Chiral c-glycosyl hydroxy ketone derivatives, methods of synthesis and use thereof

Abstract

This invention discloses a chiral C-glycoside hydroxy ketone derivative, its synthesis method, and its applications. Using aryl ethyl ketone diazo, alkyl alcohol, and 3,4-O-carbonate glycoene as raw materials, the chiral C-glycoside hydroxy ketone derivative is obtained through a one-step reaction in an organic solvent in the presence of a transition metal palladium catalyst, a metal rhodium catalyst, a phosphine ligand, chiral phosphoric acid, and a 4Å molecular sieve. The raw materials used in this invention are inexpensive and readily available, safe and non-toxic, and the synthesis method is mild, exhibiting good regioselectivity and high stereoselectivity. The synthesized chiral C-glycoside hydroxy ketone derivative possesses excellent antitumor activity and shows promising application prospects.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a chiral C-glycoside hydroxy ketone derivative, its synthesis method, and its application. Background Technology

[0002] Carbohydrates are the basic structural units of living organisms and have important biological functions. Therefore, carbohydrate compounds have long been an important area of ​​drug research. C-glycosides are a special class of glycoside compounds in which the terminal carbon atom of the sugar group is linked to the aglycone through a C-C bond. Compared to traditional O-glycosides, C-glycosides have higher bond energies, resulting in greater chemical stability and resistance to breakage. This property allows C-glycosides to exhibit significant tolerance to acidic or alkaline hydrolases in vivo, maintaining structural integrity even in complex physiological environments. C-glycosides possess greater chemical stability, resistance to enzymatic degradation, and metabolic inertness. Therefore, scientists consider C-glycosides ideal substitutes for O-glycosides, attracting significant attention in drug design, natural product synthesis, and functional materials. For example, the prototype drug for diabetes control, phlorizin, after C-glycosylation modification, yielded glibenclamide-like drugs with significantly enhanced SGLT2 inhibitory activity, resulting in improved treatment efficacy for diabetes. Furthermore, C-glycoside derivatives of KRN7000 exhibit stronger activity in inhibiting cancer cell proliferation, with efficacy more than 100 times higher than traditional KRN7000.

[0003] Therefore, the chemical synthesis of carboglycosides is of great significance, but its reaction system is more complex than that of O-glycosylation. How to synthesize carboglycosides with high efficiency and stereoselectivity has always been a research challenge, as it is difficult to achieve effective control over the diastereoselectivity of newly generated stereoisomer centers.

[0004] Therefore, this invention is proposed to solve the above-mentioned technical problems. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a chiral C-glycoside hydroxy ketone derivative, its synthesis method and application.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a chiral C-glycoside hydroxy ketone derivative, the structure of which is shown in formula (4):

[0008]

[0009] Equation (4);

[0010] Wherein, the R 1It is any one of C1-C7 substituted alkyl, C1-C4 alkyl substituted silyl, phenyl and C1-C4 alkyl substituted silyl, C1-C17 alkyl substituted acyl, and C1-C4 alkoxy substituted acyl;

[0011] R 2 It is any one of C1-C6 substituted alkyl, benzyl, haloaryl benzyl, C1-C3 alkyl-substituted aryl benzyl, methoxy-substituted aryl benzyl, naphthylmethyl, (E)-2-butenyl, and cinnamyl;

[0012] Ar can be any one of phenyl, halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, phenyl-substituted phenyl, naphthyl, or thiophene.

[0013] Preferably, the R 1 It is any one of methyl, benzyl, tert-butyldimethylsilyl, acetyl, octadecanoyl, tert-butyldiphenylsilyl, methoxyyl, and tert-butoxyyl; R 2 Ar is any one of methyl, isopropyl, 3-bromobenzyl, 4-bromobenzyl, 2,6-dichlorobenzyl, 2-methylbenzyl, 2,6-dimethylbenzyl, 2,4,6-trimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, and 2-naphthylmethyl; Ar is any one of 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-phenylphenyl, 2-naphthyl, and 3-thiophene.

[0014] This invention provides a method for synthesizing a chiral C-glycoside hydroxy ketone derivative with the structure of formula (4) as described in any one of the above technical solutions. The method uses aryl acetone diazo, alkyl alcohol and 3,4-O-carbonate glycoene as raw materials, and reacts in an organic solvent in the presence of a transition metal palladium catalyst, a metal rhodium catalyst, a phosphine ligand, chiral phosphoric acid and a 4Å molecular sieve to obtain the chiral C-glycoside hydroxy ketone derivative as shown in formula (4). The reaction process is shown in reaction formula (I):

[0015]

[0016] Reaction formula (I);

[0017] Among them, R 1 It is any one of C1-C7 substituted alkyl, C1-C4 alkyl-substituted silyl, phenyl and C1-C4 alkyl-substituted silyl, C1-C17 alkyl-substituted acyl, and C1-C4 alkoxy-substituted acyl; R 2Ar is any one of C1-C6 substituted alkyl, benzyl, haloaryl benzyl, C1-C3 alkyl-substituted aryl benzyl, methoxy-substituted aryl benzyl, naphthylmethyl, (E)-2-butenyl, cinnamyl; Ar is any one of phenyl, halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, phenyl-substituted phenyl, naphthyl, thiophene.

[0018] Specifically, it includes the following steps:

[0019] Step 1: Under a dry argon atmosphere, dissolve the palladium catalyst, phosphine ligand, and 4Å molecular sieve in an organic solvent, stir at 35°C for 0.5 hours, then add chiral phosphoric acid and stir until homogeneous;

[0020] Step 2: Dissolve the alkyl alcohol, 3,4-O-carbonate glycoene and the rhodium catalyst in an organic solvent, and add the resulting mixture to the reaction system of Step 1;

[0021] Step 3: Dissolve aryl ethyl ketone in an organic solvent and add it dropwise to the reaction system of Step 2 over 1.5 hours using a syringe pump. After the addition is complete, continue stirring at 35°C for 1-4 hours until the diazo compound is completely consumed, to obtain the chiral C-glycoside hydroxy ketone derivative shown in formula (4).

[0022] Preferably, the molar ratio of each raw material is: palladium catalyst: phosphine ligand: chiral phosphoric acid: alkyl alcohol: 3,4-O-carbonate glycoene: rhodium catalyst: aryl acetone diazo = (0.03-0.05): (0.06-0.1): (0.05-0.10): (2.5-3.0): 1.0: (0.01-0.03): (3.0-4.5).

[0023] Preferably, the volume of the organic solvent is related to the concentration of 3,4-O-carbonate glycoene by 0.02 mmol / mL, and the amount of 4Å molecular sieve added is related to the organic solvent by 50 mg / mL.

[0024] Preferably, the organic solvent is any one of dichloromethane, 1,2-dichloroethane, or trichloromethane; the palladium catalyst is [Pd(C3H5)Cl]2; the rhodium catalyst is Rh2(esp)2; the phosphine ligand is Xantphos; and the chiral phosphoric acid additive is Binol skeleton chiral phosphoric acid.

[0025] Specifically, the structural formula of the phosphine ligand is: The structural formula of chiral phosphate is: .

[0026] Preferably, the synthesis method further includes a separation and purification step after the reaction is completed: the reaction mixture is purified by silica gel column chromatography, and the eluent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of ethyl acetate:petroleum ether of 1:(3-10).

[0027] Preferably, the alkyl alcohol is also selected from alcohols derived from natural products, including piperine, crotonol, L-perillol, D-proline, citronellol, or epiandrolone.

[0028] The present invention also provides the application of the chiral C-glycoside hydroxy ketone derivatives and their pharmaceutically acceptable medicinal salts described in the above technical solutions in the preparation of antitumor drugs.

[0029] Preferably, the chiral C-glycoside hydroxy ketone derivative is a chiral C-glycoside hydroxy ketone derivative containing a citronellol fragment.

