CN114904577B - Chiral porous cross-linked oligopeptide polymer asymmetric catalyst and preparation method thereof - Google Patents

Abstract

The invention discloses a chiral porous cross-linked oligopeptide polymer asymmetric catalyst and a preparation method thereof, the preparation of the catalyst prepares the chiral porous cross-linked oligopeptide polymer asymmetric catalyst by chemically cross-linking oligopeptide with catalytic function and containing aromatic amino acid units, or preparing the asymmetric catalyst of the chiral porous cross-linked oligopeptide polymer by introducing a catalytic site through a post-modification method after chemical cross-linking of the oligopeptide containing the aromatic amino acid unit. The asymmetric catalyst of the chiral porous cross-linked oligopeptide polymer can catalyze various asymmetric reactions, and has the advantages of large specific surface area, high catalytic efficiency, high enantioselectivity, recycling and the like; compared with small molecule chiral organic catalysts such as proline, the method has the advantages of greatly shortening the reaction time and improving the conversion rate and the enantioselectivity. The catalyst has the advantages of simple preparation method, low cost, high efficiency and good market prospect.

Description

Chiral porous cross-linked oligopeptide polymer asymmetric catalyst and preparation method thereof

Technical Field

The present invention relates to the fields of porous materials, catalysts and asymmetric catalysis, and mainly to chiral porous cross-linked oligopeptide polymer asymmetric catalysts and preparation methods thereof, and specifically to the synthesis of chiral porous cross-linked oligopeptide polymers, the loading of catalytically active groups and asymmetric reactions catalyzed by the catalysts.

Background Art

In recent decades, with the continuous development and use of chiral drugs, the synthesis of new asymmetric catalysts has become one of the research hotspots. In the past few decades, the chiral catalysts used were mostly enzymes and metal complexes. In recent years, with the advent of green chemistry, heterogeneous organic catalysts have become a research focus. Heterogeneous organic catalysts are usually polymerized from small molecules and are non-toxic and inexpensive. This makes heterogeneous organic catalysts very suitable for the synthesis of drugs.

Amino acids with chiral structures are widely present in nature and are a kind of cheap and easily available chiral compounds. With the continuous deepening of research, it is found that peptides composed of 2-50 amino acids can be used as good carriers of chiral catalysts. Peptides have modular characteristics, and their reactivity and corresponding selectivity, as well as biomimetic properties, can be fine-tuned by replacing single amino acid residues. Therefore, the key factor in designing peptide catalysts is to incorporate functional groups with catalytic ability into the three-dimensional structure of the appropriate chiral environment. At the same time, the structure of the peptide can be designed to make it insoluble in commonly used organic solvents, which is convenient for multiple recycling. However, since the binding between peptides is mostly intermolecular forces, the special chiral environment is destroyed after multiple cycles, resulting in a decrease in catalytic activity.

Heterogeneous catalysts are easy to recycle and reuse, but it is difficult to identify the active sites that affect the catalytic activity. Therefore, the gap with homogeneous catalysts can be made up by designing carriers with active catalytic binding sites. Porous hypercrosslinked polymers (HCPs) have large specific surface areas, stable physicochemical properties, and a large number of surface functional groups. Porous hypercrosslinked polymers can be obtained through simple reactions. Their porous structure can increase the chances of reactants contacting with catalytic active centers. Therefore, chiral polymers synthesized by oligopeptide hypercrosslinking can be used as catalysts or carriers.

Summary of the invention

The purpose of the present invention is to provide, but not limited to, a novel chiral porous cross-linked oligopeptide polymer asymmetric catalyst which is cheap, efficient, recyclable and highly enantioselective for asymmetric catalytic reactions and a preparation method thereof.

The novel chiral porous cross-linked oligopeptide polymer asymmetric catalyst of the present invention is a hyper-cross-linked oligopeptide polymer whose structure can be fine-tuned by replacing different amino acids; the catalyst active sites are evenly distributed in the catalyst, which significantly improves the catalytic efficiency of the catalyst and effectively shortens the catalytic reaction time.

The purpose of the present invention can be achieved by the following method:

The chiral porous cross-linked oligopeptide polymer asymmetric catalyst synthesis method includes the following two methods:

Method 1: A chiral porous cross-linked oligopeptide polymer asymmetric catalyst is synthesized through an electrophilic substitution reaction between an oligopeptide containing aromatic amino acids with catalytic function and a cross-linking agent.

