阅读说明：本技术 不对称双共轭加成合成光学活性酮类化合物的方法 (Method for synthesizing optically active ketone compound by asymmetric double-conjugate addition ) 是由 柴国利 张苹 姚恩泽 常俊标 于 2021-01-11 设计创作，主要内容包括：本发明公开了不对称双共轭加成合成光学活性酮类化合物的方法,属于有机化学中的不对称合成技术领域。具体步骤如下：以二烯酮1和有机硼酸2为原料,在手性联二萘酚或手性四苯并环辛四烯类催化剂和分子筛存在下,经过不对称共轭加成反应得到酮类化合物3。反应方程式如下：本发明的优势在于：反应原料易得,催化剂结构简单,催化效率高,反应条件温和,后处理简单。(The invention discloses a method for synthesizing an optically active ketone compound by asymmetric double-conjugate addition, belonging to the technical field of asymmetric synthesis in organic chemistry. The method comprises the following specific steps: taking dienone 1 and organic boric acid 2 as raw materials, and obtaining the product by asymmetric conjugate addition reaction in the presence of chiral binaphthol or chiral tetraphenylcyclooctatetraene catalyst and molecular sieveTo the ketone compound 3. The reaction equation is as follows:)

1. The method for synthesizing the optically active ketone compound by asymmetric double-conjugate addition is characterized by comprising the following steps of: taking dienone 1 and organic boric acid 2 as raw materials, and reacting in the presence of a chiral binaphthol or chiral tetraphenylcyclooctatetraene catalyst and a molecular sieve to obtain a ketone compound 3; the reaction equation is as follows:

wherein: r¹,R²Each is independently selected from substituted phenyl, naphthyl, furyl, thienyl, C1-C6 alkyl or substituted phenylethyl, wherein the substituent in the substituted phenyl is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, C1-C4 alkoxycarbonyl or nitro; r³Is selected from substituted styryl, furyl, phenylpropyl furyl, thienyl, benzothienyl or C1-C8 alkyl alkenyl, wherein the substituted phenyl is substituted by hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, C1-C4 alkoxycarbonyl or nitro.

2. The method for synthesizing optically active ketone compounds by asymmetric biconjugate addition according to claim 1, wherein: r¹Is substituted phenyl, 2-thienyl, 2-furyl, 1-naphthyl or 2-naphthyl; r²Is substituted phenyl, 2-thienyl, 2-furyl, 1-naphthyl, 2-naphthyl, n-propyl or phenethyl; r³Is styryl, p-methylstyrene, 2-furyl, 2-benzofuryl, 2-thienyl, 2-benzothienyl or n-octenyl.

3. The asymmetric doublet of claim 1The method for synthesizing the optically active ketone compound by conjugate addition is characterized by comprising the following steps: the chiral 1,1' -binaphthol catalyst and the chiral tetrabenzocyclooctatetraene phenol catalyst are respectivelyWherein R is H, F, Cl, Br, I, Ph, 3,5-Me₂C₆H₄、3,5-(MeO)₂C₆H₄Or 3,5- (CF)₃)₂C₆H₄。

4. The method for synthesizing optically active ketone compounds by asymmetric biconjugate addition according to claim 1, wherein: the chiral 1,1' -binaphthol catalyst is selected from R ═ Br, I or 3,5- (CF)₃)₂C₆H₄。

5. The method for synthesizing optically active ketone compounds by asymmetric biconjugate addition according to claim 1, wherein: the chiral tetrabenzocyclooctatetraene phenol catalyst is selected from R ═ Cl, Br or Ph.

6. The method for synthesizing optically active ketone compounds by asymmetric biconjugate addition according to claim 1, wherein: the mol ratio of the alpha, beta-unsaturated ketone 1, the organic boric acid 2 and the catalyst is 1:2-4: 0.05-0.20.

7. The method for synthesizing optically active ketone compounds by asymmetric biconjugate addition according to claim 1, wherein: the reaction solvent is selected from toluene, dichloromethane, tetrahydrofuran, trifluorotoluene, o-xylene, 1, 2-dichloroethane, diisopropyl ether or 1, 4-dioxane.

8. The method for synthesizing optically active ketone compounds according to claim 1, wherein the step of asymmetric conjugate addition comprises the following steps: the reaction temperature is from 0 to 25 ℃.

9. According toThe method for synthesizing optically active ketones by asymmetric conjugate addition as claimed in claim 1, wherein: the molecular sieve is selected fromOrAnd (3) a molecular sieve.

10. The method for synthesizing optically active ketones by asymmetric biconjugate addition according to any one of claims 1 to 9, wherein: the whole reaction process needs to be carried out under nitrogen or argon.

