A method for synthesizing chiral dihydropyridine spirocyclic compounds by rhodium-catalyzed asymmetric dearomatization and cyclization.

Abstract

This invention discloses a rhodium-catalyzed asymmetric dearomatization cyclization method for synthesizing chiral dihydropyridine spirocyclic compounds, belonging to the field of asymmetric catalytic synthesis technology. The method uses a rhodium chiral bisphosphine complex and a base as the catalytic system, and alkynylpyridine salts and arylboronic acids as substrates to synthesize chiral dihydropyridine spirocyclic compounds through asymmetric dearomatization cyclization. The synthesis process of this invention is simple to operate, uses inexpensive and readily available reactants, operates under mild reaction conditions (not exceeding 60°C), exhibits high reactivity and enantioselectivity, complete reaction, specific products, and convenient separation, and can obtain pure products with high enantiomeric excess (up to 98%), showing excellent application prospects.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric catalytic synthesis technology, specifically relating to a method for synthesizing chiral dihydropyridine spirocyclic compounds using rhodium-catalyzed asymmetric dearomatization cyclization. Background Technology

[0002] Chiral dihydropyridine spirocyclic skeletons are important structural units of alkaloids, widely found in many natural products and physiologically active molecules. For example, histrionicotoxin is a potent nicotinic acetylcholine receptor inhibitor; the tetracyclic alkaloid Nankakurine A can induce the secretion of neurotrophic factors and promote neuronal differentiation (References: (a) Spivak, CE; Maleque, MA; Oliveira, AC; Masukawa, LM; Tokuyama, T.; Daly, JW; Albuquerque, EX. Mol. Pharmacol. 1981, 21, 351; (b) Hirasawa, Y.; Kobayashi, J.; Obara, Y.; Nakahata, N.; Kawahara, N.; Goda, Y.; Morita, H.; Nankakurine, B. Heterocycles 2006, 68, 2357.). Most current synthetic routes for chiral dihydropyridine spirocyclic compounds suffer from drawbacks such as long steps, low yields, and difficulty in controlling enantioselectivity. Therefore, developing a simple, efficient, high-yield, and highly enantioselective method for synthesizing chiral dihydropyridine spirocyclic compounds is a highly attractive research direction. Summary of the Invention

[0003] The purpose of this invention is to provide a method for synthesizing chiral dihydropyridine spirocyclic compounds by rhodium-catalyzed asymmetric dearomatization cyclization. The synthesis process of this invention is simple and practical, the raw materials are inexpensive and readily available, the reaction conditions are mild, the reaction has high enantioselectivity, high yield, and also has the advantages of high atom economy and environmental friendliness.

[0004] To achieve the above objectives, the technical solution of the present invention is as follows:

[0005] This invention provides a method for synthesizing chiral dihydropyridine spirocyclic compounds by rhodium-catalyzed asymmetric dearomatization cyclization, using a rhodium chiral bisphosphine complex and a base as the catalytic system, and alkynylpyridine salt compound 1 and arylboronic acid 2 as substrates, to synthesize chiral dihydropyridine spirocyclic compound 3 by asymmetric dearomatization cyclization;

[0006] The reaction formula is as follows:

[0007]

[0008] In the formula:

[0009] Ar' is selected from phenyl, naphthyl, substituted phenyl, thiophene-2-yl; Ar is selected from phenyl, naphthyl, substituted phenyl; R is selected from C1 to C2. 10 The alkyl, phenyl, naphthyl, or substituted phenyl groups; X is selected from iodine, bromine, trifluoromethanesulfonate, hexafluorophosphate, and tetrafluoroborate. The substituents of the substituted phenyl groups are independently selected from C1-C6 alkyl, halogen, methoxy, and phenyl groups.

[0010] The chiral bisphosphine ligand in the rhodium chiral bisphosphine complex is at least one of (S)-BINAP, (S)-SynPhos, (S)-SegPhos, (R)-P-Phos, (S)-SDP, and (S)-Xyl-SDP.