Method 2: The catalyst is prepared by the following steps

Step 1: an electrophilic substitution reaction between an oligopeptide containing aromatic amino acids without catalytic function and a cross-linking agent to form a chiral porous cross-linked oligopeptide polymer precursor.

Step 2: The chiral porous cross-linked oligopeptide polymer precursor obtained in step 1 is modified by a chemical reaction with a compound having a catalytic site, and an organic catalytic site is introduced to prepare a chiral porous cross-linked oligopeptide polymer asymmetric catalyst.

The first method is specifically as follows: under nitrogen atmosphere, an oligopeptide containing aromatic amino acids with catalytic function, a cross-linking agent, and a cross-linking catalyst are added to a reaction bottle at a certain mass ratio, and then an appropriate amount of reaction solvent is added. The reaction is carried out at a certain temperature under nitrogen protection to generate a solid, which is filtered and washed to directly obtain a chiral porous cross-linked oligopeptide polymer catalyst.

The specific step 1 of the second method is: adding an oligopeptide containing aromatic amino acids without catalytic function, a cross-linking agent, and a cross-linking catalyst to a reaction bottle at a certain mass ratio, and then adding an appropriate amount of reaction solvent. The reaction is carried out at a certain temperature under nitrogen protection to generate a solid, which is filtered and washed to obtain a chiral porous cross-linked oligopeptide polymer precursor.

Step 2 in the second method is specifically as follows: the modification of the chiral porous cross-linked oligopeptide polymer precursor can be carried out by introducing a group with a catalytic site into the cross-linked oligopeptide precursor through a nucleophilic substitution reaction, a coupling reaction, etc., to obtain a chiral porous cross-linked oligopeptide polymer asymmetric catalyst.

The aromatic amino acids include but are not limited to one or more of the aromatic ring-containing amino acids such as phenylalanine, phenylglycine, tyrosine, tryptophan, histidine, aminobenzoic acid, aminobenzenesulfonic acid, etc.; the oligopeptides containing aromatic amino acids are: optically active oligopeptides containing one or more aromatic amino acid units in the oligopeptide structure or a mixture of the above oligopeptides; the cross-linking agent includes but is not limited to one or a mixture of 1,4-dichlorobenzyl, biphenyl dichlorobenzyl, and dimethoxymethane.

The cross-linking catalyst includes, but is not limited to, one or a mixture of ferric chloride, aluminum chloride, concentrated sulfuric acid, and concentrated phosphoric acid; the reaction solvent includes, but is not limited to, one or a mixture of 1,2-dichloroethane, dimethyl sulfoxide, and nitromethane.

The compound with catalytic sites includes, but is not limited to, nitrogen-containing organic bases such as cinchona alkaloids, proline, hydroxyproline, amines, guanidine and their derivatives, and Bronsted acid derivatives such as phosphoric acid and sulfonic acid, or a mixture thereof.

The mass ratio of the aromatic amino acid-containing oligopeptide/crosslinking agent/crosslinking catalyst is 1/1 to 1.5/2 to 3; the ratio of the reaction solvent to the reactant is 5 to 50 mL/g; the reaction temperature is room temperature to 100 degrees Celsius; and the reaction time is 2 to 48 hours.

A chiral porous cross-linked oligopeptide polymer asymmetric catalyst is prepared by any of the above methods.

Compared with the prior art, the present invention has the following beneficial effects:

The present invention first synthesizes a chiral porous cross-linked oligopeptide polymer asymmetric catalyst or carrier through an electrophilic substitution reaction between an oligopeptide and a cross-linking agent. The catalytically active group is connected to the polymer carrier to prepare a chiral catalyst. The novel asymmetric catalyst of the present invention can catalyze a variety of asymmetric reactions, and has the advantages of large specific surface area, high catalytic efficiency, high enantioselectivity and recyclability; compared with small molecule chiral organic catalysts such as proline, the reaction time is greatly shortened, the conversion rate and enantioselectivity are improved, the catalyst preparation method is simple, low cost, high efficiency, and has good market prospects.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a scanning electron micrograph of a chiral porous cross-linked oligopeptide polymer asymmetric catalyst obtained in Example 1 of the present invention;

FIG2 is an infrared spectrum of the chiral porous cross-linked oligopeptide polymer asymmetric catalyst obtained in Example 1 of the present invention;

FIG3 is a nuclear magnetic resonance spectrum of the chiral porous cross-linked oligopeptide polymer asymmetric catalyst obtained in Example 1 of the present invention;

FIG4 is a nitrogen adsorption isotherm of the chiral porous cross-linked oligopeptide polymer asymmetric catalyst obtained in Example 1 of the present invention;

FIG. 5 is a chromatogram of the products of the Mannich reaction catalyzed by a chiral porous cross-linked oligopeptide polymer asymmetric catalyst in Example 1 of the present invention.