Technical Field

The invention belongs to the technical field of asymmetric synthesis in organic chemistry, and particularly relates to a method for synthesizing an optically active ketone compound by asymmetric double-conjugate addition.

Background

The asymmetric conjugate addition reaction of organic boride and alpha, beta-unsaturated carbonyl compound is an important synthesis method for constructing C-C bond. The organic boride (alkyl boric acid, organic borate and organic borate) plays an important role in modern organic synthesis due to the advantages of low toxicity, low price, easy obtaining, good stability, good functional group tolerance and the like, and the small organic molecule has many advantages of catalyzing the asymmetric conjugate addition reaction of the organic boride and the alpha, beta-unsaturated carbonyl compound, such as low toxicity of the catalyst, easy preparation, low price, good stability, simple operation, no metal residue after the reaction and the like.

So far, the chiral catalysts used in the reaction are few, and organic borate which are not stable are mostly needed to be used, and reports of directly using the organic boric acid which is simple, easy to obtain and relatively stable are few. In 2014, Sugiura et al reported that the optically active tartaric acid derivative was used to catalyze the asymmetric conjugate addition reaction between styryl boric acid and dienone to obtain mainly mono-styryl addition ketone compounds with less bi-conjugate addition products (org. Lett.2014,16, 5172-wall 5175).

Therefore, the technical problem to be solved by the invention is to develop a catalytic system which has no transition metal, good reaction activity and simple operation, and realize the asymmetric double-conjugate addition reaction of organic boric acid and dienone to obtain a series of ketone derivatives with optical activity.

Disclosure of Invention

In order to overcome the technical defects, the invention provides a method for synthesizing an optically active ketone compound by asymmetric double-conjugate addition reaction. Organic boric acid and dienone are used as raw materials, chiral binaphthol compounds or chiral tetraphenylcyclooctatetraene compounds are used as catalysts, and molecular sieves are used as additives to synthesize the optically active ketone compounds by one step through asymmetric double-conjugate addition reaction with high yield, high diastereoselectivity and enantioselectivity.

The method for synthesizing the optically active ketone compound by the asymmetric double-conjugate addition comprises the following steps: diene ketone 1 and organic boric acid 2 are used as raw materials, and the ketone compound 3 is obtained by reaction under the catalysis of chiral binaphthol or chiral tetraphenylcycloocttetraene compound and a molecular sieve. The reaction equation is as follows:

wherein: r¹,R²Each is independently selected from substituted phenyl, naphthyl, furyl, thienyl, C1-C6 alkyl or substituted phenylethyl, wherein the substituent in the substituted phenyl is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, C1-C4 alkoxycarbonyl or nitro; r³Is selected from substituted styryl, furyl, phenylpropyl furyl, thienyl, benzothienyl or C1-C8 alkyl alkenyl, wherein the substituted phenyl is substituted by hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, C1-C4 alkoxycarbonyl or nitro.

Further, in the above technical solution, R¹Is substituted phenyl, 2-thienyl, 2-furyl, 1-naphthyl or 2-naphthyl; r²Is substituted phenyl, 2-thienyl, 2-furyl, 1-naphthyl, 2-naphthyl, n-propyl or phenethyl; r³Is styryl, p-methylstyrene, 2-furyl, 2-benzofuryl, 2-thienyl, 2-benzothienyl or n-octenyl.

Further, in the above technical scheme, the chiral 1,1' -binaphthol catalyst isR＝H、F、Cl、Br、I、Ph、3,5-Me₂C₆H₄、3,5-(MeO)₂C₆H₄、3,5-(CF₃)₂C₆H₄(ii) a Under the preferable conditions, the chiral 1,1' -binaphthol catalysts are three types as follows:

further, in the above technical scheme, the chiral tetraphenylcyclooctylene phenol catalyst isR＝H、F、Cl、Br、I、Ph、3,5-Me₂C₆H₄、3,5-(MeO)₂C₆H₄、3,5-(CF₃)₂C₆H₄(ii) a The chiral tetrabenzocyclooctatetraene phenol catalysts under the preferred conditions are three as follows:

further, in the technical scheme, the molar ratio of the dienone 1 to the organic boric acid 2 to the catalyst is 1:2-4: 0.05-0.20.

Further, in the above technical solution, the reaction solvent is toluene, dichloromethane, tetrahydrofuran, trifluorotoluene, o-xylene, m-xylene, chlorobenzene, 1, 2-dichloroethane, diisopropyl ether, or 1, 4-dioxane.

Further, in the above technical scheme, the reaction temperature is 0 to 30 ℃, preferably 25 ℃. Further, in the above technical solution, the molecular sieve is selected fromOrAnd (3) a molecular sieve.

