KR20230040441A - Total and stereoselective synthesis of cudraisoflavone J - Google Patents

Abstract

The present invention relates to a method for chemically manufacturing cudraisoflavone J by using Claisen rearrangement and Suzuki coupling reaction by using 2',4',6'-trihydroxyacetophenone as a starting material. In addition, the present invention relates to a method capable of stereoselectively synthesizing cudraisoflavone J using stereoselective acylation mediated by lipase or BTM.

Description

Total and stereoselective synthesis of cudraisoflavone J {Total and stereoselective synthesis of cudraisoflavone J}

The present invention relates to a method for the total synthesis of the racemate of quad isoflavone J, a method for the stereoselective synthesis of enantiomers of quad isoflavone J, and intermediate compounds useful for the synthesis of quad isoflavone J.

Cudrania tricuspidata , a perennial plant of the Moraceae family, is widely used as a traditional medicine or health supplement in East Asia. In China, Cudrania mulberry has been used for the treatment of eczema, mumps, tuberculosis, bruises, and acute arthritis since ancient times. In Korea, juice, jam, alcoholic beverages, health supplements, and other health functional products are made from the fruits of the Cudrania mulberry tree. Currently, the medicinal and economic value of Cudrania mulberry encourages many studies related to plant chemistry and pharmacology.

Flavonoids, including flavones, flavanones, and isoflavones, are the main physiologically active components of Cudrania mulberry, and show remarkable anti-inflammatory, antioxidant, anti-tumor, hepatoprotective, neuroprotective and anti-obesity effects. In 2015, an isoflavone group was isolated from the fruit of Cudrania japonica, and a 3-hydroxy-2,2-dimethyldihydropyran group substituted on an aromatic ring was found (Fig. 1). Among them, cudraisoflavone J, which has the following structure, shows the strongest activity against 6-hydroxydopamine (6-OHDA)-induced apoptosis in human neurofibroma SH-SY5Y cells and has an EC ₅₀ value of 0.5 μM It has been reported (see Non-Patent Document 1).

Quadraisoflavone J

In view of the above experimental results, cudraisoflavone J can be a candidate drug for treating neurodegenerative diseases such as Parkinson's disease, and it is predicted that many studies will be conducted in the future.

However, until now, cudraisoflavone J has been extracted and used from the fruit of Cudrania mulberry (Patent Document 1), and a method for synthesizing it has not yet been known. Accordingly, the present inventors have developed a method for preparing quadraisoflavone J by organic synthesis.

Korean Patent Publication No. 2015-0124140 (published date: 2015. 11. 05)

Hiep et al., Phytochemistry. 2015, 111, 141-148

Accordingly, one object of the present invention is to provide a method for the total synthesis of quadraisoflavone J.

Another object of the present invention is to provide a method for the stereoselective synthesis of quadraisoflavone J.

Another object of the present invention is to provide intermediate compounds useful for the synthesis of quadraisoflavone J.

In order to achieve the above object, the present invention

(1) obtaining a compound of Formula 2 by selectively protecting the hydroxy group of 2',4',6'-trihydroxyacetophenone of Formula 1;

(2) obtaining a compound of Formula 3 by prenylating the hydroxyl group of the compound of Formula 2;

(3) obtaining a compound of Formula 4 from the compound of Formula 3 by Claisen rearrangement;

(4) obtaining a compound of Formula 5 by selectively deprotecting the hydroxy group of the compound of Formula 4;

(5) obtaining a chroman compound of Formula 6 from the compound of Formula 5 by a cyclization reaction via epoxide;

(6) obtaining a 2-en-ketone compound of Formula 7 from the chroman compound of Formula 6 through a condensation reaction;

(7) cyclizing the 2-enketone compound of Formula 7 to obtain a chromone compound of Formula 8;

(8) obtaining a compound of Formula 9 from the chromone compound of Formula 8 by a Suzuki coupling reaction; and

(9) Provided is a method for the total synthesis of quadrisoflavone J, comprising the step of deprotecting the protected hydroxyl group of the compound of formula 9 to obtain quadraisoflavone J of formula 10:

In the above formula,

R are each independently a hydroxy protecting group;

X is a leaving group.

In addition, the present invention provides (a) adding lipase to the racemic compound of Formula 9 to obtain a compound of Formula 11a; and

(b) a stereoselective synthesis method of quadraisoflavone J using lipase, comprising the step of obtaining a compound of formula 10a from the compound of formula 11a:

[Formula 9]

[Formula 10a]

[Formula 11a]

In the above formula,

R is a hydroxy protecting group.

In addition, the present invention is (a) adding ( S )- or ( R )-benzotetramisole (BTM) to the racemic compound of Formula 9 to obtain a compound of Formula 12a or 12b, respectively ; and

(b) obtaining a compound of Formula 10a or 10b from the compound of Formula 12a or 12b, respectively.

A method for the stereoselective synthesis of quadraisoflavone J via benzotetraamisole (BTM) is provided:

[Formula 9]

[Formula 10a]

[Formula 10b]

[Formula 12a]

[Formula 12b]

In the above formula,

R is a hydroxy protecting group.

Furthermore, the present invention provides novel intermediate compounds useful for the synthesis of quadraisoflavone J.

The present invention uses 2', 4', 6'-trihydroxyacetophenone as a starting material for cudraisoflavone J, a natural compound obtained by extraction from the fruit of the Cudrania mulberry tree, as a starting material, and the Claisen relocation reaction and Suzuki It can be chemically synthesized using a coupling reaction. In addition, the present invention enables the stereoselective synthesis of quad isoflavone J using lipase or BTM-mediated stereoselective acylation. Therefore, if it is confirmed that cudraisoflavone J, one of the candidate drugs for the treatment of degenerative neurological diseases such as Parkinson's disease, exhibits excellent therapeutic effects clinically, the method for synthesizing cudraisoflavone J developed in the present invention can be usefully used. There will be.

Figure 1 shows a cudrysoflavone derivative, which is a natural compound containing a 3-hydroxy-2,2-dimethyldihydropyran structure isolated from the fruit of Kudira mulberry.
FIG. 2 shows ¹ H NMR of (+)-quadraisoflavone J (compound of Formula 10a) stereoselectively synthesized according to the present invention.
3 shows ¹³ C NMR of (+)-quadraisoflavone J (compound of Formula 10a) stereoselectively synthesized according to the present invention.
4 shows chiral HPLC data of (+)-quadraisoflavone J (compound of Formula 10a) stereoselectively synthesized according to the present invention.
5 shows ¹ H NMR of (-)-quadraisoflavone J (compound of Formula 10b) stereoselectively synthesized according to the present invention.
6 shows ¹³ C NMR of (-)-quadraisoflavone J (compound of Formula 10b) stereoselectively synthesized according to the present invention.
7 shows chiral HPLC data of (-)-quadraisoflavone J (compound of Formula 10b) stereoselectively synthesized according to the present invention.
8 shows ¹ H NMR of a compound of formula (11-1)a stereoselectively synthesized according to the present invention.
9 shows ¹³ C NMR of a compound of formula (11-1)a stereoselectively synthesized according to the present invention.
10 shows chiral HPLC data of a compound of formula (11-1)a synthesized stereoselectively according to the present invention.
11 shows ¹ H NMR of a compound of formula (12-1)a stereoselectively synthesized according to the present invention.
12 shows ¹³ C NMR of a compound of formula (12-1)a synthesized stereoselectively according to the present invention.
13 shows ¹ H NMR of a compound of formula (12-1)b synthesized stereoselectively according to the present invention.
14 shows ¹³ C NMR of a compound of formula (12-1)b stereoselectively synthesized according to the present invention.
15 shows chiral HPLC data of a compound of formula (12-1)a and a compound of formula (12-1)b stereoselectively synthesized according to the present invention.

