A method for synthesizing chiral tetrahydrofuran compounds

Abstract

This invention discloses a method for synthesizing chiral tetrahydrofuran compounds, comprising the following steps: in an organic solvent, under iridium catalysis in the presence of an acid anhydride and a base, a carboxylic acid compound I and a cyclopropane compound II undergo an asymmetric cyclization reaction to obtain a high-value chiral tetrahydrofuran compound III with high yield and enantioselectivity, exhibiting high chemoselectivity and functional group tolerance; the iridium catalytic system is pre-complexed from an iridium salt and a chiral ligand, and its structure is shown in Figure IV.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a method for synthesizing chiral tetrahydrofuran compounds. Background Technology

[0002] Cyclopropanes possess π-bond-like properties, high angle strain, and fixed torsional strain, making bond breaking easier than in corresponding chain alkanes. To broaden the application range of cyclopropanes, further reduction in bond energy is needed. Since 1977, the emergence of Donor-Acceptor Cyclopropanes (DACs) has overcome the insufficient reactivity of general cyclopropanes. With the development of new catalysts and catalytic modes, DACs have become a very convenient building block in organic synthesis, participating in the synthesis of various chain and cyclic complex compounds, and are widely used in the synthesis of natural products and pharmaceuticals. Due to the push-pull electron effect between electron-donating and electron-withdrawing groups on adjacent carbon atoms of DACs, the C–C bond polarity is enhanced, making it easier to break. Under the action of appropriate catalysts, DACs can be transformed into highly reactive zwitterionic intermediates to participate in reactions. Over the past forty years, the most commonly used catalysts for activating DACs have been Lewis acids and transition metals, and the types of chemical reactions involved can be classified as ring-opening reactions, cyclization reactions, and rearrangement reactions. Notably, among the factors affecting the reactivity of DACs, the electron-donating ability of the electron-donating group has a greater impact on the transition state energy than that of the electron-withdrawing group. Therefore, finding cyclopropanes with suitable electron-donating groups is key to the success of the reaction.

[0003] DA-type vinylcyclopropanes (VCPs) represent an important branch of DA-cyclopropane research. The unsaturated double bonds outside the ring weaken the overlap between the C–C σ-orbitals and C═C π-orbitals of cyclopropane, making ring-opening easier. Under transition metal catalysis, the π-allyl transition metal intermediates formed by VCPs can participate in cyclization reactions as three-carbon or five-carbon synthons.

[0004] Carboxylic acids can participate in nucleophilic and electrophilic reactions with the aid of appropriate catalysts. When used in deprotonated form, they can serve as excellent nucleophiles. In the presence of Lewis acids, the α- group of carboxylic acids exhibits nucleophilicity and can act as a nucleophile. Furthermore, nucleophiles can be generated via decarboxylation reactions and used in asymmetric catalytic reactions. Under the influence of Lewis acids, α-, β-unsaturated, and saturated carboxylic acids can also act as electrophiles, yielding the target product in high yield and with stereoselectivity. However, reports on carbonyl cycloaddition reactions of carboxylic acids are scarce. Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, one of the objectives of this invention is to provide a synthetic method for chiral tetrahydrofuran compounds by cyclizing the carbonyl group of carboxylic acids. This invention uses iridium, a commonly used metal precursor, and easily synthesized chiral ligands to form a catalytic system, thereby achieving the synthesis of chiral tetrahydrofuran compounds.

[0006] The technical solution of the present invention is as follows:

[0007] A method for containing a chiral tetrahydrofuran compound includes the following steps:

[0008] In an organic solvent, catalyzed by an iridium metal system, and in the presence of an acid anhydride and a base, carboxylic acid compound I and cyclopropane compound II undergo a cyclization reaction to yield chiral tetrahydrofuran compound III; the iridium catalytic system consists of an iridium salt and a chiral ligand, and its structure is shown in Figure IV.

[0009]

[0010] In compound I, R1 can be methyl, aryl, methoxy, ester, acyl, etc.; the aromatic ring can be a benzene ring with different functional group substitutions, or a heterocycle such as indole, pyrimidine, or quinoline, representing drug molecules with different activities;

[0011] In compound II, R2 is a C1-C4 alkyl group, and EWG is a cyano group, ester group, sulfonyl group, lactam group, etc.

