CN111303090B - Chiral gamma, gamma-disubstituted butenolide compound and preparation method thereof - Google Patents

Chiral gamma, gamma-disubstituted butenolide compound and preparation method thereof Download PDF

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CN111303090B
CN111303090B CN202010201537.XA CN202010201537A CN111303090B CN 111303090 B CN111303090 B CN 111303090B CN 202010201537 A CN202010201537 A CN 202010201537A CN 111303090 B CN111303090 B CN 111303090B
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ethyl acetate
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CN111303090A (en
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白著双
张才荣
陈泳怡
刘爱芹
王新宇
刘学超
严楚娜
庞靖祥
朱文宁
诸葛慧
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Institute Of Materia Medica Shandong Academy Of Medical Sciences (shandong Anti-Aging Research Center Shandong New Technology Pharmaceutical Research Institute)
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The application discloses a chiral gamma, gamma-disubstituted butenolide compound and a preparation method thereof. The chiral gamma, gamma-disubstituted butenolide compound is widely present in various natural products, has important biological activity, and is also an important intermediate for constructing polyterpene compounds and medicaments. The application synthesizes a series of products with the yield as high as 98 percent and the stereoselectivity of more than 20 through vinylogous Michael addition reaction of gamma-dimer furanone and alpha, beta-unsaturated nitroolefin catalyzed by a bifunctional thiourea catalyst: 1dr and 99% ee chiral gamma, gamma-disubstituted butenolide compounds. The method can conveniently, quickly and efficiently obtain the gamma, gamma-disubstituted butenolide compounds with functional and multi-chiral centers.

Description

Chiral gamma, gamma-disubstituted butenolide compound and preparation method thereof
Technical Field
The invention belongs to the field of synthesis of medical compounds, and relates to a chiral gamma, gamma-disubstituted butenolide compound and a preparation method thereof.
Background
Chiral gamma, gamma-disubstituted butenolide compounds are core structural units in many natural products and pharmaceutically active compounds. Most processes are carried out by asymmetric catalytic Michael addition reactions of gamma-substituted dimeric vinyl alcohol compounds or 5-substituted 2- (trimethylsiloxy) furans, which have different Michael acceptors. Over the past decade, a subject group has developed various methods to synthesize these important components. Despite the great advances that have been made, the donor substituents are more sterically hindered, e.g., substantially no substituents at the 3-and 4-positions, and predominantly methyl, benzyl and aryl at the 5-position, which limits the structural diversity of the product.
Therefore, a simple and effective method for constructing chiral gamma, gamma-disubstituted butenolide compounds is urgently needed at present, so that a wide range of functional chiral gamma, gamma-disubstituted butenolide compounds can be conveniently and rapidly obtained, and the problem of compound synthesis in the field of medicine research and development at present is solved.
Disclosure of Invention
Firstly, the applicant successfully finds that the chiral gamma, gamma-disubstituted butenolide compound can be synthesized by performing vinylogous Michael addition reaction on gamma-dimer furanone and alpha, beta-unsaturated nitroolefin by using chiral difunctional thiourea as a catalyst. Then, the applicant continues to perform a series of reactions on the basis, and then obtains a chiral gamma, gamma-disubstituted butenolide compound and an enantiomer thereof, wherein the structural formula is as follows:
Figure BDA0002419551980000021
general formula (I)
R1A phenyl group, a benzyl group, a p-benzyloxy group, an m-benzyloxy group, an o-benzyloxy group, a biphenylmethoxy group, a triphenylmethoxy group, a p-phenylnitro group, an m-phenylnitro group, an o-phenylnitro group, a p-phenylnitroso group, an m-phenylnitroso group, an o-phenylnitroso group, a substituted aryl group, substituted or substituted aryl group, substituted or substituted aryl group, substituted with substituted aryl group, substituted with one or substituted with,P-benzonitrile, m-benzonitrile, o-benzonitrile, p-benzisocyano, m-benzisocyano, o-benzisocyano, trifluorobenzyl, p-tolyl, m-tolyl, o-tolyl, p-phenylhalogen, m-phenylhalogen, o-phenylhalogen, aryl, alkyl, hydrogen, naphthyl, heterocyclyl, benzoate, cycloalkyl, heteroarylalkyl, heterocyclylalkyl, benzaldehyde, or benzoate;
R2＝C1-C6alkyl, alkenyl or hydrogen of (a); r3＝C1-C6Alkyl, alkenyl or hydrogen.
Further, the structural formula of the chiral gamma, gamma-disubstituted butenolide compound is as follows:
Figure BDA0002419551980000031
secondly, a preparation method of the chiral gamma, gamma-disubstituted butenolide compound 3aa-bb comprises the following reaction steps:
Figure BDA0002419551980000032
taking the compounds 1a-d (0.25mmol), the chiral thiourea bifunctional catalyst VII (0.05mmol), the solvent dioxane (2.0mL) and the compounds 2a-y (0.50mmol), and stirring for reaction. After the reaction is finished, quenching a saturated ammonium chloride solution, extracting by ethyl acetate, performing suction filtration, spin-drying, and eluting by ethyl acetate: petroleum ether is 1: and 5, separating, purifying and spin-drying to obtain the compound 3 aa-bb.
In the preparation method of the chiral gamma, gamma-disubstituted butenolide compound, the chiral thiourea bifunctional catalyst comprises the following compounds:
Figure BDA0002419551980000041
wherein, the chiral thiourea bifunctional catalyst VII is the optimal catalyst.
