Method for synthesizing C-sugar amino acid derivative through chiral auxiliary agent assisted stereoselective glycosylation

Abstract

The invention provides a method for synthesizing a C-sugar amino acid derivative through chiral auxiliary agent assisted stereoselective glycosylation, which comprises the following steps: taking phenylglycinamide derived by taking camphor sulfamide as a chiral auxiliary agent and sugar NHP ester as raw materials, and synthesizing the C-sugar amino acid derivative through photosensitizer catalyzed stereoselective C (sp3)-C (sp3)-H glycosylation under the irradiation of blue light. Compared with a traditional synthesis method, the method does not need metal, guiding groups and chiral ligands, and post-treatment is simple and convenient; high temperature and high pressure are not needed, and conditions are relatively mild; (-) / (+) camphorsulfamide is used as a chiral auxiliary agent, and high-stereoselectivity (d.rgt; 20: 1); the method has the advantages of wide substrate application range, simple operation steps and high product yield.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary. Background Art

[0002] C-glycosyl amino acids are a unique class of compounds that are widely found in nature and have extremely diverse biological properties. Glycosylation is considered to be an effective structural modification of amino acids or peptides that can enhance the hydrophilicity of the associated molecules, thereby improving their subsequent pharmacological activity and bioavailability. More importantly, the C(sp 3 )-H glycosylation can facilitate the modification of peptide backbones. With the important role of glycosylation in the development of peptide drugs, asymmetric C(sp 3 )-H glycosylation synthesis has received increasing attention. Although significant progress has been made, the related stereoselective C(sp 3 )-C(sp 3 ) coupling still faces major challenges, especially the asymmetric C(sp 3 )-C(sp 3 )-H glycosylation. In recent years, many asymmetric glycosylation methods have been reported at home and abroad, among which photoinduced metal-catalyzed CH functionalization is a commonly used and effective means. However, in this reaction, C(sp 3 The stereoselectivity of )-H glycosylation is determined by the directing group, metal, and chiral phosphine ligand. Therefore, it is necessary to find metal-free, directing group-free, and simple operation conditions to achieve the C(sp 3 )-C(sp 3 )-H glycosylation is a milestone.

[0003] Therefore, it is necessary to develop a method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by chiral auxiliary. Summary of the invention

[0004] The present invention aims to provide a method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary, using phenylglycinamide derived from camphor sulfonamide as a chiral auxiliary and sugar NHP ester as raw materials, and stereoselective C(sp 3 )-C(sp 3 )-H glycosylation to synthesize C-sugar amino acid derivatives. The reaction conditions are mild, the operation is simple, the substrate is applicable to a wide range, and the atomic utilization rate is high, which has broad application prospects.

[0005] To achieve the above object, the present invention adopts the following technical solution:

[0006] In a first aspect of the present invention, a method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary is provided, the method comprising:

[0007] Using phenylglycinamide derived from camphor sulfonamide and sugar NHP ester as raw materials and photosensitizer as catalyst, C-sugar amino acid derivatives were synthesized under solvent and blue light irradiation conditions. The chemical reaction formula is:

[0008]

[0009] in:

[0010] R1 is hydrogen, halogen, methoxy, methyl, tert-butyl, trifluoromethyl or phenyl;

[0011] R2 is (-) camphor sulfonamide or (+) camphor sulfonamide;

[0012] n is 0 or 1; OP is an oxygen-containing alkyl group or a benzyl group.

[0013] Furthermore, the photosensitizer includes at least one of bis(2,2'-bipyridine)ruthenium dichloride, rose bengal, 3,4,5,6-tetrakis(3,6-diphenyl-9-carbazolyl)-terephthalonitrile, 10-phenyl-10H-phenothiazine or bis(2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate).

[0014] Furthermore, the solvent is selected from one of dimethyl sulfoxide, acetonitrile, tetrahydrofuran or toluene.

[0015] Furthermore, the molar ratio of the camphor sulfonamide-derived phenylglycinamide: sugar NHP ester: photosensitizer is 1:(1.2-2.0):(0.02-0.05).

[0016] Furthermore, the reaction concentration of the camphor sulfonamide-derived phenylglycinamide is 0.05-0.2 mol / L.

[0017] Furthermore, the structural formula of the sugar NHP ester is selected from the following compounds 2a-2h:

[0018]

[0019] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0020] The present invention provides a method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary, using phenylglycinamide derived from camphor sulfonamide as a chiral auxiliary and sugar NHP ester as raw materials, and stereoselective C(sp3 )-C(sp 3 )-H glycosylation to synthesize C-sugar amino acid derivatives. The reaction conditions are mild, the operation is simple, the substrate is applicable to a wide range, and the atomic utilization rate is high, which has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following is a brief introduction to the drawings required for use in the description of the embodiments. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative work.

[0022] Figure 1 The structural formula of the method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by chiral auxiliary. The left picture is (-) camphor sulfonamide; the right picture is (+) camphor sulfonamide;

[0023] Figure 2 is the H NMR spectrum of the compound of the present invention.

[0024] Figure 3 is the NMR carbon spectrum of the compound of the present invention.

[0025] Figure 4 It is the X-ray diffraction pattern of the compound of the present invention.

[0026] Figure 5 The present invention provides a reaction formula for a method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary. DETAILED DESCRIPTION

[0027] The present invention will be described in detail below in conjunction with specific implementations and examples, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific implementations and examples are used to illustrate the present invention, rather than to limit the present invention.