[0012] In compound III, substituent R1 is the same as R1 in compound I; substituent R2 is the same as R2 in compound II; the aromatic ring is the same as in compound I; and the EWG is the same as in compound II.

[0013] According to a preferred embodiment of the present invention, the solvent is N,N-dimethylacetamide, N,N-dimethylformamide, ethylene glycol dimethyl ether, toluene, dimethyl sulfoxide, or tetrahydrofuran; the solvent concentration is 0.1 mol / L; and the solvent is anhydrous.

[0014] According to a preferred embodiment of the present invention, the iridium catalyst is an iridium-ligand complex or an in-situ complexed iridium catalyst, wherein the metallic iridium is a 1,5-cyclooctadiene iridium chloride dimer and the ligand is a chiral phosphorous amide ligand; the equivalence ratio of the iridium catalyst to carboxylic acid compound I is 0.01:1; and the molar ratio of iridium to chiral ligand in the iridium catalyst is 1:1.

[0015] According to a preferred embodiment of the present invention, the acid anhydride is pentanoic acid anhydride, trifluoromethanesulfonic acid anhydride, acetic anhydride, etc., and the molar ratio of the acid anhydride to carboxylic acid compound I is 1:1.

[0016] According to a preferred embodiment of the present invention, the base is N,N-diisopropylethylamine, triethylamine, pyridine, etc., and the molar ratio of the base to carboxylic acid compound I is 1:1; the molar ratio of the compound of formula I to the compound of formula II is 1:2.

[0017] According to a preferred embodiment of the present invention, the metal iridium-ligand catalyst complex is prepared by the following method: under nitrogen protection, metal iridium, chiral ligand, silver salt and protected cinnamyl alcohol are added to anhydrous and oxygen-free tetrahydrofuran, and the reaction is carried out at room temperature until the ligand is completely converted. The resulting solution is filtered, recrystallized and washed multiple times, and then vacuum dried to obtain a yellow solid powder.

[0018] According to a preferred embodiment of the present invention, the cyclization reaction is carried out under an inert gas atmosphere, wherein the inert gas is nitrogen; the reaction temperature is 20–30°C; and the reaction time is 4–12 hours.

[0019] According to a preferred embodiment of the present invention, the cyclization reaction can proceed to carboxylic acid formation at different temperatures, under different conditions of potassium carbonate and dimethylformamide. 13 C-labeling, thereby synthesizing with 13 C-labeled tetrahydrofuran skeleton.

[0020] According to the present invention, after the cyclization reaction of carboxylic acid compound I and cyclopropane compound II, the products can be separated and characterized by conventional separation and purification methods. The specific post-reaction processing steps are as follows: the reaction solution is evaporated to dryness, and the chiral tetrahydrofuran compound III is obtained by silica gel column chromatography. The eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the mixed solvent of ethyl acetate and petroleum ether is 0.01 to 0.2:1.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] This invention uses carboxylic acid compounds I and cyclopropane compounds II with different substituents as starting materials. An intermediate formed by the carboxylic acid, anhydride, and base is combined with an allyl intermediate obtained through iridium catalysis to achieve the cyclization reaction of phenylacetic acid with vinylcyclopropane. Under mild reaction conditions, a series of chiral tetrahydrofuran derivatives were obtained in good yields with excellent enantioselectivity. This invention not only enriches the existing reaction types for synthesizing chiral tetrahydrofuran compounds but also provides ideas for the synthesis of drugs containing chiral tetrahydrofurans. Detailed Implementation

[0023] The present invention will be further described below with reference to specific embodiments, but is not limited thereto.

[0024] Furthermore, unless otherwise specified, the experimental methods described in the following embodiments are all conventional methods; and unless otherwise specified, the reagents, materials and equipment are all commercially available.

[0025] The yield described in the examples is a molar yield.

