CN113429249A - Method for synthesizing chiral 4-hydroxy amino acid derivative - Google Patents

Method for synthesizing chiral 4-hydroxy amino acid derivative Download PDF

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CN113429249A
CN113429249A CN202110671128.0A CN202110671128A CN113429249A CN 113429249 A CN113429249 A CN 113429249A CN 202110671128 A CN202110671128 A CN 202110671128A CN 113429249 A CN113429249 A CN 113429249A
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chiral
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acid derivative
ruthenium complex
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CN113429249B (en
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王超
张晓慧
马威
汤卫军
薛东
李超群
肖建良
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Shaanxi Normal University
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Abstract

The invention discloses a method for synthesizing chiral 4-hydroxy amino acid derivatives, which takes a chiral ruthenium complex of diphosphine dinitrogen as a catalyst, racemic allyl alcohol compounds and glycine imine esters as substrates, quaternary ammonium salt and 18-crown ether-6 as additives, cesium carbonate and the like as bases, and synthesizes the chiral 4-hydroxy amino acid derivatives by an asymmetric hydrogen borrowing strategy in an inert gas atmosphere, thereby realizing the stereoselectivity control of two remote chiral centers. The method has the advantages of cheap and easily-obtained substrate, no need of additionally adding an oxidant and a reducing agent, high atom economy, mild reaction conditions, simple and convenient operation, good yield of the obtained chiral compound and high stereoselectivity, wherein the chiral compound with (2R,5S) configuration or (2S,5R) configuration is taken as a main component, and the substrate can be further converted into chiral amino alcohol, chiral diol and chiral heterocyclic compound, so that the method is a green method for synthesizing the chiral 4-hydroxy amino acid derivative.

Description

Method for synthesizing chiral 4-hydroxy amino acid derivative
Technical Field
The invention belongs to the technical field of synthesis of chiral 4-hydroxy amino acid derivatives, and particularly relates to a method for synthesizing chiral 4-hydroxy amino acid derivatives by directly carrying out an asymmetric hydrogen-borrowing process on allyl alcohol compounds and glycine imine esters under the catalytic action of a chiral ruthenium complex.
Background
The chiral 4-hydroxy amino acid derivative is an important structural segment of a plurality of complex natural products, is also an important compound for constructing a plurality of bioactive natural products and medicaments, and has certain bioactivity. A common method for synthesizing chiral 4-hydroxyamino acid derivatives in the above literature is asymmetric Michael addition using ketene compounds and glycineimide esters to give 4-carbonylamino acid derivatives, which are then reduced with sodium borohydride to give 4-hydroxyamino acid derivatives (tetrahedron. Lett.1998,39, 5347-5350; Angew. chem. int. Ed.2013,52, 6981-6991). The above reaction requires the use of an additional reducing agent, requires two-step reaction, and requires low temperature reaction, and is harsh in terms of conditions. Therefore, the development of a green, efficient and simple method for synthesizing the chiral 4-hydroxy amino acid derivative has important significance.
Disclosure of Invention
The invention aims to provide a method for effectively synthesizing chiral 4-hydroxy amino acid derivatives, which has the advantages of simple reaction system, simple and convenient operation, short synthesis steps, good stereoselectivity and high atom economy.
Aiming at the purposes, the technical scheme adopted by the invention is as follows: adding an allyl alcohol compound shown in a formula I, glycine imine ester shown in a formula II, a chiral ruthenium complex A or a chiral ruthenium complex B, alkali, quaternary ammonium salt and 18-crown ether-6 into an organic solvent under an inert gas atmosphere, reacting at 25-50 ℃, and separating and purifying a product after the reaction is completed to obtain a chiral 4-hydroxy amino acid derivative shown in a formula III or a formula IV; the reaction equation is as follows:
Figure BDA0003119289750000011
in the formula R1Represents aryl, substituted aryl, heterocyclic aryl, C1～C4Any one of the alkyl groups is specifically as follows: phenyl radical, C1～C4Alkyl-substituted phenyl, C1～C4Alkoxy-substituted phenyl, halophenyl, biphenyl, naphthyl, thienyl, furyl, methyl, benzyl, and the like.
The structural formula of the chiral ruthenium complex A is shown as follows:
Figure BDA0003119289750000021
the structural formula of the chiral ruthenium complex B is shown as follows:
Figure BDA0003119289750000022
wherein Ar represents 3, 5-dimethylphenyl.
In the above synthesis method, the amount of the allyl alcohol compound is preferably 1 to 3 times of the molar amount of the glycinimine ester.
In the above synthesis method, the amount of the chiral ruthenium complex a or the chiral ruthenium complex B is preferably 1 to 2% of the molar amount of the glycinimine ester.
In the synthesis method, the quaternary ammonium salt is any one of tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide and tetrabutylammonium chloride; the amount of the quaternary ammonium salt is preferably 0.25 to 1 time of the molar amount of the glycinimine ester.
In the synthesis method, the dosage of the 18-crown ether-6 is preferably 0.25 to 1 time of the molar weight of the glycinimine ester.
In the above synthesis method, the base is any one of cesium carbonate, sodium hydroxide, sodium methoxide and potassium phosphate, and the amount of the base is preferably 1.1 to 1.5 times the molar amount of the glycinimine ester.