Further, in the above technical scheme, the whole reaction process needs to be carried out under nitrogen or argon, preferably nitrogen.

The invention has the beneficial effects that:

the invention has the advantages of easily obtained reaction raw materials, mild reaction conditions, simple post-treatment, recyclable catalyst and good to excellent product yield, diastereoselectivity and enantioselectivity.

Detailed Description

The technical solution of the present invention is further described in detail with reference to the following specific examples, but the scope of the present invention is not limited thereto.

Example 1

^aDiketene 1a (0.1mmol), trans-2-phenylvinylboronic acid 2a (0.2mmol), catalyst (0.01mmol,10 mol%), Mg (O)^tBu)₂(0.01mmol,10mol％)、Molecular sieves (100mg), 1.0mL of anhydrous solvent in N₂Under the atmosphere^bIsolated yield^cdl/meso was analyzed by HPLC on a chiral column^dee analysis by HPLC chiral column^e2a(0.3mmol)^fWithout addition of Mg (O)^tBu)₂ ^gAt 0 deg.C^hCat 5(0.005mmol,5mol％)Molecular sieve (100mg)^jWithout adding molecular sieve^kDienone 1a (0.1mmol), trans-2-phenylvinylboronic acid 2a (0.3mmol), Cat 9(0.01mmol,10 mol%),molecular sieves (100mg), 1.0mL toluene in N₂At 25 ℃ under an atmosphere.

In the screening process of reaction conditions, the influence of different chiral catalysts on the reaction is examined (labels 1-10), and Cat 2, 3 and 5 and Cat 8, 9 and 10 are determined to be the optimal catalysts. The influence of different solvents on the reaction was then examined (reference numerals 12 to 19), and finally toluene was used as the solvent. At the same time investigateProportion of feed, Mg (O)^tBu)₂Temperature, catalyst amount and effect of molecular sieves on the reaction (reference numerals 11 and 20-24), the final reaction temperature was chosen to be 25 ℃ and the catalyst amount was 10 mol%. Examination of the reaction conditions typical operation (reference 23 for example):

under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 5(7.1mg, 0.01mmol,10 mol%), dienone 1a (23.4mg, 0.1mmol) and organic boric acid 2a (44.4mg, 0.3mmol, 3.0eq), degassing 3 times, adding dry toluene (1.0mL), and stirring at 25 deg.C for 24 h. TLC plate tracing until the raw material 1a disappears, removing solvent under reduced pressure, separating and purifying by direct flash silica gel column chromatography (eluent is dichloromethane/petroleum ether volume ratio 1/3-1/1) to obtain the product 3aa with yield of 97%. White solid (42.8 mg); mp 102-; HPLC (Daicel Chiral pak IB, n-hexane/isopropanol 90:10, flow rate 0.8mL/min,. lambda.254 nm) t_R(1)＝15.4min,t_R(2)＝18.6min,t_R(3)＝26.2min,dl-/meso-＝95.8:4.2,>99％ee；[α]_D ²⁵＝–8.2(c 2.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ7.29-7.16(m,20H),6.31-6.20(m,4H),4.05(q,J＝6.8Hz,2H),2.89-2.85(m,4H)；¹³C NMR(100MHz,CDCl₃)δ206.9,143.1,137.2,132.4,130.1,128.8,128.6,127.8,127.4,126.8,126.4,49.5,43.8；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₃H₃₀ONa 465.2189；Found 465.2168.

Example 2

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieves, chiral catalyst Cat 5(7.1mg, 0.01mmol, 10)mol%), diketene 1b (26.2mg, 0.1mmol) and organoboronic acid 2a (44.4mg, 0.3mmol, 3.0eq), 3 times with purging, addition of dry toluene (1.0mL), and stirring at 25 ℃ for 24 h. TLC plate tracing until the raw material 1b disappears, removing solvent under reduced pressure, separating and purifying by direct flash silica gel column chromatography (eluent is dichloromethane/petroleum ether volume ratio 1/3-1/1) to obtain the product 3ba with 99% yield. White solid (46.8 mg); mp 75-77 ℃; HPLC (Daicel Chiral pak IB, n-hexane/isopropanol 90:10, flow rate 0.8mL/min,. lambda.254 nm) t_R(1)＝12.5min,t_R(2)＝13.8min,t_R(3)＝16.7min,dl-/meso-＝97.0:3.0,>99％ee；[α]_D ²⁵＝–10.1(c 2.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ7.25-7.21(m,8H),7.19-7.16(m,2H),7.10-7.05(m,8H),6.29-6.18(m,4H),4.02(q,J＝6.8Hz,2H),2.91-2.79(m,4H),2.29(s,6H)；¹³C NMR(100MHz,CDCl₃)δ207.1,140.0,137.3,136.3,132.7,129.9,129.5,128.5,127.6,127.3,126.4,49.5,43.4,21.1；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₅H₃₄O Na 493.2502；Found 493.2500.

