CN114956932B - Synthesis method of polysubstituted chiral tetrahydroquinoline compound - Google Patents

Synthesis method of polysubstituted chiral tetrahydroquinoline compound Download PDF

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CN114956932B
CN114956932B CN202210820788.5A CN202210820788A CN114956932B CN 114956932 B CN114956932 B CN 114956932B CN 202210820788 A CN202210820788 A CN 202210820788A CN 114956932 B CN114956932 B CN 114956932B
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CN114956932A (en
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张曈骁
张晓燕
李金生
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Northeastern University Qinhuangdao Branch
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The invention discloses a synthesis method of a polysubstituted chiral tetrahydroquinoline compound, and belongs to the technical field of organic chemistry. By DDQ and MnO 2 The combination of substrate 1 and substrate 2 is subjected to double oxidation followed by an aza-Michael/1, 6-conjugate addition reaction, i.e. in situ generated p-quinone methide and cinnamaldehyde [4+2]]Asymmetric cycloaddition. The method is an unprecedented double oxidation tandem reaction, and has the advantages of high efficiency, strong universality to substrates, high enantioselectivity and the like. Has wide application prospect in the field of asymmetric synthesis and medicine research and development.

Description

Synthesis method of polysubstituted chiral tetrahydroquinoline compound
Technical field:
the invention belongs to the technical field of organic chemistry, and particularly relates to a synthesis method of a polysubstituted chiral tetrahydroquinoline compound.
The background technology is as follows:
in recent years, the para-quinone methide is considered to be an important intermediate in organic synthesis, and has high activity and wide application. Although researchers have proposed synthesizing products by oxidizing p-quinone methide precursors followed by [4+2] cycloadditions with olefins. But by simultaneously oxidizing the para-quinone methide precursor and phenylpropionaldehyde followed by a [4+2] cycloaddition reaction under the control of a chiral catalyst, a product with chirality is obtained. The 4-phenyl substituted tetrahydroquinoline backbone is a very important building block, which is widely found in natural products and drug molecules. For example, the penicillanone I has strong bactericidal effect, the compound II and the compound III have proved to have anticancer and antibacterial properties respectively, and the compound IV has strong antitumor activity.
In 2015, team Huo Congde (Org Lett,2015,17 (20): 5028-5031) developed a novel iron-catalyzed tandem cyclization of bisoxidative dehydroglycine derivatives with tetrahydrofuran to give polysubstituted quinoline condensed lactones.
In 2018, the Hu Lihong group of topics (Org letters, 2018,20 (19): 5995-5998) reported that 4-aryl substituted tetrahydroquinoline products were obtained by the aza-Michael/1, 6-conjugate addition reaction, as a result of oxidation of a p-quinone methide precursor to produce a p-quinone methide, followed by a [4+2] cycloaddition reaction with nitroolefins.
In 2018, the Wu Xiang group of subjects (Org letters, 2018,20 (1): 32-35) reported the oxidation of 2-methyl-3-phenylmethylindole by DDQ followed by asymmetric Diels-Alder reactions of the oxidized product with α, β -unsaturated aldehydes. In the reaction, classical LUMO reduction activation energy of alpha, beta-unsaturated aldehyde is carried out under the catalysis of diaryl prolyl silyl ether to provide excellent three-dimensional control, so that the tetrahydrocarbazole derivative with chirality is obtained.
Although the above prior art can obtain the product by double oxidation and single oxidation or obtain the asymmetric product by single oxidation, the asymmetric product is obtained by double oxidation of the quinone methide precursor and phenylpropionaldehydeThe product has not been reported yet. We therefore pass through DDQ and MnO 2 Under the action of the combination and the chiral catalyst, the asymmetric polysubstituted chiral tetrahydroquinoline product is obtained through double oxidation. The synthesis of polysubstituted chiral tetrahydroquinolines by double oxidation has not been reported.
The invention comprises the following steps:
the invention aims to overcome the defects in the prior art and provide a synthetic method of tetrahydroquinoline compounds with high efficiency, strong universality to substrates and high enantioselectivity.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a synthetic method of polysubstituted chiral tetrahydroquinoline compounds comprises the following steps:
(1) Substrate 1: substrate 2: oxidizing agent: chiral catalyst: additive= (1-3): 1: (2-4): 0.15:0.1, preparing materials, wherein the oxidant is DDQ and MnO 2 The molar ratio of the two is (0.5-3): 1, a step of;
(2) Fully dissolving a substrate 1 and a substrate 2 in a reaction solvent to obtain a mixed solvent, putting an oxidant, a chiral catalyst and an additive into a Schlenk tube, adding the mixed solvent into the Schlenk tube, and stirring at room temperature for reacting for 48 hours to obtain a target product polysubstituted chiral tetrahydroquinoline compound; the reaction scheme is as follows:
in the general formula:
R 1 、R 3 selected from methyl, methoxy, trifluoromethyl, 3, 4-methylenedioxy and halogen; r is R 2 Selected from methyl and methoxy.
