CN113429249B - Method for synthesizing chiral 4-hydroxy amino acid derivative - Google Patents

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

Info

Publication number
CN113429249B
CN113429249B CN202110671128.0A CN202110671128A CN113429249B CN 113429249 B CN113429249 B CN 113429249B CN 202110671128 A CN202110671128 A CN 202110671128A CN 113429249 B CN113429249 B CN 113429249B
Authority
CN
China
Prior art keywords
chiral
amino acid
hydroxy amino
synthesizing
acid derivative
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202110671128.0A
Other languages
Chinese (zh)
Other versions
CN113429249A (en
Inventor
王超
张晓慧
马威
汤卫军
薛东
李超群
肖建良
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shaanxi Normal University
Original Assignee
Shaanxi Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shaanxi Normal University filed Critical Shaanxi Normal University
Priority to CN202110671128.0A priority Critical patent/CN113429249B/en
Publication of CN113429249A publication Critical patent/CN113429249A/en
Application granted granted Critical
Publication of CN113429249B publication Critical patent/CN113429249B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
    • B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
    • B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
    • B01J2531/0266—Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL"
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/821—Ruthenium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)

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, takes racemized allyl alcohol compounds and glycine imine ester as substrates, takes quaternary ammonium salt and 18-crown ether-6 as additives, takes cesium carbonate and the like as alkali, synthesizes chiral 4-hydroxy amino acid derivatives in an inert gas atmosphere through an asymmetric hydrogen borrowing strategy, and realizes the stereoselective control of two remote chiral centers. The substrate of the invention is cheap and easy to obtain, does not need to additionally add an oxidant and a reducing agent, has high atom economy, mild reaction conditions and simple and convenient operation, the obtained chiral compound has better yield and high stereoselectivity, wherein the chiral compound with (2R, 5S) configuration or (2S, 5R) configuration is taken as the main component, and the substrate can be further converted into chiral amino alcohol, chiral diol and chiral heterocyclic compound, thus being a green method for synthesizing chiral 4-hydroxy amino acid derivatives.