Example 3

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 5(7.1mg, 0.01mmol,10 mol%), dienone 1c (29.4mg, 0.1mmol) and organic boric acid 2a (44.4mg, 0.3mmol, 3.0eq), degassing 3 times, adding dry toluene (1.0mL), and stirring at 25 deg.C for 24 h. TLC point plate tracking until the raw material 1c disappears, decompression removing solvent, direct fast silica gel column chromatography (eluent dichloromethane/petroleum ether volume ratio 1/2-1/1) separation and purification to obtain the target product 3ca with 96% yield. White solid (48.3 mg); mp 75-76 ℃; HPLC (Daicel Chiralpak ID, n-hexane/isopropanol 90:10, flow rate 0.8mL/min,. lambda.254 nm) t_R(1)＝17.7min,t_R(2)＝19.1min,t_R(3)＝23.4min,dl-/meso-＝95.6:4.4,>99％ee；[α]_D ²⁶＝–20.5(c 2.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ7.26-7.14(m,14H),6.89-6.83(m,4H),6.37-6.28(m,4H),4.44(q,J＝6.8Hz,2H),3.79(s,6H),2.96-2.86(m,4H)；¹³C NMR(100MHz,CDCl₃)δ207.9,156.9,137.6,131.9,131.5,130.1,128.5,128.4,127.7,127.1,126.4,120.8,111.0,55.5,48.1,38.2；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₅H₃₄O₃Na 525.2400；Found 525.2368.

Example 4

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 5(7.1mg, 0.01mmol,10 mol%), dienone 1d (29.4mg, 0.1mmol) and organic boric acid 2a (44.4mg, 0.3mmol, 3.0eq), degassing 3 times, adding dry toluene (1.0mL), and stirring at 25 deg.C for 24 h. TLC plate tracing until the raw material 1d disappears, removing solvent under reduced pressure, separating and purifying by direct flash silica gel column chromatography (eluent is dichloromethane/petroleum ether volume ratio 1/2-1/1) to obtain the target product 3da with 96% yield. White solid (46.0 mg); mp 68-69 deg.C; HPLC (daicel chiralpak IB, n-hexane/isopropanol 80:20, flow rate 1.0mL/min, λ 254nm) t_R(1)＝7.6min,t_R(2)＝14.1min,t_R(3)＝18.3min,dl-/meso-＝94.0:6.0,>99％ee；[α]_D ²⁷＝–6.9(c 2.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ7.28-7.10(m,14H),6.95-6.91(m,4H),6.31-6.16(m,4H),4.04(q,J＝6.8Hz,2H),2.91-2.79(m,4H)；¹³C NMR(100MHz,CDCl₃)δ206.5,161.7(d,J＝244.0Hz,),138.6(d,J＝3.0Hz),137.0,132.1,130.3,129.2(d,J＝8.0Hz),128.6,127.6,126.3,115.6(d,J＝21.0Hz),49.5,42.9；¹⁹FNMR(376MHz,CDCl₃)δ–116.1；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₃H₂₈F₂ONa 501.2000；Found 501.1990.

Example 5

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 5(7.1mg, 0.01mmol,10 mol%), dienone 1e (30.3mg, 0.1mmol) and organic boric acid 2a (44.4mg, 0.3mmol, 3.0eq), degassing 3 times, adding dry toluene (1.0mL), and stirring at 25 deg.C for 24 h. TLC point plate tracking until the raw material 1e disappears, decompression removing solvent, direct fast silica gel column chromatography (eluent dichloromethane/petroleum ether volume ratio 1/3-1/1) separation and purification to obtain the target product 3ea, yield 92%. White solid (47.1 mg); mp 51-52 ℃; HPLC (Daicel Chiralpak IB, n-hexane/isopropanol 80:20, flow rate 1.0mL/min, λ 254nm) t_R(1)＝9.7min,t_R(2)＝17.5min,t_R(3)＝24.9min,dl-/meso-＝96.3:3.7,>99％ee；[α]_D ²³＝–8.5(c 2.0,CHCl₃)；¹H NMR(600MHz,CDCl₃)δ7.28-7.17(m,14H),7.12-7.07(m,4H),6.31-6.15(m,4H),4.03(q,J＝10.2Hz,2H),2.93-2.77(m,4H)；¹³C NMR(150MHz,CDCl₃)δ206.2,141.5,137.0,132.6,131.8,130.6,129.2,128.9,128.7,127.6,126.4,49.3,43.1；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₃H₂₈Cl₂ONa 533.1409；Found 533.1390.

