CN110845288A - Asymmetric synthesis method of chiral β -amino aldehyde compound - Google Patents
Asymmetric synthesis method of chiral β -amino aldehyde compound Download PDFInfo
- Publication number
- CN110845288A CN110845288A CN201911193727.5A CN201911193727A CN110845288A CN 110845288 A CN110845288 A CN 110845288A CN 201911193727 A CN201911193727 A CN 201911193727A CN 110845288 A CN110845288 A CN 110845288A
- Authority
- CN
- China
- Prior art keywords
- added
- asymmetric synthesis
- synthesis method
- 15min
- chiral
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- 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
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
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;
Description
(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:
example 1: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single neck round bottom flask was charged with 23mg (0.2mmol) L-proline, 10000.6g PEG (0.6mmol), 3mL redistilled acetonitrile, added with magnetons, stirred for 15min, added with 2mL benzylidene carbamic acid tert-butyl ester 0.205g (1mmol) acetonitrile solution, 2mL propionaldehyde (1.5mmol) ethyl acetate at 0 deg.CAfter 7 hours of reaction, the nitrile solution was added to 10mL of water and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and separated by column chromatography using diethyl ether and petroleum ether at a ratio of 1: 9. The expected product (0.2211g, 84.1% yield, 99% ee, dr) is obtained>2.7)。1H NMR(500MHz,CDCl3):δ＝9.722-9.667(d,J＝27.5Hz,1H),7.370-7.252(m,5H),5.193(s,1H),5.284-4.885(d,J＝199.5Hz,1H),2.88(s,1H),1.42(s,9H),1.083-1.069(d,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝202.8,155.4,139.8,128.7(×2),127.7(×2),127.0,80.1,51.6,44.9,28.2(×3),9.3。
Example 2: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 2000.12 g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magneton and stirred for 15min, added with 2mL of acetonitrile solution containing 0.205g (1mmol) of t-butyl benzylidenecarbamate and 2mL of acetonitrile solution containing 0.087g (1.5mmol) of propionaldehyde at 0 ℃, added with 10mL of water after the reaction was finished for 7h and stirred for 15min at room temperature, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and separated by column chromatography with diethyl ether, petroleum ether ═ 1: 9. The expected product (0.2099g, 79.8% yield) is obtained.
Example 3: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 4000.24 g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magneton and stirred for 15min, added with 2mL of acetonitrile solution containing 0.205g (1mmol) of t-butyl benzylidenecarbamate and 2mL of acetonitrile solution containing 0.087g (1.5mmol) of propionaldehyde at 0 ℃, added with 10mL of water after 7.2h of reaction and stirred for 15min at room temperature, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and separated by diethyl ether-petroleum ether column chromatography (1: 9). The expected product (0.1941g, 73.8% yield) was obtained.
Example 4: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 6000.36 g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution 0.205g (1mmol) of t-butyl benzylidenecarbamate at 0 ℃ and 2mL of acetonitrile solution 0.087g (1.5mmol) of propionaldehyde, added with 10mL of water after 7.5h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then dried with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1086g, 41.3% yield) is obtained.
Example 5: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 8000.48 g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magneton and stirred for 15min, added with 2mL of acetonitrile solution containing 0.205g (1mmol) of t-butyl benzylidenecarbamate and 2mL of acetonitrile solution containing 0.087g (1.5mmol) of propionaldehyde at 0 ℃, added with 10mL of water after 7.6h of reaction and stirred for 15min at room temperature, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and separated by diethyl ether-petroleum ether column chromatography (1: 9). The expected product (0.1786g, 67.9% yield) was obtained.
Example 6: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 15000.90 g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution 0.205g (1mmol) of t-butyl benzylidenecarbamate at 0 ℃ and 2mL of acetonitrile solution 0.087g (1.5mmol) of propionaldehyde, added with 10mL of water after 8.7h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then dried with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1786g, 67.9% yield) was obtained.
Example 7: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 4000.24 g (0.6mmol) of PPG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution 0.205g (1mmol) of t-butyl benzylidenecarbamate at 0 ℃ and 2mL of acetonitrile solution 0.087g (1.5mmol) of propionaldehyde, added with 10mL of water after 10.5h of reaction is finished and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then dried with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1896g, 72.1% yield) is obtained.
Example 8: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 6000.36 g (0.6mmol) of PPG, 3mL of redistilled acetonitrile, added with magneton and stirred for 15min, added with 2mL of acetonitrile solution containing 0.205g (1mmol) of t-butyl benzylidenecarbamate and 2mL of acetonitrile solution containing 0.087g (1.5mmol) of propionaldehyde at 0 ℃, added with 10mL of water after reaction for 8.5h and stirred for 15min at room temperature, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and separated by diethyl ether-petroleum ether column chromatography (1: 9). The expected product (0.1507g, 57.3% yield) is obtained.