[0026] The reaction route is shown below:

[0027] Example 1

[0028]

[0029] Under a nitrogen atmosphere, 1 (40.8 mg, 0.3 mmol), 2 (70.8 mg, 0.6 mmol), Ir-cat. (0.9 mg, 1 mmol%), pentylene anhydride (55.8 mg, 0.3 mmol), N,N-diisopropylethylamine (38.7 mg, 0.3 mmol), and DMA (3 mL) were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with ethyl acetate (20 mL × 3) and water (10 mL). The combined organic phases were washed with H2O (20 mL × 3) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The target product was obtained by silica gel column chromatography, with petroleum ether and ethyl acetate (volume ratio 1:0.05) as the eluent.

[0030] The characterization data of product 3 are as follows:

[0031] White solid (97% yield, 93% ee)

[0032] 1 H NMR(CDCl3,400MHz)δ7.60(d,J=7.2Hz,2H),7.38-7.26(m,3H),5.97(ddd,J=6.4,10.4,16.8Hz,1H),5.88(s,1H),5.57( d,J=17.1Hz,1H),5.46(d,J=10.4Hz,1H),5.19-5.13(m,1H),3.01(dd,J=12.9,5.4Hz,1H),2.58(dd,J=12.9,9.1Hz,1H);

[0033] 13 C NMR (CDCl3, 400MHz) δ146.1,133.4,133.0,128.7,128.6,127.7,120.9,113.4,104.8,82.7,42.5,38.2;

[0034] Example 2

[0035]

[0036] Under a nitrogen atmosphere, 1 (46.2 mg, 0.3 mmol), 2 (70.8 mg, 0.6 mmol), Ir-cat. (0.9 mg, 1 mmol%), pentylene anhydride (55.8 mg, 0.3 mmol), N,N-diisopropylethylamine (38.7 mg, 0.3 mmol), and DMA (3 mL) were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with ethyl acetate (20 mL × 3) and water (10 mL). The combined organic phases were washed with H2O (20 mL × 3) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The target product was obtained by silica gel column chromatography, with petroleum ether and ethyl acetate (volume ratio 1:0.05) as the eluent.

[0037] The characterization data of product 3 are as follows:

[0038] White solid (94% yield, 98% ee)

[0039] 1 H NMR(CDCl3,400MHz)δ7.65-7.51(m,2H),7.12-7.00(m,2H),5.96(ddd,J=17.0,10.4,6.6Hz,1H),5.84(s,1H),5.55(dd,J =14.1,9.8Hz,1H),5.46(d,J=10.4Hz,1H),5.19-5.13(m,1H),3.02(dd,J=12.9,5.4Hz,1H),2.58(dd,J=12.9,9.2Hz,1H);

[0040] 13 C NMR (CDCl3, 400MHz) δ163.29,160.82,145.76,132.92,130.39,130.31,121.08,115.77,115.56,113.37,103.79,82.81,42.50,38.11;

[0041] 19 FNMR (CDCl3, 400MHz) δ-113.3;

[0042] Example 3

[0043]

[0044] Under a nitrogen atmosphere, 1 (51.0 mg, 0.3 mmol), 2 (70.8 mg, 0.6 mmol), Ir-cat. (0.9 mg, 1 mmol%), pentylene anhydride (55.8 mg, 0.3 mmol), N,N-diisopropylethylamine (38.7 mg, 0.3 mmol), and DMA (3 mL) were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 3 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with ethyl acetate (20 mL × 3) and water (10 mL). The combined organic phases were washed with H2O (20 mL × 3) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The target product was obtained by silica gel column chromatography, with petroleum ether and ethyl acetate (volume ratio 1:0.05) as the eluent.

[0045] The characterization data of product 3 are as follows:

[0046] Colorless liquid (92% yield, 94% ee)

[0047] 1 H NMR(CDCl3,400MHz)δ7.58-7.48(m,1H),7.41-7.28(m,1H),5.96(ddd,J=17.0,10.4,6.6Hz,1H),5.83(s,1H),5.57(d, J=17.1Hz,1H),5.47(d,J=10.4Hz,1H),5.21-5.13(m,1H),3.02(dd,J=12.9,5.4Hz,1H),2.59(dd,J=12.9,9.2Hz,1H);

