CN105294471A - Synthetic method of alpha-amido-gamma-nitro succinate derivative - Google Patents
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- 238000004440 column chromatography Methods 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- 239000003446 ligand Substances 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 17
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- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 15
- 239000010948 rhodium Substances 0.000 claims abstract description 15
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002808 molecular sieve Substances 0.000 claims abstract description 8
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 8
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- 230000002745 absorbent Effects 0.000 claims abstract 2
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- 238000006243 chemical reaction Methods 0.000 claims description 42
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
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- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical group [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 claims description 2
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention discloses a synthetic method of an alpha-amido-gamma-nitro succinate derivative. With diazonium, arylamine and nitroolefin ester are adopted as the raw materials, rhodium complex and chiral diene ligand are adopted as catalysts, an organic solvent is adopted as a solvent, a 4A molecular sieve is adopted as a water absorbent, the synthetic method comprises the following steps: after one step reaction, removing the solvent to obtain a crude product; carrying out column chromatography to obtain the highly enantioselective alpha-amido-gamma-nitro succinate derivative. According to the synthetic method, the raw materials are simple and easy to get, the operation is easy and safe, and the synthetic method has the advantages of high atom economy, high yield, high selectivity, and the like; the product synthesized through the method is an important chemical and medical intermediate, can be used as multifarious compound skeletons, has quite important significance for new drug screening and pharmaceutical preparation technology, has inhibitory activity for XBP1 cleavage, and can be used as an antineoplastic candidate compound.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical synthetic chemistry, and particularly relates to a synthetic method of an alpha-amino-gamma-nitrosuccinate derivative, wherein the alpha-amino-gamma-nitrosuccinate derivative is an important chemical and pharmaceutical intermediate.
Background
The alpha-amino-gamma-nitro succinate derivative is an important intermediate skeleton structure of a plurality of natural products, and the traditional chemical synthesis method of the alpha-amino-gamma-nitro succinate derivative is to synthesize a complex alpha-amino-containing succinic acid derivative firstly and then construct a racemic alpha-amino-gamma-nitro succinate derivative through a Henry reaction; or firstly constructing a complex optically pure cyclopropane derivative simultaneously containing nitro and ester groups, and then using amine to open the ring to obtain the alpha-amino-gamma-nitro succinate derivative. (org.Lett.2012, 14, 444-447; org.Lett.2008, 10, 2809-2812; J.Am.chem.Soc.1985, 107, 5555-555; J.Am.chem.Soc.2002, 39, 11689-11698;) the above conventional methods for synthesizing α -amino- γ -nitrosuccinate derivatives have great limitations: the complex precursor compound is required to be constructed firstly, and multi-step synthesis is also required, so that the method has the defects of complex operation, harsh reaction conditions, narrow substrate applicability, insufficient diversity of product structures of most obtained products and the like. To date, there is no general method for synthesizing α -amino- γ -nitrosuccinate derivatives.
Disclosure of Invention
The invention aims to disclose a method for preparing an alpha-amido-gamma-nitro succinate derivative shown in a formula (I) by a one-step method, wherein the raw materials are cheap and easy to obtain, the operation is simple, the selectivity is good, and the substrate practicability is wide. The method of the invention uses diazo compound, arylamine and nitroolefin ester as raw materials, and realizes the synthesis of alpha-amido-gamma-nitro succinate derivative with high enantioselectivity under the catalysis of rhodium complex and chiral diene ligand. The method for synthesizing the compound takes diazo compound, arylamine and nitro alkene ester as raw materials to react. The reaction mechanism is that diazo is decomposed under the catalysis of metal to form metal carbene, the metal carbene and amine form amino ylide, and the amino ylide are captured by carbon-carbon double bonds in nitroolefin ester to generate Michael-like addition, so that the alpha-amino-gamma-nitrosuccinate derivative is constructed in one step.
The synthesis process of α -amino-gamma-nitro succinate derivative includes weighing diazo compound, arylamine, nitro olefine ester, rhodium complex, chiral diene ligand and water absorbentAdding a molecular sieve and an organic solvent into a reaction bottle, adding nitroolefin ester into the reaction bottle, dissolving a diazo compound and aromatic amine into the organic solvent to obtain a mixed solution, dropwise adding the mixed solution into the reaction bottle through a peristaltic pump at room temperature, stirring until the reaction is finished, removing the solvent through rotary evaporation at 40-50 ℃ to obtain a crude product, and performing column chromatography to obtain the α -amino-gamma-nitro succinate derivative pure product shown in the formula (I) with high enantioselectivity.
