CN109705014B - Novel chiral amine oxide ligand and preparation method thereof - Google Patents

Novel chiral amine oxide ligand and preparation method thereof Download PDF

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CN109705014B
CN109705014B CN201811406904.9A CN201811406904A CN109705014B CN 109705014 B CN109705014 B CN 109705014B CN 201811406904 A CN201811406904 A CN 201811406904A CN 109705014 B CN109705014 B CN 109705014B
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amine oxide
protecting group
methyl ester
chiral amine
follows
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CN109705014A (en
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李月明
高恩
蒋志
霍峰
李文琼
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Sichuan Zhongke Micro&nano Technology Co ltd
Nankai University
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Sichuan Zhongke Micro&nano Technology Co ltd
Nankai University
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Abstract

The invention provides a novel chiral amine oxide ligand and a preparation method thereof, wherein the method takes simple amino acid or amino acid derivatives as raw materials, modifies the raw materials, and then reacts with substances such as a coupling agent, alkali and the like to obtain a pincer-shaped configuration chiral ligand compound, namely the chiral amine oxide ligand. The chiral amine oxide ligand has a non-simple straight chain structure, a soft framework and recognition genes containing heteroatoms such as oxygen, nitrogen and the like in a molecular structure, can well perform coordination with a series of metals, realizes high enantioselectivity and high reactivity in asymmetric reactions, and has the advantages of simple preparation method, few steps and cheap and easily-obtained raw materials.

Description

Novel chiral amine oxide ligand and preparation method thereof
Technical Field
The invention belongs to the technical field of amine oxide ligands, and particularly relates to a novel chiral amine oxide ligand and a preparation method thereof.
Background
Asymmetric catalysis and synthesis are hot spots in the current field of organic chemistry. In asymmetric catalytic reactions, the choice of chiral ligand is important and often directly affects the effect on chiral recognition. The chiral amine oxide can be used for catalyzing various asymmetric reactions, the catalytic effect of the chiral amine oxide is closely related to the overall structure, particularly, nitrogen atoms and oxygen atoms with good coordination capacity in the chiral amine oxide can form complexes with various elements such as copper, scandium, lithium, zinc and the like, and the chiral amine oxide can be widely used for catalyzing asymmetric oxidation reactions, asymmetric hydrogenation, Aldol reactions, Mannich and Michael Addition reactions and the like, such as: the asymmetric Henry reaction product, beta-nitroalcohol, if a secondary alcohol compound, can be oxidized to form a-nitroketone. Beta-nitroalcohol is reduced to obtain beta-aminoalcohol, and the compounds have important application in the synthesis of medical intermediates and natural products, and can be used for synthesizing various medicaments or natural products with biological activity, such as: beta-receptor blockers (S) -Tliopolol, (S) -Moprolol, (S) -Propanolo. Therefore, the development of novel chiral amine oxide ligands for asymmetric catalytic reaction and synthesis and the development of application in organic synthesis have important practical significance for synthesizing a series of drug intermediates with potential biological activity.
Disclosure of Invention
In view of the above problems in the prior art, the present invention provides a novel chiral amine oxide ligand and a method for preparing the same, wherein the chiral amine oxide ligand can well coordinate with a series of metals, and high enantioselectivity and high reactivity can be achieved in a variety of asymmetric reactions.
In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
a novel chiral amine oxide ligand has a structural general formula:
Figure GDA0001920751330000021
wherein, the number of m is 1 or 2, A is nitrogen heterocycle and its derivant. Further, the structural formula of the novel chiral amine oxide ligand is as follows:
Figure GDA0001920751330000022
wherein n is 1 or 2, m is 1 or 2, R1And R2Are all H, -CH3、CH3CH2-, n-Pr, i-Pr, or Ph.
Further, the structural formula of the novel chiral amine oxide ligand is as follows:
Figure GDA0001920751330000023
wherein the number of m is 1 or 2, R1And R2Are all H, -CH3、CH3CH2-, n-Pr, i-Pr, or Ph.
Further, the structural formula of the novel chiral amine oxide ligand is as follows:
Figure GDA0001920751330000024
wherein the number of m is 1 or 2, R1And R2Are all H, -CH3、CH3CH2-, n-Pr, i-Pr, or Ph.
The preparation method of the novel chiral amine oxide ligand comprises the following steps:
(1) mixing amino alcohol, a coupling agent, alkali and a phase transfer catalyst in a molar ratio of 1-3: 0.5-2.5: 2-12: 0.1-0.4 by taking an organic solution as a solvent for reaction at the temperature of 95-115 ℃ for 12-18 h;
(2) and (2) taking a chlorinated organic solution as a solvent, purifying the product obtained in the step (1), mixing the purified product with an oxidant according to a molar ratio of 1: 2-2.5, reacting at a temperature of-5-35 ℃ for 1-18 h, and then recrystallizing the product to obtain the catalyst.
