝0.8Hz,H-2),5.16(1H,s,H-1),4.82(1H,d,J＝10.8Hz,-CH₂Ph),4.66(1H,d,J＝12.0Hz,-CH₂Ph),4.64(1H,d,J＝10.8Hz,-CH₂Ph),4.50-4.42(3H,m,-CH₂Ph),4.16-4.09(1H,m),3.92-3.87(2H,m),3.80-3.69(3H,m),3.55(1H,dd,J＝10.8,1.6Hz,H-3),2.10(3H,s,-COCH₃).¹³C NMR(100MHz,CDCl₃)δ170.4,138.5,138.4,137.9,137.6,129.2,128.8,128.6,128.5,128.4,128.1,128.0,127.9,127.4,81.9,79.0,75.4,74.7,73.7,72.1,70.2,68.9,35.0,21.3.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₃₆H₃₈NaO₆S,621.2281;Found 621.2273.

According to the standard procedure, glycosyl donor II-03 (30.9 mg,0.052 mmol), glycosyl acceptor III-04 (20.0 mg,0.043 mmol), activating reagent I-1 (5.5 mg,0.013 mmol) and molecular sieve are added into a reaction flask, after pre-cooling to 0 ℃ and adding Tf ₂ O, after the reaction is completed, the colorless syrup is obtained by treatment IV-05(37.2mg,92％).R_f＝0.59(PE:EA＝2:1).¹H NMR(400MHz,CDCl₃)δ7.39-7.10(30H,m,Ar-H),5.47-5.45(1H,m,H-2'),4.95(1H,d,J＝1.2Hz,H-1'),4.90(1H,d,J＝11.2Hz,Bn-H),4.84(1H,d,J＝10.8Hz,Bn-H),4.72-4.69(3H,m,Bn-H,H-1),4.64(1H,d,J＝12.0Hz,Bn-H),4.64(1H,d,J＝11.6Hz,Bn-H),4.61-4.55(m,2H,Bn-H),4.48(1H,d,J＝11.6Hz,Bn-H),4.46-4.40(3H,m,Bn-H),3.95(1H,dd,J＝9.2,3.2Hz,),3.92-3.83(4H,m),3.81-3.74(2H,m),3.72-3.64(3H,m),3.58(1H,dd,J＝10.8,1.2Hz,H-3),3.24(3H,s,-OMe),2.13(3H,s,-OAc).

EXAMPLE 28 Synthesis of glycosylation product IV-06

S9 was synthesized according to the literature (carbohydro. Res.,1981,93,43-52), and S9 (500 mg,1.17 mmol) was used as a starting material, and after 12 hours of reaction, the reaction system was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate and saturated sodium chloride solution in this order, followed by monitoring the reaction completion by TLC. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography to give yellow syrup II-04 (4638 mg, 93%). Alpha/beta mixture in the ratio of 3.2:1.¹H NMR(400MHz,CDCl₃)δ7.35-7.25(13H,m,Ar-H),5.63(0.31H,dd,J＝3.6,1.2Hz,H-2β),5.42(1H,dd,J＝3.6,1.6Hz,H-2α),5.17(1H,d,J＝1.2Hz,H-1α),4.90(1.35H,d,J＝10.8Hz,-CH₂Ph),4.75(0.33H,d,J＝11.2Hz,-CH₂Ph),4.66(1H,d,J＝11.2Hz,-CH₂Ph),4.63(0.33H,d,J＝0.8Hz,H-1β),4.59(1.35H,d,J＝10.8Hz,-CH₂Ph),4.52-4.46(1.35H,m,-CH₂Ph),4.07(1H,dq,J＝9.6,6.0Hz,H-5α),3.86(1H,dd,J＝9.2,3.6Hz,H-3α),3.62(0.31H,dd,J＝8.8,3.6Hz,H-3β),3.48-3.35(1.7H,m,H-4),2.71(0.66H,qd,J＝7.6,2.0Hz,-SCH₂CH₃β),2.67-2.51(2H,m,-SCH₂CH₃α),2.19(0.9H,s,OAcβ),2.14(3H,s,OAcα),1.36(0.93H,d,J＝5.6Hz,-CH₃,H-6β),1.32(3H,d,J＝6.0Hz,-CH_3,H-6α),1.30-1.23(3.9H,m,-SCH₂CH₃).