Example 6

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 5(7.1mg, 0.01mmol,10 mol%), dienone 1f (39.2mg, 0.1mmol) and organic boric acid 2a (44.4mg, 0.3mmol, 3.0eq), degassing 3 times, adding dry toluene (1.0mL), and stirring at 25 deg.C for 24 h. TLC point plate tracking until the raw material 1f disappears, decompression removing solvent, direct fast silica gel column chromatography (eluent dichloromethane/petroleum ether volume ratio 1/2-1/1) separation and purification to obtain the target product 3fa with 92% yield. White solid (55.4 mg); mp 103-104 ℃; HPLC (Daicel Chiralpak IB, n-hexane/isopropanol 70:30, flow rate 1.0mL/min,. lambda.254 nm) t_R(1)＝9.9min,t_R(2)＝16.7min,t_R(3)＝23.2min,dl-/meso-＝96.5:3.5,>99％ee；[α]_D ²⁵＝–6.2(c 2.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ7.38-7.35(m,4H),7.29-7.20(m,10H),7.06-7.04(m,4H),6.28-6.14(m,4H),4.01(q,J＝7.2Hz,2H),2.93-2.77(m,4H)；¹³C NMR(100MHz,CDCl₃)δ206.2,141.9,136.9,131.9,131.6,130.6,129.6,128.7,127.6,126.4,120.6,49.2,43.1；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₃H₂₈Br₂ONa 621.0399；Found 621.0401.

Example 7

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 5(7.1mg, 0.01mmol,10 mol%), dienone 1g (33.3mg, 0.1mmol) and organic boric acid 2a (44.4mg, 0.3mmol, 3.0eq), degassing 3 times, adding dry toluene (1.0mL), and stirring at 25 deg.C for 24 h. TLC plate tracking till 1g of raw material disappears, removing solvent under reduced pressure, separating and purifying by direct flash silica gel column chromatography (eluent is dichloromethane/petroleum ether volume ratio 1/2-1/1) to obtain target product 3ga, and collectingThe ratio was 99%. White solid (53.7 mg); mp 136-138 ℃; HPLC (Daicel Chiralpak IB, n-hexane/isopropanol 80:20, flow rate 1.0mL/min, λ 254nm) t_R(1)＝23.4min,t_R(2)＝28.4min,t_R(3)＝30.0min,dl-/meso-＝97.2:2.8,>99％ee；[α]_D ²⁰＝–14.2(c 2.0,CHCl₃)；¹H NMR(600MHz,CDCl₃)δ7.77-7.70(m,6H),7.61(s,2H),7.44-7.40(m,4H),7.32-7.30(m,2H),7.23-7.14(m,10H),6.34-6.25(m,4H),4.24-4.21(m,2H),3.06-2.92(m,4H)；¹³C NMR(150MHz,CDCl₃)δ206.7,140.5,137.2,133.7,132.5,132.3,130.4,128.6,128.5,127.9,127.8,127.4,126.37,126.31,126.22,126.17,125.7,49.4,43.8；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₄₁H₃₄ONa 565.2502；Found 565.2487.

Example 8

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 5(7.1mg, 0.01mmol,10 mol%), dienone 1h (21.4mg, 0.1mmol) and organic boric acid 2a (44.4mg, 0.3mmol, 3.0eq), degassing 3 times, adding dry toluene (1.0mL), and stirring at 25 deg.C for 24 h. TLC point plate tracking till the raw material disappears for 1h, removing solvent under reduced pressure, and separating and purifying by direct flash silica gel column chromatography (eluent is dichloromethane/petroleum ether volume ratio 1/3-1/1) to obtain the target product 3ha with yield of 94%. White solid (39.7 mg); mp 86-88 ℃; HPLC (DaicelChiralpak ID, 80:20 n-hexane/isopropanol, flow rate 1.0mL/min, 254nm) t_R(1)＝8.5min,t_R(2)＝10.8min,t_R(3)＝11.7min,dl-/meso-＝93.8:6.2,>99％ee；[α]_D ²⁴＝26.6(c 2.0,CHCl₃)；¹H NMR(600MHz,CDCl₃)δ7.32-7.19(m,12H),6.40-6.38(m,2H),6.25-6.17(m,4H),6.04-6.02(m,2H),4.18(q,J＝10.8Hz,2H),3.00(d,J＝10.2Hz,25.2Hz,2H),2.87-2.80(m,2H)；¹³C NMR(150MHz,CDCl₃)δ205.9,155.8,141.6,137.1,131.5,129.3,128.6,127.6,126.5,110.4,105.7,47.1,37.7；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₂₉H₂₆O₃Na 445.1774；Found 445.1765.