[0030] The beneficial effects of this invention are:

[0031] Compared with the prior art, the present invention provides a chiral C-glycoside hydroxy ketone derivative with the structure of formula (4). The present invention also provides a method for synthesizing chiral C-glycoside hydroxy ketone derivatives, which has the advantages of high chemoselectivity, high stereoselectivity, high universality and high yield. It can synthesize a series of chiral C-glycoside hydroxy ketone derivatives involving natural products, and some products have good and broad-spectrum antitumor activity. Moreover, the chiral carbon sugar hydroxy ketone derivative is obtained through a one-step reaction. The raw materials are cheap and readily available, safe and non-toxic, and the reaction conditions of the synthesis method are mild and the operation is simple and safe. Attached Figure Description

[0032] Figure 1 shows the 1H NMR spectrum of the chiral C-glycoside hydroxy ketone derivative of Example 1 of the present invention. Figure 1A ), 13C NMR ( Figure 1B ) Spectrum.

[0033] Figure 2 shows the 1H NMR of the chiral C-glycoside hydroxy ketone derivative of Example 2 of the present invention. Figure 2A ), 13C NMR ( Figure 2B ) Spectrum.

[0034] Figure 3 shows the 1H NMR of the chiral C-glycoside hydroxy ketone derivative of Example 3 of the present invention. Figure 3A ), 13C NMR ( Figure 3B ) Spectrum.

[0035] Figure 4 shows the 1H NMR of the chiral C-glycoside hydroxy ketone derivative of Example 4 of the present invention. Figure 4A ), 13C NMR ( Figure 4B ) Spectrum.

[0036] Figure 5 shows the 1H NMR of the chiral C-glycoside hydroxy ketone derivative of Example 6 of the present invention (…). Figure 5A ), 13C NMR ( Figure 5B ) Spectrum.

[0037] Figure 6 shows the 1H NMR of the chiral C-glycoside hydroxy ketone derivative of Example 7 of the present invention (…). Figure 6A ), 13C NMR ( Figure 6B ) Spectrum.

[0038] Figure 7 shows the 1H NMR of the chiral C-glycoside hydroxy ketone derivative of Example 8 of the present invention. Figure 7A ), 13C NMR ( Figure 7B ) Spectrum.

[0039] Figure 8 shows the 1H NMR spectrum of the chiral C-glycoside hydroxy ketone derivative of Example 10 of the present invention. Figure 8A ), 13C NMR ( Figure 8B ) Spectrum.

[0040] Figure 9 shows the 1H NMR spectrum of the chiral C-glycoside hydroxy ketone derivative of Example 13 of the present invention. Figure 9A ), 13C NMR ( Figure 9B ) Spectrum. Detailed Implementation

[0041] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0042] This invention provides a chiral C-glycoside hydroxy ketone derivative with the structure of formula (4).

[0043]

[0044] Equation (4);

[0045] Among them, R 1 It is any one of C1-C7 substituted alkyl, C1-C4 alkyl substituted silyl, phenyl and C1-C4 alkyl substituted silyl, C1-C17 alkyl substituted acyl, and C1-C4 alkoxy substituted acyl;

[0046] R 2It is any one of C1-C6 substituted alkyl, benzyl, haloaryl benzyl, C1-C3 alkyl-substituted aryl benzyl, methoxy-substituted aryl benzyl, naphthylmethyl, (E)-2-butenyl, and cinnamyl;

[0047] Ar can be any one of phenyl, halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, phenyl-substituted phenyl, naphthyl, or thiophene.

[0048] Preferably, the R 1 It is any one of methyl, benzyl, tert-butyldimethylsilyl, acetyl, octadecanoyl, tert-butyldiphenylsilyl, methoxyyl, and tert-butoxyyl; R 2 Ar is any one of methyl, isopropyl, 3-bromobenzyl, 4-bromobenzyl, 2,6-dichlorobenzyl, 2-methylbenzyl, 2,6-dimethylbenzyl, 2,4,6-trimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, and 2-naphthylmethyl; Ar is any one of 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-phenylphenyl, 2-naphthyl, and 3-thiophene.

[0049] This invention provides a method for preparing a chiral C-glycoside hydroxy ketone derivative with the structure of formula (4) as described in any one of the above technical solutions, comprising the following steps: using aryl acetone diazo, alkyl alcohol and 3,4-O-carbonate glycoene as raw materials, in the presence of a transition metal palladium catalyst, a metal rhodium catalyst, a phosphine ligand, chiral phosphoric acid and a 4Å molecular sieve, a one-step reaction is carried out in an organic solvent to obtain the chiral C-glycoside hydroxy ketone derivative as shown in formula (4), wherein the reaction process is shown in reaction formula (I):

[0050]

[0051] Reaction formula (I);

[0052] Among them, R 1 It is any one of C1-C7 substituted alkyl, C1-C4 alkyl-substituted silyl, phenyl and C1-C4 alkyl-substituted silyl, C1-C17 alkyl-substituted acyl, and C1-C4 alkoxy-substituted acyl; R 2 Ar is any one of C1-C6 substituted alkyl, benzyl, haloaryl benzyl, C1-C3 alkyl-substituted aryl benzyl, methoxy-substituted aryl benzyl, naphthylmethyl, (E)-2-butenyl, cinnamyl; Ar is any one of phenyl, halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, phenyl-substituted phenyl, naphthyl, thiophene.

[0053] Specifically, it includes the following steps:

[0054] Step 1: Under a dry argon atmosphere, dissolve the palladium catalyst, phosphine ligand, and 4Å molecular sieve in an organic solvent, stir at 35°C for 0.5 hours, then add chiral phosphoric acid and stir until homogeneous;

[0055] Step 2: Dissolve the alkyl alcohol, 3,4-O-carbonate glycoene and the rhodium catalyst in an organic solvent, and add the resulting mixture to the reaction system of Step 1;

[0056] Step 3: Dissolve aryl ethyl ketone in an organic solvent and add it dropwise to the reaction system of Step 2 over 1.5 hours using a syringe pump. After the addition is complete, continue stirring at 35°C for 1-4 hours until the diazo compound is completely consumed, to obtain the chiral C-glycoside hydroxy ketone derivative shown in formula (4).

[0057] The molar ratio of each raw material is as follows: palladium catalyst: phosphine ligand: chiral phosphoric acid: alkyl alcohol: 3,4-O-carbonate glycoene: rhodium catalyst: aryl acetone diazo = (0.03-0.05): (0.06-0.1): (0.05-0.10): (2.5-3.0): 1.0: (0.01-0.03): (3.0-4.5).

[0058] The volume of the organic solvent is related to the concentration of 3,4-O-carbonate glycoene by 0.02 mmol / mL, and the amount of 4Å molecular sieve added is related to the organic solvent by 50 mg / mL.

[0059] The organic solvent is any one of dichloromethane, 1,2-dichloroethane, or trichloromethane; the palladium catalyst is [Pd(C3H5)Cl]2; the rhodium catalyst is Rh2(esp)2; the phosphine ligand is Xantphos; and the chiral phosphoric acid additive is Binol skeleton chiral phosphoric acid.

[0060] Specifically, the structural formula of the phosphine ligand is: The structural formula of chiral phosphate is: .

[0061] The synthesis method further includes a separation and purification step after the reaction is completed: the reaction mixture is purified by silica gel column chromatography, and the eluent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:(3-10).

[0062] The alkyl alcohol is also selected from alcohols derived from natural products, including piperine, crotonol, L-perillol, D-proline, citronellol, or epiandrolone.

[0063] The present invention also provides the application of the chiral C-glycoside hydroxy ketone derivatives and their pharmaceutically acceptable medicinal salts described in the above technical solutions in the preparation of antitumor drugs.

[0064] Preferably, the chiral C-glycoside hydroxy ketone derivative is a chiral C-glycoside hydroxy ketone derivative containing a citronellol fragment.