Further, the amino alcohol is prepared by the following method:
(1) dissolving carboxylic acid methyl ester protected by a protecting group in an organic solvent, and adding an alkane Grignard reagent at zero or below zero to react to obtain amino tertiary alcohol protected by the protecting group; wherein the molar ratio of the carboxylic acid methyl ester protected by the protecting group to the alkane Grignard reagent is 1:4-6, the reaction temperature is room temperature or reflux temperature, and the reaction time is 10-18 h; the methyl carboxylate is proline methyl ester, ramiprilic acid methyl ester, piperidine methyl ester or tetrahydro isoquinoline methyl ester;
(2) and (2) carrying out deprotection reaction on the amino tertiary alcohol protected by the protecting group obtained in the step (1) to obtain the amino alcohol.
Further, the protecting group is a Boc protecting group or a Bn protecting group, and the alkane Grignard reagent is methyl magnesium bromide, ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide or phenyl magnesium bromide;
when the protecting group is a Boc protecting group, the deprotection process is: adding 2-3N hydrogen chloride alcohol solution into Boc protected amino tertiary alcohol at zero or below, stirring at room temperature for 2-3 h, removing Boc protecting group, concentrating, and drying to obtain the final product; wherein the mole ratio of the Boc protected amino tertiary alcohol to the hydrogen chloride solution is 1: 1.5-4;
when the protecting group is a Bn protecting group, the deprotection process is as follows: dissolving the amino tertiary alcohol protected by Bn into anhydrous methanol at room temperature, adding palladium carbon and glacial acetic acid, and carrying out hydrogenation reduction to obtain the product; wherein the molar ratio of the amino tertiary alcohol protected by Bn to the palladium carbon to the glacial acetic acid is 1: 0.05-0.2: 0.1-0.25.
Further, the amino alcohol is prepared by the following method: dissolving carboxylic acid methyl ester without protection of a protecting group in an organic solvent, and adding lithium aluminum hydride at zero or below zero to react to obtain amino tertiary alcohol; wherein the molar ratio of the methyl carboxylate to the lithium aluminum hydride is 1:4-6, the reaction temperature is room temperature or reflux temperature, and the reaction time is 10-18 h; the methyl carboxylate is proline methyl ester, ramiprilic acid methyl ester, piperidine methyl ester or tetrahydro isoquinoline methyl ester.
Further, the coupling agent is 1, 3-dibromopropane or 1, 4-dibromobutane.
Further, the base is sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine.
Further, the phase transfer catalyst is sodium iodide or potassium iodide.
The novel chiral amine oxide ligand and the preparation method thereof provided by the invention have the following beneficial effects:
the invention uses natural product chiral units (which can be amino acid or amino acid derivatives such as L-proline, L-2-pipecolic acid, L-ramipril intermediate hydrochloride and L-1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid) which are easily obtained in the nature to carry out simple modification to obtain a series of molecular pincer-shaped chiral amine oxide ligands, the molecular structure is a non-simple straight chain, the molecular structure has a soft framework and recognition genes containing heteroatoms such as oxygen, nitrogen and the like, the coordination effect can be well generated with a series of metals, the high enantioselectivity and the high reaction activity can be realized in the asymmetric reaction, the preparation method is simple, the steps are few, and the raw materials are cheap and easy to obtain.
Drawings
FIG. 1 is Compound 1AA-MeIs/are as follows1H NMR chart.
FIG. 2 is Compound 2AA-MeIs/are as follows1H NMR chart.
FIG. 3 is the compound 3AA-MeIs/are as follows1H NMR chart.
FIG. 4 is the compound LA-MeIs/are as follows1H NMR chart.
FIG. 5 is the compound LA-MeIs/are as follows13C NMR chart.
FIG. 6 is compound 1AA-EtIs/are as follows1H NMR chart.
FIG. 7 is the compound LA-EtIs/are as follows1H NMR chart.
FIG. 8 is the compound LA-EtIs/are as follows13C NMR chart.
FIG. 9 is Compound 1AA-PhIs/are as follows1H-NMR chart.
FIG. 10 is Compound 2AA-PhIs/are as follows1H-NMR chart.
FIG. 11 is the compound 3AA-PhIs/are as follows1H-NMR chart.
FIG. 12 is the compound 3AA-PhIs/are as follows13C NMR chart.
FIG. 13 is the compound LA-PhIs/are as follows1H-NMR chart.
FIG. 14 is the compound LA-PhIs/are as follows13C NMR chart.
FIG. 15 is a drawing of methyl N-Bn- (L) -proline ester1H-NMR chart.
FIG. 16 is N-Bn- (L) -amino alcohol 1AA-i-PrIs/are as follows1H-NMR chart.
FIG. 17 is Compound 2AA-i-PrIs/are as follows1H-NMR chart.
FIG. 18 is compound 3AA-i-PrIs/are as follows1H-NMR chart.
FIG. 19 is the compound LA-i-PrIs/are as follows1H-NMR chart.
FIG. 20 is the compound LA-i-PrIs/are as follows13C NMR chart.
FIG. 21 is a drawing of a compound L-aminoalcohol1H-NMR chart.
FIG. 22 is the compound LA-HIs/are as follows1H-NMR chart.
FIG. 23 is the compound LA-HIs/are as follows13C NMR chart.
