Preparation method of chiral trans-2, 5-disubstituted tetrahydrofuran ring product

Abstract

The invention discloses a preparation method of a chiral trans-2, 5-disubstituted tetrahydrofuran ring product, and belongs to the technical field of asymmetric catalytic organic synthesis. The preparation method comprises the following steps: mixing acrylate or beta-aryl / alkyl olefine acid ester with a cinchona alkali-derived phase transfer catalyst in an organic solvent, and sequentially adding acid, potassium permanganate and a small amount of additive. And reaction: after the initial raw materials completely react, filtering the reaction mixture. And then evaporating the solvent, and quickly purifying by using a silica gel column to obtain the chiral tetrahydrofuran ring compound with high enantioselectivity. According to the present invention, the efficient asymmetric synthesis of the chiral trans-2, 5-disubstituted tetrahydrofuran ring product is achieved, the new idea and the new method are provided for the synthesis of the chiral tetrahydrofuran ring structure, and the application range of the substrate is broadened. The method can be applied to synthesis of the esculentin C14-C23 fragment, reaction conditions in each step are mild, and the method has the advantages of easiness in purification, simplicity in operation and the like.

Description

Technical Field

[0001] The invention relates to the field of organic asymmetric catalysis, and in particular to a method for synthesizing a chiral trans-2,5-disubstituted tetrahydrofuran ring product. Background Art

[0002] Chiral trans-2,5-disubstituted tetrahydrofuran ring products are common structural units in many natural products and drugs. This structure has a wide range of applications in the field of medicinal chemistry, among which the more common natural products are (+)-cis-solamin, (+)-cis-sylvaticin, etc. Chiral 2,5-disubstituted tetrahydrofuran ring compounds exist in the synthesis of biologically active drug molecule intermediates, such as the anticancer drug Eribulin. This anticancer drug was originally synthesized from Halichondrin B extracted from marine organisms through structural and biological optimization. It has a complex non-peptide drug structure and contains 19 chiral carbon atoms. The commercial synthesis route is as long as 62 steps and has always been called the "Mount Everest" of chemical synthesis. Therefore, in the pharmaceutical industry, the development of economical and efficient single optically active isomers has become a trend.

[0003] Many methods have been developed to prepare chiral trans-2,5-disubstituted tetrahydrofuran ring compounds and obtain a series of products with high yields and excellent enantioselectivity. However, previous methods tend to use metal oxides such as MnO 4 - 、RuO 4 andOsO 4 Oxidation of 1,5-dienes generates cis-2,5-disubstituted tetrahydrofuran ring compounds. The Ru and Os introduced during the reaction are not only unsafe but also put pressure on environmental governance. On the other hand, although the oxidative cyclization of dienes can construct multiple stereocenters at a time, research on chiral catalytic oxidative cyclization of dienes is very limited. In 1990, Walba and his colleagues used Evans' oxazolidinone as a chiral auxiliary to try to construct a highly stereoselective 2,5-disubstituted tetrahydrofuran ring product, and obtained a product with dr=3:1. Later, after using camphorsulfonic acid lactam as a chiral auxiliary, a trans-2,5-disubstituted tetrahydrofuran ring product with dr>9:1 was obtained (J.Am.Chem.Soc.1990,112,5624-5625). However, this reaction is limited in synthetic efficiency and enantioselectivity, which affects its wide application.

[0004] In 2016, Robert H. Grubbs group reported the use of Ru / NaIO 4A method for synthesizing tetrahydrofuran cyclodiol structures from simple olefins by oxidation system. The method uses common dienes to undergo olefin metathesis to control the Z / E configuration of the intermediate 1,5-dienes, and then directly performs oxidative cyclization to obtain the desired tetrahydrofuran cyclodiol product in moderate yield (J.Am.Chem.Soc.2016,138,6372-6375). Summary of the invention

[0005] The present invention aims at the difficulty of synthesizing chiral trans-2,5-disubstituted tetrahydrofuran ring products, and invents an olefin oxidation method using 1,4-dienoate as olefin raw material, chiral quaternary ammonium salt as catalyst, and potassium permanganate as oxidant, to undergo oxidative cyclization, and obtain a series of trans-2,5-disubstituted tetrahydrofuran ring products with high enantioselectivity. At the same time, the reaction has a small amount of catalyst, simple operation, high reaction conversion rate, and good application prospects. The by-products of the oxidation reaction, manganese dioxide and oxidative hydroxylation products, are easy to separate, and the reaction system is clean; the manganese dioxide generated at the same time can be recovered and utilized. The purpose of the present invention is to provide a synthetic method for efficiently preparing chiral trans-2,5-disubstituted tetrahydrofuran ring products, so as to solve the problems of low enantioselectivity, large catalytic amount of catalyst used, complicated reaction steps, and expensive catalysts proposed in the above-mentioned background technology.

