Method for synthesizing N, N-dimethyl aminoglycoside through halogen bond / hydrogen bond catalytic glycosylation

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing N, N-dimethyl aminoglycoside through halogen bond / hydrogen bond catalytic glycosylation. The invention develops a new glycosylation method, and N, N-dimethyl aminoglycoside is directly synthesized through halogen bond activation. Results show that under mild halogen bond activated glycosylation conditions, the N, N-dimethylamino glycosyl donor can be coupled with a wide range of receptors by using a specific catalyst, and the required N, N-dimethylamino glycoside can be provided with good to excellent yield and excellent stereoselectivity. The glycosylation reaction is carried out under mild conditions, conversion of various sugar substrates containing N, N-dimethylamine is promoted, and the yield is moderate to excellent. Results show that the halogen bond catalyst C5 and the N, N-dimethyl tertiary amine fragment have strong interaction to form a relatively stable complex, and intramolecular activation of the N, N-dimethyl amino glycosyl donor can be promoted.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing N,N-dimethylaminoglycosides through halogen bond / hydrogen bond catalyzed glycosylation. Background Art

[0002] Amino sugars are widely present in natural oligosaccharides and natural products and exhibit many important biological activities. It has been found that about 40% of glycosylated bacterial secondary metabolites contain N,N-dimethylaminoglycosides with one or more N,N-dimethylamino sugar fragments, and these molecules play a crucial role in human health and are important in combating diseases.

[0003] In the past few decades, due to the good biological activity and unique structure of N,N-dimethylaminoglycosides, efforts have been made to find methods for synthesizing N,N-dimethylaminoglycosides. However, due to the influence of the basic nitrogen present in the structure, whether as a donor or acceptor fragment, the common challenge in these synthetic methods lies in the glycosylation of N,N-dimethylamino sugars. The previous convention was to use or Lewis acid to promote glycosylation, but this method requires an excessive amount of promoter, resulting in unsatisfactory yields and limited substrate and functional group compatibility.

[0004] Therefore, developing different glycosylation methods with strategic significance is crucial for solving some of the inherent limitations encountered in this field. Recently, halogen bond (XB) and hydrogen bond (HB) catalyzed glycosylation have received extensive attention, especially in 2-haloimidazolium salts and thiourea catalysis, which provide organic catalyst mimics of glycosyltransferases.

[0005] Based on previous research, the present invention proposes a new method for synthesizing N,N-dimethylaminoglycosides through halogen bond / hydrogen bond catalyzed glycosylation. It has been found in the research that halogen bond catalysis can effectively activate N,N-dimethylaminosugar donors.

[0006] The method for synthesizing N,N-dimethylaminoglycosides through halogen bond / hydrogen bond catalyzed glycosylation according to the present invention has the following advantages: including mild organic catalytic reaction conditions, the use of a catalytic amount of cocatalyst, a wide substrate range, controllable stereoselectivity, good to excellent yields, and applicability in the synthesis of natural products. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for synthesizing N,N-dimethylaminoglycosides through halogen bond / hydrogen bond catalyzed glycosylation, which can efficiently synthesize N,N-dimethylaminoglycosides and improve the selectivity and synthesis efficiency of the synthesis.

[0008] To achieve the above technical objectives, the present invention adopts the following technical solutions:

[0009] The present invention provides a method for synthesizing N, N-dimethylaminoglycoside, comprising the following steps:

[0010] Place the receptor and the donor in a reaction vessel, add catalyst I, add solvent I under a protective atmosphere, react at a specific temperature for a certain period of time, filter after the reaction, concentrate, and purify by column chromatography to obtain N, N-dimethylaminoglycoside.

[0011] Specifically, the specific temperature refers to -30 to 80 °C; preferably, the specific temperature refers to 30 to 80 °C; more preferably, the specific temperature refers to 30 to 50 °C.

[0012] Specifically, the reaction time is 1 h or more; preferably, the reaction time is 1 h to 3 weeks; more preferably, the reaction time is 2 days to 7 days; even more preferably, the reaction time is 24 h - 96 h.

[0013] Specifically, the method for synthesizing N, N-dimethylaminoglycoside comprises the following steps:

[0014] Place the donor and the receptor in a reaction vessel, add catalyst I and molecular sieve, displace air to form a protective atmosphere, add solvent I under the protective atmosphere, react at 30 - 40 °C (preferably 30 °C) for 2 h - 96 h (preferably 48 h - 96 h), filter after the reaction, concentrate, and purify by column chromatography to obtain N, N-dimethylaminoglycoside.

[0015] As another preferred technical solution, the method for synthesizing N, N-dimethylaminoglycoside comprises the following steps:

[0016] Place the donor and the receptor in a reaction vessel, add catalyst I, reaction additive and molecular sieve, displace air to form a protective atmosphere, add solvent I under the protective atmosphere, react at 30 - 50 °C (preferably 30 °C) for 2 h - 96 h (preferably 48 h - 96 h), filter after the reaction, concentrate, and purify by column chromatography to obtain N, N-dimethylaminoglycoside.

[0017] Preferably, before the reaction, the donor and the receptor can also be pretreated; the pretreatment operation is: co-evaporate the donor and the receptor with anhydrous toluene 2 - 3 times before feeding, and set aside.

[0018] Specifically, the structural formula of the N, N-dimethylaminoglycoside is as follows:

[0019]

[0020] Specifically, the receptor is

[0021] Specifically, the donor is

[0022] Preferably, the donor is

[0023] Specifically, R 1 is Bn or Bz;

[0024] R 2 is

[0025]

[0026] R 3 is

[0027] Specifically, the molar ratio of the receptor to the donor is 1:(1 - 3).

[0028] Specifically, the catalyst I is:

[0029]

[0030] Specifically, the molar ratio of the receptor to the catalyst I is 1:(0.1 - 1), preferably 1:(0.2 - 1).

[0031] Specifically, the protective atmosphere is an atmosphere formed by nitrogen, argon, etc.

[0032] Specifically, the solvent I is any one of PhMe, PhCF 3 , DCM, 1,4 - dioxane, THF, and CH 3 CN.

[0033] Further preferably, the donor is

[0034] Further preferably, the molar ratio of the receptor to the donor is 1:(1 - 2), and more preferably 1:1.5.

[0035] Further preferably, the molar ratio of the receptor to the catalyst I is 1:(0.5 - 1), and more preferably 1:0.5.

[0036] Specifically, the N,N - dimethylaminoglycoside is:

[0037]

[0038] Specifically, the molecular sieve is a molecular sieve, the reaction additive is 3,5-bis(trifluoromethyl)phenylboronic acid, and the molar ratio of the reaction additive to the receptor is (0.2 - 0.8):1, preferably 0.5:1.

[0039] Specifically, Ph is phenyl, Me is methyl, Bn is benzyl, Bz is benzoyl, Ac is acetyl, All is allyl, and Boc is tert-butoxycarbonyl.

[0040] Furthermore, the present invention also provides the application of the N,N-dimethylaminoglycoside in the preparation of nucleoside antibiotics containing N,N-dimethylaminosugar fragments (such as cytosamine).

[0041] Compared with the prior art, the advantages of the present invention are as follows:

[0042] The method for synthesizing N,N-dimethylaminoglycoside by glycosylation catalyzed by halogen bond provided by the present invention synthesizes a series of dimethylaminoglycoside compounds with different structures under the action of the halogen bond catalyst C5, and has high selectivity and synthesis efficiency.

[0043] The glycosylation reaction of the present invention is carried out under mild conditions, which promotes the conversion of various sugar substrates containing N,N-dimethylamine, and the yield is moderate to excellent. The results show that there is a strong interaction between the halogen bond catalyst C5 and the N,N-dimethylamine fragment, forming a relatively stable complex, which can promote the intramolecular activation of the N,N-dimethylaminosugar donor. This method has good practicability and wide application value. Specific Embodiments

[0044] The following examples further describe the present invention in detail, but the embodiments of the present invention are not limited thereto. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art.

