CN107497485A - A kind of aqueous phase asymmetric Aldol reaction catalyst and preparation method and application - Google Patents

A kind of aqueous phase asymmetric Aldol reaction catalyst and preparation method and application Download PDF

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CN107497485A
CN107497485A CN201710820388.3A CN201710820388A CN107497485A CN 107497485 A CN107497485 A CN 107497485A CN 201710820388 A CN201710820388 A CN 201710820388A CN 107497485 A CN107497485 A CN 107497485A
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immobilized
polystyrene
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tertbutyloxycarbonyl
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CN107497485B (en
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张宝华
史兰香
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Shijiazhuang University
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Abstract

The invention discloses a kind of aqueous phase asymmetric Aldol reaction catalyst and preparation method and application.The catalyst is immobilized L Pro L Trp, the L Pro L Ile and L Pro L Phe of polystyrene divinylbenzene sulfonate resin.Its preparation method comprises the following steps：A. polystyrene divinylbenzene sulfonate resin reacts with sulfonic acid chloride, prepares corresponding resin sulfonic acid chloride；B. in the basic conditions, resin sulfonic acid chloride and NαThe esterification of the hydroxyl L prolyl L amino acid methyl esters of tertbutyloxycarbonyl 4 is immobilized；C. immobilized NαTertbutyloxycarbonyl L prolyl L amino acid methyl esters take off tertbutyloxycarbonyl with trifluoroacetic acid, then are hydrolyzed with NaOH solution, and asymmetric Aldol reaction catalyst is made.The catalyst can be catalyzed asymmetric Aldol reaction in water or cushioning liquid, and product yield high, enantioselectivity is good, catalyst reusable edible.

