A method for stereoselective synthesis of 2'-deoxyribonucleosides

Abstract

The invention discloses a method for stereoselective synthesis of β-2'-deoxyribonucleosides. The method utilizes the diphenylphosphinoyl group on the glycosyl donor as a remote guiding group, so that it forms a bridged ring intermediate with the anomeric position of the glycosyl, and by shielding the same side of the sugar ring, the glycosyl acceptor can only perform nucleophilic attack on the anomeric position of the glycosyl donor from the side opposite to the group, thereby achieving stereoselective glycosidation of the opposite side. The method can efficiently control the stereoselectivity and regioselectivity of the glycosidation reaction, especially for the synthesis of nucleoside derivatives without adjacent groups participating in the C-2' group, showing great advantages. The method has mild reaction conditions and is easy to operate, and provides a new method for efficiently constructing a library of β-2'-deoxynucleoside derivatives.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and more particularly to a method for stereoselective synthesis of 2'-deoxyribonucleoside. Background Art

[0002] Nucleosides are building blocks of DNA and RNA, usually containing ribose or deoxyribose and nitrogenous bases. They play multiple important roles in cell physiology. They are not only metabolic precursors of many functional biomolecules such as ATP, DNA and RNA, but also signaling molecules and neuromodulators. In addition, since the synthesis of DNA and RNA is critical for rapid cell division and viral replication, in the medical field, nucleoside analogs can also be used to treat cancer and viral infections. In recent years, people have also shown great interest in nucleoside analogs with unnatural structures. For example, the β-L-nucleoside analog lamivudine (3TC) has been widely used to treat HIV-1 and AIDS, while several α- D -Thymine analogs have shown promise as antimalarial drugs. Therefore, efficient synthesis of single-configuration 2'-deoxynucleosides has important guiding significance for the development of new drugs.

[0003] At present, the mainstream synthesis methods of nucleosides are divided into two categories. The first category is to directly use natural nucleosides to start the synthesis, and obtain the expected product after several steps. It has the advantage of fast synthesis speed, but the limited number of natural nucleosides fundamentally limits the types of nucleoside analogs; the other method is the most classic method for synthesizing nucleosides-Vorbrüggen reaction, but this reaction often cannot control the stereoselectivity well when synthesizing C2' and C4' modified nucleoside analogs, and has the disadvantages of more severe reaction conditions and poor substrate applicability. However, for 2'-deoxyribose, due to the lack of the 2-position neighboring participating group, the stereoselectivity cannot be effectively controlled during the reaction, and α / β mixed configuration products will be obtained at the same time, resulting in difficulties in separation and purification. In addition, the chemical properties of deoxyribose are very active, and the glycosylation conditions should not be too severe; finally, there is still a problem of regioselectivity for the synthesis of purine nucleosides. Currently, the most common nucleoside drugs are N 9 Substitute. Summary of the invention

[0004] Purpose of the Invention

[0005] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a method for stereoselective synthesis of 2'-deoxynucleosides, so as to solve the problems of poor stereoselectivity and regioselectivity of the prior methods for such glycosidic bonds.

[0006] Technical Solution

[0007] In order to achieve the above object, the present invention adopts the following technical solution:

[0008] A method for stereoselective synthesis of 2'-deoxyribonucleosides, wherein the method is different for purine receptors and pyrimidine receptors:

[0009] The general reaction formula is as follows:

[0010]

[0011] The glycosyl acceptor described in formula II is Nu, which is divided into purine base and pyrimidine base.

[0012] Specifically:

[0013] For purinergic receptors:

[0014] (1) adding a glycosyl donor represented by formula I, a glycosyl acceptor represented by formula II and a fresh activated molecular sieve into an organic solvent, and then placing the reaction system at a suitable temperature under the protection of an inert gas, adding a catalyst, and reacting;

[0015] (2) After the reaction is complete, the glycosylated product represented by Formula III is obtained after filtration, vacuum concentration and column chromatography;

[0016] For pyrimidine receptors:

[0017] (1) Silylation: The glycosyl donor of formula I and the glycosyl acceptor of formula II are added to MeCN, and then N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) is added at 50°C. Under the protection of inert gas, the reaction is carried out for 30 minutes until the solution becomes clear. It should be noted that this step is that pyrimidine must be silylated by adding BSTFA in MeCN at 50°C before the subsequent reaction, while purine does not require this step.

