CN105803014B - Application of the earth-worm extractive as raw material in the asymmetric Mannich reaction of catalysis ketimide - Google Patents
Application of the earth-worm extractive as raw material in the asymmetric Mannich reaction of catalysis ketimide Download PDFInfo
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- CN105803014B CN105803014B CN201610244674.5A CN201610244674A CN105803014B CN 105803014 B CN105803014 B CN 105803014B CN 201610244674 A CN201610244674 A CN 201610244674A CN 105803014 B CN105803014 B CN 105803014B
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
Abstract
The invention discloses a kind of application of earth-worm extractive as raw material in the asymmetric Mannich reaction of catalysis ketimide and carbonyls, and the synthetic method can preferably synthesize a series of chiral beta-amino ketones through the invention, and enantioselectivity is up to 87%ee.In addition, earth-worm extractive as raw material preparation process is simple, belong to natural catalyst, provides a kind of new method for sustainable, the environmental-friendly chiral beta-amino ketones of preparation.
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of asymmetry of earth-worm extractive as raw material in catalysis ketimide
Application in Mannich reaction.
Background technique
Chiral beta-amino ketones are the important feature component parts of a variety of natural products and drug, synthesize the one of such compound
Kind effective ways are that the Mannich of unsymmetrical ketone imines reacts.However, above-mentioned reaction has the following deficiencies: due to ketimide C=
The substituent group steric hindrance at N key both ends is big, causes the chemical activity of ketimide not high；Ketimide is commonly present E and Z isomer,
There are Competitions in reaction, cause the selectivity of reaction undesirable.Up to the present, using ketimide be effectively synthesized have pair
The method for reflecting selective beta-amino ketones derivative is rarely reported.In view of using Mannich reaction synthesis beta-amino ketones derivative
The importance of object, it is necessary to be catalyzed this kind of reaction to develop sustainable, environmental-friendly catalyst.
Enzyme is as a kind of biocatalyst for having the characteristics that highly selective, reaction condition is mild, environmental-friendly, organic
Synthesis field is increasingly taken seriously.However it is the purification process higher cost of enzyme, laborious time-consuming, lead to its large-scale production and answers
With being restricted.Therefore, simple effective method is developed to obtain biocatalyst, and avoiding expensive enzyme purification process from having very much must
It wants.There are a large amount of hydrolases, such as protease, phosphatase, cellulase etc. in earthworm alimentary canal.Early-stage study finds earthworm
Extract has good catalytic activity to three components series connection Mannich-Michael reaction etc., and therefore, this research is quasi- to utilize earthworm
Earthworm extract is catalyzed the asymmetric Mannich reaction of acetone and ketimide to seek the synthesis of more suitable beta-amino ketones derivative
Method.
Summary of the invention
In view of this, the purpose of the present invention is to provide a kind of earth-worm extractive as raw material in the asymmetry for being catalyzed ketimide
The beta-amino ketones of application in Mannich reaction, acquisition have preferable enantioselectivity.
The technical solution adopted by the present invention is as follows:
1, earth-worm extractive as raw material synthesizes in beta-amino ketones in catalysis ketimide with carbonyls asymmetric Mannich reaction
Using.
Preferably, the earth-worm extractive as raw material preparation method includes rinsing, being homogenized, supernatant is collected by centrifugation, then to supernatant
Liquid carries out the step of dialysis concentration, vacuum drying.
Preferably, the carbonyls is acetone.
Preferably, the ketimide is that general structure isWherein, R1When for H, R2For 4-CH3, 3-CH3,
4-F, 4-Cl or 3-Cl；R2When for H, R1For H, 4-CH3, 4-F, 4-Cl or 3-Br.
It should be noted that 4-CH3Indicate the methyl of 4 substitutions, 3-CH3Indicate the methyl of 3 substitutions, and so on.
Preferably, the reaction dissolvent of the reaction is methanol, ethyl alcohol, dimethyl sulfoxide or dimethylformamide.