FIG. 24 shows chiral amine oxide ligand LA-EtCatalytic Henry reaction liquid phase diagram.
Detailed Description
The novel chiral amine oxide ligand provided by the invention has a structural general formula as follows:
Figure GDA0001920751330000051
wherein, the number of m is 1 or 2, A is nitrogen heterocycle and its derivant.
Specifically included are chiral amine oxide ligands of the following structure:
Figure GDA0001920751330000052
LA
wherein the number of n is 1 or 2, and the number of m is1 or 2, R1And R2Are all H, -CH3、CH3CH2-, n-Pr, i-Pr, or Ph.
Figure GDA0001920751330000061
LB
Wherein the number of m is 1 or 2, R1And R2Are all H, -CH3、CH3CH2-, n-Pr, i-Pr, or Ph.
Further, the structural formula of the novel chiral amine oxide ligand is as follows:
Figure GDA0001920751330000062
LC
wherein the number of m is 1 or 2, R1And R2Are all H, -CH3、CH3CH2-, n-Pr, i-Pr, or Ph.
The chiral amine oxide ligand is prepared from simple amino acid and derivatives thereof serving as raw materials by simple modification.
One raw material used in the reaction process is amino alcohol, and the amino alcohol is prepared by the following method:
Figure GDA0001920751330000063
the number of n is 1-2; r1And R2Are all H, -CH3(Me)、CH3CH2- (Et), n-Pr, i-Pr or Ph.
Because of the large number of specific amino alcohol species, the following is now set forth, taking the R group as Me:
when the number of n is 1, R is-CH3(Me), the following structure is obtained:
Figure GDA0001920751330000071
taking 2AA as an example, the preparation method is described in detail, and the preparation method specifically comprises the following steps:
(1) dissolving proline methyl ester protected by Boc in an organic solvent, adding a methyl magnesium bromide Grignard reagent under a zero-temperature condition, reacting for 10-18 h at room temperature to generate amino tertiary alcohol protected by Boc, and then separating and purifying by column chromatography; wherein the mole ratio of the proline methyl ester protected by the Boc to the methyl magnesium bromide Grignard reagent is 1: 4-6;
(2) under the condition of zero temperature, adding 2N hydrogen chloride ethanol solution into the product separated and purified in the step (1), and stirring for 2-3 hours at room temperature to obtain corresponding ammonium hydrochloride salt, namely 2 AA; wherein the mole ratio of the Boc protected amino tertiary alcohol to the hydrogen chloride ethanol solution is 1: 1.5-4.
2BB, 2CC, 2DD can be prepared by the same reaction.
Because of more specific novel amine oxide ligands, LA is synthesized-MeFor example, the amine oxide ligand is LA mentioned above, wherein R is Me, and the reaction formula is as follows:
Figure GDA0001920751330000072
the specific reaction process comprises the following steps:
(1) dissolving the prepared 2AA in anhydrous acetonitrile, adding potassium carbonate and sodium iodide in batches, and adding 1, 3-dibromopropane for reaction to obtain a product 3 AA; the molar ratio of 2AA, 1, 3-dibromopropane, potassium carbonate and sodium iodide is 2-2.1: 1: 6-12: 0.1-0.4, the reaction temperature is 95-115 ℃, and the reaction time is 12-18 hours;
(2) purifying the product 3AA, and reacting with hydrogen peroxide by using chloroform as a solvent to prepare a novel chiral amine oxide ligand LA; wherein the molar ratio of the 3AA to the hydrogen peroxide is 1: 2-2.5, the reaction temperature is-5-35 ℃, and the reaction time is 1-18 h.
The present invention will be further described with reference to the following specific examples.
Example 1
Novel chiral amine oxide ligand (LA-Me) The structural formula is as follows:
Figure GDA0001920751330000081
the preparation method of the novel chiral amine oxide ligand comprises the following steps:
1. preparation of N-Boc- (L) -aminoalcohol (1 AA)-Me)
(1) Synthesis of L-proline methyl ester
The structural formula of the L-proline methyl ester is as follows:
Figure GDA0001920751330000082
the synthesis process comprises the following steps: dissolving L-proline (1eq) in anhydrous methanol in a 500ml three-necked bottle with a thermometer and mechanical stirring, dropwise adding thionyl chloride (1.1eq) at room temperature, stirring at room temperature for 10-12h, directly removing redundant solvent and thionyl chloride in the system after the reaction is finished, adding a certain amount of dichloromethane, washing an organic phase with saturated sodium carbonate aqueous solution, separating the organic phase, and evaporating to dryness to obtain the product, wherein the yield is as follows: 95 percent of the total weight of the mixture,
Figure GDA0001920751330000083
(c＝0.1,CHCl3)，1H NMR(400MHz,Chloroform-d,TMS):δ3.77(dd,J＝8.6,5.9Hz,1H),3.74(s,3H),3.04(dt,J＝9.8,6.6Hz,1H),2.92(dt,J＝10.0,6.6Hz,1H),2.14-2.12(m,1H),1.86(ddt,J＝14.4,8.3,5.4Hz,1H),1.77-1.76(m,2H).
