CN108358941B - The application of chiral quinine thiocarbamide - Google Patents
The application of chiral quinine thiocarbamide Download PDFInfo
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- CN108358941B CN108358941B CN201810027686.1A CN201810027686A CN108358941B CN 108358941 B CN108358941 B CN 108358941B CN 201810027686 A CN201810027686 A CN 201810027686A CN 108358941 B CN108358941 B CN 108358941B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/32—Addition reactions to C=C or C-C triple bonds
- B01J2231/324—Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions
Abstract
The invention discloses the applications of chiral quinine thiocarbamide, and in particular to application of the chiral quinine thiocarbamide in the derivative beta, gamma-unsaturation alpha-keto ester compound of catalysis isatin and -4 hydrogen of 3- hydroxyl-chromene -4- reactive ketone is derivative with isatinβ,γIt is unsaturatedα-one acid esters and -4 hydrogen of 3- hydroxyl-chromene -4- ketone are reactant, and under the catalysis of chiral Multifunctional chiral quinine thiocarbamide, synthesis obtains product in a solvent.Method raw material disclosed by the invention is simple and easy to get, and reaction condition is mild, and post-processing is simple and convenient, and applicable substrate spectrum is wide, high income, and enantioselectivity is high, and the product thus synthesized can be used to the intermediate of synthetic drug, insecticide and photoelectric material.
Description
The present invention is a kind of entitled chiral spiro hydroxyindole-chromene -one simultaneously -3,4- dihydro-pyran chemical combination
The synthetic method of object, the applying date are on July 15th, 2016, application No. is the divisional application of 2016105581058 patent of invention,
Belong to the application obscure portions of catalyst.
Technical field
The present invention relates to the synthesis of chiral spiro compound, and in particular to and chiral quinine thiocarbamide derives β in catalysis isatin,
Application in -4 hydrogen of γ-unsaturation alpha-keto ester compound and 3- hydroxyl-chromene -4- reactive ketone.
Background technique
Chiral oxa- loop coil producing oxindoles compound is widely present in natural products and drug molecule, have it is antitumor,
Antiphytoviral, plant growth regulating, weeding, sterilization, inhibitory enzyme activity, anti-oxidant and radiation protection, destruction biological cell membrane etc.
Extensive bioactivity, and the concern by many scientists.Chiral spiro hydroxyindole-chromene -one simultaneously -3,4- dihydro -
Pyrylium compound equally has similar potential using value, therefore selects the oxa- loop coil hydroxyl of efficient method synthesis of chiral
Indoles hemiketal compound has attracted the great interest of many chemists, has emerged many synthetic methods recently.Chiral oxygen
Miscellaneous loop coil hydroxyindole hemiketal compound has continuous conjugated structure, and this continuous conjugated structure makes it be easy to happen electronics turn
Shifting and transition, therefore oxa- loop coil hydroxyindole hemiketal compound also has potential application in terms of electronics transfer, photoelectric material
Value.In organic synthesis field, the reaction being catalyzed by asymmetric small molecule with a small amount of chiral catalyst due to can only be obtained
Largely new active material and become the method for synthesizing chiral compound that is most effective, having economic value.
The method report of synthesis of chiral oxa- loop coil producing oxindoles compound is fewer in the prior art.β, γInsatiable hunger
Withα-one acid esters is as one with multiple reaction site, electron deficientβ, γUnsaturated system and activationαThe skeleton of carbonyl
Application have received widespread attention and report that and isatin is derivativeβ, γIt is unsaturatedαThe chemical reaction that -one acid esters skeleton participates in
Report it is fewer.Shi Min seminar reported in 2014 with (DHQ)2AQN is catalyst, and isatin is derivativeβ, γIt is unsaturatedαAsymmetry [3+2] cycloaddition reaction of -one acid esters and connection enester, can be with 56% 99% yield and 76% 98% mapping selection
Property obtains chiral oxa- loop coil producing oxindoles compound.(H.-B. Yang, Y.-Z. Zhao, R. Sang, Y. Wei, M.
Shi, Asymmetric Synthesis of Bioxindole-Substituted Hexahydro-furo[2,3-b]
furans via Hydroquinine Anthraquinone-1,4-diyl Di-ether-Catalyzed Domino
Annulation of Acylidenoxindoles/Isatins, Acylidenoxindoles and Allenoates.Adv. Synth. Catal.,2014, 356, 3799-380), but the catalyst amount of the reaction is larger, reaction it is non-right
It is not very high for reflecting selectivity, to limit the further application value of the reaction.
Therefore it is necessary to find the new synthesis of chiral loop coil hydroxyindole-chromene -one of one kind simultaneously -3,4- dihydro-pyrrole
It mutters the method for compound, not only high income, enantioselectivity are outstanding for this method, while also substrate being needed to be easily-synthesized, at low cost, reaction
Mild condition, it is easy to operate.
Summary of the invention
The object of the present invention is to provide a kind of chiral spiro hydroxyindole-chromene -one simultaneously -3,4- dihydro-pyran chemical combination
The process for catalytic synthesis of object and the chiral spiro thus prepared hydroxyindole-chromene -one simultaneously -3,4- dihydro-pyran compound.
To achieve the above object of the invention, the technical solution adopted by the present invention is that: a kind of oxa- loop coil hydroxyindole hemiketal
The synthetic method of object is closed, specifically: with the derivative beta, gamma-unsaturation alpha-keto ester compound of isatin and -4 hydrogen of 3- hydroxyl-chromene -4-
Ketone is reactant, and using chiral quinine thiocarbamide as catalyst, in halogenated hydrocarbon solvent, reaction obtains product chiral spiro hydroxyl Yin
Diindyl-chromene -one simultaneously -3,4- dihydro-pyran compound；
The derivative β of the isatin, γ-unsaturation alpha-keto ester compound chemical structural formula are,
Middle R1It is selected from: one of methyl, methoxy, benzyl, allyl, benzyloxycarbonyl group；R2It is selected from: hydrogen, 5- fluorine, 5- chlorine, 5-
Bromine, 5- methyl, 5- methoxyl group, 6- chlorine, 6- bromine, 6- methoxyl group, 7- fluorine, 7- methyl, 5,6- difluoro, one in 5,7- dimethyl
Kind；R3It is selected from: one of methyl, ethyl；
- 4 hydrogen of the 3- hydroxyl-chromene -4- ketone compound chemical structural formula is, wherein R be
One of hydrogen, 6- fluorine, 6- bromine, 6- methyl, 7- methoxyl group；
The structural formula of the chiral spiro hydroxyindole-chromene -one simultaneously -3,4- dihydro-pyran compound are as follows:
。
In preferred technical solution, with molar amount, the dosage of the catalyst is the derivative beta, gamma-unsaturation α -one of isatin
The 2-10% of ester compound；Further preferably 5%.
In preferred technical solution, with molar amount, -4 hydrogen of 3- hydroxyl-chromene -4- ketone compound dosage is spread out for isatin
Raw β, 1-2 times of γ-unsaturation alpha-keto ester compound；Further preferably 1.5 times.
In preferred technical solution, reaction temperature is lower than room temperature, for example -30 DEG C to room temperature；Reaction time is that 36-41 is small
When.It is preferred that -20 DEG C are reacted 40 hours.
In preferred technical solution, the catalyst is chiral quinine thiocarbamide；Its chemical structural formula is as follows:
In above-mentioned technical proposal, reaction process includes at low temperature, it is derivative that catalyst, isatin being sequentially added into reaction flask
- 4 hydrogen of 3- hydroxyl-chromene -4- ketone compound is added after stirring 15-35 minutes in beta, gamma-unsaturation alpha-keto ester compound, solvent
Reacted, after reaction, crude product chromatographed by simple column (eluant, eluent is preferably petroleum ether: ethyl acetate=2:1~
Target product 1:1) can be obtained；Such compound is many antibacterials, and the analog of antivirotic and enzyme inhibitor has huge
Big potential using value.Chiral oxa- loop coil hydroxyindole hemiketal compound has continuous conjugated structure, this continuous
Conjugated structure makes it be easy to happen electronics transfer and transition, therefore oxa- loop coil hydroxyindole hemiketal compound can be used as electronics and turn
It moves, photoelectric material.
The present invention further discloses above-mentioned chiral quinine thiocarbamide in catalysis isatin derivative β, γ-unsaturation alpha-keto ester chemical combination
Application in -4 hydrogen of object and 3- hydroxyl-chromene -4- reactive ketone.
Above-mentioned reaction process is as follows:
Due to the above technical solutions, the present invention has the following advantages over the prior art:
1. the present invention is realized for the first time with -4 hydrogen of 3- hydroxyl-chromene -4- ketone compound and isatin derivative β, γ-unsaturation α -
Keto ester compound by utilizing is reactant, chiral multi-functional quinine thiocarbamide is catalyst synthesis of chiral loop coil hydroxyindole-chromene -one
And the method for -3,4- dihydro-pyran compound, this method is easy to operate, high income, and stereoselectivity is good；
2. the post-reaction treatment of synthesis oxa- loop coil hydroxyindole hemiketal compound disclosed in this invention is simple, reaction is not
There are Dynamic Resolution process, belong to Michael addition-cyclisation tandem reaction, do not have by-product generation in system；
3. the method suitable substrates range of synthesis oxa- loop coil hydroxyindole hemiketal compound disclosed by the invention is very wide, former
Material be industrialization, product cheap and easy to get, it is pollution-free；And functional group compatibility is high, and corresponding selection is outstanding, high income.