In the step (1), the substrate 1 comprises a substrate 1a, a substrate 1b, a substrate 1c, a substrate 1d, a substrate 1e or a substrate 1f, wherein the substrate 1a is N- (2- (3, 5-di-tert-butyl-4-hydroxybenzyl) phenyl) -4-methylbenzenesulfonamide, the substrate 1b is N- (2- (3, 5-di-tert-butyl-4-hydroxybenzyl) -4-methylphenyl) -4-methylbenzenesulfonamide, the substrate 1c is N- (2- (3, 5-di-tert-butyl-4-hydroxybenzyl) -4-fluorophenyl) -4-methylbenzenesulfonamide, the substrate 1d is N- (2- (3, 5-di-tert-butyl-4-hydroxybenzyl) -4-chlorophenyl) -4-methylbenzenesulfonamide, the substrate 1e is N- (2- (3, 5-di-tert-butyl-4-hydroxybenzyl) -4-methylbenzenesulfonamide, and the substrate 1f is N- (2- (3, 5-dimethyl-4-hydroxybenzyl) -4-methylbenzenesulfonamide.
In the step (1), the substrate 2 comprises a substrate 2a, a substrate 2b, a substrate 2c, a substrate 2d or a substrate 2e, wherein the substrate 2a is phenylpropionaldehyde, the substrate 2b is 4-methylbenzyl propanal, the substrate 2c is 4-methoxyphenylpropionaldehyde, the substrate 2d is 4-fluorobenzoyl propanal, the substrate 2e is 4-chlorobenzoyl propanal, the substrate 2f is 4-bromophenylpropionaldehyde, and the substrate 2g is 4-nitrobenzoyl propanal.
In the step (2), the DDQ and the MnO firstly occur within 48 hours of stirring reaction at room temperature 2 Double oxidation of the substrate 1 and the substrate 2 is combined to respectively generate a p-quinone methide and a cinnamaldehyde intermediate in situ, and then an aza-Michael/1, 6-conjugated addition reaction is carried out in the stirring process, so that a product 3 is obtained.
In the step (1), the oxidant has a certain influence on the reaction yield and the enantioselectivity by reacting with Ag 2 CO 3 、Ag 2 O、K 2 S 2 O 8 、DDQ、PhI(OAc) 2 、MnO 2 Or DDQ/MnO 2 Research on oxidants the preferred oxidants of the invention are DDQ and MnO 2 The optimal ratio is 1:1.
in the step (1), the chiral catalyst is one of 4a, 4b, 4c, 4d, 4e or 4f, the chiral catalyst has a great influence on the enantioselectivity, the 4a is L-proline, the 4b is (S) -5-benzyl-2, 2-dimethyl imidazolin-4-one trifluoroacetate, the 4c is (2R, 5S) -5-benzyl-2-tertiary butyl imidazolidone, the 4d is (R) -2- [ diphenyl [ (trimethyl silyl) oxy ] methyl ] -pyrrolidine, the 4e is (R) - (-) -2- [ hydroxy (diphenyl) methyl ] -1-methylpyrrolidine, the 4f is (R) -2- [ di [3, 5-di (trifluoromethyl) phenyl ] [ tertiary butyl dimethylsilyl ] oxy ] methyl ] pyrrolidine, and the chiral catalyst is 4d.
In the step (1), the reaction solvent is one of 1, 2-dichloroethane, dichloromethane, chloroform, acetonitrile, 1, 4-dioxane, benzene, toluene, acetone, tetrahydrofuran or DMF organic solvent, and the dichloromethane is preferably used as the reaction solvent according to the research.
In the step (1), the optimization of the additives in the reaction comprises Cs 2 CO 3 、Na 2 CO 3 、K 2 CO 3 、Et 3 N、K 3 PO 4 DIPEA, DBU or i Pr 2 NH, the preferred additive of the invention is i Pr 2 NH。
In order to verify the universality of the substrate, the substituent on the substrate 1 is changed under the optimal conditions, and the reaction route and the corresponding products are as follows:
substrates 1a-e (0.15 mmol,1.5 equiv) and substrate 2a (0.10 mmol,1 equiv) were dissolved in 1mL of dichloromethane, and then the oxidant DDQ (0.2 mmol) and MnO 2 (0.2 mmol), 4d (15 mol%) and i Pr 2 NH (0.02 mmol) was placed in Schlenk tube, and finally the mixed solvent was added into Schlenk tube, and the reaction was stirred at room temperature for 48 hours to obtain the objective product. In the reaction, different substituents on 1 are changed, and the reaction can be successfully carried out to obtain a target product. Meanwhile, the yield of the electron donating group connected with the benzene ring is higher than that of the electron withdrawing group connected with the benzene ring, and the enantioselectivity is not great. When R of substrate 1 is used 2 When the tert-butyl group is replaced by methyl, the yield and the enantioselectivity are reduced.