[0028] Throughout the specification, unless otherwise specifically stated, the terms used herein should be understood as meanings commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. In the event of a conflict, the present specification takes precedence.

[0029] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or obtained by existing methods.

[0030] The technical solution of the embodiment of the present application is to solve the above technical problems, and the overall idea is as follows:

[0031] The chemical reaction formula of the present invention is as follows:

[0032]

[0033] in:

[0034] R1 is hydrogen, halogen, methoxy, methyl, tert-butyl, trifluoromethyl or phenyl;

[0035] R2 is (-) camphor sulfonamide or (+) camphor sulfonamide;

[0036] n is 0 or 1; OP is one or more of an oxygen-containing alkyl group and a benzyl group.

[0037] The preparation steps are as follows:

[0038] (1) adding camphor sulfonamide-derived phenylglycinamide, sugar NHP ester, photosensitizer and solvent into a clean reactor, and reacting at room temperature under blue light for 24 hours under argon protection;

[0039] (2) After the reaction is completed, the product is directly separated and purified by silica gel column chromatography to obtain the product.

[0040] The photosensitizer in step (1) is red, tris(2,2'-bipyridine)ruthenium dichloride, rose bengal, 3,4,5,6-tetrakis(3,6-diphenyl-9-carbazolyl)-terephthalonitrile, 10-phenyl-10H-phenothiazine or bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate).

[0041] The solvent in step (1) is dimethyl sulfoxide, acetonitrile, tetrahydrofuran or toluene.

[0042] In step (1), the molar ratio of camphor sulfonamide-derived phenylglycinamide: sugar NHP ester: photosensitizer is 1:(1.2-2.0):(0.02-0.05)

[0043] The reaction concentration of the phenylglycinamide compound derived from camphor sulfonamide in step (1) is 0.05-0.2 mol / L.

[0044] The present invention uses nuclear magnetic resonance hydrogen spectrum ( 1 H NMR), carbon spectrum ( 13 C NMR) and high-resolution mass spectrometry confirmed the structure of the C-sugar amino acid derivatives, as shown in the attached Figure 2 , Attachment Figure 3 . H NMR spectrum ( 1H NMR) clearly shows that the ratio of the product isomers is greater than 20:1. At the same time, the X-ray diffraction results confirm that when R2 is (-) camphor sulfonamide, the stereo configuration of the product is S configuration, as shown in the attached Figure 4 The nuclear magnetic resonance images were measured using a Varian INOVA-400 nuclear magnetic resonance instrument and a Varian INOVA-600 nuclear magnetic resonance instrument, with tetramethylsilane (TMS) as an internal standard (δ0 ppm) and deuterated chloroform as a solvent; the high-resolution mass spectra were measured using an Agilent 1946B mass spectrometer.

[0045] The present application will be described in detail below with reference to embodiments and experimental data.

[0046] Example 1: Synthesis of Compound 3a

[0047]

[0048] (1) Add a magnetic particle to a dry 10 ml reaction tube, then add phenylglycinamide compound 1a (34.8 mg, 0.1 mmol), sugar NHP ester 2a (44 mg, 0.12 mmol), 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol) in sequence, then evacuate the air and backfill with argon (3 times). Add dimethyl sulfoxide (1.0 mL), transfer the reaction tube to a blue light reactor (12 W) and irradiate it for 24 hours;

[0049] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 44.8 mg of the product as a white solid with a yield of 86% and a melting point of 202-204°C; 1 H NMR(400MHz,Chloroform-d)δ7.15(t,J=7.5Hz,2H),6.72(t,J=7.3Hz,1H),6.65(d,J=7.9Hz,2H), 5.06(s,1H),4.94–4.92(m,1H),4.84(dd,J=5.4,2.7Hz,1H),4.79(d,J=5.3Hz,1H),4.57(d,J=6.0H z,1H),4.01–3.98(m,1H),3.56–3.47(m,2H),3.37(s,3H),2.10–2.03(t,J=5.1Hz,2H),1.94–1.84 (m,3H),1.47–1.42(m,1H),1.44(s,3H),1.36–1.34(m,1H),1.28(s,3H),1.11(s,3H),0.95(s,3H). 13C NMR (100 MHz, Chloroform-d) δ 170.3, 146.3, 129.1, 118.4, 113.7, 113.1, 109.1, 88.1, 85.0, 79.5, 65.6, 59.9, 55.8, 53.2, 48.8, 47.9, 44.5, 38.2, 32.8, 26.8, 26.5, 25.4, 20.7, 19.9; HRMS (ESI) m / z: calculated value C 26 H 37 N2O7S[M+H] + 521.2316, measured value: 521.2319.