According to the standard procedure, glycosyl donor II-04 (25.8 mg,0.06 mmol), glycosyl acceptor III-05 (18.6 mg,0.05 mmol), activating reagent I-1 (6.5 mg,0.015 mmol), DTBMP (12.3 mg,0.06 mmol) and molecular sieve are added into a reaction flask, after pre-cooling to 0℃Tf ₂ O is added, after 1h of reaction, the temperature is raised to 30℃until the reaction is complete, and the colorless syrup is obtained by treatment IV-06(31.9mg,86％).R_f＝0.54(PE:EA＝3:1).¹H NMR(400MHz,CDCl₃)δ7.47-7.42(2H,m,Ar-H),7.38-7.25(15H,m,Ar-H),7.24-7.19(3H,m,Ar-H),5.48(1H,dd,J＝3.2,1.6Hz,H-2'),5.47(1H,s,-CHPh),5.13(1H,brs,H-1'),4.82(1H,d,J＝10.8Hz,Bn-H),4.75(1H,d,J＝12.0Hz,Bn-H),4.71(1H,d,J＝11.2Hz,Bn-H),4.56(1H,d,J＝12.0Hz,Bn-H),4.54-4.50(3H,m,Bn-H,H-1),4.23(1H,dd,J＝10.0,4.8Hz,H-3'),4.16-4.04(2H,m),3.91(1H,dd,J＝9.2,3.2Hz),3.80(1H,td,J＝10.0,4.4Hz),3.66(1H,t,J＝10.4Hz),3.49(1H,dd,J＝9.2,3.6Hz,H-2),3.43(1H,t,J＝9.6Hz),3.37-3.31(4H,m),2.10(3H,s,-OMe),0.92(3H,d,J＝6.4Hz,-CHCH₃).¹³C NMR(100MHz,CDCl₃)δ170.4,139.0,138.5,137.9,137.3,129.1,128.7,128.6,128.5,128.4,128.3,128.3,128.2,127.9,127.8,127.7,126.5,101.9,98.8,98.6,80.5,80.1,78.3,75.2,74.5,73.5,72.0,69.2,67.6,62.7,55.5,21.3,17.6.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₄₃H₄₈NaO₁₁ ⁺,763.3089;Found,763.3103.

EXAMPLE 29 Synthesis of glycosylation product IV-07

According to the standard procedure, glycosyl donor II-04 (25.8 mg,0.06 mmol), glycosyl acceptor III-06 (23.0 mg,0.05 mmol), activating reagent I-1 (6.5 mg,0.015 mmol), DTBMP (12.3 mg,0.06 mmol) and molecular sieve are added into a reaction flask, after pre-cooling to 0℃Tf ₂ O is added, and after 1h of reaction, a colorless syrup is obtained by treatment IV-07(35.5mg,86％).R_f＝0.15(PE:EA＝3:1).¹H NMR(400MHz CDCl₃)δ7.34-7.22(17H,m,Ar-H),7.19-7.14(3H,m,Ar-H),5.20(1H,brs,H-2'),4.99(2H,s,Bn-H),4.90(1H,s,H-1'),4.89-4.83(2H,m),4.69(1H,d,J＝10.8Hz,Bn-H),4.64-4.56(3H,m),4.53(1H,d,J＝10.8Hz,Bn-H),4.48(1H,d,J＝11.6Hz,Bn-H),4.41(1H,d,J＝12.0Hz,Bn-H),4.10(1H,dd,J＝12.0,3.2Hz,H-2),4.00(1H,td,J＝10.0,3.2Hz),3.89(1H,dd,J＝9.2,6.4Hz),3.84(1H,dd,J＝9.2,3.2Hz),3.80-3.68(2H,m),3.55(1H,t,J＝9.6Hz),3.35(1H,t,J＝9.6Hz),3.30(3H,s,-OMe),2.08(3H,s,-OAc),2.08(3H,s,-OAc),1.02(3H,d,J＝6.0Hz).¹³C NMR(100MHz,CDCl₃)δ170.9,170.6,156.0,138.8,138.2,138.0,136.4,128.7,128.6,128.5,128.4,128.4,128.3,128.2,128.0,127.9,127.8,127.7,99.1,98.4,80.1,79.7,77.7,75.7,75.5,75.3,71.8,69.2,69.1,68.9,67.2,62.7,55.5,55.0,21.3,21.0,18.0.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₄₆H₅₃NNaO₁₃ ⁺,850.3409;Found,850.3390.

EXAMPLE 30 Synthesis of glycosylation product IV-08

According to the standard procedure, glycosyl donor II-12 (38.3 mg,0.08 mmol), glycosyl acceptor III-07 (21.3 mg,0.067 mmol), activating reagent I-1 (17.2 mg,0.04 mmol) and molecular sieve are added into a reaction flask, after pre-cooling to 0 ℃ and adding Tf ₂ O, reacted for 1h, and processed to obtain colorless syrup IV-08(45.7mg,93％).R_f＝0.24(PE:EA＝2:1).¹H NMR(400MHz,CDCl3)δ7.81(2H,dd,J＝5.2,3.2Hz,Ar-H),7.74-7.68(2H,m,Ar-H),5.73(1H,dd,J＝10.8,9.2Hz),5.37(1H,d,J＝8.4Hz,H-1'),5.29(1H,t,J＝10.0Hz),5.13(1H,t,J＝9.6Hz),4.71(1H,t,J＝10.0Hz),4.64(1H,dd,J＝10.0,3.6Hz,H-2),4.41(1H,d,J＝3.6Hz,H-1),4.34-4.26(2H,m),4.13(1H,dd,J＝12.0,2.0Hz),3.87(1H,dd,J＝10.4,1.6Hz),3.85-3.76(2H,m),3.44(1H,dd,J＝10.8,7.2Hz),2.98(3H,s,-COCH₃),2.08(3H,s,-COCH₃),1.99(3H,s,-COCH₃),1.97(3H,s,-COCH₃),1.89(3H,s,-COCH₃),1.88(3H,s,-COCH₃),1.83(3H,s,-COCH₃).