Further, in the preparation method of the chiral γ, γ -disubstituted butenolide compound, the solvent comprises one or more of toluene, dioxane, dimethyl sulfoxide, acetonitrile, n-hexane, ethyl acetate, tetrahydrofuran, diethyl ether, water, methanol, ethanol, dichloromethane or dichloroethane. Wherein the most preferred solvent is dioxane.
Further, in the preparation method of the chiral gamma, gamma-disubstituted butenolide compound, the molar weight ratio of the compound 1a-d to the compound 2a-y is 1: 0.5-5. Wherein the optimal molar weight ratio of compounds 1a-d to compounds 2a-y is 1: 1.2.
in addition, according to the preparation method of the chiral gamma, gamma-disubstituted butenolide compound, the molar weight ratio of the compound 1a-d to the chiral thiourea bifunctional catalyst is 1: 0.1-5. Wherein, the optimal molar ratio of the compound 1a-d to the chiral thiourea bifunctional catalyst is 1: 0.2.
drawings
FIG. 1 is a schematic diagram of the NMR hydrogen spectrum of compound 3aa in example 1 of the present invention;
FIG. 2 is a schematic representation of the NMR carbon spectrum of compound 3aa in example 1 of the invention;
FIG. 3 is a schematic diagram of high performance liquid chromatography of Compound 3aa in example 1 of the present invention.
Advantageous effects
According to the method, a series of reactions with yield as high as 98% and stereoselectivity of more than 20 are efficiently and quickly synthesized through vinylogous Michael addition reaction of gamma-dimer furanone and alpha, beta-unsaturated nitroolefin catalyzed by bifunctional thiourea: 1dr, 99% ee chiral gamma, gamma-disubstituted butenolide compound, can conveniently and rapidly obtain wide functional chiral gamma, gamma-disubstituted butenolide compound. The structural diversity of the chiral gamma, gamma-disubstituted butenolide compound can be derived from functional groups in products, and the achievement is an urgent need for drug discovery and has great application prospects in the fields of medicines and chemical industry.
Detailed Description
The chiral thiourea bifunctional catalyst I-VII of the invention comprises:
Figure BDA0002419551980000051
1. compound 3 aa: taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding the compound 2a (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 aa.
Figure BDA0002419551980000052
Yield: 95 percent. Silica gel column chromatography (ethyl acetate/petroleum ether 1: 5);1H NMR(400MHz,CDCl3) δ7.88(1H,s),δ7.39–7.28(3H,m),δ7.20–7.15(2H,m),δ4.85(1H,dd, J＝13.4,5.0Hz),δ4.76(1H,dd,J＝13.3,10.0Hz),δ4.27(2H,q,J＝7.1Hz),δ 4.11(1H,dd,J＝9.9,5.0Hz),δ2.02(1H,dq,J＝14.8,7.4Hz),δ1.85(1H,dq, J＝14.7,7.4Hz),δ1.31(3H,t,J＝7.1Hz),δ0.88(3H,t,J＝7.4Hz).13C NMR (100MHz,CDCl3)δ166.0,162.9,159.3,133.7,129.4,129.0,128.3,127.0, 88.4,75.2,61.9,49.6,28.9,14.0,7.6.HPLC(Lux 5u Cellulose-2,hexane: i-PrOH＝80:20,1.0mL/min,tR1(major)＝24.09min,tR1(minor)＝44.04min, tR2(major)＝49.90min,tR2(minor)＝54.62min).dr＝9.7:1.92％ee.ES-HRMS: Calcd for C17H20NO6[M+H],334.12851,Found 334.12919.
2. compound 3 ab: taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding the compound 2b (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 ab.
Figure BDA0002419551980000061
Yield: 94 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ7.91(1H,s),δ7.16(2H,d,J＝7.9Hz),δ7.07(2H,d,J＝8.0Hz),δ 4.84(1H,dd,J＝13.2,5.0Hz),δ4.74(1H,dd,J＝13.2,10.1Hz),δ4.30(2H, q,J＝7.1Hz),δ4.09(1H,dd,J＝10.1,5.0Hz),δ2.33(3H,s),δ2.02(1H,td, J＝14.5,7.1Hz),δ1.85(1H,dq,J＝14.8,7.4Hz),δ1.33(4H,t,J＝7.1Hz),δ 0.89(4H,t,J＝7.4Hz).13C NMR(100MHz,CDCl3)δ166.0,163.0,159.4, 138.9,130.5,130.1,128.2,126.9,88.6,75.2,61.9,49.2,28.9,21.0,14.0,7.6. HPLC(Lux 5u Cellulose-2,hexane:i-PrOH＝80:20,1.0mL/min, tR1(major)＝27.961min,tR1(minor)＝50.287min,tR2(major)＝52.843min, tR2(minor)＝65.880min).dr＝7.2:1.92％ee.ES-HRMS:Calcd for C18H22NO6 [M+H],348.14416,Found 348.14479.
3. compound 3 ac: taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2c (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 ac.
Figure BDA0002419551980000071
Yield: 92 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ7.92(1H,s),δ7.11(2H,d,J＝8.6Hz),δ6.88(2H,d,J＝8.6Hz),δ 4.84(1H,dd,J＝13.1,4.9Hz),δ4.73(1H,dd,J＝13.1,10.3Hz),δ4.30(2H, dd,J＝13.7,6.7Hz),δ4.08(1H,dd,J＝10.5,5.1Hz),δ2.02(1H,td,J＝14.6, 7.2Hz),δ1.87(1H,td,J＝14.8,7.4Hz),δ1.34(3H,t,J＝7.1Hz),δ0.90(3 H,t,J＝7.4Hz).13C NMR(100MHz,CDCl3)δ166.1,163.23,159.9,132.3, 129.4,125.4,114.8,113.8,88.7,75.4,62.0,55.3,48.8,28.8,14.0,7.7. HPLC(Lux 5u Cellulose-2,hexane:i-PrOH＝80:20,1.0mL/min, tR(major)＝78.736min,tR2(minor)＝94.351min).dr＝12.5:1.91％ee.ES-HRMS: Calcd for C18H22NO7[M+H],364.13908,Found 364.13968.
