Use of oxime glycosyl sulfides in alkyl carbon glycoside synthesis

Abstract

The application provides application of an oxime-linked glycosyl sulfide in synthesis of alkyl carbon glycoside and belongs to the field of chemical synthesis. The application establishes a method for visible light catalytic synthesis of alkyl carbon glycoside by taking the oxime-linked glycosyl sulfide as a glycosyl radical donor and an enol silyl ether compound as a glycosyl acceptor substrate. The oxime-linked glycosyl sulfide has the advantages of stable property, simple preparation method, high yield and wide range of applicable sugars, and the application of the oxime-linked glycosyl sulfide in synthesis of carbon glycoside has the advantages of simple method and wide range of substrates, such as containing various drugs and polypeptides. This shows that the glycosyl sulfide provides a new idea for development of complex glycoconjugates and drugs, and further promotes industrialized development of carbon glycoside medicines.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to the application of oxime glycosyl thioethers in the synthesis of alkyl C-glycosides. Background Technology

[0002] Alkyl C-glycosides are a class of compounds with important biological activities, widely found in natural products and drug molecules. They exhibit good metabolic stability in vivo, thus holding significant research and application value in the fields of medicine and biochemistry. However, the synthesis of alkyl C-glycosides has always been a challenge for chemists. Traditional methods typically require the use of active reagents such as organometallic reagents or Michael acceptors, which are not only costly but also subject to harsh reaction conditions.

[0003] In the synthesis of alkyl C-glycosides, the selection of glycosylation reagents and glycosyl acceptors is crucial. Glycosylation reagents are reactants that provide glycosyl groups, while glycosyl acceptors are substrates that accept the glycosyl groups. In recent years, glycosyl thioethers have been used as radical precursors to generate glycosyl radicals via photocatalysis or copper catalysis, which then participate in the glycosylation reaction. However, current methods for synthesizing alkyl C-glycosides via glycosyl radicals suffer from problems such as poor stability of glycosyl radical donors, narrow substrate range, and low yields. Summary of the Invention

[0004] The purpose of this invention is to provide the application of oxime glycosides in the synthesis of alkyl C-glycosides.

[0005] This invention provides a method for preparing alkyl C-glycosides, the method comprising the following steps: under an inert gas protection, reacting oxime glycosyl thioethers, Mix with a catalyst and react under 450–460 nm light irradiation to obtain the product;

[0006]

[0007] Wherein, R is selected from OR' and C. 1～5 Alkoxy, phenyl, halogen, R' is C 1～5 Alkyl, phenyl.

[0008] Furthermore, the oxime glycosyl sulfide, The molar ratio of the catalyst to the catalyst is 1:2 to 4:0.01 to 0.03.

[0009] Furthermore, the oxime glycosyl sulfide, The molar ratio of the catalyst to the catalyst is 1:3:0.02.

[0010] Furthermore, the catalyst is tri(2-phenylpyridine)iridium(III).

[0011] Furthermore, the wavelength of the light irradiation is 455nm.

[0012] Furthermore, the solvent for the reaction is an organic solvent, preferably N,N-dimethylformamide.

[0013] Furthermore, the reaction temperature is 10–40°C, preferably 15–35°C.

[0014] Furthermore, the reaction time is 10 to 15 hours, preferably 12 hours.

[0015] Furthermore, after the reaction is completed, the following purification steps are included: after the reaction is completed, the reaction is quenched by adding saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain the final product.

[0016] Furthermore, the eluent for the thin-layer chromatography purification is a mixture of petroleum ether and ethyl acetate.

[0017] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0018] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0019] "Alkyl" refers to a hydrocarbon group formed by the loss of a hydrogen atom from an alkane molecule, consisting of carbon and hydrogen atoms. Alkyl groups can be straight-chain or branched, and can optionally be substituted by one or more substituents as defined in this invention. Alkyl groups include methyl, ethyl, and propyl (n-propyl and isopropyl).

[0020] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0021] "Alkoxy" refers to an alkyl group that is connected to a bonding site through an oxygen atom. Its alkane chain can be a saturated alkane chain or a non-aromatic unsaturated alkane chain containing at least one double bond. For example, methoxy refers to -OCH3.