In the method of the invention, the general formula of the alpha-amido-gamma-nitro succinate derivative is shown as the structural formula (I):
in the formula:
R1is hydrogen, phenyl, m-chlorobenzenePhenyl, m-bromophenyl, p-methylphenyl, p-methoxyphenyl;
R2is hydrogen, 4-chloro, 4-bromo, 4, 5-dimethoxy;
R3methyl, ethyl, isopropyl, tert-butyl and benzyl.
Preferably, R1Is phenyl, p-methoxyphenyl; r2Is hydrogen; r3Is isopropyl or tert-butyl.
The reaction equation for synthesizing the alpha-amino-gamma-nitro succinate derivative with high enantioselectivity in the invention is as follows:
wherein the chiral diene ligand has a structure of
Wherein,
R1is hydrogen, phenyl, m-chlorophenyl, m-bromophenyl, p-methylphenyl, p-methoxyphenyl;
R2hydrogen, 4-chlorine, 4-bromine, 4, 5-dimethoxy;
R3methyl, ethyl, isopropyl, tert-butyl and benzyl.
Preferably, R1Is phenyl, p-methoxyphenyl; r2Is hydrogen; r3Is isopropyl or tert-butyl.
The reaction mechanism in the synthesis method of the alpha-amido-gamma-nitro succinate derivative is as follows: firstly, ligand exchange is carried out between a catalyst rhodium complex (vinyl rhodium chloride) and a chiral diene ligand, then the formed chiral rhodium complex decomposes diazo 1 to form electrophilic carbene, chiral ylide is formed between the electrophilic carbene and arylamine 2 in a system, and the chiral ylide is captured by a nitroolefin ester compound 3 to form a final three-component product 4.
According to the invention, the molar ratio of the diazo compound, the arylamine, the nitroalkenyl ester, the rhodium complex and the chiral diene ligand is 1-1.2: 0.01-0.1: 0.02-0.2. Preferably, the molar ratio of the diazo compound, the aromatic amine, the nitroalkenyl ester, the rhodium complex and the chiral diene ligand is 1.2: 1: 0.02: 0.04.
In the present invention, theThe input amount of the molecular sieve is 2-5g per millimole of the diazo compound, namely, the water absorbentThe addition amount of the molecular sieve is 2-5g/mmol of nitroolefin ester. The organic solvent is chloralkane, toluene or xylene; the addition amount of the organic solvent is 25-30ml/mmol of nitroolefin ester; the amount of the organic solvent used for dissolving the diazo and the arylamine is 25 to 30ml/mmol of nitroolefin ester. The column chromatography is carried out by adopting a solution with the volume ratio of ethyl acetate to petroleum ether being 1: 10-1: 5.
In the present invention, the rhodium complex is rhodium acetate, rhodium (1, 5-cyclooctadiene) chloride.
The chiral diene ligand is (1R, 4R) -2, 5-diphenyl bicyclo [2.2.2] octa-2, 5-diene, (1S, 4S) -2, 5-diphenyl bicyclo [2.2.2] octa-2, 5-diene.
In one embodiment, the preparation method of the invention is as follows:
firstly, weighing diazo compound, arylamine, nitro alkene ester, rhodium complex and chiral diene ligand ═ 1 according to the mol ratio2: 1.2: 1: 0.02: 0.04, rhodium complex, chiral diene ligand and water absorbentAdding molecular sieve and organic solvent into reaction bottle to obtain water absorbentAdding 2-5g/mmol of nitroolefin ester into a molecular sieve, adding 25-30ml/mmol of organic solvent into the nitroolefin ester, adding the nitroolefin ester into a reaction bottle, dissolving diazo and arylamine into the organic solvent to obtain a mixed solution, dissolving the diazo and arylamine dissolved organic solvent with 25-30ml/mmol of nitroolefin ester, dropwise adding the mixed solution into the reaction bottle through a peristaltic pump at room temperature for 2 hours, continuously stirring for 1 hour, ending the reaction, removing the solvent through rotary evaporation at 40-50 ℃ to obtain a crude product, and performing column chromatography on the crude product by using a solution with the volume ratio of ethyl acetate to petroleum ether being 1: 10-1: 5 to obtain the α -amino-gamma-nitrosuccinate derivative pure product with high enantioselectivity as shown in the formula (I).
The organic solvent used in the invention, the raw materials of nitromethane and aldehydic acid ester for preparing nitroolefin ester, diazo raw material aryl acetate, azide compound, arylamine and the like can be purchased in the market. Toluene is dehydrated by calcium hydride before use, and other organic solvents are purified or distilled in advance before reaction and during column chromatography.