Preferably, the reaction temperature of the reaction is 20-50 DEG C.
Preferably, the dosage of earth-worm extractive as raw material is 25-125mg/mL solvent.
Preferably, the molar ratio of the ketimide and carbonyls is 0.1:1-6.
Preferably, the reaction carries out in methyl alcohol, and the molar ratio of ketimide and carbonyls is 0.1:5, reaction temperature
Degree is 25 DEG C, and the dosage of earth-worm extractive as raw material is 100mg/mL solvent.
2, earth-worm extractive as raw material catalysis ketimide synthesizes the side of beta-amino ketones with carbonyls asymmetric Mannich reaction
Ketimide, carbonyls, earth-worm extractive as raw material are added in solvent, are stirred to react at 20-50 DEG C 96 hours by method.
Pass through the beneficial effects of the present invention are: the present invention research shows that earth-worm extractive as raw material for acetone and ketimide not
Symmetrical Mannich reaction has preferable catalytic action, and the synthetic method can be synthesized preferably a series of through the invention
Chiral beta-amino ketones, enantioselectivity is up to 87%ee.In addition, earth-worm extractive as raw material preparation process is simple, belong to natural catalyst,
A kind of new method is provided for sustainable, the environmental-friendly chiral beta-amino ketones of preparation.
Specific embodiment
A preferred embodiment of the present invention will be described in detail below.The experiment side of actual conditions is not specified in embodiment
Method, usually according to conventional conditions or according to the manufacturer's recommendations.
Earth-worm extractive as raw material of the present invention is prepared, preparation method using Eisenia Foetida (Eisenia fetida)
As follows: earthworm living is cleaned 5 times through tap water, makes it that internal dirt spue as far as possible, is then cleaned 2 times with deionized water again,
Clean earthworm (200mL volume) is mixed with the ice-cold deionized water of 200mL homogenate, be centrifuged (relative centrifugal force=4250g, 5 points
Clock), take supernatant.Then supernatant is dialysed concentration at 4 DEG C (bag filter for loading onto clear liquid is embedded in sucrose powder).It will be dense
The earth-worm extractive as raw material of contracting squeezes out from bag filter and (is careful not to be infected with upper sucrose), is put into culture dish, culture dish is placed in very
It is dry at 25 DEG C in empty drier.It is spare by dry earth-worm extractive as raw material mortar grinder at powdered.Resulting earthworm
Extract can save 1 year (activity is constant) at 4 DEG C.
One, influence of the solvent to reaction
With ketimide 1a1dMannich reaction with acetone is model, and earth-worm extractive as raw material is anti-at 25 DEG C as catalyst
It answers 96 hours, the results are shown in Table 1.Data show, in Mannich reaction, solvent to the catalytic activity of earth-worm extractive as raw material and
Selectivity all has a great impact.When reaction is using DMSO and DMF as solvent, the high mapping of 82%ee and 89%ee has been respectively obtained
Selectivity, but yield all very low (table 1, serial number 3 and 4).When with ethanol as solvent, product ee value is 76%, but yield is also only
There is 9% (table 1, serial number 2).And when reaction methanol as solvent, yield rises to 18%, while ee value is 58% (table 1, serial number
1).In CH2Cl2, in MeCN and EtOAc, only faint product is observed.In order to obtain preferable yield, we select methanol
As reaction dissolvent.
The influence for the asymmetric Mannich reaction that 1. solvent of table is catalyzed earth-worm extractive as raw materiala
aReaction condition: ketimide 1a (0.2mmol), acetone (4.0mmol), earth-worm extractive as raw material (30mg), solvent
(1.0mL) is stirred 96 hours at 25 DEG C.
bYield after being purified by silica gel column chromatography.
cHigh performance liquid chromatography measures (AD-H chiral column).