[0048] 13 C NMR (CDCl3, 400MHz) δ146.6,133.3,132.8,131.9,129.8,128.9,121.2,121.2,113.3,103.7,83.0,42.5,38.2;

[0049] Example 4

[0050]

[0051] Under a nitrogen atmosphere, 1 (63.6 mg, 0.3 mmol), 2 (70.8 mg, 0.6 mmol), Ir-cat. (0.9 mg, 1 mmol%), pentylene anhydride (55.8 mg, 0.3 mmol), N,N-diisopropylethylamine (38.7 mg, 0.3 mmol), and DMA (3 mL) were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with ethyl acetate (20 mL × 3) and water (10 mL). The combined organic phases were washed with H2O (20 mL × 3) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The target product was obtained by silica gel column chromatography, with petroleum ether and ethyl acetate (volume ratio 1:0.05) as the eluent.

[0052] The characterization data of product 3 are as follows:

[0053] White solid (90% yield, 97% ee)

[0054] 1 H NMR(CDCl3,400MHz)δ7.70-7.58(m,6H),7.45(t,J=7.6Hz,2H),7.35(t,J=7.3Hz,1H),5.99(ddd,J=17.0,10.4,6.6Hz,1H),5.92(s, 1H),5.59(d,J=17.1Hz,1H),5.47(d,J=10.4Hz,1H),5.24-5.14(m,1H),3.03(dd,J=12.9,5.4Hz,1H),2.60(dd,J=12.9,9.1Hz,1H);

[0055] 13 C NMR (CDCl3, 400MHz) δ146.2,140.7,140.4,133.0,132.5,129.1,129.0,127.6,127.3,127.1,121.0,113.4,104.5,82.8,42.5,38.2;

[0056] Example 5

[0057]

[0058] Under a nitrogen atmosphere, 1 (58.8 mg, 0.3 mmol), 2 (70.8 mg, 0.6 mmol), Ir-cat. (0.9 mg, 1 mmol%), pentylene anhydride (55.8 mg, 0.3 mmol), N,N-diisopropylethylamine (38.7 mg, 0.3 mmol), and DMA (3 mL) were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with ethyl acetate (20 mL × 3) and water (10 mL). The combined organic phases were washed with H2O (20 mL × 3) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The target product was obtained by silica gel column chromatography, with petroleum ether and ethyl acetate (volume ratio 1:0.05) as the eluent.

[0059] The characterization data of product 3 are as follows:

[0060] White solid (90% yield, 97% ee)

[0061] 1 H NMR(CDCl3,400MHz)δ6.78(d,J=2.2Hz,2H),6.40(t,J=2.2Hz,1H),5.95(ddd,J=17.0,10.4,6.5Hz,1H),5.81(s,1H),5.56(d,J= 17.1Hz,1H),5.44(d,J=10.4Hz,1H),5.20-5.12(m,1H),3.80(s,6H),3.01(dd,J=12.9,5.4Hz,1H),2.57(dd,J=12.9,9.2Hz,1H);

[0062] 13 C NMR (CDCl3, 400MHz) δ160.9,146.5,135.0,132.9,120.8,113.4,106.7,104.9,100.2,82.8,55.5,42.4,38.2;

[0063] Example 6

[0064]

[0065] Under a nitrogen atmosphere, 1 (65.4 mg, 0.3 mmol), 2 (70.8 mg, 0.6 mmol), Ir-cat. (0.9 mg, 1 mmol%), pentylene anhydride (55.8 mg, 0.3 mmol), N,N-diisopropylethylamine (38.7 mg, 0.3 mmol), and DMA (3 mL) were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with ethyl acetate (20 mL × 3) and water (10 mL). The combined organic phases were washed with H2O (20 mL × 3) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The target product was obtained by silica gel column chromatography, with petroleum ether and ethyl acetate (volume ratio 1:0.1) as the eluent.