In addition, the present invention also alters the substituents on substrate 2, the reaction scheme and corresponding products are shown below:
substrate 1a (0.15 mmol,1.5 equiv) and substrate 2b-g (0.10 mmol,1 equiv) were dissolved in 1mL of dichloromethane, and the oxidants DDQ (0.2 mmol) and MnO 2 (0.2 mmol), 4d (15 mol%) and i Pr 2 NH (0.02 mmol) was placed in Schlenk tube, and finally the mixed solvent was added into Schlenk tube, and the reaction was stirred at room temperature for 48 hours to obtain the objective product. The present reaction achieves reactions 1 and 2 to produce 4, which is not at all addressed in the prior art. The different substituents on 2 were changed in this reaction, and it was found that they all allowed the reaction to proceed smoothly to give the product. The yield of electron donating groups attached to the benzene ring was found to be relatively better than that of electron withdrawing groups attached to the benzene ring, with little difference in enantioselectivity.
The invention has the beneficial effects that:
the application is a double oxidation tandem reaction which is not reported in the literature, and has the advantages of high efficiency, strong universality to substrates, high enantioselectivity and the like. Can be widely applied to asymmetric synthesis of natural products and molecules with pharmaceutical activity, can meet market demands, and has good conversion prospect.
The specific embodiment is as follows:
the present invention will be described in further detail with reference to examples.
Firstly, the oxidizing agent was screened, substrate 1a (0.15 mmol,1.5 equiv) and substrate 2a (0.10 mmol,1 equiv) were dissolved in 1mL of 1, 2-dichloroethane, and 0.4mmol of Ag was added to each of the Schlenk tubes 2 CO 3 、Ag 2 O、K 2 S 2 O 8 、DDQ、PhI(OAc) 2 、MnO 2 Or adding 0.2mmol of each of DDQ and MnO 2 Then 4a (15mol%) and i Pr 2 NH (0.02 mmol) and finally the mixed solvent was added to the Schlenk tube and the reaction was stirred at room temperature for 48 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate=20/1 to 2/1 to give the product 3aa. The yields were 18%, 20%, 41%, 55%, trace, 45%, 59%, respectively. Ee values are 0, 30%, 0, 83%, 79%, 80%, 86%, respectively. It can be seen that the oxidizing agents are DDQ and MnO 2 The combination of (c) gives the best yields and enantioselectivities.
The chiral catalyst is screened under optimal oxidant conditions. Substrate 1a (0.15 mmol,1.5 equiv) and substrate 2a (0.10 mmol,1 equiv) were dissolved in 1mL of 1, 2-dichloroethane, 15mol% of 4a, 4b, 4c, 4d, 4e or 4f, respectively, were added to a Schlenk tube, followed by 0.2mmol of each of DDQ and MnO 2 And i Pr 2 NH (0.02 mmol) was placed in a Schlenk tube, and finally the mixed solvent was added to the Schlenk tube and the reaction was stirred at room temperature for 48 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate=20/1 to 2/1 to give the product 3aa. The yields were 59%, 50%, 47%, 72%, 48%, 53%, respectively. Ee values were 86%, 80%, 76%, 89%, 79%, 70%, respectively. It can be seen that the chiral catalyst gives the best yields and enantioselectivities at 4d.
The reaction solvent is screened under the conditions of optimal oxidant and optimal chiral catalyst. Substrate 1a (0.15 mmol,1.5 equiv) and substrate 2a (0.10 mmol,1 equiv) were dissolved in 1mL 1, 2-dichloroethane, dichloromethane, chloroform, acetonitrile, 1, 4-dioxane, benzene, toluene, acetone, tetrahydrofuran or DMF, respectively, and the oxidants DDQ (0.2 mmol) and MnO were added 2 (0.2 mmol), 4d (15 mol%) and i Pr 2 NH (0.02 mmol) was placed in Schlenk tube, and finally the mixed solvent was added into Schlenk tube, stirred at room temperature for 48 hours, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, petroleum ether/ethyl acetate=20/1 to 2/1, to give 3aa as a product. The yields were 72%, 80%, 71%, 50%, 37%, 53%, 55%, 60%, 72%, 69%, respectively. Ee values are 89%, 93%, 77%, 81%, respectively,40%, 75%, 73%, 90%, 88%, 75%. It can be seen that methylene chloride as solvent gives the best yields and enantioselectivities.