EXAMPLE 31 Synthesis of glycosylation product IV-09

According to the standard procedure, glycosyl donor II-13 (23.3 mg,0.059 mmol), glycosyl acceptor III-08 (23.0 mg,0.049 mmol), activating reagent I-1 (12.5 mg,0.029 mmol) and molecular sieve are added into a reaction flask, after pre-cooling to 0 ℃ and adding Tf ₂ O, after reacting for 1h, a colorless syrup is obtained by treatment IV-09(36.3mg,92％).R_f＝0.23(PE:acetone＝4:1).¹H NMR(400MHz,CDCl₃)δ7.37-7.26(9H,m,Ar-H),7.26-7.21(4H,m,Ar-H),7.14(2H,dd,J＝7.6,2.0Hz,Ar-H),5.44(1H,dd,J＝3.6,2.0Hz,H-2'),5.39(1H,dd,J＝10.0,3.6Hz,H-3'),5.23(1H,t,J＝10.0Hz,H-4'),4.95(1H,d,J＝1.6Hz,H-1'),4.81(1H,d,J＝10.8Hz,Bn-H),4.77(1H,d,J＝2.0Hz,H-1),4.69(1H,d,J＝11.6Hz,Bn-H),4.65-4.58(2H,m,Bn-H),4.56(1H,d,J＝12.4Hz,Bn-H),4.48(1H,d,J＝10.8Hz,Bn-H),4.22(1H,dd,J＝12.0,5.6Hz,H-6'a),4.19-4.14(1H,m,H-5'),4.09(1H,dd,J＝12.0,2.0Hz,H-6'b),3.93(1H,t,J＝2.4Hz,H-2),3.90-3.81(2H,m,),3.75-3.68(3H,m),3.33(3H,s,OMe),2.09(3H,s,-COCH₃),2.07(3H,s,-COCH₃),1.98(3H,s,-COCH₃),1.97(3H,s,-COCH₃).

EXAMPLE 32 Synthesis of glycosylation product IV-10

According to the standard procedure, glycosyl donor II-14 (36.3 mg,0.082 mmol), glycosyl acceptor III-09 (25.0 mg,0.068 mmol), activating reagent I-1 (17.4 mg,0.041 mmol), DTBMP (16.8 mg,0.082 mmol) and molecular sieve were added to a reaction flask, pre-cooled to 0deg.C and then added with Tf ₂ O, reacted for 1h, and then treated to give colorless syrup IV-10(30.5mg,64％).R_f＝0.30(PE:EA＝3:1).¹H NMR(400MHz,CDCl₃)δ7.43(1H,dd,J＝7.6,1.2Hz,Ar-H),7.36(1H,dd,J＝7.6,1.6Hz,Ar-H),7.26(1H,dd,J＝7.2,1.6Hz,Ar-H),7.23-7.18(1H,m,Ar-H),5.35(1H,d,J＝2.8Hz,H-4'),5.11(1H,dd,J＝10.4,8.0Hz,H-2'),5.06-5.00(2H,m,H-1,H-3'),4.87(1H,d,J＝7.6Hz,H-1'),4.83(1H,d,J＝12.0Hz,-CH₂Ar),4.60(1H,d,J＝12.0Hz,-CH₂Ar),4.14-4.04(4H,m),3.86(1H,t,J＝6.4Hz),3.73(1H,dq,J＝12.4,6.4Hz,H-5),3.51(1H,dd,J＝10.0,7.2Hz),3.35(1H,hept,J＝6.8Hz,-CH(CH₃)₂),2.13(3H,s,-COCH₃),2.04(3H,s,-COCH₃),2.01(3H,s,-COCH₃),1.96(3H,s,-COCH₃),1.50(3H,s,-C(CH₃)₂),1.31(3H,s,-C(CH₃)₂),1.29-1.24(m,9H,-CHCH₃,-CH(CH₃)₂).¹³C NMRδ170.6,170.5,170.4,167.0,138.4,135.7,132.6,129.7,128.7,127.0,109.4,100.8,96.4,80.7,78.3,76.3,71.1,70.9,69.3,67.8,67.4,64.5,61.8,38.8,28.2,26.6,23.3,23.3,21.1,20.90,20.85,20.8,17.7.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₃₃H₄₆NaO₁₄S⁺,721.2500;Found,721.2481.