[0050] Example 2: Synthesis of Compound 3b

[0051]

[0052] (1) A magnetic particle was added to a dry 10 ml reaction tube, followed by the addition of phenylglycinamide compound 1b (36.2 mg, 0.1 mmol), sugar NHP ester 2a (44 mg, 0.12 mmol), and 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol), and then the air was evacuated and backfilled with argon (3 times). Dimethyl sulfoxide (0.5 mL) was added, and the reaction tube was transferred to a blue light reactor (12 W) and irradiated therein for 24 hours;

[0053] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 47 mg of the product as a white solid with a yield of 88% and a melting point of 195-197°C; 1 H NMR(400MHz,Chloroform-d)δ6.96(d,J=8.0Hz,2H),6.57(d,J=8.2Hz,2H),5.05(s,1H),4.93(dd ,J=6.0,2.6Hz,1H),4.82(dd,J=5.5,2.6Hz,1H),4.75(d,J=5.5Hz,1H),4.56(d,J=6.0Hz,1H),3. 98(t,J=6.1Hz,1H),3.55–3.46(m,2H),3.37(s,3H),2.21(s,3H),2.10–2.05(m,2H),1.92–1.84( m,3H),1.46–1.41(m,1H),1.44(s,3H),1.36–1.32(m,1H),1.28(s,3H),1.11(s,3H),0.95(s,3H). 13C NMR (100 MHz, Chloroform-d) δ 170.5, 143.9, 129.7, 127.5, 113.7, 113.0, 109.1, 88.2, 85.1, 79.6, 65.5, 60.1, 55.8, 53.2, 48.8, 47.9, 44.5, 38.2, 32.8, 26.8, 26.5, 25.4, 20.7, 20.5, 19.9; HRMS (ESI) m / z: calculated value C 27 H 39 N2O7S[M+H] + 535.2472, measured value: 535.2466.

[0054] Example 3: Synthesis of Compound 3c

[0055]

[0056] (1) A magnetic particle was added to a dry 10 ml reaction tube, followed by the addition of phenylglycinamide compound 1c (37.8 mg, 0.1 mmol), sugar NHP ester 2a (44 mg, 0.12 mmol), and 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol), and then the air was evacuated and backfilled with argon (3 times). Dimethyl sulfoxide (2.0 mL) was added, and the reaction tube was transferred to a blue light reactor (12 W) and irradiated therein for 24 hours;

[0057] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 50.7 mg of the product as a white solid with a yield of 92% and a melting point of 144-146°C; 1 H NMR(400MHz,Chloroform-d)δ6.74(d,J=9.0Hz,2H),6.61(d,J=8.8Hz,2H),5.05(s,1H),4.94(dd,J= 6.2,2.7Hz,1H),4.81(dd,J=5.3,2.6Hz,1H),4.70(d,J=5.3Hz,1H),4.56(d,J=6.0Hz,1H),3.98(t,J =6.3Hz,1H),3.71(s,3H),3.55–3.46(m,2H),3.37(s,3H),2.05(d,J=6.8Hz,2H),1.92–1.85(m,3H), 1.45–1.41(m,1H),1.44(s,3H),1.35–1.31(d,J=7.9Hz,1H),1.28(s,3H),1.10(s,3H),0.95(s,3H). 13C NMR (100 MHz, Chloroform-d) δ 169.5, 151.7, 139.3, 114.0, 113.7, 112.0, 108.1, 87.1, 84.0, 78.5, 64.5, 59.7, 54.8, 54.6, 52.1, 47.8, 46.8, 43.4, 37.1, 31.7, 25.7, 25.4, 24.3, 19.6, 18.9. HRMS (ESI) m / z: calcd. 27 H 39 N2O8S[M+H] + 551.2422, measured value: 551.2426.

[0058] Example 4: Synthesis of Compound 3d

[0059]

[0060] (1) A magnetic particle was added to a dry 10 ml reaction tube, followed by the addition of phenylglycinamide compound 1d (40.5 mg, 0.1 mmol), sugar NHP ester 2a (54 mg, 0.15 mmol), and 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol), and then the air was evacuated and backfilled with argon (3 times). Dimethyl sulfoxide (1.0 mL) was added, and the reaction tube was transferred to a blue light reactor (12 W) and irradiated therein for 24 hours;

[0061] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 47.8 mg of the product as a white solid with a yield of 83% and a melting point of 231-233°C; 1 H NMR(400MHz,Chloroform-d)δ7.17(d,J=8.5Hz,2H),6.58(d,J=8.7Hz,2H),5.06(s,1H),4.95(d d,J=6.0,2.7Hz,1H),4.83(dd,J=5.0,2.7Hz,1H),4.76(d,J=5.1Hz,1H),4.57(d,J=6.0Hz,1H),4 .02–3.99(m,1H),3.56–3.48(m,2H),3.38(s,3H),2.10–2.05(m,2H),1.93–1.84(m,3H),1.48–1 .42(m,1H),1.44(s,3H),1.36–1.31(m,1H),1.28(s,3H),1.24(s,9H),1.11(s,3H),0.95(s,3H). 13C NMR (100 MHz, Chloroform-d) δ 170.4, 143.8, 141.0, 125.9, 113.2, 113.0, 109.0, 88.2, 85.1, 79.4, 65.5, 60.1, 55.9, 53.2, 48.8, 47.9, 44.5, 38.2, 33.9, 32.8, 31.5, 26.8, 26.5, 25.5, 20.7, 19.9. HRMS (ESI) m / z: calcd. 30 H 45 N2O7S[M+H] + 577.2942, measured value: 577.2939.