[0045] Unless otherwise specified, the instrument equipment used in the following examples are all commercially available conventional instrument equipment; the reagents, raw materials, etc. used in the following examples are all conventional commercially available products and can be obtained from commercial channels without special instructions.

[0046] The abbreviations in the following examples: Ac is acetyl, Ac 2 O is acetic anhydride, AcOH is glacial acetic acid, All is allyl, Bn is benzyl, Bz is benzoyl, Boc is tert-butoxycarbonyl, tBu is tert-butyl, DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene, DCM is dichloromethane, DDQ is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMAP is 4-dimethylaminopyridine, DMF is dimethylformamide, DMSO is dimethyl sulfoxide, Et is ethyl, EA is ethyl acetate, HATU is 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Im(imid) is imidazole, i- Pr is isopropyl, Me is methyl, MS molecular sieve, Nap is 2-(methyl)naphthalene, NBS is N-bromosuccinimide, NIS is N-iodosuccinimide, PE is petroleum ether, Ph is phenyl, PivOH is pivalic acid, Py is pyridine, TBDPS is tert-butyldiphenylsilyl, TBDPSCl is tert-butyldiphenylchlorosilane, TEMPO is 2,2,6,6-tetramethylpiperidine 1-oxyl, TBS is tert-butyldimethylsilyl, TBSCl is tert-butyldimethylchlorosilane, TCA is trichloroacetic acid, Tf is trifluoromethanesulfonate, TEA is triethylamine, TFA is trifluoroacetic acid, THF is tetrahydrofuran, TMS is trimethylsilyl, TMSE is trimethylsilylethyl, TMSOTf is trimethylsilyl trifluoromethanesulfonate, TBSOTf is tert-butyldimethylsilyl trifluoromethanesulfonate, Tol is toluene, Ts is p-toluenesulfonyl, TsOH is p-toluenesulfonic acid, TMSCl is trimethylchlorosilane, TMSN 3 is trimethylsilyl azide.

[0047] Method for synthesizing N,N-dimethylaminoglycoside by halogen bond catalyzed glycosylation in Example 1

[0048] 1.1 Synthesis of donor

[0049] 1.1.1 Synthesis of monosaccharide donor 1b

[0050]

[0051] The present invention synthesizes compound 15 according to the method in the literature (Chang C W, Lin M H, Chan C K, et al. Automated quantification of hydroxyl reactivities: Prediction of glycosylation reactions. Angew. Chem. Int. Ed., 2021, 60).

[0052] Compound S2-1

[0053] Under ice-water bath conditions, NIS (2.463 g, 10.95 mmol) was added to a solution of compound 15 (2.07 g, 3.65 mmol) in acetone / H 2 O (10 / 1, v / v, 21 mL), and the mixture was stirred at room temperature for 30 minutes. After TLC showed complete consumption of the starting material, the solution was diluted with DCM and quenched with saturated Na 2 S 2 O 3 aqueous solution. Then the organic layer was washed with saturated NaHCO 3 aqueous solution and brine. The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to obtain the crude product.

[0054] Then, the crude product was dissolved in anhydrous DMF, imidazole (496 mg, 7.30 mmol) and TBSCl (1.65 g, 10.95 mmol) were added in an ice-water bath, and the mixture was stirred at 40 °C for 2 hours. The solution was diluted with EA and quenched with saturated NaHCO 3 aqueous solution, and then the organic layer was washed with saturated NaHCO 3 -aqueous solution and brine. The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo, and then purified by column chromatography (PE:EA = 200:1). Colorless oily compound S2-1 (1.97 g, 3.36 mmol, 92%) was obtained. [α] D 18 =-3.1 (c 0.5, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.21 - 7.10 (m, 13H), 7.03 (dd, J = 7.3, 2 Hz, 2H), 4.72 (d, J = 10.8 Hz, 1H, H-1), 4.63 (t, J = 11.4 Hz, 2H), 4.41 (dd, J = 11.9, 6.7 Hz, 3H), 4.35 (d, J = 6.5 Hz, 1H), 3.51 (d, J = 3.2 Hz, 2H), 3.46 (t, J = 9.0 Hz, 1H), 3.18 - 3.27 (m, 3H), 0.78 (s, 9H), 0.01 (d, J = 5.4 Hz, 6H); 13 C NMR (101 MHz, CDCl 3)δ138.2,138.1,128.5,128.4,128.0,127.9,127.8,127.6,97.2(C-1),83.0,77.8,75.5,75.1,75.0,73.5,68.8,25.7,18.0,-4.2,-5.2.HRMS(ESI)calculated for C 33 H 44 N 3 O 5 Si[M+H] + 590.3045,found 590.3056.

[0055] Compound S2-2

[0056] To a solution of compound S2-1 (1.97 g, 3.56 mmol) in THF (39.6 mL) was added triphenylphosphine (3.523 g, 13.43 mmol), Py (4.1 mL, 13.43 mmol), and H 2 O (0.9 mL, 50.36 mmol). The mixture was stirred at 50 °C for 5 h. TLC showed complete consumption of the starting material. The organic layer was concentrated in vacuo and then purified by column chromatography (PE:EA = 6:1). Obtained compound S2-2 as a light brown oil (1.47 g, 1.54 mmol, 78%). [α] D 18 = +27.1 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 - 7.06 (m, 15H), 4.82 (d, J = 11.2 Hz, 1H, H-1), 4.63 (dd, J = 27.0, 11.1 Hz, 2H), 4.51 - 4.38 (m, 3H), 4.35 (d, J = 7.5 Hz, 1H), 3.62 - 3.50 (m, 3H), 3.39 - 3.29 (m, 2H), 2.70 (dd, J = 9.8, 7.6 Hz, 1H), 0.78 (s, 9H), 0.01 (d, J = 10.3 Hz, 6H). 13 C NMR (151 MHz, CDCl 3 ) δ 138.5, 138.3, 138.1, 128.5, 128.4, 127.9, 127.8, 127.7, 127.6, 98.7 (C1), 85.0, 78.7, 75.3, 74.7, 73.5, 69.0, 58.9, 25.8, 18.0, -3.9, -5.1. HRMS(ESI) calculated for C33 H 46 NO 5 Si[M+H] + 564.3140, found 564.3139.

[0057] Compound S2-3

[0058] To a solution of compound S2-2 (858 mg, 1.52 mmol) in MeOH (17.2 mL) was added dropwise 37% formaldehyde solution (1.3 mL, 45.70 mmol) and a few drops of acetic acid, and the mixture was stirred at 80 °C for 24 h until TLC showed complete consumption of the starting material. The reaction mixture was cooled to room temperature, and NaBH 3 CN (287 mg, 4.60 mmol) was slowly added in an ice-water bath, and the reaction was stirred at room temperature for 24 h until TLC showed complete consumption of the starting material. The solution was diluted with EA, quenched with saturated NaHCO 3 aqueous solution, and then washed with saturated NaHCO 3 -aqueous solution and brine. The organic layer was dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo, and then purified by column chromatography (PE:EA = 150:1) to give compound S2-3 (803 mg, 1.37 mmol, 90%), a colorless oil. [α] D 18 = +49.2 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 - 7.19 (m, 2H), 7.18 - 7.07 (m, 11H), 7.03 - 7.05 (m, 2H), 4.81 (d, J = 10.8 Hz, 1H, H-1), 4.67 (d, J = 10.9 Hz, 1H), 4.62 - 4.52 (m, 2H), 4.48 - 4.32 (m, 3H), 3.50 (d, J = 3.4 Hz, 2H), 3.45 - 3.37 (m, 2H), 3.21 (t, J = 3.5 Hz, 1H), 2.42 (t, J = 8.1, 3.8 Hz, 1H, H-2), 2.36 (s, 6H, NMe 2 -H), 0.78 (s, 9H, TBS-H), -0.02 (d, J = 14.2 Hz, 6H, TBS-H); 13 C NMR (151 MHz, CDCl 3)δ139.2,138.5,138.4,128.3,128.1,128.0,127.7,127.6,127.5,127.4,96.5(C1),78.7,77.3,77.1,76.9,74.9,74.8,74.7,73.5,70.8,69.4,41.7,26.0,17.9,-3.5,-5.0.HRMS(ESI)calculated for C 33 H 50 NO 5 Si[M+H] + 592.3453,found 592.3453.