Description

A kind of aqueous phase asymmetric Aldol reaction catalyst and preparation method and application
Technical field
The present invention relates to catalysis organic synthesis field, specifically, it is related to a kind of aqueous phase asymmetric Aldol reaction catalyst And preparation method and application.
Background technology
Aldol condensation（Aldol）Reaction is one of important reaction for synthesizing C-C keys, and aldehyde ketone uses asymmetric addition, can have The addition product of effect ground synthesis enantiomeric excess, obtains optical activity product, such as：Beta-hydroxy aldehyde ketone, α, beta-unsaturated carbonyl Organic compound such as compound and 1,2- glycol etc..Recent years, in the synthesis with physiologically active organic molecule, utilize The asymmetric Aldol reactions of organic micromolecule catalyst catalysis are even more to receive the extensive concern of people, and numerous high activities has The catalyst that machine micromolecule catalyst can especially be catalyzed asymmetric Aldol reaction in water is reported in succession, but these Catalyst is expensive, and when being catalyzed asymmetric Aldol reactions, dosage is larger, recovery trouble.Therefore, researchers select Select and load to chiral catalyst on different carriers, on the premise of catalytic efficiency is ensured, make the recovery profit of convenient catalyst With.
In early-stage Study, it has been found that the dipeptides that the larger L-PROLINE of some volumes is formed can be catalyzed not in aqueous phase Symmetrical Aldol reacts and obtains satisfied result, but catalyst recovery trouble.Recycling catalyst for convenience, this hair The bright dipeptides that forms L-PROLINE is immobilized on polystyrene-divinylbenzene sulfonate resin, will be immobilized after catalyst should In the asymmetric Aldol reaction for using catalysis, the yield and enantioselectivity of corresponding Aldol products are constant.
The content of the invention
It is an object of the invention to provide a kind of aqueous phase asymmetric Aldol reaction catalyst and preparation method and application.
Asymmetric Aldol reaction catalyst provided by the invention, it is characterised in that including：Polystyrene-divinylbenzene The immobilized L-Pro-L-Trp of sulfonate resin, polystyrene-divinylbenzene sulfonate resin immobilized L-Pro-L-Ile and polyphenyl Ethene-immobilized the L-Pro-L-Phe of divinylbenzene sulfonic acid resin, its structure are as follows：
The present invention also provides the preparation method of the asymmetric Aldol reaction catalyst, the described method comprises the following steps：
A. polystyrene-divinylbenzene sulfonate resin and chlorosulfonic acid react 1h at 80 DEG C, filtering, successively with ethyl acetate, two Chloromethanes, tetrahydrofuran, dichloromethane washing, prepare polystyrene-divinylbenzene sulfonic acid chloride；
B. in the basic conditions, using chloroform or dichloromethane as solvent, polystyrene-divinylbenzene sulfonic acid chloride and Nα- tertiary fourth Oxygen carbonyl -4- hydroxyls-L- prolyls-L-Trp methyl esters or NαThe different bright ammonia of-tertbutyloxycarbonyl -4- hydroxyl-L- prolyls-L- Sour methyl esters or NαAt 0 DEG C esterification occurs for-tertbutyloxycarbonyl -4- hydroxyls-L- prolyls-L-phenylalanine methyl esters, filters, Dichloromethane is used successively, dichloromethane-tetrahydrofuran, water, methanol washing, corresponding immobilized N is madeα- tertbutyloxycarbonyl-L- Prolyl-L-Trp methyl esters or immobilized Nα- tertbutyloxycarbonyl-L- prolyls-ILE methyl esters or immobilized Nα- Tertbutyloxycarbonyl-L- prolyls-L-phenylalanine methyl esters.
C. immobilized Nα- tertbutyloxycarbonyl-L- prolyls-L-Trp methyl esters or immobilized Nα- tertbutyloxycarbonyl-L- Prolyl-ILE methyl esters or immobilized Nα- tertbutyloxycarbonyl-L- prolyls-L-phenylalanine methyl esters trifluoro second The de- tertbutyloxycarbonyl of acid, then hydrolyzed with NaOH solution, adjusts pH, filtering, successively with dichloromethane, dichloromethane-tetrahydrofuran, Water, methanol washing, 50 DEG C of vacuum drying 24h, the immobilized L-Pro-L-Trp of polystyrene-divinylbenzene sulfonate resin is made, The immobilized L-Pro-L-Ile of polystyrene-divinylbenzene sulfonate resin and polystyrene-divinylbenzene sulfonate resin are immobilized L-Pro-L-Phe catalyst.Its synthetic route is as follows：