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 utilizing an asymmetric hydrogen borrowing process under the catalysis of chiral ruthenium complex.
Background
Chiral 4-hydroxy amino acid derivatives are important constituent fragments of a plurality of complex natural products, and are also important compounds for constructing various bioactive natural products and medicines, and have certain bioactivity. A common method for synthesizing chiral 4-hydroxy amino acid derivatives in the literature is to use ketene compounds and glycine imine esters for asymmetric Michael addition to obtain 4-carbonyl amino acid derivatives, and then reduce the 4-carbonyl amino acid derivatives by sodium borohydride to obtain 4-hydroxy amino acid derivatives (tetrahedron. Lett.1998,39,5347-5350; angew. Chem. Int. Ed.2013,52, 6988-6991). The above reaction requires the use of an additional reducing agent, a two-step reaction, and a low-temperature reaction, and is severe in conditions. Therefore, the development of a green, efficient and simple method for synthesizing chiral 4-hydroxy amino acid derivatives 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 invention adopts the technical scheme that: under the inert gas atmosphere, adding allyl alcohol compound shown in a formula I, glycine imine ester shown in a formula II, chiral ruthenium complex A or chiral ruthenium complex B, alkali, quaternary ammonium salt and 18-crown ether-6 into an organic solvent, reacting at 25-50 ℃, and separating and purifying a product after the reaction is completed to obtain chiral 4-hydroxy amino acid derivatives shown in a formula III or a formula IV; the reaction equation is as follows:
Figure BDA0003119289750000011
wherein R is 1 Represents aryl, substituted aryl, heterocyclic aryl, C 1 ～C 4 Any one of alkyl groups, specifically, the following: phenyl, C 1 ～C 4 Alkyl-substituted phenyl, C 1 ～C 4 Alkoxy 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 a 3, 5-dimethylphenyl group.
In the above synthesis method, the allyl alcohol compound is preferably used in an amount of 1 to 3 times the molar amount of the glycine imine ester.
In the above synthesis method, the chiral ruthenium complex A or the chiral ruthenium complex B is preferably used in an amount of 1 to 2% of the molar amount of the glycine imine ester.
In the above synthetic method, the quaternary ammonium salt is any one of tetrabutylammonium bisulfate, tetrabutylammonium bromide and tetrabutylammonium chloride; preferably, the amount of quaternary ammonium salt is 0.25 to 1 time of the molar amount of glycine imine ester.
In the above synthesis method, the amount of 18-crown-6 is preferably 0.25 to 1 time the molar amount of glycine imine ester.
In the above synthesis method, the alkali is any one of cesium carbonate, sodium hydroxide, sodium methoxide and potassium phosphate, and the amount of the alkali is preferably 1.1 to 1.5 times the molar amount of the glycine imine ester.
In the above synthetic 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 beneficial effects of the invention are as follows:
according to the invention, a chiral ruthenium complex of biphosphine dinitrogen is used as a catalyst, a racemized allyl alcohol compound and glycine imine ester are used as substrates, quaternary ammonium salt and 18-crown ether-6 are used as additives, cesium carbonate and the like are used as bases, and chiral 4-hydroxy amino acid derivatives are synthesized in an inert gas atmosphere through an asymmetric hydrogen borrowing strategy, so that the stereoselectivity control of two remote chiral centers is realized. The invention has simple reaction system, low cost and easy obtainment of substrate, can obtain chiral 4-hydroxy amino acid derivative by a one-pot method, does not need to add extra hydrogen source and oxidant, has high atom economy, mild reaction condition, no harm to environment and simple post-treatment of reaction. In addition, the obtained chiral 4-hydroxy amino acid derivative has the characteristics of better yield, high stereoselectivity and the like, wherein the (2R, 5S) configuration or the (2S, 5R) configuration 4-hydroxy amino acid derivative 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 chiral 4-hydroxy amino acid derivative 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
100.1mg (0.75 mmol) of 1-phenylallyl alcohol, 89.3mg (0.3 mmol) of glycine imine ester, 3.6mg (0.003 mmol) of chiral ruthenium complex A, 51.2mg (0.15 mmol) of tetrabutylammonium bisulfate, 40.2mg (0.15 mmol) of 18-crown ether-6, 117.2mg (0.36 mmol) of cesium carbonate and 1mL of toluene are added into a thick-wall pressure-resistant tube under the protection of argon, stirred by adding magneton, reacted for 15 hours at 30 ℃, cooled to room temperature after the reaction, dichloromethane is used for transferring, dichloromethane and toluene are distilled off under reduced pressure, and a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 5:1 is taken as a leaching agent, 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%, the dr value is 93:7, and the ee value is more than 99% by high performance liquid chromatography, and the spectrum data are as follows: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 28 H 31 NO 3 [M+H] + theoretical 430.2377, found 430.2377.
Example 2
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 3-methylphenylallyl alcohol, and the other steps were the same as in example 1, to give a white solid product of the formula:
Figure BDA0003119289750000041
the white solid product of this example has a yield of 71%, a dr value of 84:16, an ee value of greater than 99% as measured by HPLC, and spectral data of： 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 29 H 33 NO 3 [M+H] + Theoretical 444.2533, found 444.2538.
Example 3
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 3-methoxyphenylallyl alcohol, and the other steps were the same as in example 1, to give a white solid product of the formula:
Figure BDA0003119289750000042
the white solid product of this example has a yield of 72%, a dr value of 84:16, and an ee value of greater than 99% as measured by high performance liquid chromatography, and the spectral data is: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 29 H 33 NO 4 [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 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 yield of the white solid product of this example was 72%, the dr value was 91:9, and the ee value was greater than 99% as measured by high performance liquid chromatography, and the spectral data were: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):170.5,169.2,162.2(d, 1 J C-F ＝241.5Hz),149.2(d, 3 J C-F ＝6.5Hz),139.1,135.9,130.4,129.9(d, 3 J C-F ＝8.2Hz),128.74,128.69,128.3,128.2,127.4,121.9(d, 4 J C-F ＝2.3Hz),113.4(d, 2 J C-F ＝20.9Hz),112.4(d, 2 J C-F ＝21.2Hz),80.4,71.6,65.4,35.4,29.6,27.6；HRMS(ESI)m/z C 28 H 30 FNO 3 [M+H] + theoretical 448.2282, found 482.2286.
Example 5