[0011] Based on the above technical solution, further, the alkali is one or more of sodium bicarbonate, sodium acetate, sodium carbonate, potassium acetate, potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide, triethylamine, and diisopropylethylamine; the molar ratio of the alkali to the alkynylpyridine salt compound 1 is 1.5:1 to 4.0:1, preferably 2.5:1.

[0012] Based on the above technical solution, further, the molar ratio of arylboronic acid 2 and alkynylpyridine salt compound 1 is 1.5:1 to 4.0:1, preferably 2.5:1.

[0013] Based on the above technical solution, further, the molar ratio of the rhodium and alkynylpyridine salt compound 1 is 0.01:1 to 0.05:1, preferably 0.025:1.

[0014] Based on the above technical solution, further, the reaction temperature is 30-60℃, preferably 40-50℃; for example, 40℃, 45℃, 50℃; the reaction time is 12-72 hours, preferably 36-60 hours, and more preferably 48 hours.

[0015] Based on the above technical solution, furthermore, the reaction solvent is one or more of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane (1,4-Dioxane), methyl tert-butyl ether (MTBE), toluene, ethyl acetate (EtOAc), and dichloromethane (DCM), preferably 1,4-dioxane, ethyl acetate, or tetrahydrofuran.

[0016] Based on the above technical solution, the chiral dihydropyridine spirocyclic compound is further selected from one of the following 3a, 3b, 3c, 3d, 3e, 3f, 3g, and 3h;

[0017]

[0018] Based on the above technical solution, the method further includes the following steps:

[0019] The rhodium precursor and chiral bisphosphine ligand were added to a solvent and stirred at room temperature for 20–60 minutes. The above system was then added to alkynylpyridine salt compound 1 and arylboronic acid 2. A base was added, and the mixture was stirred at 40–50 °C for 12–72 h. The chiral dihydropyridine spirocyclic compound was then separated by column chromatography.

[0020] Based on the above technical solution, further, the molar ratio of the rhodium precursor to the chiral bisphosphine ligand is 1:1 to 1:4, preferably 1:2; the molar ratio of the rhodium precursor to the alkynylpyridine salt compound 1 is 0.01:1 to 0.05:1, preferably 0.025:1.

[0021] Based on the above technical solution, further, the amount of solvent used is 0.5 to 5 mL of solvent per 0.2 mmol of alkynylpyridine salt compound, preferably 3 mL of solvent.

[0022] Based on the above technical solution, further, the alkynylpyridine salt compound 1 is a 5-methoxycarbonyl phenyl-substituted alkynylpyridine trifluoromethanesulfonate, the arylboronic acid 2 is phenylboronic acid, the rhodium precursor is dichloro(vinyl)rhodium dimer, the chiral bisphosphine ligand is (S)-SDP, the base is sodium carbonate, the solvent is 1,4-dioxane, the reaction temperature is 40℃, the yield is over 97%, and the enantiomeric excess is over 98%.

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] 1. The synthesis process of the present invention is simple to operate, the reaction raw materials are inexpensive and readily available, the reaction conditions are mild (not higher than 60°C), the reaction activity and enantioselectivity are high, the reaction is complete, the product is specific, the separation is convenient, and a high enantiomeric excess of pure product can be obtained (enantiomeric excess can reach 98%).

[0025] 2. The synthesis process of this invention can yield various types of chiral dihydropyridine spirocyclic compounds by selecting substrates with different substituents.

[0026] 3. The catalyst used in the synthesis process of this invention has a simple preparation process, high catalyst activity, and requires a small amount of addition.

[0027] 4. Compared with traditional synthesis methods, this invention can obtain a large number of chiral dihydropyridine spirocyclic compounds with a small amount of chiral catalyst, achieving chiral enhancement. Moreover, the reaction steps are short, and a variety of chiral dihydropyridine spirocyclic compounds can be synthesized in one step with high yield and enantioselectivity, and the substrate range is relatively broad. Detailed Implementation

[0028] The present invention is described in detail below through embodiments; however, the present invention is not limited to the embodiments described below.