[0022] "OTBS" refers to dimethyl tert-butyl silyl ether, which is a hydroxyl protecting group. Its specific structure is as follows:

[0023] The present invention achieves the following beneficial effects:

[0024] This invention, for the first time, establishes a visible-light-catalyzed method for the synthesis of β-carbonyl-α-alkyl C-glycosides using oxime-containing glycosyl thioethers as glycosyl radical donors and enol silyl ethers as glycosyl acceptors, providing a highly efficient synthetic method for the preparation of alkyl C-glycosides. The oxime-containing glycosyl thioethers of this invention possess advantages such as stable properties, simple preparation method, high yield, and wide applicability to a wide range of sugars. Applying them to the synthesis of C-glycosides offers advantages such as simple method and broad substrate scope, including various drugs and peptides. This indicates that the glycosyl thioether provides new insights for the development of complex glycoconjugates and drugs, further promoting the industrialization of C-glycoside pharmaceuticals.

[0025] Compared with the method described in the inventor's previous invention patent application (application number: 2024116751748), the method of the present invention achieves superior results. The reaction intermediate of the method in the previous invention patent application (application number: 2024116751748) is a benzyl cation, which contains byproducts that are captured by nucleophiles; while the method of the present invention avoids the generation of such byproducts and does not require the external supply of oxygen atoms.

[0026] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0027] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0028] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0029] This invention uses oxime glycosyl thioethers as glycosyl radical donors and enol silyl ethers as glycosyl acceptors to prepare a series of visible-photocatalyzed β-carbonyl-α-alkyl C-glycosides. The synthetic method includes the following steps:

[0030]

[0031] Among them, oxime glycosyl sulfides Its properties are stable, and its preparation method has the advantages of being simple, having a high yield, and being applicable to a wide range of sugars. This invention applies it to the synthesis of carbon glycosides, which has the advantages of being simple and having a wide range of substrates.

[0032] The preparation of the oxime glycosyl thioether was carried out according to the method described in Example 1 of the patent application with application number 2024116751748, and the specific method is as follows:

[0033]

[0034] (1) Synthesis of intermediate product 1

[0035] In a round-bottom flask equipped with a magnetic stirrer, add 1.2 eq. (12.00 mmol, 1.83 g) of 2-mercaptoacetone and 10 mL of dry tetrahydrofuran (reaction concentration: 0.5 M). At room temperature, add potassium tert-butoxide (1.2 eq. (12.00 mmol, 1.35 g) and stopper the flask. After stirring for 30 minutes, place the flask in an ice-water bath and cool to 0°C. Slowly add 10 mL of a dry tetrahydrofuran solution of the brominated sugar (1.0 eq. (10.00 mmol, 4.11 g). After the addition is complete, remove the ice-water bath and continue stirring at room temperature until the sugar is completely consumed (TLC monitoring, reaction time approximately 6–10 hours). After the reaction is complete, transfer the reaction mixture to a 250 mL separatory funnel, dilute with 100 mL of ethyl acetate, and wash the organic phase three times with 100 mL of water. The organic phase was washed with 100 mL of saturated saline solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the final product.

[0036] (2) Synthesis of intermediate product 2

[0037] In a round-bottom flask equipped with a magnetic stirrer, intermediate 1 (1.0 eq., 7.46 mmol, 3.6 g), hydroxylamine hydrochloride (1.5 eq., 2.28 mmol, 778 mg), and anhydrous sodium acetate (2.0 eq., 14.92 mmol, 1.22 g) were added. Then, 40 mL of a 1:1 mixture of ethanol and water (0.2 M) was added. The reaction mixture was placed in an oil bath at 100 °C and heated under reflux until compound 1 was completely consumed (TLC monitoring, reaction time approximately 4–8 hours). Subsequently, the mixture was distilled under reduced pressure to remove most of the ethanol from the reaction mixture, and then diluted with 50 mL of water. The aqueous phase was transferred to a 125 mL separatory funnel and extracted three times with 50 mL of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the final product.

