CN104651425B - A kind of method of living things catalysis synthesizing optical active al lactone - Google Patents
A kind of method of living things catalysis synthesizing optical active al lactone Download PDFInfo
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Abstract
The present invention relates to a kind of method of living things catalysis synthesizing optical active al lactone, this method includes the following steps：(1) using biocatalyst catalysis of carbonyl acid asymmetric reduction synthesizing optical activity hydroxy acid；(2) in acidic environment, make optical activity carboxylic acid cyclisation generation optically active lactone compound.Using fresh cultured Candida parapsilosis bacterium cell or cell-free extract as biocatalyst, it is catalyzed the Stereoselective reduction of 4 carbonyl capric acids and 5 carbonyl capric acids, it is then cyclized into acidic environment as lactone compound, efficient preparation 4 butyrolactone of (R) (+) 4 hexyl and 5 valerolactone of (R) (+) 5 amyl.Compared with prior art, the cell and its extract of bacterial strain of the present invention are easily prepared, stereoselectivity is strong, and its catalysis prepares the simple for process of 4 butyrolactone of (R) (+) 4 hexyl and 5 valerolactone of (R) (+) 5 amyl, it is environmental-friendly, there is good prospects for commercial application.
Description
Technical field
The invention belongs to technical field of bioengineering, and in particular to Biocatalytic Conversion synthesizing optical activity (R)-(+) -4-
The method of hexyl -4- butyrolactone and (R)-(+) -5- amyl -5- valerolactones.
Background technology
In optically active asymmetric lactone, such as (R)-(+) -4- hexyl -4- butyrolactone and (R)-(+) -5- amyls -5- penta
Ester is important spice additive, is widely used in fields such as wine brewing, food manufacturings.Chemical method fractionation is to prepare high optical voidness
The common method of asymmetric lactone is spent, common chemical resolution method is generally using racemic asymmetric lactone as starting material, in alkali
Property under the conditions of hydrolysis, then carry out esterification and alkoxy derivatization generate non-enantiomer mixture, to the mixture
It is detached, obtains the compound of single configuration, be then hydrolyzed and be cyclized again, obtain optically pure asymmetric lactone chemical combination
Object.Chemical resolution method and step is various, and separation condition is harsh, and theoretical yield is up to 50%, and optical purity of products is low, is unfavorable for
The high efficiency, low cost of optical homochiral lactone compound manufactures on a large scale.
In recent years, the living things catalysis technique based on whole cell or enzyme preparation takes in optical activity chirality compound synthesis field
Obtained immense success.At present, the asymmetric lactone of living things catalysis synthesizing optical active al substitution still falls within a newer field,
Many R＆D works are still in the starting stage.Deng using chemo-enzymatic process combination catalyze and synthesize (S)-γ of alkyl derivative-
Valerolactone (Appl.Microbiol.Biotechnol.2013,97:3865-3873) it, needs to combine using two different enzymes,
Cost is higher, and chiral substituent is shorter methyl, can not synthesize the asymmetric lactone replaced containing chain alkyl.It masses troops etc. logical
Cross the chiral alkyl lactone (Adv.Synth.Catal.2009,351 of lactone Enzyme catalyzed synthesis 2- hydroxyls substitution:2959-2966；
Chem.Commun.2010,46:2754-2756), but to 2 unsubstituted alkyl lactones to catalyze and synthesize effect bad.Cause
This, exploitation is simple, the longer alkyl-substituted asymmetric lactone compound synthesis method of living things catalysis efficiently, inexpensive, has weight
The industrial application value wanted.
Invention content
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of simple for process, environment
Close friend has the method for the living things catalysis synthesizing optical active al lactone of good prospects for commercial application.
The purpose of the present invention can be achieved through the following technical solutions：In a kind of living things catalysis synthesizing optical active al
The method of ester, which is characterized in that this method includes the following steps：
(1) using biocatalyst catalysis of carbonyl acid asymmetric reduction synthesizing optical activity hydroxy acid；
(2) in acidic environment, make optical activity carboxylic acid cyclisation generation optically active lactone compound.
The biocatalyst derives from Candida parapsilosis (Candida parapsilosis), preferably comes
Derived from Candida parapsilosis CGMCC2.3539.
The biocatalyst is Candida parapsilosis cell；After either nearly smooth Candida thalline crushes
The cell-free extract containing carbonyl reductase obtained.
The biocatalyst can be prepared by the following：
(1) preparation of resting cell
Nearly smooth candidiasis CGMCC2.3539 sterilizing (121 DEG C, 20min) rich medium (glycerine 1%,
Peptone 0.5%, beef extract 0.8%, agar 1.5%) it crosses on inclined-plane, in 30 DEG C of quiescent cultures 1-2 days.
Take a ring slant strains, access seed culture medium (glycerine 1%, peptone 0.5%, beef extract 0.8%, pH7.0)
In, 25-37 DEG C is cultivated 24-48 hours.Again using the culture solution as seed, the inoculum concentration based on fermentation medium volume is 1-
10% (v/v) is seeded in fermentation medium, is cultivated 24-48 hours on 150-250rpm shaking tables at 25-37 DEG C, culture terminates
Centrifugation obtains tranquillization wet cell afterwards.Conventional culture medium can be used in the fermentation medium, and the content of wherein each component is as follows：
Glycerine 10-50g/L, beef extract 1-20g/L, peptone 1-20g/L, KH2PO41-10g/L, Na2HPO41-10g/L, NaCl
0.1-2g/L, MgSO40.1-2g/L, pH 5-8.
(2) preparation of cell-free extract
The wet cell of harvest is weighed, is suspended in the buffer solution of 5~20 times of volume mass ratios (v/w) (50mM, pH7.0),
Break process is carried out to cell.Generally, the method using ultrasonication carries out clasmatosis, cell suspending liquid is placed in ice
In water-bath, ultrasonic power 400W, ultrasonic 4s, interval 6s are calculated as a cycle, 99 cycles are carried out altogether, by broken liquid 4
DEG C, 10000rpm high speed centrifugations, the supernatant of acquisition is cell-free extract.
Carbonyl reduction enzyme activity determination in cell-free extract：
By the carbonyl capric acids of 5- containing 2mmol/L and 1mL reaction systems (the 100mmol/L Tris- of 0.1mmol/L NADPH
HCl buffer solutions, pH 7.0) 30 DEG C are preheated to, then add in suitable cell-free extract, 30 DEG C of insulation reactions, in light splitting light
The absorbance change of NADPH at 340nm is detected on degree meter, records the changing value of 1 minute internal absorbance.
When measuring the vigor of the carbonyl reductase as stated above, enzyme activity can be calculated with following formula：
Enzyme activity (U)=EW × V × 103/(6220×1)
In formula, EW is the variation of absorbance at 340nm in 1 minute；Volumes of the V for reaction solution, unit ml；6220 are
The molar extinction coefficient of NADPH, unit are L/ (molcm)；1 is optical path length, unit cm.1 unit (U) carbonyl reduction
Enzyme corresponds to the enzyme amount needed for 1 μm of ol NADPH of oxidation per minute under above-mentioned condition.
It is described using biocatalyst catalysis of carbonyl acid asymmetric reduction the specific steps are：In the buffering that pH is 6~8
It in system, is carried out under the conditions of 25~40 DEG C, adds in substrate 4- carbonyl capric acids or 5- carbonyl capric acids, carbonyl acid concentration (concentration of substrate)
For 1~100g/L；Also include the glucose of 10~100g/L in reaction system, the glucose dehydrogenase of 0~40kU/L and 0~
The NADP of 1mM+, the reaction time is 3~12h, and intermittent sampling carries out gas chromatographic analysis, on production concentration no longer continues
Reaction was completed when rising, and generates optically active carboxylic acid.
The acquisition of the glucose dehydrogenase can refer to document report, for example, see：Journal of Industrial
Microbiology and Biotechnology 2011,38,633-641。
When the biocatalyst derives from Candida parapsilosis cell, as above-mentioned tranquillization wet cell, every liter anti-
The biocatalyst dosage for answering liquid is 10~100g Candida parapsilosis cells.
When the biocatalyst is the cell-free extract containing carbonyl reductase, the living things catalysis of every liter of reaction solution
Agent dosage is 4-40kU carbonyl reductases.
It is described in acidic environment, make the cyclisation of optical activity carboxylic acid the specific steps are：Hydroxyl will be contained obtained by step (1)
The reaction solution of base acid is acidified to pH 1~2 (being acidified reaction solution, usually using the sulfuric acid of 20% (w/v)), 60~80 DEG C of heating 1
~2h is promoted carboxylic acid cyclisation to generate corresponding lactone, is extracted using water-insoluble organic solvents, is revolved after extract liquor drying
Turn evaporation of solvent, obtain ester products in target.
The carboxylic acid is (R) -4- hydroxydecanoic acids or (R) -5- hydroxydecanoic acids.
Compared with prior art, the present invention has been carried out carbonyl biology to various yeast strains and has been urged using carbonylic acid as substrate
Change the screening of reduction activation, find the Candida parapsilosis bacterium bought with China General Microbiological culture presevation administrative center
Strain, especially the resting cell of Candida parapsilosis CGMCC2.3539 can be catalyzed 4- carbonyl capric acids or 5- as catalyst
Carbonyl capric acid asymmetric reduction, generates corresponding carboxylic acid, so acidic environment middle ring metaplasia into target product (R)-(+)-
4- hexyl -4- butyrolactone and (R)-(+) -5- amyl -5- valerolactones, product enantiomeric excess (ee) value are higher than 99%.The present invention
The isomeriaation of Candida parapsilosis bacterium CGMCC2.3539 catalysis of carbonyl capric acid is utilized, reaction condition is mild, bottom
Object concentration is high, high conversion rate, and product optical purity is good.Reduzate can generate high-optical-purity by being simply chemically treated
(R)-(+) -4- hexyl -4- butyrolactone and (R)-(+) -5- amyl -5- valerolactones, have good prospects for commercial application.
Specific embodiment
It elaborates below to the embodiment of the present invention, the present embodiment is carried out lower based on the technical solution of the present invention
Implement, give detailed embodiment and specific operating process, but protection scope of the present invention is not limited to following implementation
Example.
Examples 1 to 6：Candida parapsilosis wet cell is catalyzed the Stereoselective reduction of 5- carbonyl capric acids
A kind of method of living things catalysis synthesizing optical active al lactone, this method include the following steps：
(1) cell culture of Candida parapsilosis
Seed liquor culture medium prescription：Glycerine 1%, peptone 0.5%, beef extract 0.8%, pH 7.0.121 DEG C of high-temperature sterilizations
20min。
Fermentative medium formula：Glycerine 15g/L, beef extract 8g/L, peptone 5g/L, KH2PO42.0g/L
Na2HPO42.0g/L, NaCl 0.5g/L, MgSO40.5g/L, pH 7.0.121 DEG C of high-temperature sterilization 20min.
The inclined-plane of the Candida parapsilosis bacterium CGMCC2.3539 of 4 DEG C of preservations is taken, one ring of picking is seeded to equipped with 50ml kinds
In the shaking flask of the 250ml of sub- liquid culture medium.At 30 DEG C, 180rpm shaking table cultures for 24 hours, are forwarded to by the inoculum concentration of 5% (v/v)
In 500ml shaking flasks equipped with 100ml fermentation mediums, continue to cultivate 36h in 30 DEG C, 180rpm, wet cell is harvested by centrifugation.
(2) preparation of optical activity carboxylic acid
The Candida parapsilosis wet cell described in appropriate step (1) is weighed, is suspended in 10ml kaliumphosphate buffers
In (100mM), the 5- carbonyl capric acids of various concentration, 100g/L glucose, magnetic agitation reaction 12h, sampling progress gas phase are added in
Chromatography analysis detects reaction conversion ratio.
The 100 μ l of reaction solution containing optical activity carboxylic acid are taken, 100 μ l sulfuric acid (20%, w/v) is added in, is added in after mixing
200 μ l dichloromethane are extracted, and extract liquor adds in anhydrous sodium sulfate and is dried overnight, and is detected using gas chromatography, color
Spectrum column is CP-Chirasil-Dex CB columns, and injector and detector are 280 DEG C；Column temperature is set as：110 DEG C of holding 10min,
2 DEG C/min to 120 DEG C of holding 5min, 2 DEG C/min to 130 DEG C of holding 5min, 2 DEG C/min to 140 DEG C of holding 20min.As a result see
Table 1.
1 Candida parapsilosis wet cell of table is catalyzed the Stereoselective reduction of 5- carbonyl capric acids
Embodiment 7-8
The Stereoselective reduction of Candida parapsilosis intact cell catalysis 4- carbonyl capric acids
The appropriate Candida parapsilosis wet cell as described in embodiment 1-6 steps (1) is weighed, is suspended in 10ml potassium phosphates
In buffer solution (100mM, pH 7.0), the 4- carbonyl capric acids of 100g/L glucose and various concentration, magnetic agitation reaction are added in
12h, sampling detection reaction conversion ratio.
The 100 μ l of reaction solution containing optical activity carboxylic acid are taken, 100 μ l sulfuric acid (20%, w/v) is added in, is added in after mixing
200 μ l dichloromethane are extracted, and extract liquor adds in anhydrous sodium sulfate and is dried overnight, and is detected using gas chromatography, color
Spectrum column is CP-Chirasil-Dex CB columns, and injector and detector are 280 DEG C；Column temperature is set as：110 DEG C of holding 10min,
2 DEG C/min to 120 DEG C of holding 5min, 2 DEG C/min to 130 DEG C of holding 5min, 2 DEG C/min to 140 DEG C of holding 20min.As a result see
Table 2.
The Stereoselective reduction of 2 Candida parapsilosis intact cell catalysis 4- carbonyl capric acids of table
Embodiment 9-13
Cell-free extract is catalyzed the Stereoselective reduction of 5- carbonyl capric acids
(1) cell culture of Candida parapsilosis：Method is the same as embodiment 1-6.
(2) Candida parapsilosis cell-free extract
5g Candida parapsilosis wet cells as described in Example 1 are weighed, are suspended in 50ml kaliumphosphate buffers
In (100mM, pH 7.0), cell suspending liquid is placed in ice-water bath, ultrasonic power 400W, ultrasonic 4s, interval 6s are calculated as
One cycle carries out 99 cycles altogether, and by broken liquid at 4 DEG C, 10000rpm high speed centrifugations obtain clear supernatant, live
Power is 40kU/L.
(3) preparation of optical activity carboxylic acid
The cell-free extract described in appropriate step (2) is taken, adds in kaliumphosphate buffer (100mM, pH 7.0) to totality
Product is 10ml, adds in the 5- carbonyl capric acids of final concentration of 10g/L, 20g/L glucose, suitable glucose dehydrogenase and NADP+,
Reaction temperature maintains 30 DEG C, magnetic agitation reaction 12h, sampling detection reaction conversion ratio.It the results are shown in Table 3.
3 Candida parapsilosis cell-free extract of table is catalyzed the Stereoselective reduction of 5- carbonyl capric acids
Embodiment 14 is acellular, and extraction catalyzes and synthesizes (R)-(+) -5- amyl -5- valerolactones
Cell-free extracts of the 50ml as described in embodiment 10-14 is taken, adds in 5- carbonyl capric acid 5g, glucose 5g, grape
The NADP of glucocorticoid dehydrogenase 2000U and final concentration of 0.5mM+, magnetic agitation reaction, reaction temperature maintains 30 DEG C, 1M is added dropwise
Na2CO3Maintain reaction solution pH constant 7.0.React 12h, conversion ratio 99.7%, the ee values height of product (R) -5- hydroxydecanoic acids
In 99%.
After reaction, using sulphur acid for adjusting pH to 2 or so, 60 DEG C of heating 1h carry out cyclization, finally using 2 times of bodies
Long-pending ethyl acetate is extracted, and extraction organic phase filters after being dried overnight with anhydrous sodium sulfate, and rotary evaporation removal solvent obtains
To crude product (R)-(+) -5- amyl -5- valerolactone 4.75g, yield 94%, ee values are 99%.
15 Candida parapsilosis resting cell of embodiment catalyzes and synthesizes (R)-(+) -4- hexyl -4- butyrolactone
Catalysis reaction carries out in the glass jacket reactor recycled with water-bath, and it is wet thin as described in Example 1 to weigh 5g
Born of the same parents are suspended in 50ml KPB buffer solutions (100mM, pH 7.0), add in 4- carbonyl capric acid 1g and 5g glucose, and mechanical agitation is anti-
It should.Reaction temperature maintains 30 DEG C, and 1 M K are added dropwise2CO3Maintain reaction solution pH constant 7.0.Intermittent sampling in reaction process, gas
Facies analysis detects conversion ratio and ee values.12h is converted, reaction was completed, conversion ratio 95%, the ee values of product (R) -4- hydroxydecanoic acids
It is 98%.
After reaction, using sulphur acid for adjusting pH to 1 or so, 80 DEG C of heating 2h carry out cyclization, finally using 2 times of bodies
Long-pending ethyl acetate is extracted, and extraction organic phase filters after being dried overnight with anhydrous sodium sulfate, and rotary evaporation removal solvent obtains
To crude product (R)-(+) -4- hexyl -4- butyrolactone 0.81g, yield 80%, ee values are 98%.
16 Candida parapsilosis cell catalysis of embodiment synthesizes (R)-(+) -5- amyl -5- valerolactones
Catalysis reaction carries out in the glass jacket reactor recycled with water-bath, and it is wet thin as described in Example 1 to weigh 5g
Born of the same parents are suspended in 50ml KPB buffer solutions (100mM, pH 7.0), add in 5- carbonyl capric acid 5g and 5g glucose, and mechanical agitation is anti-
It should.Reaction temperature maintains 30 DEG C, and 1 M Na are added dropwise2CO3Maintain reaction solution pH constant 7.0.Intermittent sampling in reaction process,
Gas phase analysis detects conversion ratio and ee values.3h is converted, reaction was completed, conversion ratio 99%, the ee of product (R) -5- hydroxydecanoic acids
Value is higher than 99%.
After reaction, using sulphur acid for adjusting pH to 2 or so, 60 DEG C of heating 1h carry out lactonization reaction, finally using 2 times
The dichloromethane of volume is extracted, and organic phase filters after being dried overnight with anhydrous sodium sulfate, and rotary evaporation removal solvent obtains
Crude product (R)-(+) -5- amyl -5- valerolactone 4.25g, yield 84%, ee values are 99%.
Claims (7)
- A kind of 1. method of living things catalysis synthesizing optical active al lactone, which is characterized in that this method includes the following steps：(1) using biocatalyst catalysis of carbonyl acid asymmetric reduction synthesizing optical activity hydroxy acid；(2) in acidic environment, make optical activity carboxylic acid cyclisation generation optically active lactone compound；The biocatalyst derives from Candida parapsilosis CGMCC2.3539.
- 2. the method for living things catalysis synthesizing optical active al lactone according to claim 1, which is characterized in that described Biocatalyst is Candida parapsilosis cell；What either nearly smooth Candida thalline obtained after crushing contains carbonyl The cell-free extract of reductase.
- 3. the method for living things catalysis synthesizing optical active al lactone according to claim 1 or 2, which is characterized in that institute State using biocatalyst catalysis of carbonyl acid asymmetric reduction the specific steps are：In the buffer system for being 6~8 in pH, 25 It is carried out under the conditions of~40 DEG C, a concentration of 1~100g/L of carbonylic acid；Also include the glucose of 10~100g/L in reaction system, 0~ The glucose dehydrogenase of 40kU/L and the NADP of 0~1mM+, the reaction time is 3~12h, generates optically active carboxylic acid.
- 4. the method for living things catalysis synthesizing optical active al lactone according to claim 3, which is characterized in that described When biocatalyst is Candida parapsilosis cell, the biocatalyst dosage of every liter of reaction solution is near smooth false for 10~100g Silk yeast cells.
- 5. the method for living things catalysis synthesizing optical active al lactone according to claim 3, which is characterized in that described When biocatalyst is the cell-free extract containing carbonyl reductase, the biocatalyst dosage of every liter of reaction solution is 4-40kU Carbonyl reductase.
- 6. the method for living things catalysis synthesizing optical active al lactone according to claim 1, which is characterized in that described In acidic environment, make optical activity carboxylic acid cyclisation the specific steps are：By the reaction solution acid containing carboxylic acid obtained by step (1) Change to 1~2,60~80 DEG C of 1~2h of heating of pH, carboxylic acid cyclisation is promoted to generate corresponding lactone, it is organic molten using water-insoluble Agent is extracted, and rotary evaporation removes solvent after extract liquor drying, obtains ester products in target.
- 7. the method for the living things catalysis synthesizing optical active al lactone according to claim 1 or 6, which is characterized in that institute The carbonylic acid stated is 4- carbonyl capric acids or 5- carbonyl capric acids.
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| A novel NADH-dependent carbonyl reductase with an extremelv broad substrate range from Candida parapsilosis: Purification and characterization;Jorg Peters et al.;《Enzyme Microb. Technol.》;19931130;第15卷(第11期);第950-958页 * |
| 还原酶催化羰基不对称还原的应用进展;欧玲等;《生物加工过程》;20110315;第9卷(第2期);第72-78页 * |
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Effective date of registration: 20181207 Address after: Room 207, No. 8, Sihai Road Research Institute Road, Changshu Economic and Technological Development Zone, Suzhou City, Jiangsu Province Co-patentee after: XIAMEN OMK BIOTECHNOLOGY CO., LTD. Patentee after: Fuan, Suzhou hundred zymotechnic company limited Co-patentee after: East China University of Science and Technology Address before: Room 207, No. 8, Sihai Road Research Institute Road, Changshu Economic and Technological Development Zone, Suzhou City, Jiangsu Province Co-patentee before: XIAMEN OMK BIOTECHNOLOGY CO., LTD. Patentee before: Fuan, Suzhou hundred zymotechnic company limited |
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