[0065] This invention designs an asymmetric three-component reaction catalyzed by palladium, rhodium, and chiral phosphate: a common alcohol acts as a nucleophile, attacking a metal carbene to form a ylide; 3,4-O-carbonate glycoene serves as a precursor for the formation of an allyl cationic intermediate; the two active intermediates mutually trap each other, thereby achieving high efficiency, high β-selectivity, and high diastereoselectivity in the generation of C-glycoside hydroxyketone derivatives. This invention uses inexpensive, readily available, non-toxic, and harmless raw materials as substrates, employing a transition metal and chiral phosphate catalytic mode to achieve a one-step synthesis of chiral C-glycoside hydroxyketone derivatives with high chemoselectivity and high stereoselectivity through a simple and efficient multi-component reaction. This invention yields a novel library of glycoside compounds through a one-step multi-component reaction, offering advantages such as simple experimental operation, mild reaction conditions, and good substrate universality.

[0066] The chemical mechanism involved in the synthesis method of this invention is as follows: Diazo 1a forms a metal carbene A under rhodium catalysis, which reacts with benzyl alcohol 2a to form a ylide intermediate, which has two states, B and C. In the presence of a phosphine ligand, a palladium complex D is generated to initiate the catalytic cycle. Due to steric hindrance, the generated [Pd] species D is forced to undergo α-selective coordination with the glycosyl donor II-3a to form intermediate E, which then undergoes a decarboxylation reaction to release CO2 and generate π-allyl−Pd(II) intermediate F. Simultaneously, in the presence of chiral phosphate (CPA), the π-allyl palladium species F is a complex formed by the cationic allyl palladium and the chiral phosphonic acid anion. Subsequently, the two active intermediates C and F mutually trap each other. Due to the steric effect produced by the palladium catalyst and the sterically hindered ligand, intermediate C acts as a nucleophile to attack the carbon atom at the C1 position from the β-face of intermediate F. Subsequently, the catalyst dissociates to generate the target three-component product β-(S)-carbon glycoside compound.

[0067]

[0068] To further illustrate the present invention, the following detailed description is provided in conjunction with embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0069] Example 1

[0070]

[0071] (4-1)

[0072] In a dried 10 mL reaction tube equipped with a magnetic stirrer, [Pd(C3H5)Cl]2 (4 mol%), Xantphos (8 mol%), and 4 Å molecular sieve (200 mg) were added. After purging with an argon balloon, 1.0 mL of ultra-dry dichloromethane was added to dissolve the precipitate, and the mixture was stirred at room temperature for half an hour. Chiral phosphoric acid (5 mol%) was dissolved in 0.5 mL of ultra-dry dichloromethane and added, followed by stirring for another 5 minutes. Rh2(esp)2 (1 mol%) dissolved in 0.5 mL of ultra-dry dichloromethane, acetyl-modified 3,4-O-carbonate glycoene (0.1 mmol, 1.0 equiv.), and benzyl alcohol (0.3 mmol, 3.0 equiv.) dissolved in 1 mL of ultra-dry dichloromethane were added to the reaction system, and the resulting mixture was heated to 35 °C. Acetophenone diazo (0.4 mmol, 4.0 equiv.) was dissolved in ultra-dry dichloromethane (1.2 mL) and injected into the system via a syringe pump at a flow rate of 0.8 mL / h. The injection was completed after one and a half hours, and the reaction continued for another hour. After the reaction was monitored by TLC, the molecular sieve in the reaction solution was removed by filtration, the solution was concentrated under reduced pressure, and then the 1H NMR spectrum of the reaction solution was measured to determine the diastereoselectivity (dr). Finally, the crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain the target product. The yield was 65%, >20:1 dr. The chemical shifts of 1H NMR and 13C NMR are as follows: Figure 1A As shown in B:

[0073] 1 H NMR (500 MHz, Chloroform-d) δ 8.03 – 7.97 (m, 2H), 7.61 – 7.55 (m,1H), 7.48 – 7.43 (m, 2H), 7.34 – 7.27 (m, 5H), 6.18 – 6.13 (m, 1H), 6.01 (dd,J = 10.2, 1.7 Hz, 1H), 4.79 (d, J = 5.2 Hz, 1H), 4.70 (d, J = 11.6 Hz, 1H), 4.64 – 4.59 (m, 1H), 4.50 (d, J = 11.6 Hz, 1H), 4.24 – 4.10 (m, 2H), 3.85 –3.81 (m, 1H), 3.73 – 3.67 (m, 1H), 1.99 (s, 3H).

[0074] 13C NMR (126 MHz, Chloroform-d) δ 198.5, 170.9, 136.9, 136.1, 133.6,129.6, 128.8, 128.6, 128.5, 128.3, 128.2, 128.2, 83.0, 75.9, 75.4, 72.8,63.7, 62.0, 20.8.

[0075] Example 2

[0076]

[0077] (4-2)

[0078] The experimental method in this embodiment is basically the same as that in Example 1. The aryl acetone diazo used in this embodiment is 2-naphthyl acetone diazo, and the obtained product is shown in structural formula (4-2). The yield is 65%, >20:1dr, and the chemical shifts of 1H NMR and 13C NMR are as follows: Figure 2A As shown in B:

[0079] 1 H NMR (500 MHz, Chloroform-d) δ 8.59–8.54 (m, 1H), 8.06–7.99 (m,1H), 7.95–7.91 (m, 1H), 7.89–7.84 (m, 2H), 7.63–7.58 (m, 1H), 7.57–7.52 (m,1H), 7.35–7.22 (m, 5H), 6.19–6.14 (m, 1H), 5.93 (dd, J=10.2, 1.7 Hz, 1H), 4.87 (d, J=3.9 Hz, 1H), 4.75 (d, J=11.7 Hz, 1H), 4.72–4.69 (m, 1H), 4.47 (d,J=11.7 Hz, 1H), 4.19–4.12 (m, 2H), 3.82–3.77 (m, 1H), 3.72–3.67 (m, 1H), 1.91 (s, 3H).

[0080] 13C NMR (125 MHz, Chloroform-d) δ 198.9, 170.8, 136.8, 135.7, 133.6,132.3, 131.3, 129.8, 129.8, 128.8, 128.7, 128.6, 128.4, 128.3, 128.3, 127.8,126.9, 124.5, 82.7, 76.1, 75.5, 72.8, 63.7, 61.9, 20.8.

[0081] Example 3

[0082]

[0083] (4-3)

[0084] The experimental method in this embodiment is basically the same as that in Example 1. The aryl acetone diazo used in this embodiment is 3-thienylacetone diazo, and the product obtained is shown in structural formula (4-3). The yield is 56%, >20:1dr, and the chemical shifts of 1H NMR and 13C NMR are as follows: Figure 3A As shown in B:

[0085] 1 H NMR (500 MHz, Chloroform-d) δ 8.02–7.99 (m, 1H), 7.71–7.67 (m,1H), 7.35–7.28 (m, 5H), 7.16–7.11 (m, 1H), 6.23–6.17 (m, 1H), 5.84 (dd, , 3.86–3.80 (m, 1H), 3.74–3.69 (m, 1H), 1.96 (s, 3H).

[0086] 13 C NMR (125 MHz, Chloroform-d) δ 191.8, 170.8, 141.7, 136.5, 135.1,134.8, 129.7, 129.0, 128.6, 128.4, 128.3, 128.1, 84.1, 76.0, 75.2, 73.2,63.6, 61.8, 20.8.