Hereinafter, the present invention will be described in more detail.

In the present invention, the term "hydroxy protecting group" refers to a moiety that temporarily blocks a hydroxy reactive site in a compound. Generally, this is done to selectively carry out chemical reactions or stabilize hydroxyl groups at other reactive sites of the multifunctional compound. Hydroxy protecting groups can be selectively removed by a chemical reaction. A “hydroxy protecting group” includes, but is not limited to, groups that form ester, ether or silyl-protecting groups. For example, the formed ester protecting group is acetyl (Ac), benzoyl (Bz) or pivaloyl (Piv), but is not limited thereto. For example, the ether protecting group formed is methyl, benzyl (Bn), methoxyethoxymethyl ether (MEM), trityl (Tr), para-methoxybenzyl (PMB), dimethoxy trityl (DMT), methoxymethyl ether (MOM), tetrahydropyranyl (THP), or ethoxyethyl ether (EE), but is not limited thereto. For example, the silyl protecting group formed is trimethylsilyl (TMS), triethylsilyl (TES), tert -butyldimethylsilyl (TBDMS or TBS), tri-iso-propylsilyloxymethyl (TOM), or triisopropylsilyl (TIPS ether). ), but is not limited thereto. Other protecting groups formed are para-bromobenzoyl, para-nitrobenzoyl, triisopropylsilyl (TIPS), benzyloxymethyl (BOM), p-methoxy-benzyloxymethyl (PMBM), [(3,4-dimethoxy benzyl)oxy]-methyl (DMBM), methylthiomethyl (MTM), or 2-(trimethyl-silyl)-ethoxymethyl (SEM); other protecting groups may be used.

The term "hydroxy deprotecting agent" according to the present invention means a reagent capable of cleaving a hydroxy protecting group to form a free hydroxy group. Examples of such hydroxy deprotecting reagents are boron tribromide, tetra- n -butylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate, hydrogen bromide, hydrogen fluoride, hydrogen fluoride pyridine, silicon tetrafluoride , hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, trifluoroacetic acid, pyridinium p -toluenesulfonate, p -toluenesulfonic acid, formic acid, periodic acid, palladium on carbon, and bases It doesn't work.

The term "acid" according to the present invention includes inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Organic acids include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, carbonic acid, succinic acid, benzoic acid, p-toluenesulfonic acid, and the like.

The term "base" according to the present invention includes alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine, N-methyl morpholine, 2, 6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, or mixtures thereof.

The term "solvent" according to the present invention includes, but is not limited to, a single solvent or solvent mixture, such as water, esters, alcohols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, hydrocarbon solvents, or mixtures thereof. it is not going to be

the present invention

(1) obtaining a compound of Formula 2 by selectively protecting the hydroxy group of 2',4',6'-trihydroxyacetophenone of Formula 1;

(2) prenylating the hydroxy group of the compound of formula 2 to obtain the compound of formula 3;

(3) obtaining the compound of Formula 4 from the compound of Formula 3 by a Claisen displacement reaction;

(4) obtaining a compound of Formula 5 by selectively deprotecting the hydroxy group of the compound of Formula 4;

(5) obtaining a chroman compound of Formula 6 from the compound of Formula 5 by a cyclization reaction via epoxide;

(6) obtaining a 2-enketone compound of Formula 7 from the chroman compound of Formula 6 through a condensation reaction;

(7) cyclizing the 2-enketone compound of Formula 7 to obtain a chromone compound of Formula 8;

(8) obtaining a compound of formula 9 from the chromone compound of formula 8 through a Suzuki coupling reaction; and

(9) A method for the total synthesis of quadraisoflavone J comprising the step of deprotecting the protected hydroxyl group of the compound of formula 9 to obtain quadraisoflavone J of formula 10:

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

In the above formula,

R are each independently a hydroxy protecting group;

X is a leaving group;

The method for the total synthesis of quadraisoflavone J according to the present invention is specifically shown in Reaction Scheme 1 below.

[Scheme 1] Total synthesis of quadraisoflavone J

In the above formula,

each R is a hydroxy protecting group;

X is a leaving group;

As shown in Reaction Scheme 1, the total synthesis method of quadraisoflavone J according to the present invention uses a Claisen displacement reaction and a Suzuki coupling reaction.

In the total synthesis method of quadraisoflavone J according to the present invention, step (1) selectively protects the hydroxy group of 2', 4', 6'-trihydroxyacetophenone of formula 1 to obtain a compound of formula 2 As a step of obtaining, at this time, various hydroxy protecting groups known in the art can be used for selective protection of the hydroxy group. One of the two hydroxy groups present at the ortho position together with the hydroxy group present at the para position of the aldehyde group can be selectively protected by adjusting the amount of the hydroxy protecting group, the reaction conditions, and the like. Examples of the hydroxy group protecting group include MOM (methoxymethyl), tetrahydropyranyl ether (THP ether), t -butyl ether, allyl ether, benzyl ether (Bn-OR), t -butyldimethylsilyl ether ( t -butyldimethylsilyl ether: TBDMS ether), t -butyldiphenylsilyl ether ( t- butyldiphenylsilyl ether: TBDPS ether), acetic acid ester, pivalic acid ester, benzoic acid ester, acetonide , benzylidene acetal, etc. may be used, but is not limited thereto.

In one embodiment of the present invention, the hydroxy protecting group, namely R, may be a methoxymethyl (MOM) group. Specifically, after slowly adding 2.5-fold equivalent of N,N -diisopropylethylamine (DIPEA) to 2',4',6'-trihydroxyacetophenone in the solvent (DCM), 2.3-fold equivalent of By adding MOMCl dropwise, it is possible to selectively protect the remaining two hydroxyl groups, leaving only one hydroxyl group at the ortho position of the aldehyde.

Step (2) is a step of obtaining a compound of Formula 3 by prenylating the hydroxyl group of the compound of Formula 2, which may be performed by adding a known compound providing a prenyl group. Specifically, to prenylate the hydroxyl group of the compound of Formula 2, prenyl bromide, prenyl chloride, etc. may be used, but is not limited thereto.