Two, influence of the dosage of earth-worm extractive as raw material to reaction
In order to find suitable catalyst amount, influence (table 2) of the amount of earth-worm extractive as raw material to model reaction is studied.As a result
It has been shown that, when the dosage of earth-worm extractive as raw material is 100mg, reaction obtains 27% yield (table 2, serial number 4), and continues growing earthworm
When the dosage of extract, the yield of product is not improved.In addition, as can be seen from the table, pair of the catalyst amount to product
Selectivity is reflected to have not significant impact.Therefore, we select 100mg earth-worm extractive as raw material as the catalyst amount of reaction.
Influence of the dosage of 2. earth-worm extractive as raw material of table to asymmetric Mannich reactiona
aReaction condition: ketimide 1a (0.2mmol), acetone (4.0mmol), earth-worm extractive as raw material (25-125mg) and MeOH
(1.0ml) is stirred 96 hours at 25 DEG C.
bYield after being purified by silica gel column chromatography.
cHigh performance liquid chromatography measures (AD-H chiral column).
Three, influence of the acetone dosage to reaction
By above-mentioned optimization, the yield of reaction is still very low.A small amount of product is being generated by being monitored discovery to reaction
While, reaction is had neither part nor lot in there are also a large amount of ketimide 1a.To further increase reaction yield, the amount for continuing to inquire into acetone is to model
The influence of reaction.When the dosage of acetone is 2.0mmol, the yield of reaction is only 13% (table 3, serial number 1).Acetone amount by
During 2.0mmol rises to 10.0mmol, the yield of reaction is continuously increased.And when the raw material proportioning of reaction are as follows: acetone
(10.0mmol), ketimide 1a (0.2mmol), the yield of reaction is up to 41%.But the dosage of acetone is further increased, reaction
Yield reduces instead there is no increasing.Therefore, we select 10.0mmol for the optimum amount of acetone.
The influence for the asymmetric Mannich reaction that the dosage of 3. acetone of table is catalyzed earth-worm extractive as raw materiala
aReaction condition: ketimide 1a (0.2mmol), acetone (2.0-12.0mmol), earth-worm extractive as raw material (100mg), and
MeOH (1.0ml) is stirred 96 hours at 25 DEG C.
bYield after being purified by silica gel column chromatography.
cHigh performance liquid chromatography measures (AD-H chiral column).
Four, influence of the temperature to reaction
Since temperature is to influence the key factor of enzymic catalytic reaction, to enzyme stability, reaction selectivity and yield have aobvious
Writing influences, and therefore, influence of the research temperature to earth-worm extractive as raw material catalysis Mannich reaction is necessary.Such as 4 institute of table
Show, when reaction carries out at 25 DEG C, available preferable enantioselectivity (70%ee).Continue to increase temperature, reaction yield
It is not significantly increased, but enantioselectivity is declined.When reaction temperature rises to 50 DEG C, under the enantioselectivity of reaction is obvious
Drop, yield also substantially reduce.Comprehensively consider, we select 25 DEG C for optimal reaction temperature.
The influence for the asymmetric Mannich reaction that 4. temperature of table is catalyzed earth-worm extractive as raw materiala
aReaction condition: ketimide 1a (0.2mmol), acetone (10mmol), earth-worm extractive as raw material (100mg), MeOH
(1.0ml) is stirred 96 hours at 20-50 DEG C.
bYield after being purified by silica gel column chromatography.
cHigh performance liquid chromatography measures (AD-H chiral column).
Five, reaction substrate extends
(table 5) is extended to reaction substrate under above-mentioned optimization experiment condition, is replaced on ketimide aromatic ring as the result is shown
Base is different, and the yield and selectivity of reaction also have certain difference.For example, as R in ketimide1When for 3-Br, reaction is obtained
Best yield 51% and highest ee value 87% (table 5, serial number 5).As R in ketimide2When for 4-Cl, also obtain preferable
Yield 50% and higher ee value 84% (table 5, serial number 9).And as R in ketimide2When for 3-Cl, very low yield is had to
5% (table 5, serial number 10).The enantiomeric excess value and absolute configuration of compound are by high phase liquid phase analysis, and and bibliography
The comparisons of the data of middle respective compound and determination.
The asymmetric Mannich reaction substrate extension of 5. earth-worm extractive as raw material of table catalysisa
aReaction condition: ketimide 1 (0.2mmol), acetone (10mmol), earth-worm extractive as raw material (100mg), methanol (1.0ml)
It is stirred 72-96 hours at 25 DEG C.
bYield after being purified by silica gel column chromatography.
cHigh performance liquid chromatography measures (AD-H, OD-H, IC chiral column).
Six, control experiment
We conducted a series of control experiments, to verify catalytic action of the earth-worm extractive as raw material in Mannich reaction.From
The data of serial number 1 cannot get target product it is found that in the case where no earth-worm extractive as raw material in table 6.Under optimum reaction condition,
Earth-worm extractive as raw material is added, it is 70% that the yield of reaction, which reaches 41%, ee value, shows that earth-worm extractive as raw material really reacts Mannich
Play catalytic action.Since guanidine hydrochloride and urea can destroy the three-dimensional structure of protein, so as to cause enzyme inactivation.Therefore I
Handle earth-worm extractive as raw material respectively with guanidine hydrochloride and urea, then will treated that earth-worm extractive as raw material is used for catalytic model Mannich
Reaction, has respectively obtained 16% and 19% low yield, while ee value is also decreased obviously (table 6, serial number 3 and 5).Earth-worm extractive as raw material
After a kind of phenylmethylsulfonyl fluoride (PMSF, serpin) processing, catalytic activity is substantially reduced, and has to
5% low yield, enantioselectivity are also decreased obviously (table 6, serial number 7).In addition, since heavy metal ion will lead to protein point
Son denaturation, so that enzyme be made to lose activity.Therefore, we use AgNO3And CuSO4Earth-worm extractive as raw material is handled respectively, then by treated
Earth-worm extractive as raw material is reacted for catalytic model Mannich.The results show that AgNO3Treated, and earth-worm extractive as raw material vigor obviously drops
It is low, have to 5% low yield (table 6, serial number 9).CuSO4Treated earth-worm extractive as raw material, then lose completely to model
The catalytic action (table 6, serial number 11) of reaction.Various inhibitor itself mentioned above on model reaction without influence (table 6,
Serial number 4,6,8,10 and 12).These statistics indicate that, play catalytic action in Mannich reaction is enzyme in earth-worm extractive as raw material,
And a large amount of existing serine proteases play a key effect in earthworm alimentary canal.
6. control experiment of tablea
aUnless otherwise indicated, all reaction conditions are as follows: ketimide 1a (0.2mmol), acetone (10mmol), catalyst,
MeOH (1.0ml) is stirred 96 hours at 25 DEG C.
bYield after being purified by silica gel column chromatography.
cHigh performance liquid chromatography measures (AD-H).
dN.d.: product is not detected.
eThe mixture of earth-worm extractive as raw material (100mg), deionized water (1mL) and guanidine hydrochloride (6.0mmol) stirs at 30 DEG C
8 hours, freeze-drying.
fThe mixture of earth-worm extractive as raw material (100mg), deionized water (1mL) and urea (8.0mmol) stirs 8 at 30 DEG C
Hour, freeze-drying.
gThe mixture of earth-worm extractive as raw material (100mg), THF (1mL) and PMSF (0.6mmol) stir at 30 °C for 2 hours,
Revolving removes THF.
hEarth-worm extractive as raw material (100mg), deionized water (1mL) and AgNO3The mixture of (0.25mmol) stirs 8 at 30 DEG C
Hour, freeze-drying.
iEarth-worm extractive as raw material (100mg), deionized water (1mL) and CuSO4The mixture of (0.2mmol) stirs 8 at 30 DEG C
Hour, freeze-drying.
