CN110577485B - Norcamphor derived [2, 1] -bridged ring ketene compounds and synthesis method and application thereof - Google Patents

Norcamphor derived [2, 1] -bridged ring ketene compounds and synthesis method and application thereof Download PDF

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CN110577485B
CN110577485B CN201810596173.2A CN201810596173A CN110577485B CN 110577485 B CN110577485 B CN 110577485B CN 201810596173 A CN201810596173 A CN 201810596173A CN 110577485 B CN110577485 B CN 110577485B
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halophenyl
biphamphos
methylphenyl
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王春江
沈冲
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Wuhan University WHU
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Abstract

The invention discloses a compound with a chiral bridged ring structure, which comprises an ketene derivative with a chiral [2, 1] bridged ring structure segment and another polycyclic derivative with a chiral bridged ring spiropyrrole ring structure segment, and a synthesis method thereof, wherein the synthesis method comprises the following steps: under the protection of inert gas in an organic solvent, taking ketene derivative of racemic [2, 1] bridged ring structural fragment and imine derived from glycine methyl ester as raw materials, taking metal Lewis acid/chiral ligand complex as a catalyst, adding carbonate or organic base, reacting at the temperature of-60-25 ℃, evaporating the solvent, and carrying out column chromatography to obtain the target compound. The obtained ketene derivative of chiral [2, 1] bridge ring structural fragment can be further reacted to obtain santalol.

Description

[2, 1] -endocyclic ketene compound derived from norcamphor and synthesis method and application thereof
Technical Field
The invention belongs to the technical field of dynamic chiral resolution of ketene with a bridged ring structure and synthesis of chiral polycyclic compounds, and particularly relates to a ketene derivative with a chiral [2, 1] bridged ring structure fragment and a polycyclic derivative with a chiral bridged ring spiropyrrole ring structure fragment.
Background
Both enone derivatives having a chiral [2, 1] bridged ring structure fragment and polycyclic derivatives having a chiral bridged spiropyrrole ring structure fragment are important compounds, which are mainly applied in the synthesis of drugs, bioactive compounds and perfumes ((a) Reinhard, B.; rainer, H.; volker, T.; hansjorg, U.Eur.Pat.Appl.EP0459, 1992. (b) Suchockki J.A.; may E.L.; martin T.J.; george C.; martin B.R.J.Med.Chem.1991,34,1003. (c) Demo E.; demo C.; engg P.Helv.Chim.acta.1976,59,737 (d.) OddsF.C.Exp.in.Ther.283.Op.31, engg P.Helv.Chim.E.2006.43, 59, I.Q.; izod S.Q.Q.11, izod S.Q.11, I.T.T.T.97, ledebo S.S.J.S.D. CHErS.T.D. 9, U.E.A.
Disclosure of Invention
The invention aims to provide an ketene derivative with a chiral [2, 1] bridged ring structural fragment, a polycyclic derivative with a chiral bridged spiro pyrrole ring structural fragment, a synthetic method and application thereof.
The invention provides a norcamphor derivative [2, 1] -bridged ketene compound, which comprises a ketene derivative with a chiral [2, 1] bridged ring structural fragment and a polycyclic derivative with a chiral bridged spiropyrrole ring structural fragment,
the structural formula of the ketene derivative with the chiral [2, 1] bridge ring structural fragment is one of the following structural formulas:
structural formula (I-1):
Figure BDA0001692254140000011
structural formula (I-2):
Figure BDA0001692254140000012
structural formula (II-1):
Figure BDA0001692254140000013
structural formula (II-2):
Figure BDA0001692254140000014
structural formula (II-3):
Figure BDA0001692254140000015
the structural formula of the polycyclic derivative with the chiral bridged ring spiro-pyrrole ring structural fragment is one of the following structural formulas:
structural formula (III-1):
Figure BDA0001692254140000016
structural formula (III-2):
Figure BDA0001692254140000017
structural formula (IV-1):
Figure BDA0001692254140000018
structural formula (IV-2):
Figure BDA0001692254140000019
structural formula (IV-3):
Figure BDA0001692254140000021
wherein R is 1 Is one of hydrogen, p-halophenyl, o-halophenyl, m-halophenyl, phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, 2-naphthyl, 1-naphthyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl; r 2 Is one of p-halophenyl, o-halophenyl, m-halophenyl, phenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, p-methoxyphenyl, 2-naphthyl, 1-naphthyl, 2-thienyl and 3-thienyl; r is 3 Is hydrogen,Benzyl radical, C 1 -C 6 Straight chain alkyl of (1), C 1 -C 6 One of the branched alkyl groups of (a);
r is as defined above 1 Preferably one of hydrogen, p-chlorophenyl, p-bromophenyl, m-chlorophenyl, o-fluorophenyl, phenyl, p-methylphenyl, o-methylphenyl, p-methoxyphenyl, 2-naphthyl, 2-thienyl and 2-pyridyl; r 2 Preferably one of p-chlorophenyl, p-bromophenyl, m-chlorophenyl, m-bromophenyl, o-chlorophenyl, phenyl, p-methoxyphenyl, p-methylphenyl, o-methylphenyl, 2-naphthyl, 1-naphthyl and 2-thienyl; r 3 Preferably one of hydrogen, benzyl and methyl.
The invention also provides a synthesis method of the compound, which comprises the following steps:
in an organic solvent, under the protection of inert gas, taking ketene derivative of racemic [2, 1] bridged ring structure fragment and imine derived from glycine methyl ester as raw materials, taking metal Lewis acid/chiral ligand complex as a catalyst, adding carbonate or organic base, reacting at the temperature of-60-25 ℃, monitoring the reaction through chiral gas phase or chiral liquid phase, evaporating the solvent when the reaction equilibrium point is reached, and carrying out column chromatography to obtain a target compound
Figure BDA0001692254140000022
Wherein R is 1 Is one of hydrogen, p-halophenyl, o-halophenyl, m-halophenyl, phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, 2-naphthyl, 1-naphthyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl; r 2 Is one of p-halophenyl, o-halophenyl, m-halophenyl, phenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, p-methoxyphenyl, 2-naphthyl, 1-naphthyl, 2-thienyl and 3-thienyl; r 3 Is hydrogen, benzyl, C 1 -C 6 Straight chain alkyl group of (1), C 1 -C 6 One of the branched alkyl groups of (a).