In the synthesis method, the organic solvent is any one of toluene, tetrahydrofuran and n-pentane.
In the above synthesis method, the reaction is preferably carried out at 30 ℃ for 12 to 24 hours.
The invention has the following beneficial effects:
the invention takes a diphosphine dinitrogen chiral ruthenium complex as a catalyst, racemic allyl alcohol compounds and glycine imine ester as substrates, quaternary ammonium salt and 18-crown ether-6 as additives, cesium carbonate and the like as alkali, and synthesizes chiral 4-hydroxy amino acid derivatives by an asymmetric hydrogen-borrowing strategy in an inert gas atmosphere, thereby realizing the stereoselectivity control of two remote chiral centers. The method has the advantages of simple reaction system, cheap and easily-obtained substrate, capability of obtaining the chiral 4-hydroxy amino acid derivative by a one-pot method, no need of adding additional hydrogen source and oxidant, high atom economy, mild reaction conditions, no harm to environment and simple post-reaction treatment. In addition, the obtained chiral 4-hydroxy amino acid derivative has the characteristics of better yield, high stereoselectivity and the like, wherein the 4-hydroxy amino acid derivative with (2R,5S) configuration or (2S,5R) configuration is taken as a main component, and a substrate can be further converted into chiral amino alcohol, chiral diol and a chiral heterocyclic compound, so that the method is a green method for synthesizing the chiral 4-hydroxy amino acid derivative.
Detailed Description
The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to these examples.
Example 1
Under the protection of argon, 100.1mg (0.75mmol) of 1-phenylallyl alcohol, 89.3mg (0.3mmol) of glycineimine, 3.6mg (0.003mmol) of chiral ruthenium complex A, 51.2mg (0.15mmol) of tetrabutylammonium hydrogen sulfate, 40.2mg (0.15mmol) of 18-crown-6, 117.2mg (0.36mmol) of cesium carbonate and 1mL of toluene are added into a thick-wall pressure-resistant tube, magnetons are added for stirring, the mixture is cooled to room temperature after reaction is finished, dichloromethane is used for transferring, dichloromethane and toluene are removed by reduced pressure distillation, and a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 5:1 is used as an eluent, and the product is separated by column chromatography to obtain a white solid product with the following structural formula:
Figure BDA0003119289750000031
the yield of the white solid product is 71 percent, the dr value is 93:7, the ee value is more than 99 percent by high performance liquid chromatography, and the spectral data are as follows:1H NMR(400MHz,DMSO-d6)δ(ppm):7.53-7.51(m,5H),7.50-7.31(m,3H),7.30-7.11(m,5H),7.10-7.08(m,2H),5.15(dd,J＝8.4,4.4Hz,1H),4.46(dd,J＝11.2,5.2Hz,1H),1.86-1.83(m,1H),1.70-1.60(m,1H),1.58-1.51(m,2H),1.35(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.4,169.0,145.9,139.0,135.8,130.3,129.5,128.6,128.55,128.47,128.1,128.0,127.8,127.3,127.2,126.5,125.7,80.2,72.1,65.3,35.5,29.7,27.5；HRMS(ESI)m/z C28H31NO3[M+H]+theoretical 430.2377, found 430.2377.
Example 2
In this example, the same procedure as in example 1 was repeated except for replacing 1-phenylallyl alcohol in example 1 with an equimolar amount of 3-methylphenylallyl alcohol to give a white solid product of the formula:
Figure BDA0003119289750000041
the white solid of this example was obtained in 71% yield, 84:16 dr, and greater than 99% ee by HPLC, as shown by the following spectral data:1H NMR(400MHz,DMSO-d6)δ(ppm):7.53-7.36(m,8H),7.17(t,J＝7.5Hz,1H),7.12-7.00(m,5H),5.12-5.09(m,1H),4.43-4.13(m,1H),2.27(s,3H),1.86-1.65(m,2H),1.58-1.52(m,2H),1.34(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.6,169.1,145.9,139.1,136.9,136.0,130.4,128.74,128.70,128.3,128.2,127.9,127.42,127.38,127.3,126.5,123.0,80.4,72.2,65.5,35.5,29.8,27.6,21.2；HRMS(ESI)m/z C29H33NO3[M+H]+theoretical 444.2533, found 444.2538.
Example 3
In this example, the same procedure as in example 1 was repeated except for replacing 1-phenylallyl alcohol in example 1 with an equimolar amount of 3-methoxyphenylallyl alcohol to give a white solid product of the formula:
Figure BDA0003119289750000042
the white solid of this example was obtained in a yield of 72%, a dr value of 84:16 and an ee value of more than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.50-7.42(m,6H),7.38(t,J＝7.6Hz,2H),7.20(t,J＝7.7Hz,1H),7.10-7.08(m,2H),6.82-6.76(m,3H),5.16(t,J＝4.0Hz,1H),4.44(dd,J＝11.2,6.0Hz,1H),3.77(dd,J＝7.2,4.8Hz,1H),3.71(s,3H),1.86-1.80(m,1H),1.72-1.66(m,1H),1.58-1.50(m,2H),1.34(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.6,169.2,159.2,147.7,139.1,136.0,130.5,129.0,128.8,128.7,128.3,128.20,127.4,118.1,112.1,111.4,80.4,72.2,65.5,54.9,35.5,29.8,27.7；HRMS(ESI)m/z C29H33NO4[M+Na]+theoretical 482.2302, found 482.2308.