Specific embodiment
The present invention will be further described below with reference to examples:
Embodiment one:
Quinine thiocarbamide (5.9 mg, 0.01 mmol) and 1a (25.9mg, 0.1 mmol), 2a are sequentially added in reaction flask
(16.2 mg, 0.1 mmol) is added 1 mL methylene chloride, reacts 12 hours at room temperature, and reaction system passes through simple
Column chromatography (eluant, eluent is petroleum ether: ethyl acetate=1.8:1) can be obtained target product 3a (36.6mg), yellow solid,
Mp:198-201 DEG C, yield 87%, > 20/1 dr, 87% ee.
Quinine thiocarbamide (5.9 mg, 0.01 mmol) and 1a (25.9mg, 0.1 mmol), 2a are sequentially added in reaction flask
(16.2 mg, 0.1 mmol) is added 1 mL methylene chloride, reacts 12 hours under the conditions of zero degrees celsius, reaction system passes through
Target product 3a (33.3mg) can be obtained in simple column chromatography (eluant, eluent is petroleum ether: ethyl acetate=1.8:1), and yellow is solid
Body, mp:198-201 DEG C, yield 79%, > 20/1 dr, 96% ee.
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1a (25.9mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is stirred 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.8:1) by simple column and can obtain
To target product 3a (40.8 mg), yellow solid, mp:198-201 DEG C, yield 97%, > 20/1 dr, 98% ee.
Product 3a is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (70:30), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 13.936, t
(minor) = 24.650]; [α]D 25 = + 63.0 (c = 0.51, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.83 (s, 0.5H), 8.21 (ddd, J = 13.2, 8.0, 1.2 Hz, 1H), 7.89 (d, J = 7.6 Hz,
1H), 7.54 – 7.49 (m, 1H), 7.45 (td, J = 8.0, 1.2 Hz, 0.5H), 7.38 (td, J =8.0,
1.2 Hz, 1H), 7.33 – 7.29 (m, 1H), 7.23 – 7.18 (m, 1H), 7.15 – 7.03 (m, 2H),
6.98 (d, J = 7.8 Hz, 0.5H), 5.05 (s, 0.5H), 4.42 – 4.32 ((dq, J = 7.2, 6.8
Hz, 2H)), 3.38 (d, J = 8.0 Hz, 3H), 3.31 (d, J = 14.0 Hz, 0.5H), 3.07 (d, J =
14.8 Hz, 0.5H), 2.69 (d, J = 14.8 Hz, 0.5H), 2.33 (d, J = 14.0 Hz, 0.5H),
1.38 (dt, J = 15.8, 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 177.71, 175.47,
171.97, 171.84, 168.43, 167.33, 155.05, 154.99, 147.63, 145.48, 143.87,
143.78, 137.11, 136.67, 133.58, 133.44, 130.23, 129.86, 129.54, 128.80,
127.69, 126.32, 126.08, 124.78, 124.77, 124.60, 123.76, 123.74, 123.71,
123.41, 118.07, 117.87, 109.66, 108.61, 94.90, 93.63, 63.71, 62.80, 50.16,
49.56, 37.60, 37.51, 27.41, 27.25, 14.15, 14.08; IR: 3276.4, 2961.7, 1740.5,
1714.4, 1627.4, 1611.0, 1468.6, 1260.0, 1192.0, 1034.8, 1020.7, 796.4, 758.9,
692.5 cm-1; HRMS calcd. for C23H19NNaO7 [M+Na]+444.1054, found: 444.1065；The above number
It is demonstrated that purpose product synthesizes successfully.
Embodiment two:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1b (28.9mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.6:1) by simple column and can obtain
To target product 3b (42.8 mg), yellow solid, mp:141-144 DEG C, yield 95%, > 20/1 dr, 98% ee.
Product 3b is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (70:30), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 12.362, t
(minor) = 17.090]; [α]D 25 = + 98.0 (c = 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.48 (s, 0.3H), 8.22 (d, J = 7.2 Hz, 0.4H), 8.18 (d, J = 7.6 Hz, 0.6H), 7.93
(d, J = 7.6 Hz, 0.6H), 7.51 – 7.49 (m, 1H), 7.42 (t, J = 7.2 Hz, 0.3H), 7.36
(t, J = 7.6 Hz, 0.7H), 7.33 – 7.28 (m, 1H), 7.23 (d, J = 2.9 Hz, 0.3H), 7.21
– 7.15 (m, 1H), 7.11 – 7.04 (m, 1.7H), 5.29 (s, 0.7H), 5.29 (t, J = 10.1 Hz,
1H), 5.21 (dd, J = 10.8, 5.2 Hz, 1H), 4.36 (dq, J = 12.7, 5.7 Hz, 2H), 3.42
(d, J = 7.6 Hz, 3H), 3.30 (d, J = 13.6 Hz, 0.7H), 3.11 (d, J = 14.8 Hz,
0.3H), 2.72 (d, J = 14.8 Hz, 0.3H), 2.39 (d, J = 14.0 Hz, 0.35H), 1.37 (dt, J
= 14.2, 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.59, 176.28, 171.92,
171.75, 168.29, 167.22, 155.00, 154.96, 147.42, 145.43, 142.10, 141.90,
136.94, 136.49,133.73, 133.58, 130.34, 129.65, 129.37, 128.27, 127.82,
126.40, 126.18, 125.12, 124.86, 124.67, 123.90, 123.84, 123.74, 123.70,
117.73, 117.61, 110.10, 110.06, 94.80, 93.64, 72.17, 71.95, 63.68, 62.88,
56.61, 56.37, 50.50, 49.96, 37.78, 37.62, 14.14, 14.07; IR: 3514.9, 3282.1,
2961.4, 2928.7, 1738.7, 1720.6, 1631.9, 1620.9, 1484.3, 1467.9, 1368.6,
1341.2, 1217.1, 1194.4, 1147.4, 1103.9, 1039.2, 977.2, 923.7, 860.6, 775.0,
758.9, 701.2, 660.5, 613.3 cm-1; HRMS calcd. for C24H22NO8 [M+H]+ 452.1340,
found:452.1348。
Embodiment three:
Quinine thiocarbamide (0.002 mmol) and 1c (33.5mg, 0.1 mmol) are sequentially added in reaction flask, and 1 mL is added
Methylene chloride reacts 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol), the reaction was continued
38 hours, reaction system, which chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.8:1) by simple column, can be obtained target production
Object 3c (48.3mg), white solid, mp:141-144 °C, yield 91%, > 20/1 dr, 96% ee.
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1c (33.5mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 36 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.8:1) by simple column and can obtain
To target product 3c (48.7 mg), white solid, mp:141-144 DEG C, yield 98%, > 20/1 dr, 99% ee.
Product 3c is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (70:30), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 17.371, t
(minor) = 25.698]; [α]D 25 = + 114.0 (c = 0.50, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.83 (s, 0.4H), 8.23 (d, J = 8.0 Hz, 0.45H), 8.18 (d, J = 8.0 Hz, 0.55H),
7.94 (d, J = 7.6 Hz, 0.55H), 7.55 – 7.50 (m, 1H), 7.42 – 7.33 (m, 5H), 7.32 –
7.30 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 7.6 Hz, 0.5H), 7.06 (d,J = 7.6 Hz, 0.7H), 7.02 (d, J = 3.2 Hz, 0.5H), 7.00 (d, J = 4.4 Hz, 0.3H),
6.92 (d, J = 8.0 Hz, 0.4H), 6.85 (d, J = 7.6 Hz, 0.55H), 5.33 (s, 0.6H), 5.26
(t, J = 15.6 Hz, 1H), 4.81 (t, J = 15.2 Hz, 1H), 4.37 (dq, J = 7.2, 5.2 Hz,
2H), 3.38 (dd, J = 14.0, 2.0 Hz, 0.6H), 3.13 (d, J = 15.2 Hz, 0.4H), 2.76 (d,J = 14.8 Hz, 0.4H), 2.42 (d, J = 14.0 Hz, 0.6H), 1.38 (dt, J = 7.2, 5.2 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 177.95, 175.64, 171.97, 171.81, 168.39,
167.31, 154.00, 154.96, 147.84, 145.80, 136.90, 136.45, 135.44, 134.53,
133.66, 133.48, 130.15, 129.87, 129.44, 129.13, 128.94, 128.71, 128.32,
127.99, 127.78, 127.32, 127.30, 126.37, 126.13, 124.80, 124.70, 124.60,
123.79, 123.75, 123.69, 123.43, 117.76, 117.60, 110.65, 109.59, 94.90, 93.66,
63.64, 62.83, 50.17, 49.55, 44.63, 44.46, 37.42, 37.37, 14.13, 14.07; IR:
3484.2, 3281.4, 2959.1, 2923.7, 1739.1, 1714.4, 1632.2, 1610.4, 1485.9,
1466.6, 1364.0, 1346.3, 1284.3, 1263.4, 1216.9, 1197.6, 1182.2, 1145.9,
1081.0, 1038.4, 974.7, 947.8, 883.8, 808.3, 753.4, 734.7, 698.6, 630.1 cm-1;
HRMS calcd. for C29H24NO7 [M+H]+498.1547 found:498.1545, above data proves purpose product
It synthesizes successfully.