In one embodiment of the present invention, step (2) may be to obtain a compound of formula 3 by reacting the compound of formula 2 with prenyl bromide. The step (2) may be carried out under basic conditions. Examples of the base used for basic conditions include potassium carbonate, lithium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, 1,8- Diazabicyclo (5.4.0) undec-7-ene (DBU), N, N -diisopropylethylamine (DIPEA), triethanolamine (TEA), pyridine, sodium hydride or potassium ter-butoxide (K[OC (CH ₃ ) ₃ ]) and the like, and these can be used individually or in combination of two or more.

Step (3) is a step of obtaining the compound of Formula 4 from the compound of Formula 3 by a Claisen transfer reaction, and various reagents known to cause a Claisen transfer reaction may be used. Specifically, the Claisen displacement reaction may be performed by irradiating microwaves in N, N -diethylaniline, etc., but is not limited thereto. In one embodiment of the present invention, step (3) may be to obtain a compound of formula 4 by irradiating the compound of formula 3 with microwaves in N,N-diethylanil.

Step (4) is a step of obtaining a compound of Formula 5 by selectively deprotecting the hydroxy group in the compound of Formula 4, wherein the selective deprotection of the hydroxy group is performed by adding dichloromethane (DCM) and alcohol or sugar It can be performed according to methods known in the art. In one embodiment of the present invention, step (4) may be performed by adding dichloromethane (DCM) and an alcohol (eg methanol or ethanol) to the compound of formula 4 under acidic conditions to produce a compound of formula 5 there is. At this time, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, acetic acid, or trifluoroacetic acid may be used as the acid condition, and these may be used alone or in combination of two or more.

Step (5) is a step of obtaining a chroman compound of Formula 6 from the compound of Formula 5 by a cyclization reaction via epoxide, wherein the cyclization reaction via epoxide is m -chloroperoxybenzoic acid ( m -CPBA), hydrogen peroxide (H ₂ O ₂ ) is added to form an epoxide at the double bond site present in the reactant, and then the epoxide ring is ring-opened and bonded to the unprotected hydroxyl group on the phenyl ring to form a chroman ring. In one embodiment of the present invention, in step (5), a chroman compound of Formula 6 may be obtained by adding m -chloroperoxybenzoic acid ( m -CPBA), montmorillonite K10 and DCM to the compound of Formula 5.

Step (6) is a step for obtaining a 2-enketone compound of Formula 7 from the chroman compound of Formula 6 through a condensation reaction, and aims to increase the number of carbon atoms in the aldehyde group bonded to the chroman parent nucleus in Formula 6. This can be done by adding reagents known in the art for use. For example, dimethylacetamide, N , N -dimethylformamide dimethyl acetal (DMF-DMA), N , N -dimethylformamide diethyl acetal (DMF-DEA), etc. can be used to increase one carbon. may be, but is not limited thereto.

The leaving group represented by X in the compound of Formula 7 can be used without limitation as long as it is a residue that allows the cyclization reaction to proceed in the next reaction step (7) and can be left. For example, the leaving group may be halo (eg fluoro, bromo, iodo or chloro), -OH, -SH, -OSO ₃ H, -SO ₃ H, -OSO ₂ (C _1-6 alkyl) (eg: -OSO ₂ CH ₃ ), -N(C _1-6 alkyl)(C _1-6 alkyl) (eg: -N(CH ₃ ) ₂ ) including residues such as

In one embodiment of the present invention, in step (6), the chroman compound of Formula 6 is condensed with N , N -dimethylformamide dimethyl acetal (DMF-DMA) to obtain an enaminoketone compound of Formula 13 below.

In the above formula,

R is a hydroxy protecting group.

Step (7) is a step of obtaining a chromone compound of Formula 8 by cyclization of the 2-enketone compound of Formula 7, and various reagents known in the art may be used for the cyclization reaction. For example, N -bromosuccinimide, bromine, iodine chloride, chlorosuccinimide, etc. may be added to the cyclization reaction, which is limited thereto It is not. In one embodiment of the present invention, step (7) may generate a chromone compound of Formula 8 by adding I ₂ and an alcohol (eg, methanol or ethanol) to the enaminoketone compound of Formula 13 below.

Step (8) is a step of obtaining the compound of Formula 9 from the chromone compound of Formula 8 through a Suzuki coupling reaction, and may be performed using various Suzuki coupling reagents known in the art. For example, reagents used in the Suzuki coupling reaction include, but are not limited to, boronic acid, organohalides, palladium catalysts and bases. In one embodiment of the present invention, step (8) may produce a compound of formula 9 by a Suzuki coupling reaction between a chromone compound of formula 8 and 4-methoxyphenylboronic acid.

Step (9) is a step of deprotecting the protected hydroxy group of the compound of Formula 9 to produce quadraisoflavone J of Formula 10, and known reagents known to be usable for deprotection of the hydroxy group can be used. For example, hydroxy deprotection easily occurs under acidic conditions, and is not limited to reagents used under acidic conditions. In one embodiment of the present invention, step (9) may add dichloromethane (DCM) and methanol to the compound of formula 9 under acidic conditions to produce quadraisoflavone J of formula 10.

In one embodiment of the present invention, when the hydroxy protecting group, namely R, is a MOM (methoxymethyl) group and the compound of Formula 7 is an enamino ketone compound of Formula 13, the total synthesis process of cudraisoflavone J is shown in Scheme 2 below: is specifically shown in

[Scheme 2] Total synthesis of quadraisoflavone J

(a) MOMCl, DIPEA, DCM, 0 ℃ ~ room temperature, yield 90%

(b) prenyl bromide, K ₂ CO ₃ , acetone, reflux, yield 60%

(c) N,N -diethylaniline, microwave, yield 89%

(d) 2N HCl, MeOH, yield 93%

(e) m -CPBA, M-K10, DCM, yield 71%

(f) DMF-DMA, reflux, yield 83%

(g) I ₂ , MeOH, room temperature, yield 91%

(h) 4-methoxyphenylboronic acid, Pd(OAc) ₂ , K ₂ CO ₃ , PEG-400, yield 85%

(i) 3N HCl, DCM, MeOH, reflux, yield 73%

Specifically, 2',4', a commercially available starting material, was prepared by treatment with methoxymethyl chloride (MOMCl) and N,N -diisopropylethylamine (DIPEA) in dry dichloromethane (DCM). The compound of Formula 2-1 can be prepared by regioselectively protecting the hydroxyl group of ,6'-trihydroxyacetophenone.