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 3-chlorophenyl allyl alcohol, 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 BDA0003119289750000052
the white solid product of this example has a yield of 70%, a dr value of 85:15, and an ee value of greater than 99% as measured by high performance liquid chromatography, and the spectral data is: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 28 H 30 ClNO 3 [M+H] + theoretical 464.1987, found 464.1987.
Example 6
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 3-bromophenyl allyl alcohol, 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 yield of the white solid product of this example was 69%, the dr value was 83:17, and the ee value was greater than 99% as measured by high performance liquid chromatography, and the spectral data were: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 28 H 30 BrNO 3 [M+H] + theoretical 508.1482, found 508.1479.
Example 7
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 4-methylphenylallyl alcohol, and the other steps were the same as in example 1, to give a white solid product of the formula:
Figure BDA0003119289750000062
the yield of the white solid product of this example was 62%, the dr value was 89:11, and the ee value was greater than 99% as measured by high performance liquid chromatography, and the spectral data were: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 29 H 33 NO 3 [M+H] + theoretical 444.2533, found 444.2536.
Example 8
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 4-methoxyphenylallyl alcohol, and the other steps were the same as in example 1, to give a white solid product of the formula:
Figure BDA0003119289750000071
the white solid product of this example has a yield of 60%, a dr value of 89:11, and an ee value of greater than 99% as measured by high performance liquid chromatography, and has spectral data of: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 29 H 33 NO 4 [M+H] + theoretical 460.2482, found 460.2486.
Example 9
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 4-isopropylphenyl allyl alcohol, and the other steps were the same as in example 1, to give a white solid product of the formula:
Figure BDA0003119289750000072
this embodimentThe yield of the white solid product is 52%, the dr value is 84:16, the ee value is more than 99% by high performance liquid chromatography, and the spectrum data are as follows: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 31 H 37 NO 3 [M+H] + theoretical 472.2846, found 472.2848.
Example 10
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 4-t-butylphenylallyl alcohol, and the other steps were the same as in example 1, to obtain a white solid product having the following structural formula:
Figure BDA0003119289750000081
the white solid yield of this example was 52%, dr 88:12, ee greater than 99% by HPLC, and the spectral data were: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 32 H 39 NO 3 [M+H] + theoretical 486.3003, found 486.2999.
Example 11
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 4-biphenylallyl alcohol, 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 BDA0003119289750000082
the white solid product of this example has a yield of 32%, a dr of 89:11 and an ee of 99% by high performance liquid chromatography, and the spectral data are: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 34 H 35 NO 3 [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 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 product of this example has a yield of 59%, a dr value of 85:15, and an ee value of greater than 99% as measured by high performance liquid chromatography, and has spectral data of: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):170.6,161.1(d, 1 J C-F ＝240.5Hz),159.9,142.1(d, 4 J C-F ＝2.9Hz),139.1,135.9,130.4,128.74,128.69,128.3,128.2,127.7(d, 3 J C-F ＝7.9Hz),127.42,127.38,114.7(d, 2 J C-F ＝21.0Hz),80.4,71.5,65.5,35.6,29.7,27.6；HRMS(ESI)m/z C 28 H 30 FNO 3 [M+H] + theoretical 448.2282, found 448.2281.
Example 13
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 4-chlorophenyl allyl alcohol, 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 BDA0003119289750000092
the white solid product of this example has a yield of 71%, a dr value of 85:15, and an ee value of greater than 99% as measured by high performance liquid chromatography, and has spectral data of: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 28 H 30 ClNO 3 [M+H] + theoretical 464.1987, found 464.1986.
Example 14
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 4-bromophenyl allyl alcohol, 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 product of this example has a yield of 73%, a dr value of 88:12 and a high ee value as measured by high performance liquid chromatographyAt 99%, the spectral data are: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 28 H 30 BrNO 3 [M+H] + theoretical 508.1482, found 508.1487.
Example 15
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 2-methylphenylallyl alcohol, 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 BDA0003119289750000102
the white solid product of this example has a yield of 22%, a dr value of 76:24, and an ee value of greater than 99% as measured by high performance liquid chromatography, and the spectral data is: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 29 H 33 NO 3 [M+H] + theoretical 444.2533, found 444.2535.
Example 16
In this example, 1-phenylallyl alcohol in example 1 was replaced with equimolar 1-naphthylphenylallyl alcohol, the amount of 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 having the following structural formula:
Figure BDA0003119289750000111
the yield of the white solid product of this example was 42%, the dr value was 80:20, and the ee value was greater than 99% as measured by high performance liquid chromatography, and the spectral data were: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 32 H 33 NO 3 [M+H] + theoretical 480.2533, found 480.2533.
Example 17
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 2-naphthylallyl alcohol, and the other steps were the same as in example 1, to give a white solid product of the formula:
Figure BDA0003119289750000112
the white solid product of this example has a yield of 71%, a dr of 86:14 and an ee of greater than 99% as measured by high performance liquid chromatography, and has spectral data of: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 32 H 33 NO 3 [M+H] + theoretical 480.2533, found 480.2533.
Example 18
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 2-thiophenylallyl alcohol, and the other steps were the same as in example 1, to give a pale yellow oily product of the following structural formula:
Figure BDA0003119289750000121
the yield of the pale yellow oily product of this example was 30%, the dr value was 86:14, and the ee value was greater than 99% by high performance liquid chromatography, and the spectral data were: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 26 H 29 NO 3 S[M+H] + theoretical 436.1941, found 436.1943.
Example 19