Example IV:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1d (28.5mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.8:1) by simple column and can obtain
To target product 3d (46.0 mg), white solid, mp:158-160 DEG C, yield 97%, > 20/1 dr, 99% ee.
Product 3d is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (70:30), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 15.593, t
(minor) = 19.550]; [α]D 25 = + 97.3 (c = 0.52, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.79 (s, 0.45H), 8.21 (dd, J = 17.2, 7.6 Hz, 1H), 7.93 (d, J = 7.6 Hz,
0.50H), 7.54 – 7.50 (m, 1H), 7.41 (t, J = 7.6 Hz, 0.6H), 7.36 – 7.29 (m,
1.4H), 7.25 (d, J = 7.2 Hz, 0.5H), 7.17 (t, J = 7.6 Hz, 0.5H), 7.11 – 7.01
(m, 2H), 6.94 (d, J = 7.6 Hz, 0.5H), 5.99 – 5.88 (m, 1H), 5.34 (dd, J = 16.8,
10.6 Hz, 2H), 5.21 (s, 0.55H), 4.60 (dd, J = 16.8, 3.6 Hz, 1H), 4.36 (dt, J =
7.6, 5.6 Hz, 3H), 3.33 (d, J = 14.0 Hz, 0.55H), 3.11 (d, J = 14.8 Hz, 0.45H),
2.72 (d, J = 14.8 Hz, 0.45H), 2.38 (d, J = 14.0 Hz, 0.55H), 1.38 (dt, J =
14.4, 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 177.59, 175.22, 171.98, 171.82,
168.42, 167.32, 155.02, 149.97, 147.72, 145.61, 143.07, 142.90, 136.98,
136.52, 133.66, 133.50, 130.76, 130.16, 129.96, 129.83, 129.45, 128.72,
127.78, 126.37, 126.12, 124.80, 124.70,124.61, 123.82, 123.74, 123.70,
123.37, 118.00, 117.85, 117.68, 117.44, 110.51, 109.49, 94.88, 93.64, 63.69,
62.83, 50.16, 49.53, 43.05, 42.92, 37.50, 37.47, 14.15,14.08; IR: 3544.6,
3259.4, 2963.1, 2854.3, 1740.2, 1710.8, 1625.9, 1609.6, 1487.0, 1467.4,
1432.8, 1280.3, 1260.9, 1238.1, 1198.6, 1186.3, 1107.0, 1039.8, 1004.7,
977.5, 943.9, 884.7, 855.7, 797.5, 761.9, 702.3, 668.9, 655.5, 636.0, 619.9
cm-1; HRMS calcd. for C25H22NO7 [M+H]+448.1391, found:448.1393；Above data proves purpose
Product formation success.
Embodiment five:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1e (37.9mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 30 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.8:1) by simple column and can obtain
To target product 3e (39.4 mg), yellow solid, mp:196-198 DEG C, yield 73%, > 20/1 dr, 99% ee.
Product 3e is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (70:30), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 28.027, t
(minor) = 41.336]; [α]D 25 = + 98.4 (c = 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.82 (s, 0.45H), 8.23 (dd, J = 14.8, 7.6 Hz, 1H), 7.93 (d, J = 7.6 Hz,
0.55H), 7.54 (t, J = 7.6 Hz, 1H), 7.40 – 7.29 (m, 6.45H), 7.23 – 7.01 (m,
3H), 6.92 (d, J = 7.6 Hz, 0.5H), 6.85 (d, J = 7.6 Hz, 0.5H), 5.27 (t, J =
15.6 Hz, 1H), 5.11 (s, 0.55H), 4.82 (t, J = 14.0 Hz, 1H), 4.39 (dq, J = 12.4,
7.2 Hz, 2H), 3.39 (d, J = 14.0 Hz, 0.55H), 3.14 (d, J = 14.8 Hz, 0.45H), 2.75
(d, J = 15.2 Hz, 0.45H), 2.41 (d, J = 14.0 Hz, 0.55H), 1.40 (dt, J = 12.4,
7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.00, 175.66, 171.99, 171.85,
168.45, 167.34, 155.07, 155.02, 147.80, 143.05, 142.86, 136.95, 136.50,
135.47, 134.56, 133.69, 133.54, 130.18, 129.89, 129.50, 129.18, 128.99,
128.78, 128.38, 128.04, 127.80, 127.37, 127.36, 126.46, 126.22, 124.86,
124.75, 124.67, 123.84, 123.78, 123.47, 117.81, 117.64, 110.66, 109.64,
94.93, 93.64, 63.78, 62.90, 50.21, 49.56, 44.69, 44.52, 37.46, 14.18, 14.12;
IR: 3482.3, 3279.6, 2960.8, 2922.9, 1743.1, 1715.8, 1640.6, 1609.8, 1488.3,
1467.7, 1432.2, 1369.4, 1282.4, 1262.1, 1196.7, 1184.7, 1146.1, 1109.0,
1040.2,1013.5, 972.1, 860.0, 772.8, 753.5, 728.6, 696.9, 630.7 cm-1; HRMS
calcd. for C30H24NO9 [M+H]+542.1146, found:542.1153；Above data prove purpose product synthesis at
Function.
Embodiment six:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1f (28.7mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.8:1) by simple column and can obtain
To target product 3f (24.2 mg), yellow solid, mp:150-153 DEG C, yield 54%, > 20/1 dr, 98% ee.
Product 3f is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (70:30), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 15.747, t
(minor) = 20.035]; [α]D 25 = + 113.3 (c = 0.30, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.34 (d, J = 8.0 Hz, 0.8H), 8.31 (d, J = 6.4 Hz, 0.2H), 8.23 – 8.21 (m,
1H), 7.95 (d, J = 7.6 Hz, 0.7H), 7.56 (dd, J = 7.2, 1.2 Hz, 1H), 7.95 (d, J =
2.8 Hz, 0.3H), 7.47 – 7.40 (m, 1H), 7.34 – 7.29 (m, 1H), 7.23 (d, J = 8.0 Hz,
0.7H), 7.18 (d, J = 8.4 Hz, 0.7H), 7.14 (d, J = 8.4 Hz, 0.3H), 5.10 (s,
0.7H), 4.38 (dq, J = 15.6, 7.2 Hz, 2H), 3.32 (d, J = 14.0 Hz, 0.8H), 3.08 (d,J = 15.2 Hz, 0.2H), 2.81 (d, J = 15.2 Hz, 0.3H), 2.74 (d, J = 5.7 Hz, 3H),
2.47 (d, J = 14.0 Hz, 0.7H), 1.38 (dt, J = 15.2, 7.2 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 177.06, 171.94, 170.71, 168.06, 155.10, 147.08, 140.19, 136.56,
133.94, 133.82, 129.91, 128.76, 127.90, 127.28, 126.85, 126.41, 126.22,
125.96, 125.62, 125.08, 124.91, 123.69, 123.42, 118.05, 117.96, 117.37,
116.65, 94.46, 93.56 , 63.93, 63.21, 50.70, 50.51, 38.87, 38.56, 27.35,
27.01, 14.17, 14.13; IR: 3350.2, 2926.9, 2924.5, 1760.2, 1741.5, 1724.4,
1640.9, 1613.6, 1465.6, 1434.8, 1370.1, 1339.0, 1306.9, 1268.1, 1198.3,
1147.9, 1107.9, 1063.4, 973.7, 802.7, 763.4 cm-1; HRMS calcd. for C24H20NO8 [M+
H]+450.1183, found:450.1188；Above data proves that purpose product synthesizes successfully.
Embodiment seven:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1g (27.7mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.8:1) by simple column and can obtain
To target product 3g (35.9 mg), reddish Solid, mp:114-116 DEG C, yield 82%, > 20/1 dr, 99% ee.