Example 9

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 5(7.1mg, 0.01mmol,10 mol%), dienone 1i (26.4mg, 0.1mmol) and organic boric acid 2a (44.4mg, 0.3mmol, 3.0eq), degassing 3 times, adding dry toluene (1.0mL), and stirring at 25 deg.C for 24 h. TLC point plate tracking until the raw material 1i disappears, decompression removing solvent, direct fast silica gel column chromatography (eluent dichloromethane/petroleum ether volume ratio 1/2-1/1) separation and purification to obtain the target product 3ia, yield 85%. White solid (40.3 mg); mp 70-71 ℃; HPLC (daicel chiralpak IB, n-hexane/isopropanol 80:20, flow rate 1.0mL/min, λ 254nm) t_R(1)＝10.6min,t_R(2)＝13.0min,t_R(3)＝16.2min,t_R(4)＝17.8min,d.r.＝96.9:3.1,>99％ee；[α]_D ²⁷＝–12.3(c 2.0,CHCl₃)；¹H NMR(600MHz,CDCl₃)δ7.28-7.22(m,10H),7.20-7.15(m,5H),7.12-7.09(m,2H),6.81-6.78(m,2H),6.31-6.19(m,4H),4.08-3.98(m,2H),3.75(s,3H),2.91-2.80(m,4H)；¹³C NMR(150MHz,CDCl₃)δ207.1,158.4,143.1,137.32,137.28,135.1,132.9,132.5,130.2,129.9,128.81,128.77,128.6,127.8,127.40,127.36,126.8,126.4,114.2,55.4,49.6,49.5,43.8,43.0；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₄H₃₂O₂Na 495.2295；Found 495.2274.

Example 10

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 5(7.1mg, 0.01mmol,10 mol%), dienone 1j (20.0mg, 0.1mmol) and organoboronic acid 2a (44.4mg, 0.3mmol, 3.0equiv), purged 3 times, then dry toluene (1.0mL) was added and stirred at 25 ℃ for 24 h. TLC point plate tracking till the raw material 1j disappears, decompressing to remove solvent, and directly separating and purifying by fast silica gel column chromatography (eluent is dichloromethane/petroleum ether with the volume ratio of 1/2-1/1) to obtain the target product 3ja with the yield of 68%. A colorless oily liquid (27.8 mg); HPLC (Daicel Chiralpak IB, n-hexane/isopropanol 80:20, flow rate 1.0mL/min, λ 254nm) t_R(1)＝6.0min,t_R(2)＝6.4min,t_R(3)＝7.5min,t_R(4)＝8.4min,d.r.＝82.0:18.0,>99％ee；[α]_D ²¹＝14.7(c 1.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)mixture ofdiastereomersδ7.30-7.15(m,15H),6.37-6.25(m,3H),5.96-5.90(m,1H),4.08(q,J＝6.8Hz,1H),2.92-2.90(m,2H),2.76-2.67(m,1H),2.51-2.39(m,2H),1.33-1.23(m,4H),0.85-0.82(m,3H)；¹³C NMR(150MHz,CDCl₃)mixture of diastereomersδ208.0,143.2,143.1,137.5,137.2,133.34,133.33,132.6,130.4,130.3,130.1,128.79,128.78,128.6,127.83,127.79,127.4,127.2,126.8,126.3,126.2,49.54,49.51,49.46,49.3,43.9,38.5,37.3,20.5,20.4,14.1；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₀H₃₂ONa 431.2345；Found 431.2334.

Example 11

According to the reaction conditions of example 10, different dienone compounds 1 and different organoboron acid compounds 2 are adopted, and the reaction results are as follows:

example 12

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 9(4.9mg, 0.01mmol,10 mol%), dienone 1k (37.2mg, 0.1mmol) and organic boric acid 2a (44.4mg, 0.3mmol, 3.0eq), degassing 3 times, adding dry toluene (1.0mL), and stirring at 25 deg.C for 24 h. TLC point plate tracking until 1k disappears, decompression to eliminate solvent, direct fast silica gel column chromatography to separate and purify to obtain the target product 3ka' in 72% yield, and dichloromethane/petroleum ether ratio 1/3-1/1 as eluent. A colorless oil (53.7 mg); HPLC (Daicel Chiralpak IB, n-hexane/isopropanol 80:20, flow rate 0.8mL/min, λ 254nm) t_R(1)＝14.2min,t_R(2)＝18.8min,t_R(3)＝27.8min,dl-/meso-＝98.2:1.8,>99％ee；[α]_D ¹⁹＝19.8(c 2.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ7.35(t,J＝1.2Hz,2H),7.28-7.18(m,10H),7.15-7.13(m,4H),6.32-6.17(m,4H),4.52(q,J＝6.8Hz,2H),2.99-2.89(m,4H)；¹³C NMR(100MHz,CDCl₃)δ205.4,138.9,136.8,134.5,133.0,131.4,129.9,129.7,129.5,128.7,127.7,127.5,126.4,47.7,39.8；HRMS(ESI)m/z:[M+Na]⁺Calcd forC₃₃H₂₆Cl₄ONa 601.0630；Found 601.0613.