Example 9: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 8000.48 g (0.6mmol) of PPG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution 0.205g (1mmol) of t-butyl benzylidenecarbamate at 0 ℃ and 2mL of acetonitrile solution 0.087g (1.5mmol) of propionaldehyde, added with 10mL of water after 10.5h of reaction is finished and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then dried with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1949g, 74.1% yield) is obtained.
Example 10: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PPG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution 0.205g (1mmol) of t-butyl benzylidenecarbamate at 0 ℃ and 2mL of acetonitrile solution 0.087g (1.5mmol) of propionaldehyde, added with 10mL of water after 9h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then dehydrated with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.0668g, 25.4% yield) is obtained.
Example 11: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 7500.45 g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magneton and stirred for 15min, added with 2mL of acetonitrile solution containing 0.205g (1mmol) of t-butyl benzylidenecarbamate and 2mL of acetonitrile solution containing 0.087g (1.5mmol) of propionaldehyde at 0 ℃, added with 10mL of water after reaction for 10.5h and stirred for 15min at room temperature, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and separated by diethyl ether-petroleum ether column chromatography (1: 9). The expected product (0.2080g, 79.1% yield) is obtained.
Example 12: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single neck round bottom flask was charged with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of dichloromethane, magneton was added and stirred for 15min, 2mL of dichloromethane solution containing 0.205g (1mmol) of t-butyl benzylidenecarbamate and 2mL of propanal at 0 ℃ were added, 2mL of dichloromethane solution containing 0.087g (1.5mmol) of propanal were added after 6h of reaction, 10mL of water was added and stirred at room temperature for 15min, and extraction was performed with ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and the reaction solution was dried with ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1128g, 42.9% yield) was obtained.
Example 13: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of chloroform, stirred for 15min by adding magnetons, 2mL of chloroform solution containing 0.205g (1mmol) of t-butyl benzylidenecarbamate and 2mL of propionaldehyde solution containing 0.087g (1.5mmol) of chloroform at 0 ℃, stirred for 15min at 10mL of water at room temperature after reaction for 6h, extracted with ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then dehydrated with ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1278g, 48.6% yield) is obtained.
Example 14: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of toluene, added with magneton and stirred for 15min, added with 2mL of toluene solution containing 0.205g (1mmol) of t-butyl benzylidenecarbamate and 2mL of toluene solution containing 0.087g (1.5mmol) of propionaldehyde at 0 ℃, added with 10mL of water after 12h of reaction and stirred for 15min at room temperature, extracted with ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then treated with ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.0158g, 6% yield) was obtained.
Example 15: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of ethyl acetate, added with magneton and stirred for 15min, added with 2mL of ethyl acetate solution of 0.205g (1mmol) of t-butyl benzylidenecarbamate at 0 ℃ and 2mL of ethyl acetate solution of 0.087g (1.5mmol) of propionaldehyde, added with 10mL of water after 12h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then dried with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.0071g, 2.7% yield) is obtained.
Example 16: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of diethyl ether, added with magneton and stirred for 15min, added with 2mL of diethyl ether solution of 0.205g (1mmol) of tert-butyl benzylidenecarbamate at 0 ℃ and 2mL of diethyl ether solution of 0.087g (1.5mmol) of propionaldehyde, added with 10mL of water after 12h of reaction and stirred for 15min at room temperature, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then treated with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.0213g, 8.1% yield) was obtained.
Example 17: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of tetrahydrofuran, added with magneton and stirred for 15min, added with 2mL of a tetrahydrofuran solution containing 0.205g (1mmol) of t-butyl benzylidenecarbamate and 2mL of a tetrahydrofuran solution containing 0.087g (1.5mmol) of propionaldehyde at 0 ℃, added with 10mL of water after 12h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then dried with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1515g, 57.6% yield) is obtained.
Example 18: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single neck round bottom flask was charged with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of N, N-dimethylformamide, followed by stirring with magneton for 15min, 0.205g (1mmol) of tert-butyl benzylidenecarbamate in 2mL of N, N-dimethylformamide at 0 ℃ and 0.087g (1.5mmol) of propionaldehyde in 2mL of N, N-dimethylformamide at 0 ℃, 10mL of water was added after the reaction was completed for 10h, stirring at room temperature for 15min, extraction with ether (3X 15mL), washing the organic phase with saturated brine (20mL), drying with anhydrous sodium sulfate, desolventizing under reduced pressure, and removing with ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1602g, 60.9% yield) was obtained.