EXAMPLE 33 Synthesis of glycosylation product IV-11

According to the standard procedure, glycosyl donor II-16 (22.5 mg,0.039 mmol), glycosyl acceptor III-10 (15 mg,0.032 mmol), activating reagent I-1 (8.2 mg,0.019 mmol) and molecular sieve were added to a reaction flask, pre-cooled to-40℃and then added with Tf ₂ O, reacted for 3 hours to give a colorless syrup-like compound IV-11(18.5mg,62％).R_f＝0.11(PE-Acetone＝3:1).¹H NMR(400MHz,CDCl₃)δ7.35-7.25(15H,m,Ar-H),5.52(1H,dd,J＝8.8,1.6Hz),5.42-5.37(1H,m),4.90(1H,d,J＝10.8Hz),4.80-4.72(4H,m),4.64(1H,d,J＝12.0Hz),4.63(1H,dd,J＝9.2,2.0Hz),4.59(1H,d,J＝3.6Hz,H-1),4.42-4.15(2H,m),3.98-3.91(2H,m),3.84(1H,d,J＝12.4,6.4Hz),3.77-3.73(1H,m),3.68(3H,s),3.61(1H,dd,J＝11.2,9.2Hz),3.53(1H,dd,J＝10.0,8.8Hz),3.50(1H,dd,J＝10.0,3.6Hz),3.45(1H,dd,J＝10.8,2.0Hz),3.35(3H,s),2.89(1H,dd,J＝12.0,3.6Hz),2.09(3H,s),2.07(1H,dd,J＝13.6,12.0Hz),1.99(3H,s),1.74(3H,s).

EXAMPLE 34 Synthesis of glycosylation product IV-12

According to the standard procedure, glycosyl donor II-04 (41.4 mg,0.096 mmol), glycosyl acceptor III-11 (15.0 mg,0.04 mmol), activating reagent I-1 (10.2 mg,0.024 mmol), DTBMP (19.7 mg,0.096 mmol) and molecular sieve are added to a reaction flask, after pre-cooling to 0deg.C, tf ₂ O is added, the reaction is carried out for 1h up to 30deg.C until the reaction is complete, and a colorless syrup is obtained by treatment IV-12(33.4mg,75％).R_f＝0.30(PE:EA＝3:1).¹H NMR(400MHz,CDCl₃)δ7.36-7.25(26H,m,Ar-H),7.24-7.19(4H,m,Ar-H),5.26(1H,dd,J＝3.2,1.6Hz),5.12(1H,dd,J＝3.2,1.6Hz),5.01(1H,d,J＝10.8Hz,Bn-H),4.89(1H,d,J＝4.4Hz,H-1),4.88-4.85(2H,m),4.76(1H,d,J＝1.2Hz),4.70(1H,d,J＝5.6Hz),4.69-4.61(3H,m,Bn-H),4.61-4.54(3H,m,Bn-H),4.54-4.48(3H,m,Bn-H),3.96-3.83(3H,m),3.83-3.72(3H,m),3.66-3.62(2H,m),3.60-3.55(1H,m),3.48(1H,dd,J＝9.2,3.6Hz),3.39(2H,td,J＝9.6,3.2Hz,H-5),3.31(3H,s,-OMe),2.11(3H,s,-COCH₃),2.10(3H,s,-COCH₃),1.29(3H,d,J＝6.4Hz,-CHCH₃),0.92(3H,d,J＝6.4Hz,-CHCH₃).¹³C NMR(100MHz,CDCl₃)δ171.1,170.2,138.9,138.8,138.6,138.23,138.16,138.1,128.7,128.6,128.6,128.6,128.5,128.4,128.4,128.4,128.4,128.1,128.0,127.9,127.7,127.5,97.8,97.7,97.6,80.8,80.4,80.3,79.8,77.7,75.8,75.7,75.5,75.5,73.5,72.0,71.7,69.8,69.7,68.9,68.5,67.8,65.7,55.4,21.3,21.2,18.1,17.8.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₆₅H₇₄NaO₁₆ ⁺,1133.4869;Found,1133.4875.

EXAMPLE 35 Synthesis of glycosylation product IV-13

According to the standard procedure, glycosyl donor II-15 (42.0 mg,0.06 mmol), glycosyl acceptor III-12 (20.8 mg,0.05 mmol), activating reagent I-1 (12.8 mg,0.03 mmol) and molecular sieve are added into a reaction flask, after pre-cooling to 0℃Tf ₂ O is added, and after 1h of reaction, a white solid is obtained by treatment IV-13(29.9mg,60％).R_f＝0.45(PE:EA＝3:1).¹H NMR(400MHz,CDCl₃)δ8.01-7.96(2H,m,Ar-H),7.93-7.87(4H,m,Ar-H),7.84-7.73(4H,m,Ar-H),7.54-7.21(23H,m,Ar-H),5.87(1H,t,J＝10.0Hz,H-4),5.63(1H,t,J＝9.6Hz,H-3),5.59(1H,d,J＝8.0Hz,H-1),5.46(1H,dd,J＝9.6,8.0Hz,H-2),5.15(1H,d,J＝12.4Hz,Bn-H),5.10(1H,d,J＝12.4Hz,Bn-H),4.74(1H,d,J＝7.8Hz,-NH),4.60(1H,dd,J＝12.0,3.2Hz,H-6a),4.52-4.48(1H,m,H-5),4.41(1H,dd,J＝12.0,5.2Hz,H-6b),4.37-4.28(2H,m),4.19(1H,dd,J＝10.4,7.2Hz),4.11-4.02(2H,m),3.89(1H,dd,J＝10.4,3.2Hz).¹³C NMR(100MHz,CDCl₃)δ169.5,166.3,166.0,165.4165.3,156.1,144.0,143.9,141.5,141.5,135.4,133.7,133.5,133.5,133.4,130.0,130.0,130.0,129.7,129.3,129.0,128.9,128.8,128.6,128.6,128.5,128.4,127.9,127.9,127.3,125.4,125.3,120.2,120.2,101.6,72.8,72.5,72.0,69.7,67.7,67.2,63.2,54.6,47.3.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₅₉H₄₉NNaO₁₄ ⁺,1018.3045;Found,1018.3022.