Example 4
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 3-fluorophenylallyl alcohol, the amount of the chiral ruthenium complex was increased to 0.006mmol, and the other steps were the same as in example 1 to give a white solid product of the formula:
Figure BDA0003119289750000051
the white solid of this example was obtained in a yield of 72%, a dr value of 91:9 and an ee value of more than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.52-7.30(m,9H),7.12-7.00(m,5H),5.33-5.30(m,1H),4.52(dd,J＝10.9,5.7Hz,1H),3.78(dd,J＝7.2,4.7Hz,1H),1.89-1.66(m,2H),1.60-1.53(m,2H),1.33(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.5,169.2,162.2(d,1JC-F＝241.5Hz),149.2(d,3JC-F＝6.5Hz),139.1,135.9,130.4,129.9(d,3JC-F＝8.2Hz),128.74,128.69,128.3,128.2,127.4,121.9(d,4JC-F＝2.3Hz),113.4(d,2JC-F＝20.9Hz),112.4(d,2JC-F＝21.2Hz),80.4,71.6,65.4,35.4,29.6,27.6；HRMS(ESI)m/z C28H30FNO3[M+H]+theoretical 448.2282, found 482.2286.
Example 5
In this example, the 1-phenylallyl alcohol of example 1 was replaced with an equimolar amount of 3-chlorophenylallyl alcohol, the amount of the chiral ruthenium complex was increased to 0.006mmol, and the other steps were the same as in example 1 to obtain a white solid product of the following structural formula:
Figure BDA0003119289750000052
the white solid of this example was obtained in 70% yield, a dr value of 85:15, and an ee value of more than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.52-7.26(m,11H),7.20(d,J＝7.4Hz,1H),7.12-7.08(m,2H),5.31(t,J＝4.6Hz,1H),4.50(dd,J＝10.8,5.7Hz,1H),3.79-3.75(m,1H),1.87-1.63(m,2H),1.60-1.49(m,2H),1.34(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):171.0,169.9,148.7,139.4,136.2,133.3,130.9,130.0,129.2,129.1,128.7,128.6,127.7,127.11,127.06,126.0,125.0,124.9,81.0,71.9,65.7,35.6,29.9,28.0；HRMS(ESI)m/z C28H30ClNO3[M+H]+theoretical 464.1987, found 464.1987.
Example 6
In this example, the equimolar of 3-bromophenylallyl alcohol was substituted for 1-phenylallyl alcohol in example 1, the amount of chiral ruthenium complex was increased to 0.006mmol, and the other steps were the same as in example 1 to give a white solid product of the formula:
Figure BDA0003119289750000061
the white solid of this example was obtained in 69% yield, a dr value of 83:17, and an ee value of more than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.50-7.35(m,10H),7.29-7.21(m,2H),7.11-7.09(m,2H),5.31(t,J＝4.5Hz,1H),4.48(dd,J＝10.9,5.8Hz,1H),3.78-3.75(m,1H),1.82-1.64(m,2H),1.59-1.50(m,2H),1.34(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.6,169.3,148.9,139.1,135.9,130.5,130.3,129.6,128.8,128.7,128.6,128.3,128.2,127.4,125.0,121.6,80.5,71.5,65.4,35.4,29.6,27.7；HRMS(ESI)m/z C28H30BrNO3[M+H]+theoretical 508.1482, found 508.1479.
Example 7
In this example, the same procedure as in example 1 was repeated except for replacing 1-phenylallyl alcohol in example 1 with an equimolar amount of 4-methylphenylallyl alcohol to give a white solid product of the formula:
Figure BDA0003119289750000062
the white solid of this example was obtained in 62% yield, a dr value of 89:11, and an ee value of more than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.53-7.36(m,8H),7.14-7.08(m,6H),5.07(dd,J＝7.8,4.4Hz,1H),4.41(dd,J＝11.0,6.0Hz,1H),3.76(dd,J＝7.4,4.6Hz,1H),1.85-1.81(m,1H),1.68-1.65(m,1H),1.57-1.48(m,2H),1.34(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):171.6,169.1,143.0,139.1,135.9,135.6,130.4,128.73,128.68,128.5,128.3,128.2,127.41,127.37,125.8,80.4,72.1,65.5,35.6,29.8,27.6,20.7；HRMS(ESI)m/z C29H33NO3[M+H]+theoretical 444.2533, found 444.2536.
Example 8
In this example, the same procedure as in example 1 was repeated except for replacing 1-phenylallyl alcohol in example 1 with an equimolar amount of 4-methoxyphenylallyl alcohol to give a white solid product of the formula:
Figure BDA0003119289750000071
the white solid of this example was obtained in 60% yield, a dr value of 89:11, and an ee value of more than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.53-7.36(m,8H),7.17-7.08(m,4H),6.85(d,J＝8.6Hz,2H),5.04(t,J＝4.4,1H),4.40(dd,J＝10.9,6.1Hz,1H),3.78-3.74(m,1H),3.72(s,3H),1.83-1.80(m,1H),1.66-1.64(m,1H),1.57-1.47(m,2H),1.34(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):171.0,169.5,158.6,139.6,138.4,136.4,130.8,129.2,129.1,128.7,128.6,127.8,127.4,113.8,80.8,72.2,66.0,55.5,36.0,30.3,28.1；HRMS(ESI)m/z C29H33NO4[M+H]+theoretical 460.2482, found 460.2486.