Example 19: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of thionyl chloride, added with magneton and stirred for 15min, added with 2mL of a solution of tert-butyl benzylidenecarbamate (0.205 g (1mmol) of thionyl chloride at 0 ℃ and 2mL of a solution of propionaldehyde (0.087 g (1.5mmol) of thionyl chloride, added with 10mL of water after 4h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then treated with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.0371g, 14.1% yield) was obtained.
Example 20: (1S,2S) -2-methyl-3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester;
a25 mL single neck round bottom flask was charged with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of 1, 4-dioxane, a magneton was added and stirred for 15min, 0.205g (1mmol) of tert-butyl benzylidenecarbamate was added at 0 ℃ and 2mL of 1, 4-dioxane solution, 0.087g (1.5mmol) of propionaldehyde and 2mL of 1, 4-dioxane solution, after completion of the reaction for 8h, 10mL of water was added and stirred at room temperature for 15min, extracted with ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then extracted with ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1752g, 66.6% yield) is obtained.
Example 21: (1S,2S) -1- (4-methoxyphenyl) -2-methyl-3-oxopropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution (0.235 g (1mmol) of tert-butyl (4-methoxybenzylidene) carbamate) at 0 ℃ and 2mL of acetonitrile solution of propionaldehyde 0.087g (1.5mmol), added with 10mL of water after 7h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and washed with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1773g, 60.5% yield, 96% ee, dr) is obtained>1.1)，1H NMR(500MHz,CDCl3):δ＝9.674-9.650(d,J＝12.0Hz,1H),7.186-7.160(m,2H),6.874-6.852(m,1H),5.230-4.648(m,2H),3.786-3.782(d,J＝2.0Hz,3H),2.836-2.769(t,J＝33.5Hz,1H),1.383(s,9H),1.078-0.981(dd,J＝7.0Hz,3H).13CNMR(125MHz,CDCl3):δ＝203.4,159.0,156.5,132.0,128.0(×2),114.1(×2),79.5,55.2,52.2,51.6,28.3(×3),9.6。
Example 22: (1S,2S) -1- (2-methoxyphenyl) -2-methyl-3-oxopropyl) carbamic acid tert-butyl ester;
taking a 25mL single-neck round-bottom flask, adding 23mg (0.2mmol) of L-proline, 6g (0.6mmol) of PEG10000.6g, redistilled acetonitrile 3mL, adding magnetons, stirring for 15min, adding 2mL of acetonitrile solution (1mmol) of tert-butyl (2-methoxybenzylidene) carbamate and 2mL of acetonitrile solution (1.5mmol) of propionaldehyde at 0 ℃, adding 10mL of water at room temperature after the reaction is finished for 7h, stirring for 15min, extracting with diethyl ether (3X 15mL), washing an organic phase with saturated saline (20mL), drying with anhydrous sodium sulfate, decompressing, desolventizing, using diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1562g, 53.3% yield, 98% ee, dr) is obtained>2.8),1H NMR(500MHz,CDCl3):δ＝9.645(s,1H),7.276-6.905(m,4H),5.542-5.262(d,J＝140.0Hz,1H),5.047-5.009(d,J＝19.0Hz,1H),3.867-3.861(d,J＝3.0Hz,3H),2.979-2.938(m,1H),1.434(s,9H),1.049-0.924(dd,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝203.0,156.9,155.3,129.5,128.9,127.3,120.8,111.0,79.7,55.3,52.8,50.8,28.3(×3),9.9。
Example 23: (1S,2S) -1- (3-methoxyphenyl) -2-methyl-3-oxopropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution containing 0.235g (1mmol) of tert-butyl phosphite (3-methoxybenzylidene) carbamate and 2mL of acetonitrile solution containing 0.087g (1.5mmol) of propionaldehyde at 0 ℃, added with 10mL of water after 7h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and washed with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.2318g, 79.1% yield, 99% ee, dr) is obtained>4.8)，1H NMR(500MHz,CDCl3):δ＝9.718-9.661(d,J＝23.5Hz,1H),7.285-7.254(m,1H),6.847-6.800(m,3H),5.156(s,2H),3.805-3.795(d,J＝5.0Hz,3H),2.861(s,1H),1.424(s,9H),1.080-1.066(d,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝202.9,159.9,155.1,129.8,119.0,118.8,112.9,112.7,80.0,55.2,54.7,51.5,28.3(×3),9.2。
Example 24: (1S,2S) -2-methyl-1- (naphthalen-1-yl) -3-oxopropyl) carbamic acid tert-butyl ester;