[0066] The characterization data of product 3 are as follows:

[0067] Colorless liquid (83% yield, 96% ee)

[0068] 1 H NMR(CDCl3,400MHz)δ7.24(d,J=1.5Hz,1H),6.98(dd,J=8.1,1.6Hz,1H),6.80(d,J=8.1Hz,1H),6.01-5.90(m,3H),5.79(s,1H) ,5.56(d,J=17.1Hz,1H),5.45(d,J=10.4Hz,1H),5.18-5.08(m,1H),3.00(dd,J=12.9,5.4Hz,1H),2.57(dd,J=12.9,9.1Hz,1H);

[0069] 13 C NMR (CDCl3, 400MHz) δ147.9,147.1,144.6,133.0,127.6,123.1,120.9,113.5,108.6,108.5,104.8,101.3,82.6,42.5,38.0;

[0070] Example 7

[0071]

[0072] Under a nitrogen atmosphere, 1 (65.4 mg, 0.3 mmol), 2 (69.9 mg, 0.6 mmol), Ir-cat. (0.9 mg, 1 mmol%), pentylene anhydride (55.8 mg, 0.3 mmol), N,N-diisopropylethylamine (38.7 mg, 0.3 mmol), and DMA (3 mL) were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with ethyl acetate (20 mL × 3) and water (10 mL). The combined organic phases were washed with H2O (20 mL × 3) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The target product was obtained by silica gel column chromatography, with petroleum ether and ethyl acetate (volume ratio 1:0.2) as the eluent.

[0073] The characterization data of product 3 are as follows:

[0074] Yellow solid (95% yield, 99% ee)

[0075] 1 H NMR(CDCl3,400MHz)δ8.05-8.00(m,2H),7.82(t,J=7.5Hz,1H),7.63(t,J=7.9Hz,2 H),7.41(d,J=7.4Hz,2H),7.30(t,J=7.6Hz,2H),7.21(t,J=7.3Hz,1H),5.93(ddd,J =17.2,10.3,7.0Hz,1H),5.52(d,J=17.1Hz,1H),5.38(d,J=10.3Hz,1H),5.36-5.2 9(m,1H),4.92(s,1H),3.36(dd,J=14.3,6.0Hz,1H),2.58(dd,J=14.4,10.2Hz,1H);

[0076] 13 C NMR (CDCl3, 400MHz) δ148.5,146.2,135.8,134.9,133.8,132.6,131.7,129.3,128.6,127.4,120.0,115.4,106.8,83.4,70.0,38.4;

[0077] Example 8

[0078]

[0079] Under a nitrogen atmosphere, 1 (65.4 mg, 0.3 mmol), 2 (62.4 mg, 0.6 mmol), Ir-cat. (0.9 mg, 1 mmol%), pentylene anhydride (55.8 mg, 0.3 mmol), N,N-diisopropylethylamine (38.7 mg, 0.3 mmol), and DMA (3 mL) were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with ethyl acetate (20 mL × 3) and water (10 mL). The combined organic phases were washed with H2O (20 mL × 3) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The target product was obtained by silica gel column chromatography, with petroleum ether and ethyl acetate (volume ratio 1:0.1) as the eluent.

[0080] The characterization data of product 3 are as follows:

[0081] White solid (90% yield, 99% ee)

[0082] 1 H NMR(CDCl3,400MHz)δ7.49(d,J=7.4Hz,2H),7.31-7.25(m,2H),7.14(t,J=7.4Hz,1H),6.08(ddd,J=17.4,10.3,7.4Hz,1H ),5.51(d,J=17.1Hz,1H),5.40-5.33(m,2H),5.03(s,1H),3.43(s,3H),3.37(s,3H),2.77(ddd,J=19.0,12.6,8.0Hz,2H);

[0083] 13 C NMR (CDCl3, 400MHz) δ168.6,167.6,153.7,151.1,136.0,134.6,128.3,128.2,126.5,119.1,99.2,85.6,61.3,39.1,29.7,29.4;

[0084] Example 9

[0085]

[0086] Under a nitrogen atmosphere, 1 (63.6 mg, 0.3 mmol), 2 (62.4 mg, 0.6 mmol), Ir-cat. (0.9 mg, 1 mmol%), pentylene anhydride (55.8 mg, 0.3 mmol), N,N-diisopropylethylamine (38.7 mg, 0.3 mmol), and DMA (3 mL) were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with ethyl acetate (20 mL × 3) and water (10 mL). The combined organic phases were washed with H2O (20 mL × 3) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The target product was obtained by silica gel column chromatography, with petroleum ether and ethyl acetate (volume ratio 1:0.1) as the eluent.