4. compound 3 ad: taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2d (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 ad.
Figure BDA0002419551980000072
Yield: 89 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ7.94(s,1H),7.01(d,J＝8.8Hz,2H),6.64(d,J＝8.8Hz,2H),4.77 (dd,J＝13.0,5.0Hz,1H),4.66(dd,J＝12.8,10.5Hz,1H),4.30(q,J＝7.1Hz, 2H),4.02(dd,J＝10.3,5.0Hz,1H),2.93(s,6H),2.02–1.93(m,1H),1.87– 1.77(m,1H),1.33(t,J＝7.1Hz,3H),0.86(t,J＝7.4Hz,3H).13C NMR(100 MHz,CDCl3)δ165.2,163.5,162.6,158.5,149.5,149.5,128.9,128.0,125.7, 119.3,119.1,111.6,111.4,88.3,88.2,74.8,74.4,61.0,60.9,48.1,47.9,39.3, 39.2,28.7,27.9,13.1,13.1,6.6,6.4.HPLC(CHIRAL-OD-H,259nm,hexane: i-PrOH＝85:15,2.0mL/min,tR1(major)＝13.598min,tR1(minor)＝16.113min, tR2(minor)＝19.163min,tR2(major)＝25.232min).dr＝9.1:1.91％ee. ES-HRMS:Calcd for C19H24N2NaO6[M+Na],399.1532,Found 399.1508.
5. compound 3 ae: taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2e (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 ae.
Figure BDA0002419551980000081
Yield: 95 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5); major diastereomer:1H NMR(400MHz,CDCl3)δ7.89(s,1H),6.88–6.76(m,2H),6.64(d,J＝ 2.1Hz,1H),4.87(dd,J＝13.2,4.9Hz,1H),4.77(dd,J＝13.2,10.2Hz,1H), 4.27(q,J＝7.1Hz,2H),4.02(dd,J＝10.3,5.1Hz,1H),3.86(s,3H),3.85(s, 3H),2.02(dt,J＝14.9,7.4Hz,1H),1.93(dt,J＝14.4,7.4Hz,1H),1.31(t,J＝ 7.1Hz,3H),0.90(t,J＝7.5Hz,3H).13C NMR(100MHz,CDCl3)δ166.3, 163.5,159.3,149.5,149.4,126.6,125.9,120.7,111.5,111.0,88.7,75.5,61.9, 56.1,55.9,49.0,28.8,14.0,7.8.HPLC(CHIRAL-OJ-H,210nm,hexane: i-PrOH＝70:30,2.0mL/min,tR1(minor)＝21.645min,tR1(majorr)＝34.698min). dr＝8.3:1.99％ee.ES-HRMS:Calcd for C19H24NO8[M+H],394.1502,Found 394.1484.
6. compound 3 af: taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding the solvent dioxane (2mL), adding the compound 2f (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 af.
Figure BDA0002419551980000091
Yield: 94 percent. Silica gel column chromatographyPurification (ethyl acetate/petroleum ether ═ 1: 5); major diastereomer:1H NMR(400MHz,CDCl3)δ7.86(s,1H),6.33(s,2H),4.91(dd,J＝13.4, 4.9Hz,1H),4.81(dd,J＝13.4,9.9Hz,1H),4.25(q,J＝7.1Hz,2H),3.99(dd, J＝9.9,4.9Hz,1H),3.83(s,6H),3.79(s,3H),2.04(dt,J＝14.5,7.2Hz,1H), 1.97(dt,J＝14.4,7.3Hz,1H),1.29(t,J＝7.1Hz,3H),0.92(t,J＝7.4Hz,3H). 13C NMR(100MHz,CDCl3)δ166.4,163.2,159.3,153.8,138.4,129.3,126.4, 105.2,88.4,75.4,62.0,60.9,56.3,49.4,28.7,14.0,7.9.HPLC (CHIRAL-AD-H,210nm,hexane:i-PrOH＝90:10,2.0mL/min, tR1(minor)＝12.764min,tR1(majorr)＝315.663min,tR2(minor)＝17.695min, tR2(minor)＝18.697min).dr＝14.3:1.97％ee.ES-HRMS:Calcd for C20H26NO9 [M+H],424.1608,Found 424.1583.
7. compound 3 ag: taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding 2g of the compound (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 ag.
Figure BDA0002419551980000101
Yield: 87 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ7.87(1H,s),δ7.50(2H,d,J＝7.8Hz),δ7.08(2H,d,J＝7.6Hz),δ 4.92–4.84(1H,m),δ4.76(1H,t,J＝11.9Hz),δ4.30(2H,dd,J＝13.6,6.6 Hz),δ4.13–4.05(1H,m),δ1.33(3H,t,J＝7.1Hz),δ0.91(3H,t,J＝7.1 Hz).13C NMR(100MHz,CDCl3)δ165.8,162.6,159.2,132.6,129.9,127.2, 123.3,110.0,88.0,75.0,62.1,48.9,28.8,14.0,7.7.HHPLC(CHIRAL-OD-H, hexane:i-PrOH＝65:35,254nm,1.0mL/min,tR1(major)＝13.769min, tR1(minor)＝15.381min,tR2(major)＝22.234min,tR2(minor)＝33.377min). dr＝8.7:1.92％ee.ES-HRMS:Calcd for C17H19BrNO6[M+H],412.03903, Found412.04002.