[0059] Compound 1b

[0060] Compound S2-3 (761 mg, 1.29 mmol) was dissolved in THF (0.8 mL) and pyridine (0.8 mL), and HF / Py (4.6 mL, 65.9%) was added under an ice-water bath. The solution was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO 3 aqueous solution, extracted with EA, washed with saturated brine, and dried over anhydrous Na 2 SO 4 The organic layer was dried, filtered, and concentrated in vacuo. The product was purified by column chromatography to give a white solid intermediate (PE:EA = 1:1).

[0061] Next, the intermediate was dissolved in acetone (7.1 mL), and Cs 2 CO 3 (441 mg, 1.37 mmol) and 2,2,2-trifluoro-N-phenylacetimidoyl chloride (0.3 mL, 1.70 mmol) were added to the solution. The reactants were stirred for 5 h, then quenched with Et 3 N, filtered, and concentrated in vacuo. The product was purified by column chromatography (PE:EA = 12:1). Colorless oily Compound 1b (643 mg, 0.99 mmol, 77% over two steps, a mixture of α and β) was obtained. [α] D 18 = +100.5 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3)δ 7.41 - 7.23 (m, 15H), 7.21 - 7.13 (m, 2H), 7.13 - 7.04 (m, 1H), 6.81 (d, J = 7.8 Hz, 2H, H-1), 6.32 (s, 1H, H-1), 4.99 (d, J = 11.0 Hz, 1H), 4.88 (d, J = 11.1 Hz, 1H), 4.79 (d, J = 10.7 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.58 (d, J = 10.7 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.13 (dd, J = 10.8, 7.7 Hz, 1H), 3.88 - 3.80 (m, 3H), 3.70 (dd, J = 10.7, 1.6 Hz, 1H), 3.04 - 2.95 (m, 1H, H-2), 2.56 (s, 6H, NMe 2 -H); 13 C NMR (151 MHz, Chloroform-d) δ 143.9, 138.8, 138.0, 128.8, 128.6, 128.1, 128.0, 127.9, 127.7, 124.2, 119.5, 96.5 (C1), 79.7, 78.7, 75.1, 74.1, 73.7, 73.0, 68.4, 66.0, 43.1, 32.1, 31.6, 30.3, 29.8, 29.5. HRMS (ESI) calculated for C 37 H 40 N2O 5 [M + H] + 648.2884, found 648.2883.

[0062] 1.1.2 Synthesis of monosaccharide donor 1f

[0063]

[0064] The compound S6-1 was synthesized according to the method in the literature (Velvadapu V, Andrade R B. Concise syntheses of d-desosamine, 2-thiopyrimidinyl desosamine donors, and methyl desosaminide analogues from d-glucose [J]. Carbohydr Res., 2008, 343, 145 - 150).

[0065] Compound S6-2

[0066] In an ice-water bath, add BzCl (4.5 mL, 38.61 mmol), Et 3 N (5.4 mL, 38.61 mmol), and DMAP (786 mg, 6.44 mmol) to a solution of compound S6-1 (2.44 g, 12.87 mmol) in DCM (24 mL), and stir the reaction at room temperature for 1 hour. After TLC shows that the starting material is completely consumed, dilute the solution with DCM and the reactants, and then wash the organic layer with an aqueous solution of saturated NaHCO 3 and brine. Dry the organic layer with anhydrous Na 2 SO 4 , filter and concentrate in vacuo. Then purify the product by column chromatography (PE:EA = 8:1) to obtain compound S6-2 as a colorless oil (3.43 g, 91% yield). [α] D 18 = +101.4 (c 0.5, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (d, J = 8.0 Hz, 2H), 7.57 (t, J = 4.0 Hz 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.18 (dd, J = 11.0, 3.7 Hz, 1H, H-2), 4.91 (d, J = 3.6 Hz, 1H, H-1), 3.95 - 4.05 (m, 1H, H-5), 3.46 - 3.39 (m, 1H, H-3), 3.37 (s, 3H, OMe-H), 2.36 (s, 6H), 1.94 - 1.89 (m, 1H, H-4), 1.47 (dd, J = 24.0 Hz, J = 8.0 Hz, 1H, H-4), 1.24 (d, J = 6.3 Hz, 3H, CH 3 -H); 13 C NMR (101 MHz, CDCl 3 ) δ 174.8, 165.9, 133.1, 129.9, 128.4, 97.8 (C-1), 71.0 (C-2), 64.1 (C-5), 57.7 (C-3), 55.1, 40.3 (NMe 2 -CH 3 ), 33.4 (C-4), 21.0 (CH 3 ). HRMS (ESI) calculated for C 16 H 24 NO 4 [M + H] + 294.1700, found 294.1698.

[0067] Compound S6-3

[0068] Dissolve compound S6-2 (213 mg, 0.73 mmol) in Ac 2 O / H 2 SO 4 (33 / 1, v / v, 1.6 mL), stir at room temperature for 24 h. After TLC shows complete consumption of the starting material, dilute the solution with EA, and wash the organic layer with saturated NaHCO 3 aqueous solution and brine. Dry the organic layer with anhydrous Na 2 SO 4 , filter and concentrate in vacuo. Purify the product by column chromatography (DCM:MeOH = 50:1). Obtain compound S6-3 as a colorless oil (194 g, 83% yield). [α] D 18 = +89.7 (c 0.5, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 8.03 - 7.98 (m, 3H), 7.57 - 7.53 (m, 1.5H), 7.45 - 7.45 (m, 3H), 6.35 (d, J = 3.7 Hz, 1H, H-1), 5.77 (d, J = 8.0 Hz, 0.5H, H-2), 5.31 (d, J = 3.7 Hz, 0.5H, H-2), 5.29 (t, J = 1.9 Hz, 1H, H-2), 5.20 (dd, J = 10.5, 8.0 Hz, 0.5H), 4.17 - 4.00 (m, 1H), 3.82 - 3.77 (m, 0.5H), 3.31 (ddd, J = 12.3, 10.9, 4.1 Hz, 1H), 3.02 - 2.98 (m 0.5H), 2.34 (s, 6H, NMe 2 -H), 2.31 (s, 3H, NMe 2 -H), 2.13 (s, 3H, NMe 2 -H), 1.97 (s, 1.5H), 1.93 - 1.90 (m, 1H), 1.89 - 1.83 (m, 0.5H), 1.58 - 1.44 (m, 1.5H), 1.32 (d, J = 6.1 Hz, 1.5H), 1.24 (d, J = 6.2 Hz, 3.4H); 13 C NMR (101 MHz, CDCl 3)δ169.5,169.4,165.5,133.1,130.0,129.9,129.8,129.7,128.4,93.72(C1),90.74(C-1),70.6,70.4,69.4,67.3,63.3,58.1,40.7,40.6,32.7,31.1,21.1,21.0,20.9.HRMS(ESI)calculated for C 17 H 24 NO 5 [M+H] + 322.1649,found 322.1645.