a25 mL single neck round bottom flask was charged with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, magneton addition, stirring for 15min, and at 0 deg.C, 2mL of a solution of tert-butyl (naphthalen-1-ylmethylene) carbamate (0.255 g (1mmol) of acetonitrile, and 0.087g (1.5mmol) of propionaldehyde in ethyl acetateAfter 7 hours of reaction, 10mL of nitrile solution was added, the mixture was stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), and the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and desolventized under reduced pressure using diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1800g, 57.5% yield, 97% ee, dr) is obtained>1.5)，1H NMR(500MHz,CDCl3):δ＝9.836-9.728(d,J＝54.0Hz,1H),8.185-7.449(m,7H),6.123-5.169(d,J＝477.0Hz,1H),5.746-5.491(d,J＝127.5Hz,1H),3.082(s,1H),1.447(s,9H),1.129-1.115(d,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝202.5,155.2,134.0,131.0,130.5,129.1,128.4,126.7,125.9,125.0,123.7,122.7,80.0,51.5,50.7,28.2(×3),9.2。
Example 25: (1S,2S) -1- (furan-2-yl) -2-methyl-3-oxopropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution (0.195 g (1mmol) of tert-butyl (furan-2-ylmethylene) carbamate) at 0 ℃, 2mL of acetonitrile solution of propionaldehyde 0.087g (1.5mmol), added with 10mL of water after 7h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and washed with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product is obtained (0.1961g, 77.5% yield, 97% ee, dr)>4)，1HNMR(500MHz,CDCl3):δ＝9.761-9.685(d,J＝38.0Hz,1H),7.359-7.276(m,1H),6.330-6.319(dd,J＝2.0,7.0Hz,1H),6.225-6.219(d,J＝3.0Hz,1H),5.212-5.086(m,2H),2.941-2.914(t,J＝6.5,7.0Hz,1H),1.444(s,9H),1.104-1.090(d,J＝7.0Hz,3H).13CNMR(125MHz,CDCl3):δ＝202.7,155.0,152.1,142.2,110.4,107.2,80.2,50.8,50.0,28.3(×3),9.7。
Example 26: t-butyl ((1S,2S) -2-methyl-3-oxo-1- (p-tolyl) propyl) carbamate;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution (0.219 g (1mmol) of tert-butyl (4-methylbenzylidene) carbamate) at 0 ℃, and 2mL of acetonitrile solution of propionaldehyde 0.087g (1.5mmol), added with 10mL of water after 7h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and washed with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1471g, 53.1% yield, 91% ee, dr) is obtained>3)，1H NMR(500MHz,CDCl3):δ＝9.713-9.667(d,J＝23.0Hz,1H),7.171-7.131(m,4H),5.202-5.145(d,J＝28.5Hz,2H),2.856(s,1H),2.338(s,3H),1.424(s,9H),1.083-1.069(d,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝203.1,155.2,137.4,136.7,129.4(×2),126.6(×2),79.9,54.6,51.6,28.3(×3),21.0,9.4。
Example 27: (1S,2S) -1- (4-chlorophenyl) -2-methyl-3-oxopropyl) carbamic acid tert-butyl ester;
taking a 25mL single-neck round-bottom flask, adding 23mg (0.2mmol) of L-proline, 6g (0.6mmol) of PEG10000.6g, redistilled acetonitrile 3mL, adding magnetons, stirring for 15min, adding 0.240g (1mmol) of tert-butyl 4-chlorobenzylidene) carbamate at 0 ℃ and 2mL of acetonitrile solution of propionaldehyde 0.087g (1.5mmol), adding 10mL of water after reaction for 7h, stirring for 15min at room temperature, extracting with diethyl ether (3X 15mL), washing an organic phase with saturated saline (20mL), drying with anhydrous sodium sulfate, decompressing, desolventizing, and adding diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.2588g, 88.1% yield, 99% ee, dr) is obtained>50)，1H NMR(500MHz,CDCl3):δ＝9.681-9.633(d,J＝24.0Hz,1H),7.326-7.193(m,4H),5.386-5.154(d,J＝116.0Hz,1H),4.846-4.569(d,J＝138.5Hz,1H),2.826-2.812(d,J＝7.0Hz,1H),1.396(s,9H),1.081-1.041(dd,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝203.0,156.4,155.1,133.5,128.9(×2),128.2(×2),79.6,54.2,51.3,28.2(×3),9.3。