[0018] (2) removing MeCN, then placing the reaction system at a suitable temperature, adding an organic solvent, a catalyst and a fresh activated molecular sieve, and carrying out the reaction;

[0019] (3) After the reaction is complete, the glycosylated product represented by Formula III is obtained after filtration, vacuum concentration and column chromatography;

[0020] Furthermore, the glycosyl donor is furanose 2-deoxyribose.

[0021] Further, the protecting group (PG) in Formula I and Formula III is any one or more of benzyl (Bn), benzoyl (Bz), acetyl (Ac), tert-butyldiphenylsilyl ether (TBDPS) or tert-butyldimethylsilyl ether (TBS), and the acyl group and some larger silicon-based protecting groups affect the stereoselectivity of glycosidation in the reaction; preferably, the protecting group PG in Formula I and Formula III is benzyl;

[0022] Furthermore, the leaving group (LG) in formula I is screened, such as N-phenyl-trifluoroacetimidate, glucosinolate (CAS No.: 1384270-00-1) or o-alkynyl benzoate, wherein N-phenyl-trifluoroacetimidate assembled at the anomeric position of 2-deoxyribose is very unstable and cannot undergo subsequent glycosylation reaction; glucosinolate requires the use of stoichiometric Lewis acid as a catalyst during the glycosylation process, and the reaction effect is not good; and o-alkynyl benzoate has mild reaction conditions during the glycosylation process and excellent reaction effect; therefore, the leaving group LG in formula I is o-alkynyl benzoate.

[0023] Furthermore, the organic solvent is one of dichloromethane, toluene, dichloroethane or acetonitrile. The experiment uses PPh3AuOTf as a catalyst and performs a glycosidation reaction at 0°C, preferably dichloroethane and dichloromethane.

[0024] Table 1 shows the effects of different solvents

[0025]

[0026] Furthermore, the reaction temperature is -78°C to 25°C. In the experiment, PPh3AuOTf is used as a catalyst to carry out the glycosidation reaction in dichloroethane. Taking the yield, selectivity and experimental operability into consideration, preferably, the most suitable temperature is 0°C.

[0027] Table 2 Investigation of the influence of different temperatures

[0028]

[0029] Further, the catalyst is selected from PPh3AuBAr4 F , PPh3AuOTf or PPh3AuNTf2, any one or more thereof, using dichloroethane as solvent and carrying out glycosidation reaction at 0°C. Preferably, the optimal catalyst is PPh3AuNTf2; the inventors have verified other catalysts, but they cannot achieve the functions described in the present invention.

[0030] Table 3 Investigation of different catalysts

[0031]

[0032] Furthermore, for purine acceptors, the molar ratio of the glycosyl donor represented by formula I to the glycosyl acceptor represented by formula II is (1.2-2):(1-1.5); for pyrimidine acceptors, the molar ratio of the glycosyl donor represented by formula I to the glycosyl acceptor represented by formula II is (1.0-1.2):(1.5-3.0).

[0033] Furthermore, the glycosyl donor represented by formula I is selected from the following compounds represented by any of the structures I-1 to I-2:

[0034]

[0035] The glycosyl acceptor of the present invention can be routinely selected according to the target compound.

[0036] Furthermore, Nu in Formula II and Formula III includes but is not limited to compounds having any of the structures shown in the following II-1 to II-10:

[0037]

[0038] Furthermore, the glycosylation product represented by formula III is selected from the following compounds represented by any one of the structures of III-1 to III-12:

[0039]

[0040] In some specific embodiments, when the glycosyl donor is a 2-deoxyribose donor of a furanose type sugar, the preparation method of the glycosyl donor is as follows:

[0041]

[0042] Or:

[0043]

[0044] In some embodiments, the method for preparing an optimized glycosyl donor comprises the following steps:

[0045] (1) The corresponding donor is dissolved in anhydrous DCM, and DBU and diphenylphosphinoyl chloride are added. After the reaction is complete, column chromatography is performed to obtain a glycoside compound with a phosphorus oxide side chain installed at the 3-position.

[0046] (2) Dissolved in 80% AcOH, added SrCl2·6H2O at 50°C. TLC showed that the reaction was complete, adjusted the pH to neutral, and removed the anomeric methyl group after column chromatography.

[0047] (3) The compound was dissolved in anhydrous DCM, and then EDCI, DMAP and o-alkynylbenzoic acid were added to react at room temperature. After completion, the corresponding donor was obtained after column chromatography purification.