[0006] In order to solve the above problems, the present invention adopts the following technical scheme: a method for preparing a chiral trans-2,5-disubstituted tetrahydrofuran ring product, wherein enoate Ⅰ is subjected to asymmetric oxidative cyclization in the presence of an acid under the catalysis of a chiral quaternary ammonium salt phase transfer catalyst PTC and potassium permanganate as an oxidant, to obtain a trans-2,5-disubstituted tetrahydrofuran ring product Ⅱ with high enantioselectivity, and the preparation route is as follows:

[0007]

[0008] Among them, R 1 ,R 2 ,R 3 is an alkyl group, an aryl group, a heteroatom or hydrogen, is an alkyl group or hydrogen, R 4 ,R 5 is an alkyl group, an aryl group or hydrogen, and X is an alkoxy group, an amino group, an alkyl group or an aryl group.

[0009] Acrylate or β-aryl / alkyl acrylate Ⅰ and chiral quaternary ammonium salt phase transfer catalyst PTC are mixed in an organic solvent, and then acetic acid or isooctanoic acid, potassium permanganate and a small amount of additives are added thereto in sequence for reaction. After the starting materials are completely reacted or react for 24 hours, the reaction mixture is filtered. Then the solvent is evaporated and quickly purified with a silica gel column to obtain a chiral trans-2,5-disubstituted tetrahydrofuran ring compound Ⅱ with high enantioselectivity.

[0010] Preferably, the chiral quaternary ammonium salt phase transfer catalyst PTC can be a quaternary ammonium salt derived from cinchona alkali, with a structural formula as shown in Formula III:

[0011]

[0012] Where X=H or OMe; when R 1 When it is tert-butyl, R 2 is a halogen atom, Ar is an aryl group;

[0013] Or when R 1 When it is 3,5-di-tert-butylphenyl, R 2 is H, and Ar is aryl.

[0014] The cinchona alkali in the quaternary ammonium salt catalyst PTC derived from cinchona alkali can be any one of cinchona, dihydrocinchona, cinchonidine, dihydrocinchonidine, quinine, dihydroquinine, quinidine, and dihydroquinidine.

[0015] Preferably, the organic solvent is one of dichloromethane, methyl tert-butyl ether and toluene.

[0016] Preferably, the molar ratio of the cinchona alkaloid-derived quaternary ammonium salt catalyst PTC olefin ester is 1 to 2.5:50.

[0017] Preferably, the molar ratio of the potassium permanganate to the olefinic acid ester is 1.2 to 2.5:1.

[0018] Preferably, the molar ratio of the acetic acid or isooctanoic acid to the olefinic acid ester is 2.5 to 5:1.

[0019] Preferably, the additive is water, inorganic salt KF or KPF 6 of aqueous solution.

[0020] Preferably, the reaction temperature is -20 to 0°C, and the reaction time is 2 to 24 hours.

[0021] Preferably, the ratio of the quaternary ammonium salt catalyst derived from cinchona alkali to acrylate or β-aryl / alkyl acrylate is 1 to 2.5:50; the molar ratio of potassium permanganate to acrylate or β-aryl / alkyl acrylate is 1.2 to 2.5:1. The molar ratio of acetic acid or isooctanoic acid to acrylate or β-aryl / alkyl acrylate is 2.5 to 5:1; the reaction temperature is -20 to 0°C, and the reaction time is 2 to 24 hours.

[0022] Preferably, the chiral quaternary ammonium salt phase transfer catalyst PTC is any one of the following structures:

[0023] Beneficial Effects

[0024] Compared with the shortcomings and deficiencies of the prior art, the present invention has the following beneficial effects:

[0025] (1) The purpose of the present invention is to develop a method for synthesizing chiral trans-2,5-disubstituted tetrahydrofuran ring compounds which is simple in synthesis, has a high conversion rate, has few synthetic steps, and uses a green and environmentally friendly method.

[0026] (2) The present invention uses easily available enoic acid ester as raw material, and the prepared product is stable. The preparation method is simple and convenient, and the cost is low. Another by-product, α-hydroxy-β-keto acid ester compound, is also an important raw material for the synthesis of drug molecules.

[0027] (3) The chiral trans-2,5-disubstituted tetrahydrofuran ring compounds prepared by the present invention have an enantioselectivity of up to 96% ee.

[0028] (4) Since there are few strategies for obtaining chiral trans-2,5-disubstituted tetrahydrofuran ring compounds by oxidizing olefins in the currently known literature, the method of catalytic asymmetric oxidizing olefins used in the present invention to obtain chiral trans-2,5-disubstituted tetrahydrofuran ring compounds is more prominent and has significant results.

[0029] (5) The oxidant used in the present invention is potassium permanganate. Potassium permanganate is a green oxidant and can be used in industrial production. The oxidation byproduct manganese dioxide can be recovered.

[0030] (6) The present invention can realize the efficient asymmetric synthesis of chiral trans-2,5-disubstituted tetrahydrofuran ring compounds, provides new ideas and methods for discovering and constructing chiral trans-2,5-disubstituted tetrahydrofuran ring compounds, and broadens the application scope of the substrate.