O-prenylation of a compound of formula 2-1 in the presence of a base K ₂ CO ₃ to prepare a compound of intermediate 3-1, which can undergo para-Clizen rearrangement under microwave to give intermediate 4-1. there is. Selective deprotection of intermediate 4-1 under acidic conditions (2N HCl) affords mono-MOM protected compound 5-1. In addition, the compound of Formula 5-1 was treated with m -chloroperoxybenzoic acid ( m -CPBA) followed by in situ cyclization reaction catalyzed by montmorillonite K10 clay (M-K10) A chroman compound of Chemical Formula 6-1 can be obtained by The chroman compound of Formula 6-1 is condensed with N,N -dimethylformamide dimethyl acetal (DMF-DMA) to obtain an enaminoketone compound of Formula 7-1, and the compound of Formula _7-1 is Cyclization can produce a white solid chromone compound of Formula 8-1.

A compound of Formula 9-1 can be prepared by a Suzuki coupling reaction between a chromone compound of Formula 8-1 and 4-methoxyphenylboronic acid. Finally, the desired (±)-cudraisoflavone J (compound of Formula 10) can be produced in an overall yield of 15% by deprotecting MOM under acidic conditions (3N HCl). The ¹ H and ¹³ C NMR data of quadraisoflavone J produced according to the synthesis method were found to be consistent with those reported for natural compounds.

In one embodiment of the present invention, the present invention

(1) obtaining a compound of Formula 2-1 by selectively protecting the hydroxy group of 2',4',6'-trihydroxyacetophenone of Formula 1;

(2) prenylating the hydroxy group of the compound of Formula 2-1 to obtain the compound of Formula 3-1;

(3) obtaining a compound of Formula 4-1 from the compound of Formula 3-1 by Claisen rearrangement;

(4) obtaining a compound of Formula 5-1 by selectively deprotecting the hydroxy group of the compound of Formula 4-1;

(5) obtaining a chroman compound of Formula 6-1 from the compound of Formula 5-1 by a cyclization reaction via epoxide;

(6) obtaining an enaminoketone compound of Formula 7-1 from a chroman compound of Formula 6-1 through a condensation reaction;

(7) cyclizing the enaminoketone compound of Formula 7-1 to obtain a chromone compound of Formula 8-1;

(8) obtaining a compound of Formula 9-1 from a chromone compound of Formula 8-1 through a Suzuki coupling reaction; and

(9) A method for total synthesis of quad isoflavone J, comprising the step of deprotecting the protected hydroxyl group of the compound of formula 9-1 to obtain quad isoflavone J of formula 10:

[Formula 1]

[Formula 2-1]

[Formula 3-1]

[Formula 4-1]

[Formula 5-1]

[Formula 6-1]

[Formula 7-1]

[Formula 8-1]

[Formula 9-1]

[Formula 10]

In the above formula,

MOM is a methoxymethyl group.

Since quadraisoflavone J (compound of Chemical Formula 10) produced by the above-described total synthesis process of quadraisoflavone J is a racemate, a method for selectively synthesizing its stereoisomer is required.

Accordingly, the present invention provides a method for preparing optically active quadraisoflavone J by stereoselective acylation using a lipase biocatalyst.

Specifically, the present invention

(a) adding lipase to the racemic compound of Formula 9 to obtain a compound of Formula 11a; and

(b) a stereoselective synthesis method of quadraisoflavone J using lipase, comprising the step of obtaining a compound of formula 10a from the compound of formula 11a:

[Formula 9]

[Formula 10a]

[Formula 11a]

In the above formula,

R is a hydroxy protecting group.

The step (a) is a step of converting the racemic compound of Formula 9 into a stereoisomeric compound of Formula 11a using lipase, and as a lipase, Novozyme 435 (Novozym 435), Candida antarctica ( Candida antarctica ) Lipase, lipase derived from Pseudomonas cepacia , lipase derived from Rhizomucor miehei , lipase derived from Burkholderia cepacia , etc. can be used, It is not limited to this. Specifically, a lipase derived from Vercoolderia cepacia can be used as a lipase as a catalyst, and more specifically, Amano PS, a lipase derived from Vercoolderia cepacia, can be used.

In the step (a), diethyl ether, t -butylmethyl ether (TBME), hexane, toluene, tetrahydrofuran (THF), ethyl acetate (EtOAc), or a mixture thereof may be used as the organic solvent. It is not limited.

Groups that can be used as R hydroxy protecting groups are as described above.

In one embodiment of the present invention, a method for preparing optically active quadraisoflavone J by stereoselective acylation using lipase as a catalyst can be specifically represented by Reaction Scheme 3 below.

[Scheme 3]

(a) rac -9 (100 mg), catalyst (100 mg), vinyl acetate (1 mL), room temperature, 72 hours

(b) K ₂ CO ₃ (4 eq), 3M HCl, MeOH, reflux.

In addition, the present invention provides a method for stereoselectively synthesizing quadraisoflavone J using benzotetramisole (BTM) as a medium.

Specifically, the present invention

(a) adding ( S )- or ( R )-benzotetramisole (BTM) to the racemic compound of Formula 9 to obtain a compound of Formula 12a or 12b, respectively; and

(b) obtaining a compound of Formula 10a or 10b from the compound of Formula 12a or 12b, respectively.

It relates to a method for the stereoselective synthesis of quadraisoflavone J mediated by benzotetraamisole (BTM):

[Formula 9]

[Formula 10a]

[Formula 10b]

[Formula 12a]

[Formula 12b]

In the above formula,

R is a hydroxy protecting group.

Groups that can be used as R hydroxy protecting groups are as described above.

In one embodiment of the present invention, the stereoselective synthesis method of cudraisoflavone J using benzotetraamisole as a medium can be specifically represented by Reaction Scheme 4 below.

[Scheme 4]

(a) rac -9 (1 eq), Catalyst: ( S )-BTM or ( R )-BTM (1 eq), isobutyric anhydride (1 eq), DCM, room temperature, 2 hours

(b) K ₂ CO ₃ (4 equivalents), 3M HCl, MeOH, reflux

In addition, the present invention provides a novel intermediate compound useful for producing quadraisoflavone J. Specifically, the present invention relates to a compound having the structure of Formula 6-1:

[Formula 6-1]

In the above formula,

MOM is a methoxymethyl group.

The present invention relates to a compound having the structure of Formula 7-1:

[Formula 7-1]

In the above formula,

MOM is a methoxymethyl group.

The present invention relates to a compound having the structure of Formula 8-1:

[Formula 8-1]

In the above formula,

MOM is a methoxymethyl group.

The present invention relates to a compound having the structure of Formula 9-1:

[Formula 9-1]

In the above formula,

MOM is a methoxymethyl group.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are intended to illustrate the present invention by way of example, and the scope of the present invention is not limited by these examples.

