A method for the synthesis of chiral five-membered heterocyclic alcohol derivatives catalyzed by nickel (II)

Abstract

The present invention discloses a method for nickel(II)-catalyzed synthesis of chiral five-membered heterocyclic alcohol derivatives. The five-membered heterocyclic alcohol compounds are compounds with the following general formula or enantiomers and racemates of the compounds: The present invention uses inexpensive Ni(II) metal salts and BI-DIME as catalysts to catalyze the reductive cyclization reaction of alkynones. This reaction has high catalytic efficiency, high enantioselectivity and E / Z selectivity. A series of tetrahydrofuran / pyrrolidine derivatives with chiral tertiary alcohols are synthesized using this catalyst in the present invention. This method has the advantages of mild reaction conditions, low catalyst dosage and low cost, and has high application value and good prospects for popularization and application.

Description

Technical Field

[0001] The present invention relates to a new method for the reductive coupling of alkynones catalyzed by nickel(II) to synthesize chiral five-membered heterocyclic alcohol derivatives, and belongs to the technical field of organic synthesis. Background Art

[0002] Heterocyclic compounds with chiral alcohols, such as compounds containing tetrahydrofuran, indole and pyrrolidinol, are commonly present in the structures of natural products and chiral drugs, and compounds with such structures have important application values. For example, the tetrahydrofuran ring with chiral alcohol: Eribulin is a compound synthesized by mimicking the marine macrolide halichondrin B and shows anti-breast cancer activity in clinical trials. (+)-Viratriol is a natural product present in marine strains, which has strong cytotoxicity and good effects in anti-cancer. Jaspine B is a natural product present in sponges, which shows strong dose-dependent and time-dependent cytotoxicity against melanoma cells. For example, the pyrrole ring with chiral alcohol, such as Nifeviroc is a new antagonist of CCR5 in clinical practice and is mainly used for anti-HIV-1 infection. Alkaloids containing the Convolutamydine A skeleton are present in some bioactive compounds or natural products, and derivatives of this skeleton can be used in the synthesis of pharmaceutical intermediates and drug molecules. (S)-SM-130686 is an orally active hormone that promotes growth hormone secretion, which can be synthesized artificially and used for the treatment of growth hormone deficiency.

[0003] The reductive coupling reaction of alkynones is an important method for constructing five-membered heterocycles with chiral alcohols. Past studies mainly used noble metals such as Pd, Rh, Ru and Ir as catalytic metals. Although good reaction activities can be obtained, due to the high prices of these catalytic metals and serious environmental pollution during use, their large-scale applications are limited. It was not until Montgomery and Jamison discovered the reductive coupling reaction of alkynes and carbonyls catalyzed by nickel that people gradually paid attention to the research of its catalytic performance. However, due to various reasons such as limited scope of application, difficulty in synthesizing catalysts and high costs, its application in chiral synthesis has been progressing slowly. To sum up, there is an urgent need in this field for a method with high enantioselectivity, low synthesis cost and wide scope of application to achieve the asymmetric reductive coupling of alkynones and efficiently construct heterocyclic compounds with chiral alcohols. Summary of the Invention

[0004] In view of the above problems and defects existing in the prior art, the present invention has developed a method for constructing chiral five-membered heterocyclic alcohol derivatives by the reductive coupling of alkynones catalyzed by inexpensive nickel(II).

[0005] To achieve the above-mentioned invention object, the technical solution adopted by the present invention is as follows:

[0006] Under nitrogen protection, a certain amount of Ni(OAc)2·4H2O, (S)-BI-DIME, and tetrahydrofuran were added to a reaction flask and stirred for a certain time. Then, a certain amount of HBpin (pinacol borane), COD (1,5-cyclooctadiene), and a tetrahydrofuran solution of alkynone 1 were added respectively, and the mixture was stirred at -5°C for a certain time. After the reaction was completed, the reaction was quenched with a certain amount of saturated sodium bicarbonate, extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with saturated sodium chloride, the organic phase was separated, an appropriate amount of anhydrous sodium sulfate was added for drying for a certain time, filtered, the solvent was recovered by distillation under reduced pressure, and the target compound was obtained by silica gel column chromatography separation and purification.