The additives in the reaction are screened under the optimal conditions of an oxidant, a chiral catalyst and a solvent. Substrate 1a (0.15 mmol,1.5 equiv) and substrate 2a (0.10 mmol,1 equiv) were dissolved in 1mL of dichloromethane and 0.02mmol of Cs was added separately to a Schlenk tube 2 CO 2 、Na 2 CO 3 、K 2 CO 3 、Et 3 N、K 3 PO 4 DIPEA, DBU or i Pr 2 NH, then adding the oxidizing agent DDQ (0.2 mmol) and MnO 2 (0.2 mmol) and 4d (15 mol%), and finally the mixed solvent was added to a schlenk tube and reacted at room temperature with stirring for 48 hours, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, petroleum ether/ethyl acetate=20/1 to 2/1 to give a product 3aa. The yields were 56%, 77%, 73%, 75%, 47%, 58%, 69%, 80%, respectively. Ee values were 82%, 69%, 80%, 90%, 85%, 88%, 93%, respectively. It can be seen that i Pr 2 NH as additive gives the best yields and enantioselectivities.
From the above, it can be derived that the oxidizing agents are DDQ and MnO 2 4d is chiral catalyst, dichloromethane is solvent, i Pr 2 NH is an additive in the reaction, so that the reaction effect is the best.
Example 1: preparation of Compound 3aa
Substrate 1a (0.15 mmol,1.5 equiv) and substrate 2a (0.10 mmol,1 equiv) were dissolved in 1mL of dichloromethane, and then the oxidants DDQ (0.2 mmol) and MnO 2 (0.2 mmol), 4d (15 mol%) and i Pr 2 NH (0.02 mmol) was placed in Schlenk tube, and finally the mixed solvent was added into Schlenk tube, and the reaction was stirred at room temperature for 48 hours to obtain the objective product. Yield 80%,93% ee and high performance liquid chromatography (Chiralpak IC column, 2-propanol/n-hexane)=15%, flow rate 1.0mL/min, t R ＝17.10min(minor),t R = 19.19min (major)).
1 H NMR(500MHz,CDCl 3 )δ9.93(d,J＝6.2Hz,1H),7.77–7.72(m,2H),7.43–7.36(m,2H),7.36–7.18(m,7H),7.09–7.00(m,2H),6.88(dd,J＝1.9,1.0Hz,1H),6.57(dd,J＝7.4,2.0Hz,1H),5.17(dt,J＝7.0,1.0Hz,1H),4.18–4.12(m,1H),3.79–3.70(m,1H),2.80(s,1H),2.42(s,3H),1.37(s,18H). 13 C NMR(125MHz,CDCl 3 )δ197.99,154.30,141.71,141.17,136.29,135.49,134.88,134.60,132.89,129.36,128.74,128.49,128.16,128.07,124.34,122.59,120.14,69.87,53.91,46.60,34.50,30.33,21.63.HRMS(ESI)m/z(M+H) + calculated for C 37 H 42 NO 4 S:596.8053,observed:596.8057.
Comparative examples 1 to 1
The difference from example 1 is that the chiral catalyst is replaced by one of 4a, 4b, 4c, 4e or 4f, with the end result as shown in the following table:
comparative examples 1 to 2
The difference is that the oxidant is replaced with Ag as in example 1 2 CO 3 、Ag 2 O、K 2 S 2 O 8 Or PhI (OAc) 2 The final results are shown in the following table:
oxidizing agent Yield (%) ee(％)
1 Ag 2 CO 3 50 91
2 Ag 2 O 72 90
3 K 2 S 2 O 8 0 -
4 PhI(OAc) 2 60 88
Comparative examples 1 to 3
As in example 1, the difference is that the oxidizing agent is replaced with DDQ or MnO 2 The final results are shown in the following table: .
Oxidizing agent Yield (%) ee(％)
1 DDQ 10 92
2 MnO 2 50 93
Example 2: preparation of Compound 3ba
By the method of example 1, using substrate 1b instead of 1a, product 3ba was obtained. The yield was 76%,94% ee and the product was purified by high performance liquid chromatography (Chiralpak OD-H column, 2-propanol/n-hexane=15%, flow rate 1.0mL/min, t R ＝20.14min(minor),t R =21.98 min (major)).
1 H NMR(500MHz,CDCl 3 )δ9.90(d,J＝6.2Hz,1H),7.82–7.76(m,2H),7.40–7.26(m,6H),7.26–7.18(m,1H),7.10(dt,J＝2.2,1.1Hz,2H),6.99(ddd,J＝7.6,2.1,1.1Hz,1H),6.71(dd,J＝1.9,0.9Hz,1H),6.52(d,J＝7.5Hz,1H),5.22(dt,J＝7.0,1.0Hz,1H),4.44–4.38(m,1H),3.61(q,J＝6.9Hz,1H),2.69(s,1H),2.42(s,3H),2.36(s,3H),1.37(s,18H). 13 C NMR(125MHz,CDCl 3 )δ196.84,154.30,141.71,141.17,140.90,139.21,134.88,133.93,133.11,132.06,129.36,128.73,128.49,128.20,128.16,127.94,124.45,119.66,69.87,53.91,46.67,34.50,30.33,21.63,20.93.HRMS(ESI)m/z(M+H) + calculated for C 38 H 44 NO 4 S:610.8323,observed:610.8328.
Example 3: preparation of Compound 3ca
By the method of example 1, except that substrate 1c was used instead of 1a, product 3ca was obtained. The yield was 64%,96% ee and the product was purified by high performance liquid chromatography (Chiralpak OD-H column, 2-propanol/n-hexane=15%, flow rate 1.0mL/min, t R ＝23.34min(minor),t R = 24.89min (major)).
1 H NMR(500MHz,CDCl 3 )δ9.98(d,J＝6.2Hz,1H),δ7.75–7.69(m,2H),7.42(ddd,J＝7.5,2.0,1.0Hz,2H),7.36–7.26(m,4H),7.26–7.18(m,1H),7.09–6.97(m,2H),6.89–6.80(m,2H),6.55(dd,J＝7.5,5.7Hz,1H),5.18(dt,J＝7.0,1.1Hz,1H),3.96(q,J＝6.8Hz,1H),3.69–3.63(m,1H),2.99(s,1H),2.42(s,3H),1.37(s,18H). 13 C NMR(125MHz,CDCl 3 )δ196.84,154.30,141.71,141.17,140.90,134.88,133.93,129.36,128.73,128.49,128.16,124.45,120.45,120.38,116.64,116.48,113.38,113.22,69.87,53.91,46.68,46.65,34.50,30.33,21.63. 19 F NMR(377MHz,CDCl 3 )δ-115.76.HRMS(ESI)m/z(M+H) + calculated for C 37 H 41 FNO 4 S:614.7957,observed:614.7960.
Example 4: preparation of Compound 3da
By the method of example 1, using substrate 1d instead of 1a, product 3da was obtained. The yield was 67%,96% ee and the product was purified by high performance liquid chromatography (Chiralpak OD-H column, 2-propanol/n-hexane=15%, flow rate 1.0mL/min, t R ＝22.57min(minor),t R =24.24 min (major)).
1 H NMR(500MHz,CDCl 3 )δ9.99(d,J＝6.2Hz,1H),δ7.74–7.68(m,2H),7.46(ddd,J＝7.5,2.0,1.0Hz,2H),7.36–7.26(m,5H),7.26–7.18(m,1H),7.10(ddd,J＝10.5,2.0,1.0Hz,2H),7.02(dd,J＝7.5,2.0Hz,1H),6.51(d,J＝7.5Hz,1H),5.18(dt,J＝7.1,1.1Hz,1H),4.40–4.34(m,1H),3.90(m,1H)2.42(s,3H),2.04(s,1H),1.37(s,18H). 13 C NMR(125MHz,CDCl 3 )δ196.84,154.30,141.71,141.17,140.90,139.90,134.88,133.93,132.78,129.75,129.36,129.07,128.73,128.49,128.16,127.90,124.45,120.45,69.87,53.91,46.67,34.50,30.33,21.63.HRMS(ESI)m/z(M+H) + calculated for C 37 H 41 ClNO 4 S:631.2473,observed:631.2476.
Example 5: preparation of Compound 3ea
The product 3ea was obtained by the method of example 1, replacing 1a with substrate 1 e. The yield was 66%,95% ee and the product was purified by high performance liquid chromatography (Chiralpak OD-H column, 2-propanol/n-hexane=15%, flow rate 1.0mL/min, t R ＝25.04min(minor),t R =26.11 min (major)).
1 H NMR(500MHz,CDCl 3 )δ9.56(d,J＝6.2Hz,1H),δ7.73–7.67(m,2H),7.49–7.43(m,2H),7.38(dd,J＝2.0,1.0Hz,1H),7.36–7.26(m,4H),7.26–7.18(m,2H),7.07(ddd,J＝12.7,1.9,0.8Hz,2H),6.46(d,J＝7.5Hz,1H),5.18(dt,J＝6.9,1.0Hz,1H),4.36(dq,J＝7.2,1.2Hz,1H),3.92(q,J＝6.8Hz,1H),2.88(s,1H),2.42(s,3H),1.37(s,18H).13C NMR(125MHz,CDCl 3 )δ196.84,154.30,141.71,141.17,140.90,137.76,134.88,133.93,132.31,131.98,129.94,129.36,128.73,128.49,128.16,124.45,120.21,118.85,69.87,53.91,46.67,34.50,30.33,21.63.HRMS(ESI)m/z(M+H) + calculated for C 37 H 41 BrNO 4 S:675.7013,observed:675.7017.