[0038] (3) Synthesis of oxime glycosyl thioethers

[0039] To a round-bottom flask equipped with a magnetic stirrer, add intermediate 2 (1.0 eq., 6.43 mmol, 3.2 g) and 15 mL of dry dichloromethane, stopper with a rubber stopper, and place in an ice-water bath to cool to 0°C. Add triethylamine (1.5 eq., 9.65 mmol, 1.34 mL) dropwise. After stirring for 5 minutes, slowly add p-trifluoromethylbenzoyl chloride (1.2 eq., 7.72 mmol, 1.15 mL). Continue stirring until compound 2 is completely consumed (TLC monitoring, reaction time approximately 1–2 hours). After the reaction is complete, transfer the reaction mixture to a 250 mL separatory funnel and dilute with 100 mL of ethyl acetate. Separate the organic phase after washing three times with an equal volume of saturated sodium bicarbonate aqueous solution, drying over anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure. The residue is then purified by column chromatography to obtain the final product.

[0040] Yield: 76%. Structural characterization data for the oxime glycosyl thioether are as follows: 1 H NMR(CDCl3,400MHz)δ:8.25(d,J=8.0Hz,2H),7.77(d,J=8.2Hz,2H),7.65(tt,J=4.8,2.6Hz,1H ),7.45-7.36(m,3H),5.61(d,J=1.5Hz,1H),5.46(dd,J=3.3,1.5Hz,1H),5.33(t,J=9.9Hz,1H), 5.26(dd,J=10.0,3.3Hz,1H), 4.54(ddd,J=9.8,5.6,2.5Hz,1H), 4.32(dd,J=12.2,5.6Hz,1H), 4.12(dd,J=12.3,2.5Hz,1H),2.52(s,3H),2.14(s,3H),2.07(s,3H),2.06(s,3H),1.98(s,3H).

[0041] Example 1: Method for preparing compound 1a according to the present invention

[0042]

[0043] In an 8 mL screw-top reaction flask equipped with a magnetic stir bar and kept dry, add oxime glycosyl thioether (1.0 eq., 0.05 mmol), enol silyl ether glycosyl acceptor (3.0 eq., 0.15 mmol), and Ir(ppy)3 (0.02 eq., 1.00 μmol). In a glove box (nitrogen atmosphere), use a 1 mL syringe to add 0.5 mL of dry N,N-dimethylformamide to the reaction flask, and tighten the cap. At room temperature, the reaction solution is continuously stirred under 455 nm LED irradiation until the glycosyl donor is completely consumed (reaction time: 12 hours). After the reaction was completed, 3 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction. The aqueous phase was extracted with 4 mL of ethyl acetate. The organic phases were then combined and transferred to a 50 mL separatory funnel. After washing three times with 6 mL of water, the organic phase was separated, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by thin-layer chromatography (petroleum ether: ethyl acetate = 7:3) to finally obtain the target compound 1a.

[0044] (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(2-(2-methoxyphenyl)-2-oxoethyl)tet rahydro-2H-pyran-3,4,5-triyl triacetat, NMR yield: 76%; 1 H NMR (CDCl3, 400MHz) δ: 7.65 (dd, J=7.8, 1.9Hz, 1H), 7.46 (ddd, J=8.5, 7.3, 1.9Hz, 1H), 7.03–6.90 (m, 2H ),5.34(t,J=9.1Hz,1H),5.14(dd,J=9.3,5.8Hz,1H),4.97(t,J=9.1Hz,1H),4.90(dt,J=8.5,5.8Hz,1H) ,4.17(dd,J=12.1,5.0Hz,1H),4.02(dd,J=12.1,2.8Hz,1H),3.96–3.90(m,1H),3.89(s,3H),3.45(dd,J =16.1,5.9Hz,1H),3.29(dd,J=16.1,8.4Hz,1H),2.03(s,3H),2.015(s,3H),2.010(s,3H),1.98(s,3H).

[0045] Example 2: Method for preparing compound 1b according to the present invention

[0046]

[0047] The method is the same as in Example 1, except that... Replace with Compound 1b was obtained.

[0048] (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(2-(4-methoxyphenyl)-2-oxoethyl)tet rahydro-2H-pyran-3,4,5-triyl triacetate, NMR yield: 66%; 1 H NMR (CDCl3, 400MHz) δ: 7.89 (d, J = 9.0Hz, 2H), 6.92 (d, J = 9.0Hz, 2H), 5.32 (t, J = 8.8Hz, 1H) ,5.15(dd,J=9.0,5.5Hz,1H),5.01–4.89(m,1H),4.20(dd,J=12.2,5.3Hz,1H),4.04(dd,J =12.1,2.8Hz,1H),3.93(ddd,J=8.5,5.3,2.9Hz,1H),3.84(s,3H),3.31(dd,J=16.3,6.4H z,1H),3.19(dd,J=16.1,7.0Hz,1H),2.01(s,3H),2.00(s,3H),1.99(s,3H),1.91(s,3H).