[0007] The alkynone structure used in the present invention is as follows:

[0008]

[0009] The reaction results of different alkynones in the present invention are shown as follows:

[0010]

[0011] The advantages of the present invention are as follows: This method uses Ni(OAc)2·4H2O and chiral ligand BI-DIME as catalysts to synthesize a series of tetrahydrofuran / pyrrolidine derivatives with chiral tertiary alcohols efficiently, with high enantioselectivity and high E / Z selectivity. At the same time, this method has mild reaction conditions and is easy to operate. Due to the low cost of the catalyst, the technology of the present invention has potential application value and strong economic practicability. Description of the Drawings

[0012] Figure 1 is the 1H NMR spectrum of compound 2a.

[0013] Figure 2 is the 1H NMR spectrum of compound 2b

[0014] Figure 3 is the 1H NMR spectrum of compound 2c

[0015] Figure 4 is the 1H NMR spectrum of compound 2d

[0016] Figure 5 is the 1H NMR spectrum of compound 2e

[0017] Figure 6 is the 1H NMR spectrum of compound 2f

[0018] Figure 7 is the 1H NMR spectrum of compound 2g

[0019] Figure 8 1H NMR spectrum of compound 2h

[0020] Figure 9 1H NMR spectrum of compound 2i

[0021] Figure 10 1H NMR spectrum of compound 2j

[0022] Figure 11 1H NMR spectrum of compound 2k

[0023] Figure 12 1H NMR spectrum of compound 2l

[0024] Figure 13 1H NMR spectrum of compound 2m

[0025] Figure 14 1H NMR spectrum of compound 2n

[0026] Figure 15 1H NMR spectrum of compound 2o

[0027] Figure 16 1H NMR spectrum of compound 2p

[0028] Figure 17 1H NMR spectrum of compound 2q

[0029] Figure 18 1H NMR spectrum of compound 2r

[0030] Figure 19 1H NMR spectrum of compound 2s

[0031] Figure 20 1H NMR spectrum of compound 2t

[0032] Figure 21 1H NMR spectrum of compound 2u

[0033] Figure 22 1H NMR spectrum of compound 2v

[0034] Figure 23 1H NMR spectrum of compound 2w

[0035] Figure 24 1H NMR spectrum of compound 2x Detailed implementation mode

[0036] Examples

[0037]

[0038] Under nitrogen protection, 1.2 mg (0.005 mmol, 5 mol%) of Ni(OAc)2·4H2O, 1.6 mg (0.005 mmol, 5 mol%) of (S)-BI-DIME and 0.3 ml of tetrahydrofuran were added to a 4 ml reaction flask and stirred for five minutes. Then, 9 μL of HBpin (0.005 mmol, 1 equiv) and 3 μL of cod (0.005 mmol, 1 equiv) were added to the reaction flask and stirred. Finally, a solution of alkynone 1 (0.1 mmol, 1 equiv) in tetrahydrofuran (0.2 mL) was slowly added dropwise to the reaction vial, the bottle mouth was sealed, and the reaction flask was placed in a -5 °C low-temperature reactor and stirred for 20 hours. After the reaction was completed, tetrahydrofuran was removed by distillation under reduced pressure, and the residue obtained was separated and purified by silica gel column chromatography (ethyl acetate / n-hexane = 20 / 80) to obtain the target product 2.

[0039] The reaction results of different alkynones in the present invention are as follows:

[0040]

[0041] Compound 2a: White solid, 92% yield, >99:1 er. = +8.56 (c = 1.0, CH2Cl2; er value was determined by high performance liquid chromatography, separation conditions: chiral AD-H column, 25 °C, flow rate: 0.5 mL / min, n-hexane / isopropanol: 10 / 90, 254 nm, 10.63 min (S), 12.48 min (R). 1 H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.48–7.42 (m, 2H), 7.36–7.25 (m, 8H), 7.13 (d, J = 7.4 Hz, 2H), 6.28 (t, J = 2.4 Hz, 1H), 4.50 (dd, J = 15.0, 2.4 Hz, 1H), 4.25 (dd, J = 15.0, 2.5 Hz, 1H), 3.57 (dd, J = 22.5, 10.4 Hz, 2H), 2.50 (s, 1H), 2.41 (s, 3H).

