WO2021013155A1 - 一种新的糖基供体及其制备方法和用途 - Google Patents

一种新的糖基供体及其制备方法和用途 Download PDF

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WO2021013155A1
WO2021013155A1 PCT/CN2020/103340 CN2020103340W WO2021013155A1 WO 2021013155 A1 WO2021013155 A1 WO 2021013155A1 CN 2020103340 W CN2020103340 W CN 2020103340W WO 2021013155 A1 WO2021013155 A1 WO 2021013155A1
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compound
reaction
alkyl
ring
glycosyl
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French (fr)
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钮大文
张霞
万立强
张晨
谢德盟
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四川大学
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Priority to US17/428,562 priority Critical patent/US20220127239A1/en
Priority to CN202080048873.3A priority patent/CN114375295B/zh
Publication of WO2021013155A1 publication Critical patent/WO2021013155A1/zh

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Definitions

  • the invention relates to the technical fields of synthetic chemistry and medicinal chemistry, in particular to a new glycosyl donor and its preparation method and application.
  • Carbohydrates are an important part of organisms (including animals, plants, and microorganisms). Polysaccharides, oligosaccharides and their sugar complexes combined with proteins, esters, etc. involve cells, especially all the time and space processes of multicellular life. They are used as information molecules to participate in various recognition processes of cells: transmitting biological information, Participate in the body's immune regulation, and is closely related to cell differentiation, fertilization, embryonic development, blood system, infection, aging and many other functions. In recent years, due to the remarkable physiological activity of carbohydrate compounds, more and more chemists have attracted extensive research interest. Glycosides (Glycosides) is an important form of sugar that exists in nature.
  • Glycosides are a very important class of compounds formed by the condensation of the hemiacetal hydroxyl groups of sugars and ligands to lose a molecule of water or other small molecular compounds.
  • the sugar moiety is called glycosyl and the non-sugar moiety is called aglucone.
  • Glycoside compounds can be divided into oxoside compounds, azetoside compounds, glucosinolate compounds and carbon glycoside compounds according to the type of atoms in the molecular structure of glycoside compounds that are connected to the carbon atoms of the sugar ring. Most of them exhibit good biological functions. , Such as glycosidase inhibitory activity, antibacterial, antiviral and antitumor activity.
  • glycoside compounds There are many methods for constructing glycoside compounds, but these methods are not mild enough and have poor functional group compatibility. At the same time, most of the existing methods are difficult to prepare glycoside compounds in ⁇ configuration with high stereoselectivity.
  • glycoside compounds such as oxoside compounds, azepine compounds, glucosinolate compounds and carbon glycoside compounds.
  • the present invention provides an allyl sulfone glycosyl donor with a novel structure, and using the allyl sulfone glycosyl donor as a raw material to prepare glucosinolate compounds, oxygen glycoside compounds and carbon glycosides Compound.
  • the present invention provides a glycosyl donor, or its salt, or its stereoisomer, or its optical isomer, and the structure of the glycosyl donor is as shown in formula I:
  • the A ring is selected from R 1 , R 2 , R 3 , and R 4 are each independently selected from H, C 1-6 alkyl, aryl or heteroaryl substituted C 1-12 alkyl, C 1-6 alkoxy, C 2 -8alkynyl , C 2-8alkenyl , aryl, heteroaryl, cycloalkyl, M 1 OH, M 1 NH 2 , M 1 NHAc, M 1 OAc, M 1 OBz, M 1 OBn, M 1 N 3 , M 1 OTMS, M 1 OTBS, Or any two of R 1 , R 2 , R 3 , and R 4 are connected to form a ring; M 1 is selected from 0-3 methylene groups; M 2 , M 3 , and M 4 are selected from H, C 1-6 alkane C 1-12 alkyl, C 2-8 alkynyl, C 2-8 alkenyl, aryl, heteroaryl, or M 3 , M 4 substitute
  • R 5 is selected from C 1-10 alkyl, saturated cycloalkyl, saturated heterocyclic, H, aryl, heteroaryl, C 1-10 alkoxy, halogen, cyano, carboxy, ester;
  • R 6 , R 7 , R 8 , and R 9 are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, M 1 OH, C 2-8 alkynyl, C 2-8 Alkenyl, saturated cycloalkyl, saturated heterocyclic, H, aryl, heteroaryl, cyano, ester group; M 1 is selected from 0-3 methylene groups.
  • glycosyl donor is shown in formula II-1 or II-2:
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, aromatic Group, heteroaryl, cycloalkyl, M 1 OH, M 1 NH 2 , M 1 NHAc, M 1 OAc, M 1 OBz, M 1 OBn, M 1 N 3 , M 1 OTMS, M 1 OTBS, Or any two of R 1 , R 2 , R 3 , and R 4 are connected to form a substituted or unsubstituted ring, and the substituents on the ring are each independently selected from one or more hydrogen, deuterium, and C 1-8 Alkyl, C 1-8 alkoxy, C 2-8 alkynyl, C 2-8 alkenyl, aryl, heteroaryl, halogen, cyano, carboxyl or ester group;
  • M 1 is selected from 0-3 methylene groups
  • R 5 is selected from C 1-8 alkyl, saturated cycloalkyl, saturated heterocyclic group, H, aryl, heteroaryl, C 1-8 alkoxy, halogen, cyano, carboxyl, ester group;
  • the R 1 , R 2 , R 3 , and R 4 are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 2-3 alkynyl, C 2-3 alkene Group, aryl, heteroaryl, cycloalkyl, M 1 OH, M 1 NHAc, M 1 OAc, M 1 OBz, Or any two of R 1 , R 2 , R 3 , and R 4 are connected to form a ring, and the substituents on the ring are each independently selected from one or more hydrogen, deuterium, C 1-4 alkyl, C 1 ⁇ 4 alkoxy, C 2-3 alkynyl, C 2-3 alkenyl, phenyl, heteroaryl, halogen, cyano, carboxy or ester group; M 1 is selected from 0-1 methylene groups;
  • R 5 is selected from H, phenyl, and C 1-8 alkyl.
  • glycosyl donor is selected from:
  • glycosyl donor is selected from:
  • the present invention also provides a glucosinolate compound, or a salt thereof, or a stereoisomer, or an optical isomer thereof, the structure of the glucosinolate compound is as shown in formula III:
  • R 10 is selected from Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, The group remaining after one hydrogen atom is removed from the peptide chain, and the substituent is selected from halogen and halogenated alkyl; the above m represents an integer of 1-5;
  • Y is selected from none, NH or O;
  • R 1a and R 2a are selected from each independently selected from H, Boc, Bz, C 1-6 alkyl, C 1-6 alkoxy, aryl, heteroaryl, The remaining groups after removing a hydrogen atom from the peptide chain, Wherein m 1 and m 2 are each independently selected from an integer of 0-5;
  • R a1 is selected from substituted or unsubstituted C 1-6 alkyl, and the substituent is selected from halogen and hydroxyl;
  • R a3 is selected from substituted or unsubstituted Substituted C 1-6 alkyl, aryl, heteroaryl, and the substituent is selected from halogen and hydroxy;
  • a ring is selected from
  • R 1 , R 2 , R 3 , and R 4 are as described above.
  • glucosinolate compound is as shown in formula III-1, III-2, III-3 or III-4:
  • R 10 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted aza aromatic ring, methyl, The substituent is selected from halogen and halogenated alkyl;
  • R 1 , R 2 , R 3 , and R 4 are as described above.
  • glucosinolate compound selected from:
  • glucosinolate compound selected from:
  • the present invention also provides an oxoglycoside compound, or a salt thereof, or a stereoisomer or an optical isomer thereof, and the structure of the oxoside compound is shown in formula IV:
  • R 11 is selected from L 0 R 12 or COL 0 R 12
  • L 0 is selected from 0 to 3 alkylene groups
  • R 12 is selected from substituted or unsubstituted C 1-6 alkyl groups, substituted or unsubstituted rings
  • the substituent is one or more, and the substituents are each independently selected from CN, C 1-6 alkoxy, C 1-6 alkoxy, L 1 (COOEt)NHBz, OH, NH 2 , NHAc, OAc, OBz, OBn
  • L 1 is selected from 0 to 3 alkylene groups
  • a ring is selected from R 1 , R 2 , R 3 , and R 4 are as described above.
  • R 1 , R 2 , R 3 , R 4 are as described above;
  • L 0 is selected from 0-2 alkylene groups, and
  • R 12 is selected from substituted or unsubstituted C 1-3 alkyl groups, substituted or unsubstituted Saturated monocyclic carbocyclic ring, saturated monocyclic heterocyclic ring, bridged ring, spiro ring, condensed ring;
  • the substituents, R 13 are each independently selected from CN, C 1-3 alkoxy, C 1-3 alkoxy , L 1 (COOEt)NHBz, OH, NH 2 , NHAc, OAc, OBz, OBn,
  • L 1 is selected from 0 to 1 alkylene.
  • the structure of the oxoglycoside compound is selected from:
  • the present invention also provides a carbon glycoside compound, or a salt thereof, or a stereoisomer or an optical isomer thereof, the structure of the carbon glycoside compound is shown in formula V:
  • a ring is selected from R 1 , R 2 , R 3 , and R 4 are as described above;
  • Ring B is a saturated or unsaturated ring, preferably a benzene ring;
  • R 14 is selected from H, CN, halogenated or non-halogenated C 1-3 alkyl, halogenated or non-halogenated C 1-3 alkoxy, COOR 15 ; R 15 is selected from C 1-3 alkyl .
  • R 1 , R 2 , R 3 , R 4 , and R 14 are as described above.
  • the structure of the carbon glycoside compound is selected from:
  • the present invention also provides the use of the aforementioned glycosyl donor in the preparation of glucosinolate compounds, oxoglycoside compounds, and carbon glucoside compounds; preferably, the glucosinolate compound is as described above, and/or the oxoside compound is as described above The, and/or, the carbon glycoside compound is as described above.
  • the present invention also provides a method for preparing the aforementioned glycosyl donor, the method comprising the following steps:
  • the structure of raw material Y1 is The structure of compound Y2 is The structure of compound Y3 is The structure of compound Y4 is
  • X is selected from halogen, preferably bromine
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are as described above.
  • step (1) the molar ratio of the acetic anhydride to the hydroxyl group on the raw material Y1 is (0.8-1.5):1; the reaction is carried out under the action of triethylamine and DMAP; the reaction temperature is room temperature; The solvent is dichloromethane;
  • step (2) the molar ratio of compound Y2, thiourea, and compound Y3 is 1: (1.5 ⁇ 4.5): (1.2 ⁇ 2); the reaction temperature before adding compound Y3 is heating under reflux, and the reaction time is (2 ⁇ 6 ) Hours; the reaction before adding Y3 is carried out under the action of boron trifluoride ether; the reaction temperature after adding Y3 is heating to reflux, and the reaction time is (4-8) hours; the reaction after adding Y3 is in triethyl Under the action of amine; reaction solvent is acetonitrile;
  • step (3) the molar ratio of compound Y4 to mCPBA is 1: (1.5-4.5); the reaction time is 1 to 3 hours; the reaction solvent is dichloromethane;
  • step (1) the molar ratio of the acetic anhydride to the hydroxyl groups on the raw material Y1 is 1.2:1;
  • step (2) the molar ratio of compound Y2, thiourea, and compound Y3 is 1:3:1.5; the reaction time before adding compound Y3 is 4 hours; the reaction time after adding Y3 is 6 hours;
  • step (3) the molar ratio of compound Y4 to mCPBA is 1:2.5; the reaction temperature is room temperature, and the reaction time is 2 hours.
  • the present invention also provides a method for preparing the above-mentioned glucosinolate compound, the method is: reacting the above-mentioned glycosyl donor with the glycosyl acceptor to obtain the glucosinolate compound;
  • R 5s is selected from
  • R 10 is as described above.
  • R 5s is selected from R 10 is as described above;
  • the molar ratio of the glycosyl donor to the glycosyl acceptor is 1: (1.1 to 2.5), preferably 1: (1.2 to 2);
  • the reaction is carried out in a nitrogen atmosphere under the irradiation of a blue LED
  • the reaction temperature is 20 to 45°C, preferably room temperature to 45°C; the reaction time is 1.5 to 5 hours, preferably 2 to 4 hours;
  • the reaction is carried out under the action of a photosensitizer, which is selected from Ir[dF(CF 3 )(ppy) 2 ](dtbbpy)PF 6 , preferably Ir[dF(CF 3 )(ppy) 2 ](dtbbpy)PF 6 , more preferably Ir[dF(CF 3 )(ppy) 2 ](dtbbpy)PF 6 ;
  • the solvent of the reaction is selected from water or one or more of 1,2-DCE, DMSO, EtOAc, glyme, 1,4-dioxane, THF, MeOH, DMF, MeCN, MeCN and water in any ratio.
  • the mixed solution is selected from water or one or more of 1,2-DCE, DMSO, EtOAc, glyme, 1,4-dioxane, THF, MeOH, DMF, MeCN, MeCN and water in any ratio.
  • the present invention also provides a method for preparing the above-mentioned oxoside compound.
  • the method is: reacting the above-mentioned glycosyl donor with a glycosyl acceptor to obtain an oxoside compound; wherein the structure of the glycosyl acceptor is HO-R 11 , R 11 is as described above;
  • the molar ratio of the glycosyl donor to the glycosyl acceptor is (1.2-2.0): 1.0, preferably 1.5: 1.0; and/or, the reaction is performed in perfluoroiodobutane, hydrogen phosphate
  • the molar ratio of the glycosyl acceptor to perfluoroiodobutane, diammonium hydrogen phosphate, and triphenyloxazone is 1.0: (3-7): (3-7): (0.1-0.5), preferably 1.0:5.0:5.0:0.3; and/or, the reaction solvent is an organic solvent, preferably methyl tert-butyl ether; and/or, the The reaction is carried out in a nitrogen atmosphere under the irradiation of a blue LED; and/or, the temperature of the reaction is 20-45° C., preferably room temperature, and the reaction time is 12-36 hours, preferably 24 hours.
  • the present invention also provides a method for preparing the above-mentioned carbon glycoside compound.
  • the method comprises: reacting the above-mentioned glycosyl donor with a glycosyl acceptor to obtain a carbon glycoside compound; wherein the glycosyl acceptor is R 16 is selected from C 1-3 alkyl, preferably methyl, As mentioned above
  • the molar ratio of the glycosyl donor to the glycosyl acceptor is 1:(1.5-3.0), preferably 1:2.0; the reaction is carried out under the action of a photosensitizer and an initiator, the The photosensitizer is preferably Eosin Y, the initiator is preferably sodium trifluoromethanesulfinate, and the molar ratio of the sugar-based donor to the photosensitizer and the initiator is 1:(0.01 ⁇ 0.03):(0.1 ⁇ 0.3), preferably 1:0.025:0.2; and/or, the reaction is carried out under the irradiation of a blue LED in a nitrogen atmosphere; and/or, the temperature of the reaction is 20 to 45°C, preferably At room temperature, the reaction time is 5-12 hours, preferably 8 hours.
  • Glycosyl donor refers to a raw material containing glycosidic bonds or a raw material containing an anomeric end group that participates in the reaction when synthesizing glycosides; the other raw material that reacts with it is called the glycosyl acceptor.
  • glycosyl donor of the present invention can be prepared by any one of Routes 1 to 4 in the synthesis example of glycosyl donor, or can be prepared by other methods.
  • the glycosyl donor provided by the present invention has a novel structure, a special allyl sulfone structure, and its preparation method is simple; the present invention further uses the aforementioned glycosyl donor as a raw material and utilizes free radical reactions to prepare Oxygen glycosides, glucosinolates, and carbon glycoside compounds, most of which have a special ⁇ configuration, the preparation method is simple, the reaction conditions are mild, and the yield is high, and has very good application prospects.
  • C ab alkyl represents any alkyl group containing "a" to "b" carbon atoms.