EXAMPLE 36 Synthesis of glycosylation product IV-14

According to the standard procedure, glycosyl donor II-01 (34.4 mg,0.058 mmol), glycosyl acceptor III-13 (20.0 mg,0.048 mmol), activating reagent I-1 (6.1 mg,0.014 mmol), and molecular sieves were added to a reaction flask, pre-chilled to 0℃and then Tf ₂ O was added, after 1h of reaction, treated to give IV-14 as a white solid (39.6 mg, 85%). R _f = 0.27 (PE: EA = 3:1) melting point ：113.0-114.0℃.¹H NMR(400MHz,CDCl₃)δ7.74(2H,d,J＝7.6Hz,Ar-H),7.62(2H,t,J＝8.0Hz,Ar-H),7.38(2H,t,J＝7.2Hz,Ar-H),7.34–7.25(15H,m,Ar-H),7.20–7.13(2H,m,Ar-H),5.74(1H,d,J＝9.2Hz,-NH),4.92(1H,t,J＝8.4Hz,H-2),4.78(1H,d,J＝11.6Hz,-CH₂Ph),4.77(1H,d,J＝10.4Hz,-CH₂Ph),4.66(1H,d,J＝11.2Hz,-CH₂Ph),4.55(2H,d,J＝12.0Hz,-CH₂Ph),4.49(1H,d,J＝12.0Hz,-CH₂Ph),4.41–4.29(5H,m),4.22(1H,t,J＝7.2Hz),3.76–3.58(7H,m),3.40(1H,dt,J＝4.2,2.4Hz),1.94(3H,s,-COCH₃),1.18(3H,d,J＝6.4Hz,-CHCH₃).

EXAMPLE 37 Synthesis of glycosylation product IV-15

According to the standard procedure, glycosyl donor II-01 (50.1 mg,0.084 mmol), glycosyl acceptor III-14 (20 mg,0.07 mmol), activating reagent I-1 (9.0 mg,0.021 mmol), DTBMP (17.2 mg,0.084 mmol) and molecular sieve are added into a reaction flask, after pre-cooling to 0℃Tf ₂ O is added, after 1h of reaction, the temperature is raised to 30℃until the reaction is complete, and colorless syrup is obtained by treatment IV-15(40.0mg,75％).R_f＝0.40(PE:EA＝12:1).¹H NMR(400MHz,CDCl₃)δ7.33-7.25(13H,m,Ar-H),7.19(2H,dd,J＝7.6,2.0Hz,Ar-H),4.94(1H,t,J＝8.8Hz,H-2),4.77(2H,d,J＝11.2Hz,Bn-H),4.64(1H,d,J＝12.0Hz,Bn-H),4.61(1H,d,J＝12.4Hz,Bn-H),4.57(1H,d,J＝9.6Hz,Bn-H),4.54(1H,d,J＝12.4Hz,Bn-H),4.34(1H,d,J＝8.0Hz,H-1),3.72-3.60(7H,m),3.51-3.47(1H,m),3.47-3.41(1H,m,H-5),2.28(2H,t,J＝7.6Hz,-COCH₂-),1.92(3H,s,-COCH₃),1.65-1.52(3H,m),1.50-1.12(24H,m).¹³C NMR(100MHz,CDCl₃)δ174.5,169.6,138.5,138.5,138.2,128.6,128.6,128.6,128.3,128.1,127.9,127.8,127.7,101.0,83.4,81.0,78.4,75.4,75.2,75.2,73.8,73.7,69.3,51.7,35.0,34.4,34.3,32.2,30.1,29.8,29.7,29.5,29.3,25.2,25.2,22.9,21.2,14.3.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₄₆H₆₄NaO₉ ⁺,783.4443;Found,783.4499.