[0042] Compound 2b: Yellow oil, 90% yield, 99:1 er. = +17.86 (c = 1.0, CH2Cl2); er value was determined by high performance liquid chromatography, separation conditions: chiral AD-H column, 25 °C, flow rate: 0.5 mL / min, n-hexane / isopropanol: 10 / 90, 254 nm, 9.78 min (S), 17.67 min (R). 11H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.49–7.42 (m, 2H), 7.39–7.29 (m, 5H), 7.23 (d, J = 8.2 Hz, 2H), 6.34 (s, 1H), 4.47 (dd, J = 15.1, 2.5 Hz, 1H), 4.24 (dd, J = 15.1, 2.6 Hz, 1H), 3.59 (s, 2H), 2.55 (s, 1H), 2.43 (s, 3H).

[0043] Compound 2c: Colorless oil, 88% yield, 99:1 er, = +21.32 (c = 1.0, CH2Cl2); er value was determined by high performance liquid chromatography, separation conditions: chiral AD-H column, 25 °C, flow rate: 0.5 mL / min, n-hexane / isopropanol: 15 / 85, 254 nm, 13.37 min (S), 23.96 min (R). 1 1H NMR (500 MHz, CDCl3) δ 7.77–7.68 (d, 2H), 7.44 (d, J = 7.4 Hz, 2H), 7.38–7.28 (m, 7H), 7.05 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 8.4, 1.9 Hz, 1H), 6.86 (dd, J = 46.2, 8.9 Hz, 1H), 6.25 (d, J = 9.3 Hz, 1H), 4.45 (ddd, J = 15.0, 7.3, 2.1 Hz, 1H), 4.21 (ddd, J = 15.0, 6.8, 2.2 Hz, 1H), 3.62–3.52 (m, 2H), 2.52 (s, 1H), 2.42 (s, 3H).

[0044] Compound 2d: Yellow oil, 84% yield, >99:1 er. = +21.0 (c = 1.0, CH2Cl2); The er value was determined by high performance liquid chromatography. Separation conditions: chiral AD-H column, 25 °C, flow rate: 1 mL / min, n-hexane / isopropanol: 25 / 75, 254 nm, 10.01 min (S), 10.61 min (R). 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 7.0 Hz, 2H), 7.38–7.31 (m, 6H), 6.98 (m, J = 25.2, 15.9, 4.9 Hz, 2H), 6.84 (d, J = 10.0 Hz, 1H), 6.29 (s, 1H), 4.49 (dd, J = 15.1, 2.2 Hz, 1H), 4.25 (dd, J = 15.1, 2.3 Hz, 1H), 3.63–3.58 (q, 2H), 2.56 (d, J = 14.4 Hz, 1H), 2.45 (s, 3H).

[0045] Compound 2e: White solid, 70% yield, 98:2 er. = +9.3 (c = 1.0, CH2Cl2); The er value was determined by high performance liquid chromatography. Separation conditions: chiral AD-H column, 25 °C, flow rate: 0.5 mL / min, n-hexane / isopropanol: 10 / 90, 254 nm, 11.00 min (S), 13.44 min (R). 1 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 7.1 Hz, 2H), 7.37–7.30 (m, 5H), 7.26 (s, 1H), 7.17–7.09 (m, 2H), 7.07–7.01 (m, 1H), 6.48 (s, 1H), 4.38 (dd, J = 15.1, 2.4 Hz, 1H), 4.18 (dd, J = 15.1, 2.5 Hz, 1H), 3.64–3.56 (q, 2H), 2.43 (s, 3H), 2.35 (s, 1H).

[0046] Compound 2f: Yellow oil, 95% yield, >99:1 er, = +17.67 (c = 1.0, CH2Cl2); The er value was determined by high performance liquid chromatography. Separation conditions: chiral AD-H column, 25 °C, flow rate: 0.5 mL / min, n-hexane / isopropanol: 30 / 70, 254 nm, 8.61 min (S), 9.26 min (R). 11H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 2H), 7.58 (s, 4H), 7.38–7.31 (m, 4H), 7.28 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H), 6.26 (s, 1H), 4.52 (dd, J = 15.1, 1.8 Hz, 1H), 4.26 (dd, J = 15.1, 1.9 Hz, 1H), 3.61 (d, J = 10.5 Hz, 1H), 3.50 (d, J = 10.5 Hz, 1H), 2.62 (s, 1H), 2.43 (s, 3H).