[0029] The synthesis of the substituted alkynylquinoline trifluoromethanesulfonate in the examples is described in references Robinson, DJ; Spurlin, SP; Gorden, JD; Karimov, RRACS Catal. 2020, 10, 51;

[0030] In the examples, the chiral bisphosphine ligands were purchased from Strem or Leyen.

[0031] Example 1: Condition Optimization

[0032] Weighed dichlorovinylrhodium dimer (2.5 mol%, 0.0025 mmol) and chiral bisphosphine ligand L* (5 mol%, 0.005 mmol) were added to an ampoule. 0.5 mL of solvent was added and stirred for 30 minutes. The system was then rinsed with 1.0 mL of solvent into a 15 mL sealed tube containing 5-phenyl-substituted alkynylpyridine trifluoromethanesulfonate 1a (0.1 mmol) and phenylboronic acid 2a (0.25 mmol). Sodium carbonate (2.5 equivalents, 0.25 mmol) was added. The tube was then sealed and reacted at 40–50 °C for 48 hours. After cooling to room temperature, the solvent was removed by rotary evaporation, and the product was directly separated by column chromatography (eluent: petroleum ether, ethyl acetate, volume ratio 5:1) to obtain the pure product. The structure and reaction formula of chiral bisphosphine ligand L* are as follows:

[0033]

[0034] The yield was NMR yield, and the enantiomeric excess (ee value) of the product was determined by chiral liquid chromatography. The reaction conditions and results are shown in Table 1.

[0035] Table 1. Screening of chiral bisphosphine ligands, solvents, and reaction temperatures

[0036]

[0037] Based on the yields and enantiomeric excess results of dihydropyridine spirocyclic compounds in Experiments 1-4, the preferred chiral bisphosphine ligands are L1, L3, and L4, with L4 being particularly preferred. Based on the yields and enantiomeric excess results of dihydropyridine spirocyclic compounds in Experiments 4-8, the preferred organic solvents are THF, EtOAc, 1,4-Dioxane, and 2Me-THF, with THF, EtOAc, and 1,4-Dioxane being particularly preferred. Based on the yields and enantiomeric excess results of dihydropyridine spirocyclic compounds in Experiments 6, 9-10, the preferred reaction temperature is 40–50 °C.

[0038] Example 2: Rhodium-catalyzed asymmetric dearomatization cyclization of alkynylpyridine trifluoromethanesulfonate with arylboronic acid to synthesize chiral dihydropyridine spirocyclic compounds.

[0039] Weighed dichlorovinylrhodium dimer (2.5 mol%, 0.005 mmol) and chiral bisphosphine ligand (S)-SDP (5 mol%, 0.01 mmol) were added to an ampoule, followed by stirring for 30 minutes with 1.0 mL of 1,4-dioxane. The system was then rinsed with 2.0 mL of 1,4-dioxane into a 15 mL sealed tube containing substituted alkynylpyridine trifluoromethanesulfonate 1 (0.2 mmol) and arylboronic acid 2 (0.5 mmol). Sodium carbonate (2.5 equivalents, 0.5 mmol) was added. The tube was then sealed and reacted at 40 °C for 48 hours. After cooling to room temperature, the solvent was removed by rotary evaporation, followed by direct column chromatography (eluent: petroleum ether, ethyl acetate, volume ratio 5:1) to obtain the pure product. The reaction formula and experimental results are as follows:

[0040]

[0041] The yield was the separation yield, and the enantiomeric excess of the product was determined by chiral liquid chromatography.

[0042] This invention synthesizes chiral dihydropyridine spirocyclic compounds via rhodium-catalyzed asymmetric dearomatization cyclization of alkynylpyridine trifluoromethanesulfonate and arylboronic acid, achieving an enantiomeric excess of up to 98%. The synthetic process is simple and practical, using inexpensive and readily available raw materials, with mild reaction conditions, high enantioselectivity, high yield, and advantages such as high atom economy and environmental friendliness.

