阅读说明：本技术 一种手性β-氨基醛类化合物的不对称合成方法 (Asymmetric synthesis method of chiral β -amino aldehyde compound ) 是由 夏爱宝 白亮 盘龚健 许丹倩 于 2019-11-28 设计创作，主要内容包括：本发明公开了一种如式(I)所示的手性β-氨基醛类化合物的不对称合成方法,所述的不对称合成是以式(Ⅱ)所示的亚胺和式(Ⅲ)所示的醛作为反应物,在有机溶剂中进行反应,其特征在于：所述的反应在手性催化剂和聚合物构建的超分子催化剂作用下进行；所述的手性催化剂选择下列之一：<Image he="140" wi="700" file="DDA0002294204900000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>所述的聚合物选自PEG和/或PPG；<Image he="187" wi="700" file="DDA0002294204900000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明利用PPG/PEG与手性催化剂构建超分子催化剂用于手性β-氨基醛类化合物的不对称合成,显著提高了产物收率。(The invention discloses an asymmetric synthesis method of chiral β -amino aldehyde compounds shown in formula (I), which takes imine shown in formula (II) and aldehyde shown in formula (III) as reactants to react in an organic solvent and is characterized in that the reaction is carried out under the action of chiral catalysts and supramolecular catalysts constructed by polymers(ii) a The chiral catalyst is selected from one of the following: the polymer is selected from PEG and/or PPG; the invention utilizes PPG/PEG and chiral catalyst to construct supramolecular catalyst for asymmetric synthesis of chiral β -amino aldehyde compound, thereby remarkably improving product yield.)

1. A chiral β -amino aldehyde compound asymmetric synthesis method as shown in formula (I) takes imine as shown in formula (II) and aldehyde as shown in formula (III) as reactants, and the asymmetric synthesis method is characterized in that the reaction is carried out under the action of a chiral catalyst and a supramolecular catalyst constructed by polymers;

the chiral catalyst is selected from one of the following:

the polymer is selected from PEG and/or PPG;

in the formulae (I), (II) and (III),

R₁selected from one of the following: c₄-C₁₀Alkyl radical, C₃-C₇Cycloalkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl; the aryl is phenyl or naphthyl, the heteroaryl is furyl, thienyl or pyridyl, and the substituted aryl and the substituted heteroaryl are respectively and independently substituted by one or more of the following groups: c₁-C₂₀Alkyl radical, C₁-C₁₀Alkoxy, halogen, C₁-C₅Alkylmercapto, nitro, cyano, C₁-C₂₀A haloalkyl group;

R₂selected from one of the following: hydrogen, C₁-C₂₀Alkyl radical, C₃-C₇A cycloalkyl group.

2. The asymmetric synthesis method according to claim 1, wherein: r₁Selected from one of the following: n-butyl, cyclohexyl, phenyl, 4-methoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 1-naphthyl, 2-furyl, 2-thienyl, 2-pyridyl, 4-methylphenyl, 3-chlorophenyl, 4-fluorophenyl, 4-methylthiophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-cyanophenyl, 4-trifluoromethylphenyl.

3. The asymmetric synthesis method according to claim 1, wherein: r₂Selected from one of the following: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, cyclohexyl, n-hexyl.

4. Asymmetric synthesis method according to one of claims 1 to 3, characterized in that: the polymer is selected from at least one of the following: PEG200, PEG400, PEG600, PEG800, PEG1000, PEG1500, PPG400, PPG600, PPG800, PPG1000, PEG 750.

5. Asymmetric synthesis method according to one of claims 1 to 3, characterized in that: the ratio of the amounts of the chiral catalyst, the polymer, the imine and the aldehyde is 0.2-0.5:0.1-1:1: 1-5.

6. Asymmetric synthesis method according to one of claims 1 to 3, characterized in that: the organic solvent is selected from one or a combination of any of the following: dichloromethane, chloroform, toluene, methanol, ethanol, ethyl acetate, diethyl ether, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane and acetonitrile.

7. Asymmetric synthesis method according to one of claims 1 to 3, characterized in that: the asymmetric synthesis reaction is carried out at the temperature of-20 ℃ to 25 ℃.

8. Asymmetric synthesis method according to one of claims 1 to 3, characterized in that: the asymmetric synthesis reaction is carried out at a temperature of 0 ℃.

9. Asymmetric synthesis method according to one of claims 1 to 3, characterized in that: the asymmetric synthesis is carried out according to the following steps:

mixing a chiral catalyst, a polymer and an organic solvent, adding imine shown in a formula (II) and aldehyde shown in a formula (III) at the temperature of-20-25 ℃, preserving heat, stirring, reacting for 4-12h, and performing post-treatment to obtain a chiral β -aminoaldehyde compound shown in the formula (I), wherein the mass ratio of the chiral catalyst, the polymer, the imine and the aldehyde is 0.2-0.5:0.1-1:1: 1-5.