(2) synthesis of N-Boc- (L) -proline methyl ester
The structural formula of N-Boc- (L) -proline methyl ester is as follows:
Figure GDA0001920751330000091
the synthesis process comprises the following steps: l-proline methyl ester (1eq) was dissolved in dichloromethane,adding triethylamine (2.2eq), dropwise adding di-tert-butyl dicarbonate (1.1eq) at zero temperature, reacting the system at room temperature for 10-16 hours, adding a certain amount of 0.5N hydrochloric acid solution to wash an organic phase after the reaction is finished, standing, separating liquid, separating the organic phase, washing the organic phase with saturated sodium bicarbonate aqueous solution, finally washing with saturated salt, separating liquid, drying, and evaporating to dryness to obtain the product, wherein the yield is as follows: in the proportion of 93%,1H NMR(400MHz,Chloroform-d,TMS):δ4.33-4.21(m,1H),3.72(s,3H),3.37-3.57(m,2H),2.14-2.28(m,1H),1.92-1.98(m,3H),1.41(s,9H).
(3) N-Boc- (L) -aminoalcohol (1 AA)-Me) Synthesis of (2)
The structural formula of N-Boc- (L) -amino alcohol is as follows:
Figure GDA0001920751330000092
the synthesis process comprises the following steps: dissolving N-Boc- (L) -proline methyl ester (1eq) in anhydrous tetrahydrofuran, adding a methyl magnesium bromide reagent (4.2eq) at room temperature under an argon environment, reacting the system at room temperature for 10-12h after the addition is finished, monitoring by TLC (thin layer chromatography), quenching the system by using a saturated ammonium chloride aqueous solution after the reaction is finished, extracting a water phase by using ethyl acetate, separating an organic phase, drying and spin-drying to obtain a product, wherein the product can be refined by using ethyl acetate to obtain a pure product, and the yield is as follows: 77 percent of the total weight of the mixture,1h NMR (400MHz, Chloroform-d, TMS): delta 5.96(s,1H),3.87(t, J ═ 7.4Hz,1H),3.67(s,1H),3.25-3.11(m,1H),1.85-1.55(m,4H),1.48(s,9H),1.17(s,3H),1.08(s,3H). Compound 1AA-MeIs/are as follows1The H NMR chart is shown in FIG. 1.
2. Preparation of Compound 3AA-Me
(1) (L) -aminoalcohol hydrochloride (2 AA)-Me) Synthesis of (2)
The structural formula of the (L) -aminoalcohol hydrochloride is as follows:
Figure GDA0001920751330000101
the synthesis process comprises the following steps: dissolving N-Boc- (L) -amino alcohol in anhydrous ethanol, and adding 3N chloride below zero degreeAnd (2) stirring the mixture for 3 to 4 hours at room temperature by using a hydrogen ethanol solution, evaporating the residual solvent, and recrystallizing diethyl ether to obtain (L) -amino alcohol hydrochloride 2AA with the yield: the content of the active ingredients is 98 percent,1h NMR (400MHz, DMSO-d6) delta 9.74(s,1H),8.26(s,1H), 3.43-3.21 (m,2H), 3.20-2.93 (m,2H), 2.05-1.85 (m,2H), 1.85-1.66 (m,2H),1.23(s,3H),1.15(s,3H). Compound 2AA-MeIs/are as follows1The H NMR chart is shown in FIG. 2.
(2) Compound 3AA-MeSynthesis of (2)
Compound 3AA-MeThe chemical formula (II) is as follows:
Figure GDA0001920751330000102
the synthesis process comprises the following steps: dissolving amino alcohol hydrochloride 2AA (2eq) into anhydrous acetonitrile in a reaction vessel, adding anhydrous potassium carbonate (6eq) and sodium iodide (0.1eq), stirring at room temperature for 0.5 hour, then adding 1, 3-dibromopropane (1eq), gradually heating the system to reflux, reacting for about 12 hours, cooling to room temperature, adding a certain amount of water into the system, extracting and separating by using ethyl acetate, drying and concentrating to obtain a brown liquid product 3AA, wherein the yield is as follows: the content of the active ingredients is 92%,1H NMR(400MHz,Chloroform-d,TMS):δ3.17–2.99(m,1H),2.93–2.80(m,1H),2.60–2.49(m,1H),2.44–2.33(m,1H),1.85-1.63(m,12H),1.16(s,6H),1.11(s,6H).HRMS(ESI,M+H+)calcd.forC17H34N2O2299.2693, respectively; found 299.2698, Compound 3AA-MeIs/are as follows1The H NMR chart is shown in FIG. 3.