In the preparation method of above-mentioned asymmetric Aldol reaction catalyst, described polystyrene-divinylbenzene sulfonate resin For the polystyrene resin of 1% or 2% divinyl benzene crosslinked；Alkali in described step b is pyridine, triethylamine, sodium hydride；Institute The load capacity for stating L-Pro-L-Trp in solid-carried catalyst, L-Pro-L-Ile and L-Pro-L-Phe is 1.90-2.25mmol/g.
Present invention also offers application of the catalyst in aqueous phase asymmetric Aldol reaction., will in above-mentioned application A certain amount of aldehyde and ketone are added in a certain amount of water or cushioning liquid, add a certain amount of polystyrene-divinylbenzene sulphur The immobilized catalyst of acid resin, a certain amount of alkali and 5% surfactant, 0 DEG C of reaction certain time, filter, wash, dry, return Receive catalyst.Filtrate is extracted with ethyl acetate, concentration, column chromatography purifying, obtains corresponding asymmetric Aldol products.It reacts Formula is as follows：
In formula, R1, R2Each stand alone as alkyl, phenyl, substituted-phenyl, aryl, substituted aryl；R1, R2For cycloalkyl；R3Each Stand alone as phenyl, substituted-phenyl, aryl, substituted aryl, alkyl.
In above-mentioned application, described alkali is N-methylmorpholine, Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane；Described table Face activating agent is PEG400, lauryl sodium sulfate.The catalyst of recovery is purified to be recycled 5 times, and catalytic activity does not subtract.
Embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in This：
What embodiment 1-3 illustrated is the immobilized L-PROLINE dipeptides catalyst of the polystyrene-divinylbenzene sulfonate resin Synthesis.
What embodiment 4-8 illustrated is that the immobilized L-PROLINE dipeptides of the polystyrene-divinylbenzene sulfonate resin is urged Application of the agent in asymmetric Aldol reaction.
Embodiment 1
The immobilized L-Pro-L-Trp of polystyrene-divinylbenzene sulfonate resin preparation：
Chlorosulfonic acid 15mL is added in polystyrene-divinylbenzene sulfonate resin 4g containing 2% divinyl benzene crosslinked, 80 DEG C reaction 1h, cools down, filtering, successively with ethyl acetate, dichloromethane, tetrahydrofuran, dichloromethane washing, obtains polyphenyl second Alkene-divinyl benzene sulfonyl chloride.
Above-mentioned polystyrene-divinylbenzene sulfonic acid chloride 4g, 30mL chloroforms and 3mL triethylamines are added, adds 2.15g （5mmol）Nα- tertbutyloxycarbonyl -4- hydroxyls-L- prolyls-L-Trp methyl esters, 0 DEG C is reacted 3 days, filtering, uses dichloro successively Methane, dichloromethane-tetrahydrofuran, water, methanol washing, corresponding immobilized N is madeα- tertbutyloxycarbonyl-L- prolyl-L- colors Propylhomoserin methyl esters.
By the above-mentioned immobilized N of 4gα20mL trifluoroacetic acids and two are added in-tertbutyloxycarbonyl-L- prolyls-L-Trp methyl esters Chloromethanes（Volume ratio 1:4）Solution, 4h is stirred at room temperature, filters, successively with dichloromethane, dichloromethane-tetrahydrofuran, water, Methanol washs, and obtains solid.Add in 2mol/L NaOH solution and the mixed solution 20mL of methanol, be stirred at room temperature in solids 4h, watery hydrochloric acid adjust pH2-3, filtering, successively with dichloromethane, dichloromethane-tetrahydrofuran, water, methanol washing, dry, obtain Polystyrene-divinylbenzene sulfonate resin immobilized L-Pro-L-Trp catalyst 4.72g, load capacity 2.25mmol/g.
Catalyst loadings determine：1g supported catalyst resins, 17.25mL 1mol/L NaOH standard liquids are added, 1h, then the HCl standard liquid back titration with 1mol/L is stirred at room temperature, the 1mol/L of consumption HCl standard liquid 15mL, calculates Load capacity to catalyst is 2.25mmol/g）.
Embodiment 2
The immobilized L-Pro-L-Ile of polystyrene-divinylbenzene sulfonate resin preparation：