EXAMPLE 38 Synthesis of glycosylation product IV-16

According to the standard procedure, glycosyl donor II-01 (22.9 mg,0.038 mmol), glycosyl acceptor III-15 (20.0 mg,0.032 mmol), activating reagent I-1 (4.1 mg,0.01 mmol), DTBMP (7.9 mg,0.038 mmol) and molecular sieve were added to a reaction flask, pre-cooled to 0deg.C and then added with Tf ₂ O, and after 1h of reaction, a colorless syrup was obtained by treatment IV-16(28.0mg,80％).R_f＝0.60(PE:EA＝3:1).[α]_D ²⁵+14.5(c,1.0in CHCl₃).¹H NMR(400MHz,CDCl3)d 7.36-7.10(18H,m,Ar-H),6.55(1H,d,J＝2.0Hz,Ar-H),6.50(1H,d,J＝2.0Hz,Ar-H),4.92(1H,dd,J＝9.2,8.0Hz,H-2),4.82(1H,d,J＝8.8Hz,H-1),4.75(1H,d,J＝10.8Hz,Bn-H),4.74(1H,d,J＝11.6Hz,-CH2Ph),4.62(1H,d,J＝12.0Hz,Bn-H),4.61(1H,d,J＝11.2Hz,Bn-H),4.53(1H,d,J＝12.4Hz,Bn-H),4.52(1H,d,J＝10.4Hz),4.12-4.04(2H,m),3.74-3.66(3H,m),3.55(1H,t,J＝9.2Hz,H-4),3.42(1H,dt,J＝9.6,2.8Hz,H-5),3.08(1H,dd,J＝16.8,6.0Hz),2.78(1H,dd,J＝16.8,9.2Hz),1.84(3H,s,-COCH₃),1.37(9H,s,-OPiv),1.37(9H,s,-OPiv),1.34(18H,s,-OPiv).¹³C NMR(100MHz,CDCl₃)δ176.9,176.3,175.8,169.8,155.0,150.3,149.8,143.0,142.9,138.4,138.2,138.2,136.7,128.61,128.58,128.1,128.0,127.9,127.8,126.0,123.4,122.3,111.7,108.8,107.5,100.7,83.1,79.2,77.9,75.2,75.1,75.0,74.2,73.6,73.0,69.0,39.5,39.4,39.3,39.3,29.6,28.4,27.5,27.5,27.4,27.3,23.0,21.0.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₆₄H₇₆NaO₁₆ ⁺,1123.5026;Found,1123.5064.

EXAMPLE 39 Synthesis of glycosylation product IV-17

According to the standard procedure, glycosyl donor II-02 (45.9 mg,0.077 mmol), glycosyl acceptor III-16 (10.0 mg,0.064 mmol), activating reagent I-1 (8.2 mg,0.019 mmol) and molecular sieve are added into a reaction flask, after pre-cooling to 0℃Tf ₂ O is added, and after 1h of reaction a colorless syrup is obtained IV-17(36.7mg,91％).R_f＝0.31(PE:EA＝10:1).¹H NMR(400MHz,CDCl₃)δ7.40-7.24(15H,m,Ar-H),5.25(1H,dd,J＝10.0,8.0Hz,H-2),4.92(1H,d,J＝12.0Hz,Bn-H),4.64(1H,d,J＝12.4Hz,Bn-H),4.59(1H,d,J＝11.6Hz,Bn-H),4.49(1H,d,J＝12.0Hz,Bn-H),4.44(1H,d,J＝11.6Hz,Bn-H),4.39(1H,d,J＝12.0Hz,Bn-H),4.33(1H,d,J＝8.0Hz,H-1),3.91(1H,d,J＝2.4Hz,H-4),3.64-3.46(4H,m),3.30(1H,td,J＝10.8,4.4Hz,-OCH-),2.36-2.27(1H,m),2.01(3H,s,-COCH₃),1.94-1.86(1H,m),1.62-1.55(2H,m),1.33-1.24(1H,m),1.22-1.11(1H,m),0.95-0.86(4H,m),0.85-0.75(5H,m),0.70(3H,d,J＝7.2Hz,-CH₃).

EXAMPLE 40 Synthesis of glycosylation product IV-18

According to the standard procedure, glycosyl donor II-03 (47.2 mg,0.079 mmol), glycosyl acceptor III-17 (10.0 mg,0.067 mmol), activating reagent I-1 (8.6 mg, 0.020mmol) and molecular sieve are added into a reaction flask, pre-cooled to 0 ℃ and then added with Tf ₂ O, reacted for 1h and then treated to obtain a yellow syrup-like compound IV-18(33.3mg,80％).R_f＝0.64(PE:EA＝5:1).¹H NMR(400MHz,CDCl₃)δ7.35-7.19(13H,m,Ar-H),7.15-7.11(2H,m,Ar-H),5.24(1H,d,J＝1.6Hz,H-1),5.15(1H,dd,J＝3.2,2.4Hz,H-2),4.83(1H,d,J＝10.4Hz,Bn-H),4.68(2H,d,J＝11.6Hz,Bn-H),4.52(1H,d,J＝11.2Hz,Bn-H),4.45(1H,d,J＝12.0Hz,Bn-H),4.43(1H,d,J＝10.8Hz,Bn-H),4.03(1H,dd,J＝9.2,3.2Hz,H-3),4.00–3.96(1H,m,H-5),3.88(1H,t,J＝9.6Hz,H-4),3.80(1H,dd,J＝10.8,4.0Hz,H-6a),3.65(1H,dd,J＝10.8,1.6Hz,H-6b),2.12(s,3H),2.09(3H,brs),1.80-1.70(6H,m),1.62-1.50(6H,m).¹³C NMR(100MHz,CDCl₃)δ171.0,138.6,138.5,138.3,128.6,128.5,128.4,128.3,128.2,127.9,127.9,127.8,127.7,91.2,78.4,75.4,75.2,74.8,73.6,71.9,71.1,70.6,69.2,42.5,36.4,30.8,21.5.