[0062] Example 5: Synthesis of Compound 3e

[0063]

[0064] (1) Add a magnetic particle to a dry 10 ml reaction tube, then add phenylglycinamide compound 1e (36.6 mg, 0.1 mmol), sugar NHP ester 2a (44 mg, 0.12 mmol), and red (3.5 mg, 0.005 mmol) in sequence, then evacuate the air and backfill with argon (3 times). Add dimethyl sulfoxide (1.0 mL), transfer the reaction tube to a blue light reactor (12 W) and irradiate it for 24 hours;

[0065] (2) After the reaction was completed, silica gel column chromatography was used to separate and purify the product to obtain 36.1 mg of a white solid with a yield of 67% and a melting point of 208-210°C; 1 H NMR(400MHz,Chloroform-d)δ6.85(t,J=8.7Hz,2H),6.59(dd,J=8.8,4.3Hz,2H),5.05(s,1H), 4.91(dd,J=6.1,2.7Hz,1H),4.81(dd,J=5.2,2.7Hz,1H),4.72(d,J=5.2Hz,1H),4.56(d,J=6.0H z,1H),3.99(t,J=6.3Hz,1H),3.57–3.47(m,2H),3.37(s,3H),2.06–2.05(m,2H),1.93–1.85(m, 3H),1.47–1.42(m,1H),1.44(s,3H),1.36–1.32(m,1H),1.28(s,3H),1.11(s,3H),0.96(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-127.07. 13C NMR (100 MHz, Chloroform-d) δ 169.2, 155.4 (d, J = 235.5 Hz), 141.5 (d, J = 1.9 Hz), 114.6 (d, J = 22.5 Hz), 113.5 (d, J = 7.6 Hz), 112.1, 108.0, 87.1, 84.0, 78.3, 64.5, 59.4, 54.8, 52.1, 47.8, 46.9, 43.4, 37.1, 31.7, 25.7, 25.4, 24.3, 19.6, 18.9. HRMS (ESI) m / z: calculated value C 26 H 36 FN2O7S[M+H] + 539.2222, measured value: 539.2225.

[0066] Example 6: Synthesis of Compound 3f

[0067]

[0068] (1) Add a magnetic particle to a dry 10 ml reaction tube, then add phenylglycinamide compound 1f (41.6 mg, 0.1 mmol), sugar NHP ester 2a (44 mg, 0.12 mmol), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (5.6 mg, 0.005 mmol) in sequence, then evacuate the air and backfill with argon (3 times). Add dimethyl sulfoxide (1.0 mL), transfer the reaction tube to a blue light reactor (12 W) and irradiate it for 24 hours;

[0069] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 32.4 mg of the product as a white solid with a yield of 55% and a melting point of 196-198°C; 1 H NMR(400MHz,Chloroform-d)δ7.39(d,J=8.3Hz,2H),6.66(d,J=8.4Hz,2H),5. 06(s,1H),4.90–4.83(m,3H),4.56(d,J=5.8Hz,1H),3.99(t,J=6.0Hz,1H),3.5 9–3.49(m,2H),3.36(s,3H),2.08–2.05(m,2H),1.95–1.88(m,3H),1.48–1.44( m,1H),1.44(s,3H),1.38–1.33(m,1H),1.29(s,3H),1.13(s,3H),0.97(s,3H). 19F NMR(376MHz,Chloroform-d)δ-61.17. 13 C NMR (100 MHz, Chloroform-d) δ 169.5, 149.0, 126.6 (q, J = 3.8 Hz), 124.9 (d, J = 270.4 Hz), 119.9 (q, J = 32.3 Hz), 113.3, 112.8, 108.8, 88.0, 84.9, 79.1, 65.5, 59.1, 55.8, 53.2, 48.9, 47.9, 44.5, 38.1, 32.8, 26.8, 26.5, 25.4, 20.7, 19.9. HRMS (ESI) m / z: calculated value C 27 H 36 F3N2O7S[M+H] + 589.2190, measured value: 589.2196.

[0070] Example 7: Synthesis of Compound 3g

[0071]

[0072] (1) Add a magnetic particle to a dry 10 ml reaction tube, then add 1 g (42.5 mg, 0.1 mmol) of phenylglycinamide compound, sugar NHP ester 2a (44 mg, 0.12 mmol), 10-phenyl-10H-phenothiazine (1.1 mg, 0.004 mmol) in sequence, then evacuate the air and backfill with argon (3 times). Add dimethyl sulfoxide (1.0 mL), transfer the reaction tube to a blue light reactor (12 W) and irradiate it for 24 hours;

[0073] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 50.7 mg of the product as a white solid with a yield of 85% and a melting point of 225-227°C; 1H NMR(400MHz,Chloroform-d)δ7.52(d,J=7.7Hz,2H),7.43(d,J=8.2Hz,2H),7.37(t,J=7.6Hz,2H),7 .23(d,J=7.7Hz,1H),6.73(d,J=8.1Hz,2H),5.08(s,1H),4.96(d,J=6.0Hz,1H),4.86(s,2H),4.59(d ,J=5.9Hz,1H),4.02(t,J=6.3Hz,1H),3.58–3.49(m,2H),3.40(s,3H),2.08–2.05(m,2H),1.92–1.8 3(m,3H),1.46(s,3H),1.45–1.42(m,1H),1.37–1.34(m,1H),1.30(s,3H),1.13(s,3H),0.95(s,3H). 13 C NMR (100 MHz, Chloroform-d) δ 169.2, 144.8, 140.2, 130.2, 127.6, 126.8, 125.3, 125.0, 112.8, 112.1, 108.0, 87.1, 84.0, 78.4, 64.5, 58.7, 54.8, 52.1, 47.8, 46.9, 43.5, 37.1, 31.8, 25.8, 25.5, 24.4, 19.6, 18.9. HRMS (ESI) m / z: calcd. 32 H 41 N2O7S[M+H] + 597.2629, measured value: 597.2626.