[0031] (7) The present invention is applied to the synthesis of chiral trans-2,5-disubstituted tetrahydrofuran ring compounds by catalyzing potassium permanganate oxidation of olefins. The amount of catalyst used is small, and the synthesis method is green and beneficial to the environment. The potassium permanganate used is a green oxidant that can be applied to industrial production, and the oxidation byproduct manganese dioxide can be recovered and reused.

[0032] (8) The present invention is a new synthetic strategy applied to the synthesis of the C14-C23 fragment of the eribulin drug, which can simultaneously construct three chiral centers in one step, solving the problems of the existing synthetic route of such compounds being too long, poor selectivity, high cost, difficult purification, and difficult industrial production. It has the advantages of convergent synthesis, short route, high yield, mild conditions, and simple operation. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 HPLC chart of the chiral trans-2,4-disubstituted tetrahydrofuran ring compound prepared in Example 1 of the present invention;

[0034] Figure 2 HPLC chart of the β-aryl substituted chiral trans-2,5-disubstituted tetrahydrofuran ring compound prepared in Example 2 of the present invention;

[0035] Figure 3 HPLC chart of the β-alkyl substituted chiral trans-2,5-disubstituted tetrahydrofuran ring prepared in Example 3 of the present invention;

[0036] Figure 4 HPLC chart of the β-alkyl substituted chiral trans-2,5-disubstituted tetrahydrofuran ring prepared in Example 4 of the present invention;

[0037] Figure 5 This is the nuclear magnetic hydrogen spectrum of the C14-C23 fragment of the eribulin drug synthesized according to the present invention; DETAILED DESCRIPTION

[0038] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0039] Preparation of Examples 1, 2, 3, 4 raw materials:

[0040]

[0041] Step 1: Dissolve methoxyformylmethylenetriphenylphosphine (1.1 equiv) in chloroform, then add allyl bromide, reflux the reaction system in a 75°C oil bath overnight, monitor the reaction, and cool the reaction to room temperature after allyl bromide is consumed. At this time, the main product of the system is phosphine salt. Then add Et 3 N (3 equiv) was alkalized at room temperature for 2.5 h, then aldehyde (1.2 equiv) was added, and after heating under reflux for 6 h, the reaction solvent was dried at no higher than 35° C., and the enoate was purified by column chromatography.

[0042] Step 2: Add a mixed solvent of water and ethanol in a volume ratio of 1:1 to the flask containing the enoate, and then add a strong base LiOH·H 2 O (3 equiv), heated to reflux in an oil bath at 90 ° C. After the starting material was consumed, the ethanol was evaporated at 44 ° C by rotary evaporation, and then 1.5 M dilute hydrochloric acid was added to acidify to pH 1. Then CH 2 Cl 2 After extraction, CH 2 Cl 2 The crude acid product is obtained and can be directly used in the next step reaction without further purification.

[0043] Step 3: The crude acid was dissolved in N,N-dimethylformamide, and α-bromo-4-methoxyacetophenone (1.1 equiv) and triethylamine (1.2 equiv) were added respectively, and the reaction was carried out at room temperature overnight. After the raw materials were consumed as monitored by TLC plate, CH 2 Cl 2 and water, with CH 2 Cl 2 After three extractions, the organic phases were combined and washed with water for five times to remove N,N-dimethylformamide. The washed crude product was dried, filtered, concentrated in vacuo, and purified by column chromatography to obtain a clean enoate product.

[0044] Example 1 Raw materials

[0045] 1 H NMR (400 MHz, CDCl 3 )δ7.91(d,J=8.9Hz,2H),6.95(d,J=8.9Hz,2H),6.31(d,J=1.3Hz,1H),5.64(d,J=1.6Hz,1H),5. 38(s,2H),5.20(t,J=7.3Hz,1H),3.87(s,3H),3.05(d,J=7.3Hz,2H),1.74(s,3H),1.63(s,3H); 13 C NMR (101 MHz, CDCl 3 )δ190.51,166.52,163.83,138.77,134.16,129.91,127.05,125.52,120.11,113.85,65.80,55.33,30.03,25.60,17.51.

[0046] Example 2 Raw materials

[0047] 1 H NMR (400 MHz, CDCl 3 )δ7.94(d,J=8.9Hz,2H),7.86(s,1H),7.41–7.33(m,5H),6.97(d,J=8.9Hz,2H),5.44(s, 2H),5.23(t,J=6.5Hz,1H),3.88(s,3H),3.29(d,J=6.5Hz,2H),1.74(s,3H),1.65(s,3H); 13 C NMR (101 MHz, CDCl 3)δ190.86,167.75,163.95,140.22,135.58,133.10,131.56,130.10,129.49, 128.38,127.32,126.94,121.53,113.99,66.13,55.48,26.94,25.74,17.96.