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 3-thiophenylallyl alcohol, and the other steps were the same as in example 1, to give a white solid product of the formula:
Figure BDA0003119289750000122
the white solid product of this example has a yield of 71%, a dr of 86:14 and an ee of greater than 99% as measured by high performance liquid chromatography, and has spectral data of: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 26 H 29 NO 3 S[M+H] + theoretical 436.1941, found 436.1947.
Example 20
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 3-furylallyl alcohol, and the other steps were the same as in example 1, to give a white solid product of the formula:
Figure BDA0003119289750000131
the yield of the white solid product of this example was 56%, the dr value was 89:11, and the ee value was greater than 99% as measured by high performance liquid chromatography, and the spectral data were: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 26 H 29 NO 4 [M+H] + theoretical 420.2169, found 420.2176.
Example 21
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 3-bromo-4-fluorophenylallyl alcohol, and the other steps were the same as in example 1, to give a white solid product of the formula:
Figure BDA0003119289750000132
the white solid product of this example has a yield of 68%, a dr of 83:17 and an ee of greater than 99% as measured by high performance liquid chromatography, and has spectral data as follows: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):170.5,169.3,157.1(d, 1 J C-F ＝242.0Hz),144.2(d, 4 J C-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, 3 J C-F ＝7.5Hz),116.3(d, 2 J C-F ＝21.8Hz),107.5(d, 2 J C-F ＝20.8Hz),80.4,71.0,65.4,35.4,29.5,27.6；HRMS(ESI)m/z C 28 H 29 BrFNO 3 [M+H] + theoretical 526.1388, found 526.1392.
Example 22
In this example, the 1-phenylallyl alcohol of example 1 was replaced with equimolar 3, 5-dimethylphenylallyl alcohol, and the other steps were the same as in example 1, to give a white solid product of the formula:
Figure BDA0003119289750000141
the yield of the white solid product of this example was 55%, the dr value was 85:15, and the ee value was greater than 99% as measured by high performance liquid chromatography, and the spectral data were: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 30 H 35 NO 3 [M+H] + theoretical 458.2690, found 458.2691.
Example 23
In this example, 1-phenylallyl alcohol in example 1 was replaced with equimolar methallyl alcohol, 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 colorless oily product having the following structural formula:
Figure BDA0003119289750000142
the yield of the colorless oily product in this example was 57%, the dr value was 79:21, and the ee value was 11% by HPLC, and the spectral data were: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 23 H 29 NO 3 [M+H] + theoretical 368.2220, found 368.2224.
Example 24
In this example, 1-phenylallyl alcohol in example 1 was replaced with equimolar benzyl allyl alcohol, 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 colorless oily product having the following structural formula:
Figure BDA0003119289750000151
the yield of the colorless oily product of this example was 41%, the dr value was 84:16, and the ee value was 18% by HPLC, and the spectral data were: 1 H NMR(400MHz,DMSO-d 6 )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)； 13 C NMR(100MHz,DMSO-d 6 )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 C 29 H 33 NO 3 [M+H] + theoretical 444.2533, found 444.2534.
Example 25
In this example, an equimolar chiral ruthenium complex B was used instead of chiral ruthenium complex a, and the other steps were the same as in example 1 to give a white solid product of the formula:
Figure BDA0003119289750000152
the yield of the white solid product of this example was 61%, the dr value was 90:10, and the ee value was greater than 99% as measured by high performance liquid chromatography, and the spectral data were: 1 H NMR(400MHz,CDCl 3 )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)； 13 C NMR(100MHz,CDCl 3 )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 C 28 H 31 NO 3 [M+H] + theoretical 430.2377, found 430.2377.
The chiral 4-hydroxy amino acid derivative synthesized by the method can be oxidized by dess-martin oxidant at room temperature to obtain corresponding ketone, the obtained ketone is subjected to diphenyl and condensation to form imine under an acidic condition, pt/C is used as a catalyst, imine is reduced in hydrogen atmosphere to obtain chiral 2, 5-substituted pyrrolidine derivative, and the obtained chiral 2, 5-substituted pyrrolidine derivative can be used as a pharmaceutical intermediate to synthesize an antagonist. The compounds synthesized in example 1 and example 25 are exemplified below:
a dry 25mL eggplant-shaped bottle was taken and 0.5mmol of the compound of example 1 (designated compound 1) was dissolved in 5mL CH 2 Cl 2 To this, 0.75mmol of dess-martin oxidant was added and reacted at room temperature for 2 hours to give ketone (compound 2) in 85% yield. The mixture was filtered and concentrated by a rotary evaporator, and the crude product was dissolved in tetrahydrofuran, and 1mL of 15% strength by mass aqueous citric acid was added to continue the reaction for 2 hours, and the mixture was diphenyl-removed and condensed to an imine. After the reaction is finished, solid Na is added 2 CO 3 Neutralizing the reaction solution with CH 2 Cl 2 Extracting the reaction liquid and extractingCollecting organic phase, adding anhydrous Na 2 SO 4 Drying for 30min. The crude product obtained was filtered and concentrated by rotary evaporator, dissolved in methanol, and 5% pt/C catalyst was added, put into autoclave, charged with 10bar hydrogen, reacted in water bath at 30 ℃ for 12 hours to reduce imine, and the crude product obtained was separated by column chromatography to obtain colorless oily 2r,5 s-substituted pyrrolidine derivative (compound 3) with a yield of 60% and a dr value of 99:1. The crude phenol ligands of the 2, 5-disubstituted pyrrole skeleton were further synthesized by literature methods as intermediates for colorless oil 3 (j.am. Chem. Soc,2014,136,3016-3019).
Figure BDA0003119289750000161
The spectrum data of the obtained colorless oil 3 were: 1 H NMR(400MHz,CDCl 3 )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)； 13 C NMR(100MHz,CDCl 3 )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 C 15 H 21 NO 2 [M+H] + theoretical 248.1645, found 248.1644.
Similarly, the compound of example 25 (compound 4) gives intermediate compound 6 as described above, and the antagonist can be synthesized by the methods of the literature (Tetrahedron, 2010,66,8832-8836).
Figure BDA0003119289750000171
The yield of the colorless oil 6 was 59%, the dr value was 99:1, and the ee value was 88% by high performance liquid chromatography, and the spectrum data were: 1 H NMR(400MHz,CDCl 3 )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)； 13 C NMR(100MHz,CDCl 3 )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 C 15 H 21 NO 2 [M+H] + theoretical 248.1645, found 248.1639.