3. Preparation of the Compound LA-Me
Dissolving the 3A intermediate 3AA in anhydrous chloroform, cooling to about zero ℃, adding hydrogen peroxide (2.2eq), stirring for 0.5h, raising the temperature to room temperature, continuing stirring for 4h, adding saturated sodium thiosulfate to wash the organic phase, adding saturated sodium carbonate aqueous solution to wash the organic phase, standing for liquid separation, drying ethyl acetate, and recrystallizing to obtain brown solid LA-Me, mp:130-138 ℃; 80% of yield;
Figure GDA0001920751330000113
(c＝0.1,CHCl3)；1H NMR(400MHz,Chloroform-d,25℃,TMS):δ＝8.70(s,2H),3.98–3.68(m,2H),3.63–3.32(m,6H),3.24(t,J＝8.7Hz,2H),2.62(t,J＝7.3Hz,2H),2.53–2.39(m,2H),2.33–2.19(m,2H),2.13–1.98(m,2H),1.95–1.76(m,2H),1.50(s,6H),1.23(s,6H).13C NMR(101MHz,CDCl3)δ80.93,71.28,69.58,67.77,29.96,28.28,25.62,21.31,20.04.HRMS(ESI,M+H+)calcd.forC17H34N2O4331.2591；found 331.2595.
LA-MeIs/are as follows1FIG. 4 shows the H NMR chart, LA-MeIs/are as follows13The C NMR chart is shown in FIG. 5.
Example 2
Novel chiral amine oxide ligand (LA-Et) The structural formula is as follows:
Figure GDA0001920751330000111
the preparation of the novel chiral amine oxide ligand described above was identical to that of example 1, wherein:
compound 1AA-EtThe yield was 87%, the formula is as follows:
Figure GDA0001920751330000112
1h NMR (400MHz, Chloroform-d, TMS): delta 5.39(s,1H), 4.08-3.86 (m,1H),3.63(s,1H), 3.22-3.01 (m,1H), 2.02-1.91 (m,1H), 1.82-1.74 (m,1H), 1.69-1.55 (m,4H),1.44(s,9H),1.25(dt, J ═ 14.9,7.1Hz,2H),0.93(t, J ═ 7.4Hz,3H),0.88(t, J ═ 7.5Hz,3H). Compound 1AA-EtIs/are as follows1The H NMR chart is shown in FIG. 6.
Compound 3AA-EtYield: 90%, the structural formula is as follows:
Figure GDA0001920751330000121
1H NMR(400MHz,Chloroform-d,TMS):δ3.11–2.91(m,2H),2.76–2.54(m,6H),2.54–2.38(m,2H),1.78–1.65(m,10H),1.61–1.43(m,7H),1.39–1.20(m,3H),0.93–0.79(m,12H).HRMS(ESI,M+H+)calcd.forC21H42N2O2355.3319；found355.3324.
LA-EtThe structural formula of (A) is as follows:
Figure GDA0001920751330000122
mp:165-168℃；yield:78％；
Figure GDA0001920751330000123
(c＝0.1,CHCl3)；1H NMR(400MHz,Chloroform-d,25℃,TMS):δ＝8.53(s,2H),3.86–3.68(m,2H),3.55–3.44(m,2H),3.40(dd,J＝7.9,6.1Hz,4H),3.26(t,J＝8.8Hz,1H),2.63–2.46(m,4H),2.31–2.17(m,2H),2.15–2.03(m,2H),2.02–1.89(m,2H),1.86–1.73(m,4H),1.70–1.57(m,2H),1.37–1.25(m,2H),0.90(t,J＝7.4Hz,6H),0.78(t,J＝7.5Hz,6H)；13C NMR(100MHz,CDCl3)δ78.65,75.76,70.36,68.22,28.94,28.70,25.19,21.48,20.30,8.02,7.28.HRMS(ESI,M+H+)calcd.forC21H42N2O4,387.3217；found 387.3220.
LA-EtIs/are as follows1The H NMR chart is shown in FIG. 7,13the C NMR chart is shown in FIG. 8.
Example 3
Novel chiral amine oxide ligand (LA-Ph) The structural formula is as follows:
Figure GDA0001920751330000131
the preparation of the novel chiral amine oxide ligand described above was identical to that of example 1, wherein:
compound 1AA-PhYield of (a): 86%, structural formula as follows:
Figure GDA0001920751330000132
1H NMR(400MHz,Chloroform-d,TMS):δ7.45–7.34(m,4H),7.30–7.21(m,6H),6.48(s,1H),4.89(dd,J＝8.9,3.6Hz,1H),3.33(s,1H),2.86(s,1H),2.18–2.00(m,1H),1.97–1.83(m,1H),1.57(s,1H),1.44(s,9H),0.75(s,1H).
compound 1AA-PhIs/are as follows1The H-NMR chart is shown in FIG. 9.
Compound 2AA-PhYield of (a): 95%, the structural formula is as follows:
Figure GDA0001920751330000133
1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.16(s,1H),7.62(d,J＝7.5Hz,2H),7.53(d,J＝7.5Hz,2H),7.42–7.29(m,4H),7.29–7.17(m,2H),6.58(s,1H),4.94–4.82(m,1H),3.14(s,2H),1.97–1.78(m,4H).
compound 2AA-PhIs/are as follows1The H-NMR chart is shown in FIG. 10.
Compound 3AA-PhYield of (a): 95%, the structural formula is as follows:
Figure GDA0001920751330000134
mp:143-147℃,1H NMR(400MHz,Chloroform-d)δ7.58–7.44(m,7H),7.28-7.18(m,10H),7.18–7.07(m,3H),4.69(s,2H),3.64(dd,J＝9.0,3.5Hz,2H),3.04–2.95(m,2H),2.25–2.15(m,2H),1.88–1.76(m,2H),1.69–1.53(m,8H),1.51–1.41(m,2H),1.12–1.03(m,2H).13C NMR(101MHz,CDCl3)δ148.07,146.55,127.99,127.88,126.17,126.13,125.67,125.51,77.70,71.27,55.30,54.03,29.52,27.99,24.43.HRMS(ESI,M+H+)calcd.forC37H43N2O2,547.3325；found 547.3325.
compound 3AA-PhIs/are as follows1The H-NMR chart is shown in FIG. 11,13the C NMR chart is shown in FIG. 12.
LA-PhThe structural formula of (A) is as follows:
Figure GDA0001920751330000141
mp:212-216℃；yield:77％；
Figure GDA0001920751330000143
(c＝0.1,CHCl3)；1H NMR(400MHz,Chloroform-d,25℃,TMS):δ＝11.36(s,2H),7.71–7.61(m,4H),7.56–7.43(m,4H),7.33–7.22(m,10H),7.18–7.09(m,2H),4.22(t,J＝9.0Hz,2H),3.34(t,J＝9.2Hz,2H),3.23–3.08(m,2H),2.55–2.17(m,7H),2.17–2.03(m,2H),2.00–1.86(m,2H),1.86–1.77(m,2H),1.77–1.65(m,1H).13C NMR(101MHz,CDCl3)δ147.35,146.63,128.29,128.24,126.86,126.63,125.92,124.66,77.82,77.60,68.71,66.03,26.10,19.85,19.57.HRMS(ESI,M+H+)calcd.forC37H42N2O4,579.3217, respectively; found 579.3213, compound LA-PhIs/are as follows1The H-NMR chart is shown in FIG. 13,13the C NMR chart is shown in FIG. 14.
Example 4
Novel chiral amine oxide ligand (LA-i-Pr) The structural formula is as follows:
Figure GDA0001920751330000142
the preparation method of the novel chiral amine oxide ligand comprises the following steps:
1. preparation of N-Bn- (L) -aminoalcohol 1AA-i-Pr
(1) Synthesis of N-Bn- (L) -proline methyl ester
The structural formula of N-Bn- (L) -proline methyl ester is as follows:
Figure GDA0001920751330000151
the synthesis process comprises the following steps: dissolving L-proline methyl ester (1eq) in dichloromethane, adding triethylamine (2.4eq) at zero temperature to generate a large amount of solid in a system, filtering the solid in the system, dropwise adding benzyl bromide (1.2eq) at zero temperature to react the system at room temperature for 10-16 hours, adding a certain amount of 0.5N hydrochloric acid solution to wash an organic phase after the reaction is completed, standing and separating the organic phase, washing the organic phase with saturated sodium bicarbonate aqueous solution, finally washing with saturated salt, separating the liquid and drying, evaporating to obtain a product, and performing column chromatography to obtain the product with yield: the content of the active ingredients is 98 percent,1H NMR(400MHz,DMSO-d6)δ7.34–7.28(m,4H),7.26–7.22(m,1H),3.89(d,J＝12.8Hz,1H),3.65(s,3H),3.57(d,J＝12.8Hz,1H),3.28–3.20(m,1H),3.10–2.99(m,1H),2.46–2.31(m,1H),2.20–2.04(m,1H),2.02–1.85(m,2H),1.83–1.73(m,1H).
process for preparation of methyl N-Bn- (L) -proline ester1The H-NMR chart is shown in FIG. 15.
(2) N-Bn- (L) -amino-alcohol 1AA-i-PrSynthesis of (2)
N-Bn- (L) -amino-alcohol 1AA-i-PrThe structural formula of (A) is as follows:
Figure GDA0001920751330000152
the synthesis process comprises the following steps: dissolving N-Bn- (L) -proline methyl ester in anhydrous tetrahydrofuran, dropwise adding isopropyl magnesium bromide (4.5eq) at room temperature under an argon environment, reacting the system at room temperature until the raw materials disappear, quenching the system by using a saturated ammonium chloride aqueous solution after the addition of the isopropyl magnesium bromide is finished, extracting the quenched product by using ethyl acetate, drying and spin-drying the product, and performing column chromatography to obtain the product with the yield: in the content of 56%,1H NMR(400MHz,Chloroform-d,TMS):δ7.37–7.28(m,1H),4.05(d,J＝13.7Hz,1H),3.50(d,J＝13.8Hz,1H),3.15(d,J＝7.7Hz,1H),2.88–2.77(m,1H),2.51–2.42(m,1H),2.16–2.08(m,1H),2.04–1.96(m,1H),1.92–1.72(m,3H),1.07–0.99(m,6H),0.99–0.91(m,6H).
N-Bn- (L) -amino-alcohol 1AA-i-PrIs/are as follows1The H-NMR chart is shown in FIG. 16.