10. Asymmetric synthesis method according to one of claims 1 to 3 or 9, characterized in that: the chiral catalyst is a catalyst IV, the polymer is PEG1000, and the organic solvent is acetonitrile.

(I) technical field

The invention relates to an asymmetric synthesis method of a chiral β -amino aldehyde compound.

(II) background of the invention

In the past decades, the field of asymmetric synthesis has achieved remarkable success, and the Nobel prize in 2001 was awarded to the chemists William S, Knowles Ry ō ji Noyori and K.Barry Sharpless who worked on the field of asymmetric catalytic reaction research to show their significant contributions in the field of asymmetric catalysis. The use of small organic molecule catalysts has been in use for over a century, but has been developed vigorously over the past 10 years and has become yet another important branch of enantioselective reactions following transition metal catalysis and bio-enzyme catalysis. Wherein the transition metal has the catalytic characteristics that: (1) the reaction conditions are harsh and are generally sensitive to water and air; (2) heavy metals are inevitably introduced in the reaction, and the product and the environment are polluted. And the traditional biological enzyme has the catalytic characteristics that: (1) specificity, one enzyme can only correspond to one catalytic reaction; (2) the catalytic reaction stability is poor, the substrate is greatly limited, and the product is not easy to separate and purify; (3) the culture of enzymes is also difficult, requires strict culture conditions, and is expensive. Compared with metal catalysis and enzyme catalysis, the organic small molecule catalysis has the following characteristics: (1) healthy, non-toxic, cheap, easy to operate, commercially available; (2) the reaction condition is mild, and the reaction can be carried out under high concentration, so that the waste of a large amount of solvent is avoided; (3) the universality is good, and one catalyst can catalyze various types of reactions; (4) the catalyst can be recycled by loading the catalyst on a plurality of carriers.

Proline and derivatives thereof are also widely concerned and deeply researched as a typical organic small-molecule catalyst. Proline was first shown to be an organic catalyst in the 70's of the 20 th century, and Hajos and Eder reported the use of proline catalysts, which generally have the following advantages as small organic molecules in catalytic asymmetric reactions: (1) simple and stable, distinct in structure, definite in function, modifiable and rich in natural content, and shows good catalytic performance in various asymmetric catalytic reactions; (2) the pyrrole ring skeleton of the secondary amine structure increases the pKa value of the secondary amine structure, has nucleophilicity, and ensures that the molecule has rigidity and is easier to convert between dilute amine and imine transition state structures; (3) the structure contains carboxyl and amino, and the carboxyl and amino can be used as acid and alkali in the reaction, similar to the enzyme catalytic property; (4) the proline molecule is a chiral bidentate ligand structure and can form a metal complex with catalytic activity; (5) the catalytic reaction conditions require no strict etching and do not need strict inert atmosphere; (6) the substrate does not need to be modified during reaction; (7) the insoluble organic solvent is easy to dissolve in water, and the recycling is convenient and simple; (8) according to the requirement of catalytic reaction, proline is modified to make it possess high activity, high selectivity and wide catalytic range.

Although the organic small molecular catalyst can catalyze and synthesize medicines, pesticides and fine chemical product intermediates, the industrial application of the organic small molecular catalyst is limited due to long reaction time, large catalyst consumption, low yield or ee value, so that the design and discovery of the catalyst with higher reaction activity, higher efficiency and better yield are main targets. In recent years, chiral organic supermolecule catalyzed asymmetric reaction is a brand-new catalysis concept, the main means of the method is to form a supermolecule assembly through self-assembly of various interactions (hydrogen bond interaction, metal coordination bond interaction, electrostatic interaction and hydrophobic interaction) so as to improve the catalysis efficiency of the supermolecule assembly, on the premise that the structure of a main catalyst is not changed, the weak interaction between molecules and the catalysis environment are regulated and controlled so that the catalyst and a substrate are subjected to covalent and non-covalent combined action to guide reaction, and the yield and the ee value are improved.