[0048] Principle of the invention:

[0049] The general glycosylation reaction mechanism is: after the glycosyl donor is activated by a catalyst, the leaving group (LG) leaves to form the corresponding oxonium ion intermediate, and then the glycosyl acceptor (Nu) can undergo nucleophilic attack through one of the upper and lower faces of the furanose ring or pyranose ring, and two glycosylation products are produced accordingly: α- or β-configuration glycosides. Glycosylation reactions in nature are usually regioselective and stereospecific. When it comes to chemical synthesis, it is particularly important to ensure that a single configuration and high yield of glycoside products are obtained.

[0050]

[0051] The most commonly used method for stereoselective control is neighboring group participation. In the process of carbohydrate chemical synthesis, the main reaction process is to introduce an acyl group into the C-2 hydroxyl group adjacent to the anomeric position of the sugar ring. After activation, an unstable cyclic oxonium ion intermediate is formed. After shielding the same side of the sugar ring, it is attacked by a nucleophilic reagent to obtain a stable hetero-glycosylation product.

[0052]

[0053] However, for the synthesis of β-2'-deoxynucleosides, there is no hydroxyl group at the C-2 position of the sugar ring, and it is impossible to introduce an acyl group for neighboring group participation. At present, if we want to achieve the synthesis of β-2'-deoxynucleosides by glycosylation, we mainly use ribose as the raw material (rather than 2-deoxyribose), use the neighboring group participation to achieve β selectivity, and then try to remove the C-2 hydroxyl group, but the steps are long, and the stereoselectivity and regioselectivity are poor.

[0054] The present invention first discovered the use of commercially available diphenylphosphinoyl, which is installed at the C-3 position of the glycosyl donor as a remote directing group, so that it forms a bridged ring intermediate with the anomeric position of the glycosyl, and by shielding the same side of the sugar ring, the glycosyl receptor can only perform nucleophilic attack on the anomeric position of the glycosyl donor from the side opposite to the group, thereby achieving stereoselective glycosylation of the opposite side. This group is often used as an intermediate raw material to synthesize other related compounds in chemical synthesis. This method is the first to use it as a directing group in the synthesis of nucleosides. This method can efficiently control the stereoselectivity and regioselectivity of the glycosylation reaction, especially for the synthesis of nucleoside derivatives without adjacent participating groups at C-2', showing great advantages.

[0055]

[0056] Compared with the prior art, the present invention has the following beneficial effects:

[0057] (1) The present invention first discovered that the commercially available diphenylphosphinoyl group was used as a remote directing group (C-3) to shield the same side of the sugar ring to achieve stereoselective glycosylation on the opposite side, and efficiently synthesize β-2'-deoxyribonucleoside. This reaction is a completely new idea and reaction mechanism, which has not been reported in the literature. Among them, the diphenylphosphinoyl group (which can be directly synthesized using Ph2P(O)Cl) is widely used as a precursor for synthesizing various chiral phosphine bidentate ligands (for asymmetric synthesis), but there is no literature report on its use in the C-3 substituted protecting group of the present invention to prepare ribonucleosides.

[0058] (2) In this method, different treatment methods are used for glycosyl receptors, purine receptors and pyrimidine receptors, among which pyrimidine receptors need to be silylated. In addition, the inventors have also found that there are special requirements for the selection of leaving group (LG), and LG is o-alkynyl benzoate is the best. The catalyst is also one of the key factors, and the catalyst is selected from PPh3AuBAr4 F Any one or more of PPh3AuOTf or PPh3AuNTf2 can achieve the purpose of the present invention, but other catalysts are not effective or difficult to react. In addition, different reaction temperatures and organic solvents will also affect the yield and α / β ratio.

[0059] (3) This method has good stereoselectivity and regioselectivity. The glycosylation of purine bases as receptors is dominated by a single N- 9 Substitution products, and for pyrimidine bases, a single β-configuration product was obtained.

[0060] (4) This method can efficiently and stereoselectively synthesize β-2'-deoxyribonucleosides under mild reaction conditions without the need to add stoichiometric amounts of Lewis acid.

[0061] (5) III-1 to III-12 synthesized in the present invention are completely new compounds. DETAILED DESCRIPTION

[0062] The present invention is further described in detail below in conjunction with the examples, but the protection scope of the present invention is not limited to these examples. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are purchased from conventional biochemical reagent stores unless otherwise specified.