[0069] Compound S6-4

[0070] In an ice-water bath, a solution of compound S6-3 (434 mg, 1.35 mmol) in THF (1.9 mL) and a solution of NH 3 in MeOH (33.5 mL, 2 mol / L) were mixed and stirred at 0 °C for 5 h. After TLC showed complete consumption of the starting material. Then the organic layer was concentrated in vacuo. The product was purified by column chromatography (DCM:MeOH = 50:1). Colorless oily compound S6-4 (203 mg, 54% yield) was obtained. [α] D 18 = +62.6 (c 0.25, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ8.09 - 8.05 (m, 4.8H), 7.56 (t, J = 8.0 Hz, 2.5H), 7.44 (t, J = 8.0 Hz, 4.9H), 5.40 (d, J = 3.6 Hz, 1H, H-1), 5.13 (dd, J = 11.0, 3.6 Hz, 1H, H-2), 4.99 (dd, J = 10.4, 7.6 Hz, 1.3H), 4.66 (d, J = 7.6 Hz, 1.3H), 4.25 - 4.17 (m, J = 12.3, 6.2, 2.2 Hz, 1.4H), 3.61 - 3.69 (m, 1.5H), 3.40 - 3.33 (m, 1.2H), 2.95 - 3.02 (m, 1.5H), 2.33 (s, 6H), 2.31 (s, 7.8H), 1.80 - 1.87 (m, 2.8H), 1.52 - 1.38 (m, 2.8H), 1.27 (d, J = 6.1 Hz, 4.4H), 1.18 (d, J = 6.2 Hz, 3.4H); 13 C NMR (101 MHz, CDCl 3)δ,165.9,133.2,133.1,130.1,130.0,129.9,128.4,96.8(C-1),90.9,73.8,71.6,69.6,64.3,62.7,57.2,40.9,40.8,33.9,32.8,21.1.HRMS(ESI)calculated for C 15 H 22 NO 4 [M+H] + 280.1543,found 280.1541.

[0071] Compound 1f

[0072] To a solution of compound S6-4 (410 mg, 1.47 mmol) in DCM (14.7 mL) in an ice-water bath was slowly added DBU (109 μL / mL, 0.74 mmol) and Cl 3 CCN (1.5 mL, 14.67 mmol). The reaction was stirred at 0 °C for 2.5 h and then quenched with Et 3 N, filtered and concentrated in vacuo. The product was purified by column chromatography (PE:EA:Et3N = 8:1:0.1) to give 1f as a colorless oil (132 mg, 0.31 mmol, 21%). [α] D 19 = +30.8 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 8.42 (s, 1H), 8.06 - 7.98 (m, 2H), 7.57 - 7.50 (m, 1H), 7.40 (t, J = 7.6 Hz, 2H), 6.50 (d, J = 3.5 Hz, 1H, H-1), 5.36 (dd, J = 10.9, 3.6 Hz, 1H, H-2), 4.25 - 4.20 (m, 1H, H-5), 3.43 (td, J = 11.6, 4.0 Hz, 1H, H-3), 2.35 (s, 6H, NMe 2 -H), 1.96 - 1.91 (m, 1H, H-4), 1.62 - 1.53 (m, 1H, H-4), 1.27 (d, J = 6.0 Hz, 3H, CH 3 -H). 13 C NMR (101 MHz, CDCl 3)δ165.6,161.0,133.2,129.9,129.8,128.3,95.1(C-1),91.4,69.9(C-2),67.8(C-5),58.1(C3-),40.8(NMe 2 -C),33.2(C-4),21.1(CH 3 -C).HRMS(ESI)calculated for C 17 H 22 N 2 O 4 [M+H] + 423.0340,found 423.0642.

[0073] 1.2 Synthesis of the receptor

[0074]

[0075] The present invention synthesizes compound 2a according to the method in the literature (Viuff AH, Besenbacher LM, Kamori A, et al. Stable analogues of nojirimycin - synthesis and biological evaluation of nojiristegine and manno - nojiristegine. Org. Bio. Chem., 2015, 13, 9637 - 9658).

[0076] The present invention synthesizes compound 2h according to the method in the literature (Kong F, Du J, Wu H. Selective esterification of methyl 4,6 - di - O - benzyl - α - D - mannopyranoside. Carbohydr. Res., 1986, 147, 337 - 341).

[0077] The present invention synthesizes compound 2i according to the method in the literature (Rao KV, Patil PR, Atmakuri S, et al. Iodine - sodium cyanoborohydride - mediated reductive ring opening of 4,6 - O - benzylidene acetals of hexopyranosides. Carbohydr. Res., 2010, 345, 2709 - 2713).

[0078] The cholesterol (2c), cyclododecanol (2d), and 1-adamantanol (2e) used are all conventional commercially available products.

[0079] 1.3 Synthesis of the catalyst

[0080] Compound C5 was synthesized according to the method in the literature (Chang, Y.-P.; Tang, T.; Franz, A. K. NMR Quantification of Halogen-Bonding Ability To Evaluate Catalyst Activity. Org. Lett. 2020, 22, 6647-6652).

[0081] 1.4 Synthesis of N,N-dimethylaminoglycoside

[0082] All reagents used were of commercial grade and used as received. All moisture-sensitive reactions were carried out under a nitrogen atmosphere. The solvent (DCM) used in the glycosylation reaction was distilled over CaH 2 and stored on activated molecular sieves before use. The reactions were monitored by thin-layer chromatography (TLC) analysis, detected with ultraviolet (254 nm), and, where applicable, sprayed with a 10% sulfuric acid ethanol solution or (NH 4 ) 6 Mo 7 O 24 ·4H 2 O (25 g / L) and (NH 4 ) 4 Ce(SO 4 ) 4 ·2H 2 O (10 g / L) in 10% sulfuric acid (aqueous solution), and then carbonized at ~150 °C.

[0083] Flash column chromatography was carried out on silica gel (300-400 mesh). 1 H and 13 C spectra were recorded on a Bruker AV 400 / 600 in CDCl 3 , CD 3 COCD 3 CD 3 OD, CD 2 Cl 2 . Chemical shifts (δ) were given in ppm relative to tetramethylsilane ( 3 H NMR in CDCl 1 ) or the residual signal of the deuterated solvent as the internal standard. Coupling constants (J) were given in Hz. All 13 C spectra were proton-decoupled.

[0084] Where applicable, COSY, HSQC, NOESY, and HMBC experiments were used to further elucidate the structure. Standard splitting pattern abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). High-resolution mass spectrometry (HRMS) was recorded on an ESI-TOF or ESI-Obitrap mass spectrometer.

[0085] General procedure A: Glycosylation of N,N-dimethylaminoglycosyl donors via halogen bonding activation.

[0086] The donor (0.15 mmol, 1.5 eq) and the acceptor (1.0 eq, 0.1 mmol) were co-evaporated with anhydrous toluene (using a conventional method in the prior art, which is not the inventive point of the present invention and will not be elaborated further) three times to obtain a mixture. To the mixture was added a halogen bonding catalyst C5 (29.1 mg, 0.05 mmol), freshly activated molecular sieve and dry PhCF 3 (0.5 mL). Under a nitrogen atmosphere, the reaction mixture was stirred at 30 °C until the reaction was complete as detected by TLC. It was filtered and concentrated in vacuo. The residue was separated by gel filtration (HW-20, DCM:MeOH = 1:1) to obtain a crude product for determining stereoselectivity by NMR. Then it was purified by silica gel column chromatography to obtain the product.

[0087] General procedure B: Glycosylation of N,N-dimethylaminoglycosyl donors via halogen bonding activation in the presence of 3,5-bis(trifluoromethyl)phenylboronic acid additive.

