阅读说明：本技术 合成手性烯丙基羧酸酯的方法 (Method for synthesizing chiral allyl carboxylic ester ) 是由 唐生表 张鹏 孙江涛 于 2021-08-19 设计创作，主要内容包括：本发明属于有机合成技术领域,公开了一种合成手性烯丙基羧酸酯的方法,在铱催化剂、手性亚磷酰胺配体及添加剂的作用下,外消旋的支链芳基烯丙基醇和游离羧酸发生酯化反应,生成所述手性烯丙基羧酸酯,添加剂为氢溴酸,盐酸,氢碘酸,四氟硼酸中的任意一种或多种。具体操作步骤为：在氩气保护下,向反应管中加入铱催化剂和手性亚磷酰胺配体,随后加入支链芳基烯丙基醇,游离羧酸,4A分子筛和添加剂,然后在室温下反应,待反应完全淬灭纯化,得到手性烯丙基羧酸酯化合物。与已报道的文献方法相比,本发明方法首次采用易得的外消旋的支链芳基烯丙基醇底物,使用游离羧酸为原料,具有底物易得、适用范围广的优点。(The invention belongs to the technical field of organic synthesis, and discloses a method for synthesizing chiral allyl carboxylic ester. The specific operation steps are as follows: under the protection of argon, adding an iridium catalyst and a chiral phosphoramidite ligand into a reaction tube, then adding branched aryl allyl alcohol, free carboxylic acid, a 4A molecular sieve and an additive, then reacting at room temperature, and obtaining a chiral allyl carboxylic ester compound after the reaction is completely quenched and purified. Compared with the reported literature method, the method adopts an easily available racemic branched chain aryl allyl alcohol substrate for the first time, uses free carboxylic acid as a raw material, and has the advantages of easy availability of the substrate and wide application range.)

1. A method for synthesizing chiral allyl carboxylate is characterized by comprising the following steps: under the action of an iridium catalyst, a chiral phosphoramidite ligand and an additive, carrying out esterification reaction on racemic branched-chain aryl allyl alcohol and free carboxylic acid to generate chiral allyl carboxylic ester; the structural formula of the racemic branched aryl allyl alcohol is shown in the specificationThe additive is one or more of hydrobromic acid, hydrochloric acid, hydroiodic acid and tetrafluoroboric acid.

2. The method of synthesizing chiral allyl carboxylate according to claim 1, wherein: the method comprises the following steps: under the protection of argon, dissolving an iridium catalyst and a chiral phosphoramidite ligand in a dichloromethane solvent, placing the dichloromethane solvent and the dichloromethane solvent in a reaction tube, firstly stirring to coordinate Ir and the ligand into a complex, then sequentially adding racemic branched aryl allyl alcohol, free carboxylic acid and an additive into the reaction tube to displace argon, then reacting at room temperature for 24-72h, quenching and purifying to obtain the chiral allyl carboxylate compound.

3. The process for the synthesis of chiral allyl carboxylic acid esters according to claim 1 or 2, characterized in that: ar is a benzene ring, naphthyl or benzofuranyl group with an electron withdrawing group or an electron donating group;

and/or the iridium catalyst is [ Ir (cod) Cl]₂；

And/or, the free carboxylic acid has the formula:

wherein R is alkyl, aryl and NHBoc-amino acid, drug skeleton;

and/or the activator is 100% to 120% of carboxylic acid equivalents.

4. The process for the synthesis of chiral allyl carboxylate according to claim 2, characterized in that: the stirring time is 5-10 minutes.

5. The process for the synthesis of chiral allyl carboxylate according to claim 2, characterized in that: in the reaction tube, 4A molecular sieve is added after the free carboxylic acid is added.

6. The process for the synthesis of chiral allyl carboxylic acid esters according to claim 1 or 2, characterized in that: the molar ratio of racemic branched aryl allyl alcohol to free carboxylic acid is 2-4: 1.

7. The process for the synthesis of chiral allyl carboxylic acid esters according to claim 1 or 2, characterized in that: the molar ratio of racemic branched aryl allyl alcohol to free carboxylic acid is 3: 1.

8. The process for the synthesis of chiral allyl carboxylic acid esters according to claim 1 or 2, characterized in that: the dosage of the iridium catalyst is 2-4% of carboxylic acid equivalent; the amount of chiral phosphoramidite ligand used was 400% of the iridium catalyst equivalent.