Example 13

Under the protection of nitrogen, the nitrogen is used for protecting the air,to a 25mL Schlenk tube subjected to anhydrous anaerobic treatment was added 100mgMolecular sieve, chiral catalyst Cat 9(4.9mg, 0.01mmol,10 mol%), dienone 1l (45.2mg, 0.1mmol) and organic boric acid 2a (44.4mg, 0.3mmol, 3.0eq), degassing 3 times, adding dry toluene (1.0mL), and stirring at 25 deg.C for 24 h. TLC point plate tracking until 1l of raw material disappears, decompression removing solvent, direct fast silica gel column chromatography (eluent dichloromethane/petroleum ether volume ratio 1/3-1/1) separation and purification to obtain target product 3la', yield 72%. White solid (47.4 mg); mp 112-113 ℃; HPLC (Daicel Chiralpak ID, 80:20 n-hexane/isopropanol, flow rate 1.0mL/min, 254nm) t_R(1)＝12.2min,t_R(2)＝13.4min,t_R(3)＝23.9min,dl-/meso-＝97.9:2.1,>99％ee；[α]_D ¹⁹＝7.3(c 2.0,CHCl₃)；¹H NMR(600MHz,CDCl₃)δ7.42(d,J＝13.2Hz,2H),7.27-7.16(m,10H),6.78(d,J＝4.2Hz,2H),6.63-6.61(m,2H),6.38-6.19(m,4H),4.54(q,J＝10.2Hz,2H),3.73(s,6H),2.99-2.89(m,4H)；¹³C NMR(100MHz,CDCl₃)δ205.7,159.2,143.1,137.0,133.9,131.2,130.3,128.6,127.5,126.5,115.1,114.9,113.3,55.6,48.0,42.6；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₅H₃₂Br₂O₃Na681.0610；Found 681.0610.

Example 14

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 9(4.9mg, 0.01mmol,10 mol%), dienone 1l (45.2mg, 0.1mmol) and organic boric acid 2b (48.6mg, 0.3mmol, 3.0eq), degassing 3 times, adding dry toluene (1.0mL), and stirring at 25 deg.C for 24 h. The TLC spot plate was followed until 1l of starting material disappeared,after the solvent is removed under reduced pressure, the target product 3lb' is separated and purified by direct flash silica gel column chromatography (the eluent is dichloromethane/petroleum ether with the volume ratio of 1/3-1/1), and the yield is 99%. A colorless oily liquid (68.8 mg); HPLC (Daicel ChiralpakID, n-hexane/isopropanol 80:20, flow rate 1.0mL/min,. lambda.254 nm) t_R(1)＝12.3min,t_R(2)＝13.3min,t_R(3)＝20.1min,dl-/meso-＝93.2:6.8,>99％ee；[α]_D ¹⁹＝5.1(c 2.0,CHCl₃)；¹H NMR(600MHz,CDCl₃)δ7.43-7.41(m,2H),7.16-7.14(m,4H),7.05-7.03(m,4H),6.78-6.77(m,2H),6.63-6.61(m,2H),6.33-6.30(m,2H),6.20-6.16(m,2H),4.53-4.51(m,2H),3.73-3.73(m,6H),2.93-2.91(m,4H),2.30(s,6H)；¹³C NMR(150MHz,CDCl₃)δ205.8,159.2,143.3,137.3,134.3,133.9,131.1,129.3,126.4,115.1,114.9,113.4,55.6,48.1,42.7,21.3；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₇H₃₆Br₂O₃Na 709.0923；Found 709.0904.