[0049] Example 3: Method for preparing compound 1c according to the present invention

[0050]

[0051] The method is the same as in Example 1, except that... Replace with Compound 1c was obtained. NMR yield: 74%. Patent application number 2024116751748 reports a method for photocatalytic synthesis of glycosidic bonds using oxime glycosyl thioethers. This patent application selected... As a glycosyl acceptor, with a yield of 73%, this invention selects... As a glycosyl acceptor, the yield was 74%, indicating that the method of the present invention has a higher yield when used for such reactions.

[0052] (2R,3S,4R,5R,6R)-2-(2-([1,1'-biphenyl]-4-yl)-2-oxoethyl)-6-(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; 1H NMR(CDCl3,400MHz)δ:8.02(d,J=8.4Hz,2H),7.71(d,J=8.4Hz,2H),7.63(d,J=7.1Hz,2H),7.52–7.45(m,2H),7.45–7.37(m,1H ),5.38(t,J=8.7Hz,1H),5.22(dd,J=8.9,5.6Hz,1H),5.08–4.95(m,2H),4.25(dd,J=12.2,5.3Hz,1H),4.10(dd,J=12.3,3.0Hz,

[0053] 1H),3.98(ddd,J=8.5,5.4,2.9Hz,1H),3.42(dd,J=16.3,6.3Hz,1H),3.31( dd,J=16.3,7.0Hz,1H),2.06(s,3H),2.05(s,3H),2.04(s,3H),1.97(s,3H).

[0054] Example 4: Method for preparing compound 1d according to the present invention

[0055]

[0056] The method is the same as in Example 1, except that... Replace with Compound 1d was obtained.

[0057] (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(2-oxo-2-(4-phenoxyphenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, NMR yield: 71%; 1H NMR(CDCl3,400MHz)δ:7.90(d,J=8.9Hz,2H),7.38(dd,J=8.6,7.4Hz,2H),7.23–7.15(m,1H),7.09– 7.02(m,2H),6.99(d,J=8.9Hz,2H),5.33(t,J=8.6Hz,1H),5.17(dd,J=8.9,5.6Hz,1H),5.06–4.90(m ,2H),4.22(dd,J=12.2,5.3Hz,1H),4.07(dd,J=12.1,3.0Hz,1H),3.95(ddd,J=8.5,5.3,2.9Hz,1H) ,3.33(dd,J=16.3,6.4Hz,1H),3.21(dd,J=16.2,7.1Hz,1H),2.03(s,3H),2.02(s,6H),1.94(s,3H).

[0058] Example 5: Method for preparing compound 1e according to the present invention

[0059]

[0060] The method is the same as in Example 1, except that... Replace with Compound 1e was obtained.

[0061] (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(2-oxo-2-(thiophen-2-yl)ethyl)tetrahydroxy-2H-pyran-3,4,5-triyl triacetate, NMR yield: 74%; 1 H NMR (CDCl3, 400MHz) δ: 7.72 (dd, J=3.8, 1.2Hz, 1H), 7.66 (dd, J=5.0, 1.1Hz, 1H), 7.13 ( dd,J=5.0,3.8Hz,1H),5.32(t,J=8.8Hz,1H),5.15(dd,J=9.1,5.6Hz,1H),5.03–4.87( m,2H),4.19(dd,J=12.2,5.4Hz,1H),4.05(dd,J=12.1,2.9Hz,1H),3.95(ddd,J=8.5,5 .4,2.8Hz,1H),3.32–3.15(m,1H),2.02(s,3H),2.00(s,3H),1.99(s,3H),1.92(s,3H).

[0062] Example 6: Method for preparing compound 1f according to the present invention

[0063]

[0064] The method is the same as in Example 1, except that... Replace with Compound 1f was obtained.