[0063] The PG described in the present invention refers to: a protecting group;

[0064] The LG described in the present invention refers to: a leaving group;

[0065] OBn in the present invention refers to: benzyloxy;

[0066] Bn in the present invention refers to: benzyl;

[0067] Ac in the present invention refers to: acetyl;

[0068] The TBDPS described in the present invention refers to: tert-butyl diphenylsilyl ether;

[0069] The TBS described in the present invention refers to: tert-butyl dimethyl silyl ether;

[0070] The STol described in the present invention refers to: 4-methylphenylmercapto, the structural formula is

[0071] Ph in the present invention refers to: a benzene ring;

[0072] The PPh3AuOTf described in the present invention refers to: triphenylphosphine gold trifluoromethane sulfonate;

[0073] The PPh3AuNTf2 described in the present invention refers to: triphenylphosphine bis(trifluoromethanesulfonimide)gold (as a catalyst);

[0074] Me in the present invention refers to: methyl;

[0075] Bz in the present invention refers to: benzoyl;

[0076] The TLC described in the present invention refers to: thin layer chromatography;

[0077] All compounds of formula III of the present invention are prepared according to the following route:

[0078]

[0079] For purine bases,

[0080] The glycosyl donor (1.2 eq, 20 mM) and glycosyl acceptor (1.0 eq) were dissolved in dry dichloroethane (DCE) and added under inert gas protection. Molecular sieve (freshly activated), then the reaction system was cooled to 0°C and PPh3AuNTf2 (0.1 eq) was added. After TLC monitoring showed that the reaction was completed, the molecular sieve was filtered out through an organic filter membrane, concentrated under reduced pressure, and the corresponding product was separated by silica gel column chromatography. Unless otherwise specified, the preparation of the following glycosides all followed the above route.

[0081] For pyrimidine bases,

[0082] The glycosyl donor (1.0 eq, 20 mM) and glycosyl acceptor (1.5 eq) were dissolved in dry MeCN. Under the protection of inert gas, the temperature was raised to 50 °C, and N, O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) (3.0 eq) was added. After the solution turned from turbid to clear, the solvent was dried by spin drying, and dry dichloromethane (DCM) and fresh activated Molecular sieves were added, and then PPh3AuNTf2 (0.1 eq) was added at room temperature. After TLC monitoring showed that the reaction was completed, the molecular sieves were filtered out through an organic filter membrane, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the corresponding product. Unless otherwise specified, the preparation of the following glycosides all followed the above route.

[0083] Example 1 Compound III-1

[0084] The donor Ⅰ-1 (40 mg, 0.060 mmol) and 2,6-dichloropurine receptor (10 mg, 0.050 mmol) were dissolved in dry DCE (3.0 mL) and catalyzed by PPh3AuNTf2 (4.5 mg, 0.0060 mmol). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-1 (30 mg, 98%, α / β=1:5): 1 H NMR(600MHz,Chloroform-d)δ8.42(d,J=5.4Hz,1H),7.91–7.74(m,3H),7.62–7.28(m,10H),7.26–7.16(m,2H),6.64–6 .47(m,1H),5.26–5.16(m,1H),4.56–4.41(m,3H),3.71(dd,J=10.7,2.8Hz,1H),3.65–3.55(m,1H),2.95–2.69(m,2H); 13 C NMR(151MHz,Chloroform-d)δ152.76,152.60,152.40,151.96,151.54,151.39,144.16,144.00,137.17,136.66,132. 62,132.60,132.56,132.54,131.50,131.43,131.39,131.33,131.16,131.06,130.99,130.89,130.75,130.61,130.24 ,130.15,129.84,129.71,128.76,128.69,128.67,128.60,128.50,128.39,128.06,127.82,127.75,127.46,87.52,87.49,86.80,85.91,85.88,84.76,76.22,76.19,75.85,75.82,73.69,73.56,69.64,69.47,40.49,40.47,40.33,40.30.

[0085] Example 2 Compound III-2

[0086] The donor Ⅰ-1 (40 mg, 0.06 mmol) and 6-chloropurine receptor (7.7 mg, 0.050 mmol) were dissolved in dry DCE (3.0 mL) and catalyzed by PPh3AuNTf2 (4.5 mg, 0.0060 mmol). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-2 (21 mg, 73%, α / β=1:4): 1 H NMR(400MHz,Chloroform-d)δ8.71(d,J=8.0Hz,1H),8.45(d,J=18.8Hz,1H),7.91–7.79(m,3H),7.64–7.45(m,6H),7.38–7.2 9(m,4H),7.28–7.19(m,2H),6.74–6.54(m,1H),5.31–5.19(m,1H),4.62–4.37(m,3H),3.76–3.57(m,2H),2.96–2.79(m,2H); 13 C NMR(101MHz,Chloroform-d)δ151.93,151.84,151.32,151.03,150.88,143.67,143.45,137.37,136.92, 132.72,132.68,132.18,131.92,131.65,131.59,131.55,131.51,131.49,131.28,131.18,131.08,130. 15,130.11,128.90,128.86,128.77,128.72,128.62,128.53,128.33,128.15,127.94,127.87,127.60,87.37,86.70,85.83,85.78,84.72,76.40,76.35,75.98,75.92,73.78,73.69,69.81,69.61,40.35,29.71.