[0087] The characterization data of product 3 are as follows:

[0088] White solid (74% yield, 99% ee)

[0089] 1 H NMR(CDCl3,400MHz)δ7.54-7.39(m,7H),7.36-7.30(m,2H),7.25-7.21(m,1H),6.00(ddd,J=17.0,10.4,6.5Hz,1H),5.56 (d,J=17.1Hz,1H),5.46(d,J=10.4Hz,1H),5.10-5.00(m,1H),3.07(dd,J=12.8,5.1Hz,1H),2.68(dd,J=12.9,9.7Hz,1H);

[0090] 13 C NMR (CDCl3, 400MHz) δ142.8,137.7,136.7,133.0,131.3,129.4,129.2,128.9,128.2,127.7,120.8,119.9,113.9,112.1,81.1,45.3,37.0;

[0091] Example 10

[0092]

[0093] Under a nitrogen atmosphere, 1 (80.4 mg, 0.3 mmol), 2 (62.4 mg, 0.6 mmol), Ir-cat. (0.9 mg, 1 mmol%), pentylene anhydride (55.8 mg, 0.3 mmol), N,N-diisopropylethylamine (38.7 mg, 0.3 mmol), and DMA (3 mL) were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with ethyl acetate (20 mL × 3) and water (10 mL). The combined organic phases were washed with H2O (20 mL × 3) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The target product was obtained by silica gel column chromatography, with petroleum ether and ethyl acetate (volume ratio 1:0.05) as the eluent.

[0094] The characterization data of product 3 are as follows:

[0095] White solid (70% yield, 96% ee)

[0096] 1 H NMR (CDCl3, 400MHz) δ8.40 (d, J=2.3Hz, 1H), 7.90 (dd, J=7.7, 1.0Hz, 1H), 7.78 (dd, J= 8.6,2.4Hz,1H),7.62-7.44(m,2H),7.37(d,J=7.4Hz,1H),7.04(d,J=8.6Hz,1H),5.98 (ddd,J=17.0,10.4,6.4Hz,1H),5.91(s,1H),5.61(dd,J=18.7,7.4Hz,1H),5.47(d,J= 10.4Hz,1H),5.20(s,3H),3.03(dd,J=12.9,5.4Hz,1H),2.59(dd,J=12.9,9.2Hz,1H);

[0097] 13 C NMR(CDCl3,400MHz)δ190.9,160.5,145.9,140.6,135.5,135.2,133.0,132.9,132.2,1 29.6,129.5,128.0,127.7,125.3,121.2,120.9,113.3,103.5,82.8,73.7,42.5,38.1;

[0098] The above are only some embodiments of the present invention and are not intended to limit the present invention in any way. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the invention shall fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing a chiral tetrahydrofuran compound, wherein the chiral tetrahydrofuran compound is compound 3, comprising the following steps: Under a nitrogen atmosphere, 40.8 mg of compound 1, 70.8 mg of compound 2, 0.9 mg of Ir-cat., 55.8 mg of pentovalinic anhydride, 38.7 mg of N,N-diisopropylethylamine, and 3 mL of DMA were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with 20 mL × 3 ethyl acetate and 10 mL of water. The combined organic phases were washed with 20 mL × 3 H2O and 30 mL of saturated brine, dried over anhydrous Na2SO4, concentrated under vacuum, and separated by silica gel column chromatography to obtain compound 3. The eluent was petroleum ether and ethyl acetate in a volume ratio of 1:0.

05. Compound 3 was a white solid with a yield of 97% and an ee of 93%. The structural formulas of compounds 1, 2, 3, and Ir-cat. are as follows:

2. A method for synthesizing a chiral tetrahydrofuran compound, wherein the chiral tetrahydrofuran compound is compound 3, comprising the following steps: Under a nitrogen atmosphere, 46.2 mg of compound 1, 70.8 mg of compound 2, 0.9 mg of Ir-cat., 55.8 mg of pentovalinic anhydride, 38.7 mg of N,N-diisopropylethylamine, and 3 mL of DMA were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with 20 mL × 3 ethyl acetate and 10 mL of water. The combined organic phases were washed with 20 mL × 3 H2O and 30 mL of saturated brine, dried over anhydrous Na2SO4, concentrated under vacuum, and separated by silica gel column chromatography to obtain compound 3. The eluent was petroleum ether and ethyl acetate in a volume ratio of 1:0.

