CN110845288B - Asymmetric synthesis method of chiral beta-amino aldehyde compound - Google Patents
Asymmetric synthesis method of chiral beta-amino aldehyde compound Download PDFInfo
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- CN110845288B CN110845288B CN201911193727.5A CN201911193727A CN110845288B CN 110845288 B CN110845288 B CN 110845288B CN 201911193727 A CN201911193727 A CN 201911193727A CN 110845288 B CN110845288 B CN 110845288B
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- 238000011914 asymmetric synthesis Methods 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- 239000003054 catalyst Substances 0.000 claims abstract description 41
- 229920000642 polymer Polymers 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 150000002466 imines Chemical class 0.000 claims abstract description 11
- 230000009471 action Effects 0.000 claims abstract description 4
- 239000000376 reactant Substances 0.000 claims abstract description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 288
- 229920001223 polyethylene glycol Polymers 0.000 claims description 42
- -1 4-fluorophenyl4-methylthiophenyl Chemical group 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 5
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 229920002535 Polyethylene Glycol 1500 Polymers 0.000 claims description 2
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 claims description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 2
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 claims description 2
- 229920002593 Polyethylene Glycol 800 Polymers 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 318
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 84
- 239000000243 solution Substances 0.000 description 78
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 62
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 46
- 229960002429 proline Drugs 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 41
- 238000004440 column chromatography Methods 0.000 description 41
- 239000003208 petroleum Substances 0.000 description 41
- 229930182821 L-proline Natural products 0.000 description 40
- 239000012074 organic phase Substances 0.000 description 40
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 36
- 238000000926 separation method Methods 0.000 description 35
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 33
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 31
- XFRQMBFCAKTYIV-UHFFFAOYSA-N tert-butyl n-benzylidenecarbamate Chemical compound CC(C)(C)OC(=O)N=CC1=CC=CC=C1 XFRQMBFCAKTYIV-UHFFFAOYSA-N 0.000 description 22
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000006555 catalytic reaction Methods 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 9
- 230000003197 catalytic effect Effects 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- XFRQMBFCAKTYIV-UKTHLTGXSA-N tert-butyl (ne)-n-benzylidenecarbamate Chemical compound CC(C)(C)OC(=O)\N=C\C1=CC=CC=C1 XFRQMBFCAKTYIV-UKTHLTGXSA-N 0.000 description 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- YGHRJJRRZDOVPD-UHFFFAOYSA-N 3-methylbutanal Chemical compound CC(C)CC=O YGHRJJRRZDOVPD-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- FXHGMKSSBGDXIY-UHFFFAOYSA-N heptanal Chemical compound CCCCCCC=O FXHGMKSSBGDXIY-UHFFFAOYSA-N 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 150000003335 secondary amines Chemical group 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 238000005530 etching Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000007210 heterogeneous catalysis Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- HEEIHDRBPANCHJ-GZTJUZNOSA-N tert-butyl (ne)-n-(naphthalen-1-ylmethylidene)carbamate Chemical compound C1=CC=C2C(/C=N/C(=O)OC(C)(C)C)=CC=CC2=C1 HEEIHDRBPANCHJ-GZTJUZNOSA-N 0.000 description 1
- GOYFLHNOYTZKNH-UHFFFAOYSA-N tert-butyl dihydrogen phosphite Chemical compound CC(C)(C)OP(O)O GOYFLHNOYTZKNH-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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
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- 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 beta-amino aldehyde compounds shown in formula (I), wherein imine shown in formula (II) and aldehyde shown in formula (III) are used as reactants in the asymmetric synthesis process in an organic solvent, and the asymmetric synthesis process is characterized in that: the reaction is carried out under the action of a chiral catalyst and a supramolecular catalyst constructed by a polymer; 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 chiral beta-amino aldehyde compounds.
(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 around for centuries, but has been vigorously developed over the last 10 years and has become 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, nontoxic, 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 carrier.
