CN116199698A - Functionalized D-glucal compound and preparation method thereof - Google Patents

Abstract

The invention discloses a functionalized D-glucose compound and a preparation method thereof, wherein the functionalized D-glucose compound uses a key intermediate 4, 6-O-acetonylidene-D-glucose, and adopts different reaction technologies to install six different functional groups on a hydroxyl group at a 3-position of the functionalized D-glucose compound to obtain six corresponding functionalized glucose derivatives. The novel glycal has potential application value in the fields of synthetic chemistry and pharmaceutical chemistry.

Description

Functionalized D-glucal compound and preparation method thereof

Technical Field

The invention belongs to the fields of fine chemical industry and sugar chemistry, relates to the utilization and conversion of chiral sugar-containing intermediates, and particularly discloses a novel functionalized D-glucal compound and a preparation method thereof.

Background Art

D-glucal (I) is a very important sugar derivative that can be easily prepared from glucose or mannose. D-glucal inherits the chirality of natural sugar D-glucose, and its derivatives are widely used in organic synthesis as convenient six-carbon chiral building blocks. The more commonly used and important D-glucal derivatives include any of II, III, IV, V and VI, as follows:

Many chiral drug molecules can be prepared through these derivatives. For example, using its triacetyl derivative II as the starting material and chiral source, Restricticin, SGLT-2 inhibitor, Bergenin, Papulacandin D, Tricyclic flavonoid and Papulacandins A can be prepared. In addition, properly protected alkenyls are convenient glycosylation donors; at the same time, many interesting and useful reactions have been developed around the intracyclic alkenyl ether functional groups of glucal derivatives, and a large number of chiral compounds with novel structures have been prepared. This fully demonstrates the importance and high value of D-glucal and its derivatives in organic synthesis and medicinal chemistry.

Summary of the invention

The purpose of the present invention is to provide a novel functionalized D-glucal compound and a preparation method thereof. The novelty of the preparation method of the functionalized D-glucal compound disclosed in the present invention is that six different functional groups are installed on the 3-hydroxyl group, and these groups have the ability to react with the enol ether in the glucal ring to generate new structural derivatives.

A functionalized D-glucal compound has a general structure VII, and is represented by the following structural formulas VII-a, VII-b, VII-c, VII-d, VII-e and VII-f respectively according to the type of its functional substituent FG:

Preferably, one of them is 3-O-acryloyl-4,6-O-acetone-D-glucal (VII-a), and its general structural formula is:

The R group is selected from any one of -H, alkyl, alkenyl, alkynyl and aryl.

Preferably, one of them is 3-O-propenyl ester-4,6-O-acetone-D-glucal (VII-b), and its general structural formula is:

The R group is selected from any one of an alkyl group, a benzyl group, and an allyl group.

Preferably, one of them is 3-O-propynyl-4,6-O-acetone-D-glucal (VII-c), and its general structural formula is:

The R group is selected from any one of -H, alkyl, alkenyl, alkynyl and aryl.

Preferably, one of them is 3-O-pyridyl-4,6-O-acetone-D-glucal (VII-d), and its general structural formula is:

Wherein, the R group is selected from any one of -H, halogen, alkyl, alkenyl, alkynyl, and aryl.

Preferably, one of them is 3-O-benzyl-4,6-O-acetone-D-glucal (VII-e), and its general structural formula is:

Wherein, the R group is selected from any one of -H, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, ester and aldehyde.

Preferably, one of them is 3-O-methylenetriazole-4,6-O-acetone-D-glucal (VII-f), and its general structural formula is:

The R group is selected from any one of an alkyl group, an alkenyl group, an aryl group, and a sulfonyl group.

Preferably, the method for preparing the functionalized D-glucal compound is characterized in that the preparation route of the functionalized D-glucal compound is:

其中R基选自-H、烷基、烯基、炔基、芳基中的任一种；Among them, 3-O-acryloyl-4,6-O-acetone-D-glucal (VII-a) is prepared by condensing 4,6-O-acetone-D-glucal VI with substituted allyl carboxylic acid a, wherein the structural formula of carboxylic acid a is

Wherein the R group is selected from any one of -H, alkyl, alkenyl, alkynyl, and aryl;

其中，R基选自烷基、苄基、烯丙基中的任一种。3-O-propenyl ester-4,6-O-acetone formate-D-glucal (VII-b), the preparation method of which is to use 4,6-O-acetone formate-D-glucal VI to add propargyl ester b, the structural formula of propargyl ester b is

The R group is selected from any one of an alkyl group, a benzyl group, and an allyl group.