[0048] Example 3 Raw materials

[0049] 1 H NMR (400 MHz, CDCl 3 )δ7.91(d,J=8.9Hz,2H),6.95(d,J=8.9Hz,2H),6.72(d,J=10.1Hz,1H),5.34(s,2H),5.07(t,J=6.9H z,1H),3.87(s,3H),3.06(d,J=6.9Hz,2H),2.77–2.64(m,1H),1.67(s,6H),1.05(s,3H),1.04(s,3H); 13 C NMR (101 MHz, CDCl 3 )δ191.05,167.54,163.91,150.43,131.94,130.09,128.67,127.42,122.09,113.96,65.83,55.49,28.09,26.00,25.72,22.17,17.80.

[0050] Example 4 Raw materials

[0051] 1 H NMR (400 MHz, CDCl 3 )δ7.91(d,J=8.9Hz,2H),7.04(t,J=7.5Hz,1H),6.95(d,J=8.9Hz,2H),5.92–5.80(m,1H),5.35(s,2H),5.09–4.96(m,2H),3. 87(s,3H),3.64(t,J=6.2Hz,2H),3.14(d,J=6.1Hz,2H),2.30(q,J=7.6Hz,2H),1.73–1.62(m,2H),0.89(s,9H),0.05(s,6H); 13 C NMR (101 MHz, CDCl 3)δ190.91,166.87,163.91,135.28,130.05,129.30,127.32,115.10,1 13.95,65.83,62.30,55.45,31.62,30.78,25.86,25.15,18.22,–5.37.

[0052] Example 1

[0053] Preparation of (3S,5S)-3-hydroxy-5-(2-hydroxypropan-2-yl)tetrahydrofuran-3-carboxylic acid-2-(4-methoxyphenyl)-2-oxyylideneethyl ester:

[0054]

[0055] A mixture of 5-methyl-2-ylidenehex-4-enoic acid-2-(4-methoxyphenyl)-2-oxyylideneethyl ester (57.8 mg, 0.20 mmol), N-3,5-difluorobenzyl-O-2-bromo-3,5-di-tert-butylbenzyl-copper alkali quaternary ammonium salt phase transfer catalyst Cat.1 (7.8 mg, 5 mol%) in toluene (2 mL) was cooled to -20°C, and then acetic acid (60.0 mg, 5 equiv), potassium permanganate (79 mg, 2.5 eq) and saturated KF aqueous solution (0.1 mL) were added thereto in sequence. The mixture was reacted at -20°C for 12 hours. After the starting material was completely reacted, the reaction mixture was filtered. The solvent was then evaporated and quickly purified using a silica gel column. The yield of (3S,5S)-3-hydroxy-5-(2-hydroxypropan-2-yl)tetrahydrofuran-3-carboxylic acid-2-(4-methoxyphenyl)-2-oxyethyl ester was 48%, and the ee value of the enantiomer was 91%. The byproducts of the oxidative cyclization were mainly 2-hydroxy-4'-methoxyacetophenone and manganese dioxide.

[0056] 1 H NMR (400 MHz, CDCl 3 )δ7.88(d,J=8.9Hz,2H),6.97(d,J=8.9Hz,2H),5.52–5.38(m,2H),4.17(d,J=9.3Hz,1H),4.08(dd,J=9.4,1.4Hz,1H),4.01(dd, 13C NMR(101MHz,CDCl 3)δ189.94,173.38,164.30,130.14,126.73,114.22,86.16,81.13,78.20,71.16,66 .69,55.63,40.36,27.12,25.58;IR:3450,2977,1751,1694,1603,1229,1100,963cm –1 ; HPLC analysis: Chiralcel AD-H (Hex / IPA=60 / 40, 0.9mL / min, 254nm, 25℃), 15.4(major), 17.6min, 91%ee.

[0057] Optimization of reaction conditions:

[0058] Optimization of Acrylate Conditions

[0059]

[0060]

[0061] a Unsaturated ester (1 equiv), chiral PTC (5 mol%) and AcOH (5 equiv) were dissolved in an organic solvent and KMnO 4 (2.5equiv) and additives; b Isolated yield; c The ee value was determined by chiral HPLC.

[0062] Based on the optimization of conditions, we found an optimal condition: when using catalyst Cat.1, adding saturated KF aqueous solution and toluene as solvent at -20°C, the enantioselectivity of the product is the highest.

[0063] Phase transfer catalysts derived from cinchona alkali modified with different substituents are applied in the reaction of catalyzing the oxidation of olefins by potassium permanganate, and the specific application process is: a mixture of 5-methyl-2-ylidenehex-4-enoic acid-2-(4-methoxyphenyl)-2-oxyylideneethyl ester (57.8 mg, 0.20 mmol) and a modified cinchona alkali catalyst (5 mol%) in PhMe (2 mL) is cooled to -20°C, and then acetic acid (60.0 mg, 5 eq.), potassium permanganate (79 mg, 2 eq.) and KF aqueous solution (0.1 mL) are added thereto in sequence. The mixture is reacted at -20°C for 24 hours. After the starting material is completely reacted, the reaction mixture is filtered. Then the solvent is evaporated and quickly purified with a silica gel column to obtain a chiral trans-2,5-disubstituted tetrahydrofuran ring product.