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) are biocompatible; (2) the polymer is feasible 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 been paid more and more attention by researchers, because the chain structure of the PEG/PPG can form compounds with metal positive ions, the PEG/PPG is particularly applied to phase transfer catalyst reaction, and proline has lower 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 beta-amino aldehyde compound, so as to obviously improve the product yield.
In order to realize the purpose, the invention adopts the following technical scheme:
the asymmetric synthesis method of the chiral beta-amino aldehyde compound shown in the formula (I) takes imine shown in the formula (II) and aldehyde shown in the formula (III) as reactants, and carries out reaction in an organic solvent under the action of a chiral catalyst and a supramolecular catalyst constructed by a polymer;
the chiral catalyst is selected from one of the following components:
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, 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 ℃, keeping the temperature, stirring and reacting for 4-12h, and then carrying out post-treatment to obtain a chiral beta-amino aldehyde compound shown in a formula (I); the amount ratio of the chiral catalyst to the polymer to the imine to 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 (4) carrying out column chromatography separation on petroleum ether at 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 invention utilizes PPG/PEG and chiral catalyst to construct supramolecular catalyst for asymmetric synthesis of chiral beta-amino aldehyde compounds, thereby obviously improving the product yield.
(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 taken, added with 23mg (0.2mmol) of L-proline, 10000.6g (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 propionaldehyde (1.5mmol) at 0 ℃, added with 10mL of water and stirred for 15min at room temperature after 7h of reaction, extracted with diethyl ether (3X 15mL), the organic phase was washed with saturated saline (20mL), dried with anhydrous sodium sulfate, desolventized under reduced pressure, and separated by column chromatography using 1:9 diethyl ether, petroleum ether. 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 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 0.087g (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 separated by column chromatography using 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) performing column chromatography separation by using 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 of t-butyl benzylidenecarbamate 0.205g (1mmol) at 0 ℃, and 2mL of acetonitrile solution of propionaldehyde 0.087g (1.5mmol), added with 10mL of water after reaction for 8.7h and stirred at room temperature for 15min, extracted with diethyl ether (3X 15mL), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, desolventized under reduced pressure, and then with diethyl ether: and (4) performing column chromatography separation by using 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 of 0.205g (1mmol) of t-butyl benzylidenecarbamate at 0 ℃ and 2mL of acetonitrile solution of 0.087g (1.5mmol), 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 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) performing column chromatography separation by using 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) is 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) performing column chromatography separation by using 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) performing column chromatography separation by using 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) performing column chromatography separation by using 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 target product (0.156) is obtained2g，53.3％yield，98％ee，dr>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) L-proline and 10000.6g PEG(0.6mmol), redistilling 3mL of acetonitrile, adding magneton, stirring for 15min, adding 2mL of acetonitrile solution (0.255 g (1mmol) of tert-butyl (naphthalen-1-ylmethylene) carbamate and 2mL of acetonitrile solution (0.087 g (1.5 mmol)) at 0 ℃, adding 10mL of water after reaction for 7h, stirring for 15min at room temperature, extracting with diethyl ether (3X 15mL), washing the organic phase with saturated brine (20mL), drying with anhydrous sodium sulfate, desolventizing under reduced pressure, adding 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 (0.1961g, 77.5% yield, 97% ee, dr) is obtained>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).13C NMR(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 objective product (0.2588g,88.1％yield，99％ee，dr>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 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 (0.240 g (1mmol) of tert-butyl (3-chlorobenzylidene) 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) performing column chromatography separation by using 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: tert-butyl ((1S,2S) -2-methyl-1- (4- (methylthio) phenyl) -3-oxopropyl) 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 (0.251 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) performing column chromatography separation by using 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) performing column chromatography separation by using petroleum ether at a ratio of 1: 9. Obtain the target productSubstance (0.1840g, 63.9% yield),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 and 2mL of acetonitrile solution (0.087 g (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) performing column chromatography separation by using 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