8. compound 3 ah: taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound for 2h (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain a compound 3 ah.
Figure BDA0002419551980000111
Yield: 90 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ7.88(1H,s),7.37–7.32(2H,d,J＝8.5),7.15(2H,d,J＝8.5Hz), 4.89(1H,dd,J＝13.5Hz,4.9Hz),4.77(1H,dd,J＝13.4Hz,10.3Hz),4.30 (2H,q,J＝7.1Hz),4.10(1H,dd,J＝10.3Hz,4.8Hz),2.08–1.98(1H,m), 1.89(1H,m),1.33(3H,t,J＝7.1Hz),0.91(3H,t,J＝7.4Hz).13C NMR (100MHz,CDCl3)δ165.8,162.7,159.2,135.1,132.2,129.7,129.6,127.2, 88.1,75.1,62.1,48.8,28.8,14.0,7.7.HPLC(CHIRAL-OD-H,hexane:i-PrOH ＝80:20,1.0mL/min,tR1(major)＝19.70min,tR1(minor)＝21.73min,tR2(major) ＝45.15min,tR2(minor)＝33.50min).dr＝10.1:1.88％ee.ES-HRMS:Calcd for C17H19ClNO6[M+H],368.08954,Found 368.09026.
9. compound 3 ai: taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding the solvent dioxane (2mL), adding the compound 2i (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 ai.
Figure BDA0002419551980000112
Yield: 91 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ7.86(s,1H),7.20–7.13(m,2H),7.05(t,J＝8.5Hz,2H),4.88(dd,J ＝13.4Hz,4.8Hz,1H),4.76(dd,J＝13.3Hz,10.3Hz,1H),4.27(q,J＝7.1 Hz,2H),4.09(dd,J＝10.3Hz,4.9Hz,1H),2.02(dq,J＝14.8Hz,7.4Hz,1H), 1.89(dq,J＝14.7Hz,7.4Hz,1H),1.31(t,J＝7.1Hz,3H),0.90(t,J＝7.4Hz, 3H)；13C NMR(100MHz,CDCl3)δ165.9,163.4(d,J＝122Hz),159.21, 130.1(d,J＝9Hz),127.1,116.5(d,J＝21Hz),88.3,75.2,62.1,48.7,28.8, 14.0,7.7.HPLC(Lux 5u Cellulose-2,hexane:i-PrOH＝80:20,1.0mL/min, tR1(major)＝24.87min,tR1(minor)＝41.67min,tR2(major)＝43.68min, tR2(minor)＝51.10min).dr＝19.2:1.90％ee.ES-HRMS:Calcd for C17H19FNO6 [M+H],352.11909,Found 352.11973.
10. and a compound 3aj, namely taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2j (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the mixture by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, spin-drying, and eluting by using ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain a compound 3 aj.
Figure BDA0002419551980000121
Yield: 89 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(600MHz, CDCl3)δ8.20(d,J＝8.6Hz,1H),7.86(s,1H),7.39(d,J＝8.7Hz,2H),4.96 (dd,J＝13.8,4.6Hz,1H),4.85(dd,J＝13.8,10.4Hz,1H),4.23(q,J＝7.3Hz, 1H),4.20(dd,J＝10.6,4.8Hz,1H),2.04(td,J＝14.9,7.5Hz,1H),1.96–1.89(m,1H),1.27(t,J＝6.7Hz,3H),0.91(t,J＝7.4Hz,3H).13C NMR(100 MHz,CDCl3)δ165.4,162.6,162.0,140.9,130.5,129.4,124.6,124.4,87.6, 74.8,62.2,49.0,28.9,14.0,7.8.HPLC(CHIRAL-OD-H,hexane: i-PrOH＝90:10,1.0mL/min,tR1(minor)＝21.38min,tR1(major)＝44.08min). dr＝5.0:1.94％ee.ES-HRMS:Calcd for C17H19N2O8[M+H],379.1141,Found 379.1128.
11. taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2k (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain a compound 3 ak.
Figure BDA0002419551980000131
Yield: 81 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(600MHz, CDCl3)δ7.83(s,1H),7.66(d,J＝8.4Hz,2H),7.34(d,J＝8.3Hz,2H),4.94 (dd,J＝13.8,4.6Hz,1H),4.84(dd,J＝13.7,10.4Hz,1H),4.27(q,J＝7.1Hz, 2H),4.15(dd,J＝10.4,4.7Hz,1H),2.04(m,1H),1.93(dq,J＝14.8,7.4Hz, 1H),1.31(t,J＝7.2Hz,3H),0.92(t,J＝7.4Hz,3H).13C NMR(150MHz, CDCl3)δ165.5,162.1,158.8,139.1,133.2,133.0,129.2,127.5,87.7,75.3, 62.3,49.3,28.8,14.1,7.8.HPLC(CHIRAL-OD-H,hexane:i-PrOH＝70:30, 2.0mL/min,tR1(major)＝9.61min,tR1(minor)＝10.76min,tR2(major)＝13.02 min,tR2(minor)＝18.25min).dr＝5.0:1.84％ee.ES-HRMS:Calcd for C18H18N2NaO6[M+Na],381.1063,Found 381.1043.
12. and (3) taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding the compound 2l (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the mixture by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, spin-drying, and eluting by using ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain a compound 3 al.