[Example]

General Experimental Procedure

All commercial chemicals were of reagent grade and were used without further purification. All reactions were carried out in an argon atmosphere dried in a flame-dried glassware. Melting points were measured using a Thermo Scientific 9200 apparatus. Optical rotation was recorded on a JASCO P-2200 digital polarimeter. IR spectra were recorded on an FTIR Nicolet iS5 spectrometer (Thermo Fisher Scientific, Madison, WI, USA). ¹ H NMR spectrum was measured using a Varian (400 MHz) spectrometer (Varian Medical Systems, Inc., Palo Alto, CA, USA). Multiplicity is indicated by abbreviations such as singlet (s), doublet (d), doublet of doublets (dd), triplet (t), quartet (q), multiplet (m), and broadt (b). did Chemical shift values were expressed as δ values (ppm), and coupling constants (J) were expressed in Hertz. ¹³ C NMR spectra were recorded on a Varian (100 MHz) spectrometer. Chemical shifts are given in ppm downwards of tetramethylsilane (internal standard) and coupling constants are in hertz. Mass spectra were recorded using high-resolution mass spectrometry (HRMS, ESI-MS) obtained on a G2 QTOF mass spectrometer (Waters Corporation, Milford, MA, USA). The product was purified by column or flash column chromatography (Biotage, Sweden) using silica gel 60 (230400 mesh Kieselgel 60). The reaction was also monitored using thin layer chromatography on 0.25 mm silica plates (E. Merck, silica gel 60 F254). Spots were detected under ultraviolet (UV) light and stained with a carbonized film after immersion in anisaldehyde or basic KMnO ₄ solution. The optical purity of the synthesized compounds was established through chiral high-performance liquid chromatography (HPLC) analysis: Chiralpak IG-3 (4.6 Х 150, 3), hexane/EtOH/MeOH = 85:10:5, 1.5 mL/min and λ = 280 nm.

Example 1. Total synthesis of racemic quadraisoflavone J

Step 1: 1- (2-hydroxy-4,6-bis (methoxymethoxy) phenyl) ethanone (2-1)

A solution of 1-(2,4,6-trihydroxyphenyl)ethanone (1.0 g, 5.95 mmol) in DCM (20 ml) was cooled to 0 °C and DIPEA (2.6 mL, 14.88 mmol) was added slowly. After 20 minutes, MOMCl (1.0 mL, 13.69 mmol) was added dropwise. The mixture was held at 0° C. for 20 minutes and then brought to room temperature. After 5 h, the reaction mixture was cooled with H ₂ O (20.0 mL) then extracted with DCM (3 Х 30 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient, n-hexane/EtOAc = 19:19:1) to give compound 2-1 (1.37 g, yield 90%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ): δ 13.73 (s, 1H), 6.27 (d, J = 2.4 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.26 (s, 2H), 5.17 (s, 2H), 3.52 (s, 3H), 3.47 (s, 3H), 2.66 (s, 3H).

Step 2: 1-(2,4-bis(methoxymethoxy)-6-((3-methylbut-2-en-1-yl)oxy)-phenyl)ethanone (3-1)

To a solution containing compound 2-1 (210.0 mg, 0.64 mmol) and K ₂ CO ₃ (265.0 mg, 1.92 mmol) in acetone (10 mL) was added prenyl bromide (0.11 mL, 0.96 mmol); Refluxed in N ₂ for 21.5 hours. The reaction mixture was cooled to room temperature, filtered over EtOAc and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 9:1) to obtain O-prenyl compound 3-1 (185.1 mg, yield 60%) as a colorless oil.

^1H NMR (400 MHz, CDCl ₃ ): δ 6.43 (d, J = 1.2 Hz, 1H), 6.30 (d, J = 1.2 Hz, 1H), 5.39 (t, J = 6.6 Hz, 1H), 5.15 ( s, 2H), 5.14 (s, 2H), 4.49 (d, J = 6.8 Hz, 2H), 3.47 (s, 3H), 3.45 (s, 3H), 2.47 (s, 3H), 1.75 (s, 3H) ), 1.70 (s, 3H).

Step 3: 1- (6-hydroxy-2,4-bis (methoxymethoxy) -3- (3-methylbut-2-en-1-yl) phenyl) ethanone (4-1)

A solution of compound 3-1 (180.1 mg, 0.55 mmol) in N,N-diethylaniline (2 mL) was placed in a tube suitable for microwave irradiation and irradiated at 210°C for 1.0 hour. The mixture was washed with aqueous 10% HCl (5 mL), H ₂ O, and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 19:1) to give the title compound 4-1 (160.0 mg, yield 89%) as a colorless oil.

^1H NMR (400 MHz, CDCl ₃ ): δ 12.95 (s, 1H), 6.47 (s, 1H), 5.22 (s, 2H), 5.15 (t, J = 5.8 Hz, 1H), 4.96 (s, 2H) ), 3.52 (s, 3H), 3.46 (s, 3H), 3.31 (d, J = 6.0 Hz, 2H), 2.70 (s, 3H), 1.77 (s, 3H), 1.69 (s, 3H).

Step 4: 1- (2,6-dihydroxy-4- (methoxymethoxy) -3- (methylbut-2-en-1-yl) phenyl) ethanone (5-1)

Compound 4-1 (2.70 g, 10.0 mmol) in MeOH (50 mL) was cooled to 0 °C. Then, 2N HCl (10 mL) was added dropwise. After addition, the reaction mixture was heated to 40° C. and stirred for 3 hours. The reaction was cooled with NaHCO ₃ (aqueous) and then extracted with EtOAc (3 Х 20 mL). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane/EtOAc = 8:1) to obtain compound 5-1 (2.16 g, yield 93%) as an off-white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.18 (s, 1H), 5.20 (s, 2H), 5.18 (s, 1H), 3.47 (s, 3H), 3.35 (d, J = 7.2 Hz, 2H ), 2.67 (s, 3H), 1.83 (s, 3H), 1.76 (s, 3H).

Step 5: 1- (3,7-dihydroxy-5- (methoxymethoxy) -2,2-dimethylchroman-8-yl) ethanone (6-1)

To a solution of compound 5-1 (2.16 g, 7.69 mmol) in anhydrous DCM (30.0 mL) was added 75% m -CPBA (1.80 g, 7.80 mmol) at 0 °C and the mixture was stirred at room temperature for 20 min. After compound 5-1 (TLC) disappeared completely, montmorillonite K10 (2.1 g) was added and the mixture was further stirred at room temperature for 30 minutes. The mixture was filtered and washed with EtOAc. The organic layer was washed with saturated Na ₂ CO ₃ (aqueous), H ₂ O, and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 2:1) to give compound 6-1 (1.61 g, yield 71%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 13.71 (s, 1H), 6.23 (s, 1H), 5.20 (s, 2H), 3.81 (q, J = 5.9 Hz, 1H), 3.48 (s, 3H) ), 2.86 (dd, J = 17.1 and 5.2 Hz, 1H), 2.65 (s, 3H), 2.62 (dd, J = 16.0 and 4.0 Hz, merged, 1H), 1.82 (d, J = 7.2 Hz, 1H) , 1.42 (s, 3H), 1.39 (s, 3H).