[0064]

[0065] As shown above, the results of product HPLC show that the enantioselectivity of the product in the reaction catalyzed by the phase transfer catalyst derived from cinchona alkali modified with different substituents is 91%ee, 84%ee, 65%ee, and 66%ee, respectively. Compared with the catalytic results of the sterically hindered chiral quaternary ammonium salt catalyst derived from cinchona alkali, the sterically hindered quaternary ammonium salt catalyst derived from cinchona alkali of the present invention can significantly improve the enantioselectivity of the olefin oxidation reaction with potassium permanganate.

[0066] Example 2

[0067] Preparation of (2R,3S,5S)-3-hydroxy-5-(2-hydroxypropan-2-yl)-2-phenyltetrahydrofuran ring-3-carboxylic acid-2-(4-methoxyphenyl)-2-oxyylideneethyl ester:

[0068]

[0069] A mixture of (E)-5-methyl-2-phenylene hex-4-enoic acid-2-(4-methoxyphenyl)-2-oxy-ethyl ester (73.0 mg, 0.20 mmol), N-3,5-difluorobenzyl-O-2-bromo-3,5-di-tert-butylbenzyl cinchona alkali quaternary ammonium salt phase transfer catalyst Cat.2 (9.8 mg, 5 mol%) in toluene (2 mL) was cooled to -20°C, and then isooctanoic acid (72.1 mg, 2.5 eq.), potassium permanganate (47.4 mg, 1.5 eq.) and KF aqueous solution (0.1 mL) were added thereto in sequence. The mixture was reacted at -20°C for 24 hours. After the reaction was completed, the reaction mixture was filtered. The solvent was then evaporated and quickly purified using a silica gel column. The yield of (2R,3S,5S)-3-hydroxy-5-(2-hydroxypropan-2-yl)2-phenyltetrahydrofuran-3-carboxylic acid-2-(4-methoxyphenyl)-2-oxyylideneethyl ester was 28%, and the ee value of the enantiomer was 91%. The byproducts of the oxidative cyclization were mainly dioxidative hydroxylation products and manganese dioxide.

[0070] 1 H NMR (400 MHz, CDCl 3)δ7.78(d,J=8.8Hz,2H),7.39(d,J=6.3Hz,2H),7.33–7.25(m,3H),6.92(d, J=8.9Hz,2H),5.17(d,J=16.1Hz,1H),5.11(s,1H),4.89(d,J=16.1Hz,1H),4 .46(dd,J=9.5,6.9Hz,1H),3.95(s,1H),3.86(s,3H),2.77(dd,J=12.9,6.9H z,1H),2.49(dd,J=13.0,9.5Hz,1H),2.33(s,1H),1.34(s,3H),1.24(s,3H); 13 C NMR (101 MHz, CDCl 3 )δ189.67,173.21,164.33,137.52,130.15,128.19,128.12,126.81,125.50, 114.22,87.21,85.68,84.98,72.43,66.38,55.68,38.56,26.79,24.20; HPLC analysis: ChiralcelAD-H (Hex / IPA=70 / 30, 1mL / min, 254nm, 25℃), 16.1 (major), 18.4min, 91%ee.

[0071] Optimization of reaction conditions

[0072] Optimization of substrate conditions for β-aryl enoate

[0073]

[0074]

[0075] a Unsaturated ester (1 equiv), chiral PTC (5 mol%) and acid (5 equiv) were dissolved in an organic solvent and KMnO 4 (1.5equiv) and additives; b Isolated yield; c The ee value was determined by chiral HPLC. The reaction was carried out in a -20°C low temperature tank. The yield was the isolated yield obtained by column chromatography purification after the raw material was consumed. d 2.5 equivalents of 2-ethylhexanoic acid

[0076] According to the optimization of conditions, we found an optimal condition: using catalyst Cat.2, 1.5 equiv of KMnO at -20 °C 4 and 2.5 equiv of isooctanoic acid. When toluene is used as solvent, the enantioselectivity of the product is the highest.

[0077] Phase transfer catalysts derived from cinchona alkali modified with different substituents are applied to the reaction of catalyzing the oxidation of olefins by potassium permanganate, and the specific application process is: a mixture of β-aryl alkenoate (57.8 mg, 0.20 mmol) and a modified cinchona alkali catalyst (5 mol%) in PhMe (2 mL) is cooled to -20°C, and then acid (1.5 eq.), potassium permanganate (79 mg, 2.5 eq.) and saturated KF aqueous solution (0.1 mL) are added thereto in sequence. The mixture is reacted at -20°C for 24 hours. After the starting material is completely reacted, the reaction mixture is filtered. Then the solvent is evaporated and quickly purified with a silica gel column to obtain a chiral trans-2,5-disubstituted tetrahydrofuran ring product.