Preferably, the method for preparing the functionalized D-glucal compound is characterized in that the preparation route of the functionalized D-glucal compound is:

其中，R基选自-H、烷基、烯基、炔基、芳基中的任一种，X选自Cl、Br、OMs中的任一种；Among them, 3-O-propynyl-4,6-O-acetone-D-glucal (VII-c) is prepared by using 4,6-O-acetone-D-glucal VI and propyne halide c for nucleophilic substitution, and the structural formula of propyne halide c is

Wherein, the R group is selected from any one of -H, alkyl, alkenyl, alkynyl, and aryl, and X is selected from any one of Cl, Br, and OMs;

其中R基选自-H、卤素、烷基、烯基、炔基、芳基中的任一种，X基选自F、Cl、Br、OMs中的任一种。3-O-pyridyl-4,6-O-acetone-D-glucal (VII-d), the preparation method of which is to use 4,6-O-acetone-D-glucal VI and pyridine halide d for aromatic nucleophilic substitution, the pyridine halide d has the structural formula

The R group is selected from any one of -H, halogen, alkyl, alkenyl, alkynyl, and aryl, and the X group is selected from any one of F, Cl, Br, and OMs.

Preferably, the method for preparing the functionalized D-glucal compound is characterized in that the preparation route of the functionalized D-glucal compound is:

其中R基选自-H、卤素、烷基、烯基、炔基、芳基、硝基、酯基、醛基中的任一种，X基选自Cl、Br、OMs中的任一种；Among them, 3-O-benzyl-4,6-O-acetone-D-glucal (VII-e) is prepared by using 4,6-O-acetone-D-glucal VI and benzyl halide e for nucleophilic substitution, and the benzyl halide e has the structural formula

Wherein the R group is selected from any one of -H, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, ester, and aldehyde, and the X group is selected from any one of Cl, Br, and OMs;

3-O-methylenetriazole-4,6-O-acetone-D-glucal (VII-f), which is prepared by a [3+2] cycloaddition reaction of 3-O-propynyl-4,6-O-acetone-D-glucal (VII-c ₁ ) and azide f, wherein the structural formula of azide f is RN ₃ , wherein the R group is selected from any one of an alkyl group, an alkenyl group, an aryl group, and a sulfonyl group.

The beneficial effects of the present invention over the prior art are: for the first time, six functional groups are installed at the 3-O position of 4,6-O-acetone-D-glucal to obtain six new glucal compounds. These compounds not only have academic and potential medicinal chemical value, but can also be conveniently further converted into other new substances, especially intramolecular cyclization or rearrangement reactions can occur.

DETAILED DESCRIPTION

A functionalized D-glucal compound has a general structure VII, and is represented by the following structural formulas VII-a, VII-b, VII-c, VII-d, VII-e and VII-f respectively according to the type of its functional substituent FG:

The present invention provides a method for preparing the functionalized D-glucal compound, and the specific preparation route is:

Specifically, the six functionalized D-glucal compounds are:

其中R基选自-H、烷基、烯基、炔基、芳基中的任一种；The first method is to prepare 3-O-acryloyl-4,6-O-acetone-D-glucal VII-a by condensing 4,6-O-acetone-D-glucal VI with substituted allyl carboxylic acid a, wherein the structural formula of carboxylic acid a is

Wherein the R group is selected from any one of -H, alkyl, alkenyl, alkynyl, and aryl;

其中，R基选自烷基、苄基、烯丙基中的任一种；The second type, 3-O-propenyl ester-4,6-O-acetone foridene-D-glucal (VII-b), is prepared by adding 4,6-O-acetone foridene-D-glucal VI to propargyl ester b, the structural formula of which is

Wherein, the R group is selected from any one of an alkyl group, a benzyl group, and an allyl group;

其中，R基选自-H、烷基、烯基、炔基、芳基中的任一种，X选自Cl、Br、OMs中的任一种。The third type, 3-O-propynyl-4,6-O-acetone-D-glucal (VII-c), is prepared by using 4,6-O-acetone-D-glucal VI and propyne halide c for nucleophilic substitution. The structural formula of propyne halide c is

Wherein, the R group is selected from any one of -H, alkyl, alkenyl, alkynyl, and aryl, and X is selected from any one of Cl, Br, and OMs.