2. Preparation of Compound 2AA-i-Pr
Compound 2AA-i-PrThe structural formula of (A) is as follows:
Figure GDA0001920751330000161
the synthesis process comprises the following steps: reacting N-Bn- (L) -amino alcohol 1AA-i-PrDissolving in anhydrous methanol, adding glacial acetic acid (25%), adding anhydrous palladium carbon (10%), carrying out hydrogenation reduction, stirring at room temperature for 10-12 hours, after the reaction is finished, filtering off the palladium carbon, adjusting the Ph of a system to be more than 10, extracting with ethyl acetate, drying and evaporating to dryness to obtain the product, wherein the yield is as follows: the content of the organic solvent is 90%,1h NMR (400MHz, Chloroform-d, TMS): delta 3.45(t, J ═ 7.5Hz,1H),2.95(dt, J ═ 9.5,3.8Hz,1H), 2.92-2.84 (m,1H),2.43(s,1H),2.02-1.90(m,3H), 1.83-1.63 (m,4H), 1.04-0.94 (m,12H). Compound 2AA-i-PrIs/are as follows1The H-NMR chart is shown in FIG. 17.
3. Preparation of Compound 3AA-i-Pr
Compound 3AA-i-PrThe structural formula of (A) is as follows:
Figure GDA0001920751330000162
synthesis process and compound 3AA-MeThe synthesis process is consistent, and the yield is as follows: the content of the organic solvent is 90%,1H NMR(400MHz,Chloroform-d)δ3.56(t,J＝6.2Hz,1H),3.47(t,J＝7.0Hz,1H),3.02–2.85(m,5H),2.68–2.56(m,1H),2.53–2.40(m,3H),2.38–2.32(m,1H),2.12–1.87(m,5H),1.80–1.62(m,8H),1.15–0.82(m,24H).HRMS(ESI,M+H+)calcd.forC25H51N2O2411.3951; found411.3953, Compound 3AA-i-PrIs/are as follows1The H-NMR chart is shown in FIG. 18.
4. Preparation of the Compound LA-i-Pr
LA-i-PrThe synthesis and compound LA-MeThe synthesis of (A) is consistent: 56 percent of yield,
Figure GDA0001920751330000163
Figure GDA0001920751330000164
(c＝0.1,CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝3.89(dt,J＝13.9,7.6Hz,2H),3.54–3.26(m,8H),2.62–2.53(m,2H),2.46–2.22(m,7H),2.05–1.72(m,7H),1.10(d,J＝6.6Hz,6H),1.01(d,J＝6.9Hz,6H),0.92(d,J＝6.6Hz,3H),0.85(d,J＝6.9Hz,6H)；13C NMR(101MHz,CDCl3)δ78.79,76.55,69.73,68.28,34.33,32.41,27.64,22.58,20.20,19.30,18.20,17.99,16.82；HRMS(ESI,M+H+)calcd.forC25H50N2O4,343.3843；found 343.3843.
LA-i-PrIs/are as follows1The H-NMR chart is shown in FIG. 19,13the C NMR chart is shown in FIG. 20.
Example 5
Novel chiral amine oxide ligand (LA-H) The structural formula is as follows:
Figure GDA0001920751330000171
the preparation method of the novel chiral amine oxide ligand comprises the following steps:
1. preparation of L-aminoalcohols
The structural formula of the compound L-amino alcohol is as follows:
Figure GDA0001920751330000172
the synthesis process comprises the following steps: dissolving L-proline methyl ester into anhydrous tetrahydrofuran, adding four equivalents of lithium aluminum hydride in batches at room temperature under an argon environment, heating and refluxing the system for 10-12 hours after the addition until the raw materials disappear to generate a product, stopping the reaction, quenching the reaction by using wet sodium sulfate decahydrate, carrying out suction filtration, leaching a filter cake by using the tetrahydrofuran, collecting filtrate, drying, and carrying out spin drying to obtain the product, wherein the yield is as follows: the content of the organic solvent is 90%,1h NMR (400MHz, Chloroform-d) delta 3.91-3.77 (m,1H), 3.74-3.57 (m,2H),3.45(s,1H), 3.24-3.14 (m,2H), 2.07-1.95 (m,3H), 1.85-1.71 (m,1H) of the compound L-aminoalcohol1The H-NMR chart is shown in FIG. 21.
2. Preparation of LA-H
LA-HSynthesis and compounds LA-MeThe synthesis is consistent, and yield is 54%;
Figure GDA0001920751330000173
(c＝0.1,MeOH)；1H NMR(400MHz,Chloroform-d,25℃,TMS):δ＝4.17(d,J＝13.1Hz,2H),3.87(dd,J＝13.1,4.4Hz,2H),3.82–3.72(m,2H),3.60–3.46(m,4H),3.43–3.26(m,4H),2.74–2.60(m,2H),2.58–2.45(m,2H),2.40–2.27(m,2H),2.12–1.89(m,6H)ppm.13C NMR(101MHz,DMSO)δ74.77,66.65,63.27,58.86,8.74,23.86,20.24,19.65.HRMS(ESI,M+H+)calcd.for C13H26N2O4275.1965, respectively; found275.1970. Compound LA-HIs/are as follows1The H-NMR chart is shown in FIG. 22,13the C NMR chart is shown in FIG. 23.