9. The process for the synthesis of chiral allyl carboxylate according to claim 2, characterized in that: the solvent is any one of dichloromethane, dichloroethane, trichloromethane and diethyl ether.

And/or the additive is hydrobromic acid and the equivalent is 120% of the molar amount of carboxylic acid.

10. The process for the synthesis of chiral allyl carboxylic acid esters according to claim 1 or 2, characterized in that: the phosphoramidite chiral ligands (L) used are:

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing chiral allyl carboxylate

Background

Chiral allyl carboxylic ester and hydrolysis product thereof chiral allyl alcohol compounds are a common organic synthetic substrate and important chemical raw materials. The method is widely applied to the fields of organic synthesis, medicines, materials, chemical engineering and the like. Early chiral allyl carboxylates were prepared mainly by kinetic resolution methods (y.gao, r.m.hanson, j.m.kluder, h.masamune, k.b.sharp, j.am.chem.soc.1987,109,5165). The first strategy is: using basic chiral organic small molecule catalysts, such as: the Smith project group catalyzed the reaction of allyl alcohol and the corresponding acetic anhydride with isothiourea to give chiral allyl carboxylate in 2016 (s.f. musolino, o.s.ojo, n.j.westwood, j.e. taylor, a.d. Smith, chem.eur.j.2016,22,18916). However, the organic small molecule catalysis must use corresponding acid anhydride as raw material, the types of acid anhydride are very limited, and the acid anhydride with slightly larger molecule is difficult to prepare, which greatly limits the development of organic catalysis asymmetric esterification. The second strategy is: directly synthesized by a method of asymmetric allyl esterification catalyzed by transition metal. As early as 2005, Overman reported palladium-catalyzed allyltrichloroacetimidate and free carboxylic acid allylic substitution. However, the substrates used in this method are limited to alkyl cis-allyl trichloroacetimidate, making the reaction more limited ((a) s.f. kirsch, l.e. overlaman, j.am. chem. soc.2005,127,2866.(b) j.s.canon, s.f. kirsch, l.e. overlaman, j.am. chem. soc.2010,132, 15185.). Subsequently, the Onitsuka group reported that ruthenium catalyzes an allyl esterification reaction using allyl chloride as a substrate (N.Kanbayashi, K.J.Onitsuka, J.Am.chem.Soc.2010,132,1206), however, the preparation steps of the chiral ruthenium catalyst used in the reaction are complicated, and the conditions are severe, which seriously hampers the practical application thereof. In 2014, Helmchen reported the iridium catalyzed reaction of linear allyl phosphate esters with carboxylic acid salts to produce chiral allyl esters (j.p. qu, l.rober, g.helmchen, j.am.chem.soc.2014,136, 1272). However, this reaction requires a very sterically hindered phosphate ester as leaving group, linear allyl phosphate esters are difficult to prepare, and the atom economy of the reaction is lacking. Subsequently, a patent (CN 104402718A) filed by Zhao Xiaoming et al, college university, utilized iridium to catalyze the reaction of linear allyl chloride and a carboxylic acid salt to obtain an allyl carboxylic ester having excellent chirality. The method of the patent also faces the problem of complicated preparation of raw materials, such as: the method adopts cinnamyl halide substrates, and the general synthetic means of the compounds is to synthesize cinnamate from corresponding aryl formaldehyde, reduce the cinnamate into corresponding cinnamyl alcohol and finally convert hydroxyl into halogen; and the carboxylate solubility was poor.

Disclosure of Invention

In view of the limitations of the previously developed processes (cumbersome sources of linear allyl substrates, need for prior preparation of carboxylic acid salts or anhydrides, etc.). The invention provides a method for synthesizing chiral allyl carboxylic ester, which takes free carboxylic acid and allyl secondary alcohol which is easy to prepare and store as reaction raw materials.

In order to realize the purpose of the invention, the adopted technical scheme is as follows:

under the action of iridium catalyst, chiral phosphoramidite ligand and additive, racemic branched aryl allyl alcohol and free carboxylic acid are subjected to esterification reaction to generate chiral allyl carboxylic ester; the structural formula of the racemic branched aryl allyl alcohol is shown in the specificationWherein Ar can be a benzene ring with electron withdrawing or electron donating properties or other aryl groups (e.g., naphthyl, benzofuranyl).