DETAILED DESCRIPTION

The present invention is described in more detail below in conjunction with specific embodiments:

Embodiment 1:

1. Synthesis of chiral porous cross-linked oligopeptide polymer precursor: Under nitrogen atmosphere, add Boc-L-phenylalanine dipeptide (1.0 mmol), biphenyl dichlorobenzyl (1.0 mmol), and ferric chloride (3.0 mmol) to the reaction flask, and then add 40 ml of 1,2-dichloroethane and 10 ml of dimethoxymethane. Place the reaction flask containing the reactants in an oil bath and react at 80 degrees Celsius for 48 hours. After the reaction, filter out the solids obtained from the reaction and place them in a Soxhlet extractor for extraction with methanol for 24-96 hours. After the extraction, place the solids in ethyl acetate, add an appropriate amount of concentrated hydrochloric acid, react at room temperature for 24 hours, and remove the protecting group. Filter and wash to obtain a chiral porous cross-linked oligopeptide polymer precursor.

2. Modification of chiral porous cross-linked oligopeptide polymer precursor: 2.0 g of Fmoc-L-proline, 6.0 g of N,N'-dicyclohexylcarbodiimide, 1.0 g of super cross-linked phenylalanine dipeptide, and 20 ml of reaction solvent dichloromethane were added to the reaction bottle and reacted in a nitrogen atmosphere for 7 days. After the reaction is completed, the product is filtered under normal pressure, purified, and the solid is collected. Then it is added to ethyl acetate, and an appropriate amount of concentrated hydrochloric acid is added to react at room temperature for 24 hours. Remove the protecting group. After the reaction is completed, the product is filtered and purified under normal pressure to obtain a chiral porous cross-linked oligopeptide polymer catalyst.

3. Use the above-synthesized catalyst to catalyze the asymmetric Mannich reaction of p-methoxyaniline, p-nitrobenzaldehyde and acetone. Under a nitrogen atmosphere, add 8.0 mg of chiral mesoporous oligopeptide polymer catalyst, 2.0 ml of chloroform, 1.0 mmol acetone, 0.5 mmol p-nitrobenzaldehyde, and 0.6 mmol p-methoxyaniline to the reactor in sequence and shake well. After reacting for 50 seconds, use a filter needle to filter and recover the catalyst. Use column chromatography to separate and purify the product, using a mobile phase of n-hexane/isopropanol = 9/1 volume ratio, use a rotary evaporator to spin dry the solvent, and finally put the remaining product into a vacuum drying oven at 30 degrees Celsius and vacuum dry to constant weight, with a yield of 95%.

4. Test the enantiomeric excess of the catalytic product. Weigh 2.0 mg of the product and dissolve it in a mixed solvent (n-hexane/propanol = 9/1, volume ratio) at room temperature and pressure. Then inject the product solution into a high performance liquid chromatography for testing, using an AD-H chiral column, a mobile phase of n-hexane/isopropanol = 9/1 volume ratio, and a flow rate of 1.0 ml/min. The product enantiomeric excess is 95%.

Embodiment 2:

1. Use the above-synthesized catalyst to catalyze the asymmetric Mannich reaction of p-methoxyaniline, p-nitrobenzaldehyde and acetophenone. Under a nitrogen atmosphere, add 8.0 mg of chiral mesoporous oligopeptide polymer catalyst, 2.0 ml of chloroform, 1.0 mmol of acetophenone, 0.5 mmol of p-nitrobenzaldehyde, and 0.6 mmol of p-methoxyaniline to the reactor in sequence and shake well. After reacting for 50 seconds, use a filter needle to filter and recover the catalyst. Use column chromatography to separate and purify the product, using a mobile phase of n-hexane/isopropanol = 9/1 volume ratio, use a rotary evaporator to spin dry the solvent, and finally put the remaining product into a vacuum drying oven at 30 degrees Celsius and vacuum dry to constant weight, with a yield of 92%.

2. Test the enantiomeric excess of the catalytic product. Weigh 2.0 mg of the product and dissolve it in a mixed solvent (n-hexane/propanol = 9/1, volume ratio) at room temperature and pressure. Then inject the product solution into a high performance liquid chromatography for testing, using an AD-H chiral column, a mobile phase of n-hexane/isopropanol = 90/10 volume ratio, and a flow rate of 1.0 ml/min. The enantiomeric excess of the product is 99%.

