Production method for β-costol and β-costic acid

Abstract

To provide production methods for β-costol and β-costic acid that feature utilization of easily available raw materials and high efficiency.SOLUTION: A production method for β-costol includes: a first step of regioselectively anionizing an allylic position of β-selinene in the presence of an amine and an organic alkali metal compound represented by R-M (where R is an alkyl group or an aryl group, and M is Li, K, or Na); a second step of reacting the anionized reaction product with trialkyl borate to achieve boronation; and a third step of oxidizing and hydrolyzing the boronated compound to yield β-costol.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing β-costol and β-cost acid. [Background technology]

[0002] Phytoalexin is a general term for secondary metabolites with antibacterial activity that are synthesized as defense substances in plants. In recent years, β-costic acid, an oxidized derivative of β-selinene, has been reported as a type of terpene phytoalexin in corn, one of the world's three major cereals along with rice and wheat (Non-Patent Document 1). β-Costic acids have attracted attention due to their effective defensive properties, such as antibacterial activity against pathogens and anti-feeding activity against pests, as well as their application in food preservation.

[0003] In addition, β-costic acid is said to have acaricidal activity against Varroa destructor, a mite that parasitizes honeybees and causes Varroa disease, and shows useful biological activity, but only a very small amount can be obtained from nature. Therefore, in order to conduct detailed research such as activity testing and biosynthesis, and to put it into practical use as an acaricide, a stable supply by chemical synthesis is required (Non-Patent Document 2). It has also been reported that β-costic acid has “anti-trypanosomal protozoan activity that could lead to a treatment for Chagas disease” (Non-Patent Document 3).

[0004] In addition, the synthesis of a racemic form of β-costic acid has been reported (Non-Patent Document 4). In addition, the conversion of β-selinene to β-costic acid using a plant enzyme has been reported (Patent Document 1). Furthermore, the synthesis of an optically active form of β-costic acid has been reported (Non-Patent Document 5). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. WO 2003 / 025193 [Non-patent literature]

[0006] [Non-Patent Document 1] Y. Ding, et al., Plant Physiol., 2017, 175, 1455-1468. [Non-Patent Document 2] K. Sofou, et al., Beilstein J. Org. Chem., 2017, 13, 952-959 [Non-Patent Document 3] VS Londero, et al., Bioorg. Chem., 2020, 95, 103510. [Non-Patent Document 4] JA Marshall, et al., J. Org. Chem., 1966, 31, 2933-2941. [Non-Patent Document 5] Kenji Nemoto, Hirosato Takikawa, and Yoshisuke Ogura (66th Symposium on Fragrance, Terpene and Essential Oil Chemistry, November 2022, Okinawa, and the 48th Annual Meeting of the Pesticide Science Society of Japan, March 2023, Tokyo) Summary of the Invention [Problem to be solved by the invention]

[0007] However, the above-mentioned methods have problems in that the raw materials are difficult to obtain or expensive, and the efficiency (yield) is low. Therefore, there is a demand for the development of a method for efficiently producing β-cositol and β-costic acid using easily available and inexpensive raw materials. In addition, β-cositol can be easily converted to β-costic acid by oxidation. Therefore, an object of the present invention is to provide a method for producing β-costol and β-cost acid efficiently using easily available raw materials. [Means for solving the problem]

[0008] As a result of examining the above problems, the present inventors have devised a method for efficiently converting easily available β-selinene as a starting material into β-costol and β-cost acid. That is, in order to solve the above-mentioned problems, the method for producing β-costol of the present invention comprises: a first step of regioselectively anionizing the allylic position of β-selinene in the presence of an amine and an organic alkali metal compound represented by RM (wherein R is an alkyl group or an aryl group, and M is Li, K, or Na); a second step of reacting the anionized reactant with a trialkyl borate to borate it; and a third step of oxidizing and hydrolyzing the boronized product to produce β-costol.

[0009] In the method for producing β-costor of the present invention, it is preferable that M is K or Na, and the amine is a secondary amine. In the method for producing β-costor of the present invention, the organic alkali metal compound is preferably produced by reacting an alkoxide of K or Na with RM (wherein M is Li). In the method for producing β-costor of the present invention, it is preferable that M is Li and the amine is a tertiary amine.