[0088] The donor (0.15 mmol, 1.5 eq) and the acceptor (1.0 eq, 0.1 mmol) were co-evaporated with anhydrous toluene (using a conventional method in the prior art, which is not the inventive point of the present invention and will not be elaborated further) three times to obtain a mixture. To the mixture was added a halogen bonding catalyst C5 (29.1 mg, 0.05 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (12.9 mg, 0.05 mmol), freshly activated molecular sieve and dry PhCF 3 (0.5 mL). Under a nitrogen atmosphere, the reaction mixture was stirred at 30 °C until the reaction was complete as detected by TLC. It was filtered and concentrated in vacuo. The residue was separated by gel filtration (HW-20, DCM:MeOH = 1:1) to obtain a crude product for determining stereoselectivity by NMR. Then it was purified by silica gel column chromatography to obtain the product.

[0089] Compound 3o

[0090] According to the general procedure B, donor 1f (63.70 mg, 0.15 mmol) and acceptor 2d (18.40 mg, 0.1 mmol) were reacted in a 10 mL round-bottom flask at 30 °C for 48 hours to obtain the crude product. Then it was filtered, concentrated in vacuo, and purified by column chromatography (PE:EA = 3:1) to obtain 3o (41 mg, 92%, only β) as a colorless syrup. [α] D 20 = +15.8 (c 0.5, CHCl 3 ); 1 1H NMR (600 MHz, CDCl 3 ) δ 8.05 (1, J = 6.0 Hz 2H), 7.56 - 7.51 (m, 1H), 7.43 (t, J = 7.7 Hz, 2H), 5.09 (dd, J = 10.4, 7.5 Hz, 1H, H-2), 4.50 (d, J = 7.6 Hz, 1H, H-1), 3.72 - 3.68 (m, 1H), 3.64 - 3.59 (m, 1H, H-5), 2.96 - 2.92 (m, 1H, H-3), 2.32 (s, 6H, NMe 2 -H), 1.83 - 1.80 (m, 1H, H-4), 1.62 - 1.57 (m, 1H), 1.55 - 1.45 (m, 2H), 1.42 - 1.36 (m, 2H), 1.33 - 1.29 (m, 7H), 1.26 - 1.24 (m, 7H), 1.19 - 1.12 (m, 4H); 13 13C NMR (151 MHz, CDCl 3 ) δ 165.5 (C=O), 132.7, 130.7, 129.7, 128.2, 101.5 (C-1), 77.7, 71.8 (C-2), 69.2 (C-5), 63.4 (C-3), 40.8 (NMe 2 -C), 31.9 (C-4), 30.3, 29.0 (CH 3 -C), 24.5, 24.4, 24.1, 23.3, 23.2, 23.2, 23.0, 21.3, 20.9, 20.3. HRMS (ESI) calculated for C 27 H 44 NO 4 [M+H] + 446.3265, found 446.3265.

[0091] Compound 3p

[0092] According to general procedure B, donor 1f (63.70 mg, 0.15 mmol) and acceptor 2c (38.7 mg, 0.1 mmol) were reacted in a 10 mL round-bottom flask at 30 °C for 48 h to give the crude product. Then it was filtered, concentrated in vacuo, and purified by column chromatography (PE:EA = 3:1) to give 3p (56 mg, 87%, only β) as a colorless syrup. [α] D 19 = +12.9 (c 0.5, CHCl 3 ); 1 1H NMR (600 MHz, CDCl 3 ) δ 8.06 (d, J = 7.7 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 5.18 (dd, J = 5.2, 2.5 Hz, 1H, H-5), 5.09 (dd, J = 10.5, 7.5 Hz, 1H, H-2), 4.56 (d, J = 7.6 Hz, 1H), 3.64 - 3.59 (m, 1H), 3.49 - 3.43 (m, 1H), 2.98 - 2.94 (m, 1H, H-3), 2.33 (s, 6H, NMe 2 -C), 2.14 - 2.10 (m, 1H), 2.06 - 1.96 (m, 2H), 1.94 - 1.77 (m, 5H, H-4), 1.58 - 1.43 (m, 1H), 1.40 (d, J = 3.1 Hz, 1H), 1.39 - 1.32 (m, 4H), 1.30 (d, J = 6.2 Hz, 3H), 1.16 - 0.95 (m, 9H), 0.90 (d, J = 6.5 Hz, 3H), 0.86 (s, 5H), 0.85 (d, J = 3.0 Hz, 3H), 0.63 (s, 3H); 13 13C NMR (151 MHz, CDCl 3 ) δ 165.7 (C=O), 140.9, 132.8, 130.6, 129.7, 128.3, 121.5 (C-5), 101.1 (C-1), 79.2, 71.6 (C-2), 69.2, 63.4 (C-3), 56.8, 56.1, 50.2, 42.3, 40.8 (NMe 2 -C), 39.8, 39.5, 38.9, 37.3, 36.7 (CH 3 -C), 36.2, 35.8, 31.9, 31.8 (C-4), 29.6, 28.2, 28.0, 24.3, 23.8, 22.8, 22.6, 21.2, 21.0, 19.3, 18.7, 11.8. HRMS (ESI) calculated for C 42 H66 NO 4 [M+H] + 648.4984, found 648.4987.

[0093] Compound 3q

[0094] According to General Procedure B, donor 1f (63.70 mg, 0.15 mmol) and acceptor 2e (15.2 mg, 0.1 mmol) were reacted in a 10 mL round-bottom flask at 30 °C for 48 h to give the crude product. Then it was filtered, concentrated in vacuo, and purified by column chromatography (PE:EA = 3:1) to give 3q (28.9 mg, 70%, only β) as a colorless syrup. [α] D 18 = +15.4 (c 0.5, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J = 8.3 Hz, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 5.09 (dd, J = 10.5, 7.6 Hz, 1H, H-2), 4.76 (d, J = 7.5 Hz, 1H, H-1), 3.64 - 3.57 (m, 1H, H-5), 3.00 - 2.94 (m, 1H, H-3, NMe 2 -H), 2.32 (s, 3H, NMe 2 -H), 2.05 (s, 3H), 1.86 - 1.81 (m, 1H), 1.77 (dd, J = 11.7, 2.5 Hz, 3H, H-2), 1.65 - 1.45 (m, 10H), 1.29 (d, J = 6.2 Hz, 3H, CH 3 -H); 13 C NMR (101 MHz, CDCl 3 ) δ 165.4 (C=O), 132.7, 130.7, 129.8 128.3, 95.0 (C-1), 74.6, 71.5 (C-2), 68.8 (C-5), 63.6 (C-3), 42.5 (C-4), 40.9 (NMe 2 -C), 36.2, 32.0, 30.6 (CH 3 -C), 21.41. HRMS (ESI) calculated for C 25 H 36 NO 4 [M+H] + 414.2639, found 414.3639.