[0065] (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(2-(4-fluorophenyl)-2-oxoethyl)tetra hydro-2H-pyran-3,4,5-triyl triacetate, NMR yield: 70%; 1 H NMR(CDCl3,400MHz)δ:7.97(dd,J=8.7,5.5Hz,2H),7.16(t,J=8.6Hz,2H),5.34(t,J=8.6Hz,1 H),5.19(dd,J=8.9,5.5Hz,1H),5.03–4.92(m,2H),4.24(dd,J=12.2,5.4Hz,1H),4.10–4.06( m,1H),3.95(ddd,J=8.6,5.4,3.0Hz,1H),3.34(dd,J=16.4,6.3Hz,1H),3.24(dd,J=16.4,7.0 Hz, 1H), 2.89 (dd, J = 16.7, 3.1Hz, 1H), 2.05 (s, 3H), 2.045 (s, 3H), 2.040 (s, 3H), 1.95 (s, 3H).

[0066] Example 7: Method for preparing 1g of compound according to the present invention

[0067]

[0068] The method is the same as in Example 1, except that... Replace with 1 g of the compound was obtained with an NMR yield of 83%. Patent application number 2024116751748 reports a similar photocatalytic synthesis of glycosidic bonds using oxime glycosyl thioethers. This patent application selects... As a glycosyl acceptor, with a yield of 65%, this invention selects... As a glycosyl acceptor, the yield was 83%, indicating that the method of the present invention has a higher yield when used for such reactions.

[0069] (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(2-(4-chlorophenyl)-2-oxoethyl)tetra hydro-2H-pyran-3,4,5-triyl triacetate; 1 H NMR(CDCl3,400MHz)δ:7.88(d,J=8.6Hz,2H),7.47(d,J=8.6Hz,2H),5.34(t,J=8.6 Hz,1H),5.19(dd,J=8.8,5.4Hz,1H),5.04–4.93(m,2H),4.24(dd,J=12.1,5.4Hz,1H ),4.09(dd,J=12.1,3.0Hz,1H),3.99–3.90(m,1H),3.34(dd,J=16.4,6.4Hz,1H),3 .24(dd,J=16.4,7.0Hz,1H),2.051(s,3H),2.047(s,3H),2.04(s,3H),1.95(s,3H).

[0070] In summary, this invention provides the application of oxime glycosyl thioethers in the synthesis of alkyl C-glycosides. This invention establishes a visible-light-catalyzed method for the synthesis of alkyl C-glycosides using oxime-functionalized glycosyl thioethers as glycosyl radical donors and enol silyl ethers as glycosyl acceptor substrates. The oxime glycosyl thioethers of this invention possess advantages such as stable properties, simple preparation method, high yield, and wide applicability to a wide range of sugars. Applying them to the synthesis of C-glycosides offers advantages such as simple method and broad substrate scope, including various drugs and peptides. This indicates that these glycosyl thioethers provide new insights for the development of complex glycoconjugates and drugs, further promoting the industrialization of C-glycoside pharmaceuticals.

Claims

1. A method for preparing alkyl C-glycosides, characterized in that, The method includes the following steps: under inert gas protection, adding oxime glycosyl sulfide, Mix with a catalyst and react under 450–460 nm light irradiation to obtain the product; Wherein, R is selected from OR' and C. 1～5 Alkoxy, phenyl, halogen, R' is C 1～5 Alkyl, phenyl.

2. The method according to claim 1, characterized in that, The oxime glycosyl sulfide, The molar ratio of the catalyst to the catalyst is 1:2 to 4:0.01 to 0.

03.

3. The method according to claim 2, characterized in that, The oxime glycosyl sulfide, The molar ratio of the catalyst to the catalyst is 1:3:0.

02.

4. The method according to claim 1, characterized in that, The catalyst is tris(2-phenylpyridine)iridium(III).

5. The method according to claim 1, characterized in that, The wavelength of the light irradiation is 455nm.

6. The method according to claim 1, characterized in that, The solvent for the reaction is an organic solvent, preferably N,N-dimethylformamide.

7. The method according to claim 1, characterized in that, The reaction temperature is 10–40°C, preferably 15–35°C.

8. The method according to claim 1, characterized in that, The reaction time is 10 to 15 hours, preferably 12 hours.

9. The method according to claim 1, characterized in that, After the reaction is completed, the following purification steps are also included: after the reaction is completed, the reaction is quenched by adding saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain the final product.

10. The method according to claim 8, characterized in that, The eluent used in the thin-layer chromatography purification was a mixture of petroleum ether and ethyl acetate.

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