The invention also provides the alpha-amido-gamma-nitro succinate derivative of the formula (I) prepared by the synthesis method,
wherein R is1Is hydrogen, phenyl, m-chlorophenyl, m-bromophenyl, p-methylphenyl, p-methoxyphenyl; r2Hydrogen, 4-chlorine, 4-bromine, 4, 5-dimethoxy; r3Methyl, ethyl, isopropyl, tert-butyl and benzyl.
The beneficial effects of the invention include: the raw materials of the diazo compound, the nitro alkene ester, the arylamine and the organic solvent are cheap and easy to obtain, the cost is low, the synthetic route is simple, and the target product is constructed in one step. The method has the advantages of atom economy, high selectivity, high yield and the like, and meets the requirement of green chemistry. The alpha-amido-gamma-nitro succinate derivative with high enantioselectivity, which is simply and quickly synthesized, is an important chemical and medical intermediate, provides a diversified compound skeleton, and has very important significance for new drug screening and pharmaceutical technology. The alpha-amido-gamma-nitro succinate derivative synthesized by the method has the activity of a compound for inhibiting XBP1 shearing, and is used as an anti-tumor candidate compound.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, but the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, 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.
Example 1
Weighing (1R, 4R) -2, 5-diphenylbicyclo [2.2.2]Octa-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) were placed in a small tube reactor at room temperatureAdding 5.6 ml of redistilled toluene, then weighing isopropyl (E) -3-nitroacrylate (0.20mmol), adding the isopropyl (E) -3-nitroacrylate (0.20mmol) into the reaction tube, weighing anthranilate (0.24mmol), dissolving methyl phenyldiazoacetate (0.24mmol) in 2.8ml of redistilled toluene, injecting the mixture into the reaction system through a peristaltic pump for 2 hours, stirring the mixture for 1 hour at normal temperature after the injection is finished, filtering, performing rotary evaporation on the filtrate at 40 ℃ to remove the solvent, and separating the filtrate through column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10-1: 5) to obtain α -amino-gamma-nitrosuccinate derivative pure products with high enantioselectivity, wherein the yield is 64%, the d.r value is more than 95: 5, and the e.e. value is 95%.1HNMR(400MHz，CDCl3)＝9.12(s，1H)，7.88(d，J＝8.0Hz，1H)，7.51(d，J＝7.2Hz，2H)，7.26(d，J＝6.1Hz，3H)，6.93(d，J＝8.0Hz，1H)，6.56(d，J＝7.5Hz，1H)，5.97(d，J＝8.5Hz，1H)，4.98-4.87(m，1H)，4.70(d，J＝10.5Hz，1H)，4.60-4.49(m，1H)，4.11(dd，J＝10.3，2.1Hz，1H)，3.87(s，3H)，3.65(s，3H)，1.14(d，J＝6.2Hz，3H)，1.03(d，J＝6.2Hz，3H).13CNMR(100MHz，CDCl3)169.70，168.01，167.28，146.92，134.32，132.39，130.50，127.67，127.62，126.82，115.60，114.21，111.16，76.32，76.00，75.69，72.17，69.48，65.94，51.95，50.91，20.38，20.08.
Example 2
(1R, 4R) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) was weighed out, and they were placed in a small tube reactor, to which was added 5.6 ml of toluene which had been redistilled at room temperature. Isopropyl (E) -3-nitroacrylate (0.20mmol) was then weighed into the reaction tube. Weighing 4-chloro-anthranilate (0.24mmol) and methyl phenyl diazoacetate (0.24mmol) and dissolving in 2.8ml of redistilled toluene, injecting into a reaction system by a peristaltic pump for 2 hours, continuously stirring at normal temperature for 1 hour after injection, filtering, performing rotary evaporation on the filtrate at 40 ℃ to remove the solvent, and separating by column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10-1: 5) to obtain the alpha-amino-gamma-nitro succinate derivative pure product with high enantioselectivity. The yield was 74% and the e.e. value was 62%.
1HNMR(400MHz，CDCl3)＝9.14(s，1H)，7.84(s，1H)，7.47(d，J＝5.0Hz，2H)，7.37-7.23(m，4H)，6.87(d，J＝9.0Hz，1H)，5.89(d，J＝9.0Hz，1H)，5.02-4.87(m，1H)，4.76(dd，J＝14.9，10.7Hz，1H)，4.44(d，J＝15.1Hz，1H)，4.12-4.00(m，2H)，3.88(s，4H)，3.68(s，3H)，1.15(d，J＝6.1Hz，3H)，1.03(d，J＝6.1Hz，3H).13CNMR(100MHz，CDCl3)169.45，167.30，167.00，145.50，134.05，132.17，129.81，127.97，127.91，127.86，126.65，126.60，120.34，115.67，112.10，72.18，69.63，66.12，52.07，52.01，51.19，20.37，20.08.