[0095] Compound 3r

[0096] According to the general procedure B, the donor 1f (63.70 mg, 0.15 mmol) and the acceptor 2a (46.5 mg, 0.1 mmol) were reacted in a 10 mL round-bottom flask at 30 °C for 48 h to obtain the crude product. Then it was filtered, concentrated in vacuo, and purified by column chromatography (PE:EA = 3:1) to obtain 3r (69 mg, 95%, only β) as a colorless syrup. [α] D 20 = +18.9 (c 0.5, CHCl 3 ); 1 1H NMR (600 MHz, CDCl 3 ) δ 7.96 (d, J = 7.7 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.34 - 7.26 (m, 8H), 7.26 - 7.21 (m, 7H), 7.17 (d, J = 7.2 Hz, 1H), 6.99 (d, J = 6.0 Hz 1H), 5.20 (t, J = 8.9 Hz, 1H, H-2b), 4.86 (d, J = 11.1 Hz, 1H), 4.73 (dd, J = 12.0, 2.1 Hz, 1H), 4.67 (d, J = 11.3 Hz, 1H), 4.59 (dd, J = 12.1, 2.1 Hz, 1H), 4.52 - 4.41 (m, 2H, H-1a, H-1b), 4.34 (d, J = 10.8 Hz, 1H), 4.23 (d, J = 11.3 Hz, 1H), 4.11 (d, J = 10.2 Hz, 1H, H-6a), 3.87 - 3.84 (m, 1H, H-3a), 3.70 - 3.56 (m, 3H, H-5a), 3.46 - 3.36 (m, 2H, H-4a, H-5b), 3.22 (s, 3H, OMe-H), 2.95 - 2.90 (m, 1H, H-3b), 2.29 (s, 6H, NMe 2 -H), 1.81 (dd, J = 13.1, 4.2 Hz, 1H, H-4b), 1.54 - 1.46 (m, 1H, H-4b), 1.29 (d, J = 6.1, 3H, CH 3 -H); 13 13C NMR (151 MHz, CDCl 3)δ165.4(C=O),138.9,138.3,138.2,132.7,130.4,129.8,129.1,128.5,128.3,128.2,127.9,127.5,102.3(C-1b),98.0(C-1a),82.0(C-4a),79.6(C-5b),77.4(C-4a),75.5,74.7,73.4,71.2,69.4,67.4,63.6(C-3b).55.0,40.8(NMe 2 -C),31.6(C-4b),21.1(CH 3 -C)HRMS(ESI)calculated for C 43 H 52 NO 9 [M+H] + 726.3637,found 726.3637.

[0097] Compound 3t

[0098] According to the general procedure B, the donor 1f (63.70 mg, 0.15 mmol) and the acceptor 2i (46.5 mg, 0.1 mmol) were reacted in a 10 mL round-bottom flask at 30 °C for 48 h to obtain the crude product. Then it was filtered, concentrated in vacuo, and purified by column chromatography (PE:EA = 3:1) to obtain 3t (67 mg, 92%, only β) as a colorless syrup. [α] D 18 =+20.9(c 1.0,CHCl 3 ); 1 HNMR(600MHz,CDCl 3)δ7.92(d, J = 7.7 Hz, 2H), 7.54(t, J = 7.4 Hz, 2H), 7.46(d, J = 7.5 Hz, 2H), 7.42(t, J = 7.6 Hz, 2H), 7.38(d, J = 7.2 Hz, 2H), 7.34 - 7.32(m, 5H), 7.29 - 7.23(m, 6H), 5.06(d, J = 11.0 Hz, 1H), 4.97(dd, J = 10.5, 7.6 Hz, 1H, H - 2b), 4.82(d, J = 10.9 Hz, 1H), 4.74(d, J = 12.2 Hz, 1H, H - 4a), 4.64 - 4.54(m, 3H, H - 1b), 4.51(d, J = 3.6 Hz, 1H, H - 1a), 4.27(d, J = 12.2 Hz, 1H), 3.91 - 3.82(m, 2H, H - 3a), 3.63(dd, J = 10.6, 3.5 Hz, 1H, H - 5a), 3.49 - 3.45(m, 2H, H - 2a), 3.44 - 3.40(m, 1H), 3.36(dd, J = 10.6, 2.1 Hz, 1H, H - 6a), 3.25(s, 3H, OMe - H), 2.69 - 2.59(m, 1H, H - 3b), 2.25(s, 6H, NMe 2 -H), 1.74(dd, J = 13.5, 4.2 Hz, 1H, H - 4), 1.36(q, J = 12.1 Hz, 1H, H - 4), 1.19(d, J = 6.0 Hz, 3H, CH 3 -H); 13 C NMR(151 MHz, CDCl 3 )δ165.3(C = O), 139.7, 138.4, 138.2, 132.9, 130.4, 129.8, 129.1, 128.4, 128.4, 128.1, 128.0, 127.8, 127.8, 127.7, 127.1, 101.6(C - 1b), 98.2(C - 1a), 80.4, 79.1, 76.5(C - 3a), 75.3, 73.5(C - 4a), 72.2(C - 2b), 69.6, 69.2, 68.1(C - 6a), 63.4(C - 3b), 55.2(OMe - C), 40.7(NMe 2 -C), 31.4(C - 4b), 21.2(CH 3 -C). HRMS(ESI) calculated for C 43 H 52 NO 9 [M + H] + 726.3637, found 726.3637.

[0099] Compound 3u

[0100] According to the general procedure A, donor 1b (97.2 mg, 0.15 mmol) and acceptor 2h (46.5 mg, 0.1 mmol) were reacted in a 10 mL round-bottom flask at 30 °C for 48 h to obtain the crude product. Then it was filtered, concentrated in vacuo, and purified by column chromatography (PE:EA = 3:1) to give 3u (73 mg, 79%, only β) as a colorless syrup. [α] D 18 = +40.7 (c 1.0, CHCl 3 ); 1 1H NMR (600 MHz, CDCl 3 ) δ 7.37 - 7.21 (m, 27H), 7.18 - 7.14 (m, 2H), 7.07 - 7.05 (m, 2H), 5.11 (s, 1H), 5.07 (d, J = 11.7 Hz, 1H, H-1a)), 4.88 (t, J = 12.0 Hz, 2H), 4.81 - 4.73 (m, 3H), 4.64 (d, J = 12.2 Hz, 1H), 4.58 - 4.45 (m, 6H, H-1b, H-4b), 3.99 (t, J = 12.0 Hz, 1H, H-3a), 3.83 - 3.74 (m, 2H), 3.73 - 3.62 (m, 6H, H-3b, H-2a), 3.57 (t, J = 9.0 Hz, 1H), 3.37 (d, J = 2.1 Hz, 4H, Me-H), 2.77 (t, J = 9.0 Hz, 1H, H-2b), 2.39 (s, 6H, NMe 2 -H); 13 13C NMR (151 MHz, CDCl 3 ) δ 139.4, 139.0, 138.3, 138.2, 138.1, 128.5, 128.4, 128.3, 128.1, 128.0, 127.8, 127.7, 103.7 (C1-b), 99.9 (C1-a), 81.90, 80.9, 80.5, 79.1 (C3-a), 78.7, 75.0, 74.9, 74.7, 74.4, 73.7, 73.6, 70.0, 69.5, 68.8, 68.7 (C2-b), 55.3 (OMe-C), 42.0 (NMe 2 -C). HRMS (ESI) calculated for C 57 H 66 NO 11 [M + H] +924.4681, found 924.4681.