[0078]

[0079] As shown above, the results of product HPLC show that the enantioselectivity of the product in the reaction catalyzed by the phase transfer catalyst derived from cinchona alkali modified with different substituents is 67%ee, 991%ee, 33%ee, and 74%ee, respectively. Compared with the catalytic results of the sterically hindered chiral quaternary ammonium salt catalyst derived from cinchona alkali, cat.2 of the present invention performs well in the oxidative cyclization of β-aryl alkenoate substrates, and can significantly improve the enantioselectivity of the olefin oxidation reaction with potassium permanganate.

[0080] Example 3

[0081] Preparation of (2R,3S,5S)-3-hydroxy-5-(2-hydroxypropan-2-yl)-2-(2-methylpropyl)tetrahydrofuran-3-carboxylic acid-2-(4-methoxyphenyl)-2-oxyylideneethyl ester:

[0082]

[0083] EHA is 2-ethylhexanoic acid

[0084] A mixture of (E)-5-methyl-2-(3-methylbut-2-enyl)hex-4-enoic acid-2-(4-methoxyphenyl)-2-oxyylideneethyl ester (67.0 mg, 0.20 mmol), N-3,5-difluorobenzyl-O-2-bromo-3,5-di-tert-butylbenzyl cinchona alkali quaternary ammonium salt phase transfer catalyst Cat.3 (10.8 mg, 5 mol%) in toluene (2 mL) was cooled to -20°C, and then isooctanoic acid (72.1 mg, 2.5 eq.), potassium permanganate (37.9 mg, 1.5 eq.) and H 2O (0.1 mL). The mixture was reacted at -20 ° C for 24 hours. After the reaction was completed, the reaction mixture was filtered. Then the solvent was evaporated again and quickly purified using a silica gel column. (2R, 3S, 5S)-3-hydroxy-5-(2-hydroxypropan-2-yl)-2-(2-methylpropyl)tetrahydrofuran ring-3-carboxylic acid-2-(4-methoxyphenyl)-2-oxyylideneethyl ester was obtained in a 44% yield, and the ee value of the enantiomer was 90%. The by-products of the oxidative cyclization are mainly mono-oxidized hydroxylation products and manganese dioxide.

[0085] 1 H NMR (400 MHz, CDCl 3 )δ7.88(d,J=8.9Hz,2H),6.96(d,J=8.9Hz,2H),5.62(d,J=16.0Hz,1H),5.30(d,J=16 .0Hz,1H),4.11(t,J=7.4Hz,1H),4.03(dd,J=10.1,3.0Hz,1H),3.87(s,3H),2.67(dd, J=13.1,7.5Hz,1H),2.26(dd,J=13.1,8.6Hz,1H),1.81(tt,J=13.0,6.6Hz,1H),1.45 –1.29(m,2H),1.26(s,3H),1.17(s,3H),0.95(d,J=6.7Hz,3H),0.91(d,J=6.6Hz,3H); 13 C NMR (101 MHz, CDCl 3 )δ189.56,173.97,164.21,130.05,126.73,114.12,84.07,84.00,82.99,72. 25,66.64,55.52,38.54,38.12,26.44,25.58,24.32,23.42,21.90; Chiralcel AD-H (Hex / IPA=70 / 30, 1mL / min, 254nm, 25℃), 11.5, 12.7(major)min, 90%ee.

[0086] Optimization of reaction conditions

[0087] Optimization of substrate conditions for β-alkyl enoate a

[0088]

[0089]

[0090]

[0091] a Unsaturated ester (1 equiv), chiral PTC (5 mol%) and acid (2.5 equiv) were dissolved in an organic solvent and KMnO 4 (1.2equiv) and additives; b Isolated yield; c The ee value is determined by chiral HPLC. The reaction is carried out in a -20°C low temperature tank. The yield is the isolated yield obtained by column chromatography purification after the raw material is consumed. The ee value is determined by chiral HPLC. d Isooctanoic acid is 5 equivalents. e Acetic acid is 1.2 equivalents. EHA = 2-Ethylhexanoic acid.

[0092] Based on the optimization of conditions, we found an optimal condition: using catalyst Cat.3 and 2.5 equiv of isooctanoic acid at -20°C, the product has the highest enantioselectivity.

[0093] Phase transfer catalysts derived from cinchona alkaloids modified with different substituents are applied to the reaction of catalyzing the oxidation of olefins by potassium permanganate, and the specific application process is: a mixture of β-alkyl olefin ester (57.8 mg, 0.20 mmol) and a modified cinchona alkaloid catalyst (5 mol%) in PhMe (2 mL) is cooled to -20°C, and then acid (2.5 eq.), potassium permanganate (79 mg, 1.2 eq.) and an aqueous solution (0.1 mL) are added thereto in sequence. The mixture is reacted at -20°C for 24 hours. After the starting material is completely reacted, the reaction mixture is filtered. Then the solvent is evaporated and quickly purified with a silica gel column to obtain a chiral trans-2,5-disubstituted tetrahydrofuran ring product.