Figure BDA0002419551980000141
Yield: 80 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(600MHz, CDCl3)δ7.83(s,1H),δ7.61(d,J＝8.1Hz,2H),7.32(d,J＝8.1Hz,2H),4.91 (dd,J＝13.6,4.7Hz,1H),4.81(dd,J＝13.6,10.3Hz,1H),4.27–4.22(m, 2H),4.16(dd,J＝10.3,4.7Hz,1H),2.03(dq,J＝14.9,7.5Hz,1H),1.88(dq, J＝14.8,7.4Hz,1H),1.28(t,J＝7.2Hz,3H),0.90(t,J＝7.5Hz,3H).13C NMR(150MHz,CDCl3)δ165.7,163.1,162.4,159.2,138.1,137.9,127.4, 126.5,124.5,88.0,74.9,62.2,49.3,28.9,14.0,7.8.HPLC(CHIRAL-OD-H, hexane:i-PrOH＝65:35,1.0mL/min,tR1(major)＝9.424min,tR1(minor)＝ 11.056min,tR2(minor)＝14.619min,tR2(major)＝22.735min).dr＝11.1:1. 89.0％ee.ES-HRMS:Calcd for C18H19F3NO6[M+H],402.1164,Found 402.1140.
13. taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2m (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 am.
Figure BDA0002419551980000151
Yield: 87 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ8.02(d,J＝8.3Hz,2H),7.87(s,1H),7.28(d,J＝9.4Hz,2H),4.94 –4.87(m,1H),4.81(dd,J＝13.5,10.1Hz,1H),4.26(q,J＝7.2Hz,2H),4.17 (dd,J＝10.0,4.9Hz,1H),3.92(s,3H),2.08–1.98(m,1H),1.94–1.83(m, 1H),1.30(t,J＝7.1Hz,3H),0.90(t,J＝7.5Hz,3H).13C NMR(100MHz, CDCl3)δ166.2,165.7,162.5,159.1,138.7,130.9,130.6,128.4,127.2,88.0, 74.9,62.1,52.4,49.3,29.0,14.0,7.7.HPLC(CHIRAL-OD-H,hexane:i-PrOH ＝65:35,1.0mL/min,tR1(minor)＝16.302min,tR1(major)＝18.529min, tR2(minor)＝24.237min,tR2(major)＝32.231min).dr＝7.0:1.89％ee. ES-HRMS:Calcd for C19H22NO8[M+H],392.1345,Found 392.1320.
14. taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2n (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 an.
Figure BDA0002419551980000161
Yield: 85 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ8.03(s,1H),7.44–7.33(m,2H),7.27–7.23(m,2H),5.05–4.88 (m,2H),4.47–4.31(m,1H),4.28–4.18(m,2H),2.12–2.05(m,2H),1.28(t, J＝7.1Hz,3H),0.98(t,J＝7.4Hz,3H).13C NMR(100MHz,CDCl3)δ166.1, 162.4,159.1,134.3,131.7,130.3,130.1,128.0,127.8,126.86,88.55,74.81, 61.82,43.65,28.49,13.98,8.01；HPLC(Lux 5u Cellulose-2,hexane:i-PrOH ＝80:20,1.0mL/min,tR1(major)＝23.73min,tR1(minor)＝36.22min, tR2(major)＝45.00min,tR2(minor)＝66.87min).dr＝9.5:1.90％ee.ES-HRMS: Calcd for C17H19ClNO6[M+H],368.08954,Found 368.09006.
15. and a compound 3ao, namely taking the compound 1a (0.25mmol) and a chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2o (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 ao.
Figure BDA0002419551980000162
Yield: 85 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ7.90(1H,s),δ7.33–7.29(2H,m),δ7.20(1H,s),δ7.11(1H,dd, J＝6.0Hz,2.4Hz),δ4.88(1H,dd,J＝13.6Hz,4.8Hz),δ4.77(1H,dd,J ＝13.5Hz,10.2Hz),δ4.29(2H,dd,J＝14.3Hz,7.1Hz),δ4.10(1H,dd,J ＝10.1Hz,4.8Hz),δ2.03(1H,dq,J＝14.8Hz,7.4Hz),δ1.88(1H,dq,J ＝14.7Hz,7.4Hz),δ1.33(3H,t,J＝7.1Hz),δ0.90(3H,t,J＝7.4Hz).13C NMR(100MHz,CDCl3)δ165.8,162.5,159.2,135.8,135.3,130.7,129.3, 128.8,127.1,126.1,88.1,74.9,62.0,49.1,28.8,14.0,7.6.HPLC(Lux 5u Cellulose-2,hexane:i-PrOH＝80:20,1.0mL/min,tR1(major)＝20.82min, tR1(minor)＝44.57min,tR2(major)＝47.94min,tR2(minor)＝50.54min).dr＝12.3:1. 90％ee.ES-HRMS:Calcd for C17H19ClNO6[M+H],368.08954,Found 368.09034.
16. taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2p (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 ap.
Figure BDA0002419551980000171
Yield: 82 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ8.10(s,1H),7.61–7.53(m,1H),7.32(t,J＝7.1Hz,1H),7.26– 7.23(m,1H),7.20–7.13(m,1H),5.03(dd,J＝12.2Hz,3.5Hz,1H),4.97– 4.87(m,1H),4.33(dd,J＝8.7Hz,4.7Hz,1H),4.28–4.18(m,2H),2.10(q,J ＝7.4Hz,2H),1.38–1.17(m,3H),1.03–0.95(m,3H).13C NMR(100MHz, CDCl3)δ165.0,162.5,159.1,133.7,133.4,130.9,130.4,128.9,128.6,127.9, 88.5,75.0,61.8,46.5,28.6,14.0,8.1.HPLC(Lux 5u Cellulose-2,hexane: i-PrOH＝80:20,1.0mL/min,tR1(major)＝25.83min,tR1(minor)＝39.60min, tR2(major)＝50.48min,tR2(minor)＝74.98min).dr＝11.0:1.91％ee.ES-HRMS: Calcd for C17H19BrNO6[M+H],412.03903,Found 412.03985.