[0043] The chiral dihydropyridine spirocyclic compounds prepared in the above embodiments have a chiral dihydropyridine spirocyclic structure as their core skeleton. Currently, the core skeletons of the potent nicotinic acetylcholine receptor inhibitor hisstrionicotoxin and the tetracyclic alkaloid Nankakurine A, which induces the secretion of neurotrophic factors and promotes neuronal differentiation, both contain a chiral dihydropyridine spirocyclic structure. Therefore, the chiral dihydropyridine spirocyclic compounds prepared in the embodiments of this invention can be used as prodrug compounds for drug development and have very high application value.

[0044] The characterization data of the compounds in the examples are as follows:

[0045] (+)-Methyl(E)-4-benzylidene-1'-methyl-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-pyridine]-5'-carboxylate(3a): 63.2 mg, 88% yield, pale yellow oily liquid, novel compound, R f =0.55 (petroleum ether / ethyl acetate 5 / 1), 96% ee, [α] 20 D = +341.45(c 1.02, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.66 (dd, J=8.0, 1.3Hz, 1H), 7.59 (dd, J=7.7, 1.5Hz, 1H), 7.44-7.31 (m,

[0046]

[0047] 50.8, 39.0, 35.2, 23.2. HPLC: Chiralpak AD-H column, 254 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow = 1.0 mL / min, retention time 11.6 min (major) and 15.2 min. HRMS calculated for C 24 H 24 NO2[M+H] + 358.1802, found: 358.1800.

[0048] (+)-Methyl(E)-4-benzylidene-1',7-dimethyl-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-pyridine]-5'-carboxylate(3b): 69.5 mg, 94% yield, yellow oily liquid, novel compound, R f =0.60

[0049]

[0050] 2.37 (s, 3H), 2.23–2.12 (m, 2H). 13C NMR (100MHz, CDCl3) δ167.1,148.2,140.3,138.5,137.8,136.1,132.9,130.0,129.4,129.0,128 .3,126.8,124.6,123.8,118.3,117.9,95.3,63.4,50.8,39.0,35.2,23.2,21.4.HPLC:Chiralpak AD-H column, 254nm, 30℃, n-hexane / isopropanol=80 / 20, flow=0.9mL / min, retention time 10.7min(major)and12.5min.HRMSCalculated for C 25 H 26 NO2[M+H] + 372.1958, found: 372.1961.

[0051] (+)-Methyl(E)-4-benzylidene-7-methoxy-1'-methyl-3,4-dihydro-1'H,2H-spiro[naph-thalene-1,2'-pyridine]-5'-carboxylate(3c): 70.8 mg, 91% yield, yellow oily liquid, novel compound, R f =0.50 (petroleum ether / ethyl acetate 4 / 1), 98% ee, [α] 20 D = +323.05(c 1.01, CHCl3). 1 H

[0052]

[0053] (100MHz, CDCl3) δ160.0,148.1,141.9,137.9,135.7,129.4,128.6,128.4,126.7,126.2 ,123.0,118.2,114.7,113.8,95.6,63.6,55.5,50.8,39.0,35.0,23.2.HPLC:Chiralpak AD-Hcolumn, 254nm, 30℃, n-hexane / isopropyl alcohol=80 / 20, flow=1.0mL / min, retention time 12.7min (major) and 17.1min.HRMS Calculated for C 25 H 26 NO3[M+H] +388.1907, found: 388.1901.

[0054] (+)-Methyl(E)-4-Benzylidene-1'-methyl-3,4-dihydro-1'H,2H-spiro[anthracene-1,2'-pyridine]-5'-carboxylate(3d): 77.3 mg, 95% yield, yellow oily liquid, novel compound, R f =0.50 (petroleum ether / ethyl acetate 5 / 1), 96% ee, [α] 20 D = +219.15(c 0.72, CHCl3). 1 H NMR (400)

[0055]

[0056] 128.4, 127.9, 127.8, 127.0, 126.6, 126.3, 125.5, 123.7, 118.3, 117.5, 95.5, 63.7, 50.8, 39.1, 35.3, 23.4. HPLC: Chiralpak AD-H column, 254 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow = 1.0 mL / min, retention time 11.8 min (major) and 22.4 min. HRMS calculated for C 28 H 26 NO2[M+H] + 408.1958, found: 408.1961.