[0074] Example 8: Synthesis of Compound 2h

[0075]

[0076] (1) Add a magnetic particle to a dry 10 ml reaction tube, then add phenylglycinamide compound 1h (34.8 mg, 0.1 mmol), sugar NHP ester 2a (44 mg, 0.12 mmol), 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol) in sequence, then evacuate the air and backfill with argon (3 times). Add acetonitrile (1.0 mL), transfer the reaction tube to a blue light reactor (12 W) and irradiate it for 24 hours;

[0077] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 36.9 mg of the product as a white solid with a yield of 71% and a melting point of 194-196°C; 1H NMR(400MHz,Chloroform-d)δ7.17–7.14(m,2H),6.74–6.71(m,3H),5.54(s,1H),5.12(d,J=3.2 Hz,1H),5.00(s,1H),4.89(d,J=6.0Hz,1H),4.82(s,1H),4.62(d,J=6.0Hz,1H),3.89(dd,J=7.7, 4.7Hz,1H),3.56–3.45(m,2H),3.47(s,3H),2.10–2.05(m,1H),2.02–1.96(m,1H),1.91–1.86(m ,3H),1.48(s,3H),1.44–1.39(m,1H),1.33–1.30(m,1H),1.29(s,3H),1.21(s,3H),0.97(s,3H). 13 C NMR (100 MHz, Chloroform-d) δ 170.0, 146.9, 129.3, 118.8, 114.1, 112.3, 111.2, 87.9, 86.0, 82.7, 65.0, 59.3, 56.0, 53.0, 48.9, 47.9, 44.4, 37.9, 32.5, 26.6, 26.5, 24.8, 20.7, 19.9. HRMS (ESI) m / z: calcd. 26 H 37 N2O7S[M+H] + 521.2316, measured value: 521.2319.

[0078] Example 9: Synthesis of Compound 3i

[0079]

[0080] (1) Add a magnetic particle to a dry 10 ml reaction tube, then add phenylglycinamide compound 1i (38.3 mg, 0.1 mmol), sugar NHP ester 2a (44 mg, 0.12 mmol), tris(2,2'-bipyridine) dichlororuthenium (3.7 mg, 0.005 mmol) in sequence, then evacuate the air and backfill with argon (3 times). Add tetrahydrofuran (1.0 mL), transfer the reaction tube to a blue light reactor (12 W) and irradiate it for 24 hours;

[0081] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 33.8 mg of the product as a white solid with a yield of 61% and a melting point of 113-115°C; 1H NMR(400MHz,Chloroform-d)δ7.06(t,J=8.0Hz,1H),6.73–6.68(m,2H),6.57(dd,J=8.3,2.3Hz,1H ),5.09(d,J=3.2Hz,1H),4.99(s,1H),4.85(d,J=5.9Hz,1H),4.77(d,J=3.2Hz,1H),4.60(d,J=5.9H z,1H),3.91(dd,J=7.7,4.7Hz,1H),3.57–3.48(m,2H),3.46(s,3H),2.10–1.98(m,2H),1.93–1.84 (m,3H),1.47(s,3H),1.43–1.41(m,1H),1.34–1.32(m,1H),1.29(s,3H),1.20(s,3H),0.98(s,3H). 13 C NMR (100 MHz, Chloroform-d) δ 169.7, 148.2, 135.0, 130.3, 118.7, 114.3, 112.5, 112.1, 111.2, 87.7, 85.9, 82.6, 65.0, 59.2, 56.1, 53.0, 49.0, 47.9, 44.5, 37.9, 32.5, 26.6, 26.4, 24.8, 20.6, 19.9. HRMS (ESI) m / z: calcd. 26 H 36 ClN2O7S[M+H] + 555.1926, measured value: 555.1924.

[0082] Example 10: Synthesis of Compound 3j

[0083]

[0084] (1) A magnetic particle was added to a dry 10 ml reaction tube, followed by the addition of phenylglycinamide compound 1j (42.7 mg, 0.1 mmol), sugar NHP ester 2a (44 mg, 0.12 mmol), 3,4,5,6-tetrakis(3,6-diphenyl-9-carbazolyl)-terephthalonitrile (7 mg, 0.005 mmol), and then the air was evacuated and backfilled with argon (3 times). Toluene (1.0 mL) was added, and the reaction tube was transferred to a blue light reactor (12 W) and irradiated therein for 24 h;

[0085] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 39.6 mg of the product as a white solid with a yield of 66% and a melting point of 227-229°C; 1H NMR(400MHz,Chloroform-d)δ7.23(d,J=7.4Hz,2H),6.59(d,J=7.7Hz,2H),5.59–5.58(m,1H),5.09( d,J=3.2Hz,1H),4.99(s,1H),4.86(d,J=6.0Hz,1H),4.76–4.75(m,1H),4.60(d,J=6.0Hz,1H),3.90–3 .87(m,1H),3.56–3.48(m,2H),3.45(s,3H),2.09–2.04(m,1H),1.98(dd,J=14.0,8.0Hz,1H),1.92–1. 87(m,3H),1.47(s,3H),1.45–1.39(m,1H),1.33–1.30(m,1H),1.29(s,3H),1.20(s,3H),0.97(s,3H). 13 C NMR (100 MHz, Chloroform-d) δ 169.7, 146.1, 132.1, 115.8, 112.5, 111.1, 110.6, 87.7, 85.9, 82.6, 65.0, 59.4, 56.1, 53.0, 48.9, 47.9, 44.4, 37.9, 32.5, 26.6, 26.4, 24.8, 20.7, 19.9. HRMS (ESI) m / z: calcd. 26 H 36 BrN2O7S[M+H] + 599.1421, measured value: 599.1417.