其中R基选自-H、卤素、烷基、烯基、炔基、芳基中的任一种，X基选自F、Cl、Br、OMs中的任一种；The fourth type, 3-O-pyridyl-4,6-O-acetone-D-glucal (VII-d), is prepared by using 4,6-O-acetone-D-glucal VI to perform aromatic nucleophilic substitution with a pyridine halide d. The structural formula of the pyridine halide d is

Wherein the R group is selected from any one of -H, halogen, alkyl, alkenyl, alkynyl, and aryl, and the X group is selected from any one of F, Cl, Br, and OMs;

其中R基选自-H、卤素、烷基、烯基、炔基、芳基、硝基、酯基、醛基中的任一种，X基选自Cl、Br、OMs中的任一种；The fifth type, 3-O-benzyl-4,6-O-acetone-D-glucal (VII-e), is prepared by using 4,6-O-acetone-D-glucal VI and benzyl halide e for nucleophilic substitution. The benzyl halide e has the structural formula

Wherein the R group is selected from any one of -H, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, ester, and aldehyde, and the X group is selected from any one of Cl, Br, and OMs;

The sixth type, 3-O-methylenetriazole-4,6-O-acetone-D-glucal (VII-f), is prepared by a [3+2] cycloaddition reaction of 3-O-propynyl-4,6-O-acetone-D-glucal (VII-c ₁ ) and azide f. The structural formula of azide f is RN ₃ , wherein the R group is selected from any one of an alkyl group, an alkenyl group, an aryl group, and a sulfonyl group.

Example 1

VI (540 mg, 3.01 mmol) was dissolved in 15 mL of anhydrous dichloromethane (DCM), and compound a ₁ (681.0 mg, 3.91 mmol) and 4-dimethylaminopyridine (DMAP) (367.4 mg, 3.01 mmol) were added to the reaction bottle under a nitrogen atmosphere, and then the reaction was cooled to 0°C, 1,3-dicyclohexylcarbodiimide (DCC) (806.69 mg, 3.91 mmol) was added, and finally the reaction was gradually heated to room temperature and reacted overnight. After the reaction was detected by TLC, water was added to quench the reaction, and then extracted with dichloromethane (3x 10 mL), and then extracted with 15 mL of saturated brine, the organic phase was collected and dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure, and quickly passed through column chromatography to obtain VII-a ₁ (566.5 mg) as a white solid with a yield of 55%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.54–7.40(m,3H),7.41–7.27(m,3H),6.88(d,J＝8.7Hz,2H),6.37(dd,J＝6.1,1.4Hz,1H),6.01(d,J＝15.2Hz,1H),5.48(dt,J＝7.8,1 .7Hz,1H),4.81(dd,J＝6.1,2.0Hz,1H),4.12(dd,J＝9.8,7.9Hz,1H),3.98(t,J＝4.5Hz,1H),3.92–3.79(m,2H),1.55(s,3H),1.43(s,3H).

Example 2

VI (626.4 mg, 3.36 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, and then 1,4-diazabicyclo[2.2.2]octane (DABCO) was added under nitrogen protection, followed by slow dropwise addition of b ₁ , and the mixture was reacted at room temperature for 5 h. After the reaction, 20 mL of sodium hydroxide aqueous solution (1 M) was added to the mixture, and the mixture was extracted with ether (3 x 15 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure and purified by silica gel column to obtain VII-b ₁ (660 mg) as a white solid with a yield of 79.9%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.60 (d, J＝12.4Hz, 1H), 6.39 (dd, J＝6.2, 1.2Hz, 1H), 5.33 (d, J＝12.4Hz, 1H), 4.76 (dd, J＝6.2, 1.9Hz, 1H), 4.60 (dt, J＝7.4, 1.7Hz, 1H) ,4.09–3.91(m,2H),3.89–3.74(m,2H),3.69(s,3H),1.51(s,3H),1.43(s,3H).

Example 3

VI (500 mg, 2.69 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and then the reaction flask was cooled to 0°C. Sodium hydride (161.1 mg, 4.03 mmol, 60%) was added under nitrogen protection, and the mixture was reacted at 0°C for 30 minutes, and then c ₁ (0.28 mL, 3.22 mmol) was slowly added to the reaction system, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, ice water was added to the system to quench the reaction, and then ethyl acetate (3 x 15 mL) was used for extraction, and the organic phase was collected and dried with saturated brine (20 mL), and then the organic phase was dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure, and the product was quickly purified by silica gel column to obtain VII-c ₁ (306 mg), a colorless liquid, with a yield of 50%. ¹ H NMR (400MHz, CDCl ₃ ) δ6.30(d,J＝6.2Hz,1H),4.87–4.65(m,1H),4.42–4.16(m,3H),4.03–3.86(m,2H),3.81(t,J＝10.5Hz,1H),3.71(td,J＝10.3,5.6Hz, 1H),2.43(s,1H),1.51(s,3H),1.40(s,3H).