[0087] Example 4

[0088]

[0089] (4-4)

[0090] In a dried 10 mL reaction tube equipped with a magnetic stirrer, [Pd(C3H5)Cl]2 (3 mol%), Xantphos (6 mol%), and 4 Å molecular sieve (200 mg) were added. After purging with an argon balloon, 1.0 mL of ultra-dry dichloromethane was added to dissolve the precipitate, and the mixture was stirred at room temperature for half an hour. Chiral phosphoric acid (5 mol%) was dissolved in 0.5 mL of ultra-dry dichloromethane and added, followed by stirring for another 5 minutes. Rh2(esp)2 (1 mol%) was dissolved in 0.5 mL of ultra-dry dichloromethane, acetyl-modified 3,4-O-carbonate glycoene (0.1 mmol, 1.0 equiv.), and methanol (0.25 mmol, 2.5 equiv.) were dissolved in 1 mL of ultra-dry dichloromethane and added to the reaction system. The resulting mixture was then heated to 35 °C. Acetophenone diazo (0.3 mmol, 3.0 equiv.) was dissolved in ultra-dry dichloromethane (1.2 mL) and injected into the system via a syringe pump at a flow rate of 0.8 mL / h. The injection was completed after one and a half hours, and the reaction continued for another hour. After the reaction was monitored by TLC, the molecular sieve in the reaction solution was removed by filtration, the solution was concentrated under reduced pressure, and then the 1H NMR spectrum of the reaction solution was measured to determine the diastereoselectivity (dr) of the product. Finally, the crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain the target product. The yield was 54%, >20:1 dr. The chemical shifts of 1H NMR and 13C NMR are as follows: Figure 4A As shown in B:

[0091] 1 H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.98 (m, 2H), 7.62 – 7.56 (m,1H), 7.49 – 7.45 (m, 2H), 6.17 – 6.12 (m, 1H), 5.96 – 5.92 (m, 1H), 4.63 (d,J = 1.0 Hz, 2H), 4.16 – 4.12 (m, 2H), 3.81 – 3.77 (m, 1H), 3.70 – 3.66 (m,1H), 3.43 (s, 3H), 1.99 (s, 3H).

[0092] 13C NMR (125 MHz, Chloroform-d) δ 198.8, 170.9, 136.3, 133.5, 129.6, 129.0, 128.6, 128.4, 85.2, 75.7, 75.5, 63.6, 61.9, 58.9, 20.8.

[0093] Example 5:

[0094]

[0095] (4-5)

[0096] The experimental method in this embodiment is basically the same as that in Example 4. The alkyl alcohol used in this embodiment is isopropanol, and the obtained product is shown in structural formula (4-5). The yield is 54%, >20:1dr, and the chemical shifts of 1H NMR and 13C NMR are as follows:

[0097] 1 H NMR (500 MHz, Chloroform-d) δ 8.06 – 8.01 (m, 2H), 7.60 – 7.53 (m,1H), 7.48 – 7.42 (m, 2H), 6.25 – 6.18 (m, 1H), 5.91 (dd, J = 10.1, 1.9 Hz,1H), 4.67 – 4.63 (m, 1H), 4.61 (d, J = 3.3 Hz, 1H), 4.21 – 4.11 (m, 2H), 3.82(d, J = 6.0 Hz, 1H), 3.74 – 3.68 (m, 1H), 3.65 – 3.54 (m, 1H), 1.97 (s, 3H), 1.16 (d, J = 6.0 Hz, 3H), 1.07 (d, J = 6.1 Hz, 3H).

[0098] 13 C NMR (125 MHz, Chloroform-d) δ 200.8, 170.8, 136.4, 133.2, 129.8,129.4, 129.0, 128.2, 82.4, 76.3, 75.1, 72.9, 63.7, 61.8, 22.6, 21.4, 20.8.

[0099] Example 6:

[0100]

[0101] (4-6)

[0102] In a dried 10 mL reaction tube equipped with a magnetic stirrer, [Pd(C3H5)Cl]2 (5 mol%), Xantphos (10 mol%), and 4 Å molecular sieve (200 mg) were added. After purging with an argon balloon, 1.0 mL of ultra-dry dichloromethane was added to dissolve the precipitate, and the mixture was stirred at room temperature for half an hour. Chiral phosphoric acid (10 mol%) was dissolved in 0.5 mL of ultra-dry dichloromethane and added, followed by stirring for another 5 minutes. Rh2(esp)2 (3 mol%) was dissolved in 0.5 mL of ultra-dry dichloromethane, tert-butoxyacyl-modified 3,4-O-carbonate glycoene (0.1 mmol, 1.0 equiv.), and benzyl alcohol (0.3 mmol, 3.0 equiv.) were dissolved in 1 mL of ultra-dry dichloromethane and added to the reaction system. The resulting mixture was then heated to 35 °C. Acetophenone diazo (0.45 mmol, 4.5 equiv.) was dissolved in ultra-dry dichloromethane (1.2 mL) and injected into the system via a syringe pump at a flow rate of 0.8 mL / h. The injection was completed after one and a half hours, and the reaction continued for another hour. After the reaction was monitored by TLC, the molecular sieve in the reaction solution was removed by filtration, the solution was concentrated under reduced pressure, and then the 1H NMR spectrum of the reaction solution was measured to determine the diastereoselectivity (dr) of the product. Finally, the crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain the target product. The yield was 52%, >20:1 dr. The chemical shifts of 1H NMR and 13C NMR are as follows: Figure 5A As shown in B:

[0103] 1 H NMR (500 MHz, Chloroform-d) δ 7.93 – 7.89 (m, 2H), 7.71 – 7.65 (m,4H), 7.57 – 7.51 (m, 1H), 7.47 – 7.42 (m, 2H), 7.41 – 7.29 (m, 11H), 6.21 –6.16 (m, 1H), 5.89 (dd, J = 10.2, 1.6 Hz, 1H), 4.77 – 4.72 (m, 2H), 4.67 –4.64 (m, 1H), 4.46 (d, J = 11.9 Hz, 1H), 3.94 – 3.89 (m, 1H), 3.86 – 3.80 (m, 1H), 3.73 – 3.68 (m, 1H), 3.68 – 3.63 (m, 1H), 1.04 (s, 9H).

[0104] 13 C NMR (125 MHz, Chloroform-d) δ 198.9, 137.0, 136.4, 135.6, 135.6,133.6, 133.5, 133.3, 129.7, 129.6, 129.1, 129.1, 128.5, 128.3, 128.3, 128.2,127.7, 82.3, 78.3, 76.1, 72.6, 63.3, 61.9, 26.8, 19.2.

[0105] Example 7:

[0106]

[0107] (4-7)

[0108] The experimental method in this embodiment is basically the same as that in Example 6. The 3,4-O-carbonate glycoene used in this embodiment is a methyl-modified 3,4-O-carbonate glycoene, and the obtained product is shown in structural formulas (4-7). The yield is 60%, >20:1dr, and the chemical shifts of 1H NMR and 13C NMR are as follows: Figure 6A As shown in B:

[0109] 1 H NMR (500 MHz, Chloroform-d) δ 7.99 – 7.96 (m, 2H), 7.60 – 7.55 (m,1H), 7.47 – 7.42 (m, 2H), 7.35 – 7.30 (m, 3H), 7.29 – 7.25 (m, 2H), 6.16 –6.11 (m, 1H), 5.92 (dd, J = 10.1, 1.7 Hz, 1H), 4.84 (d, J = 4.0 Hz, 1H), 4.72(d, J = 11.7 Hz, 1H), 4.68 – 4.64 (m, 1H), 4.43 (d, J = 11.7 Hz, 1H), 3.78 –3.74 (m, 1H), 3.67 – 3.62 (m, 1H), 3.54 – 3.49 (m, 1H), 3.38 – 3.32 (m, 1H), 3.30 (s, 3H).

[0110] 13C NMR (125 MHz, Chloroform-d) δ 199.1, 136.9, 136.6, 133.4, 129.7, 129.1, 128.7, 128.5, 128.3, 128.3, 128.2, 82.1, 76.7, 75.8, 72.6, 72.5, 62.4,59.4.