Embodiment 3:

1. Use the above-synthesized catalyst to catalyze the asymmetric Michael addition reaction of cyclohexanone and trans-β-nitrostyrene. Under a nitrogen atmosphere, add 8.0 mg of chiral mesoporous oligopeptide polymer catalyst, 4.0 ml of methanol, 0.5 mmol of trans-β-nitrostyrene, and 0.6 mmol of cyclohexanone to the reactor in sequence and shake well. Place the sealed reactor in a magnetic stirrer at 25 degrees Celsius to react for 4 days. After the reaction is completed, use a filter needle to filter and recover the catalyst. Use column chromatography to separate and purify the product. The mobile phase used is n-hexane/isopropanol = 9/1 volume ratio. Use a rotary evaporator to spin dry the solvent. Finally, place the remaining product in a vacuum drying oven at 30 degrees Celsius and vacuum dry it to constant weight. The yield is 94%.

2. Test the enantiomeric excess of the catalytic product. Weigh 2 mg of the product and dissolve it in a mixed solvent (n-hexane/propanol = 9/1, volume ratio) at room temperature and pressure. Then inject the product solution into a high performance liquid chromatography for testing, using an AD-H chiral column, a mobile phase of n-hexane/isopropanol = 90/10 volume ratio, and a flow rate of 1.0 ml/min. The enantiomeric excess of the product is 97%.

In summary, the present invention discloses a chiral porous cross-linked oligopeptide polymer asymmetric catalyst and a preparation method thereof, wherein the catalyst is prepared by chemically cross-linking an oligopeptide containing an aromatic amino acid unit with a catalytic function to prepare a chiral porous cross-linked oligopeptide polymer asymmetric catalyst, or by chemically cross-linking an oligopeptide containing an aromatic amino acid unit, and then introducing a catalytic site by a post-modification method to prepare a chiral porous cross-linked oligopeptide polymer asymmetric catalyst. The chiral porous cross-linked oligopeptide polymer asymmetric catalyst of the present invention can catalyze a variety of asymmetric reactions, and has the advantages of large specific surface area, high catalytic efficiency, high enantioselectivity and recyclability; relative to small molecule chiral organic catalysts such as proline, the reaction time is greatly shortened, and the conversion rate and enantioselectivity are improved. The catalyst preparation method is simple, low cost, high efficiency, and has good market prospects.

Claims (2)

1. A method for preparing a chiral porous cross-linked oligopeptide polymer asymmetric catalyst, characterized in that the catalyst is prepared by the following steps: Synthesis of chiral porous cross-linked oligopeptide polymer precursor: under nitrogen atmosphere, 1.0 mmol Boc-L-phenylalanine dipeptide, 1.0 mmol biphenyl dichlorobenzyl, 3.0 mmol ferric chloride are added to a reaction bottle, and then 40 ml 1,2-dichloroethane and 10 ml dimethoxymethane are added; the reaction bottle containing the reactants is placed in an oil bath pot and reacted at 80 degrees Celsius for 48 hours; after the reaction is completed, the solid obtained by the reaction is filtered out and placed in a Soxhlet extractor for extraction with methanol for 24-96 hours; after the extraction is completed, the solid is placed in ethyl acetate, and an appropriate amount of concentrated hydrochloric acid is added to react at room temperature for 24 hours to remove the protecting group; the chiral porous cross-linked oligopeptide polymer precursor is obtained by filtration and washing; Modification of chiral porous cross-linked oligopeptide polymer precursor: 2.0 g of Fmoc-L-proline, 6.0 g of N,N'-dicyclohexylcarbodiimide, 1.0 g of super-cross-linked phenylalanine dipeptide, and 20 ml of reaction solvent dichloromethane were added to a reaction bottle and reacted in a nitrogen atmosphere for 7 days; after the reaction, the product was filtered under normal pressure to purify the product and the solid was collected; then it was added to ethyl acetate and placed in an appropriate amount of concentrated hydrochloric acid to react at room temperature for 24 hours; the protecting group was removed; after the reaction was completed, the product was filtered and purified under normal pressure to obtain a chiral porous cross-linked oligopeptide polymer catalyst. 2. A chiral porous cross-linked oligopeptide polymer asymmetric catalyst, characterized in that it is prepared by the preparation method described in claim 1.