17. and a compound 3aq, namely taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2q (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain a compound 3 aq.
Figure BDA0002419551980000181
Yield: 84 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ8.22(1H,d,J＝3.5Hz),δ8.10(1H,s),δ7.92(1H,s),δ7.60(2H, d,J＝5.1Hz),δ5.00(1H,dd,J＝13.7,4.7Hz),δ4.90(1H,dd,J＝13.5,10.4 Hz),δ4.26(3H,m),δ2.08(1H,td,J＝14.7,7.4Hz),δ1.96(1H,td,J＝14.6, 7.3Hz),δ1.30(3H,t,J＝7.1),δ0.95(3H,t,J＝7.4Hz).13C NMR(100MHz, CDCl3)δ165.5,162.0,158.9,148.5,136.0,133.8,130.6,127.5,124.1,123.8, 87.7,74.8,62.2,49.0,28.7,14.0,7.7.HPLC(CHIRAL-OD-H,hexane:i-PrOH ＝80:20,1.0mL/min,tR1(minor)＝49.457min,tR1(major)＝55.166min, tR2(major)＝61.024min,tR2(minor)＝82.746).dr＝5.0:1.85％ee.ES-HRMS: Calcd for C17H19N2O8[M+H],379.11359,Found 379.11439.
18. and a compound 3ar, namely taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2r (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 ar.
Figure BDA0002419551980000191
Yield: 87 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ7.98(1H,s),δ7.89–7.82(3H,m),δ7.77–7.72(1H,m),δ7.68 (1H,s),δ7.58–7.53(2H,m),δ4.95(1H,dd,J＝13.4,5.4Hz),δ4.89(1H, dd,J＝13.4,9.8Hz),δ4.35–4.29(1H,m),δ4.24(2H,q,J＝7.2Hz),δ1.97 –δ1.84(1H,m),δ1.73(1H,dd,J＝14.8,6.9Hz),δ1.29–1.23(3H,m),δ 0.92(3H,t,J＝7.4Hz).13C NMR(100MHz,CDCl3)δ166.0,162.8,159.3, 133.2,133.2,131.0,130.9,129.5,128.9,128.1,128.0,127.7,127.0,126.9, 88.6,75.3,61.9,49.8,29.1,13.9,7.6.HPLC(CHIRAL-OD-H,hexane:i-PrOH ＝70:30,2.0mL/min,tR1(minor)＝53.03min,tR1(major)＝94.60min, tR2(major)＝103.56min,tR2(minor)＝134.02min).dr＝11.8:1.94％ee. ES-HRMS:Calcd for C21H22NO6[M+H],384.14416,Found 384.14481.
19. taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2s (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 as.
Figure BDA0002419551980000201
Yield: 82 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ8.14(s,1H),7.44(s,1H),6.37(s,2H),4.60(d,J＝7.5Hz,2H),4.37 (q,J＝7.3Hz,2H),4.30(t,J＝7.5Hz,1H),1.95(dt,J＝22.4,7.6Hz,1H), 1.74(td,J＝14.6,7.3Hz,1H),1.39(t,J＝7.1Hz,3H),0.91(t,J＝7.4Hz,3H). 13C NMR(100MHz,CDCl3)δ165.8,162.9,159.4,147.1,143.5,126.9,111.0, 110.9,87.6,73.5,62.1,43.3,29.1,14.1,7.4.HPLC(CHIRAL-OJ-H,210nm, hexane:i-PrOH＝70:30,1.0mL/min,tR1(major)＝34.875min,tR1(minor)＝ 44.793min,tR2(major)＝60.858min,tR2(minor)＝73.100min).dr＝16.5:1. 91％ee.ES-HRMS:Calcd for C15H18NO7[M+H],324.1083,Found 324.1066.
20. and a compound 3at, namely taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2t (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain a compound 3 at.
Figure BDA0002419551980000202
Yield: 90 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ8.01(1H,s),δ7.28(1H,s),δ6.98(2H,s),δ4.84(1H,dd,J＝13.2, 4.4Hz),δ4.67(1H,dd,J＝15.0,8.6Hz),δ4.46(1H,dd,J＝10.1,4.3Hz),δ 4.32(2H,q,J＝7.0),δ2.04(1H,td,J＝14.7,7.4Hz),δ1.91(1H,td,J＝14.9, 7.6Hz),δ1.35(3H,t,J＝7.1Hz),δ0.94(3H,t,J＝7.4Hz).13C NMR(100 MHz,CDCl3)δ165.9,162.4,159.3,135.4,127.8,127.6,127.1,126.4,88.1, 76.3,62.0,44.7,28.8,14.0,7.7.HPLC(Lux 5u Cellulose-2,hexane:i-PrOH ＝80:20,1.0mL/min,tR1(major)＝26.86min,tR1(minor)＝49.29min,tR2(major)＝52.9 7min,tR2(minor)＝68.43min).dr＝8.9:1.90％ee.ES-HRMS:Calcd for C15H18NO6S[M+H],340.08493,Found 340.08546.
21. taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2v (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 av.