[0086] Example 11: Synthesis of Compound 3k

[0087]

[0088] (1) Add a magnetic particle to a dry 10 ml reaction tube, then add phenylglycinamide compound 1a (34.8 mg, 0.1 mmol), sugar NHP ester 2b (42 mg, 0.12 mmol), 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol) in sequence, then evacuate the air and backfill with argon (3 times). Add dimethyl sulfoxide (1.0 mL), transfer the reaction tube to a blue light reactor (12 W) and irradiate it for 24 hours;

[0089] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 43.2 mg of the product as a white solid with a yield of 85% and a melting point of 192-194°C; 1H NMR(400MHz,Chloroform-d)δ7.15–7.12(m,2H),6.73–6.67(m,3H),4.98(d,J=4.3Hz,1H),4.88(s, 1H), 4.64 (dd, J=8.1, 4.3Hz, 1H), 4.10 (dd, J=8.0, 4.6Hz, 1H), 3.95 (dd, J=7.8, 4.7Hz, 1H), 3.70 (d, J=4.6Hz,1H),3.55–3.45(m,2H),3.47(s,3H),3.30(s,3H),3.26(s,3H),2.19–2.14(m,1H),2.02–1 .97(m,1H),1.92–1.83(m,3H),1.43(t,J=9.5Hz,1H),1.35–1.30(m,1H),1.18(s,3H),0.95(s,3H). 13 C NMR (100 MHz, Chloroform-d) δ 170.0, 146.7, 129.1, 118.1, 113.7, 105.9, 81.2, 80.9, 78.9, 65.4, 58.4, 58.3, 57.8, 55.8, 53.1, 48.6, 47.9, 44.5, 37.3, 32.7, 26.6, 20.6, 20.0. HRMS (ESI) m / z: calcd. 25 H 37 N2O7S[M+H] + 509.2316, measured value: 509.2318.

[0090] Example 12: Synthesis of Compound 31

[0091]

[0092] (1) Add a magnetic particle to a dry 10 ml reaction tube, then add phenylglycinamide compound 1a (34.8 mg, 0.1 mmol), sugar NHP ester 2c (60 mg, 0.12 mmol), 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol) in sequence, then evacuate the air and backfill with argon (3 times). Add dimethyl sulfoxide (1.0 mL), transfer the reaction tube to a blue light reactor (12 W) and irradiate it for 24 hours;

[0093] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 50.9 mg of the product as a white solid with a yield of 77% and a melting point of 165-167°C; 1H NMR(400MHz,Chloroform-d)δ7.36–7.25(m,10H),7.14(t,J=7.7Hz,2H),6.73–6.68(m,3H),5. 00(d,J=4.0Hz,1H),4.90(s,1H),4.81(dd,J=8.1,3.9Hz,1H),4.67(d,J=11.9Hz,1H),4.57(d,J =11.8Hz,1H),4.42–4.34(m,3H),3.88(d,J=4.5Hz,1H),3.84–3.81(m,1H),3.49–3.40(m,2H),3 .28(s,3H),1.91–1.62(m,5H),1.33–1.26(m,1H),1.24–1.16(m,1H),0.94(s,3H),0.83(s,3H). 13 C NMR (100 MHz, Chloroform-d) δ 169.9, 146.8, 137.8, 137.6, 129.1, 128.42, 128.39, 128.1, 127.82, 127.79, 127.7, 118.1, 113.7, 106.4, 81.6, 79.1, 77.0, 72.4, 72.3, 65.3, 58.4, 55.7, 53.0, 48.6, 47.6, 44.2, 37.3, 32.6, 26.4, 20.6, 19.9. HRMS (ESI) m / z: calcd. 37 H 45 N2O7S[M+H] + 661.2942, measured value: 661.2938.

[0094] Example 13: Synthesis of Compound 3m

[0095]

[0096] (1) A magnetic particle was added to a dry 10 ml reaction tube, followed by the addition of phenylglycinamide compound 1a (34.8 mg, 0.1 mmol), sugar NHP ester 2d (47 mg, 0.12 mmol), and 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol), and then the air was evacuated and backfilled with argon (3 times). Dimethyl sulfoxide (1.0 mL) was added, and the reaction tube was transferred to a blue light reactor (12 W) and irradiated therein for 24 hours;