Step 6: ( E )-1-(3,7-dihydroxy-5-(methoxymethoxy)-2,2-dimethylchroman-8-yl)-3-(dimethylamino)prop-2-en-1-one (7-1)

After dissolving compound 6-1 (1.3 g, 4.39 mmol) in DMF, the solution was heated to 75°C in an oil bath. DMF-DMA (0.7 mL, 5.26 mmol) was then added dropwise to the flask. The mixture was stirred for 4.5 hours and then cooled to room temperature. The reaction was cooled with H ₂ O and the mixture was extracted with EtOAc (3 Х 10 mL). The extract was washed with H ₂ O, dried, filtered, and concentrated to give a dark yellow oil which was purified by silica gel column chromatography (n-hexane/EtOAc = 3:2) to give cubic yellow crystals (1.27 g, yield 83%). of which the title compound was obtained.

^1H NMR (400 MHz, CDCl ₃ ): δ 7.91 (d, J = 12.4 Hz, 1H), 6.44 (d, J = 12.4 Hz, 1H), 6.22 (s, 1H), 5.18 (s, 2H), 3.80 (q, J = 6.1 Hz, 1H), 3.47 (s, 3H), 3.16 (s, 3H), 2.92 (s, 3H), 2.88 (dd, J = 17.2 and 5.6 Hz, 1H), 2.64 (dd , J = 17.0 and 5.4 Hz, 1H), 1.75 (d, J = 8.0 Hz, 1H), 1.43 (s, 3H), 1.38 (s, 3H).

Step 7: 3-Hydroxy-9-iodo-5-(methoxymethoxy)-2,2-dimethyl-3,4-dihydropyrano[2,3- f ]chromen-10(2 H ) - on (8-1)

A mixture of compound 7-1 (170.0 mg, 0.48 mmol) in MeOH (5 mL) was stirred at room temperature for 10.5 h and then concentrated in vacuo to give a reddish black residue. To remove residual I ₂ , the mixture was treated with saturated aqueous Na ₂ S ₂ O ₃ until it became clear. The mixture was extracted with DCM and the resulting off-white solid was purified by silica gel chromatography (n-hexane/EtOAc = 3:2) to give the title compound as a white solid (107.1 mg, yield 91%).

^1H NMR (400 MHz, CDCl ₃ ): δ 8.07 (s, 1H), 6.65 (s, 1H), 5.26 (s, 2H), 3.86 (q, J = 8.0 Hz, 1H), 3.50 (s, 3H) ), 2.92 (dd, J = 17.5 and 5.2 Hz, 1H), 2.71 (dd, J = 17.5 and 5.6 Hz, 1H), 2.22 (d, J = 7.0 Hz, 1H), 1.44 (s, 3H), 1.41 (s, 3H).

Step 8: 3-Hydroxy-5-(methoxymethoxy)-9-(4-methoxyphenyl)-2,2-dimethyl-3,4-dihydropyrano[2,3- f ]chromen-10(2 H )-on (9-1)

Aryl 12 (1.0 g, 2.31 mmol), 4-methyphenylboronic acid (527.8 mg, 3.47 mmol), Pd(OAc) ₂ (10.4 mg, 2 mol %), K ₂ CO ₃ (480.1 mg , 3.47 mmol) and PEG-400 (8.0 g) were stirred at 45° C. for a period of time until the starting material was completely consumed while monitoring by gas chromatography (GC). The mixture was added to brine (15 mL) and extracted 4 times with Et ₂ O (15 mL of 4 Х). After concentration of the solvent in vacuo, the crude product was purified by silica gel column chromatography (n-hexane/EtOAc = 1:1) to obtain Compound 9-1 as a white solid (808.1 mg, yield 85%).

^1H NMR (400 MHz, CDCl ₃ ): δ 7.73 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H), 5.27 (s, 2H), 3.86 (q, J = 6.0 Hz, 1H), 3.82 (s, 3H), 3.51 (s, 3H), 2.93 (dd, J = 17.4 and 5.2 Hz, 1H), 2.72 (dd , J = 17.5 and 5.5 Hz, 1H), 2.13 (d, J = 7.4 Hz, 1H), 1.44 (s, 3H), 1.40 (s, 3H).

Step 9: 3,5-dihydroxy-9-(4-methoxyphenyl)-2,2-dimethyl-3,4-dihydropyrano[2,3- f ]chromen-10(2 H ) - on (10)

To a solution of compound 9-1 (195.5 mg, 0.47 mmol) in anhydrous MeOH (3.0 mL) was added 3N HCl (3.0 mL) and refluxed in N ₂ for 40 min. The mixture was cooled to room temperature, then quenched with water and extracted three times with EtOAc (3 Х 10 mL). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 1:1) to give the title compound (127.4 mg, yield 73%) as an off-white solid.

^1H NMR (400 MHz, DMSO- d ₆ ): δ 8.10 (s, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.45 (s, 1H) ), 5.21 (d, J = 4.6 Hz, 1H), 3.82 (s, 3H), 3.69 (q, J = 6.7 Hz, 1H), 2.81 (dd, J = 17.2 and 5.5 Hz, 1H), 2.45 (dd , J = 16.8 and 7.3 Hz, 1H), 1.34 (s, 3H), 1.23 (s, 3H).

Example 2. rac Stereoselective synthesis of quadraisoflavone J using lipase-mediated stereoselective acylation of -(9-1)

(a) rac- (9-1) (100 mg), catalyst (100 mg), vinyl acetate (1 mL), room temperature, 72 hours

(b) K ₂ CO ₃ (4 eq), 3M HCl, MeOH, reflux.

Step 1: rac Lipase-mediated stereoselective acylation of -(9-1)

Lipase (100 mg) was added to the rac- (9-1) (100 mg) solution. The suspension was stirred at room temperature. After a certain period of time, vinyl acetate (1 mL) was added, and the reaction mixture was stirred with a magnetic stirrer and observed by TLC. After about 50% conversion, the lipase was filtered, the solvent was evaporated, and the resulting gum was purified by silica gel column chromatography (n-hexane/EtOAc = 2:1) to obtain the target compound.

( S )-5-(methoxymethoxy)-9-(4-methoxyphenyl)-2,2-dimethyl-10-oxo-2,3,4,10-tetrahydropyrano[2,3- f ]Chromen-3-yl acetate ((11-1)a) (99.0% ee ). white solid. Yield 12%.

^1H NMR (400 MHz, CDCl ₃ ): δ 7.73 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.67 (s, 1H), 5.295.24 (m, 2H), 5.06 (t, J = 5.3 Hz, 1H), 3.82 (s, 3H), 3.51 (s, 3H), 3.03 (dd, J = 17.8 and 5.5 Hz, 1H), 2.72 (dd, J = 17.8 and 5.1 Hz, 1H), 2.08 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H).