Taking a 25mL single-neck round-bottom flask, adding 23mg (0.2mmol) of L-proline, 10000.6g (0.6mmol) of PEG, redistilling 3mL of acetonitrile, adding magnetons, stirring for 15min, adding t-butyl benzylidenecarbamate 0 at 0 deg.C2mL of 205g (1mmol) of acetonitrile solution, 2mL of acetaldehyde 0.4405g (10mmol) of acetonitrile solution, after completion of the reaction for 3 hours, 10mL of water was added and stirred at room temperature for 15min, followed by extraction with diethyl ether (3X 15mL), washing of the organic phase with a saturated brine (20mL), drying over anhydrous sodium sulfate, desolventizing under reduced pressure, and reaction 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: t-butyl ((1S,2S) -2-formyl-1-phenylbutyl) carbamate;
a25 mL single neck round bottom flask was charged with 23mg (0.2mmol) of L-proline and 10000.6g (0.2mmol) of PEG6mmol), redistilling 3mL of acetonitrile, adding magneton, stirring for 15min, adding 2mL of acetonitrile solution 0.205g (1mmol) of t-butyl benzylidenecarbamate and 2mL of acetonitrile solution 0.108g (1.5mmol) of butyraldehyde at 0 ℃, adding 10mL of water after 7h of reaction, stirring at room temperature for 15min, extracting with diethyl ether (3X 15mL), washing the organic phase with saturated brine (20mL), drying with anhydrous sodium sulfate, desolventizing under reduced pressure, adding 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;
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 3-methylbutyraldehyde 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 treated 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 of 0.205g (1mmol) of t-butyl benzylidenecarbamate at 0 ℃, and 2mL of acetonitrile solution of 0.150g (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 then with diethyl ether: and (4) carrying out column chromatography separation on petroleum ether at a ratio of 1: 9. The expected product was obtained (0.2898g, 95.0%)yield，99％ee，dr>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 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 0.171g (1.5mmol) of n-heptanal at 0 ℃, added with 10mL of water after the reaction was completed 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 dehydrated with diethyl ether: and (4) performing column chromatography separation by using 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 (9)
1. A method for asymmetrically synthesizing chiral beta-amino aldehyde compounds shown in formula (I) is characterized in that imine shown in formula (II) and aldehyde shown in formula (III) are used as reactants and are reacted in an organic solvent, and the method is characterized in that: the reaction is carried out under the action of a chiral catalyst and a supramolecular catalyst constructed by a polymer;
the chiral catalyst is selected from a catalyst IV:
the polymer is selected from at least one of the following: PEG200, PEG400, PEG600, PEG800, PEG1000, PEG1500, PPG400, PPG600, PPG800, PPG1000, PEG 750;
the organic solvent is selected from one or a combination of any of the following: dichloromethane, chloroform, tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane and acetonitrile;
in the formula (I), the formula (II) and the formula (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-fluorophenyl4-methylthiophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-cyanophenyl, 4-trifluoromethylphenyl.
3. The asymmetric synthesis method according to claim 1, wherein: r is2Selected from one of the following: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, cyclohexyl, n-hexyl.
4. The asymmetric synthesis method according to any 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.
5. The asymmetric synthesis method according to any one of claims 1 to 3, characterized in that: the asymmetric synthesis reaction is carried out at the temperature of-20-25 ℃.
6. The asymmetric synthesis method according to any one of claims 1 to 3, characterized in that: the asymmetric synthesis reaction is carried out at a temperature of 0 ℃.
7. The asymmetric synthesis method according to any 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-20-25 ℃, keeping the temperature, stirring and reacting for 4-12h, and performing post-treatment to obtain a chiral beta-aminoaldehyde compound shown in a formula (I); 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.
8. The asymmetric synthesis method according to any one of claims 1 to 3, characterized in that: the chiral catalyst is a catalyst IV, the polymer is PEG1000, and the organic solvent is acetonitrile.
9. The asymmetric synthesis method according to claim 7, wherein: the chiral catalyst is a catalyst IV, the polymer is PEG1000, and the organic solvent is acetonitrile.
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| WO2018178691A1 (en) * | 2017-03-28 | 2018-10-04 | Astex Therapeutics Limited | Isoindolinone inhibitors of the mdm2-p53 interaction and process for making them |
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