Example 9
In this example, the same procedure as in example 1 was repeated except for replacing 1-phenylallyl alcohol in example 1 with an equimolar amount of 4-isopropylphenylallyl alcohol to obtain a white solid product of the formula:
Figure BDA0003119289750000072
the white solid of this example was obtained in 52% yield, 84:16 dr, and greater than 99% ee by HPLCComprises the following steps:1H NMR(400MHz,DMSO-d6)δ(ppm):7.52-7.47(m,5H),7.43-7.36(m,3H),7.16-7.10(m,4H),7.10-7.08(m,2H),5.09-5.05(m,1H),4.46-4.38(m,1H),3.78(dd,J＝7.3,4.7Hz,1H),2.87-2.80(m,1H),1.88-1.82(m,1H),1.70-1.68(m,1H),1.60-1.51(m,2H),1.33(s,9H),1.18(s,3H),1.16(s,3H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.9,169.5,147.1,147.0,143.4,139.3,136.1,130.7,129.0,128.9,128.5,128.6,127.59,127.55,126.12,126.09,80.7,72.4,65.7,35.6,33.6j,30.1,27.8,24.2；HRMS(ESI)m/z C31H37NO3[M+H]+theoretical 472.2846, found 472.2848.
Example 10
In this example, the 1-phenylallyl alcohol of example 1 was replaced with an equimolar amount of 4-tert-butylphenyl allyl alcohol, and the procedure was otherwise the same as in example 1, to obtain a white solid product of the formula:
Figure BDA0003119289750000081
the white solid of this example was obtained in 52% yield and a dr value of 88:12 and an ee value of greater than 99% by HPLC, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.51-7.27(m,10H),7.19-7.09(m,4H),5.08-5.03(m,1H),5.43-4.41(m,1H),3.79-3.76(m,1H),1.85-1.82(m,1H),1.70-1.62(m,1H),1.60-1.49(m,2H),1.34(s,9H),1.26(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.6,169.2,149.0,142.9,139.1,136.0,130.4,128.8,128.7,128.3,128.2,127.4,125.6,124.7,80.4,72.1,65.5,35.5,34.2,31.3,29.9,27.7；HRMS(ESI)m/z C32H39NO3[M+H]+theoretical 486.3003, found 486.2999.
Example 11
In this example, the 1-phenylallyl alcohol in example 1 was replaced with equimolar 4-biphenylallyl alcohol, the amount of the chiral ruthenium complex was increased to 0.006mmol, and the other steps were the same as in example 1 to give a white solid product of the following structural formula:
Figure BDA0003119289750000082
the white solid of this example was obtained in 32% yield, a dr value of 89:11, and an ee value of 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.65-7.59(m,5H),7.52-7.34(m,12H),7.13-7.09(m,2H),5.23-5.20(m,1H),4.53-4.50(m,1H),4.53-4.50(m,1H),1.90-1.72(m,2H),1.63-1.56(m,2H),1.34(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.6,169.2,145.2,140.2,139.1,138.7,136.0,130.5,129.7,129.0,128.8,128.7,128.6,128.3,128.2,127.44,127.40,127.3,126.6,126.5,126.4,80.4,72.0,65.5,35.5,29.8,27.7；HRMS(ESI)m/z calc.for C34H35NO3[M+H]+theoretical 506.2690, found 506.2690.
Example 12
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 4-fluorophenylallyl alcohol, the amount of the chiral ruthenium complex was increased to 0.006mmol, and the other steps were the same as in example 1 to give a white solid product of the formula:
Figure BDA0003119289750000091
the white solid of this example was obtained in 59% yield, a dr value of 85:15, and an ee value of greater than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.53-7.36(m,8H),7.30-7.27(m,2H),7.13-7.08(m,4H),5.21(dd,J＝8.0,4.4Hz,1H),4.48(dd,J＝11.0,6.0Hz,1H),3.8(dd,J＝7.2,4.6Hz,1H),1.85-1.82(m,1H),1.70-1.66(m,1H),1.58-1.49(m,2H),1.34(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.6,161.1(d,1JC-F＝240.5Hz),159.9,142.1(d,4JC-F＝2.9Hz),139.1,135.9,130.4,128.74,128.69,128.3,128.2,127.7(d,3JC-F＝7.9Hz),127.42,127.38,114.7(d,2JC-F＝21.0Hz),80.4,71.5,65.5,35.6,29.7,27.6；HRMS(ESI)m/z C28H30FNO3[M+H]+theoretical 448.2282, found 448.2281.