Example 6: preparation of Compound 3fa
The product 3fa was obtained by the method of example 1, substituting substrate 1f for 1 a. Yield 46%,85% ee value, high performance liquid chromatography (Chiralpak IC column, 2-propanol/n-hexane=15%, flow rate 1.0mL/min, t R ＝16.64min(minor),t R =18.04 min (major)).
1 H NMR(500MHz,CDCl 3 )δ9.72(d,J＝6.2Hz,1H),δ7.73–7.67(m,2H),7.47–7.40(m,2H),7.36–7.24(m,5H),7.26–7.16(m,2H),7.01(td,J＝7.4,2.0Hz,1H),6.98(s,2H),6.57(dd,J＝7.4,2.0Hz,1H),5.31–5.26(m,1H),4.70(s,1H),4.47(q,J＝6.7Hz,1H),3.96(dd,J＝7.1,1.1Hz,1H),2.42(s,3H),2.26(s,6H). 13 C NMR(125MHz,CDCl 3 )δ192.20,151.59,141.71,141.17,140.90,136.29,135.57,132.89,129.36,128.89,128.75,128.73,128.49,128.16,128.07,123.32,122.58,120.15,69.87,53.91,46.60,21.63,16.10.HRMS(ESI)m/z(M+H) + calculated for C 31 H 30 NO 4 S:512.6433,observed:512.6437.
Example 7: preparation of Compound 3ab
By the method of example 1, the product 3ab was obtained by substituting substrate 2b for 2 a. Yield 85%,97% ee value, high performance liquid chromatography (Chiralpak OD-H column, 2-propanol/n-hexane=15%, flow rate 1.0mL/min, t) R ＝18.36min(minor),t R =18.09 min (major)).
1 H NMR(500MHz,CDCl 3 )δ9.92(d,J＝6.2Hz,1H),7.81–7.76(m,2H),7.36–7.27(m,5H),7.31–7.21(m,1H),7.12–7.02(m,4H),6.72(dd,J＝2.0,1.1Hz,1H),6.57(dd,J＝7.5,2.0Hz,1H),5.21(dt,J＝7.0,1.0Hz,1H),4.42–4.36(m,1H),3.62(q,J＝6.9Hz,1H),2.72(s,1H),2.42(s,3H),2.21(t,J＝1.0Hz,3H),1.37(s,18H). 13 C NMR(125MHz,CDCl 3 )δ192.20,154.30,141.71,141.17,136.65,136.29,136.01,135.49,134.88,132.89,129.36,129.14,128.75,128.16,128.07,127.90,124.34,122.58,120.15,69.87,53.91,46.60,34.50,30.33,21.63,21.18.HRMS(ESI)m/z(M+H) + calculated for C 38 H 44 NO 4 S:610.8323,observed:610.8327.
Example 8: preparation of Compound 3ac
By the method of example 1, using substrate 2c instead of 2a, product 3ac was obtained. The yield was 80%, the ee value was 95%, and the sample was purified by high performance liquid chromatography (Chiralpak OD-H column, 2-propanol/n-hexane=15%, flow rate 1.0mL/min, t) R ＝20.57min(minor),t R =21.98 min (major)).
1 H NMR(500MHz,CDCl 3 )δ9.98(d,J＝6.2Hz,1H),7.75–7.69(m,2H),7.33(dq,J＝7.4,1.2Hz,2H),7.26–7.12(m,5H),7.07–6.97(m,2H),6.79–6.73(m,2H),6.57(dd,J＝7.3,2.0Hz,1H),4.79(dt,J＝7.0,1.0Hz,1H),4.55(dt,J＝7.0,1.0Hz,1H),3.80(s,3H),3.54(q,J＝6.9Hz,1H),2.84(s,1H),2.42(s,3H),1.37(s,18H). 13 C NMR(125MHz,CDCl 3 )δ192.20,158.76,154.30,141.71,141.17,136.29,135.49,134.88,132.89,132.11,129.36,128.75,128.16,128.12,128.07,124.34,122.58,120.15,114.94,69.87,55.35,53.91,46.60,34.50,30.33,21.63.HRMS(ESI)m/z(M+H) + calculated for C 38 H 44 NO 5 S:626.2935,observed:626.2939.
Example 9: preparation of Compound 3ad
The product 3ad was obtained by the method of example 1, replacing 2a with substrate 2 d. Yield 77%,96% ee value, high performance liquid chromatography (Chiralpak OD-H column, 2-propanol/n-hexane=15%, flow rate 1.0mL/min, t) R ＝22.64min(minor),t R =23.99 min (major)).