[0010] The method for producing β-cost acid of the present invention comprises oxidizing the β-costol produced by the method for producing β-costol to produce β-cost acid. Effect of the Invention

[0011] According to the present invention, β-selinene, which is easily available, can be used as a starting material and efficiently converted into β-costol and β-cost acid. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Hereinafter, an embodiment of the present invention will be described. A method for producing β-costol according to an embodiment of the present invention includes a first step of regioselectively anionizing the allylic position of β-selinene in the presence of an amine and an organic alkali metal compound represented by RM (wherein R is an alkyl group or an aryl group, and M is Li, K, or Na); a second step of boronizing the anionized reactant by reacting it with a trialkyl borate; and a third step of oxidizing and hydrolyzing the boronized product to produce β-costol.

[0013] <First embodiment> In the method for producing β-costor according to the first embodiment of the present invention, the organic alkali metal compound is RK, and the amine is a secondary amine. Moreover, RK is produced by reacting potassium alkoxide with R-Li. It can be difficult to obtain RK as a reagent, but it can be easily and inexpensively obtained by reacting potassium alkoxide with R-Li.

[0014] The reaction scheme of an example of the anionization in the first step using TMP (2,2,6,6-tetramethylpiperidine) as the secondary amine, t-BuOK as the potassium alkoxide, and n-butyllithium as R-Li is as follows. [ka]

[0015] β-Selinene has two double bonds, and if the carbon next to one of these double bonds (allylic position) could be regioselectively oxidized, it could lead to β-costol, etc., and the researchers discovered an anionization method for this purpose. In the above anionization, the hydrogen atom of the terminal methyl group of the four allylic positions of β-selinene is regioselectively abstracted with the following strong base to convert it into anion.

[0016] Here, the reaction of t-BuOK with n-butyllithium produces butylpotassium, a strong base. However, in this embodiment, instead of butylpotassium, butylpotassium reacts with TMP, a secondary amine, to produce KTMP (potassium 2,2,6,6-tetramethylpiperidide), an even stronger base, which abstracts hydrogen from the methyl group at the end of β-selinene, converting it into an anion. In other words, potassium amides such as KTMP ultimately convert β-selinene into anions.

[0017] In addition to TMP, secondary amines include diisopropylamine, which is used to make the so-called LDA (lithium diisopropylamide, made from BuLi and diisopropylamine).

[0018] The anionization in the first step is preferably carried out by cooling the reaction system (using a dry ice acetone bath or a cooling device). Specifically, the reaction system is preferably carried out at, for example, -78°C to 0°C.

[0019] In an embodiment of the present invention, the amine can usually be used in a ratio of 0.1 to 2.0 moles per mole of RM. Furthermore, the solvent that can be used in the embodiment of the present invention is not limited, but for example, ether solvents such as THF (tetrahydrofuran), diethyl ether, and DME (dimethoxyethane) can be suitably used.

[0020] As shown in the following examples, the yield of β-costor was 80% in the first embodiment using RK and 24% in the second embodiment using R-Li, and thus RK was a higher yield. This is thought to be because K is a stronger base than Li.

[0021] When trimethyl borate is used as the trialkyl borate, the overall reaction scheme from the first step to the third step is as follows. [ka]

[0022] In the second step, boronation, a C—B bond is formed in the anionized reactant to produce a dialkyl boronate such as diisopropyl boronate or dimethyl boronate. Examples of trialkyl borates include triisopropyl borate, trimethyl borate, triethyl borate, etc. For boronization, the reaction system after anionization may be cooled (for example, to −78° C. to 0° C., preferably −78° C.) and trialkyl borate may be added.

[0023] In the third step, oxidation and hydrolysis of the dialkyl boronate converts the CB bond into a CO bond. Hydrogen peroxide can be suitably used as the oxidizing agent (peroxide). The oxidation and hydrolysis of the dialkyl borate may be carried out in a reaction system at, for example, −78° C. to 40° C., preferably at room temperature.

[0024] <Second embodiment> In the method for producing β-costor according to the second embodiment of the present invention, the organic alkali metal compound is R-Li, and the amine is a tertiary amine.