Product 3g is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (85:15), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 30.576]; [α]D 25
= + 135.8 (c = 0.46, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 0.3H), 8.22
(dd, J = 8.0, 1.6 Hz, 0.3H), 8.18 (dd, J = 8.0, 1.6 Hz, 0.7H), 7.69 (dd, J =
8.4, 2.4 Hz, 0.7H), 7.55 – 7.50 (m, 1H), 7.34 – 7.27 (m, 1H), 7.13 (dd, J =
8.8, 2.4 Hz, 1H), 7.10 – 7.05 (m, 1H), 7.00 – 6.96 (m, 0.7H), 6.89 (dd, J =
8.4, 4.0 Hz, 0.7H), 5.28 (d, J = 2.2 Hz, 0.7H), 4.36 (m, 2H), 3.35 (dt, J =
14.4, 7.1 Hz, 2H), 3.31 (d, J = 2.4 Hz, 0.3H), 3.27 (d, J = 2.4 Hz, 0.3H),
3.02 (d, J = 14.8 Hz, 0.3H), 2.70 (d, J = 14.8 Hz, 0.3H), 2.34 (d, J = 14.0
Hz, 0.7H), 2.09 (s, 0.6H), 1.37 (dt, J = 14.4, 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 177.40, 175.14, 171.96, 171.75, 168.21, 167.19, 160.22 (J = 243.2
Hz), 154.50 (J = 239.6 Hz), 155.02, 154.09, 147.07, 144.79, 139.79, 139.77,
137.16, 136.60, 133.72, 133.57, 131.23, 131.14, 130.71 (J = 6.4 Hz) 130.66 (J
= 6.9 Hz), 128.94, 126.36, 126.12, 124.90, 124.72, 123.71, 123.68, 118.00,
117.84, 116.75 (J = 23.6 Hz), 116.08 ( J = 26.1 Hz), 115.93 ( J = 23.6 Hz),
112.15 ( J = 25.4 Hz), 110.44 ( J = 8.1 Hz), 109.03 (J = 8.1 Hz), 94.79,
93.59, 63.73, 62.89, 50.41(J = 1.7 Hz), 49.86 (J = 1.6 Hz), 37.43, 27.58,
27.41, 14.14, 14.07; IR: 3298.6, 2927.8, 1747.9, 1722.8, 1636.2, 1613.7,
1492.8, 1469.3, 1352.8, 1258.6, 1198.5, 1151.0, 1105.5, 1030.8, 972.2, 866.1,
797.3, 734.3, 683.5 cm-1; HRMS calcd. for C23H19FNO7 [M+H]+ 440.1140, found:
440.1146；Above data proves that purpose product synthesizes successfully.
Embodiment eight:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1h (29.3 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.6:1) by simple column and can obtain
To target product 3h (42.7 mg), yellow solid, mp:128-131 DEG C, yield 77%, > 20/1 dr, 94% ee.
Product 3h is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (85:15), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 30.714, t
(minor) = 28.046]; [α]D 25 = + 188.8 (c = 0.50, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.63 (s, 0.3H), 8.21 (dd, J = 14.0, 8.0 Hz, 1H), 7.90 (d, J = 1.6 Hz,
0.7H), 7.55 – 7.51 (m, 1H), 7.42 (dd, J = 8.0, 1.6 Hz, 0.3H), 7.35 (dd, J =
8.4, 2.0 Hz, 0.77H), 7.32 – 7.28 (m, 1H), 7.21 (d, J = 1.6 Hz, 0.3H), 7.14
(d, J = 8.4 Hz, 0.7H), 7.10 (d, J = 8.8 Hz, 0.3H), 6.97 (d, J = 8.4 Hz,
0.3H), 6.90 (d, J = 8.4 Hz, 0.7H), 5.18 (s, 0.7H), 4.37 (dq, J = 14.8, 7.2
Hz, 2H), 3.35 (d, J = 9.5 Hz, 3H), 3.28 (d, J = 14.0 Hz, 0.7H), 3.03 (d, J =
14.8 Hz, 0.3H), 2.69 (d, J = 14.8 Hz, 0.3H), 2.33 (d, J = 14.0 Hz, 0.7H),
1.37 (dt, J = 14.8, 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 177.30, 175.04,
171.93, 171.73, 168.17, 167.16, 155.02, 154.96, 146.91, 144.69, 142.39,
137.18, 136.63, 133.73, 133.59, 131.22, 131.04, 130.38, 130.30, 130.25,
129.57, 128.84, 128.26, 126.39, 126.15, 124.92, 124.75, 124.39, 123.71,
118.03, 117.90, 110.64, 109.52, 94.77, 93.55, 63.78, 62.93, 50.18, 49.64,
37.44, 27.57, 27.39, 14.16, 14.09; IR: 3474.2, 2932.3, 1746.1, 1728.2,
1632.8, 1611.2, 1489.4, 1468.1, 1429.9, 1345.7, 1189.4, 1148.1, 1104.3,
1030.5, 977.3, 834.7, 808.9, 762.2, 703.7, 676.4 cm-1; HRMS calcd. for
C23H19ClNO7 [M+H]+456.0845, found:456.0832；Above data proves that purpose product synthesizes successfully.
Embodiment nine:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1i (36.5 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.8:1) by simple column and can obtain
To target product 3i (46.9 mg), white solid, mp:124-127 DEG C, yield 89%, > 20/1 dr, 93% ee.
Product 3i is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (80:20), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 22.013, t
(minor) =19.790]; [α]D 25 = + 78.6 (c = 0.60, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.61 (s, 0.3H), 8.22 (dd, J = 8.0, 1.6 Hz, 0.3H), 8.18 (dd, J = 8.0, 1.2 Hz,
0.7H), 8.03 (d, J = 1.6 Hz, 0.7H), 7.57 – 7.48 (m, 2H), 7.34 (d, J = 2.0 Hz,
0.3H), 7.31 (d, J = 8.0 Hz, 0.7H), 7.13 (d, J = 8.4 Hz, 0.7H), 7.10 (d, J =
8.4 Hz, 0.3H), 6.92 (d, J = 8.4 Hz, 0.3H), 6.85 (d, J = 8.0 Hz, 0.7H), 5.22
(s, 0.7H), 4.36 (dq, J = 14.4, 7.2 Hz, 2H), 3.35 (d, J = 9.7 Hz, 3H), 3.29
(d, J = 2.0 Hz, 0.3H), 3.26 (d, J = 2.4 Hz, 0.3H), 3.03 (d, J = 14.8 Hz,
0.3H), 2.68 (d, J = 14.8 Hz, 0.3H), 2.33 (d, J = 14.0 Hz, 0.7H), 1.36 (dt, J
= 14.4, 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 177.18, 174.93, 171.91,
171.70, 168.14, 167.15, 154.99, 154.94, 146.89, 144.69, 142.90, 142.87,
137.17, 136.62, 133.72, 133.57, 133.20, 132.46, 131.54, 130.94, 130.66,
127.09, 126.35, 126.12, 124.90, 124.73, 123.72, 123.69, , 118.02, 117.91,
117.38, 116.15, 111.09, 110.03, 94.76, 93.55, 63.75, 62.91, 50.10, 49.56,
37.46, 37.44, 27.54, 27.36, 14.15, 14.08; IR: 3494.2, 3280.2, 2961.3, 1723.3,
1364.5, 1610.4, 1480.4, 1467.2, 1339.7, 1282.0, 1218.4, 1173.6, 1146.4,
1106.2, 1040.3, 977.1, 961.1, 813.5, 797.2, 764.6, 747.7, 669.0, 643.9 cm-1;
HRMS calcd. for C23H19ClNO7 [M+H]+500.0339, found:500.0339；Above data proves that purpose produces
Object synthesizes successfully.
Embodiment ten:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1j (27.3 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 38 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.8:1) by simple column and can obtain
To target product 3j (41.7 mg), white solid, mp:226-228 DEG C, yield 99%, > 20/1 dr, 96% ee.
Product 3j is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (80:20), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 17.666, t
(minor) = 15.895]; [α]D 25 = + 24.2 (c = 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.89 (s, 0.5H), 8.22 (dd, J = 8.0, 1.6 Hz, 0.5H), 8.18 (dd, J = 8.0, 1.6 Hz,
0.5H), 7.69 (s, 0.5H), 7.53 – 7.48 (m, 1H), 7.32 – 7.28 (m, 1H), 7.22 (d, J =
8.0 Hz, 0.5H), 7.17 – 7.13 (m, 1H), 7.09 (d, J = 8.4 Hz, 0.5H), 7.02 (s,
0.5H), 6.91 (d, J = 7.6 Hz, 0.5H), 6.85 (d, J = 8.0 Hz, 0.5H), 5.08 (d, J =
2.2 Hz, 0.5H), 4.35 (dt, J = 7.2, 5.0 Hz, 2H), 3.34 (d, J = 8.0 Hz, 3H), 3.29
(dd, J = 14.0, 2.4 Hz, 0.5H), 3.04 (d, J = 14.8 Hz, 0.5H), 2.66 (d, J = 14.8
Hz, 0.5H), 2.31 (d, J = 14.0 Hz, 0.5H), 2.30 (d, J = 8.8 Hz, 3H), 1.37 (dt, J
= 16.6, 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 177.59, 175.37, 171.98,
171.84, 168.48, 167.37, 155.04, 154.99, 147.87, 145.70, 141.43, 141.36,
137.05, 136.59, 134.65, 133.52, 133.38, 132.99, 130.47, 129.86, 128.74,
128.73, 128.38, 126.28, 126.03, 124.71, 124.55, 124.47, 123.74, 123.71,
118.11, 117.94, 109.39, 108.30, 94.91, 93.64, 63.66, 62.76, 50.18, 49.61,
37.59, 27.41, 27.25, 21.32, 21.23, 14.14, 14.07; IR: 3494.7, 3282.8, 2961.6,
1745.8, 1718.6, 1636.8, 1611.3, 1499.5, 1359.2, 1282.1, 1260.8, 1196.1,
1103.7, 1037.9, 977.5, 964.8, 811.7, 796.6, 760.2, 699.6, 669.8, 647.7 cm-1;
HRMS calcd. for C24H22NO7 [M+H]+436.1391, found:436.1396；Above data proves purpose product
It synthesizes successfully.