Example 28: (1S,2S) -1- (4-fluorophenyl) -2-methyl-3-oxopropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution (0.223 g (1mmol) of tert-butyl (4-fluorobenzylidene) carbamate) at 0 ℃, and 2mL of acetonitrile solution of propionaldehyde 0.087g (1.5mmol), added with 10mL of water after 7h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and washed with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1546g, 55.0% yield, 99% ee, dr) is obtained>2)，1H NMR(500MHz,CDCl3):δ＝9.684-9.642(d,J＝21.0Hz,1H),7.250-7.223(m,2H),7.053-7.018(m,2H),5.311-4.858(d,J＝226.5Hz,1H),5.199-5.158(d,J＝20.5Hz,1H),2.854-2.806(d,J＝24.0Hz,1H),1.396(s,9H),1.088-1.033(dd,J＝7.0,6.5Hz,3H).13C NMR(125MHz,CDCl3):δ＝203.1,163.1(d,JCF＝5.5Hz),161.2(d,JCF＝5.5Hz),155.2,128.5(d,JCF＝17.3Hz)(×2),115.6(d,JCF＝21.3Hz)(×2),80.1,54.2,51.4,28.3(×3),9.5。
Example 29: (1S,2S) -1- (3-chlorophenyl) -2-methyl-3-oxopropyl) carbamic acid tert-butyl ester;
a25 mL single neck round bottom flask was charged with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, magneton was added and stirred for 15min, 2mL of a solution of tert-butyl (3-chlorobenzylidene) carbamate (0.240 g (1mmol) in acetonitrile and 2mL of a solution of propionaldehyde (0.087 g (1.5mmol) in acetonitrile were added at 0 ℃ and after 7 hours of reaction 10mL of water were addedAfter stirring at room temperature for 15min, extraction was performed with diethyl ether (3X 15mL), and the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, washed with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product is obtained (0.2029g, 68.3% yield, 95% ee, dr)>2)，1H NMR(500MHz,CDCl3):δ＝9.697-9.626(d,J＝35.5Hz,1H),7.279-7.140(m,4H),5.416-4.856(d,J＝280.0Hz,1H),5.242-5.195(d,J＝23.5Hz,1H),2.855(s,1H),1.401(s,9H),1.072-1.059(d,J＝6.5Hz,3H).13C NMR(125MHz,CDCl3):δ＝202.5,155.1,141.9,134.6,130.0,127.8,126.9,124.9,80.2,54.1,51.3,28.2(×3),9.1。
Example 30: (1S,2S) -2-methyl-1- (4- (methylthio) phenyl) -3-oxopropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution (0.251 g (1mmol) of tert-butyl (4- (methylthio) benzylidene) carbamate) at 0 ℃, and 2mL of acetonitrile solution of propionaldehyde 0.087g (1.5mmol), added with 10mL of water after 7h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and washed with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.2435g, 78.8% yield, 99% ee, dr) is obtained>10)，1H NMR(500MHz,CDCl3):δ＝9.694(s,1H),7.235-7.167(m,4H),5.183(s,1H),5.135(s,1H),2.851(s,1H),2.471(s,3H),1.416(s,9H),1.077-1.063(d,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝203.0,155.1,137.9,136.5,127.2(×2),126.8(×2),79.8,54.4,51.4,28.3(×3),15.7,9.4。
Example 31: (1S,2S) -2-methyl-1- (4-nitrophenyl) -3-oxopropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution (0.250 g (1mmol) of tert-butyl (4-nitrobenzylidene) carbamate) at 0 ℃, and 2mL of acetonitrile solution of propionaldehyde 0.087g (1.5mmol), added with 10mL of water after 7h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and washed with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1709g, 55.5% yield, 99% ee, dr) is obtained>8)，1H NMR(500MHz,CDCl3):δ＝9.698-9.608(d,J＝45.0Hz,1H),8.216-8.198(dd,J＝2.0Hz,2H),7.482-7.464(d,J＝9.0Hz,2H),5.363(s,1H),5.299(s,1H),2.924(s,1H),1.406(s,9H),1.098-1.085(d,J＝6.5Hz,3H).13C NMR(125MHz,CDCl3):δ＝202.0,155.0,147.9,147.3,127.7(×2),123.9(×2),80.6,54.2,50.9,28.2(×3),9.2。
Example 32: (1S,2S) -1- (4-cyanophenyl) -2-methyl-3-oxopropyl) carbamic acid tert-butyl ester;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution (0.230 g (1mmol) of tert-butyl (3-cyanobenzylidene) carbamate) at 0 ℃, 2mL of acetonitrile solution of 0.1087g (1.5mmol), added with 10mL of water after 7h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and treated with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1840g, 63.9% yield) was obtained,1HNMR(500MHz,CDCl3):δ＝9.679-9.601(d,J＝39.0Hz,1H),7.590-7.443(m,4H),5.387(s,1H),5.230(s,1H),2.887(s,1H),1.401(s,9H),1.078-1.064(d,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝202.1,155.0,141.7,131.3,131.2,130.3,129.5,118.5,112.8,80.4,53.9,50.9,28.2(×3),9.2。