Use 1.86g（5mmol）Nα- tertbutyloxycarbonyl -4- hydroxyls-L- prolyls-ILE methyl esters replaces 2.15g （5mmol）Nα- tertbutyloxycarbonyl -4- hydroxyls-L- prolyls-L-Trp methyl esters, other operations obtain polyphenyl with embodiment 1 Ethene-divinylbenzene sulfonic acid resin immobilized L-Pro-L-Ile catalyst 4.57g, load capacity 2.19mmol/g.
Embodiment 3
The immobilized L-Pro-L-Phe of polystyrene-divinylbenzene sulfonate resin preparation：
The polyphenyl second of 2% divinylbenzene is replaced with the polystyrene-divinylbenzene sulfonic acid of the divinylbenzene containing 1% crosslinking Alkene-divinylbenzene sulfonic acid, 3mL triethylamines are replaced with 3mL pyridines, use 2.11g（5mmol）Nα- tertbutyloxycarbonyl -4- hydroxyls - L- prolyls-L-phenylalanine methyl esters, instead of 2.15g（5mmol）Nα- tertbutyloxycarbonyl -4- hydroxyl-L- prolyl-L- colors Propylhomoserin methyl esters, other operations obtain the immobilized L-Pro-L-Phe of polystyrene-divinylbenzene sulfonate resin and urged with embodiment 1 Agent 4.68g, load capacity 1.98mmol/g.
Embodiment 4
2- [hydroxyls（2- nitrobenzophenones）Methyl] cyclohexanone preparation：
By 151mg（1mmol）2- nitrobenzaldehydes, 392mg（4mmol）Cyclohexanone and 8mL water are added in reactor, are added The immobilized L-Pro-L-Trp catalyst of 0.1g polystyrene-divinylbenzene sulfonate resin, 44.8mg 1,4- diazas Two rings [2.2.2] octane
With 80mg PEG400,0 DEG C of reaction 24h, filter, wash, dry, reclaim catalyst.Filtrate is extracted with ethyl acetate, dense Contracting, column chromatography purifying, obtains 2- [hydroxyls（2- nitrobenzophenones）Methyl] cyclohexanone.Yield 90%；mp:116-118℃; dr (anti:syn) > 99:1, ee (anti): 89%。
Embodiment 5
2- [hydroxyls（2- chlorphenyls）Methyl] cyclohexanone preparation：
By 140mg（1mmol）2- chlorobenzaldehydes, 392mg（4mmol）Cyclohexanone and 8mL water are added in reactor, are added The immobilized L-Pro-L-ILe catalyst of 0.1g polystyrene-divinylbenzene sulfonate resin, 20.2mg N-methylmorpholine With 57.6mg lauryl sodium sulfate, 0 DEG C of reaction 36h, filter, wash, dry, reclaim catalyst.Filtrate ethyl acetate Extraction, concentration, column chromatography purifying, obtain 2- [hydroxyls（2- chlorphenyls）Methyl] cyclohexanone.Yield 88%；mp:89-91℃; dr (anti:syn) : >20:1, ee (anti): >99%。
Embodiment 6
4- [hydroxyl -4-（2 '-nitro -3 ', 4 '-methylenedioxyphenyl）Methyl] cyclohexanone preparation：
By 193mg（1mmol）4- nitros piperonal, 392mg（4mmol）Cyclohexanone and 8mL water are added in reactor, are added The immobilized L-Pro-L-Phe catalyst of 0.11g polystyrene-divinylbenzene sulfonate resin, 20.2mg N-methylmorpholine With 80mg PEG400,0 DEG C of reaction 36h, filter, wash, dry, reclaim catalyst.Filtrate is extracted with ethyl acetate, concentration, Column chromatography purifies, and obtains 4- [hydroxyl -4-（2 '-nitro -3 ', 4 '-methylenedioxyphenyl）Methyl] cyclohexanone.Yield 86%；dr (anti:syn) : >20:1, ee (anti): 95%。
Embodiment 7
The preparation of 4- hydroxy-5-methyl butylcyclohexyl -2- ketone：
By 72mg（1mmol）Isopropyl aldehyde, 288mg（4mmol）2- butanone and 10mLpH8.0 buffer solution are added in reactor, Add 0.1g the immobilized L-Pro-L-Trp catalyst of polystyrene-divinylbenzene sulfonate resin and 57.6mg 12 Sodium alkyl sulfate, 0 DEG C of reaction 48h, filters, washes, dry, reclaim catalyst.Filtrate is extracted with ethyl acetate, concentration, post layer Analysis purifying, obtains 4- hydroxy-5-methyl butylcyclohexyl -2- ketone.Yield 91%；ee : 69%.
Embodiment 8
The recycling performance test of catalyst：
By taking the immobilized L-Pro-L-Trp catalyst of polystyrene-divinylbenzene sulfonate resin as an example, operation and embodiment 4 Method is identical, after catalyst recovery, is washed successively with water, methanol-water, methanol, ethyl acetate, dries, circulate in water The asymmetric Aldol reaction of 2- nitrobenzaldehydes and cyclohexanone, the results are shown in Table 1.Catalyst recycling 5 times, activity do not subtract.It is poly- The immobilized L-Pro-L-Ile catalyst of styrene-divinylbenzene sulfonate resin and polystyrene-divinylbenzene sulfonic acid tree The immobilized L-Pro-L-Phe catalyst of fat has same recycling effect.

Claims (9)

  1. A kind of 1. asymmetric Aldol reaction catalyst, it is characterised in that including：Polystyrene-divinylbenzene sulfonic group resin Immobilized L-Pro-L-Trp, polystyrene-divinylbenzene sulfonic group resin immobilized L-Pro-L-Ile and polystyrene-two The immobilized L-Pro-L-Phe of vinylbenzenesulfonic acid base resin, its structure are as follows：
    tu-3。
  2. 2. the preparation method of asymmetric Aldol reaction catalyst according to claim 1, it is characterised in that including following step Suddenly：
    A. polystyrene-divinylbenzene sulfonate resin and chlorosulfonic acid react 1h at 80 DEG C, filtering, successively with ethyl acetate, two Chloromethanes, tetrahydrofuran, dichloromethane washing, prepare polystyrene-divinylbenzene sulfonic acid chloride；
    B. in the basic conditions, using chloroform or dichloromethane as solvent, polystyrene-divinylbenzene sulfonic acid chloride and Nα- tertiary fourth Oxygen carbonyl -4- hydroxyls-L- prolyls-L-Trp methyl esters or NαThe different bright ammonia of-tertbutyloxycarbonyl -4- hydroxyl-L- prolyls-L- Sour methyl esters or NαAt 0 DEG C esterification occurs for-tertbutyloxycarbonyl -4- hydroxyls-L- prolyls-L-phenylalanine methyl esters, filters, Dichloromethane is used successively, dichloromethane-tetrahydrofuran, water, methanol washing, corresponding immobilized N is madeα- tertbutyloxycarbonyl-L- Prolyl-L-Trp methyl esters or immobilized Nα- tertbutyloxycarbonyl-L- prolyls-ILE methyl esters or immobilized Nα- Tertbutyloxycarbonyl-L- prolyls-L-phenylalanine methyl esters；
    C. immobilized Nα- tertbutyloxycarbonyl-L- prolyls-L-Trp methyl esters or immobilized Nα- tertbutyloxycarbonyl-L- dried meat ammonia Acyl-ILE methyl esters or immobilized Nα- tertbutyloxycarbonyl-L- prolyls-L-phenylalanine methyl esters is taken off with trifluoroacetic acid Tertbutyloxycarbonyl, then hydrolyzed with NaOH solution, adjust pH, filtering, successively with dichloromethane, dichloromethane-tetrahydrofuran, water, first Alcohol washs, and 50 DEG C of vacuum drying 24h, the immobilized L-Pro-L-Trp of polystyrene-divinylbenzene sulfonate resin is made respectively, The immobilized L-Pro-L-Ile of polystyrene-divinylbenzene sulfonate resin and polystyrene-divinylbenzene sulfonate resin are immobilized L-Pro-L-Phe catalyst, its synthetic route is as follows：
    tu6。
  3. 3. preparation method according to claim 2, it is characterised in that described polystyrene-divinylbenzene sulfonic acid tree Fat is the polystyrene resin of 1% or 2% divinyl benzene crosslinked.
  4. 4. preparation method according to claim 2, it is characterised in that the alkali in described step b is pyridine, triethylamine, Sodium hydride.
  5. 5. preparation method according to claim 2, it is characterised in that L-Pro-L-Trp, L- in the solid-carried catalyst Pro-L-Ile and L-Pro-L-Phe load capacity is 1.90-2.25mmol/g.
  6. 6. immobilized asymmetric Aldol reaction catalyst according to claim 1, it is characterised in that can be in water or slow Rush and be applied to asymmetric Aldol reaction in solution.
  7. 7. application according to claim 6, it is characterised in that comprise the following steps：
    A certain amount of aldehyde and ketone are added in a certain amount of water or cushioning liquid, add a certain amount of polystyrene-divinyl The immobilized catalyst of base benzene sulfonic acid resin, a certain amount of alkali and 5% surfactant, 0 DEG C of reaction certain time, filter, washing, To dry, reclaim catalyst, filtrate is extracted with ethyl acetate, and concentrates, and column chromatography purifying, obtains corresponding asymmetric Aldol products, Its reaction equation is as follows：
    Figure-dipeptides
    In formula, R1, R2Each stand alone as alkyl, phenyl, substituted-phenyl, aryl, substituted aryl；R1, R2For cycloalkyl；R3Each solely Stand as phenyl, substituted-phenyl, aryl, substituted aryl, alkyl.
  8. 8. application according to claim 7, it is characterised in that described alkali is N-methylmorpholine, Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane.
  9. 9. application according to claim 7, it is characterised in that described surfactant is PEG400, dodecyl sulphur Sour sodium.
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Cited By (3)

* Cited by examiner, † Cited by third party
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CN112479946A (en) * 2020-11-27 2021-03-12 普洛药业股份有限公司 Method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity
CN116371466A (en) * 2023-02-28 2023-07-04 西安交通大学 Molecularly imprinted polymer modified magnetic immobilized tryptophan catalyst and preparation method and application thereof
CN116371466B (en) * 2023-02-28 2024-06-07 西安交通大学 Molecularly imprinted polymer modified magnetic immobilized tryptophan catalyst and preparation method and application thereof

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