Embodiment 11:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1k (28.9 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.8:1) by simple column and can obtain
To target product 3k (44.2 mg), white solid, mp:191-193 DEG C, yield 98%, > 20/1 dr, 98% ee.
Product 3k is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (80:20), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 22.303, t
(minor) = 27.639]; [α]D 25 = + 141.6 (c = 0.50, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.95 (s, 0.5H), 8.20 – 8.16 (m, 1H), 7.55 (d, J = 2.0 Hz, 0.5H), 7.53 –
7.49 (m, 1H), 7.29 (t, J = 1.2 Hz, 1H), 7.11 (dd, J = 19.6, 8.4 Hz, 1H), 6.93
(s, 1H), 6.89 (d, J = 2.4 Hz, 0.5H), 6.84 (d, J = 18.8 Hz, 1H), 5.07 (d, J =
1.6 Hz, 0.5H), 4.34 (dq, J = 15.6, 7.2 Hz, 2H), 3.74 (d, J = 8.0 Hz, 3H),
3.33 (d, J = 7.6 Hz, 3H), 3.28 (d, J = 2.0 Hz, 0.5H), 3.04 (d, J = 14.8 Hz,
0.5H), 2.67 (d, J = 14.8 Hz, 0.5H), 2.32 (d, J = 14.0 Hz, 0.5H), 1.36 (dt, J
= 15.6, 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 177.27, 175.05, 171.92,
171.81, 168.41, 167.37, 157.49, 156.38, 155.02, 154.97, 147.62, 145.52,
137.15, 137.06, 136.99, 136.59, 136.59, 133.54, 133.42, 130.97, 129.96,
126.24, 126.02, 124.73, 124.57, 123.71, 123.69, 118.08, 117.92, 114.82,
114.58, 114.29, 110.57, 110.22, 108.92, 94.91, 93.60, 63.69 , 62.77, 55.95,
55.82, 50.51, 49.89, 37.63, 37.45, 27.47, 27.31, 14.14, 14.06; IR: 3350.6,
2963.2, 2922.7, 1748.1, 1714.7, 1652.5, 1637.1, 1611.6, 1497.2, 147.0,
1363.4, 1339.6, 1260.9, 1236.3, 1202.1, 1160.5, 1144.2, 1108.8, 1039.5,
1025.3, 977.0, 806.5, 758.1, 694.3, 679.9, 646.6 cm-1; HRMS calcd. for
C24H22NO8 [M+H]+452.1340, found: 452.1352；Above data proves that purpose product synthesizes successfully.
Embodiment 12:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1l (29.3 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.5:1) by simple column and can obtain
To target product 3l (39.1 mg), yellow solid, mp:111-113 DEG C, yield 86%, > 20/1 dr, 97% ee.
Product 3l is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (80:20), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 22.883, t
(minor) = 30.794]; [α]D 25 = + 57.2 (c = 0.65, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.58 (s, 0.3H), 8.22 (dd, J = 8.0, 1.2 Hz, 0.3H), 8.18 (dd, J = 8.0, 1.6 Hz,
0.7H), 7.82 (d, J = 8.0 Hz, 0.7H), 7.55 – 7.51 (m, 1H), 7.34 – 7.28 (m, 1H),
7.15 (d, J = 7.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 0.3H), 7.05 – 7.03 (m, 1H),
6.97 (d, J = 2.0 Hz, 0.7H), 5.19 (s, 0.7H), 4.36 (dq, J = 11.1, 5.6 Hz, 2H),
3.35 (d, J = 9.2 Hz, 3H), 3.27 (d, J = 14.4 Hz, 0.7H), 3.03 (d, J = 14.8 Hz,
0.3H), 2.67 (d, J = 14.8 Hz, 0.3H), 2.31 (d, J = 14.0 Hz, 0.7H), 1.36 (dt, J
= 11.1, 5.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 177.76, 175.49, 171.96,
171.77, 168.28, 167.21, 155.03, 154.97, 147.06, 145.02, 144.88, 137.15,
136.64, 136.18, 135.45, 133.74, 133.61, 128.85, 128.11, 127.09, 126.39,
126.13, 124.92, 124.81, 123.74, 124.67, 123.73, 123.69, 123.29, 118.03,
117.85, 110.51, 109.38, 94.80, 93.58, 63.79, 62.93, 49.84, 49.25, 37.57,
37.40, 27.56, 27.38, 14.16, 14.09; IR: 3348.8, 3277.2, 2961.0, 2923.4,
1722.4, 1365.8, 1607.2, 1468.0, 1365.6, 1281.9, 1260.5, 1188.7, 1147.4,
1103.4, 1078.4, 1025.5, 971.2, 798.4, 759.1,645.0, 621.5 cm-1; HRMS calcd. for
C23H19ClNO7 [M+H]+456.0845, found:456.0833；Above data proves that purpose product synthesizes successfully.
Embodiment 13:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1m (33.7 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.5:1) by simple column and can obtain
To target product 3m (42.9 mg), yellow solid, mp:105-107 DEG C, yield 86%, > 20/1 dr, 97% ee.
Product 3m is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (80:20), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 22.846, t
(minor) = 31.330]; [α]D 25 = + 245.2 (c = 0.25, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.57 (s, 0.3H), 8.22 (dd, J = 8.0, 1.6 Hz, 0.3H), 8.18 (dd, J = 8.0, 1.6
Hz, 0.7H), 7.76 (d, J = 8.4 Hz, 0.7H), 7.55 – 7.51 (m, 1H), 7.32 – 7.28 (m,
1.3H), 7.21 (d, J = 2.0 Hz, 0.3H), 7.19 (d, J = 1.6 Hz, 0.7H), 7.15 (d, J =
8.4 Hz, 0.7H), 7.12 (d, J = 1.6 Hz, 0.7H), 7.09 (d, J = 1.6 Hz, 0.3H), 5.13
(d, J = 2.0 Hz, 0.7H), 4.36 (dt, J = 14.4, 7.1 Hz, 2H), 3.35 (d, J = 9.3 Hz,
3H), 3.28 (dd, J = 14.4, 1.6 Hz, 0.7H), 3.02 (d, J = 14.8 Hz, 0.3H), 2.67 (d,J = 15.2 Hz, 0.3H), 2.30 (d, J = 14.0 Hz, 0.7H), 1.37 (dt, J = 14.4, 7.1 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 177.63, 175.35, 171.89, 171.72, 168.25,
167.19, 155.01, 154.96, 146.91, 145.14, 144.77, 137.16, 136.67, 133.73,
133.60, 129.17, 128.66, 127.69, 1127.61, 126.37, 126.23, 126.13, 125.12,
124.90, 124.73, 123.86, 123.70, 123.30, 118.02, 117.85, 113.27, 112.16,
94.79, 93.55, 63.80, 62.91, 49.89, 49.29, 37.49, 37.34, 27.55, 27.37, 14.15,
14.09; IR: 3396.7, 3280.6, 2961.7, 2924.1, 1723.6, 1636.6, 1602.5, 1468.6,
1365.5, 1282.9, 1260.5, 1188.9, 1149.5, 1101.7, 1025.4, 970.9, 798.9, 759.3,
707.0, 643.9, 620.5 cm-1; HRMS calcd. for C23H19BrNO7 [M+H]+ 500.0339, found:
500.0346；Above data proves that purpose product synthesizes successfully.
Embodiment 14:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1n (28.9 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.5:1) by simple column and can obtain
To target product 3n (33.4 mg), reddish Solid, mp:210-211 DEG C, yield 74%, > 20/1 dr, > 99% ee.
Product 3n is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (80:20), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 26.010]; [α]D 25
= + 186.0 (c = 0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 0.4H), 8.24 –
8.19 (m, 1H), 7.76 (d, J = 8.0 Hz, 0.5H), 7.52 (t, J = 7.6 Hz, 1H), 7.30 (dd,J = 14.4, 7.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 0.5H), 7.10 (d, J = 8.4 Hz, 1H),
6.66 – 6.59 (m, 1H), 6.56 – 6.54 (m, 1H), 4.94 (d, J = 1.8 Hz, 0.6H), 4.36
(dd, J = 14.9, 7.3 Hz, 2H), 3.86 (d, J = 7.6 Hz, 3H), 3.34 (d, J = 6.0 Hz,
3H), 3.28 (dd, J = 14.0, 2.0 Hz, 0.6H), 3.02 (d, J = 15.2 Hz, 0.4H), 2.65 (d,J = 15.2 Hz, 0.4H), 2.29 (d, J = 14.0 Hz, 0.6H), 1.38 (dd, J = 14.9, 7.3 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 178.34, 176.05, 171.99, 171.89, 168.52,
167.41, 161.64, 161.11, 155.07, 155.03, 147.89, 145.81, 145.16, 136.54,
133.43, 128.53, 126.36, 126.11, 124.75, 124.60, 124.56, 123.76, 121.88,
120.28, 118.11, 117.91, 108.28, 106.82, 97.87, 96.71, 94.98, 93.67, 63.75,
62.82, 55.88, 55.72, 49.74, 49.13, 37.77, 37.68, 27.42, 27.28, 14.18, 14.11;
IR: 3334.4, 2962.9, 2938.6, 1740.2, 1707.5, 1629.4, 1612.5, 1470.9, 1456.4,
1373.9, 1288.0, 1262.2, 1194.5, 1149.8, 1101.2, 1062.6, 969.3, 927.7, 877.8,
804.3, 758.7, 691.5, 649.3, 639.4, 617.3 cm-1; HRMS calcd. for C24H22NO8 [M+H]+
452.1340, found:452.1353；Above data proves that purpose product synthesizes successfully.