[0047] Compound 2g: White solid, 89% yield, >99:1 er, = +30.35 (c = 1.0, CH2Cl2); er value was determined by high performance liquid chromatography, separation conditions: chiral AD-H column, 25 °C, flow rate: 0.5 mL / min, n-hexane / isopropanol: 10 / 90, 254 nm, 18.26 min (S), 21.13 min (R). 1 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J = 6.6 Hz, 2H)), 7.36 (t, J = 5.8 Hz, 3H), 7.30–7.14 (m, 6H), 6.97–6.83 (m, 2H), 6.44 (d, J = 1.7 Hz, 1H), 4.35 (qd, J = 11.9, 1.9 Hz, 2H), 3.91 (d, J = 7.7 Hz, 1H), 3.83 (s, 1H), 3.70 (s, 3H), 3.37 (d, J = 7.7 Hz, 1H), 2.40 (s, 3H).

[0048] Compound 2h: Yellow oil, 87% yield, 97:3 er. = +15.45 (c = 1.0, CH2Cl2); er value was determined by high performance liquid chromatography, separation conditions: chiral AD-H column, 25 °C, flow rate: 0.5 mL / min, n-hexane / isopropanol: 10 / 90, 254 nm, 17.00 min (S), 25.82 min (R). 11H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.36–7.24 (m, 6H), 7.14 (d, J = 7.4 Hz, 2H), 7.07–7.03 (t, 1H), 6.99–6.96 (d, 1H), 6.86–6.81 (dd, 1H), 6.31 (t, J = 2.4 Hz, 1H), 4.50 (dd, J = 14.9, 2.4 Hz, 1H), 4.25 (dd, J = 14.9, 2.6 Hz, 1H), 3.80 (s, 3H), 3.60 (d, J = 10.4 Hz, 1H), 3.53 (d, J = 10.4 Hz, 1H), 2.42 (s, 3H).

[0049] Compound 2i: White solid, 72% yield, >99:1 er, = +32.09 (c = 1.0, CH2Cl2); er value was determined by high performance liquid chromatography, separation conditions: chiral AD-H column, 25 °C, flow rate: 0.5 mL / min, n-hexane / isopropanol: 10 / 90, 254 nm, 10.59 min (S), 18.65 min (R). 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2H), 7.49 (s, 1H), 7.40–7.29 (m, 8H), 7.17 (d, J = 7.4 Hz, 2H), 6.31 (t, J = 2.5 Hz, 1H), 4.55 (dd, J = 15.0, 2.4 Hz, 1H), 4.28 (dd, J = 15.0, 2.6 Hz, 1H), 3.63 (d, J = 10.5 Hz, 1H), 3.52 (d, J = 10.5 Hz, 1H), 2.46 (s, 3H).

[0050] Compound 2j: Colorless oil, 76% yield, 98:2 er. = +60.65 (c = 1.0, CH2Cl2); er value was determined by high performance liquid chromatography, separation conditions: chiral AD-H column, 25 °C, flow rate: 0.5 mL / min, n-hexane / isopropanol: 10 / 90, 254 nm, 13.62 min (S), 20.00 min (R). 11H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.32 (m, J = 8.1 Hz, 3H), 7.18 (d, J = 7.4 Hz, 2H), 7.02–6.97 (m, 2H), 6.25 (t, J = 2.3 Hz, 1H), 4.61 (dd, J = 15.1, 2.4 Hz, 1H), 4.35 (dd, J = 15.1, 2.5 Hz, 1H), 3.63 (dd, J = 30.6, 10.7 Hz, 2H), 2.45 (s, 3H), 2.34 (s, 3H), 2.17 (s, 1H), 2.07 (s, 3H).

[0051] Compound 2k: White solid, 66% yield, 99:1 er. = +3.52 (c = 1.0, CH2Cl2); er value was determined by HPLC, separation conditions: chiral AD-H column, 25 °C, flow rate: 0.5 mL / min, n-hexane / i-propanol: 15 / 85, 254 nm, 17.15 min (R), 21.11 min (S). 1 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.61–7.48 (m, 6H), 7.44 (t, J = 7.6 Hz, 2H), 7.38–7.25 (m, 6H), 7.16 (d, J = 7.4 Hz, 2H), 6.35 (t, J = 2.3 Hz, 1H), 4.52 (dd, J = 15.0, 2.4 Hz, 1H), 4.29 (dd, J = 15.0, 2.5 Hz, 1H), 3.64–3.55 (q, 2H), 2.48 (s, 1H), 2.40 (s, 3H).