Example 13
In this example, the 1-phenylallyl alcohol of example 1 was replaced with an equimolar amount of 4-chlorophenylallyl alcohol, the amount of the chiral ruthenium complex was increased to 0.006mmol, and the other steps were the same as in example 1 to obtain a white solid product of the following structural formula:
Figure BDA0003119289750000092
the white solid of this example was obtained in 71% yield, a dr value of 85:15, and an ee value of greater than 99% by HPLC, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.52-7.43(m,6H),7.40-7.34(m,4H),7.27(d,J＝8.2Hz,2H),7.10(t,J＝4.0Hz,2H),5.26(dd,J＝8.2,4.4Hz,1H),7.47(s,1H),3.78-3.74(m,1H),1.83-1.68(m,2H),1.58-1.46(m,2H),1.34(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.5,169.2,144.99,144.96,139.1,135.9,131.1,130.4,129.6,128.7,128.7,128.6,128.3,128.2,128.0,127.7,127.41,127.37,80.4,71.5,65.5,35.5,29.6,27.6；HRMS(ESI)m/z C28H30ClNO3[M+H]+theoretical 464.1987, found 464.1986.
Example 14
In this example, the equimolar of 4-bromophenylallyl alcohol was substituted for 1-phenylallyl alcohol in example 1, the amount of chiral ruthenium complex was increased to 0.006mmol, and the other steps were the same as in example 1 to give a white solid product of the formula:
Figure BDA0003119289750000101
the white solid of this example was obtained in 73% yield, 88:12 dr, and greater than 99% ee by HPLC, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.53-7.43(m,8H),7.40-7.37(m,2H),7.22(d,J＝8.4Hz,2H),7.11-7.08(m,2H),5.26(dd,J＝8.4,4.4Hz,1H),4.47-4.44(m,1H),3.78-3.74(m,1H),1.83-1.65(m,2H),1.56-1.35(m,2H),1.34(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.5,169.2,145.41,145.38,139.1,135.9,132.7,130.9,130.4,129.6,128.73,128.67,128.6,128.24,128.19,128.1,127.41,127.37,119.6,80.4,71.5,65.5,35.4,29.6,27.6；HRMS(ESI)m/z C28H30BrNO3[M+H]+theoretical 508.1482, found 508.1487.
Example 15
In this example, the 1-phenylallyl alcohol of example 1 was replaced with an equimolar amount of 2-methylphenylallyl alcohol, the amount of the chiral ruthenium complex was increased to 0.006mmol, and the other steps were the same as in example 1 to obtain a white solid product of the following structural formula:
Figure BDA0003119289750000102
the white solid of this example was obtained in 22% yield, a dr value of 76:24, and an ee value of greater than 99% by HPLC, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.59-7.35(m,9H),7.16-7.08(m,5H),5.06-5.04(m,1H),4.65-4.64(m,1H),3.80-3.77(m,1H),2.19(s,3H),1.92-1.90(m,1H),1.78-1.74(m,1H),1.51-1.50(m,2H),1.34(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.7,170.6,144.0,139.1,135.9,133.7,130.4,129.9,129.6,128.73,128.68,128.6,128.3,128.1,127.4,126.4,125.7,125.5,80.4,68.7,65.5,34.3,30.1,27.6,18.6；HRMS(ESI)m/z C29H33NO3[M+H]+theoretical 444.2533, found 444.2535.
Example 16
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 1-naphthylphenylallyl alcohol, the amount of the chiral ruthenium complex was increased to 0.006mmol, and the other steps were the same as in example 1 to give a white solid product of the formula:
Figure BDA0003119289750000111
the white solid of this example was obtained in 42% yield, a dr value of 80:20, and an ee value of more than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):8.08-8.06(m,1H),7.90(d,J＝8.2Hz,1H),7.78(d,J＝8.1Hz,1H),7.61-7.58(m,1H),7.50-7.34(m,11H),7.10-7.05(m,2H),5.37-5.33(m,1H),5.28-5.25(m,1H),3.83-3.77(m,1H),2.01-1.85(m,2H),1.82-1.76(m,1H),1.69-1.66(m,1H),1.30(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.7,169.2,141.7,139.1,136.0,133.4,130.5,130.0,128.8,128.70,128.67,128.3,128.2,127.4,127.1,125.6,123.5,122.9,80.4,69.3,65.5,34.9,30.4,27.6；HRMS(ESI)m/z C32H33NO3[M+H]+theoretical 480.2533, found 480.2533.
Example 17
In this example, the same procedure as in example 1 was repeated except for replacing 1-phenylallyl alcohol in example 1 with an equimolar amount of 2-naphthylallyl alcohol to give a white solid product of the formula:
Figure BDA0003119289750000112
the white solid of this example was obtained in 71% yield, a dr value of 86:14, and an ee value of greater than 99% by HPLC, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.86-7.84(m,3H),7.75(d,J＝7.4Hz,1H),7.50-7.35(m,11H),7.11-7.07(m,2H),5.33-5.30(m,1H),4.67-4.62(m,1H),3.81-3.77(m,1H),1.90-1.85(m,1H),1.71-1.62(m,3H),1.32(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.62,170.57,169.2,143.5,139.1,135.9,132.9,132.3,130.4,128.7,128.7,128.3,128.2,127.7,127.6,127.5,127.4,126.0,125.5,124.6,124.1,124,1,80.4,72.3,65.5,35.4,29.8,27.6；HRMS(ESI)m/z C32H33NO3[M+H]+theoretical 480.2533, found 480.2533.
Example 18
In this example, the same procedure as in example 1 was repeated except for replacing 1-phenylallyl alcohol in example 1 with an equimolar amount of 2-thiophenylallyl alcohol to give a pale yellow oily product of the formula:
Figure BDA0003119289750000121
the product of this example was a pale yellow oil with a yield of 30%, a dr value of 86:14, and an ee value of more than 99% by high performance liquid chromatography, and had the following spectral data:1H NMR(400MHz,DMSO-d6)δ(ppm):7.54-7.35(m,9H),7.12-7.10(m,2H),6.94-6.86(m,2H),5.54(t,J＝4.7Hz,1H),4.74-4.68(m,1H),3.81-3.78(m,1H),1.90-1.70(m,2H),1.67-1.60(m,2H),1.35(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):171.0,169.7,150.9,139.5,136.3,129.1,128.7,128.6,126.9,124.5,123.4,80.9,68.8,65.8,36.3,30.1,28.1；HRMS(ESI)m/z C26H29NO3S[M+H]+theoretical 436.1941, found 436.1943.
Example 19
In this example, the same procedure as in example 1 was repeated except for replacing 1-phenylallyl alcohol in example 1 by an equimolar amount of 3-thiophenylallyl alcohol to give a white solid product of the formula:
Figure BDA0003119289750000122
the white solid of this example was obtained in 71% yield, a dr value of 86:14, and an ee value of greater than 99% by HPLC, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.54-7.37(m,9H),7.21-7.20(m,1H),7.12-7.10(m,2H),7.01-7.00(m,1H),5.15-5.12(m,1H),4.56-4.51(m,1H),3.80-3.77(m,1H),1.88-1.82(m,1H),1.73-1.67(m,1H),1.60-1.55(m,2H),1.35(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.6,169.2,147.6,139.1,136.0,130.5,130.0,128.8,128.73,128.65,128.3,128.2,127.4,126.2,125.9,120.2,80.4,68.6,65.5,34.9,29.8,27.7；HRMS(ESI)m/z C26H29NO3S[M+H]+theoretical 436.1941, found 436.1947.
Example 20
In this example, the same procedure as in example 1 was repeated except for replacing 1-phenylallyl alcohol in example 1 with an equimolar amount of 3-furylallyl alcohol to give a white solid product of the formula:
Figure BDA0003119289750000131
the white solid of this example was obtained in 56% yield, a dr value of 89:11, and an ee value of more than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.55-7.46(m,6H),7.44-7.37(m,4H),7.14-7.12(m,2H),6.37(s,1H),4.99(t,J＝4.8Hz,1H),4.45-4.36(m,1H),3.82-3.78(m,1H),1.91-1.84(m,2H),1.75-1.69(m,2H),1.36(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.65,170.61,169.2,143.1,139.2,138.7,136.0,130.4,130.0,128.74,128.71,128.3,128.2,127.4,109.14,109.10,80.4,65.5,65.0,34.3,29.7,27.7；HRMS(ESI)m/z C26H29NO4[M+H]+theoretical 420.2169, found 420.2176.
Example 21
In this example, the 1-phenylallyl alcohol of example 1 was replaced with an equimolar amount of 3-bromo-4-fluorophenylallyl alcohol, and the procedure was otherwise the same as in example 1, to give a white solid product of the formula:
Figure BDA0003119289750000132
the white solid of this example was obtained in 68% yield, a dr value of 83:17, and an ee value of more than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.57-7.36(m,9H),7.29(d,J＝7.1Hz,2H),7.11-7.09(m,2H),5.36(t,J＝4.6Hz,1H),4.52-4.49(m,1H),3.79-3.76(m,1H),1.84-1.80(m,1H),1.70-1.66(m,1H),1.58-1.53(m,2H),1.33(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.5,169.3,157.1(d,1JC-F＝242.0Hz),144.2(d,4JC-F＝3.2Hz),139.1,135.9,130.6,130.4,129.6,128.7,128.5,128.25,128.20,127.4,127.1(d,3JC-F＝7.5Hz),116.3(d,2JC-F＝21.8Hz),107.5(d,2JC-F＝20.8Hz),80.4,71.0,65.4,35.4,29.5,27.6；HRMS(ESI)m/z C28H29BrFNO3[M+H]+theoretical 526.1388, found 526.1392.
Example 22
In this example, the same procedure as in example 1 was repeated except for replacing 1-phenylallyl alcohol in example 1 with an equimolar amount of 3, 5-dimethylphenylallyl alcohol to give a white solid product of the formula:
Figure BDA0003119289750000141
the white solid of this example was obtained in 55% yield, a dr value of 85:15, and an ee value of more than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.52-7.36(m,8H),7.10-7.08(m,2H),6.83(d,J＝6.3Hz,3H),5.08-5.05(m,1H),4.36(dd,J＝10.8,6.1Hz,1H),3.78(dd,J＝7.1,4.9Hz,1H),2.22(s,6H),1.86-1.79(m,1H),1.72-1.63(m,1H),1.60-1.49(m,2H),1.33(s,9H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.6,169.1,145.9,139.2,136.8,136.0,130.5,128.8,128.7,128.3,128.2,128.1,127.44,127.41,123.7,80.3,72.3,65.5,35.5,29.9,27.6,21.1；HRMS(ESI)m/z C30H35NO3[M+H]+theoretical 458.2690, found 458.2691.
Example 23
In this example, the 1-phenylallyl alcohol of example 1 was replaced with an equimolar amount of methallyl alcohol, the amount of the chiral ruthenium complex was increased to 0.006mmol, and the other steps were the same as in example 1 to give a colorless oily product of the following structural formula:
Figure BDA0003119289750000142
the yield of the product in this example was 57% as a colorless oil, dr was 79:21, and ee was 11% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,DMSO-d6)δ(ppm):7.52-7.35(m,8H),7.14-7.12(m,2H),4.41(dd,J＝8.4,4.8Hz,1H),3.79-3.75(m,1H),3.54-3.50(m,1H),1.91-1.71(m,2H),1.36(s,9H),1.26-1.21(m,2H),1.00(s,3H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.80,170.76,169.2,139.2,136.1,130.5,128.80,128.76,128.32,128.27,127.5,80.4,65.9,65.6,35.5,30.0,29.6,27.8,23.6；HRMS(ESI)m/z C23H29NO3[M+H]+theoretical 368.2220, found 368.2224.
Example 24
In this example, the 1-phenylallyl alcohol of example 1 was replaced with an equimolar amount of benzyl allyl alcohol, the amount of the chiral ruthenium complex was increased to 0.006mmol, and the other steps were the same as in example 1 to give a colorless oily product of the following structural formula:
Figure BDA0003119289750000151
the yield of the product in this example was 41% as a colorless oil, dr was 84:16, and ee was 18% by high performance liquid chromatography, and the spectral data was:1H NMR(400MHz,DMSO-d6)δ(ppm):7.50-7.39(m,8H),7.22-7.08(m,7H),4.56-4.55(m,1H),3.76-3.74(m,1H),3.60(s,1H),2.65-2.51(m,2H),1.98-1.94(m,1H),1.76-1.74(m,1H),1.35(s,9H),1.17(s,2H)；13C NMR(100MHz,DMSO-d6)δ(ppm):170.6,169.0,139.4,139.2,136.0,130.4,129.40,129.38,128.71,128.66,128.2,128.0,127.4,125.7,80.3,71.0,65.9,43.6,32.8,29.9,27.7；HRMS(ESI)m/z C29H33NO3[M+H]+theoretical 444.2533, found 444.2534.
Example 25
In this example, using equimolar chiral ruthenium complex B instead of chiral ruthenium complex a, the other procedure was the same as in example 1 to obtain a white solid product of the formula:
Figure BDA0003119289750000152
the white solid of this example was obtained in 61% yield, a dr value of 90:10, and an ee value of more than 99% by high performance liquid chromatography, and the spectral data were:1H NMR(400MHz,CDCl3)δ(ppm):7.63(d,J＝7.0Hz,2H),7.46-7.43(m,3H),7.41-7.31(m,7H),7.26-7.23(m,1H),7.17-7.15(m,2H),4.68-4.66(m,1H),4.13-4.04(m,2H),2.14-2.05(m,1H),2.00-1.92(m,1H),1.87-1.82(m,2H),1.43(s,9H)；13C NMR(100MHz,CDCl3)δ(ppm):171.1,145.3,139.3,136.6,130.6,129.0,128.8,128.7,128.5,128.3,127.7,127.4,126.0,81.4,74.6,65.4,36.3,31.1,28.2；HRMS(ESI)m/z C28H31NO3[M+H]+theoretical 430.2377, found 430.2377.
The chiral 4-hydroxy amino acid derivative synthesized by the invention can be oxidized by a dess-martin oxidant at room temperature to obtain corresponding ketone, the obtained ketone is subjected to diphenyl removal and condensation under an acidic condition to obtain imine, the imine is reduced in a hydrogen atmosphere by taking Pt/C as a catalyst to obtain a chiral 2, 5-substituted pyrrolidine derivative, and the obtained chiral 2, 5-substituted pyrrolidine derivative can be used as a drug intermediate to synthesize an antagonist. The following compounds synthesized in example 1 and example 25 are exemplified:
a dry 25mL eggplant-shaped bottle was taken, and 0.5mmol of the compound of example 1 (denoted as Compound 1) was dissolved in 5mL of CH2Cl2Then 0.75mmol of dess-martin oxidant is added, and the reaction is carried out for 2h at room temperature, and the ketone (compound 2) is obtained by oxidation, wherein the yield is 85%. Filtering and concentrating by a rotary evaporator, dissolving the crude product in tetrahydrofuran, adding 1mL of citric acid aqueous solution with the mass concentration of 15 percent, continuing to react for 2 hours, removing diphenyl and condensing to obtain imine. After the reaction is finished, solid Na is added2CO3Neutralizing the reaction solution with CH2Cl2Extracting the reaction solution for three times, collecting the organic phase and adding anhydrous Na2SO4Drying for 30 min. Filter and use the whirlwindConcentrating by a rotary evaporator, dissolving the obtained crude product in methanol, adding a 5% Pt/C catalyst, putting the mixture into an autoclave, filling 10bar of hydrogen, reacting in a water bath at 30 ℃ for 12h to reduce imine, and separating the obtained crude product by column chromatography to obtain a colorless oily 2R, 5S-substituted pyrrolidine derivative (compound 3), wherein the yield is 60%, and the dr value is 99: 1. The colorless oil 3 was used as an intermediate for further synthesis of 2, 5-disubstituted pyrrole skeleton original phenol ligands by literature methods (J.Am.chem.Soc,2014,136, 3016-3019).