[0111] Example 8:

[0112]

[0113] (4-8)

[0114] In a dried 10 mL reaction tube equipped with a magnetic stirrer, [Pd(C3H5)Cl]2 (4 mol%), Xantphos (8 mol%), and 4 Å molecular sieve (200 mg) were added. After purging with an argon balloon, 1.0 mL of ultra-dry dichloromethane was added to dissolve the precipitate, and the mixture was stirred at room temperature for half an hour. Chiral phosphoric acid (5 mol%) was dissolved in 0.5 mL of ultra-dry dichloromethane and added, followed by stirring for another 5 minutes. Rh2(esp)2 (1 mol%) dissolved in 0.5 mL of ultra-dry dichloromethane, acetyl-modified 3,4-O-carbonate glycoene (0.1 mmol, 1.0 equiv.), and piperine (0.3 mmol, 3.0 equiv.) dissolved in 1 mL of ultra-dry dichloromethane were added to the reaction system, and the resulting mixture was heated to 35 °C. Acetophenone diazo (0.4 mmol, 4.0 equiv.) was dissolved in ultra-dry dichloromethane (1.2 mL) and injected into the system via a syringe pump at a flow rate of 0.8 mL / h. The injection was completed after one and a half hours, and the reaction continued for another hour. After the reaction was monitored by TLC, the molecular sieve in the reaction solution was removed by filtration, the solution was concentrated under reduced pressure, and then the 1H NMR spectrum of the reaction solution was measured to determine the diastereoselectivity (dr). Finally, the crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain the target product. The yield was 61%, >20:1 dr. The chemical shifts of 1H NMR and 13C NMR are as follows: Figure 7A As shown in B:

[0115] 1H NMR (500 MHz, Chloroform-d) δ 7.98 – 7.93 (m, 2H), 7.61 – 7.55 (m,1H), 7.49 – 7.40 (m, 2H), 6.77 (d, J = 1.6 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 6.69 (dd, J = 7.9, 1.6 Hz, 1H), 6.18 – 6.13 (m, 1H), 5.96 – 5.93 (m, 2H), 5.89 (dd, J = 10.2, 1.7 Hz, 1H), 4.73 (d, J = 3.8 Hz, 1H), 4.64 – 4.61 (m,1H), 4.59 (d, J = 11.4 Hz, 1H), 4.33 (d, J = 11.5 Hz, 1H), 4.14 (d, J = 6.2Hz, 2H), 3.81 – 3.78 (m, 1H), 3.71 – 3.66 (m, 1H), 1.97 (s, 3H).

[0116] 13 C NMR (125 MHz, Chloroform-d) δ 199.1, 170.9, 147.9, 147.6, 136.4,133.4, 130.6, 130.2, 129.8, 129.0, 128.6, 128.4, 122.1, 109.0, 108.1, 101.1,82.1, 75.9, 75.4, 72.6, 63.7, 61.9, 20.8.

[0117] Example 9:

[0118]

[0119] (4-9)

[0120] The experimental method in this embodiment is basically the same as that in Example 8. The alkyl alcohol used in this embodiment is crotonol, and the product obtained is shown in structural formula (4-9). The yield is 56%, 16:1 dr, and the chemical shifts of 1H NMR and 13C NMR are as follows:

[0121] 1H NMR (500 MHz, Chloroform-d) δ 8.01 – 7.96 (m, 2H), 7.60 – 7.55 (m,1H), 7.49 – 7.43 (m, 2H), 6.18 – 6.13 (m, 1H), 5.94 (dd, J = 10.2, 1.7 Hz,1H), 5.69 – 5.61 (m, 1H), 5.52 – 5.45 (m, 1H), 4.73 (d, J = 3.7 Hz, 1H), 4.64– 4.60 (m, 1H), 4.16 – 4.11 (m, 2H), 4.09 – 4.03 (m,1H), 3.93 – 3.87 (m,1H), 3.81 – 3.76 (m, 1H), 3.71 – 3.66 (m, 1H), 1.98 (s, 3H), 1.66 (dd, J =6.4, 1.5 Hz, 3H).

[0122] 13 C NMR (125 MHz, Chloroform-d) δ 199.5, 170.8, 136.6, 133.3, 131.4,129.9, 129.1, 128.5, 128.3, 126.5, 82.2, 76.0, 75.3, 71.7, 63.7, 61.9, 20.8,17.7.

[0123] Example 10:

[0124]

[0125] (4-10)

[0126] The experimental method in this embodiment is basically the same as that in Example 8. The alkyl alcohol used in this embodiment is L-perillyl alcohol, and the product obtained is shown in structural formula (4-10). The yield is 59%, 18:1 dr, and the chemical shifts of 1H NMR and 13C NMR are as follows: Figure 8A As shown in B:

[0127] 1H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.98 (m, 2H), 7.60 – 7.55 (m,1H), 7.48 – 7.42 (m, 2H), 6.21 – 6.13 (m, 1H), 5.95 (dd, J = 10.2, 1.7 Hz,1H), 5.66 – 5.60 (m, 1H), 4.71 – 4.69 (m, 2H), 4.68 – 4.66 (m, 1H), 4.65 –4.62 (m, 1H), 4.18 – 4.11 (m, 2H), 3.99 (d, J = 11.4 Hz, 1H), 3.84 – 3.77 (m,2H), 3.72 – 3.66 (m, 1H), 2.13 – 2.06 (m, 2H), 2.05 – 2.01 (m, 2H), 1.98 (s,3H), 1.88 – 1.83 (m, 1H), 1.80 – 1.74 (m, 1H), 1.70 (s, 3H), 1.38 – 1.29 (m,1H).

[0128] 13 C NMR (125 MHz, Chloroform-d) δ 199.4, 170.8, 149.6, 136.5, 133.6,133.3, 129.9, 129.1, 128.5, 128.3, 126.8, 108.8, 82.3, 75.7, 75.3, 63.6,61.9, 40.9, 30.5, 27.2, 26.6, 20.8, 20.7.

[0129] Example 11:

[0130]

[0131] (4-11)

[0132] The experimental method in this embodiment is basically the same as that in Example 8. The alkyl alcohol used in this embodiment is D-prolyl, and the product obtained is shown in structural formula (4-11). The yield is 53%, >20:1 dr, and the chemical shifts of 1H NMR and 13C NMR are as follows:

[0133] 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 7.6 Hz, 2H), 7.62 (t, J =7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 5.99 – 5.93 (m, 1H), 5.79 (d, J = 10.2Hz, 1H), 4.75 (d, J = 5.5 Hz, 1H), 4.53 – 4.48 (m, 1H), 4.16 – 4.05 (m, 3H), 3.83 – 3.72 (m, 2H), 3.67 – 3.61 (m, 2H), 3.53 – 3.47 (m, 1H), 3.30 – 3.18(m, 2H), 1.94 (s, 3H), 1.91 – 1.82 (m, 3H), 1.75 – 1.68 (m, 1H), 1.38 (s,9H).

[0134] 13 C NMR (125 MHz, DMSO-d6) δ 198.8, 170.5, 154.0, 137.0, 133.4, 129.1,129.0, 128.9, 128.8, 84.2, 78.8, 76.1, 75.9, 71.7, 64.4, 61.3, 56.8, 46.8,28.6, 28.4, 23.2, 20.9.

[0135] Example 12:

[0136]

[0137] (4-12)

[0138] The experimental method in this embodiment is basically the same as that in Example 8. The alkyl alcohol used in this embodiment is citronellol, and the product obtained is shown in structural formula (4-12). The yield is 54%, >20:1 dr. The chemical shifts of 1H NMR and 13C NMR are as follows:

[0139] 11H NMR (500 MHz, Chloroform-d) δ 8.03 – 7.98 (m, 2H), 7.60 – 7.55 (m,1H), 7.45 (t, J = 7.6 Hz, 2H), 6.20 – 6.14 (m, 1H), 5.94 (dd, J = 10.1, 1.7Hz, 1H), 5.09 – 5.01 (m, 1H), 4.66 – 4.63 (m, 1H), 4.60 (d, J = 3.7 Hz, 1H),4.15 (d, J = 6.2 Hz, 2H), 3.84 – 3.77 (m, 1H), 3.73 – 3.68 (m, 1H), 3.62 –3.53 (m, 1H), 3.47 – 3.38 (m, 1H), 1.99 (s, 3H), 1.95 – 1.84 (m, 2H), 1.81 –1.76 (m, 1H), 1.67 (dd, J = 3.4, 1.5 Hz, 3H), 1.64 – 1.59 (m, 1H), 1.58 (dd,3H), 1.53 – 1.45 (m, 1H), 1.41 – 1.33 (m, 1H), 1.28 – 1.24 (m, 1H), 1.15 –1.05 (m, 1H), 0.82 (dd, J = 11.7, 6.6 Hz, 3H).