Further, the method is carried out according to the following steps: under the protection of argon, the iridium catalyst and the chiral phosphoramidite ligand are dissolved in a dichloromethane solvent (dichloromethane is an optimal solvent, and the reaction yield and the ee value of other solvents are low) and placed in a reaction tube, and the Ir and the ligand are coordinated into a complex by stirring (the stirring time is preferably 5-10 minutes, and more preferably 5 minutes). And then adding racemic branched aryl allyl alcohol, free carboxylic acid and an additive into the reaction tube in sequence, replacing argon, reacting at room temperature for 24-72h, quenching and purifying to obtain the chiral allyl carboxylic ester compound.

Furthermore, in the reaction tube, a 4A molecular sieve is added after the free carboxylic acid is added, so that the 4A molecular sieve can improve the yield on one hand, and on the other hand, when the additive contains water, the molecular sieve can play a role in removing water.

Further, the free carboxylic acid has the formula:

wherein R is any one of alkyl, aryl, NHBoc-amino acid and drug framework.

The specific reaction equation is as follows (Scheme 1):

wherein Ir is [ Ir (cod) Cl]₂And L is the chiral phosphoramidite ligand.

Further, the molar ratio of racemic branched arylallyl alcohol to free carboxylic acid is 2-4:1, more preferably 3:1, which yields the highest yield.

Further, the amount of the iridium catalyst is 2-4% of free carboxylic acid equivalent.

Further, the chiral phosphoramidite ligand is in (S) -configuration

Further, the amount of the chiral phosphoramidite ligand used is 400% of the molar amount of the iridium catalyst.

Further, the additive is any one of hydrobromic acid, hydrofluoric acid, hydroiodic acid and hydrochloric acid, wherein the best yield is achieved when the equivalent weight of the hydrobromic acid is 120 percent of the molar weight of the carboxylic acid.

Compared with the prior art, the invention has the following beneficial effects:

the process of the present invention uses readily prepared racemic allyl secondary alcohol and commercially available free carboxylic acid as starting materials for the reaction. The reaction operation is simple, the condition is mild, the substrate applicability is good, and the target optically pure allyl carboxylate compound is obtained with high regioselectivity and stereoselectivity.

Detailed Description

The present invention is not limited to the following embodiments, and those skilled in the art can implement the present invention in other embodiments according to the disclosure of the present invention, or make simple changes or modifications on the design structure and idea of the present invention, and fall into the protection scope of the present invention. It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.

Experiments prove that the invention can realize the aim through the following embodiments: under the action of an iridium catalyst, a chiral phosphoramidite ligand and an additive, carrying out esterification reaction on racemic branched aryl allyl alcohol and free carboxylic acid to generate chiral allyl carboxylic ester; the structural formula of the racemic branched aryl allyl alcohol is shown in the specificationWherein Ar can be a benzene ring with electron withdrawing or electron donating properties or other aryl groups (e.g., naphthyl, benzofuranyl). Tests prove that the iridium catalyst, the chiral phosphoramidite ligand and the additive are all indispensable.

The present invention is further described below with reference to examples, but is not limited thereto.

Example 1 was carried out:

(3aa) Synthesis:

1, 5-cyclooctadieneiridium chloride dimer (2.6mg,4 mol%), chiral ligand L (8.0mg,16 mol%) and dichloromethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Subsequently, 1a (0.3mmol,53mg), 2a (0.1mmol,18.6mg), HBr (40% Wt in water,24mg,0.12mmol) and 4A molecular sieves (40mg) were added. Then, the reaction tube was used to carry out the reaction at room temperature for 24 hours. The crude product was purified by TLC prep. plate to give (3aa) (26.2mg, 97% ee, yield: 76%) as a light yellow oil.

¹H NMR(400MHz,CDCl₃)δ8.00-7.89(m,1H),7.89-7.81(m,1H),7.78(d,J＝7.8Hz,1H),7.53-7.34(m,4H),6.77(s,2H),6.73-6.65(m,1H),5.94(ddd,J＝17.2,10.6,4.2Hz,1H),5.06(d,J＝10.6Hz,1H),4.91(d,J＝17.2Hz,1H),4.10(s,2H),2.23(s,3H),2.22(s,6H).¹³C NMR(126MHz,CDCl₃)δ169.6,136.5,136.1,134.1,132.7,131.1,130.4,129.5,128.6,127.6,127.0,125.3,124.7,124.4,122.7,114.9,72.3,38.3,19.8,19.2.HRMS(ESI)m/z calculated for C₂₄H₂₄NaO₂[M+Na]⁺:367.1669,found:367.1662.HPLC:Daicel Chiralpak OD-H column(hexane/iPrOH＝99:1,flow rate:1.0mL/min,λ＝254nm,t_R(major)＝9.88min,t_R(minor)＝9.14min.ee＝97％.