Example 4

VI (300 mg, 1.61 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, evacuated and replaced with nitrogen three times, then cooled to 0°C, sodium hydride (161.1 mg, 4.03 mmol, 60%) was added under nitrogen protection, and then stirred at 0°C for 30 minutes, and then d ₁ was added to the mixture, and reacted at room temperature for 2 hours. After the reaction was completed, 20 mL of water was added to the mixture to quench the reaction, and then the aqueous phase was extracted with ethyl acetate (3x 15 mL), the organic phase was collected, washed with saturated brine (20 mL), and then the organic phase was dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure, and the product was quickly purified by silica gel column to obtain compound VII-d ₁ (376.7 mg), a colorless liquid, with a yield of 75.8%. ¹ H NMR (400MHz, CDCl ₃ ) δ9.16–8.99(m,1H),8.36(dd,J＝9.1,2.8Hz,1H),7.04–6.63(m,1H),6.40(dd,J＝6.1,1.4Hz,1H),5.91–5.64(m,1H),4.89(dd,J＝6.1 ,2.0Hz,1H),4.30–4.17(m,1H),3.95(ddd,J=8.4,6.6,3.5Hz,3H),1.57(s,3H),1.41(s,3H).

Example 5

VI (200 mg, 1.07 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, evacuated and replaced with nitrogen three times, then cooled to 0°C, sodium hydride (85.92 mg, 2.15 mmol, 60%) was added under nitrogen protection, and then stirred at 0°C for 30 minutes, and then e ₁ was added to the mixture, and reacted at room temperature for 2 hours. After the reaction was completed, 20 mL of water was added to the mixture to quench the reaction, and then the aqueous phase was extracted with ethyl acetate (3x 15 mL), the organic phase was collected, washed with saturated brine (20 mL), and then the organic phase was dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure, and the product was quickly purified by silica gel column to obtain compound VII-e ₁ (233 mg), a colorless liquid with a yield of 61%. ¹ H NMR (400 MHz, CDCl ₃ )δ7.53(ddd,J＝4.9,3.1,1.0Hz,2H),7.31(td,J＝7.5,1.1Hz,1H),7.15(dd,J＝7.7,1.6Hz,1H),6.34(dd,J＝6.1,1.6Hz,1H),4.88–4.78(m,2H),4.75–4.68( m,1H),4.2 5(dt,J＝7.3,1.8Hz,1H),4.05(dd,J＝10.3,7.3Hz,1H),3.96(dd,J＝10.8,5.6Hz,1H),3.85(t,J＝10.5Hz,1H),3.76(dd,J＝10.3,5.6Hz,1H),1.49(s,3H),1.4 4(s,3H).

Example 6

TcCu (51.47 mg, 0.27 mmol) was dissolved in 5 mL of anhydrous toluene, and then nitrogen protection was performed. Then, compound VII-c ₁ (500 mg, 2.69 mmol) was dissolved in 15 mL of toluene solution, and compound f ₁ (582.5 mg, 2.95 mmol) was dissolved in 15 mL of toluene solution, and the two were added to thiophene-2-carboxylic acid cuprous acid (TcCu) in sequence, and reacted at room temperature. After the reaction was completed, 20 mL of water was added to the reaction system, and extracted with ethyl acetate (3 x 20 mL), and the organic phase was collected and dried with saturated brine (20 mL), and then the organic phase was dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure, and the product VII-f ₁ (802.3 mg) was quickly purified by silica gel column, and the yield was 71%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.16(s,1H),8.16(s,1H),7.99(d,J＝8.4Hz,2H),7.38(d,J＝8.1Hz,2H),6.33(dd,J＝6.1,1.4Hz,1H),4.98–4.64(m,3H),4.32–4.1 2(m,1H),4.06–3.63(m,5H),2.45(s,3H),2.17(s,1H),1.48(d,J＝13.9Hz,3H),1.45(d,J＝6.3Hz,3H).

The present invention discloses several novel glucal molecules and preparation methods thereof. Specifically, six glucal compounds functionalized on the 3-hydroxyl group and synthesis methods thereof are disclosed. The compounds use the key intermediate 4,6-O-acetone-D-glucal and adopt different reaction technologies to install six different functional groups on the 3-hydroxyl group thereof to obtain six functionalized glucal derivatives. These novel glucal molecules have potential application value in the fields of synthetic chemistry and medicinal chemistry.

Based on the above preferred embodiments of the present invention, the relevant staff can make various changes and modifications without departing from the technical concept of the present invention through the above description. The technical scope of the present invention is not limited to the content in the specification, and its technical scope must be determined according to the scope of the claims.