Figure BDA0003119289750000161
The spectroscopic data of the colorless oil 3 obtained are:1H NMR(400MHz,CDCl3)δ(ppm):7.44(d,J＝7.2Hz,2H),7.33(t,J＝7.2Hz,2H),7.27-7.23(m,1H),4.16(dd,J＝9.4,5.9Hz,1H),3.80(dd,J＝8.8,4.8Hz,1H),2.40(brs,1H),2.22-2.03(m,3H),1.70-1.65(m,1H),1.49(s,9H)；13C NMR(100MHz,CDCl3)δ(ppm):174.6,143.5,128.5,127.2,126.9,81.2,63.9,61.0,34.4,31.1,28.2；HRMS(ESI)m/z C15H21NO2[M+H]+theoretical 248.1645, found 248.1644.
Similarly, the compound of example 25 (compound 4) was prepared as an intermediate compound 6 according to the above-mentioned method, and an antagonist (Tetrahedron,2010,66,8832-8836) was synthesized by a literature method.
Figure BDA0003119289750000171
The yield of the colorless oil 6 was 59%, the dr value was 99:1, the ee value was 88% by high performance liquid chromatography, and the spectral data was:1H NMR(400MHz,CDCl3)δ(ppm):7.38(d,J＝7.4Hz,2H),7.27(t,J＝7.4Hz,2H),7.20-7.18(m,1H),4.11(dd,J＝9.3,6.0Hz,1H),3.80(dd,J＝8.4,4.6Hz,1H),2.40(s,1H),2.16-1.96(m,3H),1.67-1.56(m,1H),1.42(s,9H)；13C NMR(100MHz,CDCl3)δ(ppm):174.7,143.5,128.6,127.3,126.9,81.3,63.9,61.1,34.4,31.2,28.2；HRMS(ESI)m/z C15H21NO2[M+H]+theoretical 248.1645, found 248.1639.

Claims (9)

1. A method for synthesizing chiral 4-hydroxy amino acid derivatives, which is characterized in that: adding an allyl alcohol compound shown in a formula I, glycine imine ester shown in a formula II, a chiral ruthenium complex A or a chiral ruthenium complex B, alkali, quaternary ammonium salt and 18-crown ether-6 into an organic solvent under an inert gas atmosphere, reacting at 25-50 ℃, and separating and purifying a product after the reaction is completed to obtain a chiral 4-hydroxy amino acid derivative shown in a formula III or a formula IV;
Figure FDA0003119289740000011
in the formula R1Represents aryl, substituted aryl, heterocyclic aryl, C1～C4Any one of alkyl groups;
the structural formula of the chiral ruthenium complex A is shown as follows:
Figure FDA0003119289740000012
the structural formula of the chiral ruthenium complex B is shown as follows:
Figure FDA0003119289740000013
wherein Ar represents 3, 5-dimethylphenyl;
the quaternary ammonium salt is any one of tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide and tetrabutylammonium chloride;
the alkali is any one of cesium carbonate, sodium hydroxide, sodium methoxide and potassium phosphate.
2. The method of synthesizing a chiral 4-hydroxyamino acid derivative according to claim 1, wherein: the R is1Represents phenyl, C1～C4Alkyl-substituted phenyl, C1～C4Any one of alkoxy substituted phenyl, halogenated phenyl, biphenyl, naphthyl, thienyl, furyl, methyl and benzyl.
3. The method of synthesizing a chiral 4-hydroxyamino acid derivative according to claim 1 or 2, wherein: the using amount of the allyl alcohol compound is 1-3 times of the molar amount of the glycinimine ester.
4. The method of synthesizing a chiral 4-hydroxyamino acid derivative according to claim 1 or 2, wherein: the dosage of the chiral ruthenium complex A or the chiral ruthenium complex B is 1 to 2 percent of the molar weight of the glycinimine ester.
5. The method of synthesizing a chiral 4-hydroxyamino acid derivative according to claim 1 or 2, wherein: the dosage of the quaternary ammonium salt is 0.25-1 time of the molar weight of the glycinimine ester.
6. The method of synthesizing a chiral 4-hydroxyamino acid derivative according to claim 1 or 2, wherein: the dosage of the 18-crown ether-6 is 0.25-1 time of the molar weight of the glycinimine ester.
7. The method of synthesizing a chiral 4-hydroxyamino acid derivative according to claim 1 or 2, wherein: the dosage of the alkali is 1.1-1.5 times of the molar weight of the glycinimine ester.
8. The method of synthesizing a chiral 4-hydroxyamino acid derivative according to claim 1 or 2, wherein: the organic solvent is any one of toluene, tetrahydrofuran and n-pentane.
9. The method of synthesizing a chiral 4-hydroxyamino acid derivative according to claim 1 or 2, wherein: reacting for 12-24 hours at 30 ℃.
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