Example 2 was carried out:

synthesis of (3 ab):

1, 5-cyclooctadieneiridium chloride dimer (2.6mg,4 mol%), chiral ligand L (8.0mg,16 mol%) and dichloromethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Subsequently, 1a (0.3mmol,53mg), 2b (0.1mmol,12mg), HBr (40% Wt in water,24mg,0.12mmol) and 4A molecular sieves (40 mg). Then, the reaction tube was used to carry out the reaction at room temperature for 36 hours. The crude product was purified by TLC prep. plate to give (3ab) (21.2mg, 99% ee, yield: 76%) as a colorless oil.¹H NMR(400MHz,CDCl₃)δ8.12-7.86(m,2H),7.59-7.48(m,1H),7.42(dd,J＝10.6,4.7Hz,2H),6.94(dt,J＝4.2,2.1Hz,1H),6.84(s,2H),6.19(ddd,J＝17.2,10.6,4.2Hz,1H),5.25-5.17(m,2H),2.48(s,6H),2.24(s,3H).¹³C NMR(100MHz,CDCl₃)δ165.7,137.7,137.2,135.6,133.1,131.8,130.4,129.9,129.8,128.5,116.3,73.6,21.0,20.8.HPLC:The enantiomeric excess was determined by HPLC analysis on a Daicel Chiralpak ID column(hexane/iPrOH＝90:10),flow rate:1.0mL/min,λ＝225nm,t_R(major)＝3.99min,t_R(minor)＝5.10min.ee＝99％.

Example 3 of implementation:

(3ac) Synthesis:

1, 5-cyclooctadieneiridium chloride dimer (2.6mg,4 mol%), chiral ligand L (8.0mg,16 mol%) and dichloromethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Subsequently, 1a (0.3mmol,53mg), 2a (0.1mmol,12mg), HBr (40% Wt in water,24mg,0.12mmol) and 4A molecular sieves (40 mg). Then, the reaction tube was used to carry out the reaction at room temperature for 24 hours. The crude product was purified by TLC prep. plate to give (3ac) (18.6mg, 98% ee, yield: 68%) as a light yellow oil.¹H NMR(400MHz,CDCl₃)δ6.83(s,2H),6.71-6.69(m,1H),6.06(ddd,J＝17.2,10.6,4.4Hz,1H),5.25-5.13(m,1H),5.13-5.02(m,1H),2.41-2.26(m,2H),2.39(s,6H),2.25(s,3H),1.62(dt,J＝14.5,7.3Hz,2H),1.35-1.22(m,4H),0.87(t,J＝6.9Hz,3H).¹³C NMR(75MHz,CDCl₃)δ173.0,137.6,137.2,135.7,131.9,129.9,116.0,72.8,34.5,31.4,24.7,22.4,21.0,20.6,14.0.HRMS(ESI)m/z calculated for C₁₈H₂₆NaO₂[M+Na]⁺:297.1830,found:297.1829.HPLC:Daicel Chiralpak IE column(hexane/iPrOH＝99:1,flow rate:1.0mL/min,λ＝224nm,t_R(major)＝7.84min,t_R(minor)＝6.97min.ee＝98％.

Example 4 of implementation:

(3ad) Synthesis:

1, 5-cyclooctadieneiridium chloride dimer (2.6mg,4 mol%), chiral ligand L (8.0mg,16 mol%) and dichloromethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Then, 1a (0.3mmol,53mg), NHBoc amino acid 2d (0.1mmol,23.2mg), HBr (40% Wt in water,24mg,0.12mmol) and 4A molecular sieves (40 mg). Then, the reaction tube was used to carry out the reaction at room temperature for 24 hours. The crude product was purified by TLC prep. plate to give (3ad) (19.6mg, yield: 50%) as a pale yellow oil.

¹H NMR(400MHz,CDCl₃)δ6.82(s,1H),6.72(s,1H),6.07(ddd,J＝17.3,10.6,4.2Hz,1H),5.19(d,J＝10.6Hz,1H),5.09(d,J＝17.3Hz,1H),4.87(d,J＝8.9Hz,1H),4.39(td,J＝9.3,4.5Hz,1H),2.38(s,3H),2.25(s,2H),1.70–1.48(m,1H),1.43(s,4H),0.91(d,J＝6.4Hz,2H),0.86(d,J＝6.5Hz,2H).¹³C NMR(75MHz,CDCl₃)δ172.8,155.5,137.8,137.2,135.3,131.3,129.9,116.5,79.9,73.9,52.3,41.8,28.4,24.8,23.1,21.9,21.0,20.6.HRMS(ESI)calculated for C₂₃H₃₅NNaO₄[M+Na]⁺:412.2458,found:412.2454.