Figure BDA0002419551980000211
Yield: 79 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ7.97(s,1H),7.52(d,J＝7.9Hz,1H),7.32–7.27(m,1H),7.24– 7.15(m,2H),6.98(s,1H),4.89(dd,J＝12.9,5.2Hz,1H),4.73(dd,J＝12.9, 10.0Hz,1H),4.49(dd,J＝10.0,5.2Hz,1H),4.22(q,J＝7.5Hz,2H),3.76(s, 3H),2.14–2.03(m,1H),2.01–1.90(m,1H),1.25(t,J＝7.1Hz,3H),0.88(t, J＝7.4Hz,3H).13C NMR(100MHz,CDCl3)δ166.5,163.6,159.4,136.9, 127.6,126.8,126.7,122.6,120.2,118.4,109.8,106.9,89.4,75.6,61.8,41.3, 33.1,28.9,14.0,7.8.HPLC(CHIRAL-OD-H,210nm,hexane:i-PrOH＝80:20, 2.0mL/min,tR1(major)＝14.370min,tR1(minor)＝18.319).dr＝4.8:1.94％ee. ES-HRMS:Calcd for C20H22N2NaO6[M+Na],409.1376,Found 409.1366.
22. taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding the compound 2w (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the mixture by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, spin-drying, and eluting by using ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain a compound 3 aw.
Figure BDA0002419551980000221
Yield: 93 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ8.00(s,1H),4.48(dd,J＝13.9,5.6Hz,1H),4.37(q,J＝7.1Hz,2H), 4.28(dd,J＝13.9,5.8Hz,1H),2.87(ddd,J＝9.2,7.3,4.6Hz,1H),2.05-1.85 (m,2H)1.44–1.35(m,7H),1.26(t,J＝7.1Hz,3H),0.88(t,J＝7.3Hz,3H). 13C NMR(100MHz,CDCl3)δ166.1,163.3,159.6,127.1,89.3,75.1,62.1, 42.8,30.8,28.4,20.6,14.1,13.9,7.6.HPLC(CHIRAL-OJ-H,210nm,hexane: i-PrOH＝92:8,1.0mL/min,tR1(minor)＝63.660min,tR1(major)＝69.698min,). dr>20:1.88％ee.ES-HRMS:Calcd for C14H22NO6[M+H],300.1447,Found 300.1415.
23. and a compound 3ax, namely taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding a compound 2x (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain a compound 3 ax.
Figure BDA0002419551980000231
Yield: 83 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ8.07(s,1H),4.48(dd,J＝14.6,6.1Hz,1H),4.40–4.31(m,3H), 2.95(ddd,J＝6.4,4.4,2.3Hz,1H),2.03–1.84(m,2H),1.38(t,J＝7.1 Hz,3H),1.03(d,J＝7.0Hz,3H),0.84(t,J＝7.4Hz,3H),0.82(d,J＝6.8Hz, 3H).13C NMR(100MHz,CDCl3)δ166.1,163.8,159.7,126.9,90.2,71.9, 62.1,47.8,29.4,28.2,22.4,17.7,14.1,7.6.HPLC(CHIRAL-OD-H,210nm, hexane:i-PrOH＝95:5,1.0mL/min,tR1(minor)＝13.179min,tR1(major)＝ 18.070min,tR2(minor)＝49.909min,tR2(major)＝51.397min).dr>20:1.96％ ee.ES-HRMS:Calcd for C14H22NO6[M+H],300.1447,Found 300.1436.
24. the compound 3ay is prepared by taking the compound 1a (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding the solvent dioxane (2mL), adding the compound 2y (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 ay.
Figure BDA0002419551980000241
Yield: 92 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ8.06(s,1H),4.41(d,J＝5.5Hz,2H),4.38(q,J＝7.5Hz,2H),2.91 (td,J＝5.5,2.0Hz,1H),2.06–1.83(m,2H),1.81–1.45(m,8H),1.39(t,J＝ 7.1Hz,3H),1.19–1.05(m,3H),0.85(t,J＝7.4Hz,3H).13C NMR(100 MHz,CDCl3)δ166.0,163.7,159.7,126.9,90.1,72.6,62.1,48.2,38.8,32.6, 29.5,28.56,26.6,26.3,25.8,14.1,7.6.HPLC(CHIRAL-OJ-H,210nm, hexane:i-PrOH＝92:8,1.0mL/min,tR1(major)＝50.012min,tR1(minor)＝ 66.758min).dr>20:1.90％ee.ES-HRMS:Calcd for C17H25NNaO6[M+Na], 362.1580,Found 362.1548.
25. taking the compound 1b (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding the compound 2a (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 az.
Figure BDA0002419551980000242
Yield: 93 percent. Purification by column chromatography on silica gel (Ethyl acetate)Petroleum ether is 1: 5);1H NMR(400MHz, CDCl3)δ7.89(s,1H),7.35–7.21(m,3H),7.11(d,J＝6.5Hz,2H),4.83(dd, J＝13.4,5.1Hz,1H),4.72(dd,J＝13.4,9.9Hz,1H),4.19(q,J＝7.1Hz,2H), 3.99(dd,J＝9.9,5.1Hz,1H),1.51(s,3H),1.23(t,J＝7.1Hz,3H).13C NMR (100MHz,CDCl3)δ164.7,162.9,158.4,132.6,128.4,128.1,127.2,124.8, 84.5,74.0,60.9,49.5,22.3,13.0.HPLC(CHIRAL-OJ-H,254nm,hexane: i-PrOH＝97:3,1.0mL/min,tR1(major)＝19.984min,tR1(minor)＝40.539min, tR2(minor)＝25.931min,tR2(major)＝29.097min).dr＝14.1:1.90％ ee.ES-HRMS:Calcd for C16H18NO6[M+H],320.1134,Found 320.1113.