[0140] 13 13C NMR (125 MHz, Chloroform-d) δ 199.7, 170.8, 136.4, 133.4, 131.2,129.8, 129.1, 128.6, 128.3, 124.7, 84.2, 75.9, 75.2, 69.8, 63.7, 61.9, 37.1,36.6, 29.4, 25.7, 25.4, 20.8, 19.5, 17.7.

[0141] Example 13:

[0142]

[0143] (4-13)

[0144] The experimental method in this embodiment is basically the same as that in Example 8. The alkyl alcohol used in this embodiment is epithermone, and the product obtained is shown in structural formula (4-13). The yield is 58%, >20:1 dr. The chemical shifts of 1H NMR and 13C NMR are as follows: Figure 9A As shown in B:

[0145] 1 H NMR (600 MHz, Chloroform-d) δ 8.07 – 8.03 (m, 2H), 7.61 – 7.56 (m,1H), 7.49 – 7.44 (m, 2H), 6.27 – 6.21 (m, 1H), 5.93 (dd, J = 10.1, 1.8 Hz,1H), 4.69 (d, J = 3.3 Hz, 1H), 4.68 – 4.65 (m, 1H), 4.22 – 4.13 (m, 2H), 3.86– 3.82 (m, 1H), 3.74 – 3.69 (m, 1H), 3.31 – 3.23 (m, 1H), 2.48 – 2.40 (m, 1H), 2.11 – 2.00 (m, 1H), 2.00 (s, 3H), 1.96 – 1.86 (m, 1H), 1.83 – 1.75 (m,2H), 1.69 – 1.57 (m, 4H), 1.56 – 1.45 (m, 2H), 1.41 – 1.16 (m, 9H), 1.06 –0.99 (m, 1H), 0.93 (dtd, J = 24.8, 12.4, 6.3 Hz, 1H), 0.85 (s, 3H), 0.79 (s,3H), 0.66 – 0.59 (m, 1H).

[0146] 13 C NMR (150 MHz, Chloroform-d) δ 221.3, 200.5, 170.8, 136.4, 133.3,129.8, 129.4, 129.0, 128.2, 82.2, 79.6, 76.3, 75.1, 63.7, 61.8, 54.4, 51.4,47.8, 44.7, 36.8, 35.8, 35.0, 34.2, 31.5, 30.9, 28.6, 28.5, 21.8, 20.8, 20.5,13.8, 12.2.

[0147] Example 14:

[0148]

[0149] (4-14)

[0150] The experimental method in this embodiment is basically the same as that in Example 1. The aromatic acetone diazo used in this embodiment is 4-chloroacetoacetone diazo, and the obtained product is shown in structural formula (4-14). The yield is 56%, >20:1 dr, and the chemical shifts of 1H NMR and 13C NMR are as follows:

[0151] 1 H NMR (500 MHz, Chloroform-d) δ 7.97 (d, J = 8.3 Hz, 2H), 7.46 –7.38 (m, 2H), 7.35 – 7.27 (m, 3H), 7.25 – 7.18 (m, 2H), 6.23 – 6.17 (m, 1H), 5.88 (dd, J = 10.2, 1.6 Hz, 1H), 4.68 – 4.61 (m, 2H), 4.60 (d, J = 3.6 Hz, 1H), 4.40 (d, J = 11.7 Hz, 1H), 4.21 – 4.12 (m, 2H), 3.83 (d, J = 5.9 Hz,1H), 3.70 (t, J = 6.3 Hz (1H), 1.97 (s, 3H).

[0152] 13 C NMR (125 MHz, Chloroform-d) δ 198.6, 170.8, 139.9, 136.5, 134.5,130.8, 129.8, 128.8, 128.7, 128.6, 128.3, 128.3, 83.2, 76.0, 75.4, 73.0,63.6, 61.8, 20.8.

[0153] Example 15:

[0154]

[0155] (4-15)

[0156] The experimental method in this embodiment is basically the same as that in Example 1. The aromatic acetone diazo used in this embodiment is 4-bromoacetophenone diazo, and the obtained product is shown in structural formula (4-15). The yield is 54%, >20:1 dr, and the chemical shifts of 1H NMR and 13C NMR are as follows:

[0157] 1 H NMR (500 MHz, Chloroform-d) δ 7.91 – 7.86 (m, 2H), 7.61 – 7.55 (m,2H), 7.37 – 7.28 (m, 3H), 7.25 – 7.20 (m, 2H), 6.22 – 6.17 (m, 1H), 5.87 (dd,J = 10.1, 1.7 Hz, 1H), 4.68 – 4.61 (m, 2H), 4.59 (d, J = 3.6 Hz, 1H), 4.39 (d, J = 11.7 Hz, 1H), 4.20 – 4.13 (m, 2H), 3.85 – 3.81 (m, 1H), 3.70 (td, J =6.3, 1.8 Hz, 1H), 1.96 (s, 3H).

[0158] 13 C NMR (125 MHz, Chloroform-d) δ 198.8, 170.8, 136.5, 134.9, 131.7,130.8, 129.7, 128.9, 128.7, 128.6, 128.4, 128.3, 83.2, 76.0, 75.41, 73.0,63.6, 61.8, 20.8.

[0159] Example 16:

[0160]

[0161] (4-16)

[0162] The experimental method in this embodiment is basically the same as that in Example 1. The aromatic acetone diazo used in this embodiment is 4-methylacetophenone diazo, and the obtained product is shown in structural formula (4-16). The yield is 67%, >20:1 dr, and the chemical shifts of 1H NMR and 13C NMR are as follows:

[0163] 1H NMR (500 MHz, Chloroform-d) δ 7.91 – 7.86 (m, 2H), 7.35 – 7.26 (m,5H), 7.24 (d, J = 8.0 Hz, 2H), 6.17 – 6.12 (m, 1H), 5.89 (dd, J = 10.2, 1.7Hz, 1H), 4.75 (d, J = 3.9 Hz, 1H), 4.72 (d, J = 11.7 Hz, 1H), 4.64 – 4.61 (m,1H), 4.42 (d, J = 11.8 Hz, 1H), 4.18 – 4.10 (m, 2H), 3.80 – 3.76 (m, 1H),3.70 – 3.66 (m, 1H), 2.41 (s, 3H), 1.98 (s, 3H).

[0164] 13 C NMR (125 MHz, Chloroform-d) δ 198.4, 170.9, 144.5, 136.9, 133.9,129.9, 129.2, 129.1, 128.5, 128.5, 128.3, 128.2, 82.3, 76.0, 75.4, 72.6,63.7, 61.9, 21.7, 20.8.

[0165] Example 17:

[0166]

[0167] (4-17)

[0168] The experimental method in this embodiment is basically the same as that in Example 1. The aromatic acetone diazo used in this embodiment is 4-methoxyacetophenone diazo, and the obtained product is shown in structural formula (4-17). The yield is 78%, >20:1 dr, and the chemical shifts of 1H NMR and 13C NMR are as follows:

[0169] 1H NMR (500 MHz, Chloroform-d) δ 8.05 – 7.99 (m, 2H), 7.35 – 7.24 (m,5H), 6.95 – 6.87 (m, 2H), 6.17 – 6.12 (m, 1H), 5.89 (dd, J = 10.2, 1.7 Hz,1H), 4.72 – 4.67 (m, 2H), 4.65 – 4.60 (m, 1H), 4.41 (d, J = 11.7 Hz, 1H), 4.20 – 4.11 (m, 2H), 3.87 (s, 3H), 3.81 – 3.77 (m, 1H), 3.72 – 3.68 (m, 1H),1.98 (s, 3H).