[0052] Compound 2l: White solid, 82% yield, 99:1 er, = +8.63 (c = 1.0, CH2Cl2); The er value was determined by high performance liquid chromatography. Separation conditions: chiral AD-H column, 25 °C, flow rate: 0.5 mL / min, n-hexane / isopropanol: 30 / 70, 254 nm, 11.69 min (R), 14.93 min (S). 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.32 (d, J = 8.0 Hz, 3H), 7.21 (d, J = 7.5 Hz, 2H), 6.49 (s, 1H), 4.27 (dd, J = 14.8, 2.6 Hz, 1H), 4.13 (dd, J = 14.8, 1.8 Hz, 1H), 4.02 (d, J = 10.4 Hz, 1H), 2.82 (d, J = 10.4 Hz, 1H), 2.42 (s, 3H), 1.99 (s, 3H), 1.75–1.57 (m, 13H).

[0053] Compound 2m: White solid, yield 89%, er value: 98:2 er. = +2.6 (c = 1.0, CH2Cl2); The er value was measured by liquid phase. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: n-hexane / isopropanol: 90 / 10, 254 nm, 12.36 min (S), 14.21 min (R). 1 1H NMR (500 MHz, CDCl3) δ 7.58 (m, J = 8.3, 1.2 Hz, 2H), 7.41–7.33 (m, 4H), 7.26 (m, 1H), 7.14 (d, J = 7.4 Hz, 2H), 6.30 (t, J = 2.6 Hz, 1H), 5.09 (dd, J = 14.5, 2.4 Hz, 1H), 4.86 (dd, J = 14.5, 2.6 Hz, 1H), 4.12–3.92 (q, 2H), 2.39 (s, 1H).

[0054] Compound 2n: White liquid, yield 79%, er value: 98:2 er. = +8.6 (c = 1.0, CH2Cl2); The er value was measured by liquid phase. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: n-hexane / isopropanol: 90 / 10, 254 nm, 11.16 min (S), 12.91 min (R). 11H NMR (500 MHz, CDCl3) δ 7.64–7.53 (m, 4H), 7.40 (t, J = 7.6 Hz, 2H), 7.36–7.30 (m, 1H), 7.23 (d, J = 8.2 Hz, 2H), 6.34 (t, J = 2.5 Hz, 1H), 5.06 (dd, J = 14.7, 2.4 Hz, 1H), 4.85 (dd, J = 14.7, 2.6 Hz, 1H), 4.06 (dd, J = 42.4, 9.6 Hz, 2H), 2.82 (s, 1H).

[0055] Compound 2o: White solid, yield 82%, er value: 98:2 er. = +10.3 (c = 1.0, CH2Cl2); er value measured by liquid phase. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: n-hexane / isopropanol: 90 / 10, 254 nm, 24.17 min (S), 26.91 min (R). 1 1H NMR (500 MHz, CDCl3) δ 7.61–7.51 (m, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.22 (t, J = 2.5 Hz, 1H), 5.05 (dd, J = 14.3, 2.3 Hz, 1H), 4.82 (dd, J = 14.3, 2.5 Hz, 1H), 4.08 (d, J = 9.5 Hz, 1H), 3.95 (d, J = 9.6 Hz, 1H), 3.80 (s, 3H), 2.39 (s, 1H).

[0056] Compound 2p: Yellow oil, yield 83%, er value: 98:2 er. = +17.32 (c = 1.0, CH2Cl2); er value measured by liquid phase. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: n-hexane / isopropanol: 90 / 10, 254 nm, 14.86 min (S), 16.61 min (R). 11H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 8.3, 1.2 Hz, 2H), 7.39 (t, J = 8.2, 6.8 Hz, 2H), 7.34–7.28 (m, 3H), 7.04 (d, J = 8.5 Hz, 2H), 6.25 (t, J = 2.6 Hz, 1H), 5.02 (dd, J = 14.5, 2.5 Hz, 1H), 4.81 (dd, J = 14.5, 2.6 Hz, 1H), 4.10–3.97 (q, 2H), 2.54 (s, 1H).