Example 5 was carried out:

(3ae) Synthesis:

1, 5-cyclooctadieneiridium chloride dimer (2.6mg,4 mol%), chiral ligand L (8.0mg,16 mol%) and dichloromethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Subsequently, 1a (0.3mmol,53mg), the drug probenecid 2e (0.1mmol,28.6mg), HBr (40% Wt in water,24mg,0.12mmol), and 4A molecular sieves (40 mg). Then, the reaction tube was used to carry out the reaction at room temperature for 24 hours. The crude product was purified by TLC prep. plate to give (3ae) (32.8mg, 86% ee, yield: 74%) as a light yellow oil.

¹H NMR(300MHz,CDCl₃)δ8.18(d,J＝7.5Hz,2H),7.87(d,J＝7.6Hz,2H),6.96(dd,J＝3.7,1.5Hz,1H),6.86(s,2H),6.21-6.17(m,1H),5.30-5.25(m,1H),5.24-5.15(m,1H),3.17-3.03(m,4H),2.48(s,6H),2.25(s,3H),1.68-1.47(m,4H),0.86(td,J＝7.3,0.7Hz,6H).¹³C NMR(75MHz,CDCl₃)δ164.4,144.4,138.0,137.2,135.2,133.7,131.3,130.4,130.0,127.1,116.8,74.3,50.0,22.0,21.0,20.7,11.3.HRMS(ESI)m/z calculated for C₂₅H₃₃NNaO₄S[M+Na]⁺:466.2023,found:466.2019.HPLC:Daicel Chiralpak OD-H column(hexane/iPrOH＝90:10,flow rate:1.0mL/min,λ＝254nm,t_R(major)＝5.46min,t_R(minor)＝6.76min.ee＝86％.

Example 6 of implementation:

synthesis of (3 ba):

1, 5-cyclooctadieneiridium chloride dimer (2.6mg,4 mol%), chiral ligand L (8.0mg,16 mol%) and dichloromethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Subsequently, 1a (0.3mmol,55mg), 2a (0.1mmol,18.6mg), HBr (40% Wt in water,24mg,0.12mmol) and 4A molecular sieves (40 mg). Then, the reaction tube was used to carry out the reaction at room temperature for 24 hours. The crude product was purified by TLC prep. plate to give (3ba) (24.2mg, 87% ee, yield: 69%) as a light yellow oil.¹H NMR(400MHz,CDCl₃)δ7.93(dd,J＝17.4,8.4Hz,2H),7.87-7.72(m,4H),7.49-7.30(m,8H),6.96(d,J＝5.2Hz,1H),6.09(ddd,J＝17.1,10.6,5.3Hz,1H),5.19-5.12(m,2H),4.14(s,2H).¹³C NMR(100MHz,CDCl₃)δ170.7,135.8,134.4,134.0,133.9,132.2,130.7,130.5,129.1,128.85,128.78,128.22,126.42,126.33,125.89,125.82,125.60,125.56,125.30,123.98,117.4,74.5,39.5.HRMS(ESI)calculated for C₂₅H₂₀NaO₂[M+Na]⁺:375.1356,found:375.1355.HPLC:The enantiomeric excess was determined by HPLC analysis on a Daicel Chiralpak IC column(hexane/iPrOH＝90:10),flow rate:1.0mL/min,λ＝254nm,t_R(major)＝8.97min,t_R(minor)＝6.82min.ee＝87％.