  • C 1-8 alkyl refers to a straight or branched alkyl group containing 1-8 carbon atoms.
  • C 1-8 alkoxy refers to a linear or branched alkoxy group containing 1-8 carbon atoms.
  • Ac represents an acetyl group
  • the structure is Ph stands for phenyl
  • the structure is Bz stands for benzoyl
  • the structure is Boc stands for tert-butoxycarbonyl
  • the structure is Me represents methyl.
  • a peptide chain refers to a chain structure containing multiple peptide bonds formed by connecting multiple amino acids to each other.
  • MCPBA is m-chloroperoxybenzoic acid.
  • an aryl group is an aromatic group;
  • Ar represents an aryl group.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) groups with a conjugated ⁇ -electron system, such as phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated ⁇ -electron system On the carbon atom on the ring.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic group containing one to more heteroatoms.
  • the heteroatoms referred to here include oxygen, sulfur and nitrogen.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or unsaturated cyclic hydrocarbon substituent.
  • the cyclic hydrocarbon may be monocyclic or polycyclic.
  • saturated cycloalkyl refers to saturated cycloalkyl.
  • Heterocyclic group refers to a saturated or unsaturated cyclic hydrocarbon substituent.
  • the cyclic hydrocarbon may be monocyclic or polycyclic, and carry at least one ring heteroatom (including but not limited to O, S, or N).
  • “Saturated heterocyclic group” refers to a saturated heterocyclic group.
  • Salts are acid and/or basic salts formed by compounds with inorganic and/or organic acids and/or bases, including zwitterionic salts (inner salts), and quaternary ammonium salts, such as alkyl ammonium salts. These salts can be directly obtained in the final isolation and purification of the compound. It can also be obtained by appropriately mixing the compound with a certain amount of acid or base (e.g. equivalent). These salts may form a precipitate in the solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by freeze-drying after reaction in an aqueous medium.
  • the salt in the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butane Acid salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
  • the synthetic route of compound 3-13 is the same as that of compound 3-12, and product 3-13 can be obtained by using peracetyl 2-galactosamine as the starting material.
  • the purity is greater than 90%, and the characterization data are as follows:
  • the synthetic route of compound 3-15 is the same as that of 3-14, and product 3-15 can be obtained by using peracetyl maltose as the starting material.
  • the purity is greater than 90%, and the characterization data are as follows:
  • the above routes 1-4 can be used to synthesize substrates 3-1 to 3-16, and each example shows the effectiveness of these four synthetic routes.
  • the allyl sulfone glycosyl donor prepared above is used as a raw material to react with the glycosyl acceptor to synthesize the glucosinolate compound of the present invention.
  • the synthetic route is as follows:
  • Y is selected from NH or O
  • R 1 is selected from methyl
  • R 2 is selected from Bz, H, Boc.
  • Ar represents an aryl group.
  • Alkyl represents an alkyl group.
  • the above synthetic route of the present invention is not limited to using compound 3-1 as a raw material. Using the same method, replacing the raw material compound 3-1 with any of the allyl sulfone glycosyl donors prepared above can obtain the corresponding Glucosinolate compounds.
  • glucosinolate compounds S-1 to S-17 and S-22 of the present invention are prepared.
  • the structure and characteristics are as follows:
  • the glucosinolate compound S18 of the present invention is prepared by the same method as the above route 1, and the route is as follows:
  • glucosinolate compounds S-19 to S-21 of the present invention are prepared.
  • the structure and characteristics are as follows:
  • each glucosinolate compound S-23 of the present invention is prepared.
  • the structure and characteristics are as follows:
  • the specific preparation method is:
  • the allyl sulfone glycosyl donor prepared above is used as a raw material to react with the glycosyl acceptor to synthesize the oxoside compound of the present invention.
  • the specific implementation example is as follows:
  • Each oxoglycoside compound O-4 of the present invention is prepared with a purity greater than 90%.
  • Each oxoglycoside compound O-10 of the present invention is prepared with a purity greater than 90%.
  • the allyl sulfone glycosyl donor prepared above is used as a raw material to react with the glycosyl acceptor to synthesize the carbon glycoside compound of the present invention.
  • the synthetic route is as follows:
  • the glycosyl donor 3-1 (1.0equiv), the glycosyl acceptor pyridinium tetrafluoroborate (2.0equiv), the photosensitizer EosinY (eosin Y, 0.025equiv.), the initiator trifluoromethyl Sodium sulfinic acid (0.2 equiv.) was added to the catalytic reaction flask, DMSO was added, and stirred at room temperature for 8 hours under the irradiation of Blue LED to obtain the carbon glycoside compound CX.
  • the carbon glycoside compounds C-1, C-2, C-4, C-6, C-8 of the present invention are prepared, and the structures and characteristics are as follows:
  • the present invention provides a glycosyl donor represented by formula I and a preparation method thereof, and the glycosyl donor represented by formula I is used in the preparation of glucosides represented by formula III and formula IV.
  • the glycosyl donor provided by the present invention has a novel structure and a simple preparation method; the present invention also uses the above-mentioned glycosyl donor as a raw material to prepare oxygen glycosides, glucosinolates, and carbon glycoside compounds, most of which have The special ⁇ configuration, the preparation method is simple, the reaction conditions are mild, the yield is high, and it has very good application prospects.

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Abstract

本发明公开了一种新的糖基供体及其制备方法和用途。具体提供了一种式（I）所示的糖基供体及其制备方法，以及式（I）所示的糖基供体在制备式（III）所示的硫苷、式（IV）所示的氧苷、式（V）所示的碳苷类化合物中的用途。本发明提供的糖基供体结构新颖，制备方法简单；本发明还以上述糖基供体为原料，利用自由基反应，制备得到了氧苷、硫苷、碳苷类化合物，其中大部分具有特殊的α构型，该制备方法简单、反应条件温和、收率高，具有非常好的应用前景。

Description

一种新的糖基供体及其制备方法和用途 技术领域
本发明涉及合成化学以及药物化学技术领域，具体涉及一种新的糖基供体及其制备方法和用途。
背景技术
糖类物质是生物体(包括动物、植物、微生物)的重要组成部分。多糖、寡糖及其与蛋白质、酯类等结合成的糖复合物涉及到细胞，特别是多细胞生命的全部时间和空间过程，它们作为信息分子参与细胞的各种识别过程：传递生物信息、参与机体的免疫调节，并与细胞分化、受精、胚胎发育、血液系统、感染、衰老等多方面功能密切相关。近年来，由于糖类化合物显著的生理活性，越来越引起化学家们广泛的研究兴趣。糖苷(Glycosides)是糖在自然界存在的重要形式，它广泛存在于生物体内，具有特殊的生物活性，担负着重要的生理功能。糖苷是糖的半缩醛羟基与配基缩合失去一分子水或其它小分子化合物而形成的一类非常重要的化合物，其中糖部分称为糖基，非糖部分称为配基。根据糖苷化合物分子结构中的配基与糖环碳原子相连的原子类型可把糖苷化合物分为氧苷化合物、氮苷化合物、硫苷化合物和碳苷化合物，它们大都表现出很好的生物学功能，如糖苷酶抑制活性抗菌、抗病毒和抗肿瘤活性等。
目前已有很多构建糖苷类化合物的方法，但是，这些方法条件不够温和、官能团兼容性差。同时，大部分现有方法很难高立体选择性地制备α构型的糖苷化合物。
因此，研究结构新颖的、制备方法简单的糖基供体，对进一步制备各种糖苷化合物(比如氧苷化合物、氮苷化合物、硫苷化合物和碳苷化合物)具有非常大的应用价值。
发明内容
为了解决上述问题，本发明提供了一种结构新颖的烯丙基砜类糖基供体，并以该烯丙基砜类糖基供体为原料制得了硫苷化合物、氧苷化合物和碳苷化合物。
本发明提供了一种糖基供体、或其盐、或其立体异构体、或其旋光异构体，所述糖基供体的结构如式I所示：
Figure PCTCN2020103340-appb-000001
其中，A环选自
Figure PCTCN2020103340-appb-000002
R 1、R 2、R 3、R 4各自独立地选自H、C 1-6烷基、芳基或者杂芳基取代的C 1-12烷基、C 1-6烷氧基、C 2-8炔基、C 2-8烯基、芳香基、杂芳基、环烷基、M 1OH、M 1NH 2、M 1NHAc、M 1OAc、M 1OBz、M 1OBn、M 1N 3、M 1OTMS、M 1OTBS、
Figure PCTCN2020103340-appb-000003
Figure PCTCN2020103340-appb-000004
或者R 1、R 2、R 3、R 4中的任意2个连接成环；M 1选自0-3个亚甲基；M 2、M 3、M 4选自H、C 1-6烷基、芳基或者杂芳基取代的C 1-12烷基、C 2-8炔基、C 2-8烯基、芳香基、杂芳基，或者M 3、M 4连接成环；
R 5选自C 1-10烷基、饱和环烷基、饱和杂环基、H、芳香基、杂芳基、C 1～10烷氧基、卤素、氰基、羧基、酯基；
R 6、R 7、R 8、R 9各自独立地选自H、卤素、C 1-6烷基、C 1-6烷氧基、M 1OH、C 2-8炔基、C 2-8烯基、饱和环烷基、饱和杂环基、H、芳香基、杂芳基、氰基、酯基；M 1选自0-3个亚甲基。
进一步地，所述糖基供体的结构如式II-1或II-2所示：
Figure PCTCN2020103340-appb-000005
其中，R 1、R 2、R 3、R 4各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、芳香基、杂芳基、环烷基、M 1OH、M 1NH 2、M 1NHAc、M 1OAc、M 1OBz、M 1OBn、M 1N 3、M 1OTMS、M 1OTBS、
Figure PCTCN2020103340-appb-000006
或者R 1、R 2、R 3、R 4中的任意2个连接成取代或未取代的环，该环上的取代基各自独立的选自1个或多个氢、氘、C 1-8烷基、C 1～8烷氧基、C 2-8炔基、C 2-8烯基、芳香基、杂芳基、卤素、氰基、羧基或酯基；
M 1选自0-3个亚甲基；
R 5选自C 1-8烷基、饱和环烷基、饱和杂环基、H、芳香基、杂芳基、C 1～8烷氧基、卤素、氰基、羧基、酯基；
优选地，所述R 1、R 2、R 3、R 4各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 2-3炔基、C 2-3烯基、芳香基、杂芳基、环烷基、M 1OH、M 1NHAc、M 1OAc、 M 1OBz、
Figure PCTCN2020103340-appb-000007
或者R 1、R 2、R 3、R 4中的任意2个连接成环，该环上的取代基各自独立的选自1个或多个氢、氘、C 1-4烷基、C 1～4烷氧基、C 2-3炔基、C 2-3烯基、苯基、杂芳基、卤素、氰基、羧基或酯基；M 1选自0-1个亚甲基；
R 5选自H、苯基、C 1-8烷基。
进一步地，所述糖基供体的结构选自选自：
Figure PCTCN2020103340-appb-000008
进一步地，所述糖基供体的结构选自选自：
Figure PCTCN2020103340-appb-000009
其中，
Figure PCTCN2020103340-appb-000010
表示
Figure PCTCN2020103340-appb-000011
或二者的任意比例混合物。
本发明还提供了一种硫苷化合物、或其盐、或其立体异构体、或其旋光异构体，所述硫苷化合物的结构如式III所示：
Figure PCTCN2020103340-appb-000012
其中，R 10选自
Figure PCTCN2020103340-appb-000013
取代或未取代的芳基、取代或未取代的 杂芳基、取代或未取代的烷基、
Figure PCTCN2020103340-appb-000014
肽链去掉一个氢原子后剩下的基团，所述取代基选自卤素、卤代烷基；上述m表示1-5的整数；
上述Y选自无、NH或O；R 1a、R 2a选自各自独立地选自H、Boc、Bz、C 1-6烷基、C 1-6烷氧基、芳基、杂芳基、肽链去掉一个氢原子后剩下的基团、
Figure PCTCN2020103340-appb-000015