example 33: tert-butyl ((1S,2S) -2-methyl-3-oxo-1- (4- (trifluoromethyl) phenyl) propyl) carbamate;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution (0.273 g (1mmol) of tert-butyl (4- (trifluoromethyl) benzylidene) carbamate) at 0 ℃, 2mL of acetonitrile solution of propionaldehyde 0.087g (1.5mmol), added with 10mL of water at room temperature after 7h of reaction and stirred for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and washed with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.2334g, 70.5% yield, 99% ee, dr) is obtained>20)，1HNMR(500MHz,CDCl3):δ＝9.708(s,1H),7.620-7.604(d,J＝8.0Hz,2H),7.411-7.395(d,J＝8.0Hz,2H),5.282(s,2H),2.896(s,1H),1.418(s,9H),1.084-1.070(d,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝202.4,155.0,130.0(q),127.1,125.7(×2),125.0(×2),122.9,80.4,54.3,51.1,28.2(×3),9.2。
Example 34: ((S) -3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester
A25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution containing 0.205g (1mmol) of t-butyl benzylidenecarbamate at 0 ℃ and 2mL of acetonitrile solution containing 0.4405g (10mmol), added with 10mL of water after 3h of reaction and stirred for 15min at room temperature, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then treated with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.1992g, 80.0% yield, 99% ee) was obtained,1HNMR(500MHz,CDCl3)δ9.75(s,1H),7.38–7.26(m,5H),5.21(s,2H),2.97(s,1H),2.91(d,J＝14.7Hz,1H),1.43(s,9H).13C NMR(125MHz,CDCl3)δ＝200.2,155.1,141.1,128.8(×2),127.7(×2),126.3,80.0,50.0,29.5,28.3(×3).
example 35: ((S) -3-oxo-1-phenylpropyl) carbamic acid tert-butyl ester
Taking a 25mL single-neck round-bottom flask, adding 23mg (0.2mmol) of L-proline, distilling 3mL of acetonitrile again, adding magnetons, stirring for 15min, adding 0.205g (1mmol) of tert-butyl benzylidene carbamate and 2mL of acetonitrile solution of acetaldehyde 0.4405(10mmol) at 0 ℃, adding 10mL of water after 3h of reaction, stirring for 15min at room temperature, extracting with diethyl ether (3X 15mL), washing an organic phase with saturated saline (20mL), drying with anhydrous sodium sulfate, performing desolventization under reduced pressure, and adding diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.12699g, 50.1% yield, 99% ee) was obtained,1H NMR(500MHz,CDCl3)δ9.75(s,1H),7.38–7.26(m,5H),5.21(s,2H),2.97(s,1H),2.91(d,J＝14.7Hz,1H),1.43(s,9H).13C NMR(125MHz,CDCl3)δ＝200.2,155.1,141.1,128.8(×2),127.7(×2),126.3,80.0,50.0,29.5,28.3(×3).
example 36: tert-butyl ((1S,2S) -2-formyl-1-phenylbutyl) carbamate;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution 0.205g (1mmol) of tert-butyl benzylidenecarbamate at 0 ℃ and 2mL of acetonitrile solution 0.108g (1.5mmol), added with 10mL of water after 7h of reaction and stirred for 15min at room temperature, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then dried with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.2258g, 81.5% yield, 99% ee, dr) is obtained>99)，1H NMR(500MHz,CDCl3):δ＝9.583(s,1H),7.345-7.315(t,J＝7.0,8.0Hz,2H),7.278-7.230(m,3H),5.252(s,1H),5.064(s,1H),2.653(s,1H),1.740-1.712(t,J＝7.0Hz,1H),1.550-1.545(d,J＝2.5Hz,1H),1.416(s,9H),0.944-0.914(t,J＝7.5Hz,3H).13C NMR(125MHz,CDCl3)δ＝203.6,155.1,139.6,128.7(×2),127.7(×2),126.8,79.9,58.3,54.4,28.3(×3),18.8,11.9。
Example 37: t-butyl ((1S,2S) -2-formyl-1-phenylpentyl) carbamate;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution containing 0.205g (1mmol) of t-butyl benzylidenecarbamate and 2mL of acetonitrile solution containing 0.129g (1.5mmol) of valeraldehyde at 0 ℃, added with 10mL of water after 7h of reaction and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then dehydrated with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product is obtained (0.1798g, 61.8% yield, 99% ee, dr)>18)，1H NMR(500MHz,CDCl3):δ＝9.614-9.599(d,J＝7.5Hz,1H),7.354-7.231(m,5H),5.214(s,1H),5.066(s,1H),2.731(s,1H),1.701-1.464(m,2H),1.426(s,9H),1.265-1.250(d,J＝7.5Hz,2H),0.899-0.870(t,J＝7.0,7.5Hz,3H).13C NMR(125MHz,CDCl3):δ＝203.7,155.1,139.6,128.7(×2),127.7(×2),126.8,79.9,56.5,54.6,28.3(×3),27.7,20.7,13.9。
Example 38: tert-butyl ((1S,2S) -2-formyl-3-methyl-1-phenylbutyl) carbamate;