[0057] Compound 2q: White solid, yield 80%, er value: 99:1 er. = +13.3 (c = 1.0, CH2Cl2); er value was measured by HPLC. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: hexane / isopropanol: 90 / 10, 254 nm, 9.89 min (S), 11.38 min (R). 1 1H NMR (500 MHz, CDCl3) δ 7.59–7.56 (d, 2H), 7.39 (t, J = 7.6 Hz, 3H), 7.32 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 6.7 Hz, 2H), 6.27 (t, J = 2.5 Hz, 1H), 5.09 (dd, J = 14.4, 2.4 Hz, 1H), 4.86 (dd, J = 14.5, 2.5 Hz, 1H), 4.10 (d, J = 9.5 Hz, 1H), 3.97 (d, J = 9.6 Hz, 1H), 2.34 (s, 3H), 2.31 (s, 1H).

[0058] Compound 2r: Pale yellow oil, yield 86%, er value: 98:2 er. = +25.35 (c = 1.0, CH2Cl2); er value was measured by HPLC. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: hexane / isopropanol: 90 / 10, 254 nm, 17.82 min (S), 22.21 min (R). 11H NMR (500 MHz, CDCl3) δ 7.79 (m, J = 8.9, 4.9 Hz, 3H), 7.64–7.54 (m, 3H), 7.50–7.44 (m, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.27 (d, J = 1.3 Hz, 1H), 6.45 (t, J = 2.4 Hz, 1H), 5.19 (dd, J = 14.4, 2.3 Hz, 1H), 4.96 (dd, J = 14.5, 2.5 Hz, 1H), 4.08 (q, J = 55.2, 9.6 Hz, 2H), 2.49 (s, 1H).

[0059] Compound 2s: White solid, yield 83%, er value: 98:2 er. α = -8.3 (c = 1.0, CH2Cl2); er value measured by liquid phase. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: hexane / isopropanol: 90 / 10, 254 nm, 18.86 min (S), 23.33 min (R). 1 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 8.9 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.26 (d, J = 6.4 Hz, 1H), 7.14 (d, J = 7.3 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 6.31 (t, J = 2.6 Hz, 1H), 5.06 (dd, J = 14.5, 2.4 Hz, 1H), 4.84 (dd, J = 14.5, 2.6 Hz, 1H), 4.06 (d, J = 9.6 Hz, 1H), 3.94 (d, J = 9.6 Hz, 1H), 3.83 (s, 3H), 2.40 (s, 1H).

[0060] Compound 2t: White solid, yield 88%, er value: 98:2 er. α = +18.3 (c = 1.0, CH2Cl2); er value measured by liquid phase. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: hexane / isopropanol: 90 / 10, 254 nm, 10.56 min (S), 12.63 min (R). 11H NMR (500 MHz, CDCl3) δ 7.59–7.50 (m, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.28–7.25 (t, 1H), 7.13 (d, J = 7.4 Hz, 2H), 7.06 (t, J = 8.7 Hz, 2H), 6.28 (t, J = 2.5 Hz, 1H), 5.07 (dd, J = 14.5, 2.4 Hz, 1H), 4.84 (dd, J = 14.5, 2.6 Hz, 1H), 4.07 (d, J = 9.6 Hz, 1H), 3.93 (d, J = 9.6 Hz, 1H), 2.49 (s, 1H).

[0061] Compound 2u: Pale yellow solid, yield 89%, er value: 99:1 er. = +45.3 (c = 1.0, CH2Cl2); er value was measured by liquid phase. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: n-hexane / isopropanol: 90 / 10, 254 nm, 7.58 min (S), 9.65 min (R). 1 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.31 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 6.30 (s, 1H), 5.11 (dd, J = 14.5, 1.9 Hz, 1H), 4.90 (dd, J = 14.6, 2.1 Hz, 1H), 4.14 (d, J = 9.7 Hz, 1H), 3.99 (d, J = 9.7 Hz, 1H), 2.58 (s, 1H).

[0062] Compound 2v: Yellow oil, yield 76%, er value: 98:2 er. = +3.6 (c = 1.0, CH2Cl2); er value was measured by liquid phase. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: n-hexane / isopropanol: 80 / 20, 254 nm, 6.78 min (S), 7.86 min (R). 11H NMR (500 MHz, CDCl3) δ 7.40 (s, 1H), 7.35 (m, J = 7.5 Hz, 3H), 7.26 (s, 2H), 7.14 (t, J = 7.7 Hz, 3H), 6.31 (t, J = 2.3 Hz, 1H), 5.08 (dd, J = 14.5, 2.2 Hz, 1H), 4.85 (dd, J = 14.5, 2.4 Hz, 1H), 4.08 (d, J = 9.5 Hz, 1H), 3.98 (d, J = 9.6 Hz, 1H), 2.38 (s, 3H), 2.33 (s, 1H).