[0087] Example 3 Compound III-3

[0088] The donor Ⅰ-1 (40 mg, 0.060 mmol) and 2-iodo-6-chloropurine receptor (14 mg, 0.050 mmol) were dissolved in dry DCE (3.0 mL) and catalyzed by PPh3AuNTf2 (4.5 mg, 0.0060 mmol). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-3 (32 mg, 97%, α / β=1:10): 1H NMR(400MHz,Chloroform-d)δ8.46(s,1H),7.91–7.77(m,4H),7.62–7.48(m,6H),7.33–7.28(m,3H),7.18(dd,J=7.3,2.2Hz,2H),6.60(dd,J= 7.6,6.2Hz,1H),5.27–5.20(m,1H),4.58–4.53(m,1H),4.53–4.39(m,2 H),3.71(dd,J=10.6,3.0Hz,1H),3.63–3.56(m,1H),2.94–2.72(m,2H); 13 C NMR(101MHz,Chloroform-d)δ152.46,148.64,143.72,138.25,136.82,132.86,13 2.83,131.66,131.56,131.46,131.30,131.21,131.11,129.95,128.96,128.90,12 8.83,128.77,128.70,128.61,128.53,128.15,127.96,127.78,127.59,122.31,86.98,86.01,85.96,84.92,76.50,76.44,73.76,69.74,69.56,40.53,29.71,1.05.

[0089] Example 4 Compound III-4

[0090] The donor Ⅰ-1 (40 mg, 0.060 mmol) and 6-benzamidopurine receptor (12 mg, 0.050 mmol) were dissolved in dry DCE (3.0 mL), reacted at 50 ° C, and catalyzed by PPh3AuNTf2 (9.0 mg, 0.012 mmol) to obtain the white syrup obtained by rapid column chromatography separation of the crude product, which is the pure product of Ⅲ-4 (18 mg, 53%, α / β=1:3): 1 H NMR(400MHz,Chloroform-d)δ8.80(d,J=14.3Hz,1H),8.35(d,J=31.7Hz,1H),8.04–7.95(m,2H),7.89–7.77(m,3H),7.67–7.3 0(m,14H),7.27–7.18(m,2H),6.71–6.55(m,1H),5.28–5.22(m,1H),4.59–4.44(m,3H),3.75–3.56(m,2H),2.98–2.77(m,2H).

[0091] Example 5 Compound III-5

[0092] The donor Ⅰ-1 (40 mg, 0.060 mmol) and the uracil acceptor (10 mg, 0.090 mmol) were dissolved in dry MeCN. Under the protection of inert gas, the temperature was raised to 50 ° C, and BSTFA (3.0 eq) was added. After the solution changed from turbid to clear, the solvent was dried and added to dry DCM (3.0 mL). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-5 (20 mg, 65%, β only): 1 H NMR(400MHz,Chloroform-d)δ9.09(s,1H),7.85–7.68(m,5H),7.57–7.46(m,5H),7.37–7.28(m,3H),7.25–7.19(m,2H),6.48(dd,J=8.2,5.7Hz,1 H),5.40(dd,J=8.2,1.5Hz,1H),5.17–5.08(m,1H),4.56–4.33(m,3H),3 .79–3.59(m,2H),2.50(ddd,J=13.9,5.8,2.0Hz,1H),2.23–2.12(m,1H); 13 C NMR(101MHz,Chloroform-d)δ163.16,150.37,140.08,137.00,132.72,132.70,132.63,132.60,131.71,131.61,131.48,131. 37,128.91,128.80,128.78,128.66,128.31,128.04,102.58,85.35,85.31,85.04,76.12,76.06,73.87,69.82,39.78,39.74.