[0101] Compound 3v

[0102] According to the general procedure A, donor 1b (97.2 mg, 0.15 mmol) and acceptor 2c (38.7 mg, 0.1 mmol) were reacted in a 10 mL round-bottom flask at 30 °C for 48 h to obtain the crude product. Then it was filtered, concentrated in vacuo, and purified by column chromatography (PE:EA = 3:1) to obtain 3v (51 mg, 60%, only β) as a colorless syrup. [α] D 19 = +39.9 (c 0.5, CHCl 3 ); 1 1H NMR (400 MHz, CDCl 3 ) δ 7.37 (d, J = 7.4 Hz, 2H), 7.34 - 7.23 (m, 12H), 7.23 - 7.16 (m, 2H), 5.36 (d, J = 5.0 Hz, 1H), 4.97 (d, J = 10.7 Hz, 1H), 4.83 (d, J = 10.8 Hz, 1H), 4.73 (d, J = 10.7 Hz, 1H), 4.63 - 4.50 (m, 4H, H-1), 3.73 (d, J = 10.7 Hz, 1H), 3.65 - 3.56 (m, 3H, H-3), 3.49 (t, J = 8.9 Hz, 1H), 3.39 (t, J = 7.5 Hz, 1H), 2.64 (t, J = 8.0, 1H, H-2), 2.51 (s, 6H, NMe 2 -H), 2.37 (d, J = 6.8 Hz, 2H, H-4), 2.10 - 1.93 (m, 3H), 1.90 - 1.75 (m, 2H), 1.67 - 1.55 (m, 3H), 1.53 (d, J = 6.5 Hz, 1H), 1.52 - 1.44 (m, 3H), 1.44 (d, J = 4.5 Hz, 1H), 1.34 (d, J = 7.4 Hz, 3H), 1.27 (d, J = 11.8 Hz, 2H), 1.22 - 1.04 (m, 6H), 1.02 (s, 6H), 0.92 (d, J = 6.4 Hz, 4H), 0.87 (dd, J = 6.6, 1.7 Hz, 7H), 0.68 (s, 3H); 13 13C NMR (151 MHz, CDCl 3)δ140.8,139.2,138.4,128.3,128.1,127.9,127.6,127.5,121.8(C5),100.2(C1),81.0,79.1,78.8(C3),74.9,74.8,74.8,73.3,69.5,69.3(C2),56.8,56.2,50.2,42.3,41.7(NMe 2 -C),39.8,39.6,39.5(C4),37.3,36.8,36.2,35.8,32.0,31.9,30.1,28.2,28.0,24.3,23.8,22.8,22.6,21.0,19.4,18.7,11.9.HRMS(ESI)calculated for C 56 H 80 NO 5 [M+H] + 846.6031,found 846.6032.

[0103] Compound 3w

[0104] According to the general procedure A, the donor 1b (97.2 mg, 0.15 mmol) and the acceptor 2e (15.2 mg, 0.1 mmol) were reacted in a 10 mL round-bottom flask at 30 °C for 96 h to obtain the crude product. Then it was filtered, concentrated in vacuo, and purified by column chromatography (PE:EA = 3:1) to obtain 3w (51 mg, 60%, only β) as a colorless syrup. [α] D 18 = +10.8 (c 1.0, CHCl 3 ); 1 1H NMR (400 MHz, CDCl 3 ) δ 7.41 - 7.35 (m, 2H), 7.39 - 7.25 (s, 11H), 7.23 - 7.20 (m, 2H), 4.96 (d, J = 10.8 Hz, 1H), 4.89 - 4.71 (m, 3H, H-1), 4.65 - 4.48 (m, 3H), 3.71 (dd, J = 10.6, 2.1 Hz, 1H, H-4), 3.65 - 3.56 (m, 2H, H-3), 3.46 (t, J = 8.0 Hz, 1H, H-6), 3.41 - 3.36 (m, 1H, H-5), 2.69 (t, J = 10.0, 1H, H-2), 2.53 (s, 6H), 2.18 - 2.09 (m, 3H), 2.03 - 1.74 (m, 6H), 1.62 (t, J = 2.9 Hz, 6H); 13 13C NMR (101 MHz, CDCl3 )δ139.15, 138.49, 138.42, 128.38, 128.28, 128.12, 127.97, 127.67, 127.55, 127.45, 94.47 (C1), 78.96 (C6), 75.48, 74.77, 74.71, 74.23 (C5), 73.33, 69.81 (C4), 69.52 (C2), 43.27, 41.51, 36.32, 30.80. HRMS(ESI) calculated for C 39 H 50 NO 5 [M + H] + 612.3684, found 612.3684.

[0105] The present invention has developed a new glycosylation method for the direct synthesis of N,N - dimethylaminoglycosides through halogen - bond activation. The results show that under mild halogen - bond - activated glycosylation conditions and using a specific catalyst, N,N - dimethylaminoglycosyl donors can be coupled with a wide range of acceptors to provide the desired N,N - dimethylaminoglycosides in good to excellent yields and excellent stereoselectivity.

[0106] The glycosylation method provided by the present invention can be widely applied in the synthesis of N,N - dimethylaminoglycosides with high biological activity. And the method of the present invention can also be successfully used for the synthesis of nucleoside antibiotics containing N,N - dimethylaminosugar fragments (such as cytosamine, Cytosamine).

[0107] Reaction mechanism

[0108] To gain an in - depth understanding of the reaction mechanism of the method for synthesizing N,N - dimethylaminoglycosides by halogen - bond - catalyzed glycosylation according to the present invention, and the effect of catalyst C5 on N,N - dimethylaminoglycosyl donors, the inventors then carried out 13 13C NMR titration studies.

[0109] After a series of experiments and subsequent studies on the S N 1 or S N 2 pathway mechanism involved in the experimental process. The inventors proposed the following reaction mechanism: First, N,N - dimethylaminoglycosyl donor 1 and catalyst C5 form complex I through halogen - bond interaction. Next, through n - π* and / or π - π interactions, the trichloroacetimidate undergoes intramolecular activation to form complex II. Due to the moderate stability of complex II, C5 temporarily loses its interaction with the amine and instead interacts with the trichloroacetimidate salt to activate it. Then, after the activation of the imidate salt, a direct nucleophilic attack of acceptor 2 occurs, through S N2 pathways or generate the desired product 3 by generating an oxocarbenoid-like intermediate III. The latter can also be attacked by the receptor 2, via S N 1 pathway provides the desired product 3.

[0110] Method for synthesizing N,N-dimethylaminoglycoside by hydrogen bond catalyzed glycosylation in Example 2

[0111] 2.1 Synthesis of monosaccharide donor 4d

[0112] The donor was synthesized according to the method in the literature (Zhang Y, He H, Chen Z, et al. Merging Reagent Modulation and Remote Anchimeric Assistance for Glycosylation: Highly Stereoselective Synthesis of α-Glycans up to a 30-mer. Angew. Chem., 2021, 133, 12705-12714)

[0113] 2.2 Synthesis of compound 5b

[0114] Using commercially available methyl glucoside S9-1 as the raw material, it was synthesized according to the method in the literature (Guo Kaiyan. Glycosylation Study on Hydrogen Bond Activated Dimethylamino Sugar Receptor [D]. Jiangxi Normal University, 2024. DOI: 10.27178 / d.cnki.gjxsu.2024.001322.)

[0115] 2.3 Synthesis of the catalyst

[0116] The catalyst C3 was synthesized in this example according to the method in the literature (Ge, Qingmei; Hu, Yang; Li, Bin; Wang, Baiquan. Synthesis of Conjugated Polycyclic Quinoliniums by Rhodium(III)-Catalyzed Multiple C-H Activation and Annulation of Arylpyridiniums with Alkynes[J]. Organic Letters, 2016, Vol.18(10):2483-2486; Xiao, K.; Hu, Y.X.; Wan, Y.Y.; Li, X.X.; Nie, Q.; Yan, H.; Wang, L.M.; Liao, J.X.; Liu, D.Y.; Tu, Y.H.; Sun, J.S.; Codée, J.D.C.; Zhang, Q.J. Hydrogen bond activated glycosylation under mild conditions[J]. Chem.Sci. 2022, 13, 1600-1607).

[0117] 2.4 Synthesis of N,N-Dimethylaminoglycosides

[0118] All reagents used were commercial grade and used as received. All moisture-sensitive reactions were carried out under a nitrogen atmosphere. The solvent (DCM) used in the glycosylation reaction was distilled over CaH 2 and stored on activated molecular sieves before use. The reactions were monitored by thin-layer chromatography (TLC) analysis, detected with ultraviolet light (254 nm), and, where applicable, sprayed with a 10% sulfuric acid ethanol solution or a 10% sulfuric acid (aqueous solution) solution of (NH 4 ) 6 Mo 7 O 24 ·4H 2 O (25 g / L) and (NH 4 ) 4 Ce(SO 4 ) 4 ·2H 2 O (10 g / L), and then carbonized at ~150 °C.