EXAMPLE 41 Synthesis of glycosylation product IV-19

According to the standard procedure, glycosyl donor II-17 (25.3 mg,0.044 mmol), glycosyl acceptor III-18 (7 mg,0.037 mmol), activating reagent I-1 (4.7 mg, 0.0111 mmol) and molecular sieve are added into a reaction bottle, pre-cooled to 0 ℃ and then Tf ₂ O is added, after 1h of reaction, the temperature is raised to 30 ℃ until the reaction is complete, and the colorless syrup compound is obtained after treatment IV-19(19.7mg,84％).¹H NMR(400MHz,CDCl₃)δ8.26(1H,s,H-8),8.05-8.80(4H,m,Ar-H),7.92-7.90(2H,m,Ar-H),7.61-7.52(3H,m,Ar-H),7.46-7.34(6H,m,Ar-H),6.46(1H,d,J＝5.2Hz,H-1'),6.16(1H,t,J＝5.6Hz),6.11(1H,dd,J＝5.6,4.0Hz),4.90(1H,dd,J＝12.0,3.2Hz),4.85(1H,dd,J＝7.6,4.0Hz),4.71(1H,dd,J＝12.0,4.0Hz).

EXAMPLE 42 Synthesis of glycosylation product V-1

Glycosyl donor II-01 (35.9 mg,0.060 mmol), activating reagent I-1 (12.8 mg,0.030 mmol) were placed in a round bottom flask with water azeotropically twice followed by addition of the activating reagentMolecular sieves. Anhydrous dichloromethane (0.5 mL) was added under argon, cooled to-40℃and stirred for 10 min, and Tf ₂ O (10.7. Mu.L, 0.065 mmol) was added. Reaction was carried out at-40℃for 5 min, followed by dropwise addition of a solution of thioglycoside receptor III-19 (29.2 mg,0.05 mmol) and DTBMP (15.4 mg,0.075 mmol) in dichloromethane (0.5 mL) for 15 min. A solution of receptor III-02 (27.9 mg,0.060 mmol) in methylene chloride (0.5 mL) was added to the flask and the temperature was raised to 30℃for 24 hours. Finally, triethylamine (0.1 ml) is used for stopping the reaction, and the white bubble-shaped target trisaccharide is obtained through suction filtration, concentration and column chromatography purification V-1(50.6mg,73％).R_f＝0.35(PE:acetone＝3:1).¹H NMR(400MHz,CDCl₃)δ7.86-7.81(2H,m,Ar-H),7.54(1H,t,J＝7.2Hz,Ar-H),7.38(2H,t,J＝7.6Hz,Ar-H),7.35-7.13(35H,m,Ar-H),7.08-6.89(5H,m,Ar-H),5.14(1H,t,J＝8.4Hz,H-2"),5.06(1H,d,J＝11.6Hz,-CH₂Ph),4.99(1H,t,J＝9.2Hz,H-2'),4.91(1H,d,J＝12.0Hz,-CH₂Ph),4.80-4.68(4H,m),4.63-4.51(5H,m),4.49(1H,d,J＝3.6Hz,H-1),4.48-4.40(3H,m),4.35(2H,s,-CH₂Ph),4.28(1H,d,J＝12.0Hz,-CH₂Ph),4.18(1H,d,J＝12.0Hz,-CH₂Ph),4.01(1H,t,J＝9.2Hz),3.86-3.75(2H,m),3.75-3.63(2H,m),3.60-3.51(3H,m),3.51-3.36(5H,m),3.33(1H,d,J＝10.8Hz),3.30-3.21(4H,m),3.10(1H,d,J＝9.6Hz),1.89(3H,s,-OAc).¹³C NMR(100MHz,CDCl₃)δ169.5,165.0,139.9,138.9,138.5,138.5,138.4,138.4,138.2,138.0,133.2,130.1,130.0,128.8,128.6,128.6,128.5,128.5,128.5,128.4,128.3,128.2,128.1,128.1,128.0,127.9,127.9,127.8,127.7,127.6,127.5,127.2,127.1,100.7,100.4,98.5,83.1,80.5,80.4,79.0,78.2,75.5,75.3,75.3,75.1,74.6,73.9,73.7,73.7,73.5,73.5,69.7,68.8,67.9,67.8,55.4,21.1.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₈₄H₈₈NaO₁₈ ⁺:1407.5863,Found:1407.5899.