[0093] Example 6 Compound III-6

[0094] The donor Ⅰ-1 (40 mg, 0.060 mmol) and the thymine acceptor (12 mg, 0.090 mmol) were dissolved in dry MeCN. Under the protection of inert gas, the temperature was raised to 50 ° C, and BSTFA (3.0 eq) was added. After the solution changed from turbid to clear, the solvent was dried and added to dry DCM (3.0 mL). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-6 (19.8 mg, 62%, β only): 1H NMR(400MHz,Chloroform-d)δ8.93(s,1H),7.88–7.74(m,4H),7.60–7.43(m,7H),7.35–7. 28(m,3H),7.25–7.20(m,2H),6.52(dd,J=8.4,5.7Hz,1H),5.22–5.12(m,1H),4.57–4.42( m,2H),4.42–4.36(m,1H),3.76(dd,J=10.6,2.3Hz,1H),3.62(dd,J=10.6,2.1Hz,1H),2.5 0(ddd,J=13.9,5.7,2.0Hz,1H),2.23(ddd,J=14.1,8.5,5.8Hz,1H),1.55(d,J=1.2Hz,3H); 13 CNMR(101MHz,Chloroform-d)δ163.69,150.46,137.20,135.54,132.71,132.68,132.63,132.60,131.70,131.60,131.49,131.39,130.38,130 .12,128.90,128.80,128.77,128.67,128.62,128.09,127.50,111.36, 85.14,85.10,84.71,76.12,76.06,73.68,69.86,39.55,39.50,12.09.

[0095] Example 7 Compound III-7

[0096] The donor Ⅰ-1 (40 mg, 0.060 mmol) and 5-fluorouracil receptor (12 mg, 0.090 mmol) were dissolved in dry MeCN. Under the protection of inert gas, the temperature was raised to 50 ° C, and BSTFA (3.0 eq) was added. After the solution changed from turbid to clear, the solvent was dried and added to dry DCM (3.0 mL). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-7 (21.9 mg, 68%, β only): 1H NMR(400MHz,Chloroform-d)δ9.58(s,1H),7.93(d,J=6.3Hz,1H),7.86–7.74(m,4H),7.60– 7.43(m,6H),7.37–7.28(m,3H),7.24(dd,J=7.6,1.9Hz,2H),6.47(ddd,J=8.0,5.7,1.8Hz,1 H),5.17–5.11(m,1H),4.45(dd,J=22.8,2.8Hz,3H),3.74(dd,J=10.6,2.3Hz,1H),3.59(dd, J=10.6,2.0Hz,1H),2.50(ddd,J=14.0,5.7,1.8Hz,1H),2.15(ddd,J=14.0,8.4,5.7Hz,1H); 13 C NMR(101MHz,Chloroform-d)δ157.03,156.76,149.03,141.80,139.45,136.60,132.75,132.72,132.65,132.62,131.72,131.61,131.46,131.36, 130.32,130.01,128.92,128.81,128.79,128.69,128.31,128.22,124.27 ,123.93,85.58,85.54,85.45,76.31,76.25,74.02,69.68,39.74,39.70.

[0097] Example 8 Compound III-8

[0098] The donor Ⅰ-2 (40 mg, 0.060 mmol) and 2-iodo-6-chloropurine receptor (14 mg, 0.050 mmol) were dissolved in dry DCE (3.0 mL) and catalyzed by PPh3AuNTf2 (4.5 mg, 0.0060 mmol). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-8 (30 mg, 98%, α / β=1:8): 1 H NMR(400MHz,Chloroform-d)δ8.43(d,J=4.8Hz,1H),7.89–7.73(m,4H),7.63–7.46(m,6H),7.36–7.28(m,3H),7. 26–7.15(m,2H),6.63–6.43(m,1H),5.28–5.12(m,1H),4.57–4.41(m,3H),3.75–3.54(m,2H),2.91–2.68(m,2H); 13C NMR(101MHz,Chloroform-d)δ152.47,148.65,143.69,143.50,138.25,137.31,136.82,132.78,1 32.75,132.71,132.68,131.67,131.56,131.50,131.46,131.40,131.21,131.11,130.14,130.04 ,128.93,128.89,128.86,128.80,128.76,128.73,128.67,128.65,128.55,128.17,127.97,127.82,127.61,122.32,86.97,86.05,86.01,84.88,76.38,76.33,73.78,69.79,69.58,40.63,40.59.

[0099] Example 9 Compound III-9

[0100] The donor Ⅰ-2 (40 mg, 0.060 mmol) and 2,6-dichloropurine receptor (10 mg, 0.050 mmol) were dissolved in dry DCE (3.0 mL) and catalyzed by PPh3AuNTf2 (4.5 mg, 0.0060 mmol). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-9 (30 mg, 98%, α / β=1:5): 1 H NMR(300MHz,Chloroform-d)δ8.43(d,J=1.9Hz,1H),7.92–7.72(m,4H),7.65–7.42(m,7H),7.40–7.29(m,3H),7. 26–7.14(m,2H),6.67–6.47(m,1H),5.30–5.12(m,1H),4.63–4.36(m,3H),3.81–3.53(m,2H),3.01–2.67(m,2H); 13C NMR(101MHz,Chloroform-d)δ152.90,152.74,152.55,151.68,144.30,144.14,137.31,136.81, 132.76,132.73,132.70,132.67,131.66,131.56,131.45,131.22,131.11,131.04,130.18,130.0 9,128.92,128.85,128.79,128.76,128.72,128.64,128.54,128.20,127.96,127.89,127.60,87.68,86.94,86.07,86.02,84.91,76.36,76.31,75.94,73.84,73.71,69.79,69.62,40.65,40.61.