Embodiment 15:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1o (27.7 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.5:1) by simple column and can obtain
To target product 3o (43.5 mg), yellow solid, mp:190-192 DEG C, yield 99%, > 20/1 dr, 99% ee.
Product 3o is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (80:20), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 19.841, t
(minor) = 40.459]; [α]D 25 = + 132.9 (c = 0.54, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.65 (s, 0.4H), 8.21 (dd, J = 8.0, 1.2 Hz, 0.4H), 8.17 (dd, J = 8.0, 1.2
Hz, 0.6H), 7.71 (d, J = 7.2 Hz, 0.6H), 7.55 – 7.50 (m, 1H), 7.33 – 7.28 (m,
1H), 7.18 – 7.16 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 2.4 Hz,
0.4H), 7.12 – 7.07 (m, 1H), 7.02 – 6.97 (m, 1H), 5.20 (s, 0.6H), 4.35 (dq, J
= 14.6, 7.2 Hz, 3H), 3.56 (d, J = 2.8 Hz, 3H), 3.28 (dd, J = 14.4, 1.6 Hz,
0.6H), 3.03 (d, J = 14.8 Hz, 0.4H), 2.70 (d, J = 14.8 Hz, 0.4H), 2.34 (d, J =
14.0 Hz, 0.6H), 1.36 (dt, J = 14.6, 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
177.34, 175.14, 171.93, 171.75, 168.27, 167.19, 155.02, 154.97, 148.02 (d, J
= 244.8 Hz), 147.84 (d, J = 242.0 Hz), 147.11, 137.02, 136.57, 133.71,
136.57, 132.35 (d, J = 2.5 Hz), 131.41 (d, J = 2.7 Hz), 130.56 (d, J = 8.4
Hz), 130.53(d, J = 8.8 Hz), 126.33, 126.08, 125.45 (d, J = 6.5 Hz), 124.86,
124.67, 123.84 (d, J = 8.6 Hz), 123.68 (d, J = 4.2 Hz), 123.58 (d, J = 3.2
Hz), 119.65 (d, J = 3.3 Hz), 118.28 (d, J = 19.0 Hz), 118.03, 117.85, 117.47
(d, J = 18.8 Hz), 94.81, 93.54, 63.72, 62.86, 50.33 (d, J = 1.9 Hz), 49.69
(d, J = 2.1 Hz), 37.76, 37.59, 30.02 (d, J = 5.8 Hz), 29.84 (d, J = 6.2 Hz),
14.13, 14.06; IR: 3516.5, 3277.3, 2961.2, 2922.7, 1736.5, 1715.6, 1624.6,
1610.9, 1477.8, 1466.6, 1364.9, 1336.3, 1284.1, 1260.1, 1245.1, 1196.8,
1108.1, 1080.2, 1048.3, 1023.4, 988.0, 963.4, 800.7, 758.6, 702.5, 642.4,
628.9 cm-1; HRMS calcd. for C23H19FNO7 [M+H]+440.1140, found:440.1151；Above data
Prove that purpose product synthesizes successfully.
Embodiment 16:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1p (27.3 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.5:1) by simple column and can obtain
To target product 3p (43.0 mg), yellow solid, mp:191-194 DEG C, yield 99%, > 20/1 dr, > 99% ee.
Product 3p is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (80:20), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 31.735]; [α]D 25
= + 92.0 (c = 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 0.65H), 8.21
(dd, J = 8.0, 1.2 Hz, 0.65H), 8.17 (dd, J = 8.0, 1.6 Hz, 0.35H), 7.73 (d, J =
7.2 Hz, 0.35H), 7.53 – 7.49 (m, 1H), 7.29 (t, J =7.2 Hz, 1H), 7.18 – 7.12 (m,
1H), 7.10 – 7.07 (m, 0.35H), 7.05 – 7.02 (m, 1H), 6.93 (t, J = 7.6 Hz,
0.35H), 5.07 (s, 0.35H), 4.34 (dt, J = 16.0, 7.2 Hz, 2H), 3.62 (s, 3H), 3.28
(d, J = 14.0 Hz, 0.35H), 2.99 (d, J = 14.8 Hz, 0.35H), 2.66 (d, J = 3.2 Hz,
3H), 2.62 (d, J = 14.4 Hz, 0.65H), 2.30 (d, J = 14.4 Hz, 0.35H), 1.36 (dt, J
= 16.0, 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.28, 176.32, 171.95,
171.83, 168.44, 167.33, 155.06, 155.00, 147.92, 145.78, 141.50, 141.46,
137.04, 137.64, 133.93, 133.53, 133.38, 133.31, 130.50, 129.38, 126.25,
126.01, 125.51, 124.71, 124.59, 124.55, 123.70, 123.18, 121.64, 121.33,
120.03, 118.10, 117.90, 94.91, 93.63, 63.63, 62.73, 49.61, 49.04, 38.10,
37.95, 30.79, 30.75, 19.40, 19.01, 14.14.05; IR: 3503.2, 3277.8, 2960.2,
2924.9, 1736.6, 1694.9, 1667.7, 1648.6, 1634.0, 1612.0, 1466.3, 1377.1,
1361.1, 1287.1, 1260.5, 1195.2, 1145.4, 1111.1, 1071.5, 1021.2, 965.3, 909.4,
795.5, 763.3, 749.9, 699.7, 643.2, 623.9 cm-1; HRMS calcd. for C23H19FNO7 [M+H]+
436.1391, found:436.1400；Above data proves that purpose product synthesizes successfully.
Embodiment 17:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1q (28.7 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.7:1) by simple column and can obtain
To target product 3q (35.9 mg), yellow solid, mp:200-202 DEG C, yield 80%, > 20/1 dr, 98% ee.
Product 3q is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (80:20), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 21.379, t
(minor) = 19.769]; [α]D 25 = + 45.0 (c = 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.98 (s, 0.7H), 8.22 (dd, J = 8.0, 1.6 Hz, 0.7H), 8.18 (dd, J = 8.0, 1.6 Hz,
0.3H), 7.54 – 7.50 (m, 1.3H), 7.32 (d, J = 0.8 Hz, 0.2H), 7.29 (d, J = 8.0
Hz, 0.8H), 7.18 (d, J = 8.4 Hz, 0.3H), 7.14 (d, J = 8.4 Hz, 0.7H), 6.94 (s,
0.7H), 6.89 (s, 0.3H), 6.82 (s, 0.7H), 5.03 (d, J = 2.0 Hz, 0.3H), 4.35 (dq,J = 16.8, 7.2 Hz, 3H), 3.59 (s, 3H), 3.27 (dd, J = 14.0, 2.4 Hz, 1H), 2.98
(d, J = 14.8 Hz, 0.7H), 2.63 (d, J = 11.2 Hz, 0.6H), 2.62 (s, 3H), 2.29 (d, J
= 14.4 Hz, 0.4H), 2.23 (d, J = 7.2 Hz, 3H), 1.36 (dt, J = 16.8, 7.2 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 178.16, 176.23, 171.99, 171.87, 168.52, 167.41,
155.08, 155.03, 148.16, 146.01, 139.04, 139.00, 137.00, 136.59, 134.37,
133.76, 133.48, 133.35, 132.69, 130.61, 129.42, 126.26, 126.11, 126.01,
124.68, 124.53,123.74, 122.28, 120.99, 118.17, 117.99, 94.94, 93.64, 63.64,
62.73, 49.67, 49.12, 38.10, 38.06, 30.72, 20.97, 20.88, 19.23, 18.84, 14.14,
14.07; IR: 3151.5, 2961.7, 2921.9, 1757.4, 1710.4, 1660.6, 1632.5, 1612.4,
1485.3, 1468.8, 1442.9, 1371.2, 1287.2, 1260.4, 1200.4, 1139.1, 1099.0,
1077.0, 1025.7, 961.6, 870.6, 800.3, 761.7, 695.9, 648.9 cm-1; HRMS calcd. for
C25H24NO7 [M+H]+450.1547, found:450.1558；Above data proves that purpose product synthesizes successfully.
Embodiment 18:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1r (29.5 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.7:1) by simple column and can obtain
To target product 3r (42.5 mg), yellow solid, mp:113-115 DEG C, yield 96%, > 20/1 dr, 93% ee.
Product 3r is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (80:20), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 22.295, t
(minor) = 27.049]; [α]D 25 = + 98.2 (c = 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.54 (s, 0.2H), 8.20 (dd, J = 8.0, 1.2 Hz, 0.2H), 8.16 (dd, J = 8.0, 1.6 Hz,
0.8H), 7.82 (dd, J = 10.0, 8.0 Hz, 0.8H), 7.55 – 7.51 (m, 1H), 7.29 (t, J =
8.0 Hz, 1H), 7.14 (d, J = 8.4 Hz, 0.8H), 7.10 (t, J = 8.0 Hz, 0.2H), 6.90
(dd, J = 9.2, 6.0 Hz, 2H), 6.80 (dd, J = 9.6, 6.4 Hz, 0.8H), 5.51 (s, 0.8H),
4.36 (dq, J = 13.6, 6.4 Hz, 2H), 3.34 (d, J = 10.2 Hz, 3H), 3.25 (dd, J =
14.0, 1.6 Hz, 0.8H), 3.00 (d, J = 14.8 Hz, 0.2H), 2.69 (d, J = 15.2 Hz,
0.2H), 2.33 (d, J = 14.4 Hz, 0.8H), 1.36 (dt, J = 13.6, 6.4 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 17.54, 175.30, 171.96, 171.70, 168.10, 167.14, 154.98,
154.93, 151.39, (d, J = 248.2 Hz), 151.25 (d, J = 248.1 Hz), 146.83 (d, J =
241.4 Hz), 146.76, 146.71 (d, J = 244.3 Hz), 140.26 (d, J = 11.6 Hz), 137.19,
136.55, 136.55, 133.82, 133.68, 126.38 (s), 126.13, 124.99 (d, J = 2.9 Hz),
124.92 (d, J = 4.0 Hz), 124.80, 123.68, 123.62, 118.01 (d, J = 11.7 Hz),
117.95, 117.83 (d, J = 42.0 Hz), 98.90, 98.67, 94.76, 93.61, 63.73, 62.96,
50.06, 49.52, 37.53, 37.41, 27.69, 27.51, 14.12, 14.06; IR: 3279.2, 3070.6,
2961.2, 2161.1, 2031.0, 1979.4, 1626.2, 1613.7, 1506.3, 1428.2, 1391.7,
1368.7, 1283.9, 1252.0, 1185.7, 1152.3, 1096.7, 1024.9, 1007.6, 960.4, 873.5,
786.3, 758.8,688.3, 645.2, 618.4 cm-1; HRMS calcd. for C23H18F2NO7 [M+H]+
458.1046, found:458.1048；Above data proves that purpose product synthesizes successfully.
Embodiment 19:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1s (24.5 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2a (24.3 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.5:1) by simple column and can obtain
To target product 3s (35.8 mg), reddish Solid, mp:205-207 DEG C, yield 98%, > 20/1 dr, 98% ee.
Product 3s is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (70:30), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 20.279, t
(minor) = 32.183]; [α]D 25 = + 71.5 (c = 0.52, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.88 (s, 0.55H), 8.22 (dd, J = 8.0, 1.2 Hz, 0.6H), 8.19 (dd, J = 8.4, 1.6 Hz,
0.4H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.53 – 7.49 (m, 1H), 7.44 (td, J = 7.6,
1.2 Hz, 0.6H), 7.38 (dt, J = 8.0, 1.2 Hz, 0.45H), 7.33 – 7.29 (m, 1H), 7.20
(dd, J = 12.0, 6.4 Hz, 1H), 7.15 – 7.12 (m, 0.55H), 7.09 – 7.06 (m, 1H), 7.04
(d, J = 8.0 Hz, 0.6H), 6.97 (d, J = 7.6 Hz, 0.4H), 5.01 (d, J = 2.0 Hz,
0.45H), 3.91 (s, 3H), 3.37 (d, J = 10.8 Hz, 3H), 3.30 (dd, J = 14.0, 2.4 Hz,
0.45H), 3.07 (d, J = 14.8 Hz, 0.55H), 2.69 (d, J = 15.2 Hz, 1H), 2.33 (d, J =
14.0 Hz, 0.45H); 13C NMR (101 MHz, CDCl3) δ 177.71, 175.38, 171.94, 171.84,
168.87, 167.82, 155.06, 155.00, 147.64, 145.48, 143.86, 143.00, 137.03,
136.56, 133.62, 133.47, 130.27, 129.82, 129.57, 128.71, 127.64, 126.33,
126.08, 124.81, 124.79, 124.63, 123.75, 123.72, 123.69, 123.43, 118.08,
117.88, 109.69, 108.62, 94.97, 93.72, 54.07, 53.52, 50.15, 49.49, 37.64,
37.48, 27.43, 27.25; IR: 3316.0, 2961.4, 2922.7, 1752.1, 1725.6, 1637.8,
1610.0, 1468.3, 1432.1, 1366.3, 1351.3, 1280.3, 1270.1, 1260.5, 1219.0,
1188.0, 1146.9, 1124.0, 1070.1, 979.7, 966.8, 945.6, 811.9, 801.2, 760.7,
746.8, 660.7, 640.5, 616.8 cm-1; HRMS calcd. for C30H24NO9 [M+H]+ 408.1078,
found:408.1084；Above data proves that purpose product synthesizes successfully.
Embodiment 20:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1a (25.9 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2b (27.0 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.5:1) by simple column and can obtain
To target product 3t (37.4 mg), reddish Solid, mp:170-173 DEG C, yield 88%, > 20/1 dr, 93% ee.
Product 3t is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (70:30), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 12.258, t
(minor) = 22.094]; [α]D 25 = + 80.2 (c = 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.81 (s, 0.5H), 7.88 (dd, J = 7.6, 0.8 Hz, 0.5H), 7.84 (dd, J = 8.0, 2.8 Hz,
0.5H), 7.80 (dd, J = 8.0, 2.8 Hz, 0.5H), 7.45 (td, J = 7.6, 1.2 Hz, 0.5H),
7.38 (td, J = 7.6, 1.2 Hz, 0.5H), 7.24 – 7.21 (m, 1H), 7.20 – 7.13 (m, 1H),
7.04 (d, J = 7.6 Hz, 0.5H), 6.97 (d, J = 7.6 Hz, 0.5H), 5.17 (s, 0.5H), 4.35
(tq, J =14.4, 7.2 Hz, 2H), 3.36 (d, J = 9.6 Hz, 3H), 3.28 (d, J = 14.0 Hz,
0.5H), 3.05 (d, J = 15.2 Hz, 0.5H), 2.68 (d, J = 15.2 Hz, 1H), 2.33 (d, J =
14.4 Hz, 0.5H), 1.37 (dt, J = 14.4, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
177.58, 175.35, 171.24, 171.11, 168.33, 167.22, 159.24 (J = 245.3 Hz), 159.17
(J = 245.1 Hz), 151.33, 151.25, 148.05, 145.86, 143.82, 143.73, 136.77,
136.35, 130.33, 129.73, 129.63, 128.63, 127.70, 124.86, 124.84 (J = 6.3 Hz),
124.75 (J = 4.6 Hz), 123.78, 123.48, 120.06 (J = 14.6 Hz), 121.75 (J = 14.5
Hz), 120.26 (J = 8.1 Hz), 120.06 (J = 8.0 Hz), 110.94 (J = 27.1 Hz), 10.70 (J
= 26.9 Hz), 109.72, 108.67, 100.09, 94.97, 93.70, 63.75, 62.86, 50.16, 49.57,
37.64, 37.48, 27.44, 27.27, 14.14, 14.08; IR: 3430.1, 2987.5, 1755.6, 1711.6,
1610.3, 1483.3, 1469.4, 1369.7, 1259.8, 1186.1, 1163.3, 1100.0, 1022.9,
994.4, 852.4, 831.0, 799.5, 757.7, 691.1, 642.2 cm-1; HRMS calcd. for
C23H19FNO7 [M+H]+440.1140, found:440.1143；Above data proves that purpose product synthesizes successfully.
Embodiment 21:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1a (25.9 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2c (35.8 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.5:1) by simple column and can obtain
To target product 3u (37.4 mg), reddish Solid, mp:136-138 DEG C, yield 65%, > 20/1 dr, 92% ee.
Product 3u is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (70:30), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 15.695, t
(minor) = 31.396]; [α]D 25 = + 355.0 (c = 0.61, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.82 (s, 0.5H), 8.32 (d, J = 2.4 Hz, 0.5H), 8.27 (d, J = 2.0 Hz, 0.5H),
7.88 (d, J = 7.6 Hz, 0.5H), 7.58 (dt, J = 8.8, 2.4 Hz, 1H), 7.47 – 7.36 (m,
1H), 7.24 – 7.18 (m, 1H), 7.10 – 7.04 (m, 1H), 7.03 (d, J = 4.8 Hz, 0.5H),
6.99 – 6.96 (m, 1H), 5.22 (s, 0.5H), 4.35 (dq, J = 7.2, 4.4 Hz, 3H), 3.36 (d,J = 10.0 Hz, 3H), 3.27 (d, J = 14.0 Hz, 0.5H), 3.05 (d, J = 15.2 Hz, 0.5H),
2.68 (d, J = 15.2 Hz, 0.5H), 2.34 (d, J = 14.4 Hz, 0.5H), 1.36 (dt, J = 14.6,
7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 177.52, 175.27, 170.73, 170.59,
168.29, 167.18, 153.81, 153.75, 148.11,145.88, 143.81, 143.71, 137.27,
136.81, 136.58, 136.42, 130.36, 129.65, 128.70, 128.53, 128.46, 127.73,
125.00, 124.98, 124.88, 123.80, 123.51, 120.07, 119.87, 118.24, 118.06,
109.73, 108.67, 95.01, 93.73, 63.75, 62.88, 50.15, 49.57, 37.66, 37.46,
27.45, 27.28, 14.15, 14.08; IR: 3331.6, 2926.6, 1741.1, 1723.1, 1626.8,
1606.3, 1467.2, 1418.4, 1352.2, 1242.0, 1227.8, 1098.5, 1074.8, 987.5, 963.1,
835.7, 754.6, 660.7 cm-1; HRMS calcd. for C23H19BrNO7 [M+H]+ 500.0339, found:
500.0337；Above data proves that purpose product synthesizes successfully.