[0025] The reaction scheme of an example of the anionization in the first step using N,N,N'N'-tetramethylethylenediamine (TMEDA) as the tertiary amine and n-butyllithium as R-Li is as follows. [ka]

[0026] In the above reaction scheme, the first step of anionization is lithiation. The allylic position of β-selinene is reactive, so when an organolithium reagent such as n-butyllithium is reacted with it, the hydrogen at the allylic position is replaced by lithium, resulting in the production of a lithiation product.

[0027] Specifically, butyllithium (n-butyllithium) is most commonly used as R-Li, but methyllithium, sec-butyllithium, tert-butyllithium, etc. may also be used. As the tertiary amine, an amine having a chelating effect such as a diamine is particularly preferable. Specifically, N,N,N',N'-tetramethylethylenediamine (TMEDA) can be used as the diamine, but tetramethyl-1,3-propanediamine (TMPDA) or the like can also be used.

[0028] In the second embodiment, the second and third steps are similar to those in the first embodiment, and therefore the description thereof will be omitted.

[0029] In the method for producing β-cost acid according to an embodiment of the present invention, β-costol produced by the above-mentioned method for producing β-costol is oxidized to produce β-cost acid.

[0030] In the present invention, for example, as shown in the following reaction formula, a method can be exemplified in which β-costol is converted into β-costal, and then β-costal is converted into β-costic acid. In addition, other known methods may be used to oxidize β-costol to produce β-cost acid (NA Clanton et al., Org. Lett., 2023, 25, 277-281, etc.). [ka]

[0031] <Conversion of β-costal to β-costal> The oxidation method is not limited as long as β-cositol is oxidized. For example, in addition to the Parrick-Döring oxidation using SO3·Py as shown in the above formula, reactions using DMSO as an oxidizing agent such as Swern oxidation can be used, and Dess-Martin oxidation can also be used. In addition to these, various oxidation methods such as chromic acid oxidation (PCC oxidation) and oxygen oxidation (TEMPO-Cu catalyst) can be used. (NA Clanton et al., Org. Lett., 2023, 25, 277-281. uses oxygen oxidation (TEMPO-Cu catalyst).) The reaction temperature may be any known condition depending on the oxidation method, such as extremely low temperature, ice-cooling, room temperature, or heating.

[0032] <Conversion of β-costal to β-costic acid> The oxidation method is not limited as long as β-costal is oxidized. For example, various oxidation reactions such as Pinnick oxidation (Claus-Pinnick oxidation) using an oxidizing agent (sodium chlorite) and a buffer (phosphate buffer, sodium dihydrogen phosphate) as shown in the above formula, Jones oxidation, PDC oxidation, etc. can be used. The solvent may be, for example, a mixed solvent of water and tert-butyl alcohol. In the Pinnic oxidation, it is advisable to add a scavenger to the reaction system to trap hypochlorous acid, such as 2-methyl-2-butene. EXAMPLES

[0033] The present invention will be illustrated by the following examples, but is not intended to limit the present invention. β-Selinene was isolated and purified from celery seed oil. The main components of celery seed oil are limonene and β-selinene, and only limonene was removed by vacuum concentration. Pure β-selinene was then obtained by purifying it using silica gel chromatography.

[0034] NMR spectra were measured using a JNM-ECZ500R spectrometer ( 1 H NMR: 500.2 MHz, 13C NMR: 125.8 MHz). 1 H and 13 Reported chemical shifts for C NMR spectra are based on the internal standard tetramethylsilane (δ H = 0) or the solvent signal (CDCl3δ C = 77.0) was reported as the standard. Silica gel column chromatography was performed using Kanto Chemical silica gel 60 N (spherical, neutral, 40-50 mm). Thin-layer chromatography was performed using Merck Kieselgel 60 F. 254 was used. Anhydrous solvents (dimethyl sulfoxide (DMSO), dichloromethane (CH2Cl2), and tetrahydrofuran (THF)) were purchased from Fujifilm Wako Pure Chemical Industries, Ltd. and used as received.