[0097] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 44.7 mg of the product as a white solid with a yield of 81% and a melting point of 184-186°C; 1H NMR(400MHz,Chloroform-d)δ7.09(t,J=7.6Hz,2H),6.78(d,J=7.9Hz,2H),6.67(t,J=7.3Hz,1H),4.74(d,J =3.6Hz,1H),4.72(d,J=2.5Hz,1H),4.22(dd,J=10.0,2.5Hz,1H),3.83(dd,J=7.8,4.5Hz,1H),3.51(s,3H),3 .49(s,3H),3.43–3.36(m,6H),3.32(s,3H),3.22(t,J=9.3Hz,1H),3.09(dd,J=9.7,3.6Hz,1H),2.05–1.99(m ,1H),1.89–1.85(m,1H),1.83–1.79(m,3H),1.37–1.31(m,1H),1.23–1.18(m,1H),1.09(s,3H),0.89(s,3H). 13 C NMR (100 MHz, Chloroform-d) δ 169.2, 146.7, 128.1, 117.7, 113.8, 96.5, 83.3, 80.4, 77.9, 71.0, 64.2, 59.7, 59.4, 58.9, 57.6, 54.8, 51.9, 47.5, 46.9, 43.4, 35.5, 31.5, 25.6, 19.1, 18.9. HRMS (ESI) m / z: calcd. 27 H 41 N2O8S[M+H] + 553.2578, measured value: 553.2576.

[0098] Example 14: Synthesis of Compound 3n

[0099]

[0100] (1) A magnetic particle was added to a dry 10 ml reaction tube, followed by the addition of phenylglycinamide compound 1a (34.8 mg, 0.1 mmol), sugar NHP ester 2e (75 mg, 0.12 mmol), and 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol), and then the air was evacuated and backfilled with argon (3 times). Dimethyl sulfoxide (1.0 mL) was added, and the reaction tube was transferred to a blue light reactor (12 W) and irradiated therein for 24 hours;

[0101] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 55.4 mg of the product as a white solid with a yield of 71% and a melting point of 133-135°C; 1H NMR(400MHz,Chloroform-d)δ7.33–7.29(m,9H),7.24–7.22(m,4H),7.18–7.14(m,4H),6.82(d,J=8.0Hz,2H),6 .75(t,J=7.3Hz,1H),5.01(d,J=10.5Hz,1H),4.97(d,J=11.0Hz,1H),4.83(d,J=2.6Hz,1H),4.73–4.60(m,5H),4 .40(dd,J=9.9,2.5Hz,1H),4.05(t,J=9.1Hz,1H),3.78–3.70(m,2H),3.56(s,3H),3.54–3.53(m,1H),3.46–3.3 5(m,2H),1.85–1.69(m,2H),1.50–1.44(m,1H),1.38–1.27(m,3H),1.17–1.13(m,1H),1.08(s,3H),0.90(s,3H). 13 C NMR (100 MHz, Chloroform-d) δ 170.0, 147.5, 138.6, 138.5, 138.1, 129.1, 128.5, 128.3, 128.04, 128.00, 127.93, 127.89, 127.86, 127.5, 127.3, 118.8, 114.8, 98.1, 82.8, 80.3, 76.5, 75.7, 73.9, 73.2, 72.0, 65.3, 60.4, 56.1, 52.9, 48.5, 47.8, 44.4, 36.6, 32.4, 26.5, 20.3, 19.9. HRMS (ESI) m / z: calcd. 45 H 53 N2O8S[M+H] + 781.3517, measured value: 781.3515.

[0102] Example 15: Synthesis of Compound 3o

[0103]

[0104] (1) A magnetic particle was added to a dry 10 ml reaction tube, followed by the addition of phenylglycinamide compound 1a (34.8 mg, 0.1 mmol), sugar NHP ester 2f (53 mg, 0.12 mmol), and 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol), and then the air was evacuated and backfilled with argon (3 times). Dimethyl sulfoxide (1.0 mL) was added, and the reaction tube was transferred to a blue light reactor (12 W) and irradiated therein for 24 hours;

[0105] (2) After the reaction was completed, silica gel column chromatography was used to separate and purify the product to obtain 36.9 mg of a white solid with a yield of 62% and a melting point of 96-98°C; 1 H NMR(400MHz,Chloroform-d)δ7.33–7.27(m,5H),7.14(t,J=7.6Hz,2H),6.76–6.70(m,3 H),5.85(d,J=3.9Hz,1H),5.04(d,J=4.3Hz,1H),4.63–4.60(m,2H),4.42–4.37(m,2H), 4.20(d,J=5.7Hz,1H),3.84(t,J=6.2Hz,1H),3.47–3.39(m,2H),1.86–1.74(m,4H),1.4 9(s,3H),1.41–1.36(m,2H),1.35(s,3H),1.25–1.22(m,1H),0.87(s,3H),0.84(s,3H). 13 C NMR (100 MHz, Chloroform-d) δ 170.2, 146.5, 137.1, 129.1, 128.28, 128.26, 127.9, 118.5, 114.4, 114.3, 104.7, 85.5, 83.6, 81.9, 72.5, 65.2, 58.4, 53.0, 48.6, 47.7, 44.2, 37.6, 32.6, 27.5, 27.1, 26.4, 20.6, 19.9. HRMS (ESI) m / z: calcd. 32 H 41 N2O7S[M+H] + 597.2629, measured value: 597.2631.