EXAMPLE 43 Synthesis of glycosylation product V-2

Reference method for synthesizing Compound V-1 starting from glycosyl donor II-01 (35.9 mg,0.060 mmol), thioglycoside acceptor III-20 (24.4 mg,0.050 mmol) and acceptor III-02 (27.9 mg,0.060 mmol) to give white foam V-2(48.0mg,71％).R_f＝0.37(PE:EA＝3:1).[α]_D ²⁵+6.5(c,1.0in CHCl₃).¹H NMR(400MHz,CDCl₃)δ7.88(2H,d,J＝8.0Hz,Ar-H),7.78(2H,d,J＝8.0Hz,Ar-H),7.54-7.44(6H,m,Ar-H),7.44-7.32(8H,m,Ar-H),7.32-7.20(15H,m,Ar-H),7.19-7.10(7H,m,Ar-H),5.42(1H,t,J＝9.6Hz,H-3'),5.33(1H,dd,J＝9.2,8.4Hz,H-2'),5.07(1H,t,J＝9.6Hz,H-4'),5.01-4.95(2H,m,H-2",-CH₂Ph),4.76-4.66(6H,m,H-1',H-1"),4.62-4.55(4H,m,H-1),4.53(1H,d,J＝10.0Hz,-CH₂Ph),4.50(1H,d,J＝11.2Hz),4.44(1H,d,J＝12.0Hz,-CH₂Ph),4.33(1H,d,J＝12.0Hz,-CH₂Ph),3.97(1H,t,J＝9.6Hz),3.83-3.74(2H,m),3.71(1H,d,J＝9.2Hz),3.67-3.54(4H,m),3.53-3.44(3H,m,H-2),3.41(1H,d,J＝10.8Hz),3.36(1H,d,J＝10.8Hz),3.24(3H,s,-OCH₃),2.82-2.76(1H,m,H-5),2.04(3H,s,-COCH₃),1.94(3H,s,-COCH₃).¹³C NMR(100MHz,CDCl₃)δ170.1,170.0,165.8,164.9,139.5,138.5,138.4,138.3,137.6,133.5,133.5,130.0,129.9,129.2,129.2,129.1,128.9,128.7,128.6,128.6,128.6,128.5,128.5,128.4,128.0,127.9,127.9,127.9,127.8,127.8,127.7,127.6,100.7,99.9,98.6,83.2,80.8,80.1,76.4,74.7,74.5,74.4,73.94,73.9,73.7,73.5,73.2,72.3,69.8,69.7,68.4,67.6,67.4,55.5,21.3,20.8.HRMS(ESI-TOF)m/z:[M+Na]⁺calcd for C₇₉H₈₂NaO₂₀ ⁺:1373.5292,Found:1373.5269.

The above examples are only examples, and the symmetrical disulfide compound containing sulfoxide group obtained by the present invention may be other compounds satisfying the structural general formula (I) in addition to the compounds represented by the structural formulae I-1 to I-6, and for example, the symmetrical disulfide compound containing sulfoxide group represented by the structural general formula (I) may be used as an activating agent in glycosylation reaction at a reaction temperature of-40 to 30 ℃, for example, -40 to-20, 0, 30, or any interval range composed of these temperature values.

It will be readily appreciated by those skilled in the art that the foregoing description is merely a preferred embodiment of the invention and is not intended to limit the invention, but any modifications, equivalents, improvements or alternatives falling within the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims

1.A symmetrical disulfide compound containing sulfoxide groups is characterized in that the structural general formula of the symmetrical disulfide compound is shown as a formula (I):

Wherein O is an oxygen atom, S is a sulfur atom, R is selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and Ar is a substituted or unsubstituted aromatic ring.

2. The symmetrical disulfide compound comprising sulfoxide groups as claimed in claim 1, wherein R is selected from substituted or unsubstituted C _1～20 alkyl, substituted or unsubstituted C _6～10 aryl, wherein the substituents are one or more, independently selected from C _1～20 alkyl, unsubstituted or halogen substituted C _1～20 alkoxy;

3. The symmetrical disulfide compound containing sulfoxide groups according to claim 1, wherein R is selected from substituted or unsubstituted C _1～6 alkyl, substituted or unsubstituted phenyl, wherein the substituent is one or more, independently selected from C _1～6 alkyl, C _1～20 alkoxy which is unsubstituted or substituted by 1-20 halogens, wherein the halogens are selected from fluorine, chlorine, bromine and iodine;

4. The symmetrical disulfide compound of claim 1 wherein R is selected from the group consisting of a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, and a substituted or unsubstituted isopropyl group, wherein one or more substituents are independently selected from the group consisting of methyl group, ethyl group, and octyloxy group substituted with 1 to 20 halogens, and preferably 1 to 20 halogens

5. The symmetrical disulfide compound comprising a sulfoxide group according to claim 1, wherein the symmetrical disulfide compound comprising a sulfoxide group has a structure represented by any one of the following structural formulas I-1 to I-6:

6. use of a symmetrical disulfide compound containing sulfoxide groups according to any one of claims 1-5 as an activating reagent in glycosylation reactions;

7. A method for preparing a glycosylation product, characterized in that the method uses the symmetrical disulfide compound containing sulfoxide groups as an activating reagent, and in the presence of trifluoromethanesulfonic anhydride, a glycosyl donor shown in a structural general formula (II) is activated and reacts with an acceptor shown in a formula (III) to obtain the glycosylation product shown in a formula (IV);

The reaction equation is as follows:

8. A process for the preparation of a glycosylation product, characterized in that the process comprises using a symmetrical disulfide compound comprising a sulfoxide group as defined in any one of claims 1-5 as an activating agent, in the presence of trifluoromethanesulfonic anhydride to activate the glycosyl donor and react with the acceptor, and the resulting glycosylation product can be further activated to initiate continuous glycosylation;

The structural general formula of the glycosyl donor is specifically as follows

The structural general formula of the receptor is specifically as follows

9. The method of claim 7 or 8, wherein said Gly, gly' structural formula is independently selected from the group consisting of structural formula (II-a) and structural formula (II-b):

10. the method according to claim 7 or 8, wherein the molar ratio of the activating reagent to the trifluoromethanesulfonic anhydride is 1 (1-2), preferably 1:2;

The reaction temperature of the glycosylation reaction is-40 ℃ to 30 ℃;