05. Compound 3 was a white solid with a yield of 94% and an ee of 98%. The structural formulas of compounds 1, 2, 3, and Ir-cat. are as follows:

3. A method for synthesizing a chiral tetrahydrofuran compound, wherein the chiral tetrahydrofuran compound is compound 3, comprising the following steps: Under a nitrogen atmosphere, 51.0 mg of compound 1, 70.8 mg of compound 2, 0.9 mg of Ir-cat., 55.8 mg of pentanoic anhydride, 38.7 mg of N,N-diisopropylethylamine, and 3 mL of DMA were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 3 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with 20 mL × 3 ethyl acetate and 10 mL of water. The combined organic phases were washed with 20 mL × 3 H2O and 30 mL of saturated brine, dried over anhydrous Na2SO4, concentrated under vacuum, and separated by silica gel column chromatography to obtain compound 3. The eluent was petroleum ether and ethyl acetate in a volume ratio of 1:0.

05. Compound 3 was a colorless liquid with a yield of 92% and an ee of 94%. The structural formulas of compounds 1, 2, 3, and Ir-cat. are as follows:

4. A method for synthesizing a chiral tetrahydrofuran compound, wherein the chiral tetrahydrofuran compound is compound 3, comprising the following steps: Under a nitrogen atmosphere, 63.6 mg of compound 1, 70.8 mg of compound 2, 0.9 mg of Ir-cat., 55.8 mg of pentanoic anhydride, 38.7 mg of N,N-diisopropylethylamine, and 3 ml of DMA were added sequentially to a 4 ml reaction flask. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with 20 mL × 3 ethyl acetate and 10 mL of water. The combined organic phases were washed with 20 mL × 3 H2O and 30 mL of saturated brine, dried over anhydrous Na2SO4, concentrated under vacuum, and separated by silica gel column chromatography to obtain compound 3. The eluent was petroleum ether and ethyl acetate in a volume ratio of 1:0.

05. Compound 3 was a white solid with a yield of 90% and an ee of 97%. The structural formulas of compounds 1, 2, 3, and Ir-cat. are as follows:

5. A method for synthesizing a chiral tetrahydrofuran compound, wherein the chiral tetrahydrofuran compound is compound 3, comprising the following steps: Under a nitrogen atmosphere, 58.8 mg of compound 1, 70.8 mg of compound 2, 0.9 mg of Ir-cat., 55.8 mg of pentanoic anhydride, 38.7 mg of N,N-diisopropylethylamine, and 3 mL of DMA were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with 20 mL × 3 ethyl acetate and 10 mL of water. The combined organic phases were washed with 20 mL × 3 H2O and 30 mL of saturated brine, dried over anhydrous Na2SO4, concentrated under vacuum, and separated by silica gel column chromatography to obtain compound 3. The eluent was petroleum ether and ethyl acetate in a volume ratio of 1:0.

05. Compound 3 was a white solid with a yield of 90% and an ee of 97%. The structural formulas of compounds 1, 2, 3, and Ir-cat. are as follows:

6. A method for synthesizing a chiral tetrahydrofuran compound, wherein the chiral tetrahydrofuran compound is compound 3, comprising the following steps: Under a nitrogen atmosphere, 65.4 mg of compound 1, 70.8 mg of compound 2, 0.9 mg of Ir-cat., 55.8 mg of pentanoic anhydride, 38.7 mg of N,N-diisopropylethylamine, and 3 ml of DMA were added sequentially to a 4 ml reaction flask. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with 20 mL × 3 ethyl acetate and 10 mL of water. The combined organic phases were washed with 20 mL × 3 H2O and 30 mL of saturated brine, dried over anhydrous Na2SO4, concentrated under vacuum, and separated by silica gel column chromatography to obtain compound 3. The eluent was petroleum ether and ethyl acetate in a volume ratio of 1:0.