Example 3
(1R, 4R) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) was weighed out, and they were placed in a small tube reactor, to which was added 5.6 ml of toluene which had been redistilled at room temperature. Isopropyl (E) -3-nitroacrylate (0.20mmol) was then weighed into the reaction tube. Weighing 4-methoxy anthranilate (0.24mmol) and methyl phenyl diazoacetate (0.24mmol) to dissolve in 2.8ml of redistilled toluene, injecting the mixture into a reaction system through a peristaltic pump for 2 hours, continuously stirring the mixture for 1 hour at normal temperature after the injection is finished, filtering the mixture, performing rotary evaporation on the filtrate at 40 ℃ to remove a solvent, and separating the filtrate through column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10-1: 5) to obtain a pure product of the alpha-amino-gamma-nitro succinate derivative with high enantioselectivity. The yield was 74% and the e.e. value was 80%.
1HNMR(400MHz，CDCl3)＝8.99(s，1H)，7.49(d，J＝7.2Hz，2H)，7.33-7.22(m，5H)，5.01-4.90(m，1H)，4.71-4.62(m，1H)，4.54(d，J＝14.9Hz，1H)，4.18(d，J＝9.6Hz，1H)，3.84(s，3H)，3.72(s，3H)，3.67(s，4H)，3.22(s，3H)，1.14(d，J＝6.0Hz，4H)，1.10(d，J＝6.2Hz，3H).13CNMR(100MHz，CDCl3)169.87，167.55，167.14，152.40，143.55，139.17，134.30，127.69，126.84，111.94，102.37，98.43，72.00，69.57，66.12，55.14，54.28，51.93，51.71，50.67，20.41，20.13.
Example 4
(1R, 4R) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) was weighed out, and they were placed in a small tube reactor, to which was added 5.6 ml of toluene which had been redistilled at room temperature. Isopropyl (E) -3-nitroacrylate (0.20mmol) was then weighed into the reaction tube. Weighing 4, 5-dimethoxy anthranilate (0.24mmol) and methyl m-chlorophenyl diazoacetate (0.24mmol), dissolving in 2.8ml of redistilled toluene, injecting into the reaction system by a peristaltic pump for 2 hours, stirring at normal temperature for 1 hour after the injection is finished, filtering, performing rotary evaporation on the filtrate at 40 ℃ to remove the solvent, and separating by column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10-1: 5) to obtain the alpha-amino-gamma-nitro succinate derivative pure product with high enantioselectivity. The yield was 47%, and the e.e. value was 86%.
1HNMR(400MHz，CDCl3)＝8.95(s，1H)，7.56(s，1H)，7.39(t，J＝8.4Hz，1H)，7.33(s，1H)，7.29-7.20(m，2H)，5.02-4.85(m，1H)，4.68-4.54(m，1H)，4.18(dd，J＝9.1，4.4Hz，1H)，3.90-3.81(m，2H)，3.77-3.71(m，2H)，3.66(s，2H)，3.30(d，J＝7.2Hz，2H)，1.14(d，J＝6.2Hz，3H)，1.09(d，J＝6.3Hz，2H).13CNMR(100MHz，CDCl3)169.42，166.75，152.66，143.17，139.54，136.45，133.66，128.77，127.90，127.45，125.22，112.31，102.71，98.13，71.57，69.82，65.64，55.22，54.40，52.09，51.55，50.75，20.45，20.11.
Example 5
Weighing (1R, 4R) -2, 5-diphenylbicyclo [2.2.2]Octyl-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) was placed in a small tube reactor, 5.6 ml of toluene which was distilled off was added at room temperature, isopropyl (E) -3-nitroacrylate (0.20mmol) was then weighed out and added to the reaction tube, 4, 5-dimethoxy anthranilate (0.24mmol) was weighed out, methyl m-bromophenyl diazoacetate (0.24mmol) was dissolved in 2.8ml of toluene which was distilled off, and was injected into the reaction system by a peristaltic pump for 2 hours, after the injection was completed, stirring was continued for 1 hour at room temperature, filtration was carried out, the filtrate was subjected to rotary evaporation at 40 ℃ to remove the solvent, and α -amino- γ -nitrosuccinate derivative pure product with high enantioselectivity was isolated by column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10 to 1: 5), yield was 42%, and e.e. value was 84%.1HNMR(400MHz，CDCl3)＝9.01(s，1H)，7.78(s，1H)，7.50(t，J＝9.0Hz，2H)，7.40(s，1H)，7.22(t，J＝8.0Hz，1H)，5.58(s，1H)，5.05-4.97(m，1H)，4.70-4.64(m，2H)，4.25(dd，J＝8.5，4.8Hz，1H)，3.92(s，3H)，3.80(s，3H)，3.73(s，3H)，3.36(s，3H)，1.22(d，J＝6.2Hz，3H)，1.16(d，J＝6.2Hz，3H).13CNMR(100MHz，CDCl3)170.41，168.59，167.76，153.68，144.17，140.57，137.70，131.87，131.32，130.05，126.69，122.72，113.32，103.74，99.15，72.58，70.86，66.60，56.23，55.44，53.11，52.57，51.76，21.49，21.13.