Claims (10)

1. A functionalized D-glucal compound, characterized in that the functionalized D-glucal compound has a general structure VII, and is represented by the following structural formulas VII-a, VII-b, VII-c, VII-d, VII-e and VII-f respectively according to the type of its functional substituent FG:

2. The functionalized D-glucal compound according to claim 1, wherein one of the compounds is 3-O-acryloyl-4,6-O-acetone-D-glucal (VII-a), and the general structural formula thereof is:

The R group is selected from any one of -H, alkyl, alkenyl, alkynyl and aryl. 3. The functionalized D-glucal compound according to claim 1, wherein one of the compounds is 3-O-propenyl ester-4,6-O-acetone idene-D-glucal (VII-b), and the general structural formula thereof is:

The R group is selected from any one of an alkyl group, a benzyl group, and an allyl group. 4. The functionalized D-glucal compound according to claim 1, wherein one of the compounds is 3-O-propynyl-4,6-O-acetone-D-glucal (VII-c), and the general structural formula thereof is:

The R group is selected from any one of -H, alkyl, alkenyl, alkynyl and aryl. 5. The functionalized D-glucal compound according to claim 1, wherein one of the compounds is 3-O-pyridyl-4,6-O-acetone-D-glucal (VII-d), and the general structural formula thereof is:

Wherein, the R group is selected from any one of -H, halogen, alkyl, alkenyl, alkynyl, and aryl. 6. The functionalized D-glucal compound according to claim 1, wherein one of the compounds is 3-O-benzyl-4,6-O-acetone-D-glucal (VII-e), and the general structural formula thereof is:

Wherein, the R group is selected from any one of -H, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, ester and aldehyde. 7. The functionalized D-glucal compound according to claim 1, wherein one of the compounds is 3-O-methylenetriazole-4,6-O-acetone-D-glucal (VII-f), and the general structural formula thereof is:

The R group is selected from any one of an alkyl group, an alkenyl group, an aryl group, and a sulfonyl group. 8. The method for preparing a functionalized D-glucal compound according to claim 1, characterized in that the preparation route of the functionalized D-glucal compound is:

Among them, 3-O-acryloyl-4,6-O-acetone-D-glucal (VII-a) is prepared by condensing 4,6-O-acetone-D-glucal VI with substituted allyl carboxylic acid a, wherein the structural formula of carboxylic acid a is

Wherein the R group is selected from any one of -H, alkyl, alkenyl, alkynyl, and aryl; 3-O-propenyl ester-4,6-O-acetone formate-D-glucal (VII-b), the preparation method of which is to use 4,6-O-acetone formate-D-glucal VI to add propargyl ester b, the structural formula of propargyl ester b is

The R group is selected from any one of an alkyl group, a benzyl group, and an allyl group. 9. The method for preparing a functionalized D-glucal compound according to claim 1, wherein the preparation route of the functionalized D-glucal compound is:

Among them, 3-O-propynyl-4,6-O-acetone-D-glucal (VII-c) is prepared by using 4,6-O-acetone-D-glucal VI and propyne halide c for nucleophilic substitution, and the structural formula of propyne halide c is

Wherein, the R group is selected from any one of -H, alkyl, alkenyl, alkynyl, and aryl, and X is selected from any one of Cl, Br, and OMs; 3-O-pyridyl-4,6-O-acetone-D-glucal (VII-d), the preparation method of which is to use 4,6-O-acetone-D-glucal VI and pyridine halide d for aromatic nucleophilic substitution, the pyridine halide d has the structural formula

The R group is selected from any one of -H, halogen, alkyl, alkenyl, alkynyl, and aryl, and the X group is selected from any one of F, Cl, Br, and OMs. 10. The method for preparing a functionalized D-glucal compound according to claim 1, characterized in that the preparation route of the functionalized D-glucal compound is:

Among them, 3-O-benzyl-4,6-O-acetone-D-glucal (VII-e) is prepared by using 4,6-O-acetone-D-glucal VI and benzyl halide e for nucleophilic substitution, and the benzyl halide e has the structural formula

Wherein the R group is selected from any one of -H, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, ester, and aldehyde, and the X group is selected from any one of Cl, Br, and OMs; 3-O-methylenetriazole-4,6-O-acetone-D-glucal (VII-f), which is prepared by a [3+2] cycloaddition reaction of 3-O-propynyl-4,6-O-acetone-D-glucal (VII-c ₁ ) and azide f, wherein the structural formula of azide f is RN ₃ , wherein the R group is selected from any one of an alkyl group, an alkenyl group, an aryl group, and a sulfonyl group.