[0057] (+)-Methyl(E)-4-benzylidene-7-ethoxy-1'-methyl-3,4-dihydro-1'H,2H-spiro[naphthale-ne-1,2'-pyridine]-5'-carboxylate(3e): 78.1 mg, 97% yield, yellow oily liquid, novel compound, R f = 0.45 (petroleum ether / ethyl acetate 5 / 1), 97% ee, [α] 20 D = +365.06(c 1.22, CHCl3). 1 H NMR (400)

[0058]

[0059] J = 7.0 Hz, 3H). 13 C10 NMR (100MHz, CDCl3) δ 167.0, 159.4, 148.1, 141.8, 137.9, 135.7, 129.3, 128.4, 128.3, 126.6, 126.1, 122.8, 118.1, 118.1, 115.0, 114.4, 95.5, 63.7, 63.6, 50.8, 38.9, 35.0, 23.2, 14.8. HPLC: Chiralpak AD-H column, 254nm, 30℃, n-hexane / isopropanol = 80 / 20, flow = 1.0mL / min, retention time 10.4min (major) and 11.7min. HRMS calculated for C10 NMR. 26 H 28 NO3[M+H] + 402.2064, found: 402.2067.

[0060] (+)-Ethyl(E)-4-benzylidene-1'-methyl-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-pyridine]-5'-carboxylate(3f): 65.4 mg, 88% yield, yellow oily liquid, novel compound, R f =0.50 (petroleum ether / ethyl acetate 5 / 1), 97% ee, [α] 20 D = +351.74 (c 1.30, CHCl3). 1 HNMR (400MHz,

[0061] 7.1Hz, 3H). 13C10 NMR (100MHz, CDCl3) δ 166.7, 148.0, 140.5, 137.7, 136.2, 135.6, 129.8, 129.4, 128.6, 128.4, 127.9, 127.0, 124.8, 124.6, 118.1, 118.1, 95.7, 63.5, 59.3, 39.0, 35.2, 23.2, 14.8. HPLC: Chiralpak AD-H column, 254nm, 30℃, n-hexane / isopropanol = 80 / 20, flow = 1.0mL / min, retention time 10.4min (major) and 17.1min. HRMS Calculated for C10 NMR. 25 H 26 NO2[M+H] + 372.1958, found: 372.1963.

[0062] (+)-Methyl(E)-1'-methyl-4-(4-methylbenzylidene)-3,4-dihydro-1'H,2H-spiro[naphtha-lene-1,2'-pyridine]-5'-carboxylate (3g): 71.2mg, 96% yield, yellow oily liquid, novel compound, R f =0.55 (petroleum ether / ethyl acetate 5 / 1), 97% ee, [α] 20 D = +401.39(c 1.27, CHCl3). 1 H NMR (400)

[0063]

[0064] 129.3, 129.1, 128.4, 127.9, 124.8, 124.6, 118.2, 117.9, 95.3, 63.5, 50.8, 39.0, 35.1, 23.2, 21.4. HPLC: Chiralpak AD-H column, 254 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow = 1.0 mL / min, retention time 13.6 min (major) and 17.2 min. HRMS calculated for C 25 H 26 NO2[M+H] + 372.1958, found: 372.1964.

[0065] (+)-Methyl(E)-4-(4-chlorobenzylidene)-1'-methyl-3,4-dihydro-1'H,2H-spiro[naphtha-lene-1,2'-pyridine]-5'-carboxylate(3h): 64.4 mg, 82% yield, yellow oily liquid, new compound, R f =0.50 (petroleum ether / ethyl acetate 5 / 1), 96% ee, [α] 20 D = +438.82(c 1.22, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.64 (dd, J=7.9, 1.3Hz, 1H), 7.60 (dd, J=7.9, 1.5Hz, 1H), 7.43-7.26 (m,

[0066] Alcohol=80 / 20, flow=1.0mL / min, retention time 15.6min(major)and18.1min.HRMSCalculated for C 24 H 23 ClNO2[M+H] + 392.1412( 35 Cl)and 394.1398( 37 Cl), found: 392.1415 ( 35 Cl)and 394.1387( 37 Cl).