Example 15

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieve, chiral catalyst Cat 9(4.9mg, 0.01mmol,10 mol%), dienone 1l (45.2mg, 0.1mmol) and organic boronic acid 2c (33.6mg, 0.3mmol, 3.0equiv), purged 3 times, then added dry toluene (1.0mL) and stirred at 25 ℃ for 24 h. TLC point plate tracking until 1l of raw material disappears, decompression removing solvent, direct flash silica gel column chromatography (eluent is dichloromethane/petroleum ether volume ratio 1/3-1/1) separation and purification to obtain target product 3lc', yield 85%. A colorless oily liquid (49.8 mg); HPLC (Daicel ChiralpakID, n-hexane/isopropanol 80:20, flow rate 1.0mL/min, λ 220nm) t_R(1)＝10.8min,t_R(2)＝13.2min,t_R(3)＝16.5min,dl-/meso-＝86.1:13.9,>99％ee；[α]_D ²³＝13.7(c 2.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ7.44-7.41(m,2H),7.30-7.26(m,2H),6.65-6.62(m,4H),6.27-6.24(m,2H),6.01-5.99(m,2H),5.06-5.01(m,2H),3.71-3.72(d,6H),3.21-3.14(m,2H),3.00-2.95(m,2H)；¹³C NMR(100MHz,CDCl₃)δ204.5,159.2,154.6,142.0,141.8,133.8,115.3(115.2),114.5,113.7(113.8),110.4,107.0,55.5,46.6,39.5；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₂₇H₂₄Br₂O₅Na 608.9883；Found 608.9873.

Example 16

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieves, chiral catalyst Cat 9(4.9mg, 0.01mmol,10 mol%), dienone 1l (45.2mg, 0.1mmol) and organoboronic acid 2d (48.6mg, 0.3mmol, 3.0equiv), purged 3 times, added dry toluene (1.0mL) and stirred at 25 ℃ for 24 h. TLC point plate tracking until 1l of raw material disappears, decompression removing solvent, direct fast silica gel column chromatography (eluent is dichloromethane/petroleum ether volume ratio 1/3-1/1) separation and purification to obtain target product 3ld', yield 86%. White solid (59.1 mg); mp 70-72 ℃; HPLC (daicel chiralpak IB, n-hexane/isopropanol 80:20, flow rate 1.0mL/min, λ 254nm) t_R(1)＝8.1min,t_R(2)＝9.2min,t_R(3)＝10.1min,dl-/meso-＝83.8:16.2,>99％ee；[α]_D ²³＝13.7(c 2.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)mixture of diastereomersδ7.46-7.33(m,6H),7.22-7.13(m,4H),6.74-6.73(m,2H),6.66-6.62(m,2H),6.34-6.33(m,2H),5.22-5.18(m,2H),3.68-3.67(d,6H),3.38-3.30(m,2H),3.15-3.09(m,2H)；¹³C NMR(100MHz,CDCl₃)mixture of diastereomersδ204.10,204.05,159.3,157.6,157.55,157.53,154.9,141.1,141.0,133.89,133.87,128.50,128.48,123.9,122.8,120.89,120.86,115.49,115.45,114.65,114.64,113.9,113.8,111.2,104.2,104.1,55.5,46.4,39.9；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₅H₂₈Br₂O₅Na 709.0196；Found 709.0189.

Example 17

Under the protection of nitrogen, 100mg of a Schlenk tube subjected to anhydrous anaerobic treatment and 25mL of the tube is addedMolecular sieves, chiral catalyst Cat 9(4.9mg, 0.01mmol,10 mol%), dienone 1m (37.2mg, 0.1mmol) and organoboronic acid 2a (44.4mg, 0.3mmol, 3.0equiv), purged 3 times, added dry toluene (1.0mL) and stirred at 25 ℃ for 24 h. TLC point plate tracking until 1m of raw material disappears, decompression removing solvent, direct fast silica gel column chromatography (eluent is dichloromethane/petroleum ether volume ratio 1/3-1/1) separating and purifying to obtain target product 3ma', yield is 97%. A colorless oily liquid (56.1 mg); HPLC (daicel chiralpak IB, n-hexane/isopropanol 80:20, flow rate 1.0mL/min, λ 254nm) t_R(1)＝6.5min,t_R(2)＝19.3min,t_R(3)＝21.9min,dl-/meso-＝96.0:4.0,>99％ee；[α]_D ¹⁹＝1.3(c 2.0,CHCl₃)；¹H NMR(600MHz,CDCl₃)δ7.47-7.43(m,4H),7.39-7.32(m,4H),7.28-7.18(m,10H),6.35-6.17(m,4H),4.13(q,J＝10.8Hz,2H),3.01-2.83(m,4H)；¹³C NMR(150MHz,CDCl₃)δ205.6,144.0,136.8,131.3,131.2,131.1(q,J＝31.5Hz),131.0,129.3,128.7,127.7,126.4,124.4(q,J＝4.5Hz),124.2(q,J＝271.5Hz),123.8(q,J＝6.0Hz),49.2,43.5；¹⁹F{¹H}NMR(376MHz,CDCl₃)δ–62.5；HRMS(ESI)m/z:[M+Na]⁺Calcd for C₃₅H₂₈F₆ONa 601.1937；Found 601.1922.

The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.