CN113004321B - Method for desymmetrizing 3-substituted cyclobutanone, cyclobutene compound and application thereof - Google Patents

Method for desymmetrizing 3-substituted cyclobutanone, cyclobutene compound and application thereof Download PDF

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CN113004321B
CN113004321B CN202110265408.1A CN202110265408A CN113004321B CN 113004321 B CN113004321 B CN 113004321B CN 202110265408 A CN202110265408 A CN 202110265408A CN 113004321 B CN113004321 B CN 113004321B
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陆平
钟昶煦
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Zhuhai Fudan Innovation Research Institute
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Abstract

The invention discloses a method for desymmetrizing 3-substituted cyclobutanone, cyclobutene compounds and application thereof, wherein the method takes 3-substituted cyclobutanone as a starting material, and enantioselectively deprotonates under the action of chiral lithium amide to obtain a corresponding lithium enol intermediate; and then adopting phosphorochloridite as an electrophilic reagent to capture the lithium enol intermediate to obtain the cyclobutene compound (I), wherein the reaction process is as follows:

Description

Method for desymmetrizing 3-substituted cyclobutanone, cyclobutene compound and application thereof
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for desymmetrizing 3-substituted cyclobutanone, a cyclobutene compound and application thereof.
Background
Chiral Lithium Amide (CLAs) are widely used in asymmetric chemistry as chiral bases, chiral nucleophiles and chiral ligands. The field of enantioselective deprotonation of chiral lithium amide on cyclic ketones to give the corresponding chiral silyl enol ethers has been well studied by predecessors. Among them, the quenching capture mode of the active species, the addition of metal salts and the co-solvent effect are considered to be crucial for the construction of high enantioselectivity of the product.
The cyclobutane skeleton compound has higher ring tension and unique conformation, shows unique chemical reactivity and is an important synthetic building block in organic chemistry and pharmaceutical chemistry. Enantioselective desymmetrization of cyclobutanone compounds is an effective way to confer molecular diversity to them, however, to date, such reactions on four-membered ring backbones have not been studied much. Chiral lithium amide is utilized to carry out enantioselective deprotonation on cyclobutanone compounds in documents to construct corresponding cyclobutenol silyl ethers, but the compounds have poor stability under acidic conditions and are difficult to directly obtain alkenyl derivatives through coupling reaction.
Therefore, the technical problems that the 3-substituted cyclobutanone desymmetrization is difficult to directly convert and the cyclobutenylphosphate compound is constructed with high enantioselectivity need to be solved.
Disclosure of Invention
The invention aims to provide a method for 3-substituted cyclobutanone desymmetrization mediated by chiral lithium amide, which takes the 3-substituted cyclobutanone as a starting material, performs enantioselective deprotonation under the action of the chiral lithium amide, and captures an enol intermediate by taking chlorophosphate as an electrophilic reagent to obtain a cyclobutene compound with high enantioselectivity.
In order to achieve the aim, the invention provides a method for desymmetrizing 3-substituted cyclobutanone, which takes the 3-substituted cyclobutanone as a starting material and carries out enantioselective deprotonation under the action of chiral lithium amide to obtain a corresponding lithium enol intermediate; and then adopting phosphorochloridite as an electrophilic reagent to capture the lithium enol intermediate to obtain the cyclobutene compound (I) with high enantioselectivity, wherein the reaction process is as follows:
Figure BDA0002971461280000021
wherein R is selected from any one of phenyl, aryl, heterocyclic radical and substituted or unsubstituted alkyl; the aryl is phenyl with an electron-donating or electron-withdrawing substituent at the ortho, meta and para positions, and the heterocyclic radical is thienyl, furyl, naphthyl or pyridyl or any one of thienyl, furyl, naphthyl or pyridyl containing the electron-donating or electron-withdrawing substituent; the hydrocarbon group is any one of chain and/or cyclic alkane, olefin, alkane containing oxygen and/or nitrogen heteroatom, and alkane containing ester group and/or amide functional group.
Alternatively, R is a C1-C20 hydrocarbon group (preferably, a C1-C10 hydrocarbon group, more preferably, a C1-C5 hydrocarbon group), a C1-C20 hydrocarbon group having a functional group at the terminal (preferably, a C1-C10 hydrocarbon group, more preferably, a C1-C5 hydrocarbon group), a phenyl group, an aryl group or a heterocyclic group; wherein, in the C1-C20 hydrocarbyl with a functional group at the tail end, the functional group is selected from any one or a combination of several of carbon-carbon double bond, carbon-carbon triple bond, ester group, hydroxyl, acyl, acyloxy, acylamino and halogen; the aryl is phenyl with electron withdrawing or electron donating substitution at the ortho, meta and para positions, the heterocyclic group is thienyl, furyl, naphthyl or pyridyl, or thiophene, furan, naphthalene or pyridine containing the electron withdrawing or electron donating substituent, the electron withdrawing substituent is selected from any one or the combination of a plurality of halogen, nitro, ester group, carboxyl, acyl, amido and cyano, and the electron donating substituent is selected from any one or the combination of a plurality of alkyl, alkenyl, phenyl and alkoxy. The alkyl of C1-C5 is methyl, ethyl, n-propyl (and isomers), n-butyl (and isomers) and n-pentyl (and isomers).
Further, R may be any one selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, phenethyl, 4-chlorobutyl, 3-methylbutyl, 3-cyanopropyl, allyl, phenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, 3, 5-dimethylphenyl, m-methoxyphenyl, p-methoxyphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl, p-esterylphenyl, 1-naphthyl, 2-naphthyl, 4-indolyl, 3-thienyl, etc.
Optionally, the chiral lithium amide is formed by chiral amine under the action of n-butyl lithium.
Optionally, the alkyl lithium is any one or a combination of any two or more of methyl lithium, ethyl lithium, propyl lithium, isopropyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, amyl lithium, hexyl lithium, cyclohexyl lithium, tert-octyl lithium, n-eicosyl lithium, phenyl lithium, methylphenyl lithium, butylphenyl lithium, naphthyl lithium and butylcyclohexyl lithium.
Optionally, the chiral amine is selected from one or more of CA-1-CA-4 and enantiomers ent-CA-1-ent-CA-4 thereof;
Figure BDA0002971461280000031
wherein Ar is phenyl, aryl or heterocyclic radical, and the aryl is phenyl substituted by alkyl or alkoxy at ortho, meta and para positions; said heterocyclyl is thiophene, furan or pyridine, thiophene substituted by hydrocarbyl or hydrocarbyloxy, furan substituted by hydrocarbyl or hydrocarbyloxy, or pyridine substituted by hydrocarbyl or hydrocarbyloxy, R 1 、R 2 Each independently selected from any one of C1-C20 alkyl, C1-C20 alkyl with a functional group at the tail end, phenyl, aryl or heterocyclic radical; wherein, in the C1-C20 hydrocarbon group with the functional group at the tail end, the functional group is selected from carbon-carbon double bonds, carbon-carbon triple bonds, ester groups, hydroxyl, acyl, acyloxy, acylamino and halogen.
Optionally, the chiral amine is selected from CA-4 and/or its enantiomer ent-CA-4, and the structure of CA-4 is shown as follows:
Figure BDA0002971461280000032
wherein Ar is 1-naphthyl, 2-naphthyl or phenyl; r is 1 Is methyl or ethyl; r 2 Is methyl or ethyl.
The chiral amine is selected from one or more of CA-4a, CA-4b, CA-4c and enantiomers thereof, ent-CA-4a, ent-CA-4b and ent-CA-4 c; wherein the structures of the CA-4a, the CA-4b and the CA-4c are shown as follows:
Figure BDA0002971461280000033
alternatively, the molar ratio of the 3-substituted cyclobutanone, the alkyl lithium, the chiral amine and the chlorophosphate is 1.0: (1.0-10): (1.0-10): (1.0-10); and/or the reaction temperature is-90-60 ℃; and/or the dosage of the organic solvent is 1.0-10.0mL/mmol, based on the dosage of the 3-substituted cyclobutanone.
Optionally, the chlorophosphate is any one or more of dimethyl chlorophosphate, diethyl chlorophosphate, di-n-propyl chlorophosphate, diisopropyl chlorophosphate, di-n-butyl chlorophosphate, diisobutyl chlorophosphate, di-tert-butyl chlorophosphate, diphenyl chlorophosphate and diphenyl chlorophosphate; and/or the organic solvent is selected from any one or more of N-methyl pyrrolidone, 1, 4-dioxane, tetrahydrofuran, methyl tetrahydrofuran, acetonitrile, diethyl ether, methyl tert-butyl ether, chlorobenzene, toluene, benzotrifluoride, dichloromethane, 1-dichloroethane, 1, 2-dichloroethane, chloroform and acetic acid.
The invention also provides a cyclobutene compound (I), which has the following structural general formula:
Figure BDA0002971461280000041
wherein R is C1-C20 alkyl, C1-C20 alkyl with a functional group at the tail end, phenyl, aryl or heterocyclic radical; wherein, in the C1-C20 alkyl with the functional group at the tail end, the functional group is selected from any one or more of carbon-carbon double bond, carbon-carbon triple bond, ester group, hydroxyl, acyl, acyloxy, acylamino and halogen; the aryl is phenyl with electron withdrawing or electron donating substitution in the ortho, meta and para positions, the heterocyclic group is thienyl, furyl, naphthyl or pyridyl, or thiophene, furan, naphthalene or pyridine with electron withdrawing or electron donating substitution groups, the electron withdrawing substitution groups comprise halogen, nitro, ester groups, carboxyl, acyl, amido and cyano, and the electron donating substitution groups comprise alkyl, alkenyl, phenyl and alkoxy.
The invention also provides application of the cyclobutene compound (I), and the cyclobutene compound (I) is used for preparing the skeleton compound of the original illite natural product through Negishi coupling and D-A cycloaddition reaction.
The invention develops a chiral lithium amide mediated 3-substituted cyclobutanone desymmetrization reaction, and the generated chiral lithium enolate intermediate is captured by the chlorophosphate to obtain the chiral alkenyl phosphate compound with high stability. The compound has the characteristics of being capable of being separated by column chromatography and high stability under mild acidic conditions; meanwhile, the chiral cyclobutene derivative is used as an important reaction block, and can realize direct conversion of the phosphate compound through coupling reaction catalyzed by transition metal nickel to synthesize the chiral cyclobutene derivative.
The beneficial effects of the invention include: the method is simple to operate; the raw materials and the reagents are simple and easy to obtain, and the preparation is convenient; the substrate universality is wide; the functional group compatibility is good; the reaction has high enantioselectivity (up to 93% ee); the product is easy to separate and purify, etc. The cyclobutene compound with high optical activity can be further coupled by Negishi to obtain 1, 3-diene, and a D-A ring addition reaction is used for obtaining a skeleton of a natural product of the original illioualkane on the basis, so that a basis is provided for related researches, and the cyclobutene compound with high optical activity is an important breakthrough on the existing synthetic method.
Detailed Description
The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited. In all examples, mol means mol, THF means tetrahydrofuran, ee means percent enantiomeric excess; the specific structural formula and corresponding numbering of the related chiral amine are as follows:
Figure BDA0002971461280000051
the method for desymmetrizing the 3-substituted cyclobutanone specifically comprises the following steps:
(1) adding hydrochloride of chiral amine into a dry reaction tube, plugging the reaction tube with a rubber plug, connecting a vacuum pump, replacing argon under the argon atmosphere, and adding an organic solvent with a certain volume; cooling the reaction tube in a cooling bath at the temperature of between 90 ℃ below zero and 0 ℃, dropwise adding alkyl lithium, heating to room temperature, stirring for 15 to 60 minutes, placing the reaction tube in a low-temperature bath preset at the temperature of between 90 ℃ below zero, dropwise adding an organic solvent containing 3-substituted cyclobutanone, continuing the dropwise adding process for 10 to 60 minutes, and keeping the temperature for 30 to 90 minutes after the dropwise adding is finished. Dropwise adding electrophilic reagent chlorophosphate at the same temperature, wherein the dropwise adding process lasts for 10-60 minutes, keeping for 30-90 minutes after the dropwise adding is finished, and then heating to-78 ℃ for reaction for 0.5-12 hours; preferably, the dosage of the organic solvent is 1.0-10.0mL/mmol, preferably 5.5mL/mmol, based on the dosage of the 3-substituted cyclobutanone;
(2) After the reaction in the step (1) is completed, adding a mixed solvent of tetrahydrofuran and methanol into a reaction tube, then adding a certain volume of dilute hydrochloric acid solution, taking the reaction tube out of a low-temperature bath, recovering the room temperature, then adding a certain volume of ethyl acetate into the reaction tube, adding a small amount of water, extracting a water phase by using ethyl acetate, concentrating, and performing fast column chromatography to obtain a cyclobutene compound with high optical activity; wherein, in the mixed solvent of tetrahydrofuran and methanol, the using amount of methanol is 1.0 to 100 equivalent ratio (compared with the using amount of 3-substituted cyclobutanone), the ratio of tetrahydrofuran to methanol is 100:1 to 1:100, the using amount of ethyl acetate is 1.0 to 100mL/mmol, preferably 5.5mL/mmol, based on the using amount of 3-substituted cyclobutanone.
The present invention will be described in further detail with reference to specific examples.
Example 1
Figure BDA0002971461280000061
To a dry Schlenk reaction tube was added sequentially the hydrochloride salt of a chiral amine CA-4 c. HCl (0.127g,0.440mmol), THF (1.2 mL). After cooling to-78 deg.C, n-butyllithium (2.28M,0.39mL,0.880mmol) was added dropwise. After stirring for five minutes, the cooling bath was removed and stirring was continued for 15 minutes after returning to room temperature until the reaction system became clear. Then the reaction tube is placed in a cooling bath at the temperature of-90 ℃, A solution of 3-substituted cyclobutanone 1a (58.5mg,0.400mmol) in tetrahydrofuran (0.5mL,0.3mL wash, 0.2mL wash) was added dropwise over a period of 30 minutes. After the addition, the reaction was held for 30 minutes, and electrophile ClP (O) (OPh) was added dropwise over a period of 10 minutes 2 (0.42mL,0.540g,2.00mmol) and after maintaining the reaction for 30 minutes, the cold bath temperature was raised to-78 ℃. After continuing the reaction for about 3.5 hours, the reaction was quenched with a mixed solvent of tetrahydrofuran and methanol (3:1, 0.4mL), and 2M hydrochloric acid was added. After returning to room temperature, the organic phase was extracted with ethyl acetate, the combined organic phases were washed successively with saturated sodium bicarbonate solution and saturated brine, dried over sodium sulfate, concentrated and flash column chromatographed (eluent: petroleum ether/ethyl acetate 10/1) to give chiral cyclobutenophosphate 2a (0.115g, 76%) as a colorless oil; 94% ee (HPLC conditions: OJ-H column, cyclohexane (cyclohexane)/i-PrOH 9/1,1.0mL/min, λ 210nm, t R (Main) 14.2min, t R (secondary) 16.2 min;
Figure BDA0002971461280000062
(c 0.81,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.46–7.36(m,4H),7.36–7.22(m,11H),5.47(s,1H),3.75–3.67(m,1H),3.33(dd,J＝13.3,4.5Hz,1H),2.64(d,J＝13.3Hz,1H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.25(d,J＝7.3Hz),142.06(d,J＝9.8Hz),142.06,129.88,128.36,126.60,126.54,125.68,120.02(d,J＝4.8Hz),120.01(d,J＝5.0Hz),120.00,113.81(d,J＝7.8Hz),42.90(d,J＝5.6Hz),37.76； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.16; IR (Net, cm) -1 ):3062,3028,2970,2931,1645,1630,1589,1300,1180,1161；HRMS-ESI(m/z):[M+H] + calcd.for C 22 H 19 O 4 P, 378.1015; obtained (found), 378.1009.
Example 2
Figure BDA0002971461280000071
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted cyclobutanone 1b (64.0mg,0.400mmol),hydrochloride of chiral amine CA-4c HCl (0.127g,0.440mmol), n-butyllithium (2.25M,0.39mL,0.880mmol) and electrophile ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 10/1) afforded chiral cyclobutenophosphate 2b (0.155g, 85%) as a colorless oil; 93% ee (HPLC conditions: OD-H column, cyclohexane/i-PrOH. RTM. 95/5,1.0mL/min, λ. RTM. 210nm, t R (Main) 10.5min, t R (minor) ═ 11.8 min);
Figure BDA0002971461280000072
(c 0.50,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.41-7.32(m,4H),7.30-7.19(m,7H),7.15-7.02(m,3H),5.40(s,1H),3.64(d,J＝3.4Hz,1H),3.27(ddd,J＝13.2,4.5,1.5Hz,1H),2.57(d,J＝13.2Hz,1H),2.32(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.29(d,J＝7.3Hz),141.98(d,J＝9.9Hz),139.04,136.19,129.89,129.06,126.46,125.68,120.05(d,J＝4.9Hz),120.04(d,J＝5.0Hz),113.97(d,J＝7.8Hz),42.99(d,J＝5.6Hz),37.47,21.02； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.19; IR (Net, cm) -1 ):3070,3044,3014,2973,2941,2990,2837,1786,1716,1645,1631,1590,1488,1310,1219,1812,1611,1025,1009；HRMS-EI(m/z):[M] + calcd.for C 23 H 21 O 4 P, 392.1172; obtained as 392.1167.
Example 3
Figure BDA0002971461280000081
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted cyclobutanone 1c (47.4mg,0.272mmol), chiral amine hydrochloride CA-4c HCl (96.0g,0.330mmol), n-butyllithium (2.25M,0.29mL,0.660mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.31mL,0.400g,1.50 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 95/5) afforded chiral cyclobutenophosphate 2c (97.4mg, 88%) as a colorless oil; 93% ee (HPLC conditions: OJ-H column, cyclohexane/i-PrOH. RTM. 9/1,1.0mL/min, λ. RTM.210 nm, t R (Main) ═ 7.0min, t R (secondary) ═8.2min)；
Figure BDA0002971461280000083
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.45-7.30(m,4H),7.30-7.17(m,6H),6.85(s,3H),5.41(s,1H),3.63-3.59(m,1H),3.26(ddd,J＝13.2,4.5,1.5Hz,1H),2.59(d,J＝13.2Hz,1H),2.28(s,6H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.27(d,J＝7.3Hz),142.00,141.87(d,J＝9.9Hz),137.91,129.87,128.27,125.67,124.34,120.02(d,J＝4.9Hz),120.01(d,J＝4.9Hz),113.89(d,J＝7.8Hz),42.82(d,J＝5.6Hz),37.64,21.22； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.20; IR (Net, cm) -1 ):3072,3043,3013,2973,2943,2910,2835,1786,1716,1646,1631,1590,1489,1313,1302,1219,1184,1161,1051,1026,1010；HRMS-ESI(m/z):[M+H] + calcd.for C 24 H 23 O 4 P, 407.1407; obtained as 407.1406.
Example 4
Figure BDA0002971461280000082
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted Cyclobutanone 1d (76.0mg,0.421mmol), hydrochloride of chiral amine CA-4 c. HCl (0.127g,0.440mmol), n-butyllithium (2.25M,0.39mL,0.880mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 95/5) afforded chiral cyclobutenophosphate 2d (0.132g, 80%) as a colorless oil; 93% ee (HPLC conditions: OD-H column, cyclohexane/i-PrOH. RTM. 95/5,1.0mL/min, λ. RTM. 210nm, t R (Main) 18.0min, t R (minor) 26.4 min;
Figure BDA0002971461280000093
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.37(t,J＝7.9Hz,4H),7.32-7.19(m,8H),7.17-7.11(d,J＝8.4Hz,2H),5.38(s,1H),3.64(d,J＝3.7Hz,1H),3.28(ddd,J＝13.3,4.5,1.4Hz,1H),2.54(d,J＝13.3Hz,1H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.23(d,J＝7.2Hz),142.35(d,J＝9.7Hz),140.61,132.27,129.92,128.49,127.93,125.75,120.02(d,J＝5.0Hz),120.01(d,J＝5.1Hz),113.48(d,J＝7.9Hz),42.95(d,J＝5.7Hz),37.20； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.21; IR (Net, cm) -1 ):3070,2974,2941,2899,2839,1786,1716,1646,1631,1590,1489,1409,1312,1300,1181,1161,1090,1026,1010；HRMS-ESI(m/z):[M+H] + calcd.for C 22 H 18 ClO 4 P, 413.0704; obtained as 413.0700.
Example 5
Figure BDA0002971461280000091
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted cyclobutanone 1e (95.0mg,0.400mmol), hydrochloride of chiral amine CA-4c HCl (0.127g,0.440mmol), n-butyllithium (2.28M,0.39mL,0.880mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 5/1) afforded chiral cyclobutenophosphate 2e (0.136g, 73%) as a colorless oil; 88% ee (HPLC conditions: OZ-H column, cyclohexane/i-PrOH. RTM. 9/1,1.0mL/min, λ. RTM.210 nm, t R (Main) 43.8min, t R (minor) ═ 51.6 min);
Figure BDA0002971461280000092
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.37(t,J＝7.8Hz,4H),7.29-7.20(m,6H),6.47(s,2H),5.42(s,1H),3.82(s,3H),3.81(s,6H),3.63(s,1H),3.32-3.23(m,1H),2.61(d,J＝13.2Hz,1H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):153.26,150.26(d,J＝7.2Hz),142.35(d,J＝9.8Hz),137.94,136.70,129.91,125.74,119.99(d,J＝4.9Hz),119.98(d,J＝5.0Hz)113.69(d,J＝7.7Hz),103.37,60.82,56.04,43.09(d,J＝5.5Hz),38.13； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.16; IR (Net, cm) -1 ):3077,2972,2940,2911,2840,1783,1645,1631,1588,1506,1488,1457,1418,1342,1313,1301,1234,1183,1162,1123,1025,1009；HRMS-ESI(m/z):[M+H] + calcd.for C 25 H 26 O 7 P, 469.1411; obtained as 469.1403.
Example 6
Figure BDA0002971461280000101
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted Cyclobutanone 1f (98.5mg,0.400mmol), hydrochloride of chiral amine CA-4c HCl (0.127g,0.440mmol), n-butyllithium (2.25M,0.39mL,0.880mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 5/1) afforded chiral cyclobutenophosphate 2f (0.159g, 83%) as a colorless oil; 90% ee (HPLC conditions: OD-H column, cyclohexane/i-PrOH. RTM. 9/1,1.0mL/min, λ. RTM. 210nm, t R (Main) 20.5min, t R (minor) ═ 23.9 min);
Figure BDA0002971461280000102
(c 0.81,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.90(d,J＝8.3Hz,2H),7.37(t,J＝7.8Hz,4H),7.30-7.20(m,8H),5.42(s,1H),3.76-3.67(m,1H),3.31(ddd,J＝13.3,4.5,1.5Hz,1H),2.57(d,J＝13.3Hz,1H),1.59(s,9H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):165.62,150.22(d,J＝7.1Hz),150.18,146.96,142.35(d,J＝9.7Hz),130.47,129.91,129.57,126.39,125.75,120.01(d,J＝5.0Hz),120.00(d,J＝4.9Hz),113.40(d,J＝7.8Hz),80.83,,42.82(d,J＝5.8Hz),37.69,28.17； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.21; IR (Net, cm) -1 ):3070,3005,2976,2932,1708,1645,1631,1590,1488,1456,1415,1392,1368,1309,1291,1220,1182,1161,1115,1102,1082,1025,1009；HRMS-ESI(m/z):[M+H] + calcd.for C 27 H 27 O 6 P, 479.1618; obtained as 479.1613.
Example 7
Figure BDA0002971461280000111
The procedure is as in example 1. The raw materials and the dosage are as follows: 1g (78.5mg,0.400mmol) of 3-substituted cyclobutanone, hydrochloride of chiral amine CA-4 c. HCl (0.127g,0.440mmol), n-butyllithium (2.25M,0.39mL,0.880mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 10/1) afforded 2g (0.134g, 78%) of chiral cyclobutenophosphate as a colorless oil; 92% ee (HPLC conditions: OJ-H column, cyclohexane/i-PrOH 3/2,1.0mL/min, λ 210nm, t R (Main) 20.8min, t R (minor) ═ 26.3 min);
Figure BDA0002971461280000112
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.82-7.73(m,3H),7.66(s,1H),7.48-7.19(m,13H),5.51(s,1H),3.87-3.81(m,1H),3.35(ddd,J＝13.3,4.5,1.5Hz,1H),2.67(d,J＝13.3Hz,1H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.28(d,J＝7.2Hz),142.22(d,J＝9.8Hz),139.59,133.39,132.46,129.91,128.11,127.59,127.51,126.05,125.72,125.44,124.99,124.92,120.05(d,J＝5.0Hz),113.81(d,J＝7.8Hz),42.82(d,J＝5.7Hz),37.95； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.15; IR (clean, cm- 1 ):3094,3054,3015,2978,2928,1652,1625,1587,1485,1456,1308,1292,1220,1184,1163,1124,1071,1024,1009；HRMS-ESI(m/z):[M+H]+calcd.for C 26 H 22 O 4 P, 429.1250; obtained as 429.1246.