其中m 1、m 2各自独立地选自0-5的整数；R a1选自取代或未取代的C 1-6烷基，所述取代基选自卤素、羟基；R a3选自取代或未取代的C 1-6烷基、芳基、杂芳基，所述取代基选自卤素、羟基；
A环选自
Figure PCTCN2020103340-appb-000016
R 1、R 2、R 3、R 4如上所述。
进一步地，所述硫苷化合物的结构如式III-1、III-2、III-3或III-4所示：
Figure PCTCN2020103340-appb-000017
式III-1和式III-3中：当Y选自O时，R 1a选自甲基，R 2a选自Bz、H、
Figure PCTCN2020103340-appb-000018
当Y选自NH时，R 1a选自
Figure PCTCN2020103340-appb-000019
R 2a选自Boc；当Y选自无时，R 1a选自甲氧基，R 2a选自Bz；
式III-2和式III-4中：R 10选自取代或未取代的苯环、取代或未取代的氮 杂芳环、甲基、
Figure PCTCN2020103340-appb-000020
所述取代基选自卤素、卤代烷基；
式III-1、式III-2、III-3和III-4中：R 1、R 2、R 3、R 4如上所述。
进一步地，所述硫苷化合物的结构选自：
Figure PCTCN2020103340-appb-000021
进一步地，所述硫苷化合物的结构选自：
Figure PCTCN2020103340-appb-000022
Figure PCTCN2020103340-appb-000023
本发明还提供了一种氧苷化合物、或其盐、或其立体异构体、或其旋光 异构体，所述氧苷化合物的结构如式IV所示：
Figure PCTCN2020103340-appb-000024
其中，R 11选自L 0R 12或COL 0R 12，L 0选自0～3个亚烷基，R 12选自取代或未取代的C 1～6烷基、取代或未取代的环；所述取代基为1个或多个，所述取代基各自独立的选自CN、C 1～6烷氧基、C 1～6烷氧基、L 1(COOEt)NHBz、OH、NH 2、NHAc、OAc、OBz、OBn，L 1选自0～3个亚烷基；A环选自
Figure PCTCN2020103340-appb-000025
Figure PCTCN2020103340-appb-000026
R 1、R 2、R 3、R 4如上所述。
进一步地，所述氧苷化合物的结构如式IV-1、IV-2、IV-3、IV-4、IV-5和IV-6所示：
Figure PCTCN2020103340-appb-000027
其中，R 1、R 2、R 3、R 4如上所述；L 0选自0～2个亚烷基，R 12选自取代或未取代的C 1～3烷基、取代或未取代的饱和单环碳环、饱和单环杂环、桥环、螺环、稠环；所述取代基、R 13各自独立的选自CN、C 1～3烷氧基、C 1～3烷氧基、L 1(COOEt)NHBz、OH、NH 2、NHAc、OAc、OBz、OBn，L 1选自0～1个亚烷基。
进一步地，所述氧苷化合物的结构选自：
Figure PCTCN2020103340-appb-000028
本发明还提供了一种碳苷化合物、或其盐、或其立体异构体、或其旋光异构体，所述碳苷化合物的结构如式V所示：
Figure PCTCN2020103340-appb-000029
其中A环选自
Figure PCTCN2020103340-appb-000030
R 1、R 2、R 3、R 4如上所述；
Figure PCTCN2020103340-appb-000031
为
Figure PCTCN2020103340-appb-000032
B环为饱和或不饱和环，优选为苯环；
R 14选自H、CN、卤代或未卤代的C 1～3烷基、卤代或未卤代的C 1～3烷氧基、COOR 15；R 15选自C 1～3烷基。
进一步地，所述碳苷化合物的结构如式V-1、V-2、V-3和V-4所示：
Figure PCTCN2020103340-appb-000033
其中，R 1、R 2、R 3、R 4、R 14如上所述。
进一步地，所述碳苷化合物的结构选自：
Figure PCTCN2020103340-appb-000034
本发明还提供了上述的糖基供体在制备硫苷化合物、氧苷化合物、碳苷化合物中的用途；优选的，所述硫苷化合物如上所述，和/或，所述氧苷化合物如上所述，和/或，所述碳苷化合物如上所述。
本发明还提供了一种制备上述糖基供体的方法，所述方法包括以下步骤：
(1)原料Y1与乙酸酐反应，得到化合物Y2；
(2)化合物Y2先与硫脲反应，再加入化合物Y3，继续反应，得到化合物 Y4；
(3)化合物Y4与mCPBA反应，得到糖基供体；
其中，原料Y1的结构为
Figure PCTCN2020103340-appb-000035
化合物Y2的结构为
Figure PCTCN2020103340-appb-000036
化合物Y3的结构为
Figure PCTCN2020103340-appb-000037
化合物Y4的结构为
Figure PCTCN2020103340-appb-000038
X选自卤素，优选为溴；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9如上所述。
进一步地，步骤(1)中，所述乙酸酐与原料Y1上羟基的摩尔比为(0.8～1.5)：1；反应是在三乙胺和DMAP的作用下进行的；反应温度为室温；反应溶剂为二氯甲烷；
步骤(2)中，化合物Y2、硫脲、化合物Y3的摩尔比为1：(1.5～4.5)：(1.2～2)；加入化合物Y3前的反应温度为加热回流，反应时间为(2～6)小时；加入Y3前的反应是在三氟化硼乙醚的作用下进行的；加入Y3后的反应温度为加热回流，反应时间为(4～8)小时；加入Y3后的反应是在三乙胺的作用下进行的；反应溶剂为乙腈；
步骤(3)中，化合物Y4与mCPBA的摩尔比为1：(1.5～4.5)；反应时间为1～3小时；反应溶剂为二氯甲烷；
优选地，
步骤(1)中，所述乙酸酐与原料Y1上羟基的摩尔比为1.2：1；
步骤(2)中，化合物Y2、硫脲、化合物Y3的摩尔比为1：3：1.5；加入化合物Y3前的反应时间为4小时；加入Y3后的反应时间为6小时；
步骤(3)中，化合物Y4与mCPBA的摩尔比为1：2.5；反应温度为室温，反应时间为2小时。
本发明还提供了一种制备上述硫苷化合物的方法，所述方法为：将上述的糖基供体与糖基受体反应，得到硫苷化合物；
其中，所述糖基受体的结构为
Figure PCTCN2020103340-appb-000039
R 5s选自
Figure PCTCN2020103340-appb-000040
Figure PCTCN2020103340-appb-000041
R 10如上所述。
进一步地，所述R 5s选自
Figure PCTCN2020103340-appb-000042
R 10如上所述；
所述糖基供体与糖基受体的摩尔比为1：(1.1～2.5)，优选为1：(1.2～2)；
所述反应是在氮气氛围中、蓝色LED的照射下进行的；
所述反应的温度为20～45℃，优选为室温～45℃；反应时间为1.5～5小时，优选为2～4小时；
所述反应是在光敏剂的作用下进行的，光敏剂选自
Figure PCTCN2020103340-appb-000043
Figure PCTCN2020103340-appb-000044
Ir[dF(CF 3)(ppy) 2](dtbbpy)PF 6，优选为
Figure PCTCN2020103340-appb-000045
Ir[dF(CF 3)(ppy) 2](dtbbpy)PF 6，更优选为Ir[dF(CF 3)(ppy) 2](dtbbpy)PF 6；
所述反应的溶剂选自水或者1,2-DCE、DMSO、EtOAc、glyme、1,4-dioxane、THF、MeOH、DMF、MeCN、MeCN中的一种或多种与水在任意比例下组成的混合溶液。
本发明还提供了一种制备上述氧苷化合物的方法，所述方法为：将上述的糖基供体与糖基受体反应，得到氧苷化合物；其中，所述糖基受体的结构为HO-R 11，R 11如上所述；
优选的，所述糖基供体与糖基受体的摩尔比为(1.2～2.0)：1.0，优选为1.5：1.0；和/或，所述反应是在全氟碘代丁烷、磷酸氢二铵、三苯基氧磷的存在下反应的，所述糖基受体与全氟碘代丁烷、磷酸氢二铵、三苯基氧磷的摩尔比为1.0：(3～7)：(3～7)：(0.1～0.5)，优选为1.0：5.0：5.0：0.3；和/或，所述反应溶剂为有机溶剂，优选为甲基叔丁基醚；和/或，所述述反 应是在氮气氛围中、蓝色LED的照射下进行的；和/或，所述反应的温度为20～45℃，优选为室温，反应时间为12～36小时，优选为24小时。
本发明还提供了一种制备上述碳苷化合物的方法，所述方法为：将上述的糖基供体与糖基受体反应，得到碳苷化合物；其中，所述糖基受体为
Figure PCTCN2020103340-appb-000046
R 16选自C 1-3烷基，优选为甲基，
Figure PCTCN2020103340-appb-000047
如上所述；
优选的，所述糖基供体与糖基受体的摩尔比为1:(1.5～3.0)，优选为1:2.0；所述反应是在光敏剂、引发剂的作用下进行的，所述光敏剂优选为曙红Y，所述引发剂优选为三氟甲基亚磺酸钠，所述糖基供体与光敏剂、引发剂的摩尔比为1：(0.01～0.03)：(0.1～0.3)，优选为1:0.025:0.2；和/或，所述反应是在氮气氛围中、蓝色LED的照射下进行的；和/或，所述反应的温度为20～45℃，优选为室温，反应时间为5～12小时，优选为8小时。
糖基供体是指合成糖苷时，含有糖苷键的原料，或含有参加反应的端基异头碳的原料；而与之反应的另一种原料被称为糖基受体。
本发明的糖基供体可以采用糖基供体的合成实施例路线1～4中的任意一条制得，也可以采用其他的方法来制备。
试验证明，本发明提供的糖基供体结构新颖，具有特殊的烯丙基砜结构，并且其制备方法简单；本发明进一步以上述的糖基供体为原料，利用自由基反应，制备得到了氧苷、硫苷、碳苷类化合物，其中大部分具有特殊的α构型，该制备方法简单、反应条件温和、收率高，具有非常好的应用前景。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀C a-b烷基表示任何含“a”至“b”个碳原子的烷基。例如，C 1-8烷基是指包含1-8个碳原子的直链或支链的烷基。
类似的，C 1-8烷氧基是指包含1-8个碳原子的直链或支链的烷氧基。
本发明中，Ac表示乙酰基，结构为
Figure PCTCN2020103340-appb-000048
Ph表示苯基，结构为
Figure PCTCN2020103340-appb-000049
Bz表示苯甲酰基，结构为
Figure PCTCN2020103340-appb-000050
Boc表示叔丁氧羰基， 结构为
Figure PCTCN2020103340-appb-000051
Me表示甲基。
本发明中，肽链是指由多个氨基酸相互连接形成的含有多个肽键的链状结构。
“mCPBA”为间氯过氧苯甲酸。
本发明中，芳基即芳香基；Ar表示芳基。芳基指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。
杂芳基指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
“环烷基”指饱和或不饱和的环状烃取代基，环状烃可以是单环也可以是多环。“饱和环烷基”指饱和的环烷基。
“杂环基”指饱和或不饱和的环状烃取代基，环状烃可以是单环也可以是多环，且携带至少一个环杂原子(包括但不限于O、S或N)。“饱和杂环基”指饱和的杂环基。
“盐”是将化合物与无机和/或有机酸和/或碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。
本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
合成糖基供体：
采用以下合成路线，制备本发明的合成糖基供体：
Figure PCTCN2020103340-appb-000052
以下为本发明烯丙基砜类糖基供体的合成实施例。
1，合成路线1
1)，合成路线简图
Figure PCTCN2020103340-appb-000053
2)，操作步骤详述(以化合物3-1合成为例)
Figure PCTCN2020103340-appb-000054
a),室温下全乙酰基保护的底物1-1(10mmol)溶于乙腈(40mL)，加入硫脲(1.5eq)和三氟化硼乙醚(3eq),回流4h,冷却至室温。加入3-溴-2甲基丙烯(1.5eq)和三乙胺(3eq)回流6h后却至室温。减压旋干乙腈后二氯甲烷溶解，饱和食盐水溶液洗涤，二氯甲烷萃取，无水硫酸钠干燥，抽滤、浓缩后使用柱层析(300目-400目硅胶)分离得到相应的硫醚中间体2-1。
b),冰浴下将上步所得化合物2-1溶于二氯甲烷中，缓慢加入m-CPBA(2.5eq)后,升至室温反应2h。抽滤，用二氯甲烷洗涤固体。将滤液用饱和Na 2S 2O 3溶液洗涤一次，饱和Na 2CO 3溶液洗涤二次，二氯甲烷萃取，无水硫酸钠干燥，抽滤、浓缩后使用柱层析(300目-400目硅胶)分离得到相应的产物,即化合物3-1,纯度大于90％，总收率为75％。
Figure PCTCN2020103340-appb-000055
其结构表征如下：
1H NMR(400MHz,Chloroform-d)δ5.53(t,J＝9.6Hz,1H),5.31(t,J＝9.3Hz,1H),5.27(t,J＝1.6Hz,1H),5.20(d,J＝1.4Hz,1H),5.10(t,J＝9.8Hz,1H),4.58(d,J＝9.9Hz,1H),4.31–4.17(m,2H),3.98(d,J＝13.6Hz,1H),3.80(ddd,J＝10.1,5.1,2.7Hz,1H),3.66(d,J＝13.6Hz,1H),2.09(s,3H),2.05(s,3H),2.04(s,3H),2.03(s,3H),1.98(s,3H).
其他3-2至3-11化合物的合成采取与上述3-1相同的路线合成，其结构与表征数据如下：
Figure PCTCN2020103340-appb-000056
纯度大于90％，总收率为62％， 1H NMR(400MHz,Chloroform-d)(α:β＝1:6)(β-isomer)δ5.72(t,J＝9.9Hz,1H),5.47(d,J＝3.3Hz,1H),5.27(s,1H),5.20(s,1H),5.15(dd,J＝10.1,3.3Hz,1H),4.57(d,J＝9.8Hz,1H),4.19(m,J＝5.4Hz,2H),4.07(t,J＝6.3Hz,1H),3.99(d,J＝13.6Hz,1H),3.69(d,J＝13.6Hz,1H),2.19(s,3H),2.06(s,6H),2.00(s,3H),1.98(s,3H).
Figure PCTCN2020103340-appb-000057
纯度大于90％，总收率为62％， 1H NMR(400MHz,Chloroform-d)δ5.94(dd,J＝3.8,2.1Hz,1H),5.59(dd,J＝9.2,3.6Hz,1H),5.29(t,J＝9.7Hz,1H),5.27–5.24(m,1H),5.21–5.18(m,1H),4.99(d,J＝2.1Hz,1H),4.70(ddd,J＝9.9,5.8,2.4Hz,1H),4.27(dd,J＝12.5,5.8Hz,1H),4.17(dd,J＝12.5,2.5Hz,1H),4.00(d,J＝13.9Hz,1H),3.67(d,J＝13.9Hz,1H),2.17(s,3H),2.11(s,3H),2.07(s,3H),2.01(s,3H),1.98(s,3H).
Figure PCTCN2020103340-appb-000058
纯度大于90％，总收率为51％， 1H NMR(400MHz,Chloroform-d)(α:β＝2:1)(α-isomer)δ5.47(ddd,J＝9.7,7.7,5.1Hz,1H),5.25(s,1H),5.18(s,1H),5.05–4.94(m,2H),4.68–4.58(m,1H),4.27(dd,J＝12.5,5.6Hz,1H),4.15(dd,J＝12.4,2.5Hz,1H),3.98(d,J＝13.8Hz,1H),3.65(d,J＝13.8Hz,1H),2.82(ddd,J＝14.8,5.2,3.4Hz,1H),2.18–2.11(m,1H),2.10(s,3H),2.06(s,3H),2.05(s,3H),1.98(d,J＝1.4Hz,3H).
Figure PCTCN2020103340-appb-000059
纯度大于90％，总收率为35％， 1H NMR(400MHz,Chloroform-d)δ5.68(t,J＝9.9Hz,1H),5.31(dd,J＝3.4,1.1Hz,1H),5.27(t,J＝1.5Hz,1H),5.15(s,1H),5.12(dd,J＝10.0,3.4Hz,1H),4.47(d,J＝9.9Hz,1H),3.96–3.93(m,1H),3.92(d,J＝0.9Hz,1H),3.73(d,J＝13.5Hz,1H),2.20(s,3H),2.06(s,3H),2.00(s,3H),1.98(s,3H),1.28(d,J＝6.4Hz,3H).
Figure PCTCN2020103340-appb-000060
纯度大于90％，总收率为58％， 1H NMR(400MHz,Chloroform-d)δ5.93(dd,J＝3.7,2.0Hz,1H),5.53(dd,J＝9.4,3.7Hz,1H),5.25(p,J＝1.5Hz,1H),5.17(s,1H),5.10(t,J＝9.5Hz,1H),4.94(d,J＝2.0Hz,1H),4.55(dq,J＝9.6,6.2Hz,1H),3.97(d,J＝13.9Hz,1H),3.66(d,J＝13.9Hz,1H),2.16(s,3H),2.06(s,3H),2.00(s,3H),1.98(s,3H),1.29(d,J＝6.2Hz,3H).
Figure PCTCN2020103340-appb-000061
纯度大于90％，总收率为63％， 1H NMR(400MHz,Chloroform-d)δ5.51(t,J＝9.1Hz,1H),5.30(t,J＝8.9Hz,1H),5.26(t,J＝1.5Hz,1H),5.13(s,1H),5.02(td,J＝9.0,5.3Hz,1H),4.54(d,J＝9.2Hz,1H),4.39(dd,J＝11.6,5.3Hz,1H),3.91(d,J＝13.4Hz,1H),3.69(d,J＝13.4Hz,1H),3.47(dd,J＝11.6,9.1Hz,1H),2.10–2.00(m,9H),1.97(s,3H).
Figure PCTCN2020103340-appb-000062
纯度大于90％，总收率为56％， 1H NMR(400MHz,Chloroform-d)δ5.75(dd,J＝7.3,3.4Hz,1H),5.49(dd,J＝5.8,3.5Hz,1H),5.26(p,J＝1.5Hz,1H),5.16(s,1H),5.01(ddd,J＝5.9,4.3,3.0Hz,1H),4.76(d,J＝7.3Hz,1H),4.17(dd,J＝12.4,4.4Hz,1H),4.01(dd,J＝12.4,3.0Hz,1H),3.94(d,J＝13.6Hz,1H),3.69(d,J＝13.6Hz,1H),2.14(s,1H),2.12(s,3H),2.09(s,3H),1.98(s,3H).
Figure PCTCN2020103340-appb-000063
纯度大于90％，总收率为33％， 1H NMR(400MHz,Chloroform-d)δ5.73(t,J＝9.4Hz,1H),5.35(tt,J＝2.7,1.5Hz,1H),5.27(t,J＝1.5Hz,1H),5.22–5.10(m,1H),4.47(d,J＝9.3Hz,1H),4.24(dd,J＝12.9,2.6Hz,1H),3.92(d,J＝13.4Hz,1H),3.80(dd,J＝13.0,1.5Hz,1H),3.77–3.73(d,J＝13.4Hz,1H),2.18(s,3H),2.08(s,3H),2.04(s,3H),1.98(s,3H).
化合物3-10与化合物3-1合成步骤相同，只需在第一步中使用3-溴丙烯替代3-溴-2甲基丙烯即可，纯度大于90％，总收率为75％，
Figure PCTCN2020103340-appb-000064
1H NMR(400MHz,Chloroform-d)δ5.99–5.79(m,1H),5.58–5.47(m,3H),5.31(t,J＝9.3Hz,1H),5.10(t,J＝9.8Hz,1H),4.56(d,J＝9.9Hz,1H),4.34–4.16(m,2H),3.98(dd,J＝13.9,8.4Hz,1H),3.83–3.73(m,2H),2.10(s,3H),2.05(s,3H),2.05(s,3H),2.03(s,3H).