Step 2: Stereoselective synthesis of quadraisoflavone J

( S )-3,5-dihydroxy-9-(4-methoxyphenyl)-2,2-dimethyl-3,4-dihydropyranol[2,3- f ]chromen-10(2 H ) -on (10a) (97% ee )

To a solution of compound (11-1)a (45.9 mg, 0.10 mmol) in MeOH (4 mL) in a 25 mL flask was added K ₂ CO ₃ (55.8 mg, 0.40 mmol) and the reaction mixture was stirred overnight. When the Ac group was gently removed, 3M HCl (3 mL) was added and the solution was refluxed for 30 min. At this time, the MOM group is easily separated. MeOH was then evaporated and the residue diluted with EtOAc, washed with saturated NaHCO ₃ , H ₂ O and brine, dried and concentrated. The crude product was purified by silica gel column chromatography (n-hexane/EtOAc = 1:1) to obtain compound 10a (24.0 mg, yield 65%) as an off-white amorphous powder.

^1H NMR (400 MHz, DMSO- d ₆ ): δ 8.05 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.40 (s, 1H) ), 5.16 (d, J = 4.4 Hz, 1H), 3.78 (s, 3H), 3.64 (q, J = 5.7 Hz, 1H), 2.76 (dd, J = 17.2 and 5.6 Hz, 1H), 2.40 (dd , J = 17.2 and 7.2 Hz, 1H), 1.30 (s, 3H), 1.18 (s, 3H).

The experimental results are shown in Table 1 below.

catalyst menstruum Conversion rate [%] optical rotation ^* ee _11-1 [%] ^** ee ₁₀ [%] ^** Novozyme 435 TBME <1 - - - Novozyme 435 EtOAC <1 - - - Amano PS THF 12 +47.6 99 97

^* Optical rotations were recorded on a JACO P-2200 digital polarimeter.

^** ee was measured by chiral phase HPLC using a Chiralpak IG-3 (4.6Х150, 3) column.

Example 3. Compound rac Stereoselective synthesis of quadraisoflavone J using BTM-mediated stereoselective acylation of -9

(a) rac- (9-1) (1 eq), Catalyst: ( S )-BTM or ( R )-BTM (1 eq), isobutyric anhydride (1 eq), DCM, room temperature, 2 hours

(b) K ₂ CO ₃ (4 equivalents), 3M HCl, MeOH, reflux

Step 1: Compound rac -General procedure for BTM mediated stereoselective acylation of (9-1)

Catalyst (0.1 equiv) and compound 9-1 (1.0 equiv) were dissolved in DCM. After adding isobutyric anhydride (1.1 equivalent), the reaction vessel was capped and stirred under argon. The reaction was observed by TLC. When the reaction appeared complete, MeOH was added and then the reaction was stirred for an additional 30 minutes. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc = 2:1) to give the desired compound.

( S )-5-(methoxymethoxy)-9-(4-methoxyphenyl)-2,2-dimethyl-10-oxo-2,3,4,10-tetrahydropyrano[2,3- f ]chromen-3-yl isobutyrate ((12-1)a) (81% ee )

( S )-BTM was used as a catalyst. white solid. Yield 26%.

^1H NMR (400 MHz, CDCl ₃ ): δ 7.73 (s, 1H), 7.46 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.67 (s, 1H), 5.27 (s, 2H), 5.03 (t, J = 5.9 Hz, 1H), 3.82 (s, 3H), 3.50 (s, 3H), 3.05 (dd, J = 17.6 and 5.6 Hz, 1H), 2.65 (dd , J = 17.6 and 6.1 Hz, 1H), 2.602.53 (m, 1H), 1.43 (s, 3H), 1.40 (s, 3H), 1.18 (d, J = 7.0 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H).

( R )-5-(methoxymethoxy)-9-(4-methoxyphenyl)-2,2-dimethyl-10-oxo-2,3,4,10-tetrahydropyrano[2,3- f ]chromen-3-yl isobutyrate ((12-1)b) (88% ee ).

( R )-BTM was used as a catalyst. white solid. Yield 23%.

^1H NMR (400 MHz, CDCl ₃ ): δ 7.73 (s, 1H), 7.46 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.67 (s, 1H), 5.27 (s, 2H), 5.03 (t, J = 5.9 Hz, 1H), 3.82 (s, 3H), 3.50 (s, 3H), 3.05 (dd, J = 17.6 and 5.6 Hz, 1H), 2.65 (dd , J = 17.6 and 6.1 Hz, 1H), 2.602.53 (m, 1H), 1.43 (s, 3H), 1.40 (s, 3H), 1.18 (d, J = 7.0 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H).

Step 2: Stereoselective synthesis of quadraisoflavone J

A compound of Formula 10a and a compound of Formula 10b were prepared from the compound of Formula (12-1)a and the compound of Formula (12-1)b, respectively, through the same process as in Step 2 of Example 2.

( S )-3,5-dihydroxy-9-(4-methoxyphenyl)-2,2-dimethyl-3,4-dihydropyranol[2,3- f ]chromen-10(2 H ) -on (10a) (78% ee )

^1H NMR (400 MHz, DMSO- d ₆ ): δ 8.05 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.40 (s, 1H) ), 5.16 (d, J = 4.4 Hz, 1H), 3.78 (s, 3H), 3.64 (q, J = 5.7 Hz, 1H), 2.76 (dd, J = 17.2 and 5.6 Hz, 1H), 2.40 (dd , J = 17.2 and 7.2 Hz, 1H), 1.30 (s, 3H), 1.18 (s, 3H).

( R )-3,5-dihydroxy-9-(4-methoxyphenyl)-2,2-dimethyl-3,4-dihydropyranol[2,3- f ]chromen-10(2 H ) -on (10b) (88% ee )

^1H NMR (400 MHz, DMSO- d ₆ ): δ 8.05 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.41 (s, 1H) ), 5.17 (d, J = 4.8 Hz, 1H), 3.78 (s, 3H), 3.64 (q, J = 5.6 Hz, 1H), 2.77 (dd, J = 17.0 and 5.4 Hz, 1H), 2.41 (dd , J = 17.2 and 7.2 Hz, 1H), 1.30 (s, 3H), 1.19 (s, 3H).

The experimental results are shown in Table 2 below.

catalyst product Conversion rate [%] optical rotation ^* ee _12-11 [%] ^** ee ₁₀ [%] ^** ( S )-BTM (12-1)a 26 +45.4 81 78 ( R )-BTM (12-1)b 23 -46.8 88 88

^* Optical rotations were recorded on a JACO P-2200 digital polarimeter.

^** ee was measured by chiral phase HPLC using a Chiralpak IG-3 (4.6Х150, 3) column.

Step 3: Compounds 10a and 10b ( S )- and ( R ) - Preparation of MTPA ester derivatives

The absolute configuration of the C-2″ position of the compound of Formula 10a and the compound of Formula 10b was confirmed by Mosher's method using MTPA ester (methoxy- α- (trifluoromethyl)phenylacetyl acid ester). .