1 H NMR(500MHz,CDCl 3 )δ7.73–7.67(m,2H),7.44(ddd,J＝7.0,5.8,1.1Hz,2H),7.33(dq,J＝7.4,1.2Hz,2H),7.25(ddd,J＝7.4,2.1,1.0Hz,1H),7.14–7.05(m,5H),7.09–6.99(m,2H),6.57(dd,J＝7.4,2.1Hz,1H),5.17(dt,J＝7.1,1.1Hz,1H),4.37(dd,J＝6.9,1.2Hz,1H),3.91(q,J＝6.8Hz,1H),2.42(s,3H),2.02(s,1H),1.37(s,19H). 13 C NMR(125MHz,CDCl 3 )δ192.20,163.53,161.51,154.30,141.71,141.17,136.29,135.49,134.88,134.29,134.27,132.89,131.01,130.95,129.36,128.75,128.16,128.07,124.34,122.58,120.15,115.52,115.37,69.87,53.91,46.60,34.50,30.33,21.63. 19 F NMR(377MHz,CDCl 3 )δ-121.76.HRMS(ESI)m/z(M+H) + calculated for C 37 H 41 FNO 4 S:614.2735,observed:614.2739.
Example 10: preparation of Compound 3ae
The product 3ae was obtained by the method of example 1, substituting substrate 2e for 2 a. The yield was 65%,98% ee and the product was purified by high performance liquid chromatography (Chiralpak OD-H column, 2-propanol/n-hexane=15%, flow rate 1.0mL/min, t R ＝24.56min(minor),t R =26.03 min (major)).
1 H NMR(500MHz,CDCl 3 )δ7.73–7.67(m,2H),7.49(dd,J＝7.5,1.1Hz,2H),7.40–7.30(m,4H),7.26(ddd,J＝7.3,2.1,1.0Hz,1H),7.15–6.99(m,4H),6.57(dd,J＝7.3,2.2Hz,1H),5.16(dt,J＝7.0,1.0Hz,1H),4.42–4.36(m,1H),3.89(q,J＝6.8Hz,1H),2.77(s,1H),2.42(s,3H),1.37(s,18H). 13 C NMR(125MHz,CDCl 3 )δ192.20,154.30,141.71,141.17,136.29,135.49,135.43,134.88,134.59,132.89,129.76,129.36,128.75,128.61,128.16,128.07,124.34,122.58,120.15,69.87,53.91,46.60,34.50,30.33,21.63.HRMS(ESI)m/z(M+H) + calculated for C 37 H 41 ClNO 4 S:630.2440,observed:630.2444.
Example 11: preparation of Compound 3af
By the method of example 1, the product 3af was obtained, replacing 2a with substrate 2 f. The yield was 70%,97% ee and the product was purified by high performance liquid chromatography (Chiralpak OD-H column, 2-propanol/n-hexane=15%, flow rate 1.0mL/min, t R ＝24.69min(minor),t R =26.03 min (major)).
1 H NMR(500MHz,CDCl 3 )δ9.99(d,J＝6.2Hz,1H),7.72–7.67(m,2H),7.58–7.52(m,2H),7.40–7.30(m,4H),7.25(ddd,J＝7.3,2.1,1.0Hz,1H),7.14–7.07(m,2H),7.11–6.99(m,2H),6.57(dd,J＝7.4,2.1Hz,1H),5.18(dt,J＝6.9,1.0Hz,1H),4.39–4.33(m,1H),3.91(td,J＝7.1,6.1Hz,1H),2.42(s,3H),2.23(s,1H),1.37(s,18H). 13 C NMR(125MHz,CDCl 3 )δ192.20,154.30,141.71,141.17,136.29,135.49,135.11,134.88,132.89,131.36,129.36,128.75,128.16,128.07,127.29,124.34,122.58,121.24,120.15,69.87,53.91,46.60,34.50,30.33,21.63.HRMS(ESI)m/z(M+H) + calculated for C 37 H 41 BrNO 4 S:674.1934,observed:674.1938.
Example 12: preparation of Compound 3ag
The product 3ag was obtained by the method of example 1, substituting 2g of substrate for 2 a. Yield 50%,91% ee, high performance liquid chromatography (Chiralpak IC column, 2-propanol/n-hexane=20%, flow rate 1.0mL/min, t R ＝27.33min(minor),t R = 28.88min (major)).
1 H NMR(500MHz,CDCl 3 )δ8.10–8.04(m,2H),7.73–7.68(m,2H),7.62–7.56(m,2H),7.38–7.24(m,4H),7.20(td,J＝7.5,2.0Hz,1H),7.07–6.98(m,2H),6.57(dd,J＝7.5,2.0Hz,1H),5.37(dt,J＝7.2,1.2Hz,1H),4.47(q,J＝6.8Hz,1H),3.92–3.87(m,1H),2.97(s,1H),2.42(s,3H),1.37(s,18H). 13 C NMR(125MHz,CDCl 3 )δ192.20,154.30,147.63,141.71,141.27,141.17,136.29,135.49,134.88,132.89,129.36,128.83,128.75,128.16,128.07,124.34,123.89,122.58,120.15,69.87,53.91,46.60,34.50,30.33,21.63.HRMS(ESI)m/z(M+H) + calculated for C 37 H 41 N 2 O 6 S:641.2680,observed:641.2684.