[0094]

[0095] As shown above, the results of product HPLC show that the enantioselectivity of the product in the reaction catalyzed by the phase transfer catalyst derived from cinchona alkali modified with different substituents is 88%ee, 75%ee, 67%ee, and 84%ee, respectively. Compared with the catalytic results of the sterically hindered chiral quaternary ammonium salt catalyst derived from cinchona alkali, cat.3 of the present invention performs well in the oxidative cyclization of β-alkyl olefin ester substrates, and can significantly improve the enantioselectivity of the olefin oxidation reaction with potassium permanganate.

[0096] The chiral trans-2,5-disubstituted tetrahydrofuran ring products of the above three examples are common structural units in a variety of natural products and drugs. This structure has a wide range of applications in the field of medicinal chemistry, among which the more common natural products include (+)-cis-solamin, (+)-cis-sylvaticin, etc.

[0097] Example 4

[0098]

[0099] A mixture of 2-(4-methoxyphenyl)2-oxoethyl(E)-2-allyl-6-((tert-butyldimethylsilyl)oxy)hex-2-enoic acid (216.0 mg, 0.50 mmol), N-3,5-difluorobenzyl-O-2-bromo-3,5-di-tert-butylbenzyl cinchona alkali quaternary ammonium salt phase transfer catalyst Cat.1 (19.6 mg, 5 mol%) in toluene (2 mL) was cooled to -20°C, and then isooctanoic acid (195 μL, 2.5 eq.), potassium permanganate (117.0 mg, 1.5 eq.) and H 2 O (0.25 mL). The mixture was reacted at -20 ° C for 24 hours. After the reaction, the reaction mixture was filtered. Then the solvent was evaporated again and quickly purified using a silica gel column. (2-(4-methoxyphenyl)-2-oxoethyl (2S, 3R, 5R)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran ring-3-carboxylate was obtained in 22% yield, and the ee value of the enantiomer was 95%. The by-products of the oxidative cyclization are mainly monooxidized hydroxylation products and manganese dioxide. Chiral 2,5-disubstituted tetrahydrofuran ring compounds exist in the synthesis of biologically active drug molecule intermediates, and three chiral centers can be constructed simultaneously in one step, such as the C14-C23 fragment of the anticancer drug Eribulin.

[0100] 1 H NMR (400 MHz, CDCl 3 )δ7.88(d,J=8.9Hz,2H),6.97(d,J=8.9Hz,2H),5.59(d,J=16.0Hz,1H),5.30(d, J=16.0Hz,1H),4.42(qd,J=7.4,2.9Hz,1H),3.99(dd,J=9.3,3.6Hz,1H),3.89(s ,3H),3.74(dd,J=11.8,3.1Hz,1H),3.70–3.61(m,3H),2.84(dd,J=13.3,8.1Hz, 1H),2.10(dd,J=13.3,7.0Hz,1H),1.80–1.48(m,4H),0.88(s,9H),0.04(s,6H); 13 C NMR (101 MHz, CDCl 3)δ189.70,173.16,164.26,130.09,126.81,114.18,85.74,83.05,77.92,66.60,64.7 8,62.89,55.56,38.92,29.60,26.71,25.97,18.34,–5.28;HPLCanalysis:Chiralcel AD-H (Hex / IPA=70 / 30, 1mL / min, 254nm, 25℃), 25.3, 28.3(major)min, 95%ee.

[0101] Optimization of reaction conditions

[0102] Phase transfer catalysts derived from cinchona alkaloids modified with different substituents are applied to the reaction of catalyzing the oxidation of olefins by potassium permanganate, and the specific application process is: a mixture of β-alkyl olefin ester (57.8 mg, 0.20 mmol) and a modified cinchona alkaloid catalyst (5 mol%) in PhMe (2 mL) is cooled to -20°C, and then acid (5 eq.), potassium permanganate (79 mg, 2 eq.) and an aqueous solution (0.1 mL) are added thereto in sequence. The mixture is reacted at -20°C for 24 hours. After the starting material is completely reacted, the reaction mixture is filtered. Then the solvent is evaporated and quickly purified with a silica gel column to obtain a chiral trans-2,5-disubstituted tetrahydrofuran ring product.

[0103]

[0104] As shown above, the results of product HPLC show that the enantioselectivity of the product in the reaction catalyzed by the phase transfer catalyst derived from cinchona alkali modified with different substituents is 95%ee and 68%ee respectively. Compared with the catalytic results of the sterically hindered chiral quaternary ammonium salt catalyst derived from cinchona alkali, cat.1 of the present invention performs well in the oxidative cyclization of β-alkyl olefin ester substrates, and can significantly improve the enantioselectivity of the olefin oxidation reaction with potassium permanganate.

[0105] Comparative Example 1

[0106] Compared with the currently known literature (Tetrahedron Lett. 2001, 42, 7741-7745), the present invention avoids the use of OsO introduced during the reaction process. 4 and RuCl 3 Potassium permanganate is used as an oxidant instead of oxidants that are harmful to human health. Potassium permanganate can efficiently oxidize most olefin substrates, and the reaction conditions are mild, low in toxicity, pollution-free, and easy to operate.

[0107] From the above content, it can be seen that the present invention can realize the efficient asymmetric synthesis of chiral trans-2,5-disubstituted tetrahydrofuran ring products, and is a novel method for synthesizing chiral trans-2,5-disubstituted tetrahydrofuran ring products using acrylate or β-aryl / alkyl acrylate as raw materials, with a wide reaction substrate range and high stereoselectivity.

[0108] The present invention can significantly improve the enantioselectivity of the potassium permanganate olefin oxidation reaction, provide a new method for obtaining a chiral trans-2,5-disubstituted tetrahydrofuran ring product with high enantioselectivity, provide new ideas and methods for discovering and constructing new phase transfer catalysts, and promote the development and application of small molecule catalysts.

[0109] Those skilled in the art should recognize that the above embodiments are only used to illustrate the present invention, and are not intended to limit the present invention. As long as they are within the spirit of the present invention, any changes or modifications to the above embodiments will fall within the scope of the claims of the present invention.

Claims

1. A method for preparing a chiral trans-2,5-disubstituted tetrahydrofuran ring product, characterized in that: Acrylate or β-aryl / alkyl acrylate Ⅰ is catalyzed by chiral quaternary ammonium salt phase transfer catalyst PTC, potassium permanganate is used as an oxidant, and in the presence of acetic acid or isooctanoic acid and additives, an asymmetric oxidative cyclization is carried out in an organic solvent to obtain a chiral trans-2,5-disubstituted tetrahydrofuran ring product Ⅱ with high enantioselectivity. The preparation route is as follows: Among them, R 1 ,R 2 ,R 3 is an alkyl group, an aryl group, a heteroatom or hydrogen, R 4 ,R 5 is an alkyl group, an aryl group or hydrogen, and X is any one of an alkoxy group, an amino group, an alkyl group and an aryl group.

2. The method for preparing a chiral trans-2,5-disubstituted tetrahydrofuran ring product according to claim 1, characterized in that: The chiral quaternary ammonium salt phase transfer catalyst PTC is a quaternary ammonium salt derived from cinchona alkali, and its structural formula is as follows: Where X=H or OMe; when R 1 When it is tert-butyl, R 2 is a halogen atom, Ar is an aromatic group; when R 1 When it is 3,5-di-tert-butylphenyl, R 2 is H, and Ar is aryl.

3. The method for preparing a chiral trans-2,5-disubstituted tetrahydrofuran ring product according to claim 1, characterized in that: The organic solvent is dichloromethane, methyl tert-butyl ether or toluene.

4. The method for preparing a chiral trans-2,5-disubstituted tetrahydrofuran ring product according to claim 1, characterized in that: The molar ratio of the chiral quaternary ammonium salt catalyst to the olefinic acid ester I is 1-2.5:

50.

5. The method for preparing a chiral trans-2,5-disubstituted tetrahydrofuran ring product according to claim 1, characterized in that: The molar ratio of the potassium permanganate to the enoate ester I is 1.2-2.5:

1.

6. The method for preparing a chiral trans-2,5-disubstituted tetrahydrofuran ring product according to claim 1, characterized in that: The molar ratio of the acetic acid or isooctanoic acid to the olefinic acid ester I is 2.5-5:

1.

7. The method for preparing a chiral trans-2,5-disubstituted tetrahydrofuran ring product according to claim 1, characterized in that: The additive is water, an aqueous solution of inorganic salt KF or KPF6.

8. The method for preparing a chiral trans-2,5-disubstituted tetrahydrofuran ring product according to claim 1, characterized in that: The reaction temperature is -20 to 0°C, and the reaction time is 2 to 24 hours.

9. The method for preparing a chiral trans-2,5-disubstituted tetrahydrofuran ring product according to claim 1, characterized in that: The chiral quaternary ammonium salt phase transfer catalyst PTC is any one of the following structures:

10. The method for preparing a chiral trans-2,5-disubstituted tetrahydrofuran ring product according to claim 1, characterized in that: A mixture of 216.0 mg, 0.50 mmol, of 2-(4-methoxyphenyl)2-oxoethyl (E)-2-allyl-6-((tert-butyldimethylsilyl)oxy)hex-2-enoic acid, 19.6 mg, 5 mol% of N-3,5-difluorobenzyl-O-2-bromo-3,5-di-tert-butylbenzyl cinchona alkali quaternary ammonium salt phase transfer catalyst Cat.1 in 2 mL of toluene was cooled to -20°C, and then 195 μL, 2.5 eq. of isooctanoic acid, 117.0 mg, 1.5 eq. of potassium permanganate and 0.25 mL of H2O were added in sequence; the mixture was reacted at -20°C for 24 hours. After the reaction was completed, the reaction mixture was filtered. The solvent was then evaporated and quickly purified using a silica gel column to give (2-(4-methoxyphenyl)-2-oxoethyl (2S, 3R, 5R)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran ring-3-carboxylate in 22% yield, and the ee value of the enantiomer was 95%.

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