[0063] Compound 2w: A transparent oil, yield 79%, er value: 97:3 er. = +7.3 (c = 1.0, CH2Cl2); The er value was measured by liquid phase. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: n-hexane / isopropanol: 90 / 10, 254 nm, 19.22 min (S), 23.63 min (R). 1 1H NMR (500 MHz, CDCl3) δ 7.31 (m, J = 18.9, 13.1, 6.9 Hz, 4H), 7.20–7.17 (t, 1H), 7.16–7.08 (m, 3H), 6.89–6.83 (m, 1H), 6.32 (t, J = 2.5 Hz, 1H), 5.06 (dd, J = 14.5, 2.4 Hz, 1H), 4.84 (dd, J = 14.5, 2.6 Hz, 1H), 4.03 (q, J = 56.4, 9.6 Hz, 2H), 3.83 (s, 3H), 2.59 (s, 1H).

[0064] Compound 2x: A yellow solid, yield 92%, er value: >99:1 er. = -7.3 (c = 1.0, CH2Cl2); the er value was measured by liquid phase. Chiral column: AD-H, temperature: 25 °C, flow rate: 1 mL / min, mobile phase: n-hexane / isopropanol: 85 / 15, 254 nm, 14.18 min (S), 16.37 min (R). 1H NMR (500 MHz, CDCl3) δ 8.11–8.05 (d, 1H), 7.92 (dd, J = 7.3, 0.8 Hz, 1H), 7.88–7.80 (m, 2H), 7.44 (m, J = 8.3, 6.8, 4.8 Hz, 3H), 7.33 (t, J = 7.6 Hz, 2H), 7.27–7.22 (t, 1H), 7.10 (d, J = 7.4 Hz, 2H), 6.34 (t, J = 2.4 Hz, 1H), 5.07 (qd, J = 14.5, 2.5 Hz, 2H), 4.48 (d, J = 9.5 Hz, 1H), 4.12 (d, J = 9.5 Hz, 1H), 2.77 (s, 1H).

Claims

1. A method for the synthesis of chiral five-membered heterocyclic alcohol derivatives catalyzed by nickel (II), characterized in that: COD (1,5-cyclooctadiene) as an additive, HBPin (pinacolborane) as a reducing agent, and chiral phosphine ligand S )-BI-DIME / Ni(OAc)2·4H2O as a catalyst to catalyze the reduction cyclization reaction of alkynones as shown below: ； The structure of the alkynone is as follows: ； R in the compound 2 1 and R 2 correspond to the corresponding substituents of the alkynone.

2. The method for catalytic synthesis of chiral five-membered heterocyclic alcohol derivatives by nickel (II) according to claim 1, wherein: The molar ratio of Ni(OAc)2·4H2O and chiral phosphine ligand ( S )-BI-DIME is: 1:

1.

3. A method for synthesizing chiral five-membered heterocyclic alcohol derivatives catalyzed by nickel (II) as claimed in claim 1, characterized in that: The molar ratio of Ni(OAc)2·4H2O to alkynone 1 is: 1:

20.

4. A method for the synthesis of chiral five-membered heterocyclic alcohol derivatives catalyzed by nickel (II), characterized in that: The molar ratio of alkynone 1 to HBPin is: 1:

1.

5. A method for the synthesis of chiral five-membered heterocyclic alcohol derivatives catalyzed by nickel (II), characterized in that: The molar ratio of alkynone 1 to COD is: 1:

1.

6. The method for catalytic synthesis of chiral five-membered heterocyclic alcohol derivatives by nickel (II) according to claim 1, wherein: The solvent used in the reaction is tetrahydrofuran, and the dosage is 5 mL of tetrahydrofuran / 1 mmol of alkynone.

7. A method for the synthesis of chiral five-membered heterocyclic alcohol derivatives catalyzed by nickel (II), characterized in that: The reaction temperature is -5 °C, and the reaction time is 20 hours.

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