The synthesis process of other ligands LB and LC is basically the same as that of the embodiment 1-5.
With chiral amine oxide ligand LA-EtFor example, the good catalytic activity of the ligand in asymmetric synthesis is illustrated, and the specific method is as follows: ligand LA-EtThe ligand can be successfully applied to henry reaction, and through screening of different substrates, the ligand can effectively catalyze aldehyde and nitromethane without the substrates to obtain the nitroalcohol compound with high stereoselectivity. The o-chlorobenzaldehyde and nitromethane are used as a model reaction, a certain catalytic amount of ligand and Lewis acid are added into a chlorinated reagent to catalyze the reaction, and a high stereoselectivity nitroalcohol compound (85% ee) HPLC (Chiralcel OD-H, n-hexane/i-PrOH,90:10v/v,1.0mL/min, UV 254nm) tR(minor)＝25.7min,tR(major) ═ 29.3min., see figure 24 and table 1.
TABLE 1
Entry R.T.(min) Height Area Area％
1 25.712 47442 2511869 6.099
2 29.327 398302 25709110 91.099

Claims (7)

1. A novel chiral amine oxide ligand characterized by the structural formula:
Figure FDA0002944133950000011
wherein n is 1, m is 1, R1And R2Are all H, -CH3、CH3CH2-, i-Pr or Ph.
2. A process for the preparation of a novel chiral amine oxide ligand according to claim 1, comprising the steps of:
(1) mixing amino alcohol, a coupling agent, alkali and a phase transfer catalyst in a molar ratio of 1-3: 0.5-2.5: 2-12: 0.1-0.4 by taking an organic solution as a solvent for reaction at the temperature of 95-115 ℃ for 12-18 h;
(2) and (2) taking a chlorinated organic solution as a solvent, purifying the product obtained in the step (1), mixing the purified product with an oxidant according to a molar ratio of 1: 2-2.5, reacting at a temperature of-5-35 ℃ for 1-18 h, and then recrystallizing the product to obtain the catalyst.
3. The process for preparing a novel chiral amine oxide ligand according to claim 2, wherein the amino alcohol is prepared by the following method:
(1) dissolving carboxylic acid methyl ester protected by a protecting group in an organic solvent, and adding an alkane Grignard reagent at zero or below zero to react to obtain amino tertiary alcohol protected by the protecting group; wherein the molar ratio of the carboxylic acid methyl ester protected by the protecting group to the alkane Grignard reagent is 1:4-6, the reaction temperature is room temperature or reflux temperature, and the reaction time is 10-18 h; the methyl carboxylate is proline methyl ester, ramiprilic acid methyl ester, piperidine methyl ester or tetrahydro isoquinoline methyl ester;
(2) and (2) carrying out deprotection reaction on the amino tertiary alcohol protected by the protecting group obtained in the step (1) to obtain the amino alcohol.
4. The process for preparing a novel chiral amine oxide ligand according to claim 3, wherein the protecting group is a Boc protecting group or a Bn protecting group, and the alkane Grignard reagent is methyl magnesium bromide, ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, phenyl magnesium bromide;
when the protecting group is a Boc protecting group, the deprotection process is: adding 2-3N hydrogen chloride alcohol solution into Boc protected amino tertiary alcohol at zero or below, stirring at room temperature for 2-3 h, removing Boc protecting group, concentrating, and drying to obtain the final product; wherein the mole ratio of the Boc protected amino tertiary alcohol to the hydrogen chloride solution is 1: 1.5-4;
when the protecting group is a Bn protecting group, the deprotection process is as follows: dissolving the amino tertiary alcohol protected by Bn into anhydrous methanol at room temperature, adding palladium carbon and glacial acetic acid, and carrying out hydrogenation reduction to obtain the product; wherein the molar ratio of the amino tertiary alcohol protected by Bn to the palladium carbon to the glacial acetic acid is 1: 0.05-0.2: 0.1-0.25.
5. The process for preparing a novel chiral amine oxide ligand according to claim 2, wherein the amino alcohol is prepared by the following method: dissolving carboxylic acid methyl ester without protection of a protecting group in an organic solvent, and adding lithium aluminum hydride at zero or below zero to react to obtain amino tertiary alcohol; wherein the molar ratio of the methyl carboxylate to the lithium aluminum hydride is 1:4-6, the reaction temperature is room temperature or reflux temperature, and the reaction time is 10-18 h; the methyl carboxylate is proline methyl ester, ramiprilic acid methyl ester, piperidine methyl ester or tetrahydro isoquinoline methyl ester.
6. The method for preparing a novel chiral amine oxide ligand according to claim 2, wherein the coupling agent is 1, 3-dibromopropane or 1, 4-dibromobutane.
7. The process for preparing a novel chiral amine oxide ligand according to claim 2, wherein the base is sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine; the phase transfer catalyst is sodium iodide or potassium iodide.
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