Example 6
(1R, 4R) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) was weighed out, and they were placed in a small tube reactor, to which was added 5.6 ml of toluene which had been redistilled at room temperature. Isopropyl (E) -3-nitroacrylate (0.20mmol) was then weighed into the reaction tube. Weighing anthranilate (0.24mmol) and methyl m-bromophenyl diazoacetate (0.24mmol), dissolving in 2.8ml redistilled toluene, injecting into a reaction system through a peristaltic pump for 2 hours, continuing stirring at normal temperature for 1 hour after injection, filtering, performing rotary evaporation on the filtrate at 40 ℃ to remove a solvent, and separating through column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10-1: 5) to obtain the pure alpha-amino-gamma-nitro succinate derivative with high enantioselectivity. The yield was 48% and the e.e. value was 84%.
1HNMR(400MHz，CDCl3)＝9.09(s，1H)，7.89(d，J＝7.9Hz，1H)，7.40(s，4H)，6.98(s，1H)，6.59(s，1H)，5.90(d，J＝8.4Hz，1H)，4.96-4.83(m，1H)，4.63(dd，J＝38.8，12.8Hz，2H)，4.06(d，J＝9.6Hz，1H)，3.87(s，3H)，3.63(d，J＝6.4Hz，3H)，1.13(d，J＝5.9Hz，3H)，1.02(d，J＝6.0Hz，3H).13CNMR(100MHz，CDCl3)169.38，168.00，166.98，146.57，133.28，132.59，130.93，130.81，130.68，128.88，128.75，122.00，115.98，113.91，111.30，71.77，69.68，65.40，52.12，51.67，51.00，20.39，20.04.
Example 7
(1R, 4R) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) was weighed out, and they were placed in a small tube reactor, to which was added 5.6 ml of toluene which had been redistilled at room temperature. Isopropyl (E) -3-nitroacrylate (0.20mmol) was then weighed into the reaction tube. Weighing anthranilate (0.24mmol) and methyl p-methoxyphenyl diazoacetate (0.24mmol) to dissolve in 2.8ml of redistilled toluene, injecting the mixture into a reaction system through a peristaltic pump for 2 hours, continuously stirring the mixture at normal temperature for 1 hour after the injection is finished, filtering the mixture, performing rotary evaporation on the filtrate at 40 ℃ to remove the solvent, and separating the filtrate through column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10-1: 5) to obtain the pure alpha-amino-gamma-nitro succinate derivative with high enantioselectivity. The yield was 60% and the e.e. value was 88%.
1HNMR(400MHz，CDCl3)＝9.07(s，1H)，7.87(dd，J＝8.0，1.5Hz，1H)，7.42(d，J＝8.9Hz，2H)，6.98-6.93(m，1H)，6.78(d，J＝9.0Hz，2H)，6.55(t，J＝7.5Hz，1H)，6.00(d，J＝8.4Hz，1H)，4.97-4.88(m，1H)，4.71(dd，J＝15.2，10.5Hz，1H)，4.53(dd，J＝15.2，3.0Hz，1H)，4.06(dd，J＝10.5，3.0Hz，1H)，3.86(s，3H)，3.72(s，3H)，3.64(s，3H)，1.15(d，J＝6.2Hz，3H)，1.06(d，J＝6.3Hz，3H).13CNMR(100MHz，CDCl3)169.88，168.00，167.32，158.51，146.97，132.43，130.46，128.11，125.98，115.52，114.20，112.92，111.07，72.16，69.45，65.48，54.23，52.10，51.92，50.91，20.41，20.12.
Example 8
(1R, 4R) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) was weighed out, and they were placed in a small tube reactor, to which was added 5.6 ml of toluene which had been redistilled at room temperature. Isopropyl (E) -3-nitroacrylate (0.20mmol) was then weighed into the reaction tube. Weighing anthranilate (0.24mmol), methyl p-methylphenyl diazoacetate (0.24mmol) and methyl p-methylphenyl diazoacetate (0.24mmol) to dissolve in 2.8ml redistilled toluene, injecting into a reaction system by a peristaltic pump for 2 hours, continuously stirring at normal temperature for 1 hour after injection, filtering, performing rotary evaporation on the filtrate at 40 ℃ to remove a solvent, and separating by column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10-1: 5) to obtain the pure alpha-amino-gamma-nitro succinate derivative with high enantioselectivity. The yield was 68% and the e.e. value was 94%.