[0119] Flash column chromatography was performed on silica gel (300 - 400 mesh). 1 H and 13 C spectra were recorded in CDCl 3 、CD 3 COCD 3, CD 3 OD, CD 2 Cl 2 on a Bruker AV 400 / 600 in. Relative to tetramethylsilane (CDCl 3 in 1 as the internal standard) or the residual signal of the deuterated solvent, the chemical shift (δ) is given in ppm. The coupling constant (J) is given in Hz. All 13 C spectra are proton-decoupled.

[0120] When applicable, COSY, HSQC, NOESY, and HMBC experiments were used to further elucidate the structure. Standard splitting pattern abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). High-resolution mass spectrometry (HRMS) was recorded on an ESI-TOF or ESI-Obitrap mass spectrometer.

[0121] Compound 6q

[0122] The receptor 5b (40.1 mg, 0.1 mmol) and the pure α-configured donor 4d-α or the pure β-configured donor 4d-β (129 mg, 0.2 mmol) were placed in a 10 mL round-bottom flask and co-evaporated with anhydrous toluene (using a conventional method in the prior art, which is not the inventive point of the present invention and will not be elaborated further) three times. Then, the thiourea catalyst C3 (63.7 mg, 0.03 mmol), activated (100 mg) and anhydrous toluene (1 ml) were added. The reaction mixture was stirred at 40 °C under a nitrogen atmosphere for 4 days. After the reaction, it was filtered, concentrated, and purified by column chromatography (PE:EA = 3:1, Rf = 0.2 - 0.4), thereby obtaining compound 6q with an α / β mixture (α:β = 2.6:1) using the pure 4d-α donor, or compound 6q with an α / β mixture (α:β = 3.6:1) using the pure 4d-β donor. The NMR data for the preparation of compound 6q from the donor 4d-α are: [α] D 22 = +117.0 (c 0.1, Acetone); 1 1H NMR (400 MHz, CDCl 3) δ 7.43 - 7.20 (m, 46H), 5.01 (dd, J = 10.9, 4.6 Hz, 2H), 4.95 (d, J = 10.8 Hz, 0.6H), 4.85 (s, 1H), 4.81 (d, J = 4.5 Hz, 2H, H-1a), 4.79 - 4.73 (m, 3H), 4.71 (d, J = 7.2 Hz, 4H), 4.66 (d, J = 11.9 Hz, 3H), 4.57 (d, J = 3.2 Hz, 1.4H), 4.56 - 4.53 (m, 1.3H), 4.51 (d, J = 3.5 Hz, 1H, H-1α), 4.49 - 4.45 (m, 1.5H), 4.44 - 4.40 (m, 1H, H-1β), 4.20 (d, J = 9.2 Hz, 1.6H), 4.15 (d, J = 8.7 Hz, 2H), 4.07 (dd, J = 11.5, 7.1 Hz, 3.5H), 3.99 (dd, J = 10.0, 3.5 Hz, 1.7H), 3.83 (dd, J = 10.0, 2.9 Hz, 2H), 3.72 (q, J = 9.7 Hz, 8H), 3.50 (dd, J = 9.3, 3.5 Hz, 2H), 3.41 - 3.35 (m, 0.6H), 3.31 (s, 1.6H), 3.26 (s, 5H), 2.60 (t, J = 9.7 Hz, 2H), 2.43 (s, 3H), 2.40 (s, 9H), 1.10 - 1.03 (m, 22H), 0.98 (s, 14H); 13 C NMR (101 MHz, CDCl 3 ) δ 139.3, 139.2, 139.1, 139.0, 138.8, 138.3, 128.5, 128.4, 128.4, 128.4, 128.3, 128.2, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 104.4, 98.3, 97.8, 97.7, 82.2, 82.1, 81.2, 78.5, 77.4, 76.6, 75.3, 74.4, 74.0, 73.9, 73.2, 73.1, 71.4, 71.3, 70.8, 70.3, 70.2, 69.9, 69.1, 68.4, 67.4, 67.2, 64.5, 55.3 (6q-β-C-OMe), 55.2 (6q-α-C-OMe), 42.5 (6q-α-C-N(Me) 2 ), 27.8, 27.7, 27.4, 23.6, 20.9, 20.8. HRMS (ESI) calculated for C 51 H 70 NO 10Si[M+H] + 884.4764, found 884.4762.

[0123] Reaction mechanism

[0124] To gain a deeper understanding of the reaction mechanism of the method for synthesizing N,N-dimethylaminoglycosides by hydrogen bond catalyzed glycosylation according to the present invention, the inventors subsequently carried out 13 13C NMR titration studies between the thiourea catalyst C3 and cyclohexyl trichloroacetimidate.

[0125] After a series of experiments and subsequent studies on the S N 1 or S N 2 pathway mechanism involved in the experimental process. The inventors proposed the following reaction mechanism: First, the N,N-dimethylaminoglycosyl donor 4 and the catalyst C3 form a complex I' through hydrogen bond interaction, and this complex is in equilibrium with the complex II'. Next, the complex II’ activates the imidate donor 4 through hydrogen bond interaction to form a complex III’, and the complex III can follow the S N 2- or S N 1-like reaction to provide the desired β-product 6.

Claims

1. A method for synthesizing N,N-dimethylaminoglycoside, characterized in that: The steps include: The acceptor and the donor are placed in a reaction container, a catalyst I is added, and a solvent I is added under a protective atmosphere. The reaction is carried out at a specific temperature for a certain time. After the reaction, the product is filtered, concentrated, separated and purified by column chromatography to obtain N,N-dimethylaminoglycoside.

2. The synthesis method according to claim 1, characterized in that The specific temperature is -30 to 80°C; the reaction time is more than 1 hour.

3. The synthesis method according to claim 1, characterized in that The steps include: The donor and the acceptor are placed in a reaction container, and catalyst I and molecular sieves are added. Solvent I is added under a protective atmosphere, and the reaction is carried out at 30-40° C. for 2 h to 96 h. After the reaction, the reaction is filtered, concentrated, and purified by column chromatography to obtain N,N-dimethylaminoglycoside.

4. The synthesis method according to claim 1, characterized in that The steps include: The donor and the acceptor are placed in a reaction container, and a catalyst I, a reaction additive and a molecular sieve are added. Under a protective atmosphere, a solvent I is added, and the reaction is carried out at 30 to 50° C. for 2 h to 96 h. After the reaction, the reaction is filtered, concentrated, and purified by column chromatography to obtain N, N-dimethylaminoglycoside.

5. The synthesis method according to any one of claims 1 to 4, characterized in that: The structural formula of the N,N-dimethylaminoglycoside is as follows:

6. The synthesis method according to any one of claims 1 to 4, characterized in that: The receptor is The donor is The molar ratio of acceptor to donor is 1:(1-3).

7. The synthesis method according to claim 5, characterized in that R1 is Bn or Bz; R2 is R3 is 8. The synthesis method according to any one of claims 1 to 4, characterized in that: The catalyst I is: The molar ratio of the acceptor to the catalyst I is 1:(0.1-1); The solvent I is any one of PhMe, PhCF3, DCM, 1,4-dioxane, THF and CH3CN.

9. The synthesis method according to claim 6, characterized in that The N,N-dimethylaminoglycoside is:

10. The synthesis method according to claim 3 or 4, wherein the molecular sieve is The molecular sieve is characterized in that the reaction additive is 3,5-bis(trifluoromethyl)phenylboronic acid, and the molar ratio of the reaction additive to the acceptor is (0.2-0.8):1.

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