adding 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG into 25mL single-neck round-bottom flask, redistilling 3mL acetonitrile, adding magneton, stirring for 15min, adding benzylidene at 0 deg.CAfter reaction for 7 hours, 0.205g (1mmol) of tert-butyl carbamate in acetonitrile 2mL, 0.129g (1.5mmol) of 3-methylbutyraldehyde in acetonitrile 2mL, 10mL of water was added and the mixture was stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and the mixture was removed with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product is obtained (0.2415g, 83.0% yield, 95% ee, dr)>20)，1H NMR(500MHz,CDCl3):δ＝9.504-9.496(d,J＝4.0Hz,1H),7.335-7.231(m,5H),5.163(s,1H),5.113(s,1H),2.507(s,1H),2.117-2.105(d,J＝6.0Hz,1H),1.410(s,9H),1.141-1.127(d,J＝7.0Hz,3H),1.034-1.020(d,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝204.9,154.9,139.8,128.8(×2),127.8(×2),127.2,79.8,62.0,53.4,28.3(×3),21.2(×2),19.0。
Example 39: tert-butyl ((1S,2S) -2-formyl-1-phenylhexyl) carbamate;
a25 mL single-neck round-bottom flask was taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, added with magnetons and stirred for 15min, added with 2mL of acetonitrile solution 0.205g (1mmol) of tert-butyl benzylidenecarbamate at 0 ℃, and 2mL of acetonitrile solution 0.150g (1.5mmol), added with 10mL of water after 7h of reaction and stirred for 15min at room temperature, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then dried with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.2898g, 95.0% yield, 99% ee, dr) is obtained>10)，1H NMR(500MHz,CDCl3):δ＝9.597(s,1H),7.358-7.233(m,5H),5.213(s,1H),5.069(s,1H),2.711(s,1H),1.671–1.656(m,2H),1.428(s,9H),1.355-1.334(m,2H),0.928-0.900(m,2H),0.873-0.845(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝203.8,178.7,155.2,128.7(×2),127.7(×2),126.8,80.0,56.7,54.6,29.6,28.3(×3),25.3,22.6,13.8。
Example 40: (1S,2S) -2-formyl-1-phenylheptyl) carbamic acid tert-butyl ester.
A25 mL single-neck round-bottom flask was charged with 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, 3mL of redistilled acetonitrile, magneton for 15min, 0.205g (1mmol) of t-butyl benzylidenecarbamate in acetonitrile 2mL at 0 ℃ and n-heptanal in acetonitrile 2mL at 0.171g (1.5mmol), 10mL of water was added after the reaction was completed, the mixture was stirred at room temperature for 15min, extracted with ether (3X 15mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and the reaction solution was dried with ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product (0.2153g, 67.5% yield, 96% ee, dr) is obtained>8.5)，1H NMR(500MHz,CDCl3):δ＝9.611-9.587(t,J＝4.0,8.0Hz,1H),7.349-7.228(m,5H),5.249-5.5.235(d,J＝7.0Hz,1H),5.062(s,1H),2.712(s,1H),1.694-1.683(d,J＝5.5Hz,2H),1.421(s,9H),1.251-1.231(m,6H),0.853-0.835(t,J＝7.0Hz,3H).13CNMR(125MHz,CDCl3):δ＝203.6,155.0,139.5,128.6(×2),127.5(×2),126.7,79.8,56.7,54.5,31.6,28.2(×3),27.0,25.4,22.2,13.8。
Claims (10)
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911193727.5A CN110845288B (en) | 2019-11-28 | 2019-11-28 | Asymmetric synthesis method of chiral beta-amino aldehyde compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911193727.5A CN110845288B (en) | 2019-11-28 | 2019-11-28 | Asymmetric synthesis method of chiral beta-amino aldehyde compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110845288A true CN110845288A (en) | 2020-02-28 |
| CN110845288B CN110845288B (en) | 2022-07-19 |
Family
ID=69605991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911193727.5A Active CN110845288B (en) | 2019-11-28 | 2019-11-28 | Asymmetric synthesis method of chiral beta-amino aldehyde compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110845288B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090281346A1 (en) * | 2006-07-19 | 2009-11-12 | Studiengesellschaft Kohle Mbh | Method for the production of chiral aminocarbonyl compounds |
| CN102531911A (en) * | 2011-12-22 | 2012-07-04 | 浙江工业大学 | Chiral dicyclic compound and asymmetric syntheses method thereof |
| WO2018178691A1 (en) * | 2017-03-28 | 2018-10-04 | Astex Therapeutics Limited | Isoindolinone inhibitors of the mdm2-p53 interaction and process for making them |
-
2019
- 2019-11-28 CN CN201911193727.5A patent/CN110845288B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090281346A1 (en) * | 2006-07-19 | 2009-11-12 | Studiengesellschaft Kohle Mbh | Method for the production of chiral aminocarbonyl compounds |
| CN102531911A (en) * | 2011-12-22 | 2012-07-04 | 浙江工业大学 | Chiral dicyclic compound and asymmetric syntheses method thereof |
| WO2018178691A1 (en) * | 2017-03-28 | 2018-10-04 | Astex Therapeutics Limited | Isoindolinone inhibitors of the mdm2-p53 interaction and process for making them |
Non-Patent Citations (4)
| Title |
|---|
| LOUIS C. MORRILL,等: "Isothiourea-mediated asymmetric Michael-lactonisation of trifluoromethylenones: a synthetic and mechanistic study", 《CHEM. SCI.》 * |
| SAMANTHA CAPUTO,等: "Diversity-Oriented Synthesis of Various Enantiopure Heterocycles by Coupling Organocatalysis with Multicomponent Reactions", 《EUR. J. ORG. CHEM.》 * |
| YUKIHIRO FUKATA,等: "Asymmetric Net Cycloaddition for Access to Diverse Substituted 1,5-Benzothiazepines", 《J. ORG. CHEM.》 * |
| 夏爱宝: "脯氨硫醚催化不对称反应研究", 《中国博士学位论文全文数据库 工程科学I辑》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110845288B (en) | 2022-07-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103351270B (en) | Method for catalyzing Knoevenagel condensation reaction by using function ion liquid | |
| WO2017012478A1 (en) | Functionalized cyanosilane and synthesis method and use thereof | |
| Pahadi et al. | Aza-Henry reaction of ketimines catalyzed by guanidine and phosphazene bases | |
| CN113583015A (en) | Method for synthesizing chiral oxygen-containing eight-membered ring compound through palladium-catalyzed asymmetric allylic cycloaddition reaction | |
| CN114591344B (en) | Synthesis method of chiral spiro tetrahydrofuran-pyrazolone compound | |
| CN113549062B (en) | Chiral quaternary ammonium salt phase transfer catalyst with high steric hindrance derived from cinchona alkaloid and synthesis method thereof | |
| CN110845288B (en) | Asymmetric synthesis method of chiral beta-amino aldehyde compound | |
| CN105646382A (en) | Preparation method of 1,3,5-trisubstituted 1,2,4-triazole compound | |
| CN102408442B (en) | Synthesis method for calix [4] arenes substituted by 2-diphenylphosphine benzoyl and application | |
| CN101585780A (en) | Method for asymmetric synthesis of chiral paclitaxel lateral chain | |
| CN110724112A (en) | Bisoxazoline ligand compound and synthetic method thereof | |
| CN111229312B (en) | Solvent-free catalyst and preparation method and application thereof | |
| Wang et al. | NO 2-Fe (III) PcCl@ C-catalyzed one-pot synthesis of tetrahydropyridine derivatives | |
| CN108129424A (en) | A kind of method of bidentate phosphine ligands Polymer-supported palladium catalyst catalysis furfural analog derivative decarbonylation reaction | |
| CN101073779B (en) | Quaternary-ammonium poly-L-leucine catalyst, its production and use | |
| CN104860911A (en) | Synthesis method of chiral 3,4-dihydrocoumarin derivative compound | |
| Yu et al. | L‐Proline‐based Phosphamides as a New Kind of Organocatalyst for Asymmetric Direct Aldol Reactions | |
| CN110003083B (en) | Process method for preparing S-indoline-2-carboxylic acid by using Ir catalyst | |
| CN101343263A (en) | Method for synthesis of 5-nitryl-4, 5-dihydrofuran derivant | |
| CN110194760B (en) | Process for preparing 3-benzylidene-2- (7' -quinoline) -2, 3-dihydro-isoindol-1-ones | |
| CN114602558B (en) | Metallic iridium photocatalyst and preparation method and application thereof | |
| CN114524751B (en) | Aryl nitrile compound and preparation method thereof | |
| CN115304557B (en) | Enamine derivative and preparation method thereof | |
| CN111718309B (en) | Synthesis method of paclitaxel side chain and analogues thereof | |
| CN112574164B (en) | Method for synthesizing chiral spiro molecule based on chiral binaphthol |
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 |