EXAMPLES example 7

1, 5-cyclooctadieneiridium chloride dimer (2.6mg,4 mol%), chiral ligand L (8.0mg,16 mol%) and dichloromethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Subsequently, 1e (0.3mmol,63mg), 2a (0.1mmol,18.6mg), HBr (40% Wt in water,24mg,0.12mmol) and 4A molecular sieves (40 mg). Then, the reaction tube was used to carry out the reaction at room temperature for 24 hours. The crude product was purified by TLC prep. plate to give (3aa) (26.7mg, 99% ee, yield: 71%) as a light yellow oil.¹H NMR(400MHz,CDCl₃)δ8.01-7.94(m,1H),7.93-7.86(m,1H),7.83(d,J＝7.9Hz,1H),7.57-7.49(m,2H),7.48-7.19(m,11H),6.34(d,J＝5.5Hz,1H),5.88(ddd,J＝16.2,10.5,5.4Hz,1H),5.09(d,J＝10.5Hz,1H),4.91(d,J＝17.2Hz,1H),4.11(d,J＝1.4Hz,2H).¹³C NMR(100MHz,CDCl₃)δ170.2,141.5,140.5,136.5,136.4,133.9,132.2,130.6,130.1,129.3,128.8,128.3,128.2,127.9,127.7,127.4,126.9,126.4,125.9,125.6,124.0,116.9,74.1,39.4.HRMS(ESI)calculated for C₂₇H₂₆NO₂[M+NH₄]⁺:396.1958,found:396.1957.HPLC:The enantiomeric excess was determined by HPLC analysis on a Daicel Chiralpak IC column(hexane/iPrOH＝95:5),flow rate:1.0mL/min,λ＝225nm,t_R(major)＝5.63min,t_R(minor)＝5.05min.ee＝99％.

Example 6

(3aa) Synthesis:

1, 5-cyclooctadiene iridium chloride dimer (2.6mg,4 mol%), chiral ligand L (8.0mg,16 mol%) and 1, 2-dichloroethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Subsequently, 1a (0.3mmol,53mg), 2a (0.1mmol,18.6mg), HBr (40% Wt in water,24mg,0.12mmol) and (4A molecular sieves (40mg) were added to the reaction tube, and the reaction was carried out at room temperature for 24 hours the crude product was purified by TLC prep to give (3aa) (17.1mg, 97% ee, yield: 50%) as a pale yellow oil.

Example 9

(3aa) Synthesis:

1, 5-cyclooctadieneiridium chloride dimer (1.3mg,2 mol%), chiral ligand L (4.0mg,8 mol%) and dichloromethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Subsequently, 1a (0.3mmol,53mg), 2a (0.1mmol,18.6mg), HBr (40% Wt in water,24mg,0.12mmol) and (4A molecular sieves (40mg) were added to the reaction tube, and the reaction was carried out at room temperature for 24 hours the crude product was purified by TLC prep to give (3aa) (16.8mg, 97% ee, yield: 49%) as a pale yellow oil.

Example 10

(3aa) Synthesis:

1, 5-cyclooctadieneiridium chloride dimer (2.6mg,4 mol%), chiral ligand L (8.0mg,16 mol%) and dichloromethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Subsequently, 1a (0.3mmol,53mg), 2a (0.1mmol,18.6mg), HBr (40% Wt in water,24mg,0.12mmol) and 4A molecular sieves (40 mg). Then, the reaction tube was used to carry out the reaction at room temperature for 72 hours. The crude product was purified by TLC prep. plate to give (3aa) (26.0mg, 97% ee, yield: 75%) as a light yellow oil.

Example 11

(3aa) Synthesis:

1, 5-cyclooctadieneiridium chloride dimer (2.6mg,4 mol%), chiral ligand L (8.0mg,16 mol%) and dichloromethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Subsequently, 1a (0.2mmol,36mg), 2a (0.1mmol,18.6mg), HBr (40% Wt in water,24mg,0.12mmol) and 4A molecular sieves (40 mg). Then, the reaction tube was used to carry out the reaction at room temperature for 24 hours. The crude product was purified by TLC prep. plate to give (3aa) (16.0mg, 96% ee, yield: 48%) as a light yellow oil.

Example 12

(3aa) Synthesis:

1, 5-cyclooctadieneiridium chloride dimer (2.6mg,4 mol%), chiral ligand L (8.0mg,16 mol%) and dichloromethane (1.0mL) were added to the reaction tube under an argon atmosphere, and stirred at room temperature for 5 minutes. Subsequently, 1a (0.4mmol,70mg), 2a (0.1mmol,18.6mg), HBr (40% Wt in water,24mg,0.12mmol) and 4A molecular sieves (40mg) were added. Then, the reaction tube was used to carry out the reaction at room temperature for 24 hours. The crude product was purified by TLC prep. plate to give (3aa) (26.6mg, 95% ee, yield: 78%) as a light yellow oil.

The present invention is not limited to the above-described embodiments, and any obvious improvements, substitutions or modifications can be made by those skilled in the art without departing from the spirit of the present invention.