化合物3-11与化合物3-1合成步骤相同，只需在第一步中使用3-溴-2苯基丙烯替代3-溴-2甲基丙烯即可，纯度大于90％，总收率为71％，
Figure PCTCN2020103340-appb-000065
1H NMR(400MHz,Chloroform-d)δ7.50–7.46(m,2H),7.43–7.36(m,3H),5.77(s,1H),5.60(s,1H),5.50(t,J＝9.6Hz,1H),5.16(t,J＝9.3Hz,1H),5.03(t,J＝9.8Hz,1H),4.51(d,J＝14.2Hz,1H),4.17(d,J＝9.9Hz,1H),4.10–4.03(m,3H),3.29(dt,J＝10.1,3.5Hz,1H),2.10(s,3H),2.02(s,3H),2.01(s,3H),2.00(s,3H).
2，合成路线2
1)，合成路线简图
Figure PCTCN2020103340-appb-000066
2)，操作步骤详述(以化合物3-12合成为例)
Figure PCTCN2020103340-appb-000067
a),0℃下，全乙酰基基保护的2-氨基葡萄糖底物1-12(10mmol)溶于DCM(30mL)中，缓慢滴加33％氢溴酸乙酸溶液(30mL)并搅拌5小时。原料反应完全后，用冰水淬灭，在冰水浴下用饱和碳酸钾水溶液中和反应液，用二氯甲烷萃取，冰的饱和碳酸氢钠水溶液和冰的饱和食盐水洗涤，无水硫酸钠干燥有机相，抽滤，在空气冷凝下旋干滤液，得到粗品1-12-1。无需纯化，直接投下一步；
b),粗品1-12-1和硫脲(1.5eq)溶于丙酮(20mL)中，60℃下回流搅拌10分钟，有大量固体析出。待反应液降至室温后，抽滤得到固体即为中间体1-12-2。
c),中间体1-12-2和无水碳酸钾(2.0eq)溶于丙酮/水(2:1,20mL)中，滴加3-溴-2甲基丙烯(1.5eq)室温搅拌过夜，旋干溶剂后，经二氯甲烷萃取，水和饱和食盐水洗涤，无水硫酸钠干燥有机相，抽滤并旋干滤液，采用柱层析法纯化得到硫醚中间体2-12。
d),冰浴下将上步所得化合物2-12溶于二氯甲烷中，缓慢加入m-CPBA(2.5eq)后,升至室温反应2h。抽滤，用二氯甲烷洗涤固体。将滤液用饱和Na 2S 2O 3溶液洗涤一次，饱和Na 2CO 3溶液洗涤二次，二氯甲烷萃取，无水硫酸钠干燥，抽滤、浓缩后使用柱层析(300目-400目硅胶)分离得到相应的产物,即化合物3-12,纯度大于90％，总收率为31％。
其表征数据如下：
Figure PCTCN2020103340-appb-000068
1H NMR(400MHz,Chloroform-d)δ6.07(d,J＝7.9Hz,1H),5.72(t,J＝9.7Hz,1H),5.25(s,1H),5.21–5.15(m,2H),5.05(t,J＝9.2Hz,1H),4.25(dd,J＝12.6,2.5Hz,1H),4.20(dd,J＝12.6,5.3Hz,1H),4.10–4.03(m,1H),4.00(d,J＝13.6Hz,1H),3.89(ddd,J＝10.3,5.2,2.5Hz,1H),3.69(d,J＝13.5Hz,1H),2.09(s,3H),2.05(d,J＝1.6Hz,6H),1.96(s,3H),1.94(s,3H).
化合物3-13的合成路线与3-12相同，使用全乙酰基2-氨基半乳糖为起始原料即可获得产物3-13.纯度大于90％，其表征数据如下：
Figure PCTCN2020103340-appb-000069
1H NMR(400MHz,Chloroform-d)δ6.28(d,J＝8.0Hz,1H),5.72(dd,J＝10.8,3.3Hz,1H),5.46(d,J＝3.3Hz,1H),5.20(s,1H),5.17(d,J＝10.2Hz,1H),4.25(m,1H),4.22–4.11(m,3H),4.02(d,J＝13.5Hz,1H),3.73(d,J＝13.5Hz,1H),2.18(s,3H),2.05(s,3H),2.01(s,3H),1.96(s,3H),1.94(s,3H).
3，合成路线3
1)，合成路线简图
Figure PCTCN2020103340-appb-000070
2)，操作步骤详述(以化合物3-14合成为例)
Figure PCTCN2020103340-appb-000071
a),0℃下，化合物1-14(10mmol)溶于二氯甲烷(30mL)中，先后缓慢滴加硫代乙酸(24mmol)和三氟化硼乙醚(30mmol)，随后升至室温搅 拌过夜。原料反应完全后，用冰水淬灭，二氯甲烷萃取，饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥有机相，抽滤并旋干滤液，得到中间体1-14-1。
b),中间体1-14-1和半胱酸甲酯盐酸盐(2.05g,12mmol)溶于DMF(10mL)中，加入三乙胺(1.7mL,12mmol)室温搅拌8小时。TLC监测中间体1-14-1反应完全后，经乙酸乙酯萃取，半饱和食盐水洗涤后，用无水硫酸钠干燥有机相，抽滤并旋干滤液，采用柱层析法纯化得到产物中间体1-14-2。
c),物中间体1-14-2和无水碳酸钾(2.5eq)溶于丙酮/水(2:1,20mL)中，滴加3-溴-2甲基丙烯(2.5eq)室温搅拌过夜，旋干溶剂后，经二氯甲烷萃取，水和饱和食盐水洗涤，无水硫酸钠干燥有机相，抽滤并旋干滤液，采用柱层析法纯化得到硫醚物中间体2-14。
d),冰浴下将上步所得化合物2-14溶于二氯甲烷中，缓慢加入m-CPBA(2.5eq)后,升至室温反应2h。抽滤，用二氯甲烷洗涤固体。将滤液用饱和Na 2S 2O 3溶液洗涤一次，饱和Na 2CO 3溶液洗涤二次，二氯甲烷萃取，无水硫酸钠干燥，抽滤、浓缩后使用柱层析(300目-400目硅胶)分离得到相应的产物,即化合物3-14,纯度大于90％，总收率为48％。
其表征数据如下：
Figure PCTCN2020103340-appb-000072
1H NMR(400MHz,Chloroform-d)δ5.41(d,J＝4.1Hz,1H),5.39–5.32(m,3H),5.27(t,J＝1.5Hz,1H),5.21(s,1H),5.05(t,J＝9.9Hz,1H),4.87(dd,J＝10.6,4.0Hz,1H),4.73–4.67(m,1H),4.64(dd,J＝12.4,2.6Hz,1H),4.24(ddd,J＝24.7,12.4,4.6Hz,2H),4.08(dd,J＝12.4,2.3Hz,1H),4.04–3.94(m,3H),3.79(ddd,J＝9.7,5.1,2.5Hz,1H),3.59(d,J＝13.7Hz,1H),2.14(s,3H),2.11(s,3H),2.06–2.01(m,12H),2.00(s,3H),1.97(s,3H).
化合物3-15的合成路线与3-14相同，使用全乙酰基麦芽糖为起始原料即可获得产物3-15.纯度大于90％，其表征数据如下：
Figure PCTCN2020103340-appb-000073
1H NMR(400MHz,Chloroform-d)δ5.47(t,J＝9.4Hz,1H),5.38–5.35(m,1H),5.32(d,J＝9.0Hz,1H),5.27–5.23(m,1H),5.18(s,1H),5.11(dd,J＝10.5,7.9Hz,1H),4.98(dd,J＝10.4,3.4Hz,1H),4.65–4.57(m,2H),4.52(d,J＝7.8Hz,1H),4.18–4.04(m,3H),3.97(d,J＝13.7Hz,1H),3.89(t,J＝6.7Hz,1H),3.82(t,J＝9.4Hz,1H),3.76–3.66(m,1H),3.57(d,J＝13.7Hz,1H),2.15(s,3H),2.12(s,3H),2.07(s,3H),2.06(s,3H),2.05(s,3H),2.04(s,3H),1.97(s,6H).
4，合成路线4
1)，合成路线简图
Figure PCTCN2020103340-appb-000074
a),0℃下，化合物1-16(10mmol)溶于二氯甲烷(30mL)中，先后缓慢滴加3-巯基-2甲基丙烯(2.5eq)和三氟化硼乙醚(30mmol)，0℃搅拌8h。原料反应完全后，用冰水淬灭，二氯甲烷萃取，饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥有机相，抽滤并旋干滤液，得到硫醚中间体2-16。
b),冰浴下将上步所得化合物2-16溶于二氯甲烷中，缓慢加入m-CPBA(2.5eq)后,升至室温反应2h。抽滤，用二氯甲烷洗涤固体。将滤液用饱和Na 2S 2O 3溶液洗涤一次，饱和Na 2CO 3溶液洗涤二次，二氯甲烷萃取，无水硫酸钠干燥，抽滤、浓缩后使用柱层析(300目-400目硅胶)分离得到相应的产物,即化合物3-16,纯度大于90％，总收率为48％。
其表征数据如下：
Figure PCTCN2020103340-appb-000075
1H NMR(400MHz,Chloroform-d)δ5.95–5.85(m,1H),5.68(t,J＝3.2Hz,1H),5.54(dd,J＝8.2,3.2Hz,1H),5.47(t,J＝6.1Hz,1H),5.30–5.21(m,2H),5.21–5.08(m,2H),5.04(d,J＝2.6Hz,1H),4.74(m,2H),4.50(dd,J＝12.3,3.4Hz,1H),4.45–4.37(m,1H),4.21(m,2H),3.94(m,2H),3.82(dd,J＝11.2,9.0Hz,1H),3.68(d,J＝13.5Hz,1H),3.60(t,J＝14.7Hz,1H),2.16(s,3H),2.15(s,3H),2.11(s,6H),2.07(s,3H),2.05(s,3H),1.98(s,3H),1.97(s,3H).
利用上述路线1-4均可对底物3-1至3-16进行合成，各实施例表明了此4条合成路线的有效性。
化合物3-17至3-19的合成
Figure PCTCN2020103340-appb-000076
具体步骤如下：
室温下，将由上述1-4路线合成的全乙酰基保护的糖基溶解在10mL甲醇中，然后将反应液降至0℃，缓慢加入氢氧化锂固体(0.5eq)，加入完毕后继续保持0℃反应4h；反应结束后，直接在反应液中加入2g硅胶，减压蒸馏甲醇后过柱纯化得到目标产物。
化合物3-17至3-19均按照上述方法制得，其表征数据如下：
Figure PCTCN2020103340-appb-000077
纯度大于90％， 1H NMR(400MHz,Methanol-d 4)δ5.14(m,2H),4.37(d,J＝9.6Hz,1H),4.05(d,J＝13.6Hz,1H),3.81(dd,J＝12.5,2.1Hz,1H),3.77–3.67(m,2H),3.58(dd,J＝12.5,6.2Hz,1H),3.36(t,J＝8.9Hz,1H),3.34–3.28(m,1H),3.23–3.18(t,J＝9.4Hz,1H),1.87(s,3H).
Figure PCTCN2020103340-appb-000078
纯度大于90％， 1H NMR(400MHz,Deuterium Oxide)δ5.28–5.24(m,1H),5.13(s,1H),4.67(d,J＝10.3Hz,1H),4.37(t,J＝10.3Hz,1H),4.11(d,J＝13.7Hz,1H),3.96(d,J＝3.2Hz,1H),3.91(d,J＝13.7Hz,1H),3.77(m,3H),3.74–3.67(m,1H),1.93(s,3H),1.84(s,3H).
Figure PCTCN2020103340-appb-000079
纯度大于90％， 1H NMR(400MHz,Deuterium Oxide)δ5.27(s,1H),5.14(s,1H),4.45(d,J＝8.0Hz,1H),4.11(d,J＝14.0Hz,1H),3.98–3.75(m,5H),3.66(m,4H),3.45–3.20(m,5H),1.86(s,3H).
化合物3-20的合成
Figure PCTCN2020103340-appb-000080
具体步骤如下：
室温下，将化合物3-17，苯甲酰氯(6.0eq),三乙胺(6.0eq),DMAP(0.2eq)在20mL二氯甲烷中，室温搅拌12h；反应结束后，加入冰山50Ml,二氯甲烷萃取，合并有机层，饱和柠檬酸水溶液洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱柱纯化得到目标产物3-20，纯度大于90％。其表征数据如下：
1H NMR(400MHz,Chloroform-d)δ8.04–7.99(m,1H),7.97–7.86(m,3H),7.85–7.80(m,1H),7.61–7.27(m,10H),6.07(t,J＝9.5Hz,1H),5.99(t,J＝9.3Hz,1H),5.69(t,J＝9.6Hz,1H),5.25–5.11(m,2H),4.93(d,J＝9.6Hz,1H),4.73(dd,J＝12.5,2.8Hz,1H),4.53(dd,J＝12.5,5.7Hz,1H),4.28(ddd,J＝8.6,5.5,2.7Hz,1H),4.05(d,J＝13.6Hz,1H),3.71(d,J＝13.6Hz,1H),1.94(s,3H).
化合物3-21的合成
Figure PCTCN2020103340-appb-000081
具体步骤如下：
(1)2,3,4,6-四-o-苄基-D-吡喃葡萄糖(即1-21，5.4g,10mmol)溶于50mL二氯甲烷中，0℃下，向反应液中缓慢滴加草酰氯(1.7mL,20mmol)，随后升至室温搅拌18h。加入冰水淬灭草酰氯至不再有气体放出，加入二氯甲烷萃取，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，抽滤并旋干滤液，得到中间体1-21-1,无需纯化直接投下一步。
(2)将中间体1-21-1与硫脲(1.2g,15mmol)溶于乙睛(30mL)中，回流2h，冷却至室温，依次加入三乙胺(15mmol),3-溴-2甲基丙烯(15mmol),回流4h后却至室温。减压旋干乙腈后加入二氯甲烷与水，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩后得到相应的中间体2-21，无需纯化直接投下一步。
(3)0℃下，上步所得粗品中间体2-21溶解于二氯甲烷(10mL)中，缓慢加入间氯过氧苯甲酸(2.5eq)，继续搅拌2小时。TLC监测中间体2-21反应完全后，抽滤，将滤液用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥有机相，抽滤并旋干滤液，采用柱层析法纯化得到产物3-21(4.5g,纯度大于90％，三步总收率70％)(即化合物3-21)。
Figure PCTCN2020103340-appb-000082
1H NMR(CDCl 3,400MHz)δ:7.44–7.22(m,18H),7.16(dd,J＝6.1,3.1Hz,2H),5.21(s,0.32H),5.16(d,J＝1.6Hz,1H),5.09(s,0.68H),5.04(d,J＝6.0Hz,0.69H),4.99(d,J＝9.7Hz,0.33H),4.94(d,J＝11.1Hz,0.34H),4.90–4.66(m,4.6H),4.58–4.38(m,4.0H),4.15–4.06(m,1H),4.04(d,J＝13.7Hz,0.34H),3.94(d,J＝13.5Hz,0.69H),3.80–3.74(m,0.35H),3.74–3.50(m,4.6H),1.96(s,1H),1.94(s,2H).
化合物3-22至3-38的合成
Figure PCTCN2020103340-appb-000083
具体步骤如下：
a),室温下，将由上述1-4路线合成的全乙酰基保护的硫醚底物溶解在10mL甲醇中，然后将反应液降至0℃，缓慢加入氢氧化锂固体(0.5eq)，加入完毕后继续保持0℃反应1h；反应结束后，旋干，粗品溶于DMF(10mL),0℃下分批缓慢加入60％NaH(-OH/1.5eq)，搅拌30Min,加入苄溴(-OH/1.5eq)，搅拌30Min后移至室温，继续搅拌12h，反应完全后，加入冰水，二氯甲烷萃取，合并有机层，水洗，饱和食盐水洗涤，无数硫酸钠干燥，过滤，浓缩，柱柱纯化得全苄基保护的硫醚中间体。
b),0℃下，上步所得中间体溶解于二氯甲烷(10mL)中，缓慢加入间氯过氧苯甲酸(2.5eq)，继续搅拌2小时。TLC监测原料反应完全后，抽滤，将滤液用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥有机相，抽滤并旋干滤液，采用柱层析法纯化得到产物3-22至3-38。
其表征数据如下
Figure PCTCN2020103340-appb-000084
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.42–7.20(m,20H),5.14(d,J＝1.6Hz,2H),4.96(d,J＝11.5Hz,2H),4.82(d,J＝9.7Hz,1H),4.74(d,J＝2.6Hz,2H),4.61(d,J＝11.7Hz,1H),4.48–4.38(m,4H),3.97(d,J＝13.7Hz,1H),3.88(d,J＝2.7Hz,1H),3.68–3.56(m,4H),3.49(dd,J＝7.9,4.4Hz,1H),1.95(d,J＝1.3Hz,3H).
Figure PCTCN2020103340-appb-000085
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.43–7.24(m,15H),5.17(t,J＝1.6Hz,1H),5.08(s,1H),5.01(d,J＝11.7Hz,1H),4.97(d,J＝9.7Hz,1H),4.83(d,J＝9.7Hz,1H),4.78(d,J＝11.9Hz,1H),4.74(d,J＝11.8Hz,1H),4.70(d,J＝11.7Hz,1H),4.49–4.38(m,2H),3.96(d,J＝13.6Hz,1H),3.69–3.51(m,4H),1.96(d,J＝1.1Hz,3H),1.24(d,J＝6.4Hz,3H).
Figure PCTCN2020103340-appb-000086
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.39–7.24(m,15H),5.17(t,J＝1.6Hz,1H),5.11(s,1H),4.92(d,J＝2.4Hz,1H),4.84(d,J＝11.2Hz,1H),4.69(d,J＝11.9Hz,1H),4.63(dd,J＝12.2,6.0Hz,3H),4.56(d,J＝11.1Hz,1H),4.44(t,J＝2.9Hz,1H),4.35–4.26(m,1H),4.08(dd,J＝8.4,3.4Hz,1H),3.90(d,J＝13.8Hz,1H),3.60(t,J＝8.8Hz,1H),3.54(d,J＝13.8Hz,1H),1.92(s,3H),1.31(d,J＝6.2Hz,3H).
Figure PCTCN2020103340-appb-000087
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.40–7.24(m,15H),5.20(t,J＝1.6Hz,1H),5.08(s,1H),4.94–4.90(m,1H),4.90–4.84(m,2H),4.78(d,J＝9.8Hz,1H),4.69(d,J＝11.7Hz,1H),4.59(d,J＝11.6Hz,1H),4.46(d,J＝9.2Hz,1H),4.11(dd,J＝11.4,5.0Hz,1H),4.05(t,J＝8.8Hz,1H),3.89(d,J＝13.6Hz,1H),3.76–3.64(m,2H),3.61(d,J＝13.5Hz,1H),3.30(dd,J＝11.5,9.1Hz,1H),1.95(s,3H).
Figure PCTCN2020103340-appb-000088
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.39–7.19(m,15H),5.17(t,J＝1.7Hz,1H),5.09(s,1H),4.85(d,J＝6.8Hz,1H),4.67(dd,J＝11.7,3.5Hz,2H),4.58(dd,J＝11.7,5.8Hz,2H),4.50(d,J＝3.1Hz,2H),4.35(dd,J＝6.8,3.0Hz,1H),4.02(dd,J＝11.9,4.3Hz,1H),3.93–3.83(m,3H),3.67–3.63(m,1H),3.61(d,J＝13.7Hz,1H),1.94(s,3H).
Figure PCTCN2020103340-appb-000089
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.42–7.26(m,15H),5.18(q,J＝1.6Hz,1H),5.08(s,1H),4.90(d,J＝10.0Hz,1H),4.85(d,J＝10.0Hz,1H),4.75(d,J＝12.5Hz,1H),4.71–4.59(m,3H),4.51–4.38(m,2H),4.23(dd,J＝12.4,3.0Hz,1H),3.91(d,J＝13.6Hz,1H),3.76(td,J＝3.0,1.4Hz,1H),3.71–3.61(m,2H),3.38(dd,J＝12.5,1.5Hz,1H),1.96(s,3H).
Figure PCTCN2020103340-appb-000090
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.34–7.12(m,35H),5.51(d,J＝3.7Hz,1H),5.17(s,2H),4.95–4.72(m,6H),4.64–4.34(m,9H),4.16(t,J＝8.8Hz,1H),4.09–3.97(m,2H),3.87(t,J＝9.4Hz,2H),3.80–3.68(m,3H),3.68–3.52(m,4H),3.48(dt,J＝10.5,3.1Hz,2H),1.96(s,3H).
Figure PCTCN2020103340-appb-000091
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.37–7.22(m,15H),5.18(ddt,J＝7.4,5.7,2.9Hz,1H),4.90(t,J＝10.1Hz,1H),4.81–4.37(m,7H),4.26–4.11(m,1H),3.99(dd,J＝26.0,13.7Hz,1H),3.78–3.53(m,4H),3.53–3.45(m,1H),1.94(s,3H).
Figure PCTCN2020103340-appb-000092
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.37–7.26(m,13H),7.19(dd,J＝7.3,2.3Hz,2H),5.77(d,J＝7.0Hz,1H),5.22–5.10(m,3H),4.85(d,J＝11.5Hz,1H),4.81(d,J＝11.0Hz,1H),4.68(d,J＝11.5Hz,1H),4.57(d,J＝10.8Hz,1H),4.55–4.46(m,3H),3.97(d,J＝13.6Hz,1H),3.79–3.43(m,7H),1.92(s,3H),1.85(s,3H).
Figure PCTCN2020103340-appb-000093
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.44–7.26(m,13H),7.16(dd,J＝7.3,2.3Hz,2H),5.26–5.20(m,1H),5.17(s,1H),4.91(d,J＝1.8Hz,1H),4.81(d,J＝11.1Hz,1H),4.75(s,2H),4.58(d,J＝12.1Hz,1H),4.51–4.45(m,3H),4.42(ddd,J＝9.8,5.1,2.3Hz,1H),4.34(dd,J＝8.7,3.9Hz,1H),3.97(d,J＝13.9Hz,1H),3.85(t,J＝9.2Hz,1H),3.69–3.54(m,3H),1.94(s,3H).
Figure PCTCN2020103340-appb-000094
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.42–7.24(m,48H),7.16(dd,J＝7.0,2.5Hz,6H),5.98–5.80(m,3H),5.51–5.33(m,6H),5.00(d,J＝6.3Hz,2H),4.96(d,J＝6.5Hz,1H),4.92(d,J＝7.9Hz,1H),4.87(d,J＝4.2Hz,2H),4.83(d,J＝9.0Hz,2H),4.78(d,J＝8.3Hz,3H),4.76–4.73(m,2H),4.70(d,J＝11.5Hz,2H),4.55(d,J＝11.6Hz,3H),4.51(d,J＝11.8Hz,3H),4.48(d,J＝9.1Hz,2H),4.46–4.43(m,2H),4.43–4.36(m,3H),4.13–4.05(m,3H),3.98(dt,J＝13.9,8.8Hz,3H),3.77(t,J＝8.5Hz,1H),3.74–3.48(m,12H).
Figure PCTCN2020103340-appb-000095
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.33–7.19(m,15H),5.17(s,1H),5.14(t,J＝1.6Hz,1H),4.94(d,J＝9.7Hz,1H),4.89(d,J＝11.0Hz,1H),4.82(d,J＝11.0Hz,1H),4.78(d,J＝11.0Hz,1H),4.71(d,J＝9.7Hz,1H),4.59(d,J＝11.0Hz,1H),4.45(d,J＝9.5Hz,1H),4.07–3.95(m,2H),3.83–3.66(m,3H),3.58–3.47(m,2H),3.34(ddd,J＝9.7,5.1,1.8Hz,1H),1.93(d,J＝1.2Hz,3H),0.84(s,9H),0.02(s,3H),0.00(s,3H).
Figure PCTCN2020103340-appb-000096
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.32–7.28(m,13H),7.17(dt,J＝7.2,2.4Hz,2H),5.00(d,J＝9.7Hz,1H),4.97(d,J＝11.1Hz,1H),4.89(d,J＝10.7Hz,1H),4.85(d,J＝7.8Hz,1H),4.84(s,1H),4.74(d,J＝9.7Hz,1H),4.59(d,J＝10.8Hz,1H),4.48(dd,J＝12.1,1.7Hz,1H),4.03–3.97(m,1H),3.79(t,J＝8.6Hz,1H),3.70–3.63(m,2H),3.60–3.51(m,4H),2.04(s,3H),1.98(s,3H).
Figure PCTCN2020103340-appb-000097
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.58–7.27(m,15H),5.59(s,1H),5.22(s,1H),5.07(s,1H),5.02–4.75(m,4H),4.58(d,J＝9.4Hz,1H),4.37(dd,J＝10.5,5.0Hz,1H),4.16(t,J＝8.9Hz,1H),3.96–3.81(m,3H),3.77(t,J＝9.4Hz,1H),3.66(d,J＝13.6Hz,1H),3.52(dt,J＝9.8,4.9Hz,1H),1.97(s,3H).
Figure PCTCN2020103340-appb-000098
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.47–7.41(m,2H),7.39–7.27(m,8H),5.14(p,J＝1.5Hz,1H),4.99–4.90(m,2H),4.84(d,J＝10.5Hz,1H),4.77(d,J＝10.5Hz,1H),4.64(d,J＝11.9Hz,1H),4.53–4.44(m,2H),4.38(dq,J＝9.0,6.1Hz,1H),3.89(d,J＝13.0Hz,1H),3.71(d,J＝12.8Hz,1H),3.52(dd,J＝8.9,4.3Hz,1H),1.89(t,J＝1.2Hz,3H),1.32(d,J＝6.1Hz,3H).
Figure PCTCN2020103340-appb-000099
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.41–7.17(m,15H),5.23(t,J＝1.6Hz,1H),5.18(s,1H),4.96(d,J＝3.6Hz,1H),4.74(dd,J＝4.8,3.7Hz,1H),4.70(d,J＝11.7Hz,1H),4.59–4.43(m,6H),4.22(dd,J＝8.5,4.8Hz,1H),3.96(d,J＝13.7Hz,1H),3.75–3.62(m,2H),3.56(dd,J＝11.5,4.5Hz,1H),1.99(s,3H).
Figure PCTCN2020103340-appb-000100
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ7.39–7.24(m,15H),5.20(t,J＝1.6Hz,1H),5.15(s,1H),5.02(d,J＝1.5Hz,1H),4.68(d,J＝11.8Hz,1H),4.61–4.42(m,6H),4.39(d,J＝11.6Hz,1H),4.02(dd,J＝8.2,5.2Hz,1H),3.87(d,J＝13.8Hz,1H),3.69(dd,J＝11.0,3.1Hz,1H),3.61(dd,J＝11.0,6.5Hz,1H),3.52(d,J＝13.7Hz,1H),1.94(s,3H).
3-39至3-40化合物的合成采取与上述3-1相同的路线合成，其结构与表征数据如下：
Figure PCTCN2020103340-appb-000101
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ5.96(ddt,J＝16.6,10.0,5.9Hz,1H),5.32(dd,J＝17.2,1.7Hz,1H),5.24–5.18(m,2H),5.13(s,1H),4.44(d,J＝7.9Hz,1H),4.37–4.22(m,4H),4.17(dd,J＝12.6,4.3Hz,1H),4.11(dd,J＝8.0,6.1Hz,1H),3.95(d,J＝13.6Hz,1H),3.89(dd,J＝12.5,4.0Hz,1H),3.67(d,J＝13.6Hz,1H),1.98(d,J＝1.4Hz,3H),1.54(s,3H),1.37(s,3H).
Figure PCTCN2020103340-appb-000102
(2R,3R,4S,5R)-2-(acetoxymethyl)-6-((2-methylenedecyl)sulfonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
纯度大于90％， 1H NMR(400MHz,Chloroform-d)δ5.53(t,J＝9.6Hz,1H),5.31(t,J＝9.4Hz,1H),5.28–5.19(m,2H),5.10(t,J＝9.8Hz,1H),4.57(d,J＝10.0Hz,1H),4.25(dd,J＝5.4,3.8Hz,2H),3.95(d,J＝13.6Hz,1H),3.80(dq,J＝7.4,2.5Hz,1H),3.68(d,J＝13.6Hz,1H),2.26(t,J＝7.7Hz,2H),2.19–1.95(m,12H),1.46(dt,J＝14.7,7.2Hz,2H),1.38–1.15(m,10H),0.88(t,J＝6.6Hz,3H). 13C NMR(101MHz,Chloroform-d)δ170.37,170.09,169.20,169.13,136.99,119.74,85.59,73.16,67.54,66.11,61.64,55.84,35.73,31.85,29.41,29.23,29.09,27.33,22.65,20.68,20.60,20.54,20.52,14.10.
合成硫苷化合物：
然后利用以上制得的烯丙基砜类糖基供体为原料，与糖基受体反应，合成本发明的硫苷化合物。以上述化合物3-1作为原料为例，合成路线如下所示：
路线1：在氮气氛围下，将化合物3-1(1.0equiv)、糖基受体a(1.2equiv)、光敏剂Ir[dF(CF 3)(ppy) 2](dtbbpy)PF 6(0.01equiv)加入到催化反应瓶中，加入乙腈(使化合物3-1的浓度为0.1mol/L)，在Blue LED的照射下室温搅拌4h，即得硫苷化合物S-a。
Figure PCTCN2020103340-appb-000103
其中，Y选自NH或O，R 1选自甲基、
Figure PCTCN2020103340-appb-000104
R 2选自Bz、H、
Figure PCTCN2020103340-appb-000105
Boc。
路线2：在氮气氛围下，将化合物3-1(1.0equiv)、二硫化合物b(2.0equiv)、光敏剂Ir[dF(CF 3)(ppy) 2](dtbbpy)PF 6(0.01equiv)加入到催化反应瓶中，加入乙腈(使化合物3-1的浓度为0.1mol/L)，在Blue LED的照射下45℃搅拌2h，即得硫苷化合物S-b。
Figure PCTCN2020103340-appb-000106
其中，Ar表示芳基。
路线3：在氮气氛围下，将化合物3-1(1.0equiv)、二硫化合物c(2.0equiv)、光敏剂Ir[dF(CF 3)(ppy) 2](dtbbpy)PF 6(0.01equiv)加入到催化反应瓶中，加入乙腈(0.1mol/L)，室温下Blue LED照射下反应2h，即得硫苷化合物S-c。
Figure PCTCN2020103340-appb-000107
其中，Alkyl表示烷基。
路线4：在氮气氛围下，将化合物3-x(1.0equiv)、糖基二硫受体d(1.2equiv)、光敏剂Ir[dF(CF 3)(ppy) 2](dtbbpy)PF 6(0.01equiv)加入到催化反应瓶中，加入乙腈(使化合物3-1的浓度为0.1mol/L)，在Blue LED的照射下室温搅拌4h，即得硫苷化合物S-d。
Figure PCTCN2020103340-appb-000108
本发明上述合成路线不限于以化合物3-1为原料，采用相同的方法，将原料化合物3-1替换为本发明上述制得的任一烯丙基砜类糖基供体，可以得到对应的硫苷化合物。
以下为本发明具体硫苷化合物的合成实施例。
实施例17、本发明硫苷化合物S-1～S-17、S-22的合成
采用上述路线1相同的方法，制得本发明各硫苷化合物S-1～S-17、S-22。结构及表征如下：
Figure PCTCN2020103340-appb-000109
甲基N-苯甲酰基-S-(2,3,4,6-四氧乙酰基-l-α-D-葡萄糖基)-L-半胱氨酸(纯度大于90％，Yield＝92％)
1H NMR(400MHz,Chloroform-d)δ7.83(m,2H),7.58–7.49(m,1H),7.43(m,3H),5.64(d,J＝5.8Hz,1H),5.32–5.20(m,2H),5.07–4.94(m,2H),4.37(ddd,J＝10.3,5.0,2.2Hz,1H),4.25(dd,J＝12.6,5.0Hz,1H),4.16(dd,J＝10.6,2.2Hz,1H),3.80(s,2H),3.35(dd,J＝14.6Hz,J＝3.5Hz,1H),3.13(dd,J＝14.6,3.5Hz,1H),2.07(s,3H),2.02(s,3H),2.02(s,3H),1.99(s,3H).
Figure PCTCN2020103340-appb-000110
甲基N-苯甲酰基-S-(2,3,4,6-四氧乙酰基-2-去氧氨基-α-D-葡萄糖基)-L-半胱氨酸(纯度大于90％，Yield＝70％)
1H NMR(400MHz,Chloroform-d)δ7.89–7.84(m,2H),7.57–7.50(m,2H),7.43(m,2H),5.80(d,J＝8.8Hz,1H),5.41(d,J＝5.3Hz,1H),5.35–5.29(m,1H),5.14–5.07(t,J＝9.6Hz,1H),4.98(dd,J＝11.3,9.3Hz,1H),4.54(ddd,J＝11.3,8.8,5.3Hz,1H),4.32(dt,J＝10.1,3.6Hz,1H),4.20(d,J＝3.7Hz,2H),3.80(s,3H),3.41(dd,J＝14.7,4.7Hz,1H),3.17(dd,J＝14.6,3.3Hz,1H),2.04(s,3H),2.03(s,3H),1.97(s,3H),1.96(s,3H).
Figure PCTCN2020103340-appb-000111
Figure PCTCN2020103340-appb-000112
甲基N-苯甲酰基-S-(2,3,4,6-四氧乙酰基-l-α-D-甘露糖基)-L-半胱氨酸(纯度大于90％，Yield＝88％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.85(m,2H),7.57–7.50(m,1H),7.43(m,2H),5.38(dd,J＝3.3,1.7Hz,1H),5.32–5.24(m,3H),5.18(dd,J＝10.0,3.3Hz,1H),4.33(d,J＝4.4Hz,1H),4.26–4.15(m,2H),3.80(s,3H),3.38(dd,J＝14.5,4.9Hz,1H),3.22(dd,J＝14.5,3.6Hz,1H),2.14(s,3H),2.05(s,3H),1.99(s,3H),1.95(s,3H).
Figure PCTCN2020103340-appb-000113
甲基N-苯甲酰基-S-(2,3,4–三氧乙酰基-l-α-D-鼠李糖基)-L-半胱氨酸(纯度大于90％，Yield＝87％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.86(m,2H),7.57–7.50(m,1H),7.43(m,2H),5.34(dd,J＝3.4,1.6Hz,1H),5.22(d,J＝1.6Hz,1H),5.18(dd,J＝10.0,3.4Hz,1H),5.11–5.04(m,2H),4.21–4.07(m,1H),3.35(dd,J＝13.9,5.0Hz,1H),3.16(dd,J＝13.9,4.9Hz,1H),2.09(s,3H),2.05(s,3H),1.97(s,3H),1.23(d,J＝6.2Hz,3H).
Figure PCTCN2020103340-appb-000114
甲基N-苯甲酰基-S-(3,4,6–三氧乙酰基-2-去氧-α-D-葡萄糖基)-L-半胱氨酸(纯度大于90％，Yield＝72％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.86(m,2H),7.57–7.50(m,1H),7.43(m,2H),5.43–5.39(m,d,J＝5.1Hz,1H),5.29–5.23(m,1H),5.21–5.13(m,1H),4.96(t,J＝9.6Hz,1H),4.33(ddd,J＝9.8,5.3,2.0Hz,1H),4.27(dd,J＝12.3,5.3Hz,1H),4.13(dd,J＝12.3,2.0Hz,1H),3.79(s,3H),3.35(dd,J＝14.6,5.0Hz,1H),3.16(dd,J＝14.6,3.6Hz,1H),2.35(ddd,J＝13.4,5.2,1.4Hz,1H),2.25–2.14(m,1H),2.04(s,3H),2.00(s,3H),1.97(s,3H).
Figure PCTCN2020103340-appb-000115
甲基N-苯甲酰基-S-(2’,3’,6’,2,3,4,6–七氧乙酰基-α-D麦芽糖基)-L-半胱氨酸(纯度大于90％，Yield＝75％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.86(m,2H),7.57–7.50(m,1H),7.43(m,2H),5.50(d,J＝5.7Hz,1H),5.42–5.32(m,2H),5.30–5.21(m,2H),5.12–5.04(t,J＝9.8Hz,1H),4.91(m,2H),4.51(d,J＝2.3Hz,1H),4.31(ddd,J＝9.8,5.2,2.2Hz,1H),4.24(dd,J＝12.4,3.8Hz,1H),4.15(dd,J＝12.3,5.3Hz,1H),4.07(dd,J＝12.5,2.4Hz,1H),4.03–3.97(m,1H),3.87(dd,J＝9.8,7.9Hz,1H),3.83(s,3H),3.34(dd,J＝14.6,4.7Hz,1H),3.16(dd,J＝14.6,3.6Hz,1H),2.10(s,3H),2.06(s,3H),2.05(s,2H),2.04(s,3H),2.03(s,3H),2.01(s,2H),2.00(s,3H).
Figure PCTCN2020103340-appb-000116
甲基N-苯甲酰基-S-(2’,3’,6’,2,3,4,6–七氧乙酰基-α-D乳糖基)-L-半胱氨酸(纯度大于90％，Yield＝80％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.86(m,2H),7.57–7.51(m,1H),7.42(m,2H),5.56(d,J＝5.7Hz,1H),5.35(d,J＝3.4Hz,1H),5.27(t,J＝9.5Hz,1H),5.22(m,1H),5.10(dd,J＝10.4,7.9Hz,1H),4.99–4.93(m,2H),4.54–4.47(m,2H),4.27(ddd,J＝10.1,5.4,1.9Hz,1H),4.18–4.05(m,3H),3.89(t,J＝6.9Hz,1H),3.78(s,3H),3.75–3.70(t,J＝9.4Hz,1H),3.30(dd,J＝14.5,5.0Hz,1H),3.11(dd,J＝14.5,3.6Hz,1H),2.14(s,3H),2.06(s,3H),2.05(s,6H),2.04(s,3H),2.01(s,3H),1.96(s,3H).
Figure PCTCN2020103340-appb-000117
甲基N-苯甲酰基-S-(2,3,4–三氧乙酰基-α-L-来苏糖基)-L-半胱氨酸(纯度大于90％，Yield＝63％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.86(m,2H),7.57–7.51(m,1H),7.42(m,2H),5.29(dd,J＝4.5,3.3Hz,1H),5.22(dd,J＝8.1,3.3Hz,1H),5.15 (dt,J＝8.3,4.3Hz,1H),5.13–5.06(m,1H),5.05–5.02(m,1H),3.86(d,J＝2.3Hz,1H),3.80(s,3H),3.79(d,J＝2.8Hz,1H),3.41(dd,J＝14.5,4.7Hz,1H),3.15(dd,J＝14.5,3.9Hz,1H),2.09(s,3H),2.07(s,3H),2.04(s,3H).
Figure PCTCN2020103340-appb-000118
甲基N-苯甲酰基-S-(2,3,4–三氧乙酰基-α-D-阿拉伯糖基)-L-半胱氨酸(纯度大于90％，Yield＝76％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.86(m,2H),7.57–7.51(m,1H),7.42(m,2H),5.72(d,J＝5.3Hz,1H),5.30–5.27(m,1H),5.23(dd,J＝10.1,5.1Hz,1H),5.17–5.13(m,1H),5.08–5.03(m,1H),4.21–4.15(dd,J＝13.2,1.5Hz,1H),3.80(s,3H),3.35(dd,J＝14.1,4.6Hz,1H),3.05(dd,J＝14.1,5.3Hz,1H),2.11(s,3H),2.05(s,2H),2.00(s,3H).
Figure PCTCN2020103340-appb-000119
甲基N-苯甲酰基-S-(2,3,5–三氧乙酰基-α-D-核糖基)-L-半胱氨酸(纯度大于90％，Yield＝78％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.86(m,2H),7.57–7.51(m,1H),7.42(m,2H),5.48(t,J＝3.2Hz,1H),4.92(d,J＝7.7Hz,1H),5.02(m,3H),3.97(dd,J＝11.6,4.4Hz,1H),3.80(s,3H),3.71(dd,J＝11.6,8.3Hz,1H),3.34(dd,J＝14.3,4.7Hz,1H),3.20(dd,J＝14.3,5.3Hz,1H),2.05(s,3H),2.04(s,3H),2.03(s,3H).
Figure PCTCN2020103340-appb-000120
甲基N-苯甲酰基-S-(2,3,4,6–四氧乙酰基-α-D-半乳糖基)-L-半胱氨酸(纯度大于90％，Yield＝63％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.86(m,2H),7.57–7.51(m,1H),7.42(m,2H),5.72(d,J＝5.6Hz,1H),5.44(d,J＝3.3,1H),5.27(dd,J＝11.1,5.6Hz,1H),5.20(m,1H),5.14(dd,J＝11.0,3.3Hz,1H),4.56(t,J＝6.4Hz, 1H),4.17(dd,J＝11.4,5.2Hz,1H),4.03(dd,J＝11.4,7.4Hz,1H),3.80(s,3H),3.34(dd,J＝14.5,4.9Hz,1H),3.13(dd,J＝14.4,3.8Hz,1H),2.15(s,3H),2.07(s,3H),1.99(s,3H),1.91(s,3H).
Figure PCTCN2020103340-appb-000121
甲基N-苯甲酰基-S-(2,3,4–三氧乙酰基-α-L-岩藻糖基)-L-半胱氨酸(纯度大于90％，Yield＝71％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.86(m,2H),7.57–7.51(m,1H),7.42(m,2H),5.82(d,J＝5.1Hz,1H),5.26(m,1H),5.22–5.16(m,2H),5.08(m,1H),4.40(q,J＝6.5Hz,1H),3.81(s,3H),3.28(dd,J＝14.0,4.6Hz,1H),3.05(dd,J＝14.0,5.2Hz,1H),2.15(s,3H),2.04(s,3H),1.98(s,3H),1.15(d,J＝6.5Hz,3H).
Figure PCTCN2020103340-appb-000122
甲基N-苯甲酰基-S-(2,3,4–三氧乙酰基-α-L-木糖基)-L-半胱氨酸(纯度大于90％，Yield＝73％)
1H NMR(400MHz,Chloroform-d)δ5.50(d,J＝5.3Hz,1H),5.23(t,J＝9.2Hz,1H),5.17(m,1H),5.05(m,1H),4.99–4.87(m,4H),4.54(d,J＝9.2Hz,1H),4.10(dd,J＝11.6,5.3Hz,1H),3.98–3.89(m,1H),3.80(s,3H),3.38(s,3H),3.38–3.30(m,2H),3.20(dd,J＝14.4,5.3Hz,1H),3.11(dd,J＝14.5,3.8Hz,1H),2.07(s,3H),2.04(s,3H),2.03(s,6H),1.99(s,6H).
Figure PCTCN2020103340-appb-000123
甲基N-(N-叔丁氧基-L-缬氨酸基)-S-(2,3,4,6–四氧乙酰基-D-葡萄糖基)-L-半胱氨酸(纯度大于90％，Yield＝70％)
1H NMR(400MHz,Chloroform-d)δ5.60(d,J＝5.8Hz,1H),5.25(d,J＝9.8Hz,1H),5.17–5.07(m,1H),5.02–4.96(m,1H),4.91(m,1H),4.35–4.28(m,2H),4.26–4.20(m,1H),4.01(m,1H),3.78(s,3H),3.16–3.03(m,2H),2.22–2.15(m,1H),2.11(s,3H),2.06(s,2H),2.04(s,3H),2.01(s,3H),1.46(s,9H),1.00–0.97(d,J＝6.9Hz,3H),0.93(d,J＝6.9Hz,3H).
Figure PCTCN2020103340-appb-000124
甲基N-(N-叔丁氧基-L-苏氨酸基)-S-(2,3,4,6–四氧乙酰基-D-葡萄糖基)-L-半胱氨酸(纯度大于90％，Yield＝90％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.86(m,2H),7.65(t,J＝7.4Hz,1H),7.59–7.52(m,2H),7.48(d,J＝7.9Hz,1H),5.67(d,J＝5.7Hz,1H),5.54(d,J＝7.7Hz,1H),5.27(t,J＝9.8Hz,1H),5.08–5.01(m,1H),4.96(dd,J＝10.4,5.8Hz,1H),4.94–4.88(m,1H),4.40(dd,J＝6.6,2.4Hz,1H),4.33(dt,J＝10.1,3.6Hz,1H),4.25(d,J＝2.6Hz,2H),4.19–4.14(m,1H),3.76(s,3H),3.08(d,J＝4.8Hz,2H),2.12(s,3H),2.06(s,3H),2.04(s,3H),2.01(s,3H),1.48(s,9H),1.21(d,J＝6.3Hz,3H)
Figure PCTCN2020103340-appb-000125
甲基N-(N-叔丁氧基-L-酪氨酸基)-S-(2,3,4,6–四氧乙酰基-D-葡萄糖基)-L-半胱氨酸(纯度大于90％，Yield＝70％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.86(m,2H),7.65(t,J＝7.4Hz,1H),7.59–7.52(m,2H),5.42(d,J＝5.7Hz,1H),5.27(d,J＝10.0Hz,1H),5.14–5.03(m,1H),4.96(dd,J＝10.4,5.7Hz,1H),4.87–4.72(m,2H),4.38(m,1H),4.34–4.25(m,2H),4.19(d,J＝10.5Hz,1H),3.77(s,3H),3.11(dd,J＝14.0,6.0Hz,1H),3.04m,2H),2.94(dd,J＝14.0,6.4Hz,1H),2.10(s,3H),2.05(s,3H),2.05(s,3H),2.03(s,3H),1.44(s,9H).
Figure PCTCN2020103340-appb-000126
甲基N-(N-叔丁氧基-L-色氨酸基)-S-(2,3,4,6–四氧乙酰基-D-葡萄糖基)-L-半胱氨酸(纯度大于90％，Yield＝81％)
1H NMR(400MHz,Chloroform-d)δ8.81(s,1H),7.63(d,J＝7.9Hz,1H),7.38(d,J＝8.0Hz,1H),7.22–7.15(m,1H),7.15–7.08(m,2H),6.93(d,J＝7.9Hz,1H),5.23–5.14(t,J＝9.8Hz,1H),5.09(m,2H),4.89(dd,J＝10.3,5.8Hz,2H),4.85–4.79(m,1H),4.58(s,1H),4.24(dt,J＝10.2,3.7Hz,1H),4.17(s,1H),3.68(s,3H),3.47(dd,J＝14.6,4.7Hz,1H),3.15(dd,J＝14.6,6.1Hz,1H),2.95(dd,J＝14.3,5.6Hz,2H),2.78(m,1H),2.07(s,3H),2.04(s,3H),2.04(s,3H),2.02(s,3H),1.46(s,9H).
Figure PCTCN2020103340-appb-000127
(2,3,4,6-四乙酰基-1-α-D-吡喃葡萄糖基)-L-半胱氨酸甲酯(纯度大于90％，Yield＝28％)
1H NMR(400MHz,Chloroform-d)δ5.71(d,J＝5.8Hz,1H),5.34(t,J＝9.8Hz,1H),5.07–4.98(m,2H),4.41(ddd,J＝10.1,4.8,2.2Hz,1H),4.29(dd,J＝12.4,5.1Hz,1H),4.14–4.10(m,1H),3.74(s,3H),3.71(m,1H),2.92(d,J＝5.9Hz,2H),2.10(s,3H),2.07(s,3H),2.04(s,3H),2.01(s,3H).
实施例18、本发明硫苷化合物S-18的合成
采用与上述路线1相同的方法，制得本发明硫苷化合物S18，路线如下：
Figure PCTCN2020103340-appb-000128
甲基N-(N-叔丁氧基-L-蛋氨酸基)-S-(2,3,4,6–四氧乙酰基-D-葡萄糖基)-L-半胱氨酸(纯度大于90％，Yield＝80％)
1H NMR(400MHz,Chloroform-d)δ7.90–7.87(m,2H),7.67–7.62(m,1H),7.55(m,2H),5.68(d,J＝5.8Hz,1H),5.48(d,J＝8.2Hz,1H),5.34–5.28(m,1H),5.08–5.00(m,2H),4.68(m,1H),4.39(ddd,J＝10.0,4.5,2.5Hz,1H),4.33 (dd,J＝12.3,4.5Hz,1H),4.16(dd,J＝12.3,2.5Hz,0H),3.77(s,3H),3.12(dd,J＝14.1,6.7Hz,1H),2.93(dd,J＝14.0,5.1Hz,1H),2.52(t,J＝7.4Hz,2H),2.22–2.13(m,2H),2.10(s,3H),2.09(s,3H),2.07(s,3H),2.03(s,3H),2.01(s,3H),1.46(s,9H).
实施例19、本发明硫苷化合物S-19～S-21的合成
采用上述路线2相同的方法，制得本发明各硫苷化合物S-19～S-21。结构及表征如下：
Figure PCTCN2020103340-appb-000129
苯基-2,3,4,6-四乙酰基-1-硫-α-D-吡喃葡萄糖(纯度大于90％，Yield＝84％)
1H NMR(400MHz,Chloroform-d)δ7.46–7.42(m,2H),7.33–7.27(m,3H),5.92(d,J＝5.7Hz,0H),5.48–5.40(t,J＝10.0Hz,1H),5.09(m,1H),4.57(ddd,J＝10.3,5.2,2.2Hz,1H),4.28(dd,J＝12.4,5.2Hz,1H),4.04(dd,J＝12.3,2.3Hz,1H),2.11(s,3H),2.06(s,1H),2.04(s,3H),2.03(s,3H).
Figure PCTCN2020103340-appb-000130
2-吡啶基-2,3,4,6-四乙酰基-1-硫-α-D-吡喃葡萄糖(纯度大于90％，Yield＝82％)
1H NMR(400MHz,Chloroform-d)δ7.78(m,1H),7.30(m,1H),7.08(m,1H),6.68(d,J＝5.7Hz,1H),5.41(t,J＝9.8Hz,1H),5.26(dd,J＝10.3,5.7Hz,1H),5.13(t,J＝9.8Hz,1H),4.38(ddd,J＝10.2,4.5,2.3Hz,1H),4.27(dd,J＝12.4,4.6Hz,1H),4.01(dd,J＝12.4,2.3Hz,1H),2.04(s,3H),2.04(s,3H),2.02(s,3H),1.98(s,3H).
Figure PCTCN2020103340-appb-000131
甲基-2,3,4,6-四乙酰基-1-硫-α-D-吡喃葡萄糖(纯度大于90％，Yield＝75％)
1H NMR(400MHz,Chloroform-d)δ5.55(d,J＝5.8Hz,1H),5.42–5.36(t,J＝9.8Hz,1H),5.09–5.01(m,2H),4.39(ddd,J＝10.2,4.9,2.3Hz,1H),4.30(dd,J＝12.3,4.9Hz,1H),4.09(dd,J＝12.3,2.3Hz,1H),2.09(s,3H),2.06(s,3H),2.06(s,3H),2.03(s,3H),2.01(s,3H).
实施例20、本发明硫苷化合物S-23的合成
采用上述路线4相同的方法，制得本发明各硫苷化合物S-23。结构及表征如下：
Figure PCTCN2020103340-appb-000132
(2,3,4,6-四氧乙酰基-α-D-葡萄糖基)-2,3,4,6-四氧乙酰基-1-硫-β-D-葡萄糖苷(纯度大于90％，Yield＝74％)
1H NMR(400MHz,Chloroform-d)δ5.94(d,J＝5.6Hz,1H),5.30(t,J＝9.9Hz,1H),5.20-4.97(m,5H),4.56(d,J＝9.9Hz,1H),4.41-4.38(m,2H),4.20-4.08(m,3H),3.74-3.72(m,1H),2.11,2.10,2.03,2.02,2.00(5 x s,24H,8 x CH3)
实施例21、本发明硫苷化合物S-24的合成
采用以下合成路线，制得本发明各硫苷化合物S-24。结构及表征如下：
Figure PCTCN2020103340-appb-000133
5-三氟甲基吡啶-1-硫-(2,3,4,6-四氧乙酰基-β-D-葡萄糖基)二硫化物
1H NMR(400MHz,Chloroform-d)δ8.74–8.51(s,1H),8.02(d,J＝8.5Hz,1H),7.83(dd,J＝8.6,2.3Hz,1H),5.31–5.20(m,2H),5.10–5.02(m,1H),4.73–4.64(m,1H),4.10–3.95(m,2H),3.70(ddd,J＝10.1,4.4,2.8Hz,1H),2.09(s,3H),2.01(s,6H),1.87(s,3H).
具体制备方法为：
0℃下，将10mmol的Ⅰ-24溶于二氯甲烷(30mL)中，先后缓慢滴加硫代乙酸(1.7mL,24mmol)和三氟化硼乙醚(3.7mL,30mmol)，随后升至室温搅拌过夜。原料反应完全后，用冰水淬灭，二氯甲烷萃取，饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥有机相，抽滤并旋干滤液，得到产物Ⅱ-24。
Ⅱ-24和半胱氨酸甲酯盐酸盐(2.05g,12mmol)溶于DMF(10mL)中，加入三乙胺(1.7mL,12mmol)室温搅拌8小时。TLC监测Ⅱ反应完全后，经乙酸乙酯萃取，半饱和食盐水洗涤后，用无水硫酸钠干燥有机相，抽滤并旋干滤液，采用柱层析法纯化得到产物Ⅲ-24。
Ⅲ-24(1.82g,5mmol)和2,2’-双(5-三氟甲基吡啶基)二硫(3.6g,10mmol)溶于二氯甲烷(20mL)中，室温搅拌1小时，旋干溶剂后，采用柱层析法纯化得到产物S-24，纯度大于90％，三步产率57％。
合成氧苷化合物：
然后利用以上制得的烯丙基砜类糖基供体为原料，与糖基受体反应，合成本发明的氧苷化合物。具体实施例如下：
实施例22、本发明氧苷化合物O-1的合成
在氮气氛围下，将烯丙基砜类糖基供体(化合物16-1，1.5equiv)、糖基受体(1.0equiv)加入到催化反应瓶中，加入引发剂全氟碘代丁烷(5.0equiv)、磷酸氢二铵(5.0equiv)、三苯基氧磷(0.3equiv)、甲基叔丁基醚0.5mL，在Blue LED的照射下室温搅拌24h，即得氧苷化合物O-1，纯度大于90％。
Figure PCTCN2020103340-appb-000134
氧苷化合物O-1的表征： 1H NMR(400MHz,Chloroform-d)δ7.37–7.24(m,18H),7.13(dd,J＝7.3,2.2Hz,2H),4.96(d,J＝10.8Hz,1H),4.83(d,J＝3.7Hz,1H),4.82–4.77(m,2H),4.74(d,J＝3.6Hz,1H),4.63(d,J＝12.1Hz,1H),4.57(d,J＝12.1Hz,1H),4.48(d,J＝7.5Hz,1H),4.45(d,J＝8.8Hz,1H),3.96(t,J＝9.3Hz,1H),3.84–3.75(m,2H),3.73–3.59(m,4H),3.57(dd,J＝9.7,3.7Hz,1H),2.61(t,J＝6.5Hz,2H)； 13C NMR(101MHz,Chloroform-d)δ138.78,138.20,137.87,128.59,128.47,128.44,128.23,128.09,128.00,127.96,127.93,127.82,127.78,127.70,117.65,97.78,81.87,79.95,75.83,75.12,73.63,73.57,70.89,68.46,63.22,18.79。
实施例23、本发明氧苷化合物O-4的合成
Figure PCTCN2020103340-appb-000135
采用与氧苷化合物O-1相同的方法，区别仅在于将糖基受体从
Figure PCTCN2020103340-appb-000136
替换为
Figure PCTCN2020103340-appb-000137
制得本发明各氧苷化合物O-4，纯度大于90％。结构表征如下： 1H NMR(400MHz,Chloroform-d)δ7.26–7.15(m,18H), 7.06(dd,J＝7.4,2.1Hz,2H),5.21(d,J＝3.7Hz,1H),4.91(d,J＝10.8Hz,1H),4.75(d,J＝10.7Hz,1H),4.72(d,J＝10.9Hz,1H),4.60(s,2H),4.55(d,J＝12.1Hz,1H),4.39(d,J＝8.9Hz,1H),4.36(d,J＝10.3Hz,1H),3.98–3.89(m,2H),3.68(dd,J＝10.5,3.6Hz,1H),3.60–3.50(m,2H),3.46(dd,J＝9.7,3.7Hz,1H),2.05(t,J＝3.2Hz,3H),1.76(dt,J＝13.9,11.2Hz,6H),1.53(q,J＝5.5,4.7Hz,6H)； 13C NMR(101MHz,Chloroform-d)δ139.14,138.44,138.39,138.17,128.40,128.37,128.33,128.17,128.00,127.92,127.86,127.77,127.69,127.61,127.49,89.90,82.14,80.17,78.23,75.56,75.12,74.58,73.49,72.89,69.76,68.88,42.52,36.35,30.72.
实施例24、本发明氧苷化合物O-10的合成
Figure PCTCN2020103340-appb-000138
采用与氧苷化合物O-1相同的方法，区别仅在于将糖基受体从
Figure PCTCN2020103340-appb-000139
替换为
Figure PCTCN2020103340-appb-000140
制得本发明各氧苷化合物O-10，纯度大于90％。结构表征如下： 1H NMR(400MHz,Chloroform-d)δ7.62(d,J＝1.7Hz,1H),7.55(d,J＝8.5Hz,1H),7.45(d,J＝8.8Hz,1H),7.34(dd,J＝8.5,1.9Hz,1H),7.32–7.22(m,13H),7.20(d,J＝6.4Hz,2H),7.13(ddd,J＝11.5,6.9,2.0Hz,4H),7.07(dd,J＝6.7,2.9Hz,2H),7.06–7.00(m,2H),6.43(d,J＝3.2Hz,1H),4.73(d,J＝10.8Hz,1H),4.57(t,J＝11.9Hz,2H),4.48–4.38(m,4H),4.31(d,J＝11.1Hz,1H),3.91(q,J＝7.1Hz,1H),3.83(s,3H),3.79(ddd,J＝9.9,3.6,2.1Hz,1H),3.68–3.61(m,1H),3.60(d,J＝2.2Hz,1H),3.59–3.53(m,2H),3.48(t,J＝9.2Hz,1H),1.59(d,J＝7.1Hz,3H)； 13C NMR(100MHz,Chloroform-d)δ172.81,157.58,138.63,138.12,137.86,137.72,135.36,133.69,129.35,128.90,128.41,128.38,128.28,128.27,128.16,127.95,127.80,127.75,127.49,126.96,126.74,126.26,118.82,105.54,90.45,81.22,79.47,76.70,75.36,75.07,73.52,73.19,72.98,68.22,55.26,55.24,45.51,18.03.
合成碳苷化合物：
然后利用以上制得的烯丙基砜类糖基供体为原料，与糖基受体反应，合成本发明的碳苷化合物。以上述化合物3-1作为原料为例，合成路线如下所示：
Figure PCTCN2020103340-appb-000141
在氮气氛围下，将糖基供体3-1(1.0equiv)、糖基受体四氟硼酸吡啶盐(2.0equiv)、光敏剂EosinY(曙红Y,0.025equiv.)、引发剂三氟甲基亚磺酸钠(0.2equiv.)加入到催化反应瓶中，加入DMSO，在Blue LED的照射下，室温搅拌8h，即得到碳苷化合物C-X。
以下为合成碳苷化合物的具体实施例：
实施例25、本发明碳苷化合物的合成
采用上述路线相同的方法，制得本发明的碳苷化合物C-1、C-2、C-4、C-6、C-8，结构及表征如下：
Figure PCTCN2020103340-appb-000142
(2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(4-cyanopyridin-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate(C-1)，纯度大于90％。 1H NMR(400MHz,Chloroform-d)δ8.84(d,J＝5.0Hz,1H),7.68(d,J＝1.5Hz,1H),7.53(d,J＝5.0Hz,1H),5.78(t,J＝6.6Hz,1H),5.50–5.26(m,2H),5.21–5.00(m,1H),4.58–4.32(m,2H),4.23–4.05(m,1H),2.18–2.00(m,9H),1.85(d,J＝1.2Hz,3H).
Figure PCTCN2020103340-appb-000143
(2R,3S,4R,5S,6R)-2-(acetoxymethyl)-6-(4-cyanopyridin-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate(C-2)，纯度大于90％。 1H NMR(400MHz,Chloroform-d)δ8.74(d,J＝5.0Hz,1H),7.61(s,1H),7.45(dd,J＝4.9,1.5Hz,1H),5.69(dd,J＝6.8,3.3Hz,1H),5.57–5.42(m,2H),5.34(d,J＝4.1Hz,1H),4.64–4.56(m,1H),4.50(dd,J＝12.0,8.4Hz,1H),4.11(dd,J＝12.0,4.2Hz,1H),2.09(d,J＝4.5Hz,6H),2.00(s,3H),1.81(s,3H).
Figure PCTCN2020103340-appb-000144
(2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((2R,3R,4S,5S,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-(4-cyanopyridin-2-yl)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate(C-4)，纯度大于90％。 1H NMR(400MHz,Chloroform-d)δ8.83–8.69(m,1H),7.79(s,1H),7.48(dd,J＝5.0,1.5Hz,1H),5.81–5.61(m,1H),5.44–5.34(m,2H),5.28(d,J＝3.9Hz,1H),5.17(dd,J＝10.4,7.8Hz,1H),5.03(dd,J＝10.5,3.4Hz,1H),4.69(d,J＝7.9Hz,1H),4.32(s,3H),4.11(dd,J＝6.7,3.0Hz,2H),3.99(t,J＝6.7Hz,1H),3.82–3.67(m,1H),2.18–2.11(m,9H),2.09(s,3H),2.05(s,3H),1.98(s,3H),1.85(s,3H).
Figure PCTCN2020103340-appb-000145
(2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(4-(trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate(C-6)，纯度大于90％。 1H NMR(400MHz,Chloroform-d)δ8.85(d,J＝5.1Hz,1H),7.63(s,1H),7.51(dd,J＝5.1,1.6Hz,1H),5.86(t,J＝6.4Hz,1H),5.38(d,J＝6.4Hz,2H),5.11(t,J＝7.2Hz,1H),4.48(ddd,J＝7.9,5.8,3.1Hz,1H),4.38(dd,J＝12.2,5.8Hz,1H),4.12(dd,J＝12.2,3.2Hz,1H),2.19–2.00(m,9H),1.83(s,3H).