[0035] Example 1: First embodiment Under an argon atmosphere, n-BuLi (2.6 M hexane solution, 1.2 mL, 3.00 mmol) was added to a solution of dry THF (15 mL) and t-BuOK (1 M THF solution, 3.0 mL, 3.00 mmol) at -78 °C, and the mixture was stirred for 15 minutes. Next, 2,2,6,6-tetramethylpiperidine (TMP, 520 μL, 3.06 mmol) was added and stirred for 15 minutes, after which β-selinene (300 mg, 1.47 mmol) was added and stirred for 1 hour. i PrO)3B (690 μL, 3.12 mmol) was added, and the mixture was slowly cooled to room temperature. Then, 30% H2O2aq. (680 μL, 6.00 mmol) was added, and the mixture was stirred at room temperature for 30 minutes.

[0036] After that, the mixture was cooled to 0 °C, water (15 mL) was added, and the mixture was extracted with EtOAc. The extracted organic layer was washed with 1 M HCl aqueous solution, saturated Na2S2O3 aqueous solution, and brine, dried over MgSO4, suction filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by flash column chromatography (Hexane : EtOAc = 90 : 10, silica gel 40 g) to obtain β-costol (259 mg, 80%).

[0037] β-costol: 1 H NMR (500.2 MHz, CDCl3 / TMS): δ= 5.06-5.03 (m, 1H), 4.97-4.93 (m, 1H), 4.73-4.69 (m, 1H), 4.44-4.41 (m, 1H), 4.15 (d, 2H, J = 6.3 Hz), 2.34-2.27 (m, 1H), 2.16-1.90 (m, 2H), 1.86-1.80 (dd, 2H, J = 1.1, 12.0 Hz), 1.65-1.57 (m, 4H), 1.54-1.42 (m, 3H), 1.38-1.22 (m, 4H), 0.73 (s, 3H) ppm; 13 C NMR (125.8 MHz, CDCl3 / TMS): δ= 154.1, 150.8, 107.7, 105.4, 65.2, 49.9, 41.8, 41.5, 41.1, 36.8, 35.9, 29.9, 27.3, 23.4, 16.3 ppm.

[0038] <Example 2: Second embodiment> Under an argon atmosphere, n-BuLi (1.6 M in hexane, 7.5 mL, 12 mmol) was added with N,N,N′,N′-tetramethylethylenediamine (TMEDA, 1.6 mL, 11 mmol) and β-selinene (469 mg, 2.30 mmol) under ice cooling, and stirred at room temperature for 17 hours. After that, the mixture was cooled to -78 °C, and (MeO)3B (400 μL, 12.9 mmol) was added dropwise. Then, 30% H2O2aq. (1.80 mL, 17.9 mmol) was added dropwise at -30 °C, and the mixture was stirred at room temperature for 3 hours, after which water (3 mL) was added and the mixture was extracted with EtOAc. The extracted organic layer was washed with saturated Na2S2O3 aqueous solution and brine, dried over MgSO4, suction filtered, and concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by flash column chromatography (Hexane: EtOAc = 85:15, silica gel 40 g) to give β-costol (123 mg, 24%) and β-selinene (326 mg, 69%).

[0039] β-costol: 1 H NMR (500.2 MHz, CDCl3 / TMS): δ= 5.06-5.03 (m, 1H), 4.97-4.93 (m, 1H), 4.73-4.69 (m, 1H), 4.44-4.41 (m, 1H), 4.15 (d, 2H, J = 6.3 Hz), 2.34-2.27 (m, 1H), 2.16-1.90 (m, 2H), 1.86-1.80 (dd, 2H, J = 1.1, 12.0 Hz), 1.65-1.57 (m, 4H), 1.54-1.42 (m, 3H), 1.38-1.22 (m, 4H), 0.73 (s, 3H) ppm; 13 C NMR (125.8 MHz, CDCl3 / TMS): δ= 154.1, 150.8, 107.7, 105.4, 65.2, 49.9, 41.8, 41.5, 41.1, 36.8, 35.9, 29.9, 27.3, 23.4, 16.3 ppm.