[0101] Example 10 Compound III-10

[0102] The donor Ⅰ-2 (40 mg, 0.06 mmol) and 6-chloropurine receptor (7.7 mg, 0.050 mmol) were dissolved in dry DCE (3.0 mL) and catalyzed by PPh3AuNTf2 (4.5 mg, 0.0060 mmol). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-10 (22 mg, 75%, α / β=1:6): 1 H NMR(400MHz,Chloroform-d)δ8.70(d,J=7.7Hz,1H),8.44(d,J=18.1Hz,1H),7.90–7.70(m,4H),7.65–7.43(m,6H),7.38–7.2 8(m,3H),7.26–7.16(m,2H),6.71–6.54(m,1H),5.33–5.13(m,1H),4.60–4.33(m,3H),3.77–3.47(m,2H),2.95–2.71(m,2H); 13C NMR(75MHz,Chloroform-d)δ151.93,151.32,151.02,143.67,143.45,136.92,132.7 5,132.71,131.92,131.74,131.70,131.67,131.61,131.53,131.47,131.30,129.93, 129.89,128.92,128.88,128.77,128.74,128.70,128.62,128.53,128.15,127.93,127.87,127.60,86.69,85.83,85.77,84.71,76.40,76.33,73.78,69.61,40.39,40.34.

[0103] Example 11 Compound III-11

[0104] The donor Ⅰ-2 (40 mg, 0.060 mmol) and the uracil acceptor (10 mg, 0.090 mmol) were dissolved in dry MeCN. Under the protection of inert gas, the temperature was raised to 50 ° C, and BSTFA (3.0 eq) was added. After the solution changed from turbid to clear, the solvent was dried and added to dry DCM (3.0 mL). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-11 (20 mg, 65%, β only): 1 H NMR(400MHz,Chloroform-d)δ8.92(s,1H),7.85–7.76(m,4H),7.70(d,J=8.1Hz,1H),7.58–7.45(m,6H),7.37–7.30(m,3H),7.22(dd,J=7.4,2.0Hz,2H ),6.48(dd,J=8.2,5.7Hz,1H),5.39(d,J=8.1Hz,1H),5.17–5.10(m,1H),4 .54–4.38(m,3H),3.78–3.59(m,2H),2.53–2.46(m,1H),2.21–2.12(m,1H); 13C NMR(101MHz,Chloroform-d)δ163.04,150.32,140.04,137.01,132.70,132 .67,132.60,132.57,131.82,131.71,131.61,131.47,131.37,130.45,130. 14,128.89,128.78,128.76,128.66,128.51,128.30,128.26,128.03,127. 55,102.56,85.35,85.32,85.02,76.06,76.01,73.87,69.82,39.79,39.74.

[0105] Example 12 Compound III-12

[0106] The donor Ⅰ-2 (40 mg, 0.060 mmol) and 5-fluorouracil receptor (12 mg, 0.090 mmol) were dissolved in dry MeCN. Under the protection of inert gas, the temperature was raised to 50 ° C, and BSTFA (3.0 eq) was added. After the solution changed from turbid to clear, the solvent was dried and added to dry DCM (3.0 mL). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-12 (22 mg, 69%, β only): 1 H NMR(300MHz,Chloroform-d)δ9.19(d,J=4.8Hz,1H),7.96(d,J=6.3Hz,1H),7.88– 7.75(m,4H),7.65–7.45(m,6H),7.39–7.30(m,3H),7.26(dd,J=7.4,2.2Hz,2H),6. 54–6.43(m,1H),5.20–5.10(m,1H),4.47(dd,J=17.4,1.9Hz,3H),3.77(dd,J=10. 6,2.2Hz,1H),3.61(dd,J=10.6,1.9Hz,1H),2.58–2.46(m,1H),2.24–2.10(m,1H). 13C NMR(101MHz,Chloroform-d)δ157.03,156.76,149.03,141.80,139.45,136.60,132.75,132.72,132.65,132.62,131.72,131.61,131.46,131.36, 130.32,130.01,128.92,128.81,128.79,128.69,128.31,128.22,124.27 ,123.93,85.58,85.54,85.45,76.31,76.25,74.02,69.68,39.74,39.70.