The ketene derivative of the racemic [2, 1] bridge ring structural fragment is one of 3-methylene-2-norborneone, 3-p-chlorobenzylidene-2-norborneone, 3-p-bromobenzylidene-2-norborneone, 3-m-chlorobenzylidene-2-norborneone, 3-o-fluorobenzylidene-2-norborneone, 3-p-methylbenzylidene-2-norborneone, 3-m-methylbenzylidene-2-norborneone, 3-p-methoxybenzylidene-2-norborneone, 3- (2-naphthylmethylene) -2-norborneone, 3- (2-thienylmethylene) -2-norborneone, 3- (2-pyridylidene) -2-norborneone, exo-6-methyleneoctahydro-4, 7-methylindene-5-one, endo-6-methyleneoctahydro-4, 7-methylindene-5-one.
The molar ratio of the ketene derivative of the racemic [2, 1] bridge ring structural fragment to the glycine methyl ester-derived imine is 1:0.5 or 1.
The metal Lewis acid/chiral ligand complex is prepared by the following method: at room temperature, dissolving the metal Lewis acid and the chiral ligand TF-Biphamphos in an organic solvent according to the mole number of the metal Lewis acid not more than that of the chiral ligand, and reacting to obtain the chiral ligand TF-Biphamphos. The metal Lewis acid/chiral ligand complex can be a silver salt/TF-Biphamphos complex or a copper salt/TF-Biphamphos complex. The organic solvent is dichloromethane.
The structures of chiral ligands (S) -TF-BiphamPhos and (R) -TF-BiphamPhos are disclosed in Chinese patent publication No. CN 101440037B, entitled 3,3 '-dibromo-4, 4',6 '-tetra (trifluoromethyl) biphenyl-2, 2' -diamine and a preparation method thereof.
The structural formula of the (S) -TF-BiphamPhos is as follows:
Figure BDA0001692254140000031
the structural formula of (R) -TF-BiphamPhos is as follows:
Figure BDA0001692254140000032
in the structural formula of (S) -TF-BiphamPhos or (R) -TF-BiphamPhos, R 1 Can be phenyl, 3, 5-dimethylphenyl, 3, 5-bistrifluoromethylphenyl, or cyclohexyl; r 2 And may be hydrogen or bromine.
4) The carbonate or the organic base is used in a catalytic amount.
5) The column chromatography takes silica gel as a filling material and a mixed solvent of petroleum ether and ethyl acetate as an eluent, and the following steps of: the volume ratio of petroleum ether to ethyl acetate is 20 to 1.
The chiral [2, 1] prepared by the synthesis method]Placing ketene derivatives of bridge ring structural fragments in a methanol solvent, using Pd/C as a catalyst, and hydrogenating to obtain first derivatives
Figure BDA0001692254140000033
Figure BDA0001692254140000034
Wherein R is 1 Is one of hydrogen, p-halophenyl, o-halophenyl, m-halophenyl, phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, 2-naphthyl, 1-naphthyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
Placing the first derivative prepared by the synthesis method in trichloromethane, and carrying out Bayer-Villiger (Baeyer-Villiger) oxidation reaction by using m-chloroperoxybenzoic acid as an oxidant under the alkaline condition of sodium bicarbonate to obtain a second derivative
Figure BDA0001692254140000035
Figure BDA0001692254140000036
Wherein R is 1 Is one of hydrogen, p-halophenyl, o-halophenyl, m-halophenyl, phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, 2-naphthyl, 1-naphthyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
The chiral [2, 1] prepared by the synthesis method]Placing ketene derivative of bridge ring structural fragment in methanol/tetrahydrofuran solvent, and dissolving with trifluoromethanesulfonic acidA third derivative compound obtained by reducing calcium carbonate serving as a catalyst by sodium borohydride
Figure BDA0001692254140000041
Figure BDA0001692254140000042
Wherein R is 1 Is one of hydrogen, p-halophenyl, o-halophenyl, m-halophenyl, phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, 2-naphthyl, 1-naphthyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
Putting the compound with the structure shown in the formula IX-2 in the second derivative prepared by the synthesis method into a tetrahydrofuran solvent, taking lithium diisopropylamide as a base, and reacting with an alkyl reagent (Stowell iodide) to obtain a fourth derivative
Figure BDA0001692254140000043
Wherein R is 1 Is one of hydrogen, p-halophenyl, o-halophenyl, m-halophenyl, phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, 2-naphthyl, 1-naphthyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
The fourth class of derivatives can be used as important intermediates of fragrance santalol.
Compared with the prior art, the invention has the following advantages:
1) The method has the advantages of simple synthesis, low cost and high yield, and the obtained reaction target compound has good corresponding selectivity, the yield is 57-94%, and the excess of most corresponding selectivity is more than or equal to 90%; the yield of recovered raw material is 40-50% (theoretical yield = 50%), corresponding to a selectivity excess of > 90%.
2) The fourth derivative compound synthesized by the method can be used as an important intermediate of the fragrance santalol;
3) The complex of the catalyst metal Lewis acid/chiral ligand adopted by the method has the advantages of high catalytic reaction speed and low catalyst consumption in the reaction.
Detailed Description
In order that the invention may be better understood, reference will now be made to the following examples. The chiral ligand (S) -TF-Biphamphos used in the following examples have the structural formula
Figure BDA0001692254140000044
The structural formula of the (R) -TF-Biphamphos is shown in the specification
Figure BDA0001692254140000045
Example 1:
Figure BDA0001692254140000051
preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.20mmol of methyl 2- (p-chlorobenzylideneamino) acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine at-40 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a light yellow solid, wherein the yield is 91%, the melting point is 109-111 ℃, the enantioselectivity of the product is over 94%, and performing HPLC (Chiralpak AD-H, i-propanol/hexane =10/90, the flow rate is 1.0mL/min, lambda =220nm, t r ＝12.94and 23.80min)；[α] 30 D ＝+21.5(c 0.52,CH 2 Cl 2 ) (ii) a HRMS calculated value C 18 H 20 ClNNaO 3 ([M+Na] + ) 356.1024, measurement 356.1022.
Example 2
Figure BDA0001692254140000052
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 And 0.022mmol of (S) -TF-BiphamPhos,adding 2mL of dichloromethane under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.20mmol of methyl 2- (m-chlorobenzylideneamino) acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine at-40 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a white solid, wherein the yield is 88%, the melting point is 130-132 ℃, the enantioselectivity of the product is excessive 95%, and performing HPLC (Chiralpak AS-H, i-propanol/hexane =5/95, the flow rate is 1.0mL/min, lambda =220nm, t r ＝14.72and 24.80min.)；[α] 30 D ＝+42.1(c 0.3,CH 2 Cl 2 ) (ii) a Calculated value C 18 H 21 ClNO 3 ([M+H] + ) 334.1204, measurement value 334.1207.
Example 3
Figure BDA0001692254140000053
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then adding 0.20mmol of methyl 2- (p-bromophenylideneamino) acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine into the mixture in sequence at-40 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a white solid, wherein the yield is 84%, the melting point is 108-110 ℃, the enantioselectivity of the product is 95%, and performing HPLC (Chiralpak AD-H, i-propenol/hexane =10/90, the flow rate is 1.0mL/min, lambda =220nm, t r ＝13.83and 25.28min.)；[α] 30 D ＝+12.3(c 0.33,CH 2 Cl 2 ) (ii) a Calculated value C 18 H 20 BrNNaO 3 ([M+Na] + ) 400.0519, and the measured value is 400.0520.
Example 4
Figure BDA0001692254140000054
Preparation of (2)
0 was added to a 25mL reaction tube.02mmol Cu(CH 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.20mmol of 2- (m-bromobenzylidene amino) methyl acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine at-40 ℃, after stirring for 60H, the solvent was evaporated and the product was chromatographed on a silica gel column (petrol ether/ethyl acetate 3/1-1/1) to give a white solid in 85% yield, mp 117-118 ℃, enantioselectivity of the product 94%, HPLC (Chiralpak AS-H, i-propanol/hexane =5/95, flow rate 1.0mL/min, lambda =220nm, t r ＝18.15and 32.73min.)；[α] 30 D ＝+36.2(c 0.46,CH 2 Cl 2 ) (ii) a Calculated value C 18 H 20 BrNNaO 3 ([M+Na] + ) 400.0519, and the measured value is 400.0521.
Example 5
Figure BDA0001692254140000061
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 And 0.022mmol (S) -TF-BiphamPhos, adding 2mL dichloromethane under the protection of nitrogen, stirring for half an hour at room temperature, then adding 0.20mmol 2- (o-chlorobenzylideneamino) methyl acetate, 0.40mmol 3-methylene-2-norborneone and 0.06mmol triethylamine in sequence at-40 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a white solid, wherein the yield is 94%, the melting point is 128-130 ℃, the enantioselectivity of the product is excessive by 94%, and performing HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, the flow rate is 1.0mL/min, lambda =220nm, t and r ＝10.39and 18.26min.)；[α] 30 D ＝+53.5(c 0.53,CH 2 Cl 2 )； 1 calculated H NMR C 18 H 21 ClNO 3 ([M+H] + ) 334.1204, and 334.1204.
Example 6
Figure BDA0001692254140000062
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then adding 0.20mmol of 2- (benzylideneamino) methyl acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine into the mixture in sequence at-20 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a white viscous liquid, wherein the yield is 88%, the enantioselectivity of the product is over 93%, and performing HPLC (ChiralpakAD-H, i-propanol/hexane =5/95, the flow rate is 1.0mL/min, and the lambda =220nm, t r ＝16.86and 28.61min.)；[α] 30 D ＝+44.7(c0.43,CH 2 Cl 2 ) (ii) a Calculated value C 18 H 22 NO 3 ([M+H] + ) 300.1594, and measurement 300.1597.
Example 7
Figure BDA0001692254140000063
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then adding 0.20mmol of methyl 2- (p-methoxybenzylideneamino) acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine into the mixture at-20 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain yellow viscous liquid with the yield of 59 percent, the enantioselectivity of the product is over 95 percent, and performing HPLC (Chiralpak OD-H, i-propanol/hexane =10/90, the flow rate is 1.0mL/min, the lambda =220nm, and the t is the concentration of the product is higher than that of the corresponding salt of the compound is higher than that of the corresponding salt of the compound is higher than the corresponding salt of the compound r ＝16.72and 22.88min.)；[α] 30 D ＝+36.2(c 0.39,CH 2 Cl 2 ) (ii) a Calculated value C 18 H 22 NO 3 ([M+H] + ) 330.1700, measured 330.1700.
Example 8
Figure BDA0001692254140000071
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then adding 0.20mmol of methyl 2- (p-methylbenzylideneamino) acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine into the mixture at-20 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a yellow solid, wherein the yield is 74%, the melting point is 76-78 ℃, the enantioselectivity of the product is over 93%, and performing HPLC (Chiralpak AD-H, i-propanol/hexane =10/90, the flow rate is 1.0mL/min, lambda =220nm, t r ＝11.78and 20.79min.)；[α] 30 D ＝+49.4(c 0.36,CH 2 Cl 2 ) (ii) a Calculated value C 19 H 23 NO 3 ([M+H] + ) 314.1751, measured 314.1751.
Example 9
Figure BDA0001692254140000072
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then adding 0.20mmol of methyl 2- (m-methylbenzylideneamino) acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine into the mixture at-20 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain yellow viscous liquid, wherein the yield is 66%, the enantioselectivity of the product is over 94%, and performing HPLC (Chiralpak AD-H, i-propenol/hexane =10/90, the flow rate is 1.0mL/min, lambda =220nm, t r ＝12.47and 15.41min.)；[α] 30 D ＝+40.6(c 0.48,CH 2 Cl 2 ) (ii) a Calculated value C 19 H 23 NO 3 ([M+H] + ) 314.1751, and measures 314.1751.
Example 10
Figure BDA0001692254140000073
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.20mmol of methyl 2- (o-tolyleneamino) acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine at-20 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a white solid, wherein the yield is 64%, the melting point is 126-128 ℃, the enantioselectivity of the product is over 97%, and performing HPLC (Chiralpak AD-H, i-prodiol/hexane =10/90, the flow rate is 1.0mL/min, lambda =220nm, t r ＝8.67and 12.03min.)；[α] 30 D ＝+58.7(c 0.45,CH 2 Cl 2 ) (ii) a Calculated value C 19 H 23 NO 3 ([M+H] + ) 314.1751, and measures 314.1751.
Example 11
Figure BDA0001692254140000081
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 And 0.022mmol (S) -TF-BiphamPhos, adding 2mL dichloromethane under the protection of nitrogen, stirring for half an hour at room temperature, then adding 0.20mmol 2- (1-naphthylmethyleneamino) methyl acetate, 0.40mmol 3-methylene-2-norborneone and 0.06mmol triethylamine in sequence at-20 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a yellow solid, wherein the yield is 73%, the melting point is 123-125 ℃, the enantioselectivity excess of the product is 95%, and performing HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, the flow rate is 1.0mL/min, lambda =220nm, t and r ＝10.80and 17.05min.)；[α] 30 D ＝+77.0(c 0.46,CH 2 Cl 2 ) (ii) a Calculated value C 22 H 24 NO 3 ([M+H] + ) 350.1751, measurementThe value is 350.1751.
Example 12
Figure BDA0001692254140000082
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then adding 0.20mmol of methyl 2- (2-naphthylmethyleneamino) acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine into the mixture at-20 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a yellow solid, wherein the yield is 88%, the melting point is 138-140 ℃, the enantioselectivity of the product is over 93%, and performing HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, the flow rate is 1.0mL/min, lambda =220nm, t r ＝14.89and 23.96min.)；[α] 30 D ＝+34.4(c 0.43,CH 2 Cl 2 ) (ii) a Calculated value C 22 H 24 NO 3 ([M+H] + ) 350.1751, and measures 350.1751.
Example 13
Figure BDA0001692254140000083
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 And 0.022mmol (S) -TF-BiphamPhos, adding 2mL dichloromethane under the protection of nitrogen, stirring for half an hour at room temperature, then adding 0.20mmol methyl 2- (p-chlorobenzylideneamino) propionate, 0.40mmol 3-methylene-2-norborneone and 0.06mmol triethylamine at-20 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a yellow solid, wherein the yield is 70%, the melting point is 116-118 ℃, the enantioselectivity of the product is over 97%, and performing HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, the flow rate is 1.0mL/min, the lambda =220nm, t is t r ＝6.25and10.23min.)；[α] 30 D ＝+14.1(c 1.02,CH 2 Cl 2 ) (ii) a Calculated value C 19 H 23 ClNO 3 ([M+H] + ) 348.1361 and measured value 348.1361.
Example 14
Figure BDA0001692254140000091
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 0.022mmol (S) -TF-BiphamPhos, adding 2mL dichloromethane under the protection of nitrogen, stirring at room temperature for half an hour, then sequentially adding 0.20mmol 2- (p-methoxybenzylideneamino) methyl propionate, 0.40mmol 3-methylene-2-norborneone and 0.06mmol triethylamine at-20 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a white solid, wherein the yield is 57%, the melting point is 106-109 ℃, and the enantioselectivity of the product is excessive>99%, HPLC (Chiralpak AD-H, i-propanol/hexane =30/70, flow rate 1.0mL/min, λ =220nm, t r ＝6.58and 9.45min.)；[α] 30 D ＝+7.6(c 0.46,CH 2 Cl 2 ) (ii) a Calculated value C 20 H 26 NO 4 ([M+H] + ) 344.1856, measured 344.1856.
Example 15
Figure BDA0001692254140000092
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.20mmol of methyl 2- (2-thienylmethyleneamino) propionate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine at-20 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain a yellow solid, wherein the yield is 64%, the melting point is 94-96 ℃, the enantioselectivity of the product is 96%, and performing HPLC (Chiralpak AS-H, i-propanol/hexane =3/97, the flow rate is 1.0mL/min, and the lambda =220nm, t r ＝30.50and 34.22min.)；[α] 30 D ＝+3.1(c 0.32,CH 2 Cl 2 ) (ii) a Calculated value C 17 H 21 NNaO 3 S + ([M+Na] + ) 342.1134, and measured value 342.1137.
Example 16
Figure BDA0001692254140000093
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.20mmol of methyl 2- (p-chlorobenzylideneamino) phenylpropionate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of cesium carbonate at-0 ℃, stirring for 60 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) on the product to obtain colorless viscous liquid, wherein the yield is 68%, and the enantioselectivity of the product is excessive>99%, HPLC (Chiralpak OD-H, i-propanol/hexane =5/95, flow rate 1.0mL/min, lambda =220nm, t r ＝7.65and 9.10min.)；[α] 30 D ＝-16.3(c 0.42,CH 2 Cl 2 ) (ii) a Calculated value C 25 H 26 ClNNaO 3 + ([M+Na] + ) 446.1493, and 446.1493.
Example 17
Figure BDA0001692254140000094
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of 2- (p-chlorobenzylideneamino) methyl acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine at-60 ℃, monitoring the reaction by chiral gas chromatography, evaporating the solvent after the reaction is finished, performing silica gel column chromatography (petroleum ether/ethyl acetate 20/1-10/1), recovering the obtained raw material, obtaining colorless liquid with the yield of 44%, and recovering the enantiomer of the raw materialSelective excess of 92%, GC (Chiral Select-1000, 30mX0.25 mm, column temperature: 150 ℃ C., carrier gas: N 2 ,1.0mL/min,t r ＝4.75and 4.95min.)；[α] 30 D ＝-3.0(c 0.29,CH 2 Cl 2 )；
Figure BDA0001692254140000101
Preparation of
The product was subjected to increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a white solid in 46% yield with 94% enantioselectivity excess of the product.
Example 18
Figure BDA0001692254140000102
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of 2- (p-chlorobenzylideneamino) methyl acetate, 0.40mmol of 3-benzylidene-2-norborneone and 0.06mmol of triethylamine at-20 ℃, monitoring the reaction by Chiral gas chromatography, evaporating the solvent after the reaction is finished, and performing silica gel column chromatography (20/1-10/1) to recover a raw material, namely yellow liquid with the yield of 46%, the enantioselectivity of the recovered raw material is 94%, GC (Chiral Select-1000, 30mx 0.25mm, the column temperature is 180 ℃, and the carrier gas is N 2 ,1.0mL/min,t r ＝29.13and 30.76min.)；[α] 30 D ＝-552.1(c 0.38,CH 2 Cl 2 )；
Figure BDA0001692254140000103
Preparation of (2)
The product is passed through an increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a colorless viscous liquid with a yield of 48% and an enantioselectivity of the product of 93%, HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, flow: 1.0mL/min, lambda =220nm, t r ＝6.56and15.95min.)；[α] 30 D ＝+57.5(c 0.28,CH 2 Cl 2 ) (ii) a Calculated value C 24 H 24 ClNNaO 3 + ([M+Na] + ) 432.1337, and a measurement of 432.1337.
Example 19
Figure BDA0001692254140000104
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of methyl 2- (p-chlorobenzylideneamino) acetate, 0.40mmol of 3-p-chlorobenzylidene-2-norborneone and 0.06mmol of triethylamine at-20 ℃, monitoring the reaction by chiral liquid chromatography, evaporating the solvent after the reaction is finished, performing silica gel column chromatography (petroleum ether/ethyl acetate 20/1-10/1), recovering to obtain a raw material, namely a light yellow solid, the yield is 45%, the enantioselectivity of the recovered raw material is excessive 97%, and performing HPLC (Chiralpak OJ-H, i-propanol/hexane =2/98, the flow rate is 1.0mL/min, lambda =300nm, t% r ＝11.00and 12.42min.)；[α] 30 D ＝-415.9(c 0.27,CH 2 Cl 2 )； 1 H NMR
Figure BDA0001692254140000111
Preparation of (2)
The product is passed through an increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a yellow solid in 49% yield, melting point 145-147 ℃, enantioselectivity excess 93% of the product, HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, flow rate 1.0mL/min, lambda =220nm, t r ＝6.35and 16.73min.)；[α] 30 D ＝+21.5(c 0.67,CH 2 Cl 2 ) (ii) a Calculated value C 24 H 23 Cl 2 NNaO 3 + ([M+Na] + ) 466.0947, measurement 466.0949.
Example 20
Figure BDA0001692254140000112
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of methyl 2- (p-chlorobenzylideneamino) acetate, 0.40mmol of 3-p-bromobenzylidene-2-norborneone and 0.06mmol of triethylamine at-20 ℃, monitoring the reaction by chiral liquid chromatography, evaporating the solvent after the reaction is finished, and performing silica gel column chromatography (20/1-10/1 of petroleum ether/ethyl acetate) to recover a raw material, a white solid, a melting point of 85-86 ℃, a yield of 45 percent, enantioselectivity excess of the recovered raw material of 97 percent, HPLC (Chiralpak OJ-H, i-propanol/hexane =2/98, flow rate of 1.0mL/min, lambda =300nm, t r ＝12.94and 13.78min.)；[α] 30 D ＝-331.4(c 0.36,CH 2 Cl 2 ) (ii) a Calculated value C 14 H 13 BrNaO + ([M+Na] + ) 299.0042 and a measurement value 299.1110.
Figure BDA0001692254140000113
Preparation of (2)
The product is passed through an increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a yellow solid with a yield of 50%, a melting point of 148-150 ℃, an enantioselectivity of the product of 93%, HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, flow rate 1.0mL/min, lambda =220nm, t r ＝6.58and 16.81min.)；[α] 30 D ＝+15.3(c 0.17,CH 2 Cl 2 ) (ii) a Calculated value C 24 H 23 BrClNNaO 3 + ([M+Na] + ) 510.0442, and measured value 510.0446.
Example 21
Figure BDA0001692254140000114
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of methyl 2- (p-chlorobenzylideneamino) acetate, 0.40mmol of 3-m-chlorobenzylidene-2-norborneone and 0.06mmol of triethylamine at-20 ℃, monitoring the reaction by chiral liquid chromatography, evaporating the solvent after the reaction is finished, performing silica gel column chromatography (petroleum ether/ethyl acetate 20/1-10/1), recovering to obtain a raw material, a yellow liquid, the yield is 45%, the enantioselectivity of the recovered raw material is excessive 96%, and performing HPLC (Chiralpak OJ-H, i-propanol/hexane =2/98, the flow rate is 1.0mL/min, lambda =300nm, t r ＝9.97and 11.39min.)；[α] 30 D ＝-313.1(c 0.26,CH 2 Cl 2 ) (ii) a Calculated value C 14 H 13 ClNaO + ([M+Na] + ) 255.0547, measurement 255.0551.
Figure BDA0001692254140000121
Preparation of
The product is passed through an increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a white solid with a yield of 48%, a melting point of 123-125 ℃, an enantioselectivity of the product of 93%, HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, flow rate 1.0mL/min, lambda =220nm, t r ＝6.91and 16.93min.)；[α] 30 D ＝+39.0(c 0.41,CH 2 Cl 2 ) (ii) a Calculated value C 24 H 23 Cl 2 NNaO 3 + ([M+Na] + ) 466.0947, measurement 466.0953.
Example 22
Figure BDA0001692254140000122
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 0.022mmol (S) -TF-BiphamPhos, adding 2mL dichloromethane under the protection of nitrogen, stirring at room temperature for half an hour, and then sequentially adding 0.60mmol 2- (p-chlorobenzylideneamino) methyl acetate, 0.40mmol 3-o-fluorobenzylidene-2-norborneone and 0.06mmolTriethylamine, monitoring the reaction by chiral liquid chromatography, evaporating the solvent after the reaction is finished, and performing silica gel column chromatography (20/1-10/1 petroleum ether/ethyl acetate) to recover a raw material, wherein the yellow liquid has a yield of 43 percent, the enantioselectivity of the recovered raw material is over 99 percent, and the raw material is subjected to HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, the flow rate is 1.0mL/min, lambda =290nm, t is r ＝7.13and 8.03min.)；[α] 25 D ＝-261.1(c 0.26,CH 2 Cl 2 ) (ii) a Calculated value C 14 H 13 FNaO + ([M+Na] + ) 239.0843, measurement 239.0845.
Figure BDA0001692254140000123
Preparation of
The product was passed through an increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a yellow liquid, yield 51%, enantioselectivity of the product 83%, HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, flow rate 1.0mL/min, lambda =220nm, t r ＝7.47and 13.42min.)；[α] 30 D ＝+48.6(c 0.66,CH 2 Cl 2 ) (ii) a Major calculated value C 24 H 23 ClFNNaO 3 + ([M+Na] + ) 450.1243 and the measurement value is 450.1243.
Example 23
Figure BDA0001692254140000131
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of methyl 2- (p-chlorobenzylideneamino) acetate, 0.40mmol of 3-p-methylbenzylidene-2-norborneone and 0.06mmol of triethylamine at-20 ℃, monitoring the reaction by chiral liquid chromatography, evaporating the solvent after the reaction is finished, performing silica gel column chromatography (petroleum ether/ethyl acetate 20/1-10/1), recovering to obtain a raw material, obtaining a yellow liquid, obtaining the yield of 46%, and recovering the enantioselectivity of the raw material to be excessive 97%, and performing HPLC (Chiralpak OJ-H, i-propanol/he)xane =2/98, flow rate 1.0mL/min, λ =300nm r ＝8.59and 11.27min.)；[α] 30 D ＝-529.1(c 0.47,CH 2 Cl 2 )； 1 H NMR
Figure BDA0001692254140000132
Preparation of (2)
The product is passed through an increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a white solid with a yield of 48%, a melting point of 124-126 ℃, an enantioselectivity of the product of 93%, HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, flow rate 1.0mL/min, lambda =220nm, t r ＝5.70and 12.29min.)；[α] 30 D ＝+40.8(c 0.66,CH 2 Cl 2 ) (ii) a Calculated value C 25 H 26 ClNNaO 3 + ([M+Na] + ) 446.1493, and 446.1497.
Example 24
Figure BDA0001692254140000133
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of methyl 2- (p-chlorobenzylideneamino) acetate, 0.40mmol of 3-m-methylbenzylidene-2-norborneone and 0.06mmol of triethylamine at-20 ℃, monitoring the reaction by chiral liquid chromatography, evaporating off the solvent after the reaction is finished, and performing silica gel column chromatography (petroleum ether/ethyl acetate 20/1-10/1), recovering to obtain a raw material, a yellow liquid, the yield is 47%, the enantioselectivity of the recovered raw material is over 94%, and performing HPLC (Chiralpak OJH, i-propanol/hexane =2/98, the flow rate is 1.0mL/min, lambda =300nm, t% r ＝8.22and 10.05min)；[α] 30 D ＝-293.9(c 0.36,CH 2 Cl 2 ) (ii) a Calculated value C 15 H 16 NaO + ([M+Na] + ) 235.1093, and a measurement of 235.1104.
Figure BDA0001692254140000134
Preparation of
The product is subjected to increased eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a white solid with a yield of 46% and a melting point of 118-120 ℃ The enantioselectivity of the product was 93%, HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, flow rate 1.0mL/min, lambda =220nm, t r ＝5.70and 12.29min.)；[α] 30 D ＝+45.1(c 0.90,CH 2 Cl 2 ) (ii) a Calculated value C 25 H 26 ClNNaO 3 + ([M+Na] + ) 446.1493, and a measured value 446.1493.
Example 25
Figure BDA0001692254140000141
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of methyl 2- (p-chlorobenzylideneamino) acetate, 0.40mmol of 3-p-methoxybenzylidene-2-norbornenone and 0.06mmol of triethylamine at-20 ℃, monitoring the reaction through chiral liquid chromatography, evaporating off the solvent after the reaction is finished, and performing silica gel column chromatography (petroleum ether/ethyl acetate 10/1-5/1), recovering to obtain a raw material, a yellow liquid, the yield is 50%, the enantioselectivity of the recovered raw material is excessive 87%, and performing HPLC (Chiralpak OJ-H, i-propanol/hexane =2/98, the flow rate is 1.0mL/min, lambda =300nm, t is t% r ＝23.87and 30.81min.)；[α] 30 D ＝-416.0(c 0.30,CH 2 Cl 2 )；
Figure BDA0001692254140000142
Preparation of
The product is passed through an increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a white solid in 42% yield, m.p. 140-141 ℃, an enantioselectivity excess of the product of 97%, HPLC (Chiralpak AS-H, i-propanol/hexane =10/90Flow rate 1.0mL/min, λ =220nm, t r ＝8.61and 19.50min.)；[α] 30 D ＝+36.0(c 0.42,CH 2 Cl 2 ) (ii) a Calculated value C 25 H 26 ClNNaO 4 + ([M+Na] + ) 462.1443, and a measurement value 462.1443.
Example 26
Figure BDA0001692254140000143
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 And 0.022mmol (S) -TF-BiphamPhos, adding 2mL dichloromethane under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol methyl 2- (p-chlorobenzylideneamino) acetate, 0.40mmol 3- (2-naphthylmethylene) -2-norborneone and 0.06mmol triethylamine at-20 ℃, monitoring the reaction by chiral liquid chromatography, evaporating off the solvent after the reaction is finished, and performing silica gel column chromatography (20/1-10/1 petroleum ether/ethyl acetate), recovering to obtain a raw material, a yellow solid, the yield is 46%, the melting point is 91-93 ℃, the enantioselectivity of the recovered raw material is excessive 95%, HPLC (Chiralpak IA, i-propanol/hexane =1/99, the flow rate is 1.0mL/min, lambda =300nm, t is t r ＝11.41and 12.92min.)；[α] 30 D ＝-504.2(c 0.28CH 2 Cl 2 ) (ii) a Calculated value C 18 H 16 NaO + ([M+Na] + ) 271.1093, and a measurement of 271.1100.
Figure BDA0001692254140000151
Preparation of
The product is passed through a strong eluent with polarity (petroleum ether/ethyl acetate 3/1-1/1) to obtain a white solid with a yield of 46%, a melting point of 140-142 ℃, the enantioselectivity of the product was 94%, HPLC (Chiralpak AS-H, i-propanol/hexane =20/80, flow rate 1.0mL/min, lambda =220nm, t r ＝5.79and 11.80min.)；[α] 30 D ＝+10.5(c 0.75,CH 2 Cl 2 ) (ii) a Calculated value C 28 H 26 ClNNaO 3 + ([M+Na] + ) 482.1493, testMagnitude 482.1493.
Example 27
Figure BDA0001692254140000152
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of methyl 2- (p-chlorobenzylideneamino) acetate, 0.40mmol of 3- (2-thienylmethylene) -2-norborneone and 0.06mmol of triethylamine at-20 ℃, monitoring the reaction by chiral liquid chromatography, evaporating the solvent after the reaction is finished, and performing silica gel column chromatography (petroleum ether/ethyl acetate 20/1-10/1), recovering to obtain a raw material, a yellow liquid, the yield is 46%, the enantioselectivity of the recovered raw material is excessive 91%, and performing HPLC (Chiralpak OJ-H, i-propanol/hexane =10/90, the flow rate is 1.0mL/min, lambda =320nm, t r ＝8.51and 9.51min.)；[α] 30 D ＝-513.5(c 0.17,CH 2 Cl 2 ) (ii) a Calculated value C 12 H 12 NaOS + ([M+Na] + ) 227.0501 and measurement 227.0486.
Figure BDA0001692254140000153
Preparation of
The product is passed through an increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a yellow solid in 45% yield, melting point 157-159 ℃, enantioselectivity of the product 94%, HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, flow rate 1.0mL/min, lambda =220nm, t r ＝7.61and 15.38min.)；[α] 30 D ＝+82.6(c 0.35,CH 2 Cl 2 )； 1 Calculated H NMR C 22 H 22 ClNNaO 3 S + ([M+Na] + ) 416.1082, measurement 416.1085.
Example 28
Figure BDA0001692254140000154
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of 2- (p-chlorobenzylideneamino) methyl acetate, 0.40mmol of 3- (2-pyridylmethylene) -2-norborneone and 0.06mmol of triethylamine at-20 ℃, the reaction was monitored by chiral liquid chromatography, after the reaction was completed, the solvent was evaporated, and the raw material was recovered by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) to give a brown liquid with a yield of 45% and an enantioselectivity of the recovered raw material of 98%, HPLC (Chiralpak OJ-H, i-propanol/hexane =2/98, flow rate 1.0mL/min, λ =300nm, t% r ＝13.88and 17.92min.)；[α] 30 D ＝-219.2(c 0.25,CH 2 Cl 2 ) (ii) a Calculated value C 13 H 14 NO + ([M+Na] + ) 200.1070, and a measurement of 200.1068.
Figure BDA0001692254140000161
Preparation of (2)
The product was passed through increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a yellow solid in 45% yield, m.p. 162-164 ℃, enantioselectivity of the product 97%, HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, flow rate 1.0mL/min, λ =220nm, t, m.p./g./g/ r ＝9.05and 15.24min.)；[α] 30 D ＝+15.0(c 0.24,CH 2 Cl 2 ) (ii) a Calculated value C 23 H 23 ClN 2 NaO 3 + ([M+Na] + ) 433.1289, and measured value 433.1287.
Example 29
Figure BDA0001692254140000162
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring at room temperature for half an hour, and then stirring at-20 DEG CUnder the conditions of 0.60mmol of 2- (p-chlorobenzylideneamino) methyl acetate, 0.40mmol of exo-6-methyleneoctahydro-4, 7-methylidene-5-one and 0.06mmol of triethylamine, the reaction is monitored by chiral liquid chromatography, the solvent is evaporated after the reaction is finished, and the raw material is recovered by silica gel column chromatography (petroleum ether/ethyl acetate 20/1-10/1), colorless liquid is obtained, the yield is 45%, the enantioselectivity of the recovered raw material is over 91%, HPLC (Chiralpak AS-H, i-propanol/hexane =2/98, the flow rate is 1.0mL/min, lambda =220nm, t is obtained r ＝7.55and 8.47min.)；[α] 30 D ＝-0.7(c 0.19,CH 2 Cl 2 )；
Figure BDA0001692254140000163
Preparation of
The product was passed through an increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a yellow liquid in 48% yield with 96% enantioselectivity of the product, HPLC (Chiralpak IA, i-propanol/hexane =10/90, flow rate 1.0mL/min, lambda =220nm, t r ＝11.25and 25.54min.)；[α] 30 D ＝-37.8(c 0.27,CH 2 Cl 2 ) (ii) a Calculated value C 21 H 25 ClNO 3 + ([M+H] + ) 374.1517, measured value 374.1517.
Example 30
Figure BDA0001692254140000164
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of methyl 2- (p-chlorobenzylideneamino) acetate, 0.40mmol of endo-6-methyleneoctahydro-4, 7-methylidene-5-one and 0.06mmol of triethylamine at-20 ℃, monitoring the reaction by chiral liquid chromatography, evaporating the solvent after the reaction is finished, performing silica gel column chromatography (petroleum ether/ethyl acetate 20/1-10/1), recovering to obtain a raw material, obtaining a colorless liquid, obtaining the yield of 44%, recovering the enantioselectivity of the raw material by 90%, and performing HPLC (Ch)iralpak AS-H, i-propanol/hexane =2/98, flow rate 1.0mL/min, λ =220nm, t r ＝5.27and 6.35min.)；[α] 30 D ＝+25.0(c 0.02,CH 2 Cl 2 )；
Figure BDA0001692254140000171
Preparation of (2)
The product was passed through increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a white liquid with a yield of 45% and an enantioselectivity of the product of 85%, HPLC (Chiralpak AD-H, i-propanol/hexane =10/90, flow rate 1.0mL/min, lambda =220nm, t r ＝15.47and25.34min.)；[α] 30 D ＝+2.1(c 0.33,CH 2 Cl 2 ) (ii) a Calculated value C 21 H 24 ClNNaO 3 + ([M+Na] + ) 396.1337, and 396.1337.
Example 31
Figure BDA0001692254140000172
Preparation of (2)
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol (S) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then adding 0.60mmol of methyl 2- (p-chlorobenzylideneamino) acetate, 0.40mmol of 3-methylene-3, 4-dihydro-1, 4-methanonaphthalenone-2-one and 0.06mmol of triethylamine in sequence at-20 ℃, monitoring the reaction by chiral liquid chromatography, evaporating the solvent after the reaction is finished, performing silica gel column chromatography (petroleum ether/ethyl acetate 20/1-10/1), recovering the obtained raw material to obtain a white solid, wherein the yield is 46%, the enantioselectivity of the recovered raw material is 90%, and performing HPLC (Chiralpak OJ-H, i-panol/hexane =10/90, the flow rate is 1.0mL/min, lambda =220nm, t r ＝13.95and 18.83min.)；[α] 30 D ＝+36.3(c 0.47,CH 2 Cl 2 ) (ii) a Calculated value C 22 H 20 ClNNaO 3 + ([M+H] + ) 404.1024, and a measured value of 404.1024.
Example 32
Figure BDA0001692254140000173
Preparation of
A25 mL reaction tube was charged with 0.02mmol of Cu (CH) 3 CN) 4 BF 4 Adding 2mL of dichloromethane into 0.022mmol of (R) -TF-BiphamPhos under the protection of nitrogen, stirring for half an hour at room temperature, then sequentially adding 0.60mmol of 2- (p-chlorobenzylideneamino) methyl acetate, 0.40mmol of 3-methylene-2-norborneone and 0.06mmol of triethylamine at-60 ℃, monitoring the reaction by chiral gas chromatography, evaporating the solvent after the reaction is finished, performing silica gel column chromatography (petroleum ether/ethyl acetate 20/1-10/1), recovering to obtain a raw material, obtaining a colorless liquid, obtaining the yield of 40%, and recovering the enantioselectivity excess of the raw material>99%, GC (Chiral Select-1000, 30mx 0.25mm, column temperature: 150 ℃ C., carrier gas: N 2 ,1.0mL/min,t r ＝4.75and 4.95min.)；[α] 30 D ＝+5.7(c 0.51,CH 2 Cl 2 )；
Figure BDA0001692254140000174
Preparation of
The product was passed through increasing eluent polarity (petroleum ether/ethyl acetate 3/1-1/1) to give a white solid in 51% yield with an enantioselectivity of 85% for the product.
Example 33
Figure BDA0001692254140000175
Preparation of
2.50mmol of the recovered raw material of example 32 was charged into a 25mL reaction tube, 50mg 10% of Pd/C, 5mL of methanol was added, and a pressure of H was applied 2 Stirring at room temperature for 2 hr, evaporating solvent, and subjecting the product to silica gel column chromatography (petroleum ether/diethyl ether 20/1) to obtain colorless liquid with yield of 99% and enantioselectivity of the product in excess>99% GC (Chiral Select-1000, 30mX0.25 mm, column temperature: 150 ℃ C., carrier gas: N 2 ,1.0mL/min,t r ＝8.88and 9.42min.)；[α] 30 D ＝-46.1(c 0.54,CH 2 Cl 2 ) (ii) a HRMS calculated value for C 8 H 12 NaO + ([M+Na] + ) 147.0780, measurement 147.0780.
Example 34
Figure BDA0001692254140000181
Preparation of
Adding 0.80mmol of raw material with enantioselectivity excess of 95% to a 25mL reaction tube, 1695g 10% of Pd/C, adding 4mL of methanol, passing H under a pressure 2 Stirring at room temperature for 4 hours, evaporating the solvent, and subjecting the product to silica gel column chromatography (petrol ether/ether 20/1) to give a colorless liquid in 81% yield with 95% enantioselectivity for the product, HPLC (Chiralpak OJ-H, i-propanol/hexane =5/95, flow rate 1.0mL/min, lambda =220nm, t r ＝11.08and 11.86min.)；[α] 30 D ＝-35.3(c 0.37,CH 2 Cl 2 ) (ii) a HRMS calculated value for C 14 H 16 NaO + ([M+Na] + ) 223.1093, and measured value 223.1093.