[0170] 13 C NMR (125 MHz, Chloroform-d) δ 197.2, 170.9, 163.9, 137.0, 131.71,130.01, 129.23, 128.49, 128.43, 128.26, 128.14, 113.60, 82.64, 76.04, 75.33,72.6, 63.7, 61.9, 55.5, 20.8.

[0171] Example 18:

[0172]

[0173] (4-18)

[0174] The experimental method in this embodiment is basically the same as that in Example 4. The alkyl alcohol used in this embodiment is 3-bromobenzyl alcohol, and the product obtained is shown in structural formula (4-18). The yield is 60%, >20:1 dr, and the chemical shifts of 1H NMR and 13C NMR are as follows:

[0175] 1H NMR (500 MHz, Chloroform-d) δ 8.01 – 7.96 (m, 2H), 7.65 – 7.59 (m,1H), 7.53 – 7.41 (m, 4H), 7.24 – 7.17 (m, 2H), 6.19 (ddd, J = 10.2, 5.9, 2.2Hz, 1H), 5.93 (dd, J = 10.2, 1.7 Hz, 1H), 4.80 (d, J = 4.0 Hz, 1H), 4.75 –4.64 (m, 2H), 4.43 (d, J = 11.9 Hz, 1H), 4.17 (d, J = 6.2 Hz, 2H), 3.82 (s,1H), 3.78 – 3.69 (m, 1H), 2.01 (s, 3H).

[0176] 13 C NMR (125 MHz, Chloroform-d) δ 198.7, 170.8, 139.3, 136.3, 133.6,131.2, 131.1, 130.1, 129.7, 129.1, 128.7, 128.5, 126.6, 122.6, 82.6, 75.9,75.4, 71.8, 63.6, 61.9, 20.9.

[0177] Example 19:

[0178]

[0179] (4-19)

[0180] The experimental method in this embodiment is basically the same as that in Example 4. The alkyl alcohol used in this embodiment is 2-methylbenzyl alcohol, and the product obtained is shown in structural formula (4-19). The yield is 68%, >20:1 dr, and the chemical shifts of 1H NMR and 13C NMR are as follows:

[0181] 1H NMR (500 MHz, Chloroform-d) δ 7.99 – 7.94 (m, 2H), 7.60 – 7.55 (m,1H), 7.48 – 7.42 (m, 2H), 7.24 – 7.20 (m, 1H), 7.18 – 7.13 (m, 3H), 6.16 –6.10 (m, 1H), 5.86 (dd, J = 10.2, 1.7 Hz, 1H), 4.75 (d, J = 3.9 Hz, 1H), 4.72(d, J = 11.6 Hz, 1H), 4.64 – 4.61 (m, 1H), 4.43 (d, J = 11.6 Hz, 1H), 4.12(d, J = 6.2 Hz, 2H), 3.79 – 3.76 (m, 1H), 3.70 – 3.66 (m, 1H), 2.30 (s, 3H), 1.98 (s, 3H).

[0182] 13 C NMR (125 MHz, Chloroform-d) δ 199.1, 170.8, 137.4, 136.5, 134.7,133.5, 130.5, 129.8, 129.6, 129.0, 128.5, 128.4, 125.9, 82.3, 76.0, 75.4,71.0, 63.7, 61.9, 20.8, 18.9.

[0183] Example 20:

[0184]

[0185] (4-20)

[0186] The experimental method in this embodiment is basically the same as that in Example 4. The alkyl alcohol used in this embodiment is 2,6-dichlorobenzyl alcohol, and the product obtained is shown in structural formula (4-20). The yield is 54%, >20:1 dr. The chemical shifts of 1H NMR and 13C NMR are as follows:

[0187] 1H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.95 (m, 2H), 7.57 (t, J =7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.20 (t, J =8.0 Hz, 1H), 6.16 – 6.07 (m, 1H), 5.82 (dd, J = 10.3, 1.7 Hz, 1H), 4.98 (d, J= 11.2 Hz, 1H), 4.81 – 4.73 (m, 2H), 4.66 – 4.59 (m, 1H), 4.17 – 4.08 (m,2H), 3.77 (s, 1H), 3.70 – 3.63 (m, 1H), 1.97 (s, 3H).

[0188] 13 C NMR (125 MHz, Chloroform-d) δ 198.9, 170.8, 137.1, 136.3, 133.3,132.4, 130.4, 129.7, 129.2, 128.5, 128.5, 128.3, 83.1, 75.8, 75.3, 67.1,63.7, 61.9, 20.8.

[0189] Example 21:

[0190]

[0191] (4-21)

[0192] The experimental method in this embodiment is basically the same as that in Example 4. The alkyl alcohol used in this embodiment is cyclohexanol, and the product obtained is shown in structural formula (4-21). The yield is 72%, >20:1 dr. The chemical shifts of 1H NMR and 13C NMR are as follows:

[0193] 1H NMR (500 MHz, Chloroform-d) δ 8.07 – 8.03 (m, 2H), 7.58 – 7.54 (m,1H), 7.47 – 7.42 (m, 2H), 6.27 – 6.20 (m, 1H), 5.92 (dd, J = 10.1, 1.9 Hz,1H), 4.68 – 4.65 (m, 1H), 4.63 (d, J = 3.3 Hz, 1H), 4.18 – 4.14 (m, 2H), 3.85– 3.80 (m, 1H), 3.74 – 3.68 (m, 1H), 3.31 – 3.24 (m, 1H), 1.98 (s, 3H), 1.89– 1.81 (m, 1H), 1.72 – 1.66 (m, 2H), 1.63 – 1.58 (m, 1H), 1.48 – 1.43 (m,1H), 1.36 – 1.28 (m, 1H), 1.28 – 1.05 (m, 4H).

[0194] 13 C NMR (125 MHz, Chloroform-d) δ 200.8, 170.8, 136.4, 133.2, 129.9,129.5, 129.0, 128.1, 82.3, 78.7, 76.3, 75.0, 63.7, 61.8, 32.6, 31.4, 25.5,23.9, 23.9, 20.8.

[0195] Example 22:

[0196]

[0197] (4-22)

[0198] The experimental method in this embodiment is basically the same as that in Example 6. The 3,4-O-carbonate glycoene used in this embodiment is tert-butyldimethylsilyl-modified 3,4-O-carbonate glycoene, and the obtained product is shown in structural formula (4-22). The yield is 62%, >20:1 dr, and the chemical shifts of 1H NMR and 13C NMR are as follows:

[0199] 1H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.97 (m, 2H), 7.62 – 7.57 (m,1H), 7.46 (t, J = 7.6 Hz, 2H), 7.36 – 7.31 (m, 3H), 7.30 – 7.28 (m, 2H), 6.22– 6.17 (m, 1H), 5.90 – 5.84 (m, 1H), 4.77 – 4.71 (m, 2H), 4.69 – 4.65 (m,1H), 4.46 (d, J = 11.8 Hz, 1H), 3.90 – 3.84 (m, 1H), 3.77 – 3.72 (m, 1H),3.65 – 3.60 (m, 1H), 3.57 – 3.53 (m, 1H), 1.77 – 1.70 (m, 1H), 0.87 (s, 8H), 0.04 (s, 3H), 0.02 (s, 3H).

[0200] 13 C NMR (125 MHz, Chloroform-d) δ 199.1, 137.0, 136.5, 133.3, 129.6,129.2, 129.1, 128.5, 128.4, 128.3, 128.1, 82.6, 78.2, 76.2, 72.7, 62.5, 61.7,25.9, 18.3, -5.4, -5.4.