The reactivity and selectivity have been significantly improved in certain conversion reactions using supramolecular catalytic strategies, but asymmetric reactions with non-covalent interactions of achiral PEG/PPG hosts with chiral molecular guests by simple, inexpensive and readily available, have been rarely reported and present significant challenges. PEG/PPG as a novel green solvent, and PEG/PPG as a solvent has the advantages that: (1) is biocompatible; (2) the polymer is viable within an acceptable price range; (3) only a low concentration amount of catalyst is required; (4) high practicability and simple inspection process. The PEG/PPG has received attention of more and more researchers, and the chain structure of the PEG/PPG can form a compound with metal positive ions, so that the PEG/PPG is particularly applied to phase transfer catalyst reaction, and proline has low solubility in general organic solvents, and is heterogeneous catalysis similar to phase transfer catalysts. According to the work before this group and related studies, the addition of PEG/PPG series forms supramolecular catalysts, mainly modifying tunable hydrogen bond donor groups to increase double activation capability, or to enhance the solubility of the catalyst in organic solvents.

Disclosure of the invention

The invention aims to provide an asymmetric synthesis method of a chiral β -amino aldehyde compound, so as to obviously improve the product yield.

In order to achieve the purpose, the invention adopts the following technical scheme:

a is shown in formula (I) chiral β -amino aldehyde compound asymmetric synthesis method, the said asymmetric synthesis regards imine shown in formula (II) and aldehyde shown in formula (III) as reactant, carry on the reaction in organic solvent, the said reaction is carried on under the influence of chiral catalyst and polymer constructed supermolecule catalyst;

the chiral catalyst is selected from one of the following:

the polymer is selected from PEG and/or PPG;

in the formulae (I), (II) and (III),

R₁selected from one of the following: c₄-C₁₀Alkyl radical, C₃-C₇Cycloalkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl; the aryl is phenyl or naphthyl, the heteroaryl is furyl, thienyl or pyridyl, and the substituted aryl and the substituted heteroaryl are respectively and independently substituted by one or more of the following groups: c₁-C₂₀Alkyl radical, C₁-C₁₀Alkoxy, halogen, C₁-C₅Alkylmercapto, nitro, cyano, C₁-C₂₀A haloalkyl group;

R₂selected from one of the following: hydrogen, C₁-C₂₀Alkyl radical, C₃-C₇A cycloalkyl group.

Preferably, R₁Selected from one of the following: n-butyl, cyclohexyl, phenyl, 4-methoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 1-naphthyl, 2-furyl, 2-thienyl, 2-pyridyl, 4-methylphenyl, 3-chlorophenyl, 4-fluorophenyl, 4-methylthiophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-cyanophenyl, 4-trifluoromethylphenyl.

Preferably, R₂Selected from one of the following: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, cyclohexyl, n-hexyl.

Preferably, the chiral catalyst is a catalyst IV.

Preferably, the polymer is selected from at least one of the following: PEG200, PEG400, PEG600, PEG800, PEG1000, PEG1500, PPG400, PPG600, PPG800, PPG1000, PEG750, more preferably PEG 1000.

Preferably, the ratio of the amount of the chiral catalyst, the polymer, the imine and the aldehyde is 0.2-0.5:0.1-1:1: 1-5.

Preferably, the organic solvent is selected from one or a combination of any of the following: dichloromethane, chloroform, toluene, methanol, ethanol, ethyl acetate, diethyl ether, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane, and acetonitrile, more preferably acetonitrile.

Preferably, the volume usage amount of the organic solvent is 1-15 mL/mmol, more preferably 7mL/mmol, based on the amount of the imine compound represented by the formula (II).

Preferably, the asymmetric synthesis reaction is carried out at a temperature of-20 ℃ to 25 ℃, more preferably at 0 ℃.

As a further preference, the asymmetric synthesis is carried out according to the following steps:

mixing a chiral catalyst, a polymer and an organic solvent, adding imine shown in a formula (II) and aldehyde shown in a formula (III) at the temperature of-20-25 ℃, preserving heat, stirring, reacting for 4-12h, and performing post-treatment to obtain a chiral β -aminoaldehyde compound shown in the formula (I), wherein the mass ratio of the chiral catalyst, the polymer, the imine and the aldehyde is 0.2-0.5:0.1-1:1: 1-5.

More preferably, the post-treatment method is as follows: after the reaction is finished, adding water, fully stirring at room temperature, extracting with diethyl ether (preferably for multiple times), washing an organic phase with saturated saline water, drying with anhydrous sodium sulfate, performing desolventizing under reduced pressure, and adding diethyl ether: and (3) carrying out column chromatography separation on petroleum ether in a ratio of 1: 9-1: 3 to obtain a target product.

Compared with the prior art, the invention has the beneficial effects that the PPG/PEG and the chiral catalyst are utilized to construct the supramolecular catalyst for the asymmetric synthesis of the chiral β -amino aldehyde compound, and the product yield is obviously improved.

(IV) detailed description of the preferred embodiments

The technical solution of the present invention is further illustrated by the following specific examples, but the scope of the present invention is not limited thereto: