CN114921507B - Resolution method of prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-en-3-one - Google Patents
Resolution method of prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-en-3-one Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 26
- RYBPGUMSFWGGLP-UHFFFAOYSA-N 3,3a,6,6a-tetrahydrocyclopenta[b]furan-2-one Chemical compound C1=CCC2OC(=O)CC21 RYBPGUMSFWGGLP-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 150000003180 prostaglandins Chemical class 0.000 title description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 108090001060 Lipase Proteins 0.000 claims abstract description 14
- 102000004882 Lipase Human genes 0.000 claims abstract description 14
- 239000004367 Lipase Substances 0.000 claims abstract description 14
- 239000007853 buffer solution Substances 0.000 claims abstract description 14
- 235000019421 lipase Nutrition 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims abstract description 14
- 239000011259 mixed solution Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000006911 enzymatic reaction Methods 0.000 claims abstract description 6
- 230000006340 racemization Effects 0.000 claims abstract description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 6
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 5
- 229910001424 calcium ion Inorganic materials 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- 230000020477 pH reduction Effects 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- RYBPGUMSFWGGLP-WDSKDSINSA-N (3ar,6as)-3,3a,6,6a-tetrahydrocyclopenta[b]furan-2-one Chemical group C1=CC[C@@H]2OC(=O)C[C@@H]21 RYBPGUMSFWGGLP-WDSKDSINSA-N 0.000 claims description 2
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 241000589774 Pseudomonas sp. Species 0.000 claims description 2
- 239000008055 phosphate buffer solution Substances 0.000 claims description 2
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 claims description 2
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 6
- 239000011541 reaction mixture Substances 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000001514 detection method Methods 0.000 description 8
- 239000000758 substrate Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 108090000604 Hydrolases Proteins 0.000 description 4
- 102000004157 Hydrolases Human genes 0.000 description 4
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940117803 phenethylamine Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 1
- 108010084311 Novozyme 435 Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- STICKWIUXCNKRE-UHFFFAOYSA-N oct-6-en-3-one Chemical compound CCC(=O)CCC=CC STICKWIUXCNKRE-UHFFFAOYSA-N 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
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Abstract
The invention provides a resolution method of 2-oxabicyclo- [3.3.0] oct-6-en-3-one, which comprises the following steps: adding lipase into the solution of the racemization compound I, and then carrying out enzymatic reaction to obtain a reaction mixed solution; the solvent of the solution is single-phase buffer solution or multiphase mixed solution composed of buffer solution and organic solvent; separating the hydrolyzed L-shaped product from the reaction mixture; and acidifying to obtain the L-compound. The method has the advantages of simple operation, high optical purity of the product, environmental protection and the like.
Description
Technical Field
The invention belongs to the field of medicine preparation, and in particular relates to a resolution method of a prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-ene-3-one.
Background
Prostaglandins are active substances composed of a class of unsaturated fatty acids present in animals and humans and having a variety of physiological actions. Can be prepared by biosynthesis or total synthesis and can be widely applied to clinic as a medicament.
The general intermediate of the total synthetic route of the existing prostaglandin drugs is the left-handed structure of 2-oxabicyclo- [3.3.0] oct-6-en-3-one. Currently, chiral resolution of 2-oxabicyclo- [3.3.0] oct-6-en-3-one is mostly a chemical resolution method, i.e., by chiral resolving agents such as phenethylamine and the like. Patent CN201911281872.9 and CN201610523094.X report that phenethylamine reacts with 2-oxabicyclo- [3.3.0] oct-6-ene-3-ketone, and the two chiral products generated can be resolved by a precipitation crystallization method because of the difference of solubility, but the resolution process has certain defects, the solubility difference of the two products is not great, so that the chiral purity of the products is lower, the chiral purity qualified products can be obtained only by repeated precipitation for several times, the yield is poor, and the chiral resolving agent is expensive. Patent CN202011614247.4 reports resolution of a substrate by a hydrolase, however, the applicant found from experiments that a common hydrolase is not selective for the substrate and cannot produce the diol product.
Disclosure of Invention
Aiming at the problems in the prior art, the invention discloses a resolution method of a prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-en-3-one, in particular to a method for catalyzing and resolving by lipase, which solves the problems of multiple steps, low chiral purity, low atomic utilization rate and the like of a chemical resolution method in the prior art.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a method for resolution of 2-oxabicyclo- [3.3.0] oct-6-en-3-one, comprising the steps of:
(1) Adding lipase into the solution of the racemization compound I, and then carrying out enzymatic reaction to obtain a reaction mixed solution; the solvent of the solution is single-phase buffer solution or multiphase mixed solution composed of buffer solution and organic solvent;
(2) Separating the hydrolyzed L-form product;
(3) Acidifying the levorotatory product obtained in the step (2) to obtain a compound IV; the compound IV is (1S, 5R) -2-oxabicyclo- [3.3.0] oct-6-en-3-one.
The resolution method comprises the following reaction routes:
preferably, when the solvent of the solution in step (1) is a single-phase buffer solution, the separation method in step (2) is as follows:
adding calcium ions into the reaction mixed solution to enable the compound II to react with the calcium ions to obtain a precipitate; i.e., such that the levorotatory product is separated from the reaction mixture in precipitated form;
when the solvent of the solution in the step (1) is a multiphase mixed solution composed of a buffer solution and an organic solvent, the separation method in the step (2) is as follows: the mixture was allowed to stand for delamination and the aqueous layer was collected. I.e. such that the levorotatory product is separated from the reaction mixture in the form of an aqueous solution.
Preferably, the calcium ions are derived from calcium carbonate.
Preferably, step (2) further comprises the step of obtaining unhydrolyzed right-hand product from the remaining solution after separation of the hydrolyzed left-hand product.
Preferably, the enzyme described in step (1) is a Pseudomonas sp.
Preferably, the buffer solution in the step (1) is phosphate buffer solution, and the pH value is 6-9.
Preferably, the organic solvent in the step (1) is one or two of n-hexane or n-heptane.
Preferably, the temperature of the enzymatic reaction in step (1) is 20 to 40 ℃.
Preferably, the time of the enzymatic reaction in step (1) is 10 to 14 hours.
Preferably, the final concentration of lipase in step (1) is 0.01-0.02 g/ml.
Preferably, the acidification in step (3) is to adjust the pH to 2-3.5.
Preferably, the acidification in step (3) is one or both of the addition of hydrochloric acid or sulfuric acid.
The invention has the beneficial effects that:
(1) The method has the advantages of cheap and easily obtained raw materials, simple and convenient method and mild reaction conditions.
(2) Lipase is selected as a resolution means, so that the selectivity is high, and the yield of the levorotatory product is high.
(3) The method can be carried out under multiphase conditions or under homogeneous conditions, the homogeneous conditions are more environment-friendly because no organic solvent is used, and the homogeneous conditions do not need to stand for layering, so that the separation efficiency is high.
Drawings
FIG. 1 is a liquid chromatogram of the product obtained in example 1.
FIG. 2 is a liquid chromatogram of the product obtained in comparative example 1.
FIG. 3 is a liquid chromatogram of the product obtained in comparative example 2.
Detailed Description
Example 1
The chiral detection mode of the reaction substrate and the product is that a chromatographic column is DAICEL OD-H (4.6X250 mmL,5 μm) mobile phase is V (n-hexane): V (isopropanol) =90:10; flow rate: 0.7mL/min; the detection wavelength is 205nm; column temperature: 25 ℃; sample injection amount: 10uL.
Into a 25ml stoppered, ground Erlenmeyer flask were added rac 2-oxabicyclo- [3.3.0] oct-6-en-3-one (3 g) and Lipase AK (20 mg/ml) to 10ml phosphate buffer: n-hexane=2: 8 (v/v) in a mixed solvent, wherein the pH of the buffer solution is 7.5, the reaction is carried out for 10 hours at 160r/min under the condition of 20 ℃, the mixture is stood for layering after completion, and the water layer is collected, hydrochloric acid is added into the water layer to ensure that the pH is 2, the conversion rate reaches 27 percent, and the optical purity of the levo-2-oxabicyclo- [3.3.0] oct-6-en-3-one
＝98％ee。
Example 2
Into a 25ml stoppered, ground Erlenmeyer flask were added racemic compound I (3 g) and Lipase AK (20 mg/ml) to 10ml phosphate buffer: n-hexane=2: 8 (v/v) in a mixed solvent, wherein the buffer pH is 9, at 160r/min at 20 ℃, in a shaking table for 14h, standing and layering after completion and collecting the water layer, adding sulfuric acid to the water layer to make the pH 3, and the conversion rate reaches 36%, wherein the optical purity of the levo-2-oxabicyclo- [3.3.0] oct-6-en-3-one=99%ee. The chiral detection of the substrates and products was performed in the same manner as in example 1.
Example 3
Into a 25ml stoppered, ground Erlenmeyer flask was added Compound 1 (3 g) and Lipase AK (20 mg/ml) to 10ml phosphate buffer: n-heptane=2: 8 (v/v) in a mixed solvent, wherein the pH of the buffer solution is 7.5, 160r/min at 30 ℃, reacting for 12h in a shaking table, standing and layering after completion, collecting an aqueous layer, adding hydrochloric acid to the aqueous layer to make the pH 3.5, and the conversion rate reaches 40%, wherein the optical purity of the levo-2-oxabicyclo- [3.3.0] oct-6-en-3-one=99.3%ee. The chiral detection of the substrates and products was performed in the same manner as in example 1. The experimental pattern is shown in figure 1.
Example 4
Into a 25ml stoppered, ground Erlenmeyer flask were added racemic compound 1 (3 g) and Lipase AK (20 mg/ml) to 10ml phosphate buffer: n-hexane=2: 8 (v/v) in a mixed solvent, wherein the buffer pH is 6, at 160r/min at 40 ℃, in a shaking table, standing and layering after completion and collecting an aqueous layer, adding hydrochloric acid to the aqueous layer to make the pH to be 3, and the conversion rate reaches 37%, wherein the optical purity of the levo-2-oxabicyclo- [3.3.0] oct-6-en-3-one=99.1%ee. The chiral detection of the substrates and products was performed in the same manner as in example 1.
Example 5
Racemic compound 1 (0.5 g) and Lipase AK (10 mg/ml) were added to a 15 x 150mm tube and added to 3ml phosphate buffer at pH 7.5 at 40 ℃ at 160r/min, reacted in a shaker for 12h, followed by calcium carbonate (0.3 g), washed after sufficient reaction, evaporated to dryness and the precipitate collected, and the resulting precipitate was added to a hydrochloric acid solution at pH 3 to give the levorotatory product with a conversion of 43% and optical purity of levo2-oxabicyclo- [3.3.0] oct-6-en-3-one=98.9% ee. The chiral detection of the substrates and products was performed in the same manner as in example 1.
Comparative example 1
Using the method described in patent CN202011614247.4, an aqueous acetonitrile solution of racemic compound I (3 g) and hydrolase (Novozym 435) were added to a 25ml stoppered and ground Erlenmeyer flask, and after reaction in a shaker at 160r/min under normal temperature conditions, chiral detection was performed, the liquid chromatogram was as shown in FIG. 2, the chiral peak was shown at 13min in the figure, and chiral resolution of 2-oxabicyclo- [3.3.0] oct-6-en-3-one could not be achieved without change from before the reaction.
Comparative example 2
By the method described in patent CN202011614247.4, an acetonitrile aqueous solution of a racemic compound I (3 g) and hydrolase (PPL) are added into a 25ml plug-and-grind conical flask, and after the mixture is reacted for 24 hours in a shaking table at 160r/min under normal temperature, chiral detection is carried out, a liquid chromatogram is shown in FIG. 3, a chiral peak is shown at 13min in the graph, and chiral resolution of 2-oxabicyclo- [3.3.0] oct-6-en-3-one cannot be realized without change compared with the prior reaction.
Claims (6)
1. A process for the resolution of 2-oxabicyclo- [3.3.0] oct-6-en-3-one, comprising the steps of:
(1) Adding lipase into the solution of the racemization compound I, and then carrying out enzymatic hydrolysis reaction to obtain a reaction mixed solution; the solvent of the solution is single-phase buffer solution or multiphase mixed solution composed of buffer solution and organic solvent; the enzyme is Pseudomonas sp Lipase AK Lipase; the buffer solution is phosphate buffer solution, and the pH value is 6-9; the organic solvent is one or two of n-hexane or n-heptane;
(2) Separating the hydrolyzed L-form product shown by the structural formula of the compound II;
(3) Acidifying the levorotatory product obtained in the step (2) to obtain a compound IV; the compound IV is (1S, 5R) -2-oxabicyclo- [3.3.0] oct-6-en-3-one;
wherein, when the solvent of the solution in the step (1) is a single-phase buffer solution, the separation method in the step (2) is as follows: adding calcium ions into the reaction mixed solution to enable the compound II to react with the calcium ions to obtain precipitation, so that the levorotatory product is separated from the reaction mixed solution in a precipitation form;
when the solvent of the solution in the step (1) is a multiphase mixed solution composed of a buffer solution and an organic solvent, the separation method in the step (2) is as follows: standing for layering and collecting a water layer;
the structural formula of the raceme compound I isThe method comprises the steps of carrying out a first treatment on the surface of the The structural formula of the compound II is +.>The method comprises the steps of carrying out a first treatment on the surface of the The structural formula of the compound IV is +.>。
2. The resolution process according to claim 1, wherein step (2) further comprises a step of obtaining a non-hydrolyzed dextrorotatory product from the remaining solution after separating the hydrolyzed levorotatory product.
3. The resolution method according to claim 1, wherein the temperature of the enzymatic reaction in step (1) is 20 to 40 ℃.
4. The resolution method according to claim 1, wherein the time of the enzymatic reaction in step (1) is 10 to 14 hours.
5. The resolution method according to claim 1, wherein the final concentration of lipase in the step (1) is 0.01-0.02 g/ml.
6. The resolution method according to claim 1, wherein the acidification in the step (3) is to adjust the pH to 2 to 3.5.
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| CN202210596398.4A CN114921507B (en) | 2022-05-30 | 2022-05-30 | Resolution method of prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-en-3-one |
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| CN202210596398.4A CN114921507B (en) | 2022-05-30 | 2022-05-30 | Resolution method of prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-en-3-one |
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| US5248609A (en) * | 1986-11-13 | 1993-09-28 | Schering Aktiengesellschaft | Racemic separation of 7α-acyloxy-6β-hydroxymethyl-2-oxabicyclo[3.]-octan-3-ones by stereospecific enzymatic acylate hydrolysis |
| EP1086942A1 (en) * | 1999-09-21 | 2001-03-28 | Chisso Corporation | Optically active alcohols and processes for the preparation thereof |
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| CN112680497A (en) * | 2020-12-31 | 2021-04-20 | 南京赛信生物科技有限公司 | Method for separating prostanoid drug key intermediate (1S,5R) -Corey lactone by using biological enzyme |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1853719B1 (en) * | 2005-03-04 | 2009-09-02 | Teva Pharmaceutical Industries Ltd | Enzymatic transformation of a prostaglandin (bimatoprost) intermediate |
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|---|---|---|---|---|
| US5248609A (en) * | 1986-11-13 | 1993-09-28 | Schering Aktiengesellschaft | Racemic separation of 7α-acyloxy-6β-hydroxymethyl-2-oxabicyclo[3.]-octan-3-ones by stereospecific enzymatic acylate hydrolysis |
| EP1086942A1 (en) * | 1999-09-21 | 2001-03-28 | Chisso Corporation | Optically active alcohols and processes for the preparation thereof |
| CN109161577A (en) * | 2018-09-26 | 2019-01-08 | 厦门欧瑞捷生物科技有限公司 | A kind of left-handed Corey lactone diol intermediates, preparation method and its medicinal application |
| CN112939911A (en) * | 2019-12-11 | 2021-06-11 | 常州工程职业技术学院 | Chiral resolution process for preparing key intermediate of levo-Corey lactone |
| CN112680497A (en) * | 2020-12-31 | 2021-04-20 | 南京赛信生物科技有限公司 | Method for separating prostanoid drug key intermediate (1S,5R) -Corey lactone by using biological enzyme |
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| Title |
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| Significant Effect of Acyl Groups on Enantioselectivity in Lipase-Catalyzed Transesterifications;Tadashl Ema等;Tetrahedron: Asymmetry;第7卷(第3期);全文 * |
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