Embodiment 22:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1a (25.9 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2d (26.4 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.4:1) by simple column and can obtain
To target product 3v (42.2 mg), yellow solid, mp:106-108 DEG C, yield 97%, > 20/1 dr, 98% ee.
Product 3v is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (70:30), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 19.812, t
(minor) = 41.106]; [α]D 25 = + 52.8 (c = 0.60, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.81 (s, 0.5H), 7.97 (dd, J = 18.8, 1.2 Hz, 0.5H), 7.88 (d, J = 7.6 Hz,
0.5H), 7.43 (td, J = 8.0, 1.2 Hz, 0.5H), 7.36 (td, J = 8.0, 1.2 Hz, 0.5H),
7.32 – 7.29 (m, 1H), 7.21 – 7.14 (m, 1H), 7.07 (dd, J = 7.6, 0.8 Hz, 0.5H),
7.02 (d, J = 8.4 Hz, 0.5H), 6.97 (d, J = 3.2 Hz, 0.5H), 6.95 (d, J = 2.4 Hz,
0.5H), 5.15 (s, 0.5H), 4.39 (dq, J = 16.8, 7.2 Hz, 2H), 3.35 (d, J = 8.4 Hz,
3H), 3.28 (d, J = 14.0 Hz, 0.5H), 3.04 (d, J = 14.8 Hz, 0.5H), 2.66 (d, J =
14.8 Hz, 0.5H), 2.36 (d, J = 5.6 Hz, 3H), 2.32 (d, J = 14.0 Hz, 0.5H), 1.36
(dt, J = 16.8, 7.2 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 177.74, 175.52, 172.02,
171.88, 168.45, 167.35, 153.37, 153.30, 147.52, 145.35, 143.84, 143.75,
136.96, 136.51, 134.90, 134.77, 134.74, 134.52, 130.17, 129.93, 129.47,
128.85, 127.68, 125.43, 125.18, 124.73, 123.72, 123.37, 117.79, 117.60,
109.62, 108.56, 94.85, 93.63, 63.62, 62.76, 50.15, 49.56, 37.62, 37.51,
27.38, 27.21, 20.86, 14.13, 14.06; IR: 3283.4, 2936.0, 1717.8, 1611.6,
1488.4, 1471.8, 1368.8, 1278.3, 1191.7, 1161.4, 1129.7, 1031.4, 961.7, 692.2,
662.7 cm-1; HRMS calcd. for C24H22NO7 [M+H]+436.1391, found:436.1381；Above data card
The Product formation success of improving eyesight.
Embodiment 23:
Quinine thiocarbamide (3.0 mg, 0.005 mmol) and 1a (25.9 mg, 0.1 mmol) are sequentially added in reaction flask,
1 mL methylene chloride is added, is reacted 20 minutes under subzero 20 degrees celsius, is added 2e (28.8 mg, 0.15 mmol),
The reaction was continued 40 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.4:1) by simple column and can obtain
To target product 3w (44.6 mg), yellow solid, mp:218-220 DEG C, yield 99%, > 20/1 dr, 99% ee.
Sequentially added in reaction flask quinine thiocarbamide (90.65 mg, 0.005 mmol) and 1a (906.5 mg, 3.5
Mmol), 5 mL methylene chloride are added, are reacted 20 minutes under subzero 20 degrees celsius, 2e (1.51g 5.25 is added
Mmol), the reaction was continued 41 hours, and reaction system chromatographs (eluant, eluent is petroleum ether: ethyl acetate=1.4:1) by simple column
It can be obtained target product 3w (1.76 g), yellow solid, mp:218-220 DEG C, yield 92%, > 20/1 dr, 99%
ee。
Product 3w is analyzed, it is as a result as follows: to measure [Daicel Chiralpak IA, hexane/ with HPLCi-
PrOH (70:30), flow rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 16.022, t
(minor) = 23.611]; [α]D 25 = + 43.6 (c = 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.80 (s, 0.5H), 8.11 (d, J = 9.2 Hz, 0.5H), 8.05 (d, J = 8.8 Hz, 0.5H), 7.92
(d, J = 7.2 Hz, 0.5H), 7.45 (t, J = 8.4 Hz, 0.5H), 7.39 (t, J = 7.2 Hz,
0.5H), 7.24 – 7.17 (m, 1H), 7.11 – 7.04 (m, 1H), 6.98 (d, J = 8.0 Hz, 0.5H),
6.85 (ddd, J = 15.6, 8.8, 2.0 Hz, 1H), 6.49 (d, J = 2.4 Hz, 0.5H), 6.44 (d, J
= 2.0 Hz, 0.5H), 5.41 (s, 0.5H), 4.36 (q, J = 7.2 Hz, 2H), 3.77 (s, 3H), 3.37
(d, J = 8.0 Hz, 3H), 3.25 (d, J = 14.0 Hz, 0.5H), 3.04 (d, J = 14.8 Hz,
0.5H), 2.67 (d, J = 14.8 Hz, 0.5H), 2.34 (d, J = 14.0 Hz, 0.5H), 1.37 (dt, J
= 16.9, 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 177.74, 175.61, 171.50,
171.27, 168.44, 167.36, 164.14, 164.03, , 156.86, 156.77, 147.09, 144.90,
143.83, 143.73, 137.00, 136.50, 130.16, 129.94, 129.44, 128.86, 127.77,
127.58, 127.27, 124.75, 123.76, 123.40, 117.60, 117.49, 114.60, 114.49,
109.65, 108.65, 99.92, 94.86, 93.72, 63.52, 62.76, 55.89, 55.85, 50.07 (,
49.53, 37.76, 37.60, 27.40, 27.24, 14.12, 14.05; IR: 3287.6, 2962.2, 1733.3,
1609.8, 1446.5, 1422.9, 1368.4, 1265.9, 1167.8, 1153.7, 1100.4, 1028.0,
973.5, 833.4, 748.5, 694.1, 635.9 cm-1; HRMS calcd. for C24H22NO8 [M+H]+
452.1340, found:452.1343；Above data proves that purpose product synthesizes successfully.
Claims (5)
1. chiral quinine thiocarbamide is in catalysis isatin derivative β, γ-unsaturation alpha-keto ester compound and 3- hydroxyl -4 hydrogen-chromene -4-
Ketone compound is reacted in halogenated hydrocarbon solvent generates chiral spiro hydroxyindole-chromene -one simultaneously -3,4- dihydro-pyran
Close the application of object, it is characterised in that: with molar amount, the dosage of the chirality quinine thiocarbamide is the derivative beta, gamma-unsaturation of isatin
The 2-10% of alpha-keto ester compound；
The derivative β of the isatin, γ-unsaturation alpha-keto ester compound chemical structural formula are, wherein R1Choosing
From: one of methyl, methoxy, benzyl, allyl, benzyloxycarbonyl group；R2It is selected from: hydrogen, 5- fluorine, 5- chlorine, 5- bromine, 5- first
One of base, 5- methoxyl group, 6- chlorine, 6- bromine, 6- methoxyl group, 7- fluorine, 7- methyl, 5,6- difluoro, 5,7- dimethyl；R3Choosing
From: one of methyl, ethyl；
- 4 hydrogen of the 3- hydroxyl-chromene -4- ketone compound chemical structural formula is, wherein R is hydrogen, 6-
One of fluorine, 6- bromine, 6- methyl, 7- methoxyl group；
The structural formula of the chiral spiro hydroxyindole-chromene -one simultaneously -3,4- dihydro-pyran compound are as follows:
；
The chemical structural formula of the chirality quinine thiocarbamide are as follows:
。
2. application according to claim 1, it is characterised in that: the halogenated hydrocarbon solvent is methylene chloride.
3. application according to claim 1, it is characterised in that: with molar amount, -4 hydrogen of the 3- hydroxyl-chromene -4- ketone
Dosage be the derivative β of isatin, 1-2 times of γ-unsaturation alpha-keto ester compound.
4. application according to claim 1, it is characterised in that: the reaction time is 36-41 hours；The reaction temperature
Degree is -30 DEG C to room temperature.
5. application according to claim 1, it is characterised in that: the derivative β of catalyst, isatin is sequentially added into reactor,
- 4 hydrogen of 3- hydroxyl-chromene -4- ketone is added after stirring 15-35 minutes in γ-unsaturation alpha-keto ester compound, halogenated hydrocarbon solvent
Compound is reacted, and after reaction, chiral spiro hydroxyindole-chromene -one can be obtained by column chromatography in crude product
And -3,4- dihydro-pyran compound.
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