Claims (7)

1. A method for synthesizing a chiral 4-hydroxy amino acid derivative, characterized by: under the inert gas atmosphere, adding allyl alcohol compound shown in a formula I, glycine imine ester shown in a formula II, chiral ruthenium complex A or chiral ruthenium complex B, alkali, quaternary ammonium salt and 18-crown ether-6 into an organic solvent, reacting at 25-50 ℃, and separating and purifying a product after the reaction is completed to obtain chiral 4-hydroxy amino acid derivatives shown in a formula III or a formula IV;
Figure FDA0004223849580000011
wherein R is 1 Represents phenyl, C 1 ～C 4 Alkyl-substituted phenyl, C 1 ～C 4 Any one of alkoxy substituted phenyl, halogenated phenyl, biphenyl, naphthyl, thienyl, furyl, methyl and benzyl;
the structural formula of the chiral ruthenium complex A is shown as follows:
Figure FDA0004223849580000012
the structural formula of the chiral ruthenium complex B is shown as follows:
Figure FDA0004223849580000013
wherein Ar represents a 3, 5-dimethylphenyl group;
the quaternary ammonium salt is any one of tetrabutylammonium bisulfate, tetrabutylammonium bromide and tetrabutylammonium chloride;
the alkali is any one of cesium carbonate, sodium hydroxide, sodium methoxide and potassium phosphate;
the organic solvent is any one of toluene, tetrahydrofuran and n-pentane.
2. The method for synthesizing a chiral 4-hydroxy amino acid derivative according to claim 1, characterized in that: the dosage of the allyl alcohol compound is 1 to 3 times of the molar quantity of the glycine imine ester.
3. The method for synthesizing a chiral 4-hydroxy amino acid derivative according to claim 1, characterized in that: the dosage of the chiral ruthenium complex A or the chiral ruthenium complex B is 1-2% of the molar weight of glycine imine ester.
4. The method for synthesizing a chiral 4-hydroxy amino acid derivative according to claim 1, characterized in that: the dosage of the quaternary ammonium salt is 0.25-1 times of the molar quantity of the glycine imine ester.
5. The method for synthesizing a chiral 4-hydroxy amino acid derivative according to claim 1, characterized in that: the dosage of the 18-crown ether-6 is 0.25 to 1 time of the molar quantity of the glycine imine ester.
6. The method for synthesizing a chiral 4-hydroxy amino acid derivative according to claim 1, characterized in that: the dosage of the alkali is 1.1 to 1.5 times of the molar quantity of the glycine imine ester.
7. The method for synthesizing a chiral 4-hydroxy amino acid derivative according to claim 1, characterized in that: reacting for 12-24 hours at 30 ℃.
CN202110671128.0A 2021-06-17 2021-06-17 Method for synthesizing chiral 4-hydroxy amino acid derivative Active CN113429249B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110671128.0A CN113429249B (en) 2021-06-17 2021-06-17 Method for synthesizing chiral 4-hydroxy amino acid derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110671128.0A CN113429249B (en) 2021-06-17 2021-06-17 Method for synthesizing chiral 4-hydroxy amino acid derivative