1HNMR(400MHz，CDCl3)＝9.10(s，1H)，7.87(d，J＝8.0Hz，1H)，7.37(d，J＝7.6Hz，2H)，7.06(d，J＝7.8Hz，2H)，6.95(s，1H)，6.55(s，1H)，5.99(d，J＝8.4Hz，1H)，5.00-4.84(m，1H)，4.71(dd，J＝15.0，10.9Hz，1H)，4.51(d，J＝14.9Hz，1H)，4.08(d，J＝10.5Hz，1H)，3.86(s，3H)，3.65(s，3H)，2.25(s，3H)，1.15(d，J＝6.2Hz，3H)，1.05(d，J＝6.1Hz，3H).13CNMR(100MHz，CDCl3)170.80，169.00，168.34，147.98，138.48，133.39，132.24，131.45，129.40，127.62，116.49，115.21，112.05，73.21，70.46，66.76，52.97，52.92，51.91，21.41，21.08，20.98.
Example 9
(1R, 4R) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) was weighed out, and they were placed in a small tube reactor, to which was added 5.6 ml of toluene which had been redistilled at room temperature. Ethyl (E) -3-nitroacrylate (0.20mmol) was then weighed into the reaction tube. Weighing anthranilate (0.24mmol) and methyl phenyl diazoacetate (0.24mmol), dissolving in 2.8ml redistilled toluene, injecting into the reaction system by a peristaltic pump for 2 hours, continuing stirring at normal temperature for 1 hour after the injection, filtering, performing rotary evaporation on the filtrate at 40 ℃ to remove the solvent, and separating by column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10-1: 5) to obtain the pure alpha-amino-gamma-nitro succinate derivative with high enantioselectivity. The yield was 53%, and the e.e. value was 50%.
1HNMR(400MHz，CDCl3)＝9.12(s，1H)，7.88(d，J＝7.9Hz，1H)，7.51(d，J＝6.5Hz，2H)，7.27(d，J＝5.3Hz，3H)，6.95(t，J＝7.8Hz，1H)，6.56(t，J＝7.5Hz，1H)，5.97(d，J＝8.5Hz，1H)，4.71(d，J＝10.5Hz，1H)，4.54(d，J＝15.2Hz，1H)，4.14(d，J＝10.5Hz，1H)，4.11-4.00(m，2H)，3.87(s，3H)，3.64(d，J＝13.9Hz，3H)，1.11(t，J＝7.1Hz，4H).13CNMR(100MHz，CDCl3)169.69，168.05，167.81，146.86，134.32，132.42，130.51，127.73，127.67，126.68，115.66，114.19，111.20，72.01，65.97，61.35，52.02，51.84，50.93，12.64.
Example 10
(1R, 4R) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) was weighed out, and they were placed in a small tube reactor, to which was added 5.6 ml of toluene which had been redistilled at room temperature. Then, benzyl (E0-3-nitroacrylate (0.20mmol) is weighed and added into the reaction tube, anthranilate (0.24mmol) is weighed, methyl phenyl diazoacetate (0.24mmol) is dissolved in 2.8ml of redistilled toluene and is injected into the reaction system through a peristaltic pump for 2 hours, after the injection is finished, the mixture is stirred for 1 hour at normal temperature, the mixture is filtered, the filtrate is subjected to rotary evaporation at 40 ℃ to remove the solvent, and then the pure alpha-amino-gamma-nitrosuccinate derivative with high enantioselectivity is obtained through column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10-1: 5), the yield is 67%, and the e.e. value is 40%.
1HNMR(400MHz，CDCl3)＝9.11(s，1H)，7.88(t，J＝8.5Hz，1H)，7.44(s，2H)，7.24(d，J＝7.1Hz，7H)，6.94(t，J＝7.1Hz，1H)，6.55(t，J＝7.4Hz，1H)，5.97(d，J＝8.2Hz，1H)，5.08(d，J＝11.9Hz，1H)，4.98(d，J＝12.0Hz，1H)，4.71(dd，J＝14.8，10.5Hz，1H)，4.56(d，J＝14.7Hz，1H)，4.23(d，J＝9.5Hz，1H)，4.05(d，J＝7.0Hz，1H)，3.84(s，3H)，3.53(s，3H).13CNMR(100MHz，CDCl3)169.59，168.05，167.70，146.83，134.11，133.42，132.42，130.53，127.76，127.69，127.56，127.48，126.64，115.75，114.23，111.29，71.97，67.15，67.09，66.04，51.95，51.80，50.92.
Example 11
(1R, 4R) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) was weighed out, and they were placed in a small tube reactor, to which was added 5.6 ml of toluene which had been redistilled at room temperature. Methyl (E) -3-nitroacrylate (0.20mmol) was then weighed into the reaction tube. Weighing anthranilate (0.24mmol) and methyl phenyl diazoacetate (0.24mmol), dissolving in 2.8ml redistilled toluene, injecting into the reaction system by a peristaltic pump for 2 hours, continuing stirring at normal temperature for 1 hour after the injection, filtering, performing rotary evaporation on the filtrate at 40 ℃ to remove the solvent, and separating by column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10-1: 5) to obtain the pure alpha-amino-gamma-nitro succinate derivative with high enantioselectivity. The yield was 72% and the e.e. value was 85%.
1HNMR(400MHz，CDCl3)＝9.11(s，1H)，7.88(dd，J＝8.0，1.5Hz，1H)，7.50(dd，J＝7.8，1.7Hz，2H)，7.27(t，J＝5.5Hz，3H)，7.01-6.87(m，1H)，6.56(t，J＝7.3Hz，1H)，5.97(d，J＝8.5Hz，1H)，4.74(dd，J＝15.3，10.5Hz，1H)，4.52(dd，J＝15.4，2.9Hz，1H)，4.16(dd，J＝10.4，2.8Hz，1H)，3.87(s，3H)，3.66(s，3H)，3.63(s，3H).
Example 12
(1R, 4R) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene (0.008mmol), (1, 5-cyclooctadiene) rhodium (I) chloride (0.004mmol) was weighed out, and they were placed in a small tube reactor, to which was added 5.6 ml of toluene which had been redistilled at room temperature. Tert-butyl (E) -3-nitroacrylate (0.20mmol) was then weighed into the reaction tube. Weighing anthranilate (0.24mmol) and methyl phenyl diazoacetate (0.24mmol), dissolving in 2.8ml redistilled toluene, injecting into the reaction system by a peristaltic pump for 2 hours, continuing stirring at normal temperature for 1 hour after the injection, filtering, performing rotary evaporation on the filtrate at 40 ℃ to remove the solvent, and separating by column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 10-1: 5) to obtain the pure alpha-amino-gamma-nitro succinate derivative with high enantioselectivity. The yield was 45% and the e.e. value was 76%.
1HNMR(400MHz，CDCl3)＝9.06(s，1H)，7.87(dd，J＝8.0，1.5Hz，1H)，7.53(dd，J＝7.6，1.9Hz，2H)，7.26(d，J＝1.5Hz，2H)，6.98-6.92(m，1H)，6.55(t，J＝7.3Hz，1H)，5.98(d，J＝8.5Hz，1H)，4.68(dd，J＝15.1，10.6Hz，1H)，4.51(dd，J＝15.1，2.9Hz，1H)，4.04(dd，J＝10.5，3.0Hz，1H)，3.86(s，3H)，3.65(s，4H)，1.31(s，9H).13CNMR(100MHz，CDCl3)169.76，167.99，166.74，147.00，134.53，132.40，130.47，127.60，127.54，126.96，115.53，114.19，111.10，82.80，72.48，65.88，52.58，51.88，50.90，44.86，28.68.
Example 13 biological Activity assay
Screening models:
name: B16-F10-XBP1-DBD-Luc
English is called as a whole: B16-F10-XBP1-DBD-Luc
Brief introduction: cell models to measure XBP1mRNA splicing levels. The research finds that the XBP1 gene in the tumor cell is in a high expression state, the expression of the XBP1 active protein needs to be cut by endoplasmic reticulum membrane protein IRE1, the model has the function of judging the cutting level of XBP1, and a compound inhibiting the XBP1 cutting is expected to be screened on the model and used as a candidate compound for resisting the tumor.
The screening method comprises the following steps:
method number: 92
The method name is as follows: evaluation of B16-F10-XBP1-DBD-Luc
The instrument comprises the following steps:
envision2101 multifunctional microplate enzyme label
Materials:
384-hole culture plate
Luciferase assay substrates
The process is as follows:
1. seed cells 8000/50 μ l/well in 96-well white plates with DMEM, 10% FBS.
2. And culturing at 37 ℃ for 24 hours in a 5% carbon dioxide environment.
3. Tunicamycin (final concentration 1. mu.g/ml) 50. mu.l.
4. Mu.l of the solution obtained in the third step was added to the plate in the first step.
5. And culturing at 37 ℃ for 8 hours in a 5% carbon dioxide environment.
6. Adding 20 microliter Luc substrate, culturing at room temperature for 20 minutes, and detecting by a luminous counter.
7. Reading Luc
Sample treatment:
the samples were dissolved in DMSO and stored at low temperature, and the concentration of DMSO in the final system was controlled within a range that did not affect the detection activity.
Data processing and results description:
the activity of the sample is tested under a single concentration condition, e.g., 20. mu.g/ml, for primary screening. For samples that exhibit activity under certain conditions, e.g., an Inhibition% Inhibition of greater than 50, the activity dose dependence, i.e., IC50/EC50 values, were tested by nonlinear fitting of sample activity to sample concentration, the software used was GraphpadPrism4, the model used was sigmoidal dose-response (varibleslope), and for most inhibitor screening models, the bottom and top of the fitted curve were set to 0 and 100. In general, each sample was subjected to duplicate wells (n.gtoreq.2) in the test, and the results were expressed as Standard Deviation (SD) or Standard Error (SE).
Test compound data:
experiments show that: the alpha-amino-gamma-nitro succinate derivatives (including the products synthesized in the above examples 1-12) synthesized by the invention have a certain degree of XBP1 shearing inhibition activity, and can be used as candidate compounds for resisting tumors. For example, the activity of the product obtained in example 4 was 66.8% inhibition, and the activity of the product of example 5 was 66% inhibition. Other example products also have similar activity.
Claims (10)
1. A process for synthesizing α -amino-gamma-nitro succinate derivative features that the rhodium complex, chiral diene ligand and water absorbent are usedAdding a molecular sieve and an organic solvent into a reaction bottle; then adding the nitro alkenyl ester into a reaction bottle; dissolving the diazo compound and the arylamine in an organic solvent to obtain a mixed solution; then, at room temperature, the mixed solution is dripped into a reaction bottle through a peristaltic pumpStirring until the reaction is finished, and removing the solvent by rotary evaporation to obtain a crude product, and performing column chromatography to obtain α -amino-gamma-nitro succinate derivative with high enantioselectivity, which is shown in the following reaction formula;
wherein the chiral diene ligand has a structure of
Wherein R is1Is hydrogen, phenyl, m-chlorophenyl, m-bromophenyl, p-methylphenyl, p-methoxyphenyl; r2Hydrogen, 4-chlorine, 4-bromine, 4, 5-dimethoxy; r3Methyl, ethyl, isopropyl, tert-butyl and benzyl.
2. The synthetic method of claim 1 wherein R is1Is phenyl, p-methoxyphenyl; r2Is hydrogen; r3Is isopropyl or tert-butyl.
3. The synthetic method according to claim 1, wherein the molar ratio of the diazo compound, the arylamine, the nitroalkenyl ester, the rhodium complex and the chiral diene ligand is 1-1.2: 0.01-0.1: 0.02-0.2.
4. The method of claim 3 wherein the diazo compound, aromatic amine, nitroalkenyl ester, rhodium complex, and chiral diene ligand are present in a molar ratio of diazo compound, aromatic amine, nitroalkenyl ester, rhodium complex, and chiral diene ligand of 1.2: 1: 0.02: 0.04.
5. The method of synthesis according to claim 1, characterized in thatCharacterized in that the water-absorbing agentThe addition amount of the molecular sieve is 2-5g/mmol of nitroolefin ester.
6. The method of synthesis according to claim 1, wherein the organic solvent is a chlorinated alkane, toluene or xylene; the addition amount of the organic solvent is 25-30ml/mmol of nitroolefin ester; the amount of the organic solvent for dissolving the diazo and the aromatic amine is 25-30ml/mmol of nitroalkenyl ester.
7. The synthetic method of claim 1, wherein the column chromatography is performed using a solution of ethyl acetate and petroleum ether in a volume ratio of 1: 10 to 1: 5.
8. The method of synthesis of claim 1, wherein the rhodium complex is rhodium acetate or (1, 5-cyclooctadiene) rhodium chloride.
9. The method of claim 1, wherein the chiral diene ligand is (1R, 4R) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene or (1S, 4S) -2, 5-diphenylbicyclo [2.2.2] octa-2, 5-diene.
10. The alpha-amino-gamma-nitrosuccinate derivatives synthesized according to the method of claim 1, wherein the alpha-amino-gamma-nitrosuccinate derivatives are represented by the formula (I),
wherein R is1Is hydrogen, phenyl, m-chlorophenyl, m-bromophenyl, p-methylphenyl, p-methoxyphenyl; r2Hydrogen, 4-chlorine, 4-bromine, 4, 5-dimethoxy; r3Methyl, ethyl, isopropyl, tert-butyl and benzyl.
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