First, 2.0 mg compound 10a in 900 μL of pyridine- d ₅ was transferred into clean NMR tubes in two portions. ( _R ) -()- α -methoxy- α- (trifluoromethyl)phenylacetyl chloride (( R )-( ) -α- Methoxy- α- (trifluoromethyl)phenylacetyl (MTPA) chloride) (20 μL ) and ( S )-(+)- α -MTPA chloride (20 μL ) were added to each NMR tube. The solution was then carefully mixed. The tube was left at 50° C. for 12 hours. ¹ H NMR data were obtained directly from the reaction NMR tube. An ambiguous array of ¹ H NMR data was used for one-dimensional nuclear Overhauser effect spectroscopy (1D NOESY) experiments. The same procedure was performed to obtain esters of ( S )- and ( R )-MTPA compound 10b (10bs and 10br).

( S )-MTPA ester of compound 10a (compound 10as): ¹ H NMR (500 MHz, pyridine- d ₅ ) δ _H 5.56 (t, J = 5.0 Hz, 1H, H-2″), 3.29 (overlap, 1H , H-1″a), 3.01 (dd, J = 15.0, 5.0 Hz, 1H, H _b -1″), 1.58 (s, 3H, 4″-Me), 1.53 (s, 3H, 5″-Me ).

( R )-MTPA ester of compound 10a (compound 10ar): ¹ H NMR (500 MHz, pyridine- d ₅ ) δ _H 5.60 (t, J = 5.0 Hz, 1H, 2″), 3.37 (overlap, 1H, H _a -1″), 3.10 (dd, J = 15.0 and 5.0 Hz, 1H, H _b -1″), 1.51 (s, 3H, 4″-Me), 1.45 (s, 3H, 5″-Me).

( S )-MTPA ester of compound 10b (compound 10bs): ¹ H NMR (500 MHz, pyridine- d ₅ ) δ _H 5.60 (t, J = 5.0 Hz, 1H, H-2″), 3.33 (overlap, 1H , H _a -1″), 3.11 (dd, J = 15.0 and 5.0 Hz, 1H, H _b -1″), 1.51 (s, 3H, 4″-Me), 1.45 (s, 3H, 5″-Me ).

( R )-MTPA ester of compound 10b (compound 10br): ¹ H NMR (500 MHz, pyridine- d ₅ ) δ _H 5.60 (t, J = 5.0 Hz, 1H, H-2″), 3.29 (overlap, 1H , H _a -1″), 3.02 (dd, J = 15.0 and 5.0 Hz, 1H, H _b -1″), 1.59 (s, 3H, 4″-Me), 1.53 (s, 3H, 5″-Me ).

The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the test examples described above should be understood as illustrative in all respects and not limiting.

Claims (16)

(1) obtaining a compound of Formula 2 by selectively protecting the hydroxy group of 2',4',6'-trihydroxyacetophenone of Formula 1;
(2) obtaining a compound of Formula 3 by prenylating the hydroxyl group of the compound of Formula 2;
(3) obtaining a compound of Formula 4 from the compound of Formula 3 by Claisen rearrangement;
(4) obtaining a compound of Formula 5 by selectively deprotecting the hydroxy group of the compound of Formula 4;
(5) obtaining a chroman compound of Formula 6 from the compound of Formula 5 by a cyclization reaction via epoxide;
(6) obtaining a 2-en-ketone compound of Formula 7 from the chroman compound of Formula 6 through a condensation reaction;
(7) cyclizing the 2-enketone compound of Formula 7 to obtain a chromone compound of Formula 8;
(8) obtaining a compound of Formula 9 from the chromone compound of Formula 8 by a Suzuki coupling reaction; and
(9) A method for the total synthesis of cudraisoflavone J comprising the step of deprotecting the protected hydroxyl group of the compound of formula 9 to obtain cudraisoflavone J of formula 10:
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

In the above formula,
R are each independently a hydroxy protecting group;
X is a leaving group;
According to claim 1,
A method for the total synthesis of quadraisoflavone J, wherein the hydroxy protecting group is methoxymethyl (MOM).
According to claim 1,
In step (2), the compound of formula 2 is reacted with prenyl bromide to obtain the compound of formula 3.
According to claim 1,
In step (3), the compound of formula 3 is irradiated with microwaves in N ,N -diethylaniline to obtain the compound of formula 4.
According to claim 1,
In step (5), a chroman compound of formula 6 is obtained by adding m -chloroperoxybenzoic acid ( m -CPBA) and montmorillonite K10 to the compound of formula 5.
According to claim 1,
Step (6) is the total synthesis of quadrisoflavone J, which is condensation of the chroman compound of formula 6 with N , N -dimethylformamide dimethyl acetal (DMF-DMA) to obtain an enaminoketone compound of formula 13 below. method.
[Formula 13]

In the above formula,
R is a hydroxy protecting group.
According to claim 1,
In step (7), a chromone compound of Formula 8 is produced by adding I ₂ and methanol to an enaminoketone compound of Formula 13 below.
[Formula 13]

In the above formula,
R is a hydroxy protecting group.
According to claim 1,
Step (8) is a method for the total synthesis of quadraisoflavone J, wherein the compound of formula 9 is produced by a Suzuki coupling reaction between the chromone compound of formula 8 and 4-methoxyphenylboronic acid.
According to claim 1,
Step (9) is a process for the total synthesis of quadrisoflavones J, wherein dichloromethane (DCM) and methanol are added to the compound of formula 9 under acidic conditions to produce quadraisoflavone J of formula 10:
(a) adding lipase to the racemic compound of Formula 9 to obtain a compound of Formula 11a; and
(b) a stereoselective synthesis method of quadraisoflavone J using lipase, comprising the step of obtaining a compound of formula 10a from the compound of formula 11a:
[Formula 9]

[Formula 10a]

[Formula 11a]

In the above formula,
R is a hydroxy protecting group.
According to claim 10,
A method for stereoselective synthesis of quadraisoflavone J, wherein the lipase is a lipase derived from Vercoolderia cepacia.
(a) adding ( S )- or ( R )-benzotetramisole (BTM) to the racemic compound of Formula 9 to obtain a compound of Formula 12a or 12b, respectively; and
(b) obtaining a compound of Formula 10a or 10b from the compound of Formula 12a or 12b, respectively.
Method for stereoselective synthesis of cudraisoflavone J via benzotetraamisole (BTM):
[Formula 9]

[Formula 10a]

[Formula 10b]

[Formula 12a]

[Formula 12b]

In the above formula,
R is a hydroxy protecting group.
A compound having a structure represented by Formula 6-1:
[Formula 6-1]

In the above formula,
MOM is methoxymethyl.
A compound having a structure represented by Formula 7-1:
[Formula 7-1]

In the above formula,
MOM is methoxymethyl.
A compound having a structure represented by Formula 8-1:
[Formula 8-1]

In the above formula,
MOM is methoxymethyl.
A compound having a structure represented by Formula 9-1:
[Formula 9-1]

In the above formula,
MOM is a methoxymethyl group.

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