[0107] Example 13 Compound III-13

[0108] The donor Ⅰ-2 (40 mg, 0.060 mmol) and thymine acceptor (12 mg, 0.090 mmol) were dissolved in dry MeCN. Under the protection of inert gas, the temperature was raised to 50 ° C, and BSTFA (3.0 eq) was added. After the solution changed from turbid to clear, the solvent was dried and added to dry DCM (3.0 mL). The crude product was separated by rapid column chromatography to obtain a white syrup, which was the pure product of Ⅲ-13 (19.8 mg, 62%, β only): 1 H NMR(400MHz,Chloroform-d)δ8.93(s,1H),7.88–7.74(m,4H),7.60–7.43(m,7H),7.35–7. 28(m,3H),7.25–7.20(m,2H),6.52(dd,J=8.4,5.7Hz,1H),5.22–5.12(m,1H),4.57–4.42( m,2H),4.42–4.36(m,1H),3.76(dd,J=10.6,2.3Hz,1H),3.62(dd,J=10.6,2.1Hz,1H),2.5 0(ddd,J=13.9,5.7,2.0Hz,1H),2.23(ddd,J=14.1,8.5,5.8Hz,1H),1.55(d,J=1.2Hz,3H); 13CNMR(101MHz,Chloroform-d)δ163.69,150.46,137.20,135.54,132.71,132.68,132.63,132.60,131.70,131.60,131.49,131.39,130.38,130.12,128.90,128.80,128.77,128.67,128.62,128.09,127.50,111.36,85.14,85.10,84.71,76.12,76.06,73.68,69.86,39.55,39.50,12.09。

Claims

1. A method for stereoselective synthesis of 2'-deoxyribonucleosides, characterized in that: The general reaction formula is as follows: Among them: PG is a protecting group; LG is a leaving group; Nu is a glycosyl acceptor; Nu is divided into a purine acceptor or a pyrimidine acceptor; For purinergic receptors: (1) adding a glycosyl donor, a glycosyl acceptor and a fresh activated molecular sieve represented by formula I into an organic solvent, and then placing the reaction system at a suitable temperature under the protection of an inert gas, adding a catalyst and reacting; (2) After the reaction is complete, the glycosylated product represented by Formula III is obtained after filtration, vacuum concentration and column chromatography; For pyrimidine receptors: (1) Silylation: The glycosyl donor and glycosyl acceptor of formula I are added to MeCN, and then N,O-bis(trimethylsilyl)trifluoroacetamide is added at 50°C. Under the protection of inert gas, the reaction is carried out for 30 minutes until the solution becomes clear; (2) removing MeCN, then placing the reaction system at a suitable temperature, adding an organic solvent, a catalyst and a fresh activated molecular sieve, and carrying out the reaction; (3) After the reaction is complete, the glycosylated product represented by Formula III is obtained after filtration, vacuum concentration and column chromatography; The glycosyl donor is 2-deoxy-D-ribose or 2-deoxy-L-ribose of furanose; The protecting group PG in Formula I and Formula III is any one or more of benzyl, benzoyl, acetyl, tert-butyldiphenylsilyl ether or tert-butyldimethylsilyl ether; The leaving group LG in formula I is o-alkynyl benzoate; The molecular sieve is MS; The organic solvent is one or more of dichloromethane, toluene, trifluorotoluene, dichloroethane, ether or acetonitrile; The catalyst is selected from PPh3AuBAr4 F , PPh3AuOTf or PPh3AuNTf2, any one or more thereof; The reaction temperature is -78°C to 25°C.

2. A method for stereoselective synthesis of 2'-deoxyribonucleosides according to claim 1, characterized in that: The molar ratio of the glycosyl donor represented by formula I to the glycosyl acceptor represented by formula II is 1.2-2:1-1.

5.

3. A method for stereoselective synthesis of 2'-deoxyribonucleosides according to claim 1, characterized in that: The glycosyl donor represented by formula I is selected from the following compounds represented by any of the structures of I-1 and I-2:

4. A method for stereoselective synthesis of 2'-deoxyribonucleosides according to claim 1, characterized in that: The compound represented by formula II is selected from the compounds represented by any of the structures shown in the following II-1 to II-7:

5. A method for stereoselective synthesis of 2'-deoxyribonucleosides according to claim 1, characterized in that: The glycosylation product represented by formula III is selected from the compounds represented by any of the structures shown in the following III-1 to III-12:

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