1. Compound 3 was a colorless liquid with a yield of 83% and an ee of 96%. The structural formulas of compounds 1, 2, 3, and Ir-cat. are as follows:

7. A method for synthesizing a chiral tetrahydrofuran compound, wherein the chiral tetrahydrofuran compound is compound 3, comprising the following steps: Under a nitrogen atmosphere, 65.4 mg of compound 1, 69.6 mg of compound 2, 0.9 mg of Ir-cat., 55.8 mg of pentanoic anhydride, 38.7 mg of N,N-diisopropylethylamine, and 3 ml of DMA were added sequentially to a 4 ml reaction flask. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with 20 mL × 3 ethyl acetate and 10 mL of water. The combined organic phases were washed with 20 mL × 3 H2O and 30 mL of saturated brine, dried over anhydrous Na2SO4, concentrated under vacuum, and separated by silica gel column chromatography to obtain compound 3. The eluent was petroleum ether and ethyl acetate in a volume ratio of 1:0.

2. Compound 3 was a yellow solid with a yield of 95% and an ee of 99%. The structural formulas of compounds 1, 2, 3, and Ir-cat. are as follows:

8. A method for synthesizing a chiral tetrahydrofuran compound, wherein the chiral tetrahydrofuran compound is compound 3, comprising the following steps: Under a nitrogen atmosphere, 65.4 mg of compound 1, 62.4 mg of compound 2, 0.9 mg of Ir-cat., 55.8 mg of pentanoic anhydride, 38.7 mg of N,N-diisopropylethylamine, and 3 mL of DMA were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with 20 mL × 3 ethyl acetate and 10 mL of water. The combined organic phases were washed with 20 mL × 3 H2O and 30 mL of saturated brine, dried over anhydrous Na2SO4, concentrated under vacuum, and separated by silica gel column chromatography to obtain compound 3. The eluent was petroleum ether and ethyl acetate in a volume ratio of 1:0.

1. Compound 3 was a white solid with a yield of 90% and an ee of 99%. The structural formulas of compounds 1, 2, 3, and Ir-cat. are as follows:

9. A method for synthesizing a chiral tetrahydrofuran compound, wherein the chiral tetrahydrofuran compound is compound 3, comprising the following steps: Under a nitrogen atmosphere, 63.6 mg of compound 1, 62.4 mg of compound 2, 0.9 mg of Ir-cat., 55.8 mg of pentovalinic anhydride, 38.7 mg of N,N-diisopropylethylamine, and 3 mL of DMA were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with 20 mL × 3 ethyl acetate and 10 mL of water. The combined organic phases were washed with 20 mL × 3 H2O and 30 mL of saturated brine, dried over anhydrous Na2SO4, concentrated under vacuum, and separated by silica gel column chromatography to obtain compound 3. The eluent was petroleum ether and ethyl acetate in a volume ratio of 1:0.

1. Compound 3 was a white solid with a yield of 74% and an ee of 99%. The structural formulas of compounds 1, 2, 3, and Ir-cat. are as follows:

10. A method for synthesizing a chiral tetrahydrofuran compound, wherein the chiral tetrahydrofuran compound is compound 3, comprising the following steps: Under a nitrogen atmosphere, 80.4 mg of compound 1, 62.4 mg of compound 2, 0.9 mg of Ir-cat., 55.8 mg of pentanoic anhydride, 38.7 mg of N,N-diisopropylethylamine, and 3 mL of DMA were added sequentially to a 4 mL reaction flask. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into a separatory funnel and extracted with 20 mL × 3 ethyl acetate and 10 mL of water. The combined organic phases were washed with 20 mL × 3 H2O and 30 mL of saturated brine, dried over anhydrous Na2SO4, concentrated under vacuum, and separated by silica gel column chromatography to obtain compound 3. The eluent was petroleum ether and ethyl acetate in a volume ratio of 1:0.

05. Compound 3 was a white solid with a yield of 70% and an ee of 96%. The structural formulas of compounds 1, 2, 3, and Ir-cat. are as follows: 。

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