Example 35
Figure BDA0001692254140000182
Preparation of
A25 mL reaction tube was charged with 0.22mmol m-chloroperoxybenzoic acid, 0.12mmol sodium bicarbonate, 6mL dichloromethane, followed by dropwise addition of 1mL of a 0.20mmol solution of the product of example 34 in dichloromethane at 0 deg.C, recovery at room temperature with stirring for 6 hours, evaporation of the solvent, column chromatography of the product over silica gel (petroleum ether/ethyl acetate 10/1-3/1) to give a white solid in 98% yield, melting point 70-72 deg.C, enantioselectivity of the product 96%, HPLC (Chiralpak AS-H, i-propanol/hexane =10/90, flow rate 1.0mL/min,. Lambda = nm 210t, t r ＝27.92and 44.25min.)；[α] 30 D ＝+20.7(c 0.15,CH 2 Cl 2 ) (ii) a HRMS calculated value for C 14 H 16 NaO 2 + ([M+Na] + ) 239.1043 and measurement value 239.1043.
Example 36
Figure BDA0001692254140000183
Preparation of
A25 mL reaction tube was charged with 0.80mmol of starting material with 95% enantiomeric excess, 0.50mmol of calcium triflate, 0.5mL of methanol, 6mL of 2.00mmol of sodium borohydride in tetrahydrofuran was added dropwise, the mixture was stirred at room temperature for 0.5 hour, the solvent was evaporated, and the product was chromatographed on silica gel (petroleum ether/ethyl acetate 10/1-5/1) to give a white solid with 88% yield, melting point 108-110 ℃, enantiomeric excess of 95% product, HPLC (Chiralpak AS-H, i-propanol/hexane =5/95, flow rate 1.0mL/min,. Lambda. =254nm, t. r ＝7.20and8.05min.)；[α] 30 D ＝-300.8(c 0.41,CH 2 Cl 2 )。
Example 37
Figure BDA0001692254140000184
Preparation of
Adding 1.60mmol of diisopropylethylamine and 2mL of tetrahydrofuran into a 25mL reaction tube under the atmosphere of nitrogen, dropwise adding 0.6mL of 2.5M n-butyllithium tetrahydrofuran solution at 0 ℃, stirring for 10 minutes, then adding 1.00mmol of the product in the example 33, then adding an alkylating reagent (Stowell iodide), reacting for 30 minutes, refluxing for 20 hours, evaporating the solvent, and performing silica gel column chromatography (petroleum ether/ethyl acetate/triethylamine 85/15/1) on the product to obtain a yellow liquid, wherein the yield is 70%, and the enantioselectivity of the product is excessive>99％，[α] 22 D ＝-79.3(c 3.10,CHCl 3 )；
The yields and corresponding selective excesses of the compounds obtained in examples 1 to 31 are shown in Table 1.
Table 1 yield and enantiomeric excess of the compound obtained in the example
Figure BDA0001692254140000191
Figure BDA0001692254140000201
Example 38: detection of bactericidal activity
The concentration of the liquid medicine is 50ppm, the prepared agar sheets are taken by a 5mm puncher, respectively picked into each culture dish, a blank control is arranged, the agar sheets are cultured in a constant temperature incubator at 27 ℃ for 48-72 hours, the diameter of bacterial plaque is checked, and the inhibition rate = (the diameter of the control bacterial plaque-the diameter of sample bacterial plaque)/the diameter of the control bacterial plaque multiplied by 100 percent is repeated at the same time. The results are shown in Table 2.
Cosolvent: dimethyl phthalide amine; emulsifier: tween-80; preparing a solution: sterile water. Wherein, dimethyl phthalide amine/H 2 O =1/1000; emulsifier/H 2 O =5/1000 (weight percentage).
TABLE 2 bacteriostatic ratio of the compounds of the invention
Figure BDA0001692254140000202
Figure BDA0001692254140000211
Figure BDA0001692254140000221
Figure BDA0001692254140000231
Figure BDA0001692254140000241
Figure BDA0001692254140000251
Figure BDA0001692254140000261
Figure BDA0001692254140000271
Figure BDA0001692254140000281
Finally, the above embodiments are merely illustrative and not restrictive, and it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the present invention, which is to be covered by the claims.

Claims (3)

1. A norcamphor-derived [2, 1] -bridged ketene compound, characterized in that: the structural formula is one of the following structural formulas:
structural formula (III-1):
Figure FDA0003848764910000011
structural formula (III-2):
Figure FDA0003848764910000012
structural formula (IV-1):
Figure FDA0003848764910000013
structural formula (IV-2):
Figure FDA0003848764910000014
structural formula (IV-3):
Figure FDA0003848764910000015
wherein the content of the first and second substances,
R 1 is one of hydrogen, p-halophenyl, o-halophenyl, m-halophenyl, phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, 2-naphthyl, 1-naphthyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl;
R 2 is one of p-halophenyl, o-halophenyl, m-halophenyl, phenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, p-methoxyphenyl, 2-naphthyl, 1-naphthyl, 2-thienyl and 3-thienyl;
R 3 is hydrogen, benzyl, C 1 -C 6 Straight chain alkyl group of (1), C 1 -C 6 One of the branched alkyl groups of (a).
2. A process for the synthesis of norcamphor-derived [2, 1] -cycloalkenone compounds of claim 1, comprising the steps of: in an organic solvent, under the protection of inert gas, taking ketene derivatives of racemic [2, 1] bridged ring structural fragments and imine derived from glycine methyl ester as raw materials, taking metal Lewis acid/chiral ligand complex as a catalyst, adding carbonate or organic base, reacting at the temperature of-60-22 ℃, monitoring the reaction through a chiral gas phase or a chiral liquid phase, evaporating the solvent when the reaction equilibrium point is reached, and carrying out column chromatography to obtain a target compound; the metal Lewis acid/chiral ligand complex is a copper salt/TF-Biphamphos complex or a silver salt/TF-Biphamphos complex.
3. The method of claim 2, wherein: the molar ratio of the ketene derivative of the racemic [2, 1] bridged ring structural fragment to the glycine methyl ester-derived imine is 1:0.2 or 1:1.2; the metal Lewis acid/chiral ligand complex is prepared by the following method: at room temperature, dissolving metal Lewis acid and chiral ligand TF-Biphamphos in an organic solvent according to the mole number of the metal Lewis acid not more than that of the chiral ligand, and reacting to obtain the product.
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