Example 8
Figure BDA0002971461280000121
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted cyclobutanone 1h (81.0mg,0.413mmol), chiral amine hydrochloride CA-4c HCl (0.127g,0.440mmol), n-butyllithium (2.25M,0.39mL,0.880mmol), and the electrophilic reagent ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 10/1) afforded chiral cyclobutenophosphate 2h (0.153g, 86%) as a colorless oil; 93% ee (HPLC conditions: OD-H column, cyclohexane)alkane/i-PrOH 9/1,1.0mL/min, λ 210nm, t R (Main) 12.1min, t R (secondary) ═ 14.1 min);
Figure BDA0002971461280000122
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):8.00-7.93(m,1H),7.89-7.85(m,1H),7.74(d,J＝8.1Hz,1H),7.55-7.46(m,2H),7.44-7.17(m,12H),5.67(s,1H),4.34(d,J＝3.6Hz,1H),3.53(ddd,J＝13.0,4.6,1.5Hz,1H),2.62(d,J＝13.0Hz,1H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.27(d,J＝7.4Hz),150.25(d,J＝7.2Hz),141.92(d,J＝9.8Hz),138.11,133.52,131.59,129.89,128.77,127.17,126.01,125.70,125.65,125.37,123.31,123.10,120.07(d,J＝4.9Hz),120.05(d,J＝5.0Hz),111.80(d,J＝7.8Hz),42.08(d,J＝5.8Hz),34.93； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.13; IR (Net, cm) -1 ):3062,3064,2974,2942,2900,2834,1786,1716,1647,1634,1590,1488,1457,1396,1301,1219,1184,1161,1072,1025,1009；HRMS-ESI(m/z):[M+H] + calcd.for C 26 H 22 O 4 P, 429.1250; obtained as 429.1247.
Example 9
Figure BDA0002971461280000123
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted cyclobutanone 1i (0.136g,0.400mmol), hydrochloride of chiral amine CA-4 c. HCl (0.127g,0.440mmol), n-butyllithium (2.28M,0.39mL,0.880mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 3/1) gave chiral cyclobutenophosphate 2i (91.0mg, 40%) as a solid; 93% ee (HPLC conditions: AD-H column, cyclohexane/i-PrOH 3/2,1.0mL/min, λ 210nm, t R (Main) 34.8min, t R (minor) ═ 38.3 min);
Figure BDA0002971461280000131
(c1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.86(d,J＝8.3Hz,1H),7.78-7.73(m,2H),7.55(d,J＝3.7Hz,1H),7.39-7.31(m,4H),7.28-7.18(m,9H),7.07(d,J＝7.4Hz,1H),6.72(dd,J＝3.7,0.6Hz,1H),5.49(s,1H),3.97-3.93(m,1H),3.34(ddd,J＝13.2,4.5,1.5Hz,1H),2.66(d,J＝13.2Hz,1H),2.33(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.21(d,J＝7.3Hz),144.91,142.01(d,J＝9.8Hz),135.25,134.83,134.68,129.89,129.86,129.16,126.82,125.99,125.72,124.53,120.53,120.01(d,J＝4.9Hz),120.00(d,J＝4.9Hz),112.95(d,J＝7.8Hz),111.95,106.79,41.89(d,J＝5.7Hz),35.57,21.53； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.15; IR (clean, cm- 1 ):3061,2043,2977,2938,1786,1730,1646,1631,1590,1527,1487,1421,1372,1301,1282,1179,1161,1130,1089,1025,1009；HRMS-ESI(m/z):[M+H]+calcd.for C 31 H 27 NO 6 PS, 572.1291; obtained as 572.1290.
Example 10
Figure BDA0002971461280000132
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted Cyclobutanone 1j (50.5mg,0.400mmol), hydrochloride of chiral amine CA-4 c. HCl (0.127g,0.440mmol), n-butyllithium (2.25M,0.39mL,0.880mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 98/2) afforded chiral cyclobutenophosphate 2j (0.103g, 72%) as a colorless oil; 87% ee (HPLC conditions: AD-H column, cyclohexane/i-PrOH 95/5,1.0mL/min, λ 210nm, t R (minor) 20.0min, t R (main) ═ 23.5 min);
Figure BDA0002971461280000141
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.39-7.32(m,4H),7.27-7.18(m,6H),5.18(s,1H),2.68(ddd,J＝13.4,4.4,1.6Hz,1H),2.45(d,J＝13.4Hz,1H),2.34(s,1H),0.87(s,9H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.32(d,J＝7.3Hz),141.50(d,J＝10.2Hz),129.83,125.57,120.02(d,J＝5.0Hz),112.82(d,J＝7.7Hz),44.76,34.31(d,J＝5.6Hz),31.21,26.43； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.12; IR (Net, cm) -1 ):3072,2957,2867,1642,1627,1590,1489,1365,1313,1301,1285,1221,1180,1161,1071,1025,1009；HRMS-EI(m/z):[M] + calcd.for C 20 H 23 O 4 P, 358.1328; obtained as 358.1328.
Example 11
Figure BDA0002971461280000142
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted cyclobutanone 1k (89.6mg,0.410mmol), hydrochloride of chiral amine CA-4c HCl (0.127g,0.440mmol), n-butyllithium (2.25M,0.39mL,0.880mmol), and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 98/2) afforded chiral cyclobutenophosphate 2k (0.133g, 74%) as a colorless oil; 90% ee (HPLC conditions: OD-H column, cyclohexane/i-PrOH. RTM. 9/1,1.0mL/min, λ. RTM. 210nm, t R (Main) 14.0min, t R (secondary) 24.0 min;
Figure BDA0002971461280000143
Figure BDA0002971461280000144
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.31-7.20(m,8H),7.20-7.08(m,7H),5.15(s,1H),4.40(s,1H),2.79-2.67(m,2H),2.62-2.56(m,1H),1.16(d,J＝2.0Hz,6H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.26(d,J＝7.3Hz),142.06(d,J＝9.9Hz),139.80,129.85,128.24,127.09,125.62,120.03(d,J＝5.0Hz),112.02(d,J＝7.8Hz),75.47,64.11,42.93,34.88(d,J＝5.7Hz),22.75,22.11； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.17; IR (Net, cm) -1 ):3062,2973,2901,2833,1786,1711,1631,1590,1489,1313,1220,1185,1160,1054,1026,1009；HRMS-ESI(m/z):[M+H] + calcd.for C 26 H 28 O 5 P, 451.1671; obtained (451.1)671。
Example 12
Figure BDA0002971461280000151
The procedure is as in example 1. The raw materials and the dosage are as follows: 1l (93.0mg,0.400mmol) of 3-substituted cyclobutanone, hydrochloride of chiral amine CA-4 c. HCl (0.127g,0.440mmol), n-butyllithium (2.25M,0.39mL,0.880mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 10/1) afforded chiral cyclobutenophosphate 2l (0.153g, 83%) as a colorless oil; 81% ee (HPLC conditions: OJ-H column, cyclohexane/i-PrOH. RTM. 9/1,1.0mL/min, λ. RTM.210 nm, t R (Main) 14.5min, t R (secondary) 16.8 min;
Figure BDA0002971461280000152
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.38-7.29(m,4H),7.25-7.17(m,6H),6.83(s,2H),5.22(s,1H),4.49(s,2H),3.47(ddd,J＝16.6,9.3,6.9Hz,2H),2.90(ddd,J＝13.5,4.2,1.4Hz,1H),2.79-2.69(m,1H),2.40(d,J＝13.5Hz,1H),2.33(s,6H),2.24(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.22(d,J＝7.3Hz),141.99(d,J＝9.9Hz),137.69,137.54,131.11,129.83,128.92,125.63,125.62,120.02(d,J＝4.9Hz),112.38(d,J＝7.9Hz),73.42,67.13,36.96(d,J＝5.8Hz),33.57,20.92,19.50； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.25; IR (Net, cm) -1 ):3069,2974,2940,2901,2483,1791,1716,1642,1629,1590,1489,1313,1302,1220,1185,1161,1083,1053,1026,1009；HRMS-ESI(m/z):[M+H] + calcd.for C 27 H 29 O 5 P, 465.1825; obtained as 465.1825.
Example 13
Figure BDA0002971461280000153
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted cyclobutanone1M (76.1mg,0.400mmol), the hydrochloride of the chiral amine CA-4c HCl (0.127g,0.440mmol), n-butyllithium (2.44M,0.36mL,0.880mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 10/1) afforded chiral cyclobutenophosphate 2m (0.136g, 81%) as a colorless oil; 83% ee (HPLC conditions: OJ-H column, cyclohexane/i-PrOH. RTM. 95/5,1.0mL/min, λ. RTM. 210nm, t R (minor) 27.4min, t R (main) ═ 29.2 min);
Figure BDA0002971461280000163
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.38-7.26(m,9H),7.27-7.17(m,6H),5.24(s,1H),4.52(s,2H),3.47(ddd,J＝26.0,9.4,7.0Hz,2H),2.95-2.87(m,1H),2.82-2.73(m,1H),2.43(d,J＝13.5Hz,1H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.24(d,J＝7.3Hz),142.02(d,J＝9.7Hz),138.29,129.85,128.38,127.65,127.62,125.65,120.04(d,J＝5.0Hz),112.30(d,J＝7.9Hz),73.40,73.18,36.86(d,J＝5.8Hz),33.54； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.17; IR (Net, cm) -1 ):3062,3029,2978,2936,2865,2848,1783,1723,1702,1641,1626,1589,1488,1455,1311,1301,1219,1184,1160,1093,1025,1009；HRMS-ESI(m/z):[M+H] + calcd.for C 24 H 24 O 5 P, 423.1356; obtained as 423.1350.
Example 14
Figure BDA0002971461280000161
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted Cyclobutanone 1n (81.8mg,0.400mmol), chiral amine hydrochloride CA-4c HCl (0.127g,0.440mmol), n-butyllithium (2.49M,0.35mL,0.880mmol), and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 6/1) afforded chiral cyclobutenophosphate 2n (0.110g, 63%) as a colorless oil; 81% ee (HPLC conditions: OJ-H column, cyclohexane/i-PrOH. RTM. 9/1,1.0mL/min, λ. RTM.210 nm, t R (minor) 39.2min,t R (main) ═ 43.9 min);
Figure BDA0002971461280000162
(c0.58,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):8.03(d,J＝7.6Hz,1H),7.55(t,J＝7.4Hz,1H),7.41(t,J＝7.7Hz,1H),7.35(t,J＝7.8Hz,2H),7.27-7.17(m,3H),5.27(s,1H),4.42-4.27(m,1H),3.05-2.86(m,1H),2.59(d,J＝13.4Hz,1H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):166.44,150.19(d,J＝7.2Hz),142.26(d,J＝9.8Hz),132.96,130.10,129.88,129.57,128.34,125.72,120.01(d,J＝4.9Hz),111.47(d,J＝7.9Hz),67.18,36.54(d,J＝5.9Hz),32.61； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.25; IR (Net, cm) -1 ):3060,2982,2949,2882,2829,1716,1629,1588,1488,1452,1313,1269,1183,1160,1110,1070,1025,1009；HRMS-ESI(m/z):[M+H] + calcd.for C 24 H 22 O 6 P, 437.1149; obtained as 437.1141.
Example 15
Figure BDA0002971461280000171
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted cyclobutanone 1o (0.264,0.800mmol), hydrochloride of chiral amine CA-4c HCl (0.255g,0.880mmol), n-butyllithium (2.49M,0.71mL,1.76mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.84mL,1.08g,4.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 6/1) afforded chiral cyclobutenophosphate 2o (0.369g, 82%) as a colorless oil; 90% ee (HPLC conditions: IA column, cyclohexane/i-PrOH 9/1,1.0mL/min, λ 210nm, t R (Main) ═ 87.9min, t R (minor) ═ 94.9 min);
Figure BDA0002971461280000172
(c0.50,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.46(d,J＝8.1Hz,2H),7.35(t,J＝7.2Hz,4H),7.31-7.27(m,3H),7.25(d,J＝4.0Hz,2H),7.21(t,J＝8.7Hz,6H),7.05-6.99(m,2H),4.99(s,1H),3.59(d,J＝7.1Hz,2H),2.79(dd,J＝13.6,3.7Hz,1H),2.59(d,J＝4.5Hz,1H),2.42(s,3H),2.38(d,J＝13.7Hz,1H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.15(d,J＝7.3Hz),143.41,141.85(d,J＝9.9Hz),139.44,135.23,129.86,129.39,129.06,128.97,128.07,127.66,125.67,119.99(d,J＝4.9Hz),112.21(d,J＝7.9Hz),54.58,37.13(d,J＝5.9Hz),33.12,21.52； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.32; IR (Net, cm) -1 ):3060,2839,2796,1794,1639,1626,1588,1489,1349,1337,1302,1278,1222,1187,118178,1163,1027,1009；HRMS-ESI(m/z):[M+H] + calcd.for C 30 H 28 NO 6 PS, 562.1448; obtained as 562.1445.
Example 16
Figure BDA0002971461280000181
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted cyclobutanone 1p (79.0mg,0.400mmol), the hydrochloride of chiral amine CA-4c HCl (0.127g,0.440mmol), n-butyllithium (2.25M,0.39mL,0.88mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/acetone 7/1) gave chiral cyclobutenophosphate 2p (86.8mg, 51%) as a colorless oil; 70% ee (HPLC conditions: IA column, cyclohexane/i-PrOH 97/3,1.0mL/min, λ 210nm, t R (minor) ═ 53.7min, t R (main) 57.7 min;
Figure BDA0002971461280000182
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.44-7.30(m,4H),7.30-7.16(m,6H),5.47(s,1H),3.83-3.70(m,1H),3.34-3.21(m,1H),3.17(d,J＝12.8Hz,1H),2.64(d,J＝12.8Hz,1H),1.45(s,3H),1.40(t,J＝6.1Hz,6H),1.22-1.14(dd,J＝6.3,2.7Hz,6H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):170.19,150.14(d,J＝7.5Hz),150.10(d,J＝7.5Hz),142.18(d,J＝9.5Hz),129.82,125.67,125.66,120.06(d,J＝4.9Hz),120.05(d,J＝4.9Hz),110.63(d,J＝8.3Hz),48.11,45.68,37.29,36.83(d,J＝5.7Hz),20.81(d,J＝5.5Hz),20.46(d,J＝5.8Hz)； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.31; IR (clean, cm- 1 ):3096,3068,2999,2966,2932,2873,1632,1589,1488,1440,1371,1342,1313,1301,1269,1216,1282,1160,1315,1072,1025,1009；HRMS-EI(m/z):[M]+calcd.for C 23 H 28 NO 5 P, 429.1700; obtained as 429.1700.
Example 17
Figure BDA0002971461280000191
The procedure is as in example 1. The raw materials and the dosage are as follows: 1q (51.3mg,0.400mmol) of 3-substituted cyclobutanone, hydrochloride of chiral amine CA-4 c. HCl (0.127g,0.440mmol), n-butyllithium (2.25M,0.39mL,0.88mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/acetone 5/1) afforded chiral cyclobutenophosphate 2p (0.118g, 82%) as a colorless oil; 47% ee (HPLC conditions: IC column, cyclohexane/i-PrOH 9/1,1.0mL/min, λ 210nm, t R (minor) ═ 33.0min, t R (main) ═ 37.2 min);
Figure BDA0002971461280000192
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.40(7.40-7.33,4H),7.29-7.19(m,6H),5.25(s,1H),3.70(s,3H),3.34-3.29(m,1H),3.11-2.92(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):173.17,150.14(d,J＝7.4Hz),150.12(d,J＝7.4Hz),150.11,150.08,143.58(d,J＝9.5Hz),129.91,125.80,120.05(d,J＝4.9Hz),109.98(d,J＝8.1Hz),51.99,37.13(d,J＝6.2Hz),36.33； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.46; IR (Net, cm) -1 ):3075,2952,2844,1735,1648,1634,1590,1488,1457,1436,1340,1302,1222,1183,1161,1072,1026,1010；HRMS-ESI(m/z):[M+H] + calcd.for C 18 H 18 O 6 P, 361.0836; obtained as 361.0831.
Example 18
Figure BDA0002971461280000193
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted Cyclobutanone 1r (84.7mg,0.400mmol), chiral amine hydrochloride CA-4c HCl (0.127g,0.440mmol), n-butyllithium (2.49M,0.35mL,0.88mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/acetone 7/1) afforded chiral cyclobutenophosphate 2r (0.160g, 90%) as a colorless oil; 17% ee (HPLC conditions: OZ-H column, cyclohexane/i-PrOH. RTM. 9/1,1.0mL/min, λ. RTM.210 nm, t R (minor) 14.9min, t R (main) ═ 32.2 min);
Figure BDA0002971461280000201
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.40-7.30(m,4H),7.30-7.15(m,6H),5.47(s,1H),3.85-3.68(m,1H),3.33-3.21(m,1H),3.17(d,J＝12.8Hz,1H),2.64(dd,J＝12.8,1.1Hz,1H),1.44(d,J＝8.1Hz,3H),1.40(t,J＝6.2Hz,6H),1.21-1.13(m,6H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):172.64,150.11(d,J＝7.4Hz),150.06(d,J＝7.3Hz),141.24(d,J＝9.0Hz),129.79,125.64,125.63,120.02(d,J＝4.9Hz),119.99(d,J＝4.8Hz),116.63(d,J＝8.2Hz),48.50,45.89,44.44,44.23(d,J＝5.3Hz),22.82,20.46,20.43,20.27,20.23； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.24; IR (Net, cm) -1 ):3064,2979,2921,1659,1628,1587,1488,1345,1329,1290,1266,1215,1185,1166,1085,1070,1037,1027,1009；HRMS-EI(m/z):[M] + calcd.for C 24 H 30 NO 5 P, 443.1856; obtained as 443.1858.
Example 19
Figure BDA0002971461280000202
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted cyclobutanone 1s (135.8mg,0.400mmol), hydrochloride of chiral amine CA-4 c. HCl (0.127g,0.440mmol), n-butyllithium (2.25M,0.39mL,0.88mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.42mL,0.540g,2.00 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 10/1) afforded chiral cyclobutenophosphate 2s (0.133g, 78%) as a colorless oil; 10% ee (HPLC conditions: OJ-H column, cyclohexane/i-PrOH. RTM. 9/1,1.0mL/min, λ. RTM.210 nm, t R (minor) ═ 11.6min, t R (main) ═ 21.5 min);
Figure BDA0002971461280000203
(c 0.50,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.35(t,J＝7.9Hz,4H),7.30-7.18(m,10H),5.55(s,1H),2.95-2.76(m,2H),1.53(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.23(d,J＝7.4Hz),150.21(d,J＝7.2Hz),144.66,141.86(d,J＝9.8Hz),131.85,129.88,128.23,127.33,125.72,125.71,120.03(d,J＝4.9Hz),117.38(d,J＝7.6Hz),48.60(d,J＝5.6Hz),41.60,26.87； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 18.12; IR (Net, cm) -1 ):3062,2973,2892,2834,1781,1722,1648,1633,1590,1488,1312,1301,1286,1206,1184,1161,1088,1073,1026,1010；HRMS-ESI(m/z):[M+H] + calcd.for C 23 H 20 ClO 4 P, 427.0860; obtained as 427.0858.
Example 20
Figure BDA0002971461280000211
To a dry Schlenk reaction tube were added, in order, cyclobutenophosphate 2a (37.8mg,0.100mmol) and toluene (1.0 mL). Heating the reaction tube to 80 ℃ for reaction for 12 hours, cooling to room temperature, concentrating, and performing flash column chromatography (eluent: petroleum ether/ethyl acetate 5/1) to obtain ring-opened product, namely, phosphate 3a (32.7mg, 87%) as a light yellow oily substance; 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.41-7.19(m,15H),6.66(d,J＝15.8Hz,1H),6.54(dd,J＝15.8,2.6Hz,1H),5.25(t,J＝2.2Hz,1H),4.95(t,J＝2.5Hz,1H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):151.34(d,J＝8.1Hz),150.51(d,J＝7.5Hz),135.74,131.13,129.85,128.63,128.37,126.90,125.62(d,J＝1.1Hz),121.84(d,J＝6.9Hz),120.20(d,J＝4.9Hz),102.18(d,J＝3.5Hz)； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 17.93; IR (Net, cm) -1 ):3062,3026,2246,1948,1817,1750,1639,1589,1488,1449,1298,1274,1214,1184,1161,1072,1009；HRMS-ESI(m/z):[M+H] + calcd.for C 22 H 20 O 4 P, 379.1094; obtained as 379.1091.
Example 21
Figure BDA0002971461280000212
To a dry Schlenk reaction tube were added, in order, 2m (42.2mg,0.100mmol) of cyclobutenophosphate and toluene (1.0 mL). Heating the reaction tube to 140 deg.C for 20 hr, cooling to room temperature, concentrating, and performing flash column chromatography (eluent: petroleum ether/ethyl acetate 10/1) to obtain ring-opened product phosphate 3m (23.8mg, 56%) as colorless oil; 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.42-7.15(m,15H),6.22-6.12(m,1H),5.99(dt,J＝15.5,5.1Hz,1H),5.17(s,1H),4.84(t,J＝2.2Hz,1H),4.50(s,2H),4.09-3.99(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ(ppm):150.71(d,J＝8.1Hz),150.46(d,J＝7.4Hz),137.99,129.82,129.35,128.41,127.70,127.66,125.56(d,J＝1.1Hz),124.89(d,J＝6.8Hz),120.15(d,J＝4.9Hz),101.79,72.38,69.22； 31 P NMR(162MHz,CDCl 3 ) Delta (ppm): 17.88; IR (Net, cm) -1 ):3063,3030,2850,2790,1955,1809,1725,1662,1610,1589,1488,1455,1360,1300,1271,1211,1185,1162,1115,1071,1009；HRMS-EI(m/z):[M] + calcd.for C 24 H 24 O 5 P, 423.1356; obtained as 423.1354.
Example 22
Figure BDA0002971461280000221
NiCl was added sequentially to a dry Schlenk reaction tube 2 (dmpe) (9.9mg, 35.5. mu. mol) and a 2M (0.300g,0.71mmol) solution of chiral cyclobutenophosphate in ether (4mL,3mL wash) were added with an olefinic zinc reagent (0.51M,2.0mL,1.07mmol) at 0 ℃. After stirring for three hours at room temperature,adding saturated ammonium chloride solution into the system to quench the reaction, adding a small amount of water for dilution, extracting the water phase by using diethyl ether, washing the combined organic phase by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating, and performing flash column chromatography (eluent: petroleum ether/ethyl acetate 98/2) to obtain conjugated diene 4a (0.134g, 88%) as colorless oily matter;
Figure BDA0002971461280000222
(c 0.71,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.35(d,J＝4.4Hz,4H),7.31-7.27(m,1H),6.00(s,1H),4.89(d,J＝12.4Hz,2H),4.54(s,2H),3.65-3.36(m,2H),2.97(dd,J＝11.9,6.3Hz,1H),2.73(dd,J＝13.0,4.5Hz,1H),2.23(dd,J＝13.0,1.6Hz,1H),1.82(s,3H)； 13 C NMR(101MHz,CDCl 3 ) δ (ppm) 148.69,138.95,138.57,129.35,128.35,127.66,127.51,112.19,74.08,73.12,37.77,31.98, 17.59; IR (Net, cm) -1 ):3086,3064,3031,2943,2917,2851,1583,1496,1453,1435,1375,1361,1141,1094,1028；HRMS-EI(m/z):[M] + calcd.for C 15 H 18 O, 214.1352; obtained as 214.1357.
A toluene solution (7ml) of conjugated diene 4a (0.134g,0.624mmol) and N-methylmaleimide (0.138g,1.24mmol) were successively added to a dried Schlenk reaction tube, and the reaction tube was left to react at 85 ℃ for 48 hours. After the reaction system was cooled to room temperature, it was concentrated and flash column chromatographed (eluent: dichloromethane, petroleum ether/ethyl acetate 3/1) to give cycloaddition product 5a (0.195g, 97%) as a colorless oil;
Figure BDA0002971461280000231
(c 0.50,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.39-7.27(m,5H),4.56(q,J＝12.0Hz,2H),3.59(ddd,J＝15.2,9.7,4.9Hz,2H),3.18(dd,J＝11.1,8.6Hz,1H),3.10-2.98(m,1H),2.97(s,3H),2.96-2.91(m,1H),2.64-2.38(m,4H),2.17-2.05(m,1H),1.58(s,3H)； 13 C NMR(101MHz,CDCl 3 ) δ (ppm) 180.04,178.04,138.63,131.29,128.30,127.57,127.45,122.17,72.84,72.54,41.93,40.66,39.75,37.93,29.82,27.03,24.86, 17.76; IR (Net, cm) -1 ):2972,2942,2901,2846,1773,1694,1592,1492,1432,1382,1314,1282,1189,1163,1063,1075,1052,1027；HRMS-ESI(m/z):[M+H] + calcd.for C 20 H 24 O 3 N, 326.1751; obtained as 326.1751.
Example 23
Figure BDA0002971461280000232
The procedure was as in example 22. The raw materials and the dosage are as follows: NiCl 2 (dmpe) (2.8mg, 10.0. mu. mol), cyclobutenophosphate 2k (0.103g,0.229mmol), diethyl ether (2mL), and an olefinic zinc reagent (0.51M,0.67mL,0.334 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 98/2) afforded conjugated diene 4b (47.5mg, 86%) as a colorless oil;
Figure BDA0002971461280000233
(c 0.50,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.38-7.29(m,4H),7.26-7.21(m,6H),5.98(s,1H),4.90(d,J＝13.4Hz,2H),4.55-4.47(m,2H),2.99(d,J＝4.2Hz,1H),2.60(dd,J＝12.9,4.7Hz,1H),2.44(dd,J＝12.9,2.0Hz,1H),1.84(s,3H),1.25(d,J＝2.7Hz,6H)； 13 C NMR(101MHz,CDCl 3 ) δ (ppm) 148.47,140.08,138.84,129.32,128.22,127.19,127.02,111.98,76.21,64.20,46.91,30.19,22.97,22.32, 17.69; IR (Net, cm) -1 ):3081,3055,3034,2972,2919,2887,1582,1453,1382,1363,1266,1235,1145,1085,1061,1028；HRMS-ESI(m/z):[M+H] + calcd.for C 17 H 23 O 3 243.1743; obtained as 243.1740.
The procedure was as in example 22. The raw materials and the dosage are as follows: conjugated diene 4b (47.5g,0.196mmol), toluene (2ml) and N-methylmaleimide (48.0mg,0.430 mmol). Flash column chromatography (eluent: dichloromethane, petroleum ether/ethyl acetate 5/1) afforded cycloaddition product 5b (46.5mg, 66%) as a colorless oil;
Figure BDA0002971461280000241
(c 1.04,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.38-7.30(m,4H),7.28-7.22(m,1H),4.50(dd,J＝16.0,12.0Hz,2H),3.23-3.14(m,1H),3.11(t,J＝9.5Hz,1H),3.07-3.02(m,1H),2.97(s,3H),2.79-2.70(m,1H),2.59-2.37(m,3H),2.17-2.07(m,1H),1.57(s,3H),1.35(s,3H),1.21(s,3H)； 13 C NMR(101MHz,CDCl 3 ) Delta (ppm) 180.21,178.19,140.30,131.32,128.16,126.96,126.91,122.13,74.66,63.49,47.28,42.18,41.33,37.82,27.70,26.60,24.94,23.03,22.53, 17.69; IR (clean, cm- 1 ):3088,3062,3030,2968,2929,2908,2868,2852,2728,1772,1696,1497,1434,1383,1364,1319,1283,1243,1212,1163,1132,1089,1059,1027；HRMS-ESI(m/z):[M+H]+calcd.for C 22 H 28 NO 3 354.2064; obtained as 354.2064.
Example 24
Figure BDA0002971461280000242
The procedure was as in example 22. The raw materials and the dosage are as follows: NiCl 2 (dmpe) (3.5mg, 12.5. mu. mol), cyclobutenophosphate 2p (0.125g,0.250mmol), diethyl ether (3mL), olefin zinc reagent (0.51M,0.73mL,0.325 mmol). Flash column chromatography (eluent: petroleum ether/ethyl acetate 5/1) afforded conjugated diene 4c (72.0mg, 91%) as a colorless oil;
Figure BDA0002971461280000243
(c 0.82,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.50-7.46(m,2H),7.32-7.28(m,3H),7.24(d,J＝8.5Hz,2H),7.07-7.02(m,2H),5.70(s,1H),4.84(s,2H),3.63(dd,J＝7.3,1.4Hz,2H),2.80-2.68(m,1H),2.57(dd,J＝13.0,4.5Hz,1H),2.42(s,3H),2.17(dd,J＝13.1,1.7Hz,1H),1.74(s,3H)； 13 C NMR(101MHz,CDCl 3 ) δ (ppm) 148.30,143.23,139.60,138.67,135.48,129.34,129.07,129.00,128.93,127.92,127.70,112.55,54.76,36.98,32.25,21.53, 17.52; IR (clean, cm- 1 ):3064,3034,2981,2943,2900,2822,1581,1487,1347,1163,1090,1061,1043；HRMS-EI(m/z):[M]+calcd.for C 21 H 23 NO 2 S, 353.1444; obtained as 353.1440.
The procedure was as in example 22. The raw materials and the dosage are as follows: conjugated dienes4c (72.0mg,0.204mmol), toluene (5ml) and N-methylmaleimide (44.0mg,0.396 mmol). Flash column chromatography (eluent: dichloromethane, petroleum ether/ethyl acetate 2/1) afforded cycloaddition product 5c (86.6mg, 93%) as a colorless oil;
Figure BDA0002971461280000251
(c 1.0,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.40-7.35(m,2H),7.26-7.16(m,6H),7.03-6.98(m,2H),3.63(ddd,J＝18.3,12.9,7.3Hz,2H),3.05-2.95(m,1H),2.94-2.87(m,1H),2.79-2.71(m,1H),2.69(s,3H),2.42-2.33(m,5H),2.31-2.20(m,1H),2.09-1.88(m,2H),1.46(s,3H)； 13 C NMR(101MHz,CDCl 3 ) Delta (ppm) 179.73,177.76,143.35,138.94,134.82,130.13,129.35,128.76,128.63,127.75,127.71,122.12,54.00,41.70,41.64,40.36,37.02,31.37,26.71,24.62,21.51, 17.82; IR (Net, cm) -1 ):3061,3045,2974,2943,2900,2840,1774,1696,1594,1492,1432,1381,1345,1305,1188,1161,1091,1050,1026；HRMS-ESI(m/z):[M+H] + calcd.for C 26 H 29 N 2 O 4 465.1843; obtained as 465.1842.
Example 25
Figure BDA0002971461280000252
NiCl was added sequentially to a dry Schlenk reaction tube 2 (dmpe) (1.3mg, 4.50. mu. mol) and chiral cyclobutenophosphate 2a (34.2mg, 90.0. mu. mol) in ether (0.3mL,0.2mL wash) and olefinic zinc reagent (0.52M,0.26mL,0.135mmol) was added at 0 ℃. After stirring at room temperature for two hours, a solution of 4-phenyl-1, 2, 4-triazole-3, 5-dione (47.3mg,0.270mmol) in dichloromethane (0.3mL,0.2mL washing) was added to the system, after overnight reaction, a saturated ammonium chloride solution was added to quench the reaction, after dilution with a small amount of water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and flash column chromatography (eluent: petroleum ether/ethyl acetate: 3/1) gave cycloaddition product 5d (16.2mg, 52%) as a white solid;
Figure BDA0002971461280000253
(c 0.59,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.56(d,J＝7.6Hz,2H),7.53-7.48(m,2H),7.48-7.42(m,2H),7.38-7.32(m,3H),7.26-7.22(m,1H),4.70-4.61(m,1H),4.37(d,J＝15.8Hz,1H),3.95(d,J＝15.8Hz,1H),3.71(dd,J＝15.9,8.7Hz,1H),3.32-3.21(m,1H),3.06-2.95(m,1H),1.82(s,3H)； 13 C NMR(101MHz,CDCl 3 ) δ (ppm) 152.99,151.03,140.58,131.10,129.09,128.41,128.05,127.06,126.87,125.50,124.07,118.12,62.51,46.56,44.72,34.92, 14.66; IR (Net, cm) -1 ):3077,3061,3031,2970,2935,2893,2868,2839,1801,1772,1706,1600,1502,1456,1412,1381,1361,1330,1278,1245,1177,1133,1067,1031；HRMS-ESI(m/z):[M+H] + calcd.for C 21 H 20 N 3 O 2 346.1550; obtained as 346.1547.
Example 26
Figure BDA0002971461280000261
Palladium on carbon (10%) (27.0mg, 25.4. mu. mol) was added to a dry Schlenk reaction tube, the reaction tube was replaced with a balloon under hydrogen atmosphere (repeated three times), and then a solution of cycloaddition product 5a (82.8mg,0.254mmol) in methanol (1.0mL, 1.0mL wash) was added. After reacting at room temperature for 27 hours, filtering with celite to remove palladium on carbon, eluting with ethyl acetate, concentrating, and performing flash column chromatography (eluent: petroleum ether/ethyl acetate 2/1) to obtain chiral alcohol 6(54.5mg, 92%) as a white solid;
Figure BDA0002971461280000262
(c 0.50,CHCl 3 )。 1 H NMR(400MHz,CDCl 3 )δ(ppm):3.49(qd,J＝11.2,6.2Hz,2H),3.05-2.96(m,1H),2.99(s,3H),2.94-2.87(m,1H),2.54-2.43(m,1H),2.08-1.99(m,1H),1.90-1.78(m,2H),1.77-1.55(m,5H),0.90(d,J＝6.7Hz,3H)； 13 C NMR(101MHz,CDCl 3 ) δ (ppm) 181.21,180.29,67.59,39.69,39.66,38.72,37.24,32.59,29.49,26.56,24.67,19.46, 17.06; IR (Net, cm) -1 ):3472,2957,2929,2901,2869,1800,1763,1674,1438,1384,1325,1313,1284,1213,1169,1132,1091,1074,1051,1032；HRMS-ESI(m/z):[M+H] + calcd.for C 13 H 20 NO 3 238.1438; obtained as 238.1438.
Example 27
Figure BDA0002971461280000263
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted cyclobutanone 1a (58.8mg,0.400mmol), hydrochloride of chiral amine CA-4a HCl (0.115g,0.440mmol), n-butyllithium (2.28M,0.39mL,0.880mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.25mL,0.321g,1.20mmol), flash column chromatography (eluent: petroleum ether/ethyl acetate 10/1) afforded chiral cyclobutenophosphate 2a (0.134g, 88%) as a colorless oil; 88% ee.
Example 28
Figure BDA0002971461280000271
The procedure is as in example 1. The raw materials and the dosage are as follows: 3-substituted Cyclobutanone 1a (58.8mg,0.400mmol), hydrochloride of chiral amine CA-4a HCl (0.159g,0.440mmol), n-butyllithium (2.35M,0.38mL,0.880mmol) and the electrophilic reagents ClP (O) (OPh) 2 (0.18mL,0.231g,0.88mmol), flash column chromatography (eluent: petroleum ether/ethyl acetate 10/1) afforded chiral cyclobutenophosphate 2a (0.130g, 86%) as a colorless oil; 73% ee.
In conclusion, the invention provides a method for 3-substituted cyclobutanone desymmetrization mediated by chiral lithium amide, which takes the 3-substituted cyclobutanone as a starting material, performs enantioselective deprotonation under the action of the chiral lithium amide, and captures an enol intermediate by taking chlorophosphate as an electrophilic reagent to obtain a cyclobutene compound with high enantioselectivity. Simple operation, easily obtained raw materials and reagents, wide substrate universality, good functional group compatibility and high enantioselectivity (the highest enantiomeric selectivity can reach 93 percent ee) in the reaction. The cyclobutene compound with high optical activity obtained by the invention can be further used for preparing the skeleton of the original illide natural product through Negishi coupling and D-A ring addition reaction.
While the present invention has been described in detail with reference to the preferred embodiments, it should be understood that the above description should not be taken as limiting the invention. Various modifications and alterations to this invention will become apparent to those skilled in the art upon reading the foregoing description. Accordingly, the scope of the invention should be determined from the following claims.

Claims (7)

1. A3-substituted cyclobutanone desymmetrization method is characterized in that 3-substituted cyclobutanone is used as a starting material, and enantioselectively deprotonates under the action of chiral lithium amide in an organic solvent to obtain a corresponding lithium enol intermediate; and then adopting chlorophosphate as an electrophilic reagent to capture the lithium enol intermediate to obtain the cyclobutene compound (I), wherein the reaction process is as follows:
Figure FDA0003663356260000011
wherein R is selected from any one of phenyl, aryl, heterocyclic radical and substituted or unsubstituted alkyl; the aryl is phenyl with an electron-donating substituent or an electron-withdrawing substituent at the ortho, meta and para positions, and the heterocyclic radical is thienyl, furyl or pyridyl or any one of thienyl, furyl and pyridyl containing the electron-donating substituent or the electron-withdrawing substituent; the alkyl is chain and/or cyclic alkyl, and is selected from any one of alkyl, alkylene, oxygen and/or nitrogen heteroatom-containing alkyl, and ester group and/or amide function-containing alkyl;
The lithium amide is formed by chiral amine under the action of alkyl lithium; the chiral amine is selected from one or more of CA-1-CA-4 and enantiomers ent-CA-1-ent-CA-4 thereof;
Figure FDA0003663356260000012
wherein Ar is phenyl and aryl, and the aryl is phenyl substituted by alkyl or alkoxy at ortho, meta and para positions; r 1 、R 2 Each independently selected from any one of C1-C20 alkyl, C1-C20 alkyl with a functional group at the end, phenyl and aryl; wherein, in the C1-C20 hydrocarbon group with the terminal functional group, the functional group is selected from carbon-carbon double bond, carbon-carbon triple bond, ester group, hydroxyl, acyl, acyloxy, acylamino and halogen; the aryl is phenyl substituted by alkyl or alkoxy in the ortho, meta and para positions.
2. The method of desymmetrizing a 3-substituted cyclobutanone according to claim 1, wherein R is a C1-C20 hydrocarbyl group, a C1-C20 hydrocarbyl group with a functional group at the end, a phenyl group, an aryl group, or a heterocyclic group; wherein, in the C1-C20 hydrocarbyl with a functional group at the tail end, the functional group is selected from any one or a combination of several of carbon-carbon double bond, carbon-carbon triple bond, ester group, hydroxyl, acyl, acyloxy, acylamino and halogen; the aryl is phenyl with electron withdrawing or electron donating substitution at the ortho, meta and para positions, the heterocyclic group is thienyl, furyl or pyridyl, or thienyl, furyl or pyridyl containing the electron withdrawing or electron donating substituent, the electron withdrawing substituent is selected from any one or the combination of a plurality of halogens, nitro, ester groups, carboxyl, acyl, acylamino and cyano, and the electron donating substituent is selected from any one or the combination of a plurality of alkyl, alkenyl, phenyl and alkoxy.
3. The method of claim 1, wherein the alkyl lithium is any one or a combination of any two or more of methyl lithium, ethyl lithium, propyl lithium, isopropyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, amyl lithium, hexyl lithium, cyclohexyl lithium, tert-octyl lithium, n-eicosyl lithium, phenyl lithium, methylphenyl lithium, butylphenyl lithium, naphthyl lithium, and butylcyclohexyl lithium.
4. The method for the desymmetrization of 3-substituted cyclobutanone according to claim 1, wherein the chiral amine is selected from CA-4 and/or its enantiomer ent-CA-4, and the structure of CA-4 is as follows:
Figure FDA0003663356260000021
wherein Ar is phenyl; r 1 Is methyl or ethyl; r 2 Is methyl or ethyl.
5. The method of 3-substituted cyclobutanone desymmetrization of claim 1, wherein the molar ratio of 3-substituted cyclobutanone, alkyl lithium, chiral amine, chlorophosphate is 1.0: (1.0-10): (1.0-10): (1.0-10); and/or the reaction temperature is-90-60 ℃; and/or the dosage of the organic solvent is 1.0-10.0mL/mmol, based on the dosage of the 3-substituted cyclobutanone.
6. The method of desymmetrizing a 3-substituted cyclobutanone as claimed in claim 1, wherein said chlorophosphate is any one or more of dimethyl chlorophosphate, diethyl chlorophosphate, di-n-propyl chlorophosphate, diisopropyl chlorophosphate, di-n-butyl chlorophosphate, diisobutyl chlorophosphate, di-t-butyl chlorophosphate, diphenyl chlorophosphate, and diphenyl chlorophosphate; and/or the organic solvent is selected from any one or more of N-methyl pyrrolidone, 1, 4-dioxane, tetrahydrofuran, methyl tetrahydrofuran, acetonitrile, diethyl ether, methyl tert-butyl ether, chlorobenzene, toluene, benzotrifluoride, dichloromethane, 1-dichloroethane, 1, 2-dichloroethane, chloroform and acetic acid.
7. A method for removing the symmetry of 3-substituted cyclobutanone is characterized in that the method takes the 3-substituted cyclobutanone as a starting material, and the 3-substituted cyclobutanone is subjected to enantioselective deprotonation in an organic solvent under the action of chiral lithium amide to obtain a corresponding lithium enol intermediate; and then adopting chlorophosphate as an electrophilic reagent to capture the lithium enol intermediate to obtain the cyclobutene compound (I), wherein the reaction process is as follows:
Figure FDA0003663356260000031
wherein, R is selected from any one of phenyl, aryl, heterocyclic radical and substituted or unsubstituted alkyl;
the aryl is phenyl with an electron-donating substituent or an electron-withdrawing substituent at the ortho, meta and para positions, and the heterocyclic radical is thienyl, furyl or pyridyl or any one of thienyl, furyl and pyridyl containing the electron-donating substituent or the electron-withdrawing substituent; the alkyl is chain and/or cyclic alkyl, and is selected from any one of alkyl, alkylene, oxygen and/or nitrogen heteroatom-containing alkyl, and ester group and/or amide function-containing alkyl; the lithium amide is formed by chiral amine under the action of alkyl lithium; the chiral amine is CA-4 and/or an enantiomer ent-CA-4 thereof, and the structure of the CA-4 is shown as follows:
Figure FDA0003663356260000041
Wherein Ar is 1-naphthyl or 2-naphthyl; r 1 Is methyl or ethyl; r 2 Is methyl or ethyl.
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Chiral Synthesis of 3-Substituted and 3,3-Disubstituted y_Butyrolactones by Enantioselective Deprotonatkm Strategy;Toshio Honda et al.;《Tetrahedron：Asymmetry》;19931231;第1475-1478页 *
Enantioselective Synthesis of 3-Substituted Cyclobutenes by Catalytic Conjugate Addition/Trapping Strategies;Zhong, Changxu et al.;《Angewandte Chemie, International Edition》;20191211;第2750-2754页 *

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