[0201] Example 23:

[0202]

[0203] (4-23)

[0204] The experimental method in this embodiment is basically the same as that in Example 6. The 3,4-O-carbonate glycoene used in this embodiment is octadecanoyl-modified 3,4-O-carbonate glycoene, and the obtained product is shown in structural formula (4-23). ​​The yield is 68%, >20:1 dr. The chemical shifts of 1H NMR and 13C NMR are as follows:

[0205] 1H NMR (500 MHz, Chloroform-d) δ 7.97 (d, J = 7.7 Hz, 2H), 7.57 (t, J= 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.34 – 7.28 (m, 3H), 7.28 – 7.24 (m,2H), 6.19 – 6.13 (m, 1H), 5.89 (dd, J = 10.1, 1.7 Hz, 1H), 4.74 (d, J = 3.8Hz, 1H), 4.71 (d, J = 11.7 Hz, 1H), 4.66 – 4.61 (m, 1H), 4.42 (d, J = 11.7Hz, 1H), 4.17 – 4.10 (m, 2H), 3.80 – 3.75 (m, 1H), 3.68 (t, J = 6.3 Hz, 1H), 2.21 (t, J = 7.6 Hz, 2H), 1.72 – 1.65 (m, 1H), 1.55 – 1.49 (m, 2H), 1.27 –1.18 (m, 28H), 0.88 (t, J = 6.8 Hz, 3H).

[0206] 13 C NMR (125 MHz, Chloroform-d) δ 199.2, 173.6, 136.9, 136.4, 133.4,129.9, 129.1, 128.6, 128.5, 128.4, 128.3, 128.2, 82.5, 76.0, 75.4, 72.7,63.4, 61.9, 34.2, 31.9, 29.7, 29.7, 29.6, 29.5, 29.4, 29.3, 29.1, 24.9, 22.7,14.1.

[0207] Actual test

[0208] Test Example 1

[0209] Taking a chiral C-glycoside hydroxy ketone derivative containing a citronellol fragment as an example, the MTT assay was used to evaluate the inhibitory activity of the experimental drug on MV4-11, LNCap, 22RV, HepG2, HCT116, and NCL-H128 cells. The specific experimental method was as follows: MV4-11, LNCap, 22RV, HepG2, HCT116, and NCL-H128 cells were seeded into 96-well plates. After adhesion, the experimental drug was added and cultured for 48 h, followed by incubation with MTT solution for another 4 h. The OD value was measured at 490 nm using a microplate reader, and the half-maximal inhibitory concentration (IC50) of the experimental drug on cell viability was calculated. Citronellol was used as the positive control. The test results are shown in Table 1 below.

[0210] Table 1

[0211]

[0212] Data represents the mean value ± SD (n = 3).

[0213] As shown in the table, the method of this invention can achieve high-efficiency, high β-selectivity, and high diastereoselectivity in the generation of C-glycoside hydroxyketone derivatives. The resulting chiral C-glycoside hydroxyketone derivatives containing citronellol fragments exhibit promising anticancer activity against human colorectal cancer cells HepG2 and human small cell lung cancer cells NCL-H128. The results indicate that compound 4-12 possesses broad-spectrum antitumor activity, particularly showing promising anticancer activity against human prostate cancer cells LNCap and human liver cancer cells HCT116. Compound 4-12 showed an IC50 of 32 ± 2 μmol / L against human leukemia cells MV4-11 (n=3), 25 ± 3 μmol / L against human prostate cancer cells LNCap (n=3), 35 ± 3 μmol / L against human prostate cancer cells 22RV (n=3), 15 ± 2 μmol / L against human colorectal cancer cells HepG2 (n=3), 20 ± 2 μmol / L against human liver cancer cells HCT116 (n=3), and 11 ± 2 μmol / L against human small cell lung cancer cells NCL-H128 (n=3).

[0214] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A chiral C-glycoside hydroxy ketone derivative, characterized in that, Its structure is shown in equation (4): Equation (4); Among them, R 1 It is any one of C1-C7 substituted alkyl, C1-C4 alkyl substituted silyl, phenyl and C1-C4 alkyl substituted silyl, C1-C17 alkyl substituted acyl, and C1-C4 alkoxy substituted acyl; R 2 It is any one of C1-C6 substituted alkyl, benzyl, haloaryl benzyl, C1-C3 alkyl-substituted aryl benzyl, methoxy-substituted aryl benzyl, naphthylmethyl, (E)-2-butenyl, and cinnamyl; Ar can be any one of phenyl, halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, phenyl-substituted phenyl, naphthyl, or thiophene.

2. The chiral C-glycoside hydroxy ketone derivative according to claim 1, characterized in that, R 1 It is any one of methyl, benzyl, tert-butyldimethylsilyl, acetyl, octadecanoyl, tert-butyldiphenylsilyl, methoxyyl, and tert-butoxyyl; R 2 Ar is any one of methyl, isopropyl, 3-bromobenzyl, 4-bromobenzyl, 2,6-dichlorobenzyl, 2-methylbenzyl, 2,6-dimethylbenzyl, 2,4,6-trimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, and 2-naphthylmethyl; Ar is any one of 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-phenylphenyl, 2-naphthyl, and 3-thiophene.

3. A method for synthesizing a chiral C-glycoside hydroxy ketone derivative, characterized in that, Using aryl acetone diazo, alkyl alcohol and 3,4-O-carbonate glycoene as raw materials, a chiral C-glycoside hydroxy ketone derivative was obtained in a one-step reaction in an organic solvent in the presence of a transition metal palladium catalyst, a metal rhodium catalyst, a phosphine ligand, chiral phosphoric acid and a 4Å molecular sieve, as shown in reaction formula (I). Reaction formula (I); Among them, R 1 It is any one of C1-C7 substituted alkyl, C1-C4 alkyl-substituted silyl, phenyl and C1-C4 alkyl-substituted silyl, C1-C17 alkyl-substituted acyl, and C1-C4 alkoxy-substituted acyl; R 2 Ar is any one of C1-C6 substituted alkyl, benzyl, haloaryl benzyl, C1-C3 alkyl-substituted aryl benzyl, methoxy-substituted aryl benzyl, naphthylmethyl, (E)-2-butenyl, cinnamyl; Ar is any one of phenyl, halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, phenyl-substituted phenyl, naphthyl, thiophene.

4. The synthesis method according to claim 3, characterized in that, The molar ratio of each raw material is as follows: palladium catalyst: phosphine ligand: chiral phosphoric acid: alkyl alcohol: 3,4-O-carbonate glycoene: rhodium catalyst: aryl acetone diazo = (0.03-0.05): (0.06-0.1): (0.05-0.10): (2.5-3.0): 1.0: (0.01-0.03): (3.0-4.5).

5. The synthesis method according to claim 3, characterized in that, The volume of the organic solvent is related to the concentration of 3,4-O-carbonate glycoene by 0.02 mmol / mL, and the amount of 4Å molecular sieve added is related to the organic solvent by 50 mg / mL.

6. The synthesis method according to claim 3, characterized in that, The organic solvent is any one of dichloromethane, 1,2-dichloroethane, or trichloromethane; the palladium catalyst is [Pd(C3H5)Cl]2; the rhodium catalyst is Rh2(esp)2; the phosphine ligand is Xantphos; and the chiral phosphoric acid additive is Binol skeleton chiral phosphoric acid.

7. The synthesis method according to claim 3, characterized in that, The synthesis method further includes a separation and purification step after the reaction is completed: the reaction mixture is purified by silica gel column chromatography, and the eluent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of ethyl acetate:petroleum ether of 1:(3-10).

8. The synthesis method according to claim 3, characterized in that, The alkyl alcohol is also selected from alcohols derived from natural products, including piperine, crotonol, L-perillol, D-proline, citronellol, or epiandrolone.

9. The use of the chiral C-glycoside hydroxy ketone derivative according to any one of claims 1 to 2 or the chiral C-glycoside hydroxy ketone derivative prepared by the synthetic method according to any one of claims 3 to 8, and the pharmaceutically acceptable pharmaceutical salt thereof, in the preparation of antitumor drugs.

10. The application according to claim 9, characterized in that, The chiral C-glycoside hydroxy ketone derivative is a chiral C-glycoside hydroxy ketone derivative containing a citronellol fragment.

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