Publications (2)

Publication Number Publication Date
CN113429249A CN113429249A (en) 2021-09-24
CN113429249B true CN113429249B (en) 2023-06-16

Family

ID=77756184

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110671128.0A Active CN113429249B (en) 2021-06-17 2021-06-17 Method for synthesizing chiral 4-hydroxy amino acid derivative

Country Status (1)

Country Link
CN (1) CN113429249B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5691356A (en) * 1994-03-21 1997-11-25 Bristol-Myers Squibb Company Disubstituted heterocyclic thrombin inhibitors
CN102858788A (en) * 2010-04-28 2013-01-02 高砂香料工业株式会社 Ruthenium complex and method for preparing optically active alcohol compound
CN109809967A (en) * 2019-03-04 2019-05-28 陕西师范大学 A kind of method of synthesis of chiral alcohol
CN111320591A (en) * 2020-03-30 2020-06-23 陕西师范大学 Method for synthesizing chiral gamma-amino alcohol

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5691356A (en) * 1994-03-21 1997-11-25 Bristol-Myers Squibb Company Disubstituted heterocyclic thrombin inhibitors
CN102858788A (en) * 2010-04-28 2013-01-02 高砂香料工业株式会社 Ruthenium complex and method for preparing optically active alcohol compound
CN109809967A (en) * 2019-03-04 2019-05-28 陕西师范大学 A kind of method of synthesis of chiral alcohol
CN111320591A (en) * 2020-03-30 2020-06-23 陕西师范大学 Method for synthesizing chiral gamma-amino alcohol