[0106] Example 16: Synthesis of Compound 16

[0107]

[0108] (1) Add a magnetic particle to a dry 10 ml reaction tube, then add phenylglycinamide compound 1a (34.8 mg, 0.1 mmol), sugar NHP ester 2 g (50 mg, 0.12 mmol), 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol) in sequence, then evacuate the air and backfill with argon (3 times). Add dimethyl sulfoxide (1.0 mL), transfer the reaction tube to a blue light reactor (12 W) and irradiate it for 24 hours;

[0109] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 45.5 mg of the product as a white solid with a yield of 79% and a melting point of 175-177°C; 1 H NMR(400MHz,Chloroform-d)δ7.14(t,J=7.7Hz,2H),6.74(d,J=8.0Hz,2H),6.69(t,J=7.4Hz,1H),4.90–4.88(m ,1H),4.56–4.52(m,2H),4.19(dd,J=7.7,2.1Hz,1H),3.91(t,J=6.3Hz,1H),3.84(dd,J=13.2,2.2Hz,1H),3.77 (d,J=13.1Hz,1H),3.44(d,J=13.6Hz,1H),3.38(d,J=13.6Hz,1H),1.99–1.96(m,2H),1.88–1.82(m,3H),1.65( s,3H),1.48(s,3H),1.46(s,3H),1.44–1.39(m,1H),1.36(s,3H),1.33–1.29(m,1H),1.20(s,3H),0.94(s,3H). 13 C NMR (100 MHz, Chloroform-d) δ 169.0, 145.1, 128.1, 117.2, 112.9, 108.3, 108.1, 103.3, 72.0, 69.4, 69.2, 64.2, 62.8, 60.2, 51.9, 47.0, 46.8, 43.5, 36.8, 31.5, 25.7, 25.20, 25.16, 24.1, 22.8, 19.3, 19.1. HRMS (ESI) m / z: calcd. 29 H 41 N2O8S[M+H] + 577.2578, measured value: 577.2580.

[0110] Example 17: Synthesis of Compound 17

[0111]

[0112] (1) Add a magnetic particle to a dry 10 ml reaction tube, then add phenylglycinamide compound 1a (34.8 mg, 0.1 mmol), sugar NHP ester 2h (50 mg, 0.12 mmol), 10-phenyl-10H-phenothiazine (1.4 mg, 0.005 mmol) in sequence, then evacuate the air and backfill with argon (3 times). Add dimethyl sulfoxide (1.0 mL), transfer the reaction tube to a blue light reactor (12 W) and irradiate it for 24 hours;

[0113] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 42.1 mg of the product as a white solid with a yield of 73% and a melting point of 182-184°C; 1 H NMR(400MHz,Chloroform-d)δ7.17(t,J=7.8Hz,2H),6.78–6.72(m,3H),5.16(s,1H),4.58(dd,J=7 .9,2.6Hz,1H),4.37(d,J=2.6Hz,1H),4.18(dd,J=7.9,2.0Hz,1H),3.88–3.84(m,2H),3.71(d,J=1 3.0Hz,1H),3.41(d,J=13.6Hz,1H),3.31(d,J=13.7Hz,1H),2.12–1.99(m,2H),1.86–1.83(m,3H), 1.69(s,3H),1.56(s,3H),1.44(s,3H),1.36(s,3H),1.35–1.31(m,2H),1.19(s,3H),0.93(s,3H). 13 C NMR (100 MHz, Chloroform-d) δ 170.2, 145.5, 129.2, 118.6, 114.1, 109.2, 105.0, 70.9, 70.3, 70.2, 65.2, 62.0, 58.8, 53.0, 48.2, 47.9, 44.6, 38.0, 32.6, 26.8, 26.6, 26.1, 25.4, 23.5, 20.3, 20.0. HRMS (ESI) m / z: calcd. 29 H 41 N2O8S[M+H] + 577.2578, measured value: 577.2576.

[0114] Finally, it should be noted that the terms "comprises," "includes," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements that are inherent to such process, method, article, or apparatus.

[0115] Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0116] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary, characterized in that: The method comprises: Using phenylglycinamide derived from camphor sulfonamide and sugar NHP ester as raw materials and photosensitizer as catalyst, C-sugar amino acid derivatives were synthesized under solvent and blue light irradiation conditions. The chemical reaction formula is: in: R1 is hydrogen, halogen, methoxy, methyl, tert-butyl, trifluoromethyl or phenyl; R2 is (-) camphor sulfonamide or (+) camphor sulfonamide; n is 0 or 1; OP is an oxygen-containing alkyl group or a benzyl group.

2. The method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary according to claim 1, characterized in that: The photosensitizer includes at least one of bis(2,2'-bipyridine)ruthenium dichloride, rose bengal, 3,4,5,6-tetrakis(3,6-diphenyl-9-carbazolyl)-terephthalonitrile, 10-phenyl-10H-phenothiazine or bis(2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate).

3. The method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary according to claim 1, characterized in that: The solvent is selected from one of dimethyl sulfoxide, acetonitrile, tetrahydrofuran or toluene.

4. The method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary according to claim 1, characterized in that: The molar ratio of the camphor sulfonamide-derived phenylglycinamide: sugar NHP ester: photosensitizer is 1:(1.2-2.0):(0.02-0.05).

5. The method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary according to claim 1, characterized in that: The reaction concentration of the camphor sulfonamide-derived phenylglycinamide is 0.05-0.2 mol / L.

6. The method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary according to claim 1, characterized in that: The structural formula of the sugar NHP ester is selected from the following compounds 2a-2h:

7. A method for synthesizing C-sugar amino acid derivatives by stereoselective glycosylation assisted by a chiral auxiliary prepared by the method according to any one of claims 1 to 6.

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