26. taking the compound 1c (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding the compound 2a (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain the compound 3 ba.
Figure BDA0002419551980000251
Yield: 91 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ7.90(s,1H),7.44–7.29(m,3H),7.22–7.13(m,2H),4.86(dd,J＝ 13.4,5.0Hz,1H),4.77(dd,J＝13.4,10.0Hz,1H),4.26(q,J＝7.1Hz,2H), 4.10(dd,J＝10.0,5.0Hz,1H),1.99–1.74(m,2H),1.41–1.18(m,5H),0.91 (t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ166.0,163.3,159.3,133.6, 129.4,129.0,128.3,126.5,88.2,75.2,62.0,49.8,37.7,16.8,14.1,13.9.HPLC (CHIRAL-OJ-H,254nm,hexane:i-PrOH＝97:3,2.0mL/min,tR1(minor) ＝36.733min,tR1(major)＝40.539min,tR2(minor)＝45.309min,tR2(major)＝52.316min).dr＝16.3:1.92％ee.ES-HRMS:Calcd for C18H22NNaO6[M+Na], 370.1267,Found 370.1248.
27. and (3 bb) taking the compound 1d (0.25mmol) and the chiral thiourea bifunctional catalyst VII (0.05mmol), adding a solvent dioxane (2mL), adding the compound 2a (0.50mmol), and stirring for reaction. After the reaction is finished, quenching the reaction product by using a saturated ammonium chloride solution, extracting by using ethyl acetate, performing suction filtration, and spin-drying, wherein an eluent is ethyl acetate: petroleum ether is 1:5, separating and purifying, and spin-drying to obtain a compound 3 bb.
Figure BDA0002419551980000261
Yield: 85 percent. Purifying by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1: 5);1H NMR(400MHz, CDCl3)δ7.87(s,1H),7.32–7.24(m,3H),7.11(dd,J＝7.8,1.6Hz,2H),4.79 (dd,J＝13.4,5.1Hz,1H),4.70(dd,J＝13.4,9.9Hz,1H),4.05(dd,J＝9.9, 5.1Hz,1H),3.75(s,3H),1.96(dq,J＝14.8,7.4Hz,1H),1.80(dq,J＝14.7, 7.4Hz,1H),0.81(t,J＝7.4Hz,3H).13C NMR(100MHz,CDCl3)δ165.0, 162.6,158.7,132.6,128.4,128.1,127.2,125.6,87.6,74.1,51.7,48.5,27.8,6.6. HPLC(CHIRAL-OD-H,210nm,hexane:i-PrOH＝70:30,1.0mL/min, tR1(major)＝30.03min,tR1(minor)＝55.70min).dr＝12.9:1.80％ee. ES-HRMS:Calcd for C16H18NO6[M+H],320.1134,Found 320.1120.
28. tables of yield, ee value, dr value of compound 3 aa-bb:
Figure BDA0002419551980000271
as can be seen from the above table, the present invention successfully synthesized a series of synthetic methods with yield as high as 98% and stereoselectivity > 20: 1dr and 99% ee chiral gamma, gamma-disubstituted butenolide compounds, a method for performing vinylogous Michael addition reaction on gamma-dimer furanone (shown in a formula I) and alpha, beta-unsaturated nitroolefin (shown in a formula II) by utilizing a bifunctional thiourea catalyst is developed, and the problem of synthesizing the chiral gamma, gamma-disubstituted butenolide compounds is solved.

Claims (3)

1. A preparation method of chiral gamma, gamma-disubstituted butenolide compounds is characterized by comprising the following steps:
Figure FDA0003336255760000011
wherein R is1A phenyl group, a benzyl group, a p-benzyloxy group, an m-benzyloxy group, an o-benzyloxy group, a bisphenylmethoxy group, a trityloxy group, a p-phenylnitro group, an m-phenylnitro group, an o-phenylnitroso group, a p-phenylcyano group, an m-phenylcyano group, an o-phenylcyano group, a p-phenylisocyano group, an m-phenylisocyano group, an o-phenylisocyano group, a t-phenyltrifluoromethyl group, a p-phenylcarbomethoxy group, an m-phenylcarbomethoxy group, a p-phenylhalogeno group, an m-phenylhalogeno group, an o-phenylhalogeno group, a hydrogen group, a naphthyl group, or a benzoic acid group;
R2＝C1-C6alkyl or hydrogen of (a);
R3＝C1-C6alkyl or hydrogen of (a);
a) dissolving the compound 2a-y and a chiral thiourea bifunctional catalyst VII in a solvent dioxane;
b) adding the compounds 1a-d under stirring, and stirring for reaction;
c) after the reaction is finished, carrying out post-treatment to obtain a compound 3 aa-bb;
the chiral thiourea bifunctional catalyst VII has the structure as follows:
Figure FDA0003336255760000012
2. the process according to claim 1, wherein the molar weight ratio of compounds 1a-d to compounds 2a-y is 1: 0.5-5.
3. The method of claim 1, wherein the reaction is carried out byCompound 1a-d and chiral thiourea bifunctional catalyst VII
Figure FDA0003336255760000021
Is 1: 0.1-5.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A vinylogous Michael reaction of 2-furanone dimers with α,β-unsaturated nitroolefins for constructing chiral γ,γ-disubstituted butenolides;Zhushuang Bai et al.;《Org. Chem. Front.》;20200509;第2910-2915页 *
双官能团硫脲催化的γ-单取代呋喃酮与α, β-不饱和硝基烯烃的Vinylogous Michael 加成反应;白著双等;《中国化学会第九届全国有机化学学术会议》;20150731;第378页 *

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