Claims (6)

1. The synthesis method of the polysubstituted chiral tetrahydroquinoline compound is characterized by comprising the following steps:
(1) Substrate 1: substrate 2: oxidizing agent: chiral catalyst: additive= (1-3): 1: (2-4): 0.15:0.1, preparing materials, wherein the oxidant is DDQ and MnO 2 The molar ratio of the two is (0.5-3): 1, a step of;
(2) Fully dissolving a substrate 1 and a substrate 2 in a reaction solvent to obtain a mixed solvent, putting an oxidant, a chiral catalyst and an additive into a reaction container, adding the mixed solvent into the reaction container, and stirring and reacting for 48 hours at room temperature to obtain a target product polysubstituted chiral tetrahydroquinoline compound; the reaction scheme is as follows:
in the step (1), the substrate 1 is a substrate 1a, a substrate 1b, a substrate 1c, a substrate 1d, a substrate 1e or a substrate 1f, wherein the substrate 1a is N- (2- (3, 5-di-tert-butyl-4-hydroxybenzyl) phenyl) -4-methylbenzenesulfonamide, the substrate 1b is N- (2- (3, 5-di-tert-butyl-4-hydroxybenzyl) -4-methylphenyl) -4-methylbenzenesulfonamide, the substrate 1c is N- (2- (3, 5-di-tert-butyl-4-hydroxybenzyl) -4-fluorophenyl) -4-methylbenzenesulfonamide, the substrate 1d is N- (2- (3, 5-di-tert-butyl-4-hydroxybenzyl) -4-chlorophenyl) -4-methylbenzenesulfonamide, the substrate 1e is N- (2- (3, 5-di-tert-butyl-4-hydroxybenzyl) -4-bromophenyl) -4-methylbenzenesulfonamide, and the substrate 1f is N- (2- (3, 5-dimethyl-4-hydroxybenzyl) -4-methylbenzenesulfonamide;
the substrate 2 is a substrate 2a, a substrate 2b, a substrate 2c, a substrate 2d, a substrate 2e or a substrate 2f, wherein the substrate 2a is phenylpropionaldehyde, the substrate 2b is 4-methylbenzaldehyde, the substrate 2c is 4-methoxyphenylpropionaldehyde, the substrate 2d is 4-fluorobenzoyl aldehyde, the substrate 2e is 4-chlorobenzoyl aldehyde, and the substrate 2f is 4-bromophenylpropionaldehyde;
the chiral catalyst is one of 4a, 4b, 4c, 4d, 4e or 4f, wherein 4a is L-proline, 4b is (S) -5-benzyl-2, 2-dimethyl imidazolin-4-one trifluoroacetate, 4c is (2R, 5S) -5-benzyl-2-tert-butyl imidazolidinone, 4d is (R) -2- [ diphenyl [ (trimethylsilyl) oxy ] methyl ] -pyrrolidine, 4e is (R) - (-) -2- [ hydroxy (diphenyl) methyl ] -1-methylpyrrolidine, and 4f is (R) -2- [ di [3, 5-bis (trifluoromethyl) phenyl ] [ tert-butyl dimethylsilyl ] oxy ] methyl ] pyrrolidine.
2. The method for synthesizing polysubstituted chiral tetrahydroquinoline compounds according to claim 1, wherein in the step (1), DDQ and MnO are present 2 The molar ratio of (2) is 1:1.
3. the method for synthesizing polysubstituted chiral tetrahydroquinoline compounds according to claim 1, wherein in the step (1), the chiral catalyst is 4d.
4. The method for synthesizing the polysubstituted chiral tetrahydroquinoline compound according to claim 1, wherein in the step (1), the reaction solvent is one of 1, 2-dichloroethane, dichloromethane, chloroform, acetonitrile, 1, 4-dioxane, benzene, toluene, acetone, tetrahydrofuran or DMF.
5. The method for synthesizing polysubstituted chiral tetrahydroquinoline compounds according to claim 1, wherein in the step (1), the additive is Cs 2 CO 3 、Na 2 CO 3 、K 2 CO 3 、Et 3 N、K 3 PO 4 DIPEA, DBU or i Pr 2 One of NH.
6. The method for synthesizing polysubstituted chiral tetrahydroquinoline compounds according to claim 1, wherein in the step (1), the additive is i Pr 2 NH。
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