[0040] <Conversion of β-costal to β-costal> Under an argon atmosphere, Et3N (4.60 mL, 33.0 mmol) was added to a solution of β-costol (1.04 g, 4.72 mmol) in dry DMSO (24 mL) and dry CHCl (24 mL) at room temperature. After cooling on ice, SO3·pyridine (2.25 g, 14.2 mmol) was added and the mixture was stirred for 1 hour under ice cooling. Water (260 mL) was then added and the mixture was extracted with EtOAc. The extracted organic layer was washed with brine, dried over MgSO4, suction filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (Hexane:Toluene = 50:50, silica gel 160 g) to obtain β-costal (979 mg, 95%).

[0041] β-costal: 1 H NMR (500.2 MHz, CDCl3 / TMS): δ= 9.53 (s, 1H), 6.92 (s, 1H), 5.98 (s, 1H), 4.70 (d, 1H, J = 1.7 Hz), 4.38 (d, 1H, J = 1.1 Hz), 2.60-2.52 (m, 1H), 2.33-2.27 (m, 1H), 2.05-1.97 (m, 1H), 1.94-1.87 (dd, 1H, J = 1.1, 12.5 Hz), 1.65-1.56 (m, 4H), 1.54-1.48 (dt, 1H, J = 2.8, 12.0 Hz), 1.48-1.39 (m, 2H), 1.39-1.24 (m, 3H), 0.75 (s, 3H) ppm; 13 C NMR (125.8 MHz, CDCl3 / TMS): δ= 194.7, 155.1, 150.6, 132.9, 105.4, 49.7, 41.8, 40.9, 36.8, 36.3, 35.9, 29.4, 26.9, 23.4, 16.3 ppm.

[0042] <Conversion of β-costal to β-costic acid> Next, to a solution of the β-costal (979 mg, 4.48 mmol) and 2-methyl-2-butene (12.5 g, 179 mmol) obtained above in t-BuOH (95 mL) was slowly added a solution of NaClO2 (3.39 g, 37.5 mmol) and NaH2PO4·2H2O (4.02 mg, 25.8 mmol) in water (33 mL) at room temperature, and the mixture was stirred for 1 hour and 20 minutes, and then extracted with EtOAc. The extracted organic layer was washed with brine, dried over MgSO4, suction filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (Hexane: EtOAc = 85:15, silica gel 100 g) to quantitatively obtain β-costic acid (1.05 g).

[0043] β-costic acid: 1 H NMR (500.2 MHz, CDCl3 / TMS): δ= 6.32 (s, 1H), 5.69 (s, 1H), 4.71 (d, 1H, J = 1.1 Hz), 4.43-4.39 (m, 1H), 2.58-2.49 (m, 1H), 2.34-2.27 (m, 1H), 2.05-1.96 (m, 1H), 1.92-1.86 (dd, 1H, J = 1.1, 12.0 Hz), 1.71-1.56 (m, 5H), 1.55-1.50 (m, 1H), 1.49-1.40 (m, 2H), 1.38-1.23 (m, 3H), 0.74 (s, 3H) ppm; 13 C NMR (125.8 MHz, CDCl3 / TMS): δ= 172.8, 150.6, 145.2, 125.0, 105.5, 49.8, 41.8, 41.0, 39.3, 36.8, 35.9, 29.9, 27.2, 23.4, 16.4 ppm.

Claims

1. a first step of regioselectively anionizing the allylic position of β-selinene in the presence of an amine and an organic alkali metal compound represented by R-M (wherein R is an alkyl group or an aryl group, and M is Li, K, or Na); a second step of reacting the anionized reactant with a trialkyl borate to borate the reactant; a third step of oxidizing and hydrolyzing the boron compound to produce β-cositol; The method for producing β-costor, comprising the steps of:

2. The method for producing β-costor according to claim 1, wherein M is K or Na, and the amine is a secondary amine.

3. 3. The method for producing β-costor according to claim 2, wherein the organic alkali metal compound is produced by reacting an alkoxide of K or Na with RM (wherein M is Li).

4. The method for producing β-costor according to claim 1, wherein M is Li and the amine is a tertiary amine.

5. A method for producing β-costoic acid, comprising oxidizing the β-costoic acid produced by the method for producing β-costoic acid according to claim 1 or 2.

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