Figure PCTCN2020103340-appb-000146
(2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(pyridin-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate(C-8)。 1H NMR(400MHz,Chloroform-d)δ8.68(dd,J＝4.8,1.7Hz,1H),7.71(td,J＝7.7,1.8Hz,1H),7.33(d,J＝7.8Hz,1H),7.28(q,J＝5.0,4.3Hz,1H),6.17(t,J＝8.1Hz,1H),5.39–5.24(m,2H),5.16(t,J＝8.4Hz,1H),4.62–4.48(m,1H),4.30(dd,J＝12.3,4.7Hz,1H),4.06(dd,J＝12.3,2.8Hz,1H),2.07(d,J＝3.7Hz,9H),1.82(s,3H).
综上所述，本发明提供了一种式I所示的糖基供体及其制备方法，以及式I所示的糖基供体在制备式III所示的硫苷、式IV所示的氧苷、式V所示的碳苷类合物中的用途。本发明提供的糖基供体结构新颖，制备方法简单；本发明还以上述糖基供体为原料，利用自由基反应，制备得到了氧苷、硫苷、碳苷类化合物，其中大部分具有特殊的α构型，该制备方法简单、反应条件温和、收率高，具有非常好的应用前景。

Claims (21)

  1. 一种糖基供体、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述糖基供体的结构如式I所示：
    Figure PCTCN2020103340-appb-100001
    其中，A环选自
    Figure PCTCN2020103340-appb-100002
    R 1、R 2、R 3、R 4各自独立地选自H、C 1-6烷基、芳基或者杂芳基取代的C 1-12烷基、C 1-12烷氧基、C 2-8炔基、C 2-8烯基、芳香基、杂芳基、环烷基、M 1OH、M 1NH 2、M 1NHAc、M 1OAc、M 1OBz、M 1OBn、M 1N 3、M 1OTMS、M 1OTBS、
    Figure PCTCN2020103340-appb-100003
    Figure PCTCN2020103340-appb-100004
    或者R 1、R 2、R 3、R 4中的任意2个连接成环；M 1选自0-3个亚甲基；M 2、M 3、M 4选自H、C 1-6烷基、芳基或者杂芳基取代的C 1-12烷基、C 2-8炔基、C 2-8烯基、芳香基、杂芳基，或者M 3、M 4连接成环；
    R 5选自C 1-10烷基、饱和环烷基、饱和杂环基、H、芳香基、杂芳基、C 1～10烷氧基、卤素、氰基、羧基、酯基；
    R 6、R 7、R 8、R 9各自独立地选自H、卤素、C 1-6烷基、C 1-6烷氧基、M 1OH、C 2-8炔基、C 2-8烯基、饱和环烷基、饱和杂环基、H、芳香基、杂芳基、氰基、酯基；M 1选自0-3个亚甲基。
  2. 根据权利要求1所述的糖基供体、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述糖基供体的结构如式II-1或II-2所示：
    Figure PCTCN2020103340-appb-100005
    其中，R 1、R 2、R 3、R 4各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、芳香基、杂芳基、环烷基、M 1OH、M 1NH 2、M 1NHAc、M 1OAc、M 1OBz、M 1OBn、M 1N 3、M 1OTMS、M 1OTBS、
    Figure PCTCN2020103340-appb-100006
    或 者R 1、R 2、R 3、R 4中的任意2个连接成取代或未取代的环，该环上的取代基各自独立的选自1个或多个氢、氘、C 1-8烷基、C 1～8烷氧基、C 2-8炔基、C 2-8烯基、芳香基、杂芳基、卤素、氰基、羧基或酯基；
    M 1选自0-3个亚甲基；
    R 5选自C 1-8烷基、饱和环烷基、饱和杂环基、H、芳香基、杂芳基、C 1～8烷氧基、卤素、氰基、羧基、酯基；
    优选地，所述R 1、R 2、R 3、R 4各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 2-3炔基、C 2-3烯基、芳香基、杂芳基、环烷基、M 1OH、M 1NHAc、M 1OAc、M 1OBz、
    Figure PCTCN2020103340-appb-100007
    或者R 1、R 2、R 3、R 4中的任意2个连接成环，该环上的取代基各自独立的选自1个或多个氢、氘、C 1-4烷基、C 1～4烷氧基、C 2-3炔基、C 2-3烯基、苯基、杂芳基、卤素、氰基、羧基或酯基；M 1选自0-1个亚甲基；
    R 5选自H、苯基、C 1-8烷基。
  3. 根据权利要求1或2所述的糖基供体、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述糖基供体的结构选自选自：
    Figure PCTCN2020103340-appb-100008
  4. 根据权利要求1～3任一项所述的糖基供体、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述糖基供体的结构选自选自：
    Figure PCTCN2020103340-appb-100009
    其中，
    Figure PCTCN2020103340-appb-100010
    表示
    Figure PCTCN2020103340-appb-100011
    或二者的任意比例混合物。
  5. 一种硫苷化合物、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述硫苷化合物的结构如式III所示：
    Figure PCTCN2020103340-appb-100012
    其中，R 10选自
    Figure PCTCN2020103340-appb-100013
    取代或未取代的芳基、取代或未取代的 杂芳基、取代或未取代的烷基、
    Figure PCTCN2020103340-appb-100014
    肽链去掉一个氢原子后剩下的基团，所述取代基选自卤素、卤代烷基；上述m表示1-5的整数；
    上述Y选自无、NH或O；R 1a、R 2a选自各自独立地选自H、Boc、Bz、C 1-6烷基、C 1-6烷氧基、芳基、杂芳基、肽链去掉一个氢原子后剩下的基团、
    Figure PCTCN2020103340-appb-100015
    其中m 1、m 2各自独立地选自0-5的整数；R a1选自取代或未取代的C 1-6烷基，所述取代基选自卤素、羟基；R a3选自取代或未取代的C 1-6烷基、芳基、杂芳基，所述取代基选自卤素、羟基；
    A环选自
    Figure PCTCN2020103340-appb-100016
    R 1、R 2、R 3、R 4如权利要求1～4任一项所述。
  6. 根据权利要求5所述的硫苷化合物、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述硫苷化合物的结构如式III-1、III-2、III-3或III-4所示：
    Figure PCTCN2020103340-appb-100017
    式III-1和式III-3中：当Y选自O时，R 1a选自甲基，R 2a选自Bz、H、
    Figure PCTCN2020103340-appb-100018
    当Y选自NH时，R 1a选自
    Figure PCTCN2020103340-appb-100019
    R 2a选自Boc；当Y选自无时，R 1a选自甲氧 基，R 2a选自Bz；
    式III-2和式III-4中：R 10选自取代或未取代的苯环、取代或未取代的氮杂芳环、甲基、
    Figure PCTCN2020103340-appb-100020
    所述取代基选自卤素、卤代烷基；
    式III-1、式III-2、III-3和III-4中：R 1、R 2、R 3、R 4如权利要求1～4任一项所述。
  7. 根据权利要求6所述的硫苷化合物、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述硫苷化合物的结构选自：
    Figure PCTCN2020103340-appb-100021
  8. 根据权利要求7所述的硫苷化合物、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述硫苷化合物的结构选自：
    Figure PCTCN2020103340-appb-100022
    Figure PCTCN2020103340-appb-100023
  9. 一种氧苷化合物、或其盐、或其立体异构体、或其旋光异构体，其特 征在于：所述氧苷化合物的结构如式IV所示：
    Figure PCTCN2020103340-appb-100024
    其中，R 11选自L 0R 12或COL 0R 12，L 0选自0～3个亚烷基，R 12选自取代或未取代的C 1～6烷基、取代或未取代的环；所述取代基为1个或多个，所述取代基各自独立的选自CN、C 1～6烷氧基、C 1～6烷氧基、L 1(COOEt)NHBz、OH、NH 2、NHAc、OAc、OBz、OBn，L 1选自0～3个亚烷基；A环选自
    Figure PCTCN2020103340-appb-100025
    Figure PCTCN2020103340-appb-100026
    R 1、R 2、R 3、R 4如权利要求1～4任一项所述。
  10. 根据权利要求9所述的氧苷化合物、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述氧苷化合物的结构如式IV-1、IV-2、IV-3、IV-4、IV-5和IV-6所示：
    Figure PCTCN2020103340-appb-100027
    其中，R 1、R 2、R 3、R 4如权利要求1～4任一项所述；L 0选自0～2个亚烷基，R 12选自取代或未取代的C 1～3烷基、取代或未取代的饱和单环碳环、饱和单环杂环、桥环、螺环、稠环；所述取代基、R 13各自独立的选自CN、C 1～3烷氧基、C 1～3烷氧基、L 1(COOEt)NHBz、OH、NH 2、NHAc、OAc、OBz、OBn，L 1选自0～1个亚烷基。
  11. 根据权利要求10所述的氧苷化合物、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述氧苷化合物的结构选自：
    Figure PCTCN2020103340-appb-100028
  12. 一种碳苷化合物、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述碳苷化合物的结构如式V所示：
    Figure PCTCN2020103340-appb-100029
    其中A环选自
    Figure PCTCN2020103340-appb-100030
    R 1、R 2、R 3、R 4如权利要求1～4任一项所述；
    Figure PCTCN2020103340-appb-100031
    为
    Figure PCTCN2020103340-appb-100032
    B环为饱和或不饱和环，优选为苯环；
    R 14选自H、CN、卤代或未卤代的C 1～3烷基、卤代或未卤代的C 1～3烷氧基、COOR 15；R 15选自C 1～3烷基。
  13. 根据权利要求12所述的碳苷化合物、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述碳苷化合物的结构如式V-1、V-2、V-3和V-4所示：
    Figure PCTCN2020103340-appb-100033
    其中，R 1、R 2、R 3、R 4、R 14如权利要求12所述。
  14. 根据权利要求12或13所述的碳苷化合物、或其盐、或其立体异构体、或其旋光异构体，其特征在于：所述碳苷化合物的结构选自：
    Figure PCTCN2020103340-appb-100034
  15. 权利要求1-4任一项所述的糖基供体在制备硫苷化合物、氧苷化合物、碳苷化合物中的用途；优选的，所述硫苷化合物如权利要求5～8任一项所述，和/或，所述氧苷化合物如权利要求9～11任一项所述，和/或，所述碳苷化合物如权利要求12～14任一项所述。
  16. 一种制备权利要求1-4任一项所述糖基供体的方法，其特征在于： 所述方法包括以下步骤：
    (1)原料Y1与乙酸酐反应，得到化合物Y2；
    (2)化合物Y2先与硫脲反应，再加入化合物Y3，继续反应，得到化合物Y4；
    (3)化合物Y4与mCPBA反应，得到糖基供体；
    其中，原料Y1的结构为
    Figure PCTCN2020103340-appb-100035
    化合物Y2的结构为
    Figure PCTCN2020103340-appb-100036
    化合物Y3的结构为
    Figure PCTCN2020103340-appb-100037
    化合物Y4的结构为
    Figure PCTCN2020103340-appb-100038
    X选自卤素，优选为溴；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9如权利要求1～4任一项所述。
  17. 根据权利要求16所述的方法，其特征在于：
    步骤(1)中，所述乙酸酐与原料Y1上羟基的摩尔比为(0.8～1.5)：1；反应是在三乙胺和DMAP的作用下进行的；反应温度为室温；反应溶剂为二氯甲烷；
    步骤(2)中，化合物Y2、硫脲、化合物Y3的摩尔比为1：(1.5～4.5)：(1.2～2)；加入化合物Y3前的反应温度为加热回流，反应时间为(2～6)小时；加入Y3前的反应是在三氟化硼乙醚的作用下进行的；加入Y3后的反应温度为加热回流，反应时间为(4～8)小时；加入Y3后的反应是在三乙胺的作用下进行的；反应溶剂为乙腈；
    步骤(3)中，化合物Y4与mCPBA的摩尔比为1：(1.5～4.5)；反应时间为1～3小时；反应溶剂为二氯甲烷；
    优选地，
    步骤(1)中，所述乙酸酐与原料Y1上羟基的摩尔比为1.2：1；
    步骤(2)中，化合物Y2、硫脲、化合物Y3的摩尔比为1：3：1.5；加入化合物Y3前的反应时间为4小时；加入Y3后的反应时间为6小时；
    步骤(3)中，化合物Y4与mCPBA的摩尔比为1：2.5；反应温度为室温，反应时间为2小时。
  18. 一种制备权利要求5-8任一项所述硫苷化合物的方法，其特征在于：所述方法为：将权利要求1-4任一项所述的糖基供体与糖基受体反应，得到硫苷化合物；
    其中，所述糖基受体的结构为
    Figure PCTCN2020103340-appb-100039
    R 5s选自
    Figure PCTCN2020103340-appb-100040
    Figure PCTCN2020103340-appb-100041
    R 10如权利要求5-8任一项所述。
  19. 根据权利要求18所述的方法，其特征在于：所述R 5s选自
    Figure PCTCN2020103340-appb-100042
    Figure PCTCN2020103340-appb-100043
    R 10如权利要求5-8任一项所述；
    所述糖基供体与糖基受体的摩尔比为1：(1.1～2.5)，优选为1：(1.2～2)；
    所述反应是在氮气氛围中、蓝色LED的照射下进行的；
    所述反应的温度为20～45℃，优选为室温～45℃；反应时间为1.5～5小时，优选为2～4小时；
    所述反应是在光敏剂的作用下进行的，光敏剂选自
    Figure PCTCN2020103340-appb-100044
    Figure PCTCN2020103340-appb-100045
    Ir[dF(CF 3)(ppy) 2](dtbbpy)PF 6，优选为
    Figure PCTCN2020103340-appb-100046
    Ir[dF(CF 3)(ppy) 2](dtbbpy)PF 6，更优选为Ir[dF(CF 3)(ppy) 2](dtbbpy)PF 6；
    所述反应的溶剂选自水或者1,2-DCE、DMSO、EtOAc、glyme、1,4-dioxane、THF、MeOH、DMF、MeCN、MeCN中的一种或多种与水在任意比例下组成的混合溶液。
  20. 一种制备权利要求9-11任一项所述氧苷化合物的方法，其特征在于： 所述方法为：将权利要求1-4任一项所述的糖基供体与糖基受体反应，得到氧苷化合物；其中，所述糖基受体的结构为HO-R 11，R 11如权利要求9-11任一项所述；
    优选的，所述糖基供体与糖基受体的摩尔比为(1.2～2.0)：1.0，优选为1.5：1.0；和/或，所述反应是在全氟碘代丁烷、磷酸氢二铵、三苯基氧磷的存在下反应的，所述糖基受体与全氟碘代丁烷、磷酸氢二铵、三苯基氧磷的摩尔比为1.0：(3～7)：(3～7)：(0.1～0.5)，优选为1.0：5.0：5.0：0.3；和/或，所述反应溶剂为有机溶剂，优选为甲基叔丁基醚；和/或，所述述反应是在氮气氛围中、蓝色LED的照射下进行的；和/或，所述反应的温度为20～45℃，优选为室温，反应时间为12～36小时，优选为24小时。
  21. 一种制备权利要求12-14任一项所述碳苷化合物的方法，其特征在于：所述方法为：将权利要求1-4任一项所述的糖基供体与糖基受体反应，得到碳苷化合物；其中，所述糖基受体为
    Figure PCTCN2020103340-appb-100047
    R 16选自C 1-3烷基，优选为甲基，
    Figure PCTCN2020103340-appb-100048
    如权利要求12-14任一项所述；
    优选的，所述糖基供体与糖基受体的摩尔比为1:(1.5～3.0)，优选为1:2.0；所述反应是在光敏剂、引发剂的作用下进行的，所述光敏剂优选为曙红Y，所述引发剂优选为三氟甲基亚磺酸钠，所述糖基供体与光敏剂、引发剂的摩尔比为1：(0.01～0.03)：(0.1～0.3)，优选为1:0.025:0.2；和/或，所述反应是在氮气氛围中、蓝色LED的照射下进行的；和/或，所述反应的温度为20～45℃，优选为室温，反应时间为5～12小时，优选为8小时。
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