[0067] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; modifications or equivalent substitutions may be made to the technical solutions described in the foregoing embodiments, and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing chiral dihydropyridine spirocyclic compounds by rhodium-catalyzed asymmetric dearomatization cyclization, characterized in that, Using a rhodium chiral bisphosphine complex and a base as a catalytic system, and alkynylpyridine salt compound 1 and arylboronic acid 2 as substrates, a chiral dihydropyridine spirocyclic compound 3 was synthesized. The reaction formula is as follows: In the formula: Ar' is selected from phenyl, naphthyl, substituted phenyl, thiophene-2-yl; Ar is selected from phenyl, naphthyl, substituted phenyl; R is selected from C1 to C2. 10 The alkyl, phenyl, naphthyl, or substituted phenyl groups; X is selected from iodine, bromine, trifluoromethanesulfonate, hexafluorophosphate, or tetrafluoroborate; the substituents of the substituted phenyl groups are independently selected from C1 to C6 alkyl, halogen, methoxy, or phenyl groups; The chiral bisphosphine ligand in the rhodium chiral bisphosphine complex is at least one of (S)-BINAP, (S)-SynPhos, (S)-SegPhos, (R)-P-Phos, (S)-SDP, and (S)-Xyl-SDP.

2. The method as described in claim 1, characterized in that, The base is one or more of sodium bicarbonate, sodium acetate, sodium carbonate, potassium acetate, potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide, triethylamine, and diisopropylethylamine; the molar ratio of the base to the alkynylpyridine salt compound 1 is 1.5:1 to 4.0:1, preferably 2.5:

1.

3. The method as described in claim 1, characterized in that, The molar ratio of arylboronic acid 2 to alkynylpyridine salt compound 1 is 1.5:1 to 4.0:1, preferably 2.5:1; the molar ratio of rhodium to alkynylpyridine salt compound 1 is 0.01:1 to 0.05:1, preferably 0.025:

1.

4. The method as described in claim 1, characterized in that, The reaction temperature is 30–60°C, preferably 40–50°C; the reaction time is 12–72 hours, preferably 36–60 hours, and more preferably 48 hours.

5. The method as described in claim 1, characterized in that, The reaction solvent is one or more of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane (1,4-Dioxane), methyl tert-butyl ether (MTBE), toluene, ethyl acetate (EtOAc), and dichloromethane (DCM), preferably 1,4-dioxane, ethyl acetate, or tetrahydrofuran.

6. The method as described in claim 1, characterized in that, The chiral dihydropyridine spirocyclic compound is selected from one of the following 3a, 3b, 3c, 3d, 3e, 3f, 3g, and 3h; 7. The method according to any one of claims 1-6, characterized in that, The method includes the following steps: The rhodium precursor and chiral bisphosphine ligand were added to a solvent and stirred at room temperature for 20–60 minutes. The above system was then added to alkynylpyridine salt compound 1 and arylboronic acid 2. A base was added, and the mixture was stirred at 40–50 °C for 12–72 h. The chiral dihydropyridine spirocyclic compound was then separated by column chromatography.

8. The method as described in claim 7, characterized in that, The molar ratio of the rhodium precursor to the chiral bisphosphine ligand is 1:1 to 1:4, preferably 1:2; the molar ratio of the rhodium precursor to the alkynylpyridine salt compound 1 is 0.01:1 to 0.05:1, preferably 0.025:

1.

9. The method as described in claim 7, characterized in that, The amount of solvent used is 0.5 to 5 mL of solvent per 0.2 mmol of alkynylpyridine salt compound, preferably 3 mL of solvent.

10. The method as described in claim 7, characterized in that, The alkynylpyridine salt compound 1 is a 5-methoxycarbonyl phenyl-substituted alkynylpyridine trifluoromethanesulfonate, the arylboronic acid 2 is phenylboronic acid, the rhodium precursor is dichloro(vinyl)rhodium dimer, the chiral bisphosphine ligand is (S)-SDP, the base is sodium carbonate, the solvent is 1,4-dioxane, the reaction temperature is 40℃, the yield is over 97%, and the enantiomeric excess is over 98%.

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