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
An Iron/Amine-Catalyzed Cascade Process for the Enantioselective Functionalization of Allylic Alcohols;Adrien Quintard等;Angew. Chem. Int. Ed.;第52卷;12883-12887 *
Asymmetric Ruthenium-Catalyzed Hydroalkylation of Racemic Allylic Alcohols for the Synthesis of Chiral Amino Acid Derivatives;Xiaohui Zhang等;Angew. Chem. Int. Ed.;第61卷;e202203244（1-7） *
Methylene-Bridged Bis(imidazoline)-Derived 2-Oxopyrimidinium Salts as Catalysts for Asymmetric Michael Reactions;Andrey E. Sheshenev等;Angew. Chem. Int. Ed.;第52卷;6988-6991 *
Recent Achievements in Enantioselective Borrowing Hydrogen by the Combination of Iron- and Organocatalysis;Mylène Roudier et al.;The French connecTion;第70卷(第1/2期);97-101 *
Triple Iron/Copper/Iminium Activation for the Efficient Redox Neutral Catalytic Enantioselective Functionalization of Allylic Alcohols;Mylène Roudier等;ACS Catal.;第6卷;5236-5244 *
相转移催化法和手性催化加氢法立体选择性地合成Fmoc保护的(S)-3,5-二溴苯丙氨酸;王沁婷;赵帅;金雷;陈新;;有机化学(09);2242-2246 *

Also Published As

Publication number Publication date
CN113429249A (en) 2021-09-24

Similar Documents

Publication Publication Date Title
Gerspacher et al. 2-Amino-2-deoxyhexoses as chiral educts for hydroxylated indolizidines. Synthesis of (+)-castanospermine and (+)-6-epicastanospermine
CN102153557B (en) Chiral center nitrogen heterocyclic carbine precursor salt with quadrol skeleton, synthetic method and application
JP2007538041A (en) Method for producing diphenylazetidinone derivative
CN108409602B (en) Method for preparing α -aryl nitrile compound
CN110698467A (en) Synthetic method of engagliflozin
CN113429249B (en) Method for synthesizing chiral 4-hydroxy amino acid derivative
CN110981779B (en) Synthesis method of R-2- (2, 5-difluorophenyl) pyrrolidine
SU818484A3 (en) Method of preparing 4a,9b-trans-hexahydro-gamma-carbolin
CN115108937B (en) Synthesis method of alpha-azido ketone containing three-level stereo center
CN113024489A (en) Preparation method of oseltamivir synthesis process impurity
CN114057625B (en) C2-acyloxy-3-indolinone derivative and preparation method and application thereof
KR20120091971A (en) Preparation method for entecavir
CN104220433A (en) Process for the preparation of gamma amino acids and intermediates used in the process
CN106496263B (en) Process for producing hexahydrofurofuranol derivative, intermediate therefor, and process for producing the intermediate
CN106554301A (en) A kind of preparation method of BMS-477118 key intermediate
CN115745718B (en) Preparation method of delta-hydroxy substituted aromatic acetonitrile derivative
CN111018869B (en) Preparation method of chiral fused ring pyrano-dihydropyrrole compound
CN110683927A (en) Asymmetric synthesis method of pyrroline derivative with spiro structure
JP2001151765A (en) Method for producing alkali metal salt of l-ascorbic acid
Ivšić et al. Synthesis of GABOB and GABOB‐Based Chiral Units Possessing Distinct Protecting Groups
CN108047196B (en) Method for catalytically synthesizing 2, 5-dihydrothiophene compound containing chiral quaternary carbon
CN116675629A (en) Chiral dicarboxylic acid tetradentate binuclear rhodium catalyst based on natural amino acid, synthesis method and application thereof
CN107746396B (en) Novel compound 6, 6-dimethyl tetrahydropyrane-2-methanol and preparation method thereof
CN117658861A (en) Preparation method of N, N-disubstituted cyanamide derivative
CN115160355A (en) Method for efficiently synthesizing organic silicon compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant