阅读说明：本技术 叔α-芳基环酮的制备方法 (Process for preparing tertiary alpha-aryl cyclic ketones ) 是由 刘运亭 栾鹏仟 姜艳军 高静 于 2021-02-18 设计创作，主要内容包括：本发明提供了一种叔α-芳基环酮的制备方法,该制备方法包括中间产物制备步骤和叔α-芳基环酮制备步骤,且中间产物制备步骤包括依次加入2-碘-2-环己烯酮、苯硼酸衍生物、碱、Pd催化剂和溶剂,并搅拌进行偶联反应得到具有生成的中间产物的反应液,叔α-芳基环酮制备步骤包括模式一或模式二,其中模式一包括调节反应液pH,加入含有老黄酶和葡萄糖脱氢酶全细胞的冻干粉,使细胞重新悬浮分散后加入NADPH和葡萄糖反应,以及反应完毕后进行萃取、干燥,待抽滤脱溶后,再经硅胶柱层析得到叔α-芳基环酮。本发明的叔α-芳基环酮的制备方法可利用该化学-酶法不对称催化得到含有手性中心的光学活性叔α-芳基环酮,并具有很好的应用效果。(The invention provides a preparation method of tertiary alpha-aryl cyclic ketone, which comprises an intermediate product preparation step and a tertiary alpha-aryl cyclic ketone preparation step, wherein the intermediate product preparation step comprises the steps of sequentially adding 2-iodo-2-cyclohexenone, a phenylboronic acid derivative, alkali, a Pd catalyst and a solvent, stirring for coupling reaction to obtain a reaction solution with a generated intermediate product, the tertiary alpha-aryl cyclic ketone preparation step comprises a first mode or a second mode, wherein the first mode comprises the steps of regulating the pH of the reaction solution, adding freeze-dried powder containing whole cells of old yellow enzyme and glucose dehydrogenase, adding NADPH and glucose for reaction after the cells are suspended and dispersed again, extracting and drying after the reaction is finished, and performing silica gel column chromatography to obtain the tertiary alpha-aryl cyclic ketone after the filtration and the desolventization. The preparation method of the tertiary alpha-aryl cyclic ketone can utilize the chemical-enzymatic method to asymmetrically catalyze to obtain the optically active tertiary alpha-aryl cyclic ketone containing the chiral center, and has good application effect.)

1. A preparation method of tertiary alpha-aryl cyclic ketone is characterized by comprising the following steps: the preparation method comprises the following steps:

a. an intermediate preparation step, and the intermediate preparation step comprises:

sequentially adding 2-iodine-2-cyclohexenone, a phenylboronic acid derivative, alkali, a Pd catalyst and a solvent into a reaction vessel, and stirring at 60-80 ℃ for coupling reaction for 4-12h to obtain a reaction solution with a generated intermediate product;

b. a tertiary alpha-aryl cyclic ketone preparation step, and the tertiary alpha-aryl cyclic ketone preparation step includes the following mode one or mode two, wherein:

the first mode comprises the following steps:

b11. b, when the reaction liquid in the step a is reduced to room temperature, adjusting the pH value of the reaction liquid to 6-8;

b12. adding freeze-dried powder containing the whole cells of the old yellow enzyme and the glucose dehydrogenase into the reaction solution, and repeatedly blowing to ensure that the cells are suspended and dispersed again;

b13. adding NADPH and glucose into the reaction solution, and stirring at 25-35 ℃ for reaction for 6-18 h;

b14. after the reaction is finished, extracting and drying, and after the extraction, the filtration and the desolventization, carrying out silica gel column chromatography to obtain the white solid tertiary alpha-aryl cyclic ketone;

the second mode includes:

b21. b, extracting the reaction liquid in the step a by using dichloromethane, drying by using anhydrous magnesium sulfate, and separating and purifying to obtain a generated intermediate product;

b22. dissolving the separated and purified intermediate product in a solvent to obtain a reaction solution;

b23. adding freeze-dried powder containing the whole cells of the old yellow enzyme and the glucose dehydrogenase into the reaction solution, and repeatedly blowing to ensure that the cells are suspended and dispersed again;

b24. adding NADPH and glucose into the reaction solution, and stirring at 25-30 ℃ to react for 6-18 h;

b25. after the reaction is finished, extracting and drying are carried out, and after the extraction filtration and the desolventization, the tertiary alpha-aryl cyclic ketone in white solid is obtained by silica gel column chromatography.

2. The process according to claim 1 for the preparation of a tertiary alpha-aryl cyclic ketone, characterized in that: the phenylboronic acid derivative is one of phenylboronic acid, 2-methylphenylboronic acid, 3-methylphenylboronic acid, 4-chlorophenylboronic acid, 2-methyl-4-chlorophenylboronic acid, 4-methoxyphenylboronic acid and 2-naphthylboronic acid.

3. The process according to claim 1 for the preparation of a tertiary alpha-aryl cyclic ketone, characterized in that: the alkali is alkali metal hydroxide or alkali metal carbonate.

4. The process according to claim 1 for the preparation of a tertiary alpha-aryl cyclic ketone, characterized in that: the preparation of the Pd catalyst comprises the following steps:

c1. preparing an aminated modified magnetic mesoporous silica nanoparticle;

c2. dissolving magnetic mesoporous silica nanoparticles in deionized water, and performing ultrasonic dispersion to obtain a mixed solution;

c3. pd precursor NaPdCl₄Dissolving in deionized water, dripping into the mixed solution, and stirring at 30 deg.C for reaction;

c4. reacting NaBH₄Dissolving in deionized water, dripping into the mixed solution, and continuously stirring at 30 ℃ for reaction;

c5. after the reaction is finished, Pd @ MMSN is obtained by magnetic separation.

5. The process according to claim 1 for the preparation of a tertiary alpha-aryl cyclic ketone, characterized in that: the solvent is DMF, DMSO, DME, THF, acetone, n-hexane, isooctane, ionic liquid [ BMim][PF₆]And an ionic liquid [ BMIm][NTF₂]A mixed solvent composed of one of the above and a buffer solution.

6. The process according to claim 1 for the preparation of a tertiary alpha-aryl cyclic ketone, characterized in that: in the step a, the concentration of the added 2-iodo-2-cyclohexenone is 5-50mM, the molar ratio of the added 2-iodo-2-cyclohexenone to the Pd catalyst is 1:2-2:1, and the molar ratio of the added 2-iodo-2-cyclohexenone to the base is 1:4-1: 1.

7. The process of claim 6, wherein:

in the step a, the concentration of the added 2-iodo-2-cyclohexenone is 25mM, the molar ratio of the added 2-iodo-2-cyclohexenone to the Pd catalyst is 1:1, the molar ratio of the added 2-iodo-2-cyclohexenone to the base is 1:2, and the coupling reaction is carried out for 6 hours at 70 ℃ by mechanical stirring;

in step b, b11 was performed to adjust the pH of the reaction solution to 7, and NADPH and glucose were added in steps b13 and b24, followed by stirring at 30 ℃ for 12 hours.

8. The process according to claim 1 for the preparation of a tertiary alpha-aryl cyclic ketone, characterized in that: adding freeze-dried powder containing the whole cells of the old yellow enzyme and the glucose dehydrogenase, and repeatedly blowing and beating by using a pipette to re-suspend and disperse the cells.

9. The process according to claim 1 for the preparation of a tertiary alpha-aryl cyclic ketone, characterized in that: the ratio of petroleum ether to ethyl acetate in the silica gel column is 10: 1.

10. The process according to claim 1 for the preparation of a tertiary alpha-aryl cyclic ketone, characterized in that: in the step b, the step b14 and the step b25 are extracted by dichloromethane after the reaction is finished, and dried by anhydrous magnesium sulfate.

Technical Field

The invention relates to the technical field of compound preparation, in particular to a preparation method of tertiary alpha-aryl cyclic ketone.

Background

Tertiary alpha-aryl cyclic ketones are important building blocks in drugs, bioactive molecules and natural products and, because of their wide application, are attractive synthetic targets. However, the synthetic approaches to tertiary alpha-aryl cyclic ketones are very limited compared to their widespread use.

Asymmetric alpha-arylation of carbon-based compounds is one of the most effective means for synthesizing optically active alpha-aryl cyclic ketones, but this means is often used for synthesizing quaternary alpha-aryl cyclic ketones. For the synthesis of the tertiary alpha-aryl compound, on one hand, the tertiary alpha-aryl compound contains acidic alpha-H and can undergo racemization reaction under alkaline environment, so that the means is limited, and in the prior literature report, the bridge ring framework is constructed while the tertiary alpha-aryl cyclic ketone is synthesized mainly through dynamic kinetic resolution and desymmetry reaction so as to effectively avoid racemization by utilizing the rigid bicyclic structure of the tertiary alpha-aryl cyclic ketone. On the other hand, when an optically active α -aryl cyclic ketone is synthesized by asymmetric α -arylation reaction of a carbon-based compound, polyarylation and aldol condensation reaction also occur when a ketone substrate having a small number of arylation substituents is arylated. The prior art also mainly utilizes alkalescent enol compounds to effectively prevent polyarylation and aldol condensation reactions.

In addition to the above asymmetric alpha-arylation reactions of carbon-based compounds, Lewis acid is currently used for assistanceThe asymmetric protonation reaction of the acid catalyst to the achiral enol compound can also realize the high-efficiency synthesis of the alpha-phenyl cyclic ketone. Meanwhile, the asymmetric epoxidation of benzyl cyclobutane and the rearrangement reaction of epoxy compound also realize the more challenging asymmetric synthesis of tertiary alpha-aryl cyclopentanone.

However, the direct catalytic synthesis of optically active α -aryl cyclic ketones using ketone compounds as substrates still faces a great limitation. Although asymmetric hydrogenation of simple, readily available achiral enol compounds using transition metals or organic catalysts is considered the most straightforward and simple method for the synthesis of chiral ketones, great progress has been made in the study of hydrogenation of acyclic and exocyclic enones.

However, few studies have been made on cyclic enones, particularly on α -substituted substrates, and asymmetric hydrogenation of α -aryl cyclic enones remains a challenging goal, whether in chemical or biocatalysis. In addition, while chemo-enzymatic coupling reactions, which combine the broad catalytic capabilities of chemical catalysts with the precise selectivity of biocatalysts, provide a new approach to asymmetric synthesis, the instability of biocatalysts and the incompatibility between the two catalytic domains make this concept still very challenging.

Disclosure of Invention

In view of the above, the present invention is directed to a method for preparing a tertiary α -aryl cyclic ketone, so as to prepare the tertiary α -aryl cyclic ketone.

In order to achieve the purpose, the technical scheme of the invention is realized as follows:

a process for preparing a tertiary α -aryl cyclic ketone, the process comprising:

a. an intermediate preparation step, and the intermediate preparation step comprises:

sequentially adding 2-iodine-2-cyclohexenone, a phenylboronic acid derivative, alkali, a Pd catalyst and a solvent into a reaction vessel, and stirring at 60-80 ℃ for coupling reaction for 4-12h to obtain a reaction solution with a generated intermediate product;

b. a tertiary alpha-aryl cyclic ketone preparation step, and the tertiary alpha-aryl cyclic ketone preparation step includes the following mode one or mode two, wherein:

the first mode comprises the following steps:

b11. b, when the reaction liquid in the step a is reduced to room temperature, adjusting the pH value of the reaction liquid to 6-8;

b12. adding freeze-dried powder containing the whole cells of the old yellow enzyme and the glucose dehydrogenase into the reaction solution, and repeatedly blowing to ensure that the cells are suspended and dispersed again;

b13. adding NADPH and glucose into the reaction solution, and stirring at 25-35 ℃ for reaction for 6-18 h;

b14. after the reaction is finished, extracting and drying, and after the extraction, the filtration and the desolventization, carrying out silica gel column chromatography to obtain the white solid tertiary alpha-aryl cyclic ketone;

the second mode includes:

b21. b, extracting the reaction liquid in the step a by using dichloromethane, drying by using anhydrous magnesium sulfate, and separating and purifying to obtain a generated intermediate product;

b22. dissolving the separated and purified intermediate product in a solvent to obtain a reaction solution;

b23. adding freeze-dried powder containing the whole cells of the old yellow enzyme and the glucose dehydrogenase into the reaction solution, and repeatedly blowing to ensure that the cells are suspended and dispersed again;

b24. adding NADPH and glucose into the reaction solution, and stirring at 25-30 ℃ to react for 6-18 h;

b25. after the reaction is finished, extracting and drying are carried out, and after the extraction filtration and the desolventization, the tertiary alpha-aryl cyclic ketone in white solid is obtained by silica gel column chromatography.

Further, the phenylboronic acid derivative is one of phenylboronic acid, 2-methylphenylboronic acid, 3-methylphenylboronic acid, 4-chlorophenylboronic acid, 2-methyl-4-chlorophenylboronic acid, 4-methoxyphenylboronic acid and 2-naphthylboronic acid.

Further, the alkali is alkali metal hydroxide or alkali metal carbonate.

Further, the preparation of the Pd catalyst comprises:

c1. preparing an aminated modified magnetic mesoporous silica nanoparticle;

c2. dissolving magnetic mesoporous silica nanoparticles in deionized water, and performing ultrasonic dispersion to obtain a mixed solution;

c3. pd precursor NaPdCl₄Dissolving in deionized water, dripping into the mixed solution, and stirring at 30 deg.C for reaction;

c4. reacting NaBH₄Dissolving in deionized water, dripping into the mixed solution, and continuously stirring at 30 ℃ for reaction;

c5. after the reaction is finished, Pd @ MMSN is obtained by magnetic separation.

Further, the solvent is DMF, DMSO, DME, THF, acetone, n-hexane, isooctane, ionic liquid [ BMIm][PF₆]And an ionic liquid [ BMIm][NTF₂]A mixed solvent composed of one of the above and a buffer solution.

Further, in the step a, the concentration of the added 2-iodo-2-cyclohexenone is 5-50mM, the molar ratio of the added 2-iodo-2-cyclohexenone to the Pd catalyst is 1:2-2:1, and the molar ratio of the added 2-iodo-2-cyclohexenone to the base is 1:4-1: 1.

Further, in the step a, the concentration of the added 2-iodo-2-cyclohexenone is 25mM, the molar ratio of the added 2-iodo-2-cyclohexenone to the Pd catalyst is 1:1, the molar ratio of the added 2-iodo-2-cyclohexenone to the base is 1:2, and the coupling reaction is carried out for 6 hours at 70 ℃ by mechanical stirring;

in step b, b11 was performed to adjust the pH of the reaction solution to 7, and NADPH and glucose were added in steps b13 and b24, followed by stirring at 30 ℃ for 12 hours.

Furthermore, after freeze-dried powder containing whole cells of the old yellow enzyme and the glucose dehydrogenase is added, the cells are repeatedly blown by a pipette gun to be resuspended and dispersed.

Further, the ratio of the petroleum ether to the ethyl acetate in the silica gel column is 10: 1.

In the step b, the step b14 and the step b25 are extracted by dichloromethane after the reaction is finished, and dried by anhydrous magnesium sulfate.

Compared with the prior art, the invention has the following advantages:

the preparation method of the tertiary alpha-aryl cyclic ketone takes 2-iodine-2-cyclohexenone which is simply and easily prepared as a substrate, generates an intermediate product through a Suzuki-Miyaura coupling reaction catalyzed by palladium, introduces aryl to an alpha position through a Suzuki-Miyaura cross coupling reaction catalyzed by Pd in the reaction process through an enzyme-catalyzed asymmetric hydrogenation reaction, and constructs a stereo center containing acidic alpha-H through asymmetric hydrogenation of ketene catalyzed by old yellow enzyme, so that the optically active tertiary alpha-aryl cyclic ketone containing a chiral center can be obtained through the chemical-enzyme method asymmetric catalysis.

The preparation method disclosed by the invention has the advantages that the carbonyl group does not need to be protected in the reaction process, the optical purity of the product is high, and the preparation method is a novel preparation method which is efficient, high in selectivity, good in operability and environment-friendly. And particularly, when the mode I is adopted in the step b, the optically active tertiary alpha-aryl cyclic ketone containing the chiral center can be efficiently and selectively prepared in one pot, the yield is higher than that of a two-step two-pot mode, the complicated separation step of an intermediate product can be avoided, and the application effect is good.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an embodiment of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:

FIG. 1 is a reaction sequence for the preparation of tertiary alpha-aryl cyclic ketones in accordance with an embodiment of the present invention;

FIG. 2 is an SEM image of a Pd catalyst prepared by an example of the invention;

FIG. 3 is a TEM-Mapping image of Pd catalyst prepared by the inventive example.

Detailed Description

It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.

In addition, unless otherwise specified, all terms and processes related to the present embodiment should be understood according to the conventional knowledge and conventional methods in the art.

The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.

This example relates to a process for the preparation of a tertiary alpha-aryl cyclic ketone, which, in its overall design, comprises an intermediate preparation step a and a tertiary alpha-aryl cyclic ketone preparation step b.

Wherein, for the intermediate product preparation step a, the step specifically comprises:

adding 2-iodine-2-cyclohexenone, a phenylboronic acid derivative, alkali, a Pd catalyst and a solvent into a reaction vessel in sequence, and stirring at 60-80 ℃ for coupling reaction for 4-12h to obtain a reaction solution with a generated intermediate product.

In the above step, the phenylboronic acid derivative may be one of phenylboronic acid, 2-methylphenylboronic acid, 3-methylphenylboronic acid, 4-chlorophenylboronic acid, 2-methyl-4-chlorophenylboronic acid, 4-methoxyphenylboronic acid and 2-naphthylboronic acid.

As the alkali, an alkali metal hydroxide or an alkali metal carbonate can be used, and as the above alkali metal hydroxide, for example, potassium hydroxide or sodium hydroxide can be used, and as the above alkali metal carbonate, for example, potassium carbonate or sodium carbonate can be used.

The Pd catalyst is prepared by using NaPdCl as Pd precursor₄By NaBH₄And (3) in-situ reduction of the Pd catalyst product on the mesoporous channel of the aminated silicon-based material. Moreover, the silicon-based material in the amination modified silicon-based material can be inorganic silicon, organic silicon or organic-inorganic hybrid silicon, and preferably, the silicon-based material is Magnetic Mesoporous Silica Nanoparticles (MMSN).

Taking an example of an optimal magnetic mesoporous silica nanoparticle, the preparation of the Pd catalyst of this embodiment specifically includes the following steps:

c1. preparing an aminated modified magnetic mesoporous silica nanoparticle;

c2. dissolving magnetic mesoporous silica nanoparticles in deionized water, and performing ultrasonic dispersion to obtain a mixed solution;

c3. pd precursor NaPdCl₄Dissolving in deionized water, dripping into the mixed solution, and stirring at 30 deg.C for reaction;

c4. reacting NaBH₄Dissolving in deionized water, dripping into the mixed solution, and continuously stirring at 30 ℃ for reaction;

c5. after the reaction is finished, Pd @ MMSN is obtained by magnetic separation.

In the above preparation process of the Pd catalyst, the magnetic mesoporous silica nanoparticles can be synthesized, for example, according to literature (j.gao, w.kong, l.zhou, y.he, l.ma, y.yun, l.yan, y.jiang, chem.eng.j.2017,309, 70). And the amination modification of the prepared magnetic mesoporous silica nanoparticles specifically comprises the steps of adding the magnetic mesoporous silica nanoparticles and n-hexane into a reactor, carrying out ultrasonic treatment, adding 3-Aminopropyltriethoxysilane (APTES), then placing the reactor into a water bath kettle at 80 ℃, and carrying out condensation reflux for 12 hours to obtain a product. Then separating the product by using a magnet, and washing the product by using absolute ethyl alcohol and ultrapure water for three times respectively to obtain the aminated MMSN.

Furthermore, it should be noted that in the preparation of the Pd catalyst, the NaPdCl precursor was added by adjusting the amount of Pd added₄While different Pd-supported Pd catalysts can be obtained, it is preferred to use 10% supported Pd catalyst in this example.

In this embodiment, the solvent is DMF, DMSO, DME, THF, acetone, n-hexane, isooctane, and ionic liquid [ BMim ]][PF₆]And an ionic liquid [ BMIm][NTF₂]A mixed solvent composed of one of the above and a buffer solution. Further, it is preferable to use a mixed solvent of an ionic liquid and a buffer solution, and the buffer solution may be prepared according to the preparation conditions of the present embodiment, and for example, potassium phosphate buffer may be used.

In a specific preparation, the concentration of 2-iodo-2-cyclohexenone added in step a above may be 5 to 50mM, preferably 25 mM. The molar ratio of 2-iodo-2-cyclohexenone and Pd catalyst added may be 1:2 to 2:1, preferably 1: 1. The molar ratio of 2-iodo-2-cyclohexenone and base added may be from 1:4 to 1:1, preferably 1: 2.

In addition, the coupling reaction in step a may preferably be a mechanical stirring reaction at 70 ℃ for 6 h.

The step b of preparing the tertiary α -aryl cyclic ketone in this embodiment specifically includes a mode one or a mode two, wherein, for the mode one, the mode is a two-step one-pot cascade reaction mode, and as shown in fig. 1, the method includes:

b11. b, when the reaction liquid in the step a is reduced to room temperature, adjusting the pH value of the reaction liquid to 6-8;

b12. adding freeze-dried powder containing the whole cells of the old yellow enzyme and the glucose dehydrogenase into the reaction solution, and repeatedly blowing to ensure that the cells are suspended and dispersed again;

b13. adding NADPH and glucose into the reaction solution, and stirring at 25-35 ℃ for reaction for 6-18 h;

b14. after the reaction is finished, extracting and drying are carried out, and after the extraction filtration and the desolventization, the tertiary alpha-aryl cyclic ketone in white solid is obtained by silica gel column chromatography.

The second mode is a two-step two-pot mode which is different from the first mode and is a one-pot two-step mode, and the mode specifically comprises the following steps:

b21. b, extracting the reaction liquid in the step a by using dichloromethane, drying by using anhydrous magnesium sulfate, and separating and purifying to obtain a generated intermediate product;

b22. dissolving the separated and purified intermediate product in a solvent to obtain a reaction solution;

b23. adding freeze-dried powder containing the whole cells of the old yellow enzyme and the glucose dehydrogenase into the reaction solution, and repeatedly blowing to ensure that the cells are suspended and dispersed again;

b24. adding NADPH and glucose into the reaction solution, and stirring at 25-30 ℃ to react for 6-18 h;

b25. after the reaction is finished, extracting and drying are carried out, and after the extraction filtration and the desolventization, the tertiary alpha-aryl cyclic ketone in white solid is obtained by silica gel column chromatography.

In the above two modes, it is preferable that the b11 step is specifically to adjust the pH of the reaction solution to 7, and the b13 and b24 steps are to stir the reaction at 30 ℃ for 12 hours after addition of NADPH and glucose.

In addition, in the step b, after the freeze-dried powder containing the aged yellow enzyme and the glucose dehydrogenase whole cells is added, the cells can be re-suspended and dispersed by repeatedly blowing with a pipette. In addition, the ratio of petroleum ether to ethyl acetate in the silica gel column is 10:1, and the b14 step and the b25 step are specifically carried out by extracting with dichloromethane after the reaction is finished and drying with anhydrous magnesium sulfate.

Based on the above description of the overall design, the preparation of the tertiary alpha-aryl cyclic ketones of this example is further illustrated in the following specific examples.

Example 1

This example relates to the preparation of Pd catalyst, and example 1 specifically exemplifies 10% loading.

Dissolving 56mg of prepared Magnetic Mesoporous Silica Nanoparticles (MMSN) in 10mL of deionized water, and performing ultrasonic dispersion for 20 min. Then, the product is processed10mg of NaPdCl as Pd precursor₄Dissolved in 10mL of deionized water, added dropwise to the mixture obtained above, and stirred at 30 ℃ for 4 hours. Finally, 6.1mg of NaBH₄Dissolved in 2mL of deionized water, added dropwise to the mixture and stirred at 30 ℃ for 2 h. After the reaction is finished, Pd @ MMSN-10 is obtained by magnetic separation.

SEM and TEM-Mapping graphs of Pd @ MMSN-10 prepared in example 1 are shown in FIGS. 2 and 3, respectively, and f, g, h, i in FIG. 3 represent a Si element distribution diagram, an O element distribution diagram, an Fe element distribution diagram, and a Pd element distribution diagram, respectively.

Example 2

This example relates to the preparation of a tertiary alpha-aryl cyclic ketone based on the Pd catalyst prepared in example 1, and example 2 employs mode one above, which is a one-pot mode.

0.25mmol of 2-iodo-2-cyclohexenone, 0.25mmol of a phenylboronic acid derivative, 0.5mmol of potassium carbonate, 10mol of Pd @ MMSN-10, 8mL of a buffer solution and 2mL of an ionic liquid [ BMIm ] were sequentially added to a reaction vessel][PF₆]And carrying out mechanical stirring reaction at 70 ℃ for 6 hours to carry out coupling reaction to obtain an intermediate product.

After the reaction is finished, the pH value of the reaction liquid system is adjusted to 7 after the temperature of the reaction liquid is reduced to room temperature. Then 0.2g of freeze-dried powder containing the aged yellow enzyme and glucose dehydrogenase whole cells is added into the system, and the mixed solution is repeatedly blown by a 5mL liquid transfer gun to resuspend and disperse the cells.

Finally, NADPH (0.2mM) and glucose (0.2M) were added, and the reaction was stirred at 30 ℃ for 12 hours. After the reaction is finished, dichloromethane is used for extraction, anhydrous magnesium sulfate is used for drying, and after suction filtration and desolventization, white solid-shaped tertiary alpha-aryl cyclic ketone is obtained through silica gel column chromatography.

Example 3

This example relates to the preparation of a tertiary alpha-aryl cyclic ketone based on the Pd catalyst prepared in example 1, and example 2 employs mode two, which is a two-step, two-pot model as described above.

0.25mmol of 2-iodo-2-cyclohexenone, 0.25mmol of phenylboronic acid derivative, 0.5mmol of potassium carbonate, 10mol of Pd @ MMSN-10, 8mL of buffer solution and 2mL of ionic liquid [ BMIm ] [ PF6] are sequentially added into a reaction vessel, and the mixture is mechanically stirred at 70 ℃ for 6 hours to perform a coupling reaction, so that an intermediate product is obtained.

After the reaction, dichloromethane is used for extraction, anhydrous magnesium sulfate is used for drying, and the intermediate product is separated and purified.

The purified intermediate was dissolved in 8mL of buffer solution and 2mL of ionic liquid [ BMIm][PF₆]0.2g of freeze-dried powder containing the whole cells of the old yellow enzyme and the glucose dehydrogenase is added into the mixed solution, and the mixed solution is repeatedly blown by a 5mL pipette to resuspend and disperse the cells.

Finally, NADPH (0.2mM) and glucose (0.2M) were added, and the reaction was stirred at 30 ℃ for 12 hours. After the reaction is finished, dichloromethane is used for extraction, anhydrous magnesium sulfate is used for drying, and after suction filtration and desolventization, white solid tertiary alpha-aryl cyclic ketone is obtained through silica gel column chromatography.

The nmr spectra and hplc data of the tertiary α -aryl cyclic ketones obtained in example 2 and example 3 are shown in the table below, wherein the conversion is determined by nmr and the enantioselectivity of the compound is determined by lc.

As can be seen from the above table, in the preparation method of this embodiment, the effect of the mode one in the step b is significantly better than that of the mode two in yield, and a better ee value is obtained in some products, which fully illustrates that compared to the two-step two-pot mode of the mode two, the one-pot mode of the chemo-enzymatic preparation of the tertiary α -aryl cyclic ketone can not only omit the complicated intermediate separation and purification steps, but also reduce the loss of the intermediate and the product, and has better application effect, and is a preferred preparation mode.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.