Pass through above-mentioned a series of experiments, it is final to determine reaction are as follows: ketimide 1 (0.2mmol), earth-worm extractive as raw material (100mg),
The mixture of acetone (10.0mmol) and MeOH (1.0ml) are stirred to react at 25 DEG C, are monitored by TLC, until reacting no longer
Obvious progress filters off earth-worm extractive as raw material (using 40mm Buchner funnel and qualitative filter paper), filter cake washed with ethyl acetate (3 ×
10ml), revolving remove filtrate in solvent, crude product by silica gel column chromatography purifying (petroleum ether: ethyl acetate=15-10:
1 (v/v)), obtain target product.Enantiomeric excess value is measured by high performance liquid chromatography using chiral column.Disappear outside corresponding
Body is revolved to obtain using nafoxidine catalysis Mannich reaction.The present invention studies have shown that earth-worm extractive as raw material for acetone and ketimide
Asymmetric Mannich reaction have catalytic action.The synthetic method can preferably synthesize a series of hands through the invention
Property beta-amino ketones, enantioselectivity is up to 87%ee.
Finally, it is stated that preferred embodiment above is only used to illustrate the technical scheme of the present invention and not to limit it, although logical
It crosses above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand that, can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (8)
1. earth-worm extractive as raw material synthesizes answering in beta-amino ketones with carbonyls asymmetric Mannich reaction in catalysis ketimide
It is with, which is characterized in that the general structure of the ketimide, wherein R1When for H, R2For 4-CH3, 3-CH3,
4-F, 4-Cl or 3-Cl；R2When for H, R1For H, 4-CH3, 4-F, 4-Cl or 3-Br；The carbonyls is acetone.
2. application according to claim 1, which is characterized in that the earth-worm extractive as raw material preparation method include rinsing, homogenate,
The step of supernatant is collected by centrifugation, dialysis concentration, vacuum drying then are carried out to supernatant.
3. application according to claim 1, which is characterized in that the reaction dissolvent of the reaction is methanol, ethyl alcohol, dimethyl
Sulfoxide or dimethylformamide.
4. application according to claim 1, which is characterized in that the reaction temperature of the reaction is 20-50 DEG C.
5. application according to claim 1, which is characterized in that the dosage of earth-worm extractive as raw material is 25-125mg/mL solvent.
6. application according to claim 1, which is characterized in that the molar ratio of the ketimide and carbonyls is 0.1:
1-6。
7. application according to claim 1, which is characterized in that the reaction carries out in methyl alcohol, ketimide and carbonylation
The molar ratio for closing object is 0.1:5, and reaction temperature is 25 DEG C, and the dosage of earth-worm extractive as raw material is 100mg/mL solvent.
8. the method that earth-worm extractive as raw material catalysis ketimide synthesizes beta-amino ketones with carbonyls asymmetric Mannich reaction,
It is characterized in that, ketimide, carbonyls, earth-worm extractive as raw material is added in solvent, are stirred to react at 20-50 DEG C 96 hours；
The general structure of the ketimide is, wherein R1When for H, R2For 4-CH3, 3-CH3, 4-F, 4-Cl or 3-Cl；
R2When for H, R1For H, 4-CH3, 4-F, 4-Cl or 3-Br；The carbonyls is acetone.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101765369A (en) * | 2007-03-19 | 2010-06-30 | 俄勒冈州由俄勒冈州立大学代表州高等教育委员会行使 | Mannich base N-oxide drugs |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101765369A (en) * | 2007-03-19 | 2010-06-30 | 俄勒冈州由俄勒冈州立大学代表州高等教育委员会行使 | Mannich base N-oxide drugs |
Non-Patent Citations (2)
| Title |
|---|
| Catalytic earthworms: in three-component cascade Mannich-Michael reactions;Yan-Hong He等;《Tetrahedron》;20150612;第71卷(第33期);摘要，正文第5251页右栏第2段、第5252页左栏第1段，表7 |
| Direct Organocatalytic Asymmetric Mannich Addition of 3-Substituted-2H-1,4-Benzoxazines: Access to Tetrasubstituted Carbon Stereocenters;You-Qing Wang等;《Adv. Synth. Catal.》;20131113;第355卷(第17期);摘要，表1 |
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