阅读说明：本技术 一种可见光驱动下合成手性α-非天然氨基酸衍生物的方法 (Method for synthesizing chiral alpha-unnatural amino acid derivative under drive of visible light ) 是由 许兆青 王锐 王超 齐如鹏 于 2021-07-20 设计创作，主要内容包括：本发明公开了一种可见光驱动下铜复合物催化的手性α-非天然氨基酸衍生物的合成方法,以甘氨酸衍生物为原料,与金属铜盐和手性膦配体共同反应形成铜复合物,再与脂肪酸NHPI酯、碱和溶剂在可见光照射下反应,得到手性α-非天然氨基酸衍生物。本发明采用可见光驱动的合成策略,条件温和且绿色,转化过程中官能团耐受性优异；原料廉价易得,产物结构丰富；产率高,立体选择性优秀,并可以通过不同构型手性膦配体的使用,选择性地合成D型或L型氨基酸,并高效实现多肽分子的立体选择性修饰；建立了全新催化方式；避免了消旋α-非天然氨基酸在使用前的手性拆分步骤,在化学合成领域具备更加显著的应用价值。(The invention discloses a method for synthesizing a chiral alpha-unnatural amino acid derivative catalyzed by a copper compound under the drive of visible light, which comprises the steps of taking a glycine derivative as a raw material, reacting the glycine derivative with a metal copper salt and a chiral phosphine ligand to form a copper compound, and reacting the copper compound with fatty acid NHPI ester, alkali and a solvent under the irradiation of visible light to obtain the chiral alpha-unnatural amino acid derivative. The invention adopts a synthesis strategy driven by visible light, the conditions are mild and green, and the tolerance of functional groups in the conversion process is excellent; the raw materials are cheap and easy to obtain, and the product structure is rich; the yield is high, the stereoselectivity is excellent, D-type or L-type amino acid can be selectively synthesized by using chiral phosphine ligands with different configurations, and the stereoselective modification of polypeptide molecules is efficiently realized; a brand new catalysis mode is established; avoids the chiral resolution step of the racemic alpha-unnatural amino acid before use, and has more obvious application value in the field of chemical synthesis.)

1. a method for synthesizing chiral alpha-unnatural amino acid derivatives under the drive of visible light is characterized in that: the method comprises the steps of taking a glycine derivative as a raw material, reacting the glycine derivative with a metal copper salt and a chiral phosphine ligand to form a copper compound, and reacting the copper compound with fatty acid NHPI ester, alkali and a solvent under the irradiation of visible light to obtain the chiral alpha-unnatural amino acid derivative.

2. The method of synthesizing the chiral α -unnatural amino acid derivative catalyzed by copper complexes under visible light drive as claimed in claim 1, wherein: the structural formula of the glycine derivative is as follows:in the formula, R¹Is AQ or MQ, R²Selected from alkoxy, alkylamino, amino acid amino or polypeptide amino.

3. The method for synthesizing copper complex catalyzed chiral α -unnatural amino acid derivatives as claimed in claim 1 or 2, comprising the steps of:

(1) adding a glycine derivative into a dry reaction container with a stirrer, adding a metal copper salt and a chiral phosphine ligand, adding a solvent in an argon atmosphere, and stirring to obtain a solution containing a copper compound;

(2) adding a mixed solution of a solvent, fatty acid NHPI ester and alkali into the solution containing the copper compound obtained in the step (1) in an argon atmosphere;

(3) transferring the reaction vessel into a visible light reactor, and irradiating the reaction vessel with visible light at-10-10 ℃ for 36-60 h;

(4) after the reaction is finished, the chiral alpha-unnatural amino acid derivative is obtained by carrying out separation, purification and elution through silica gel column chromatography after quenching, ethyl acetate extraction, saturated saline solution washing, anhydrous sodium sulfate drying and reduced pressure concentration.

4. The method of claim 3 for the synthesis of chiral alpha-unnatural amino acid derivatives catalyzed by copper complexes under visible light drive, wherein: the concentration of the glycine derivative in the step (1) is 0.033-0.067 mmol/L.

5. The method of synthesizing the chiral α -unnatural amino acid derivative catalyzed by copper complexes under visible light drive as claimed in claim 4, wherein: in the step (1), the metal copper salt is tetra-acetonitrile copper hexafluorophosphate, tetra-acetonitrile copper tetrafluoroborate or copper trifluoromethanesulfonate, and the mass ratio of the metal copper salt to the glycine derivative is 0.05:1-0.2: 1; the chiral phosphine ligand is (S) -binaphthyl (3, 5-xylyl) phosphine or (R) -binaphthyl (3, 5-xylyl) phosphine, and the mass ratio of the metal copper salt to the chiral phosphine ligand is 1:1.1-1: 2.

6. The method of claim 5 for the synthesis of chiral alpha-unnatural amino acid derivatives catalyzed by copper complexes under visible light drive, wherein: in the step (1), the copper compound is a copper compound I or a copper compound II, and the structural formula of the copper compound I is as follows:the structural formula of the copper compound II is as follows:wherein X is selected from hydrogen or methoxy; ar is 3, 5-xylyl.

7. The method of claim 6 for the synthesis of chiral alpha-unnatural amino acid derivatives catalyzed by copper complexes under visible light drive, wherein: in the step (2), the solvent is N, N-dimethylformamide or N, N-dimethylacetamide.

8. The method of claim 7 for the synthesis of chiral alpha-unnatural amino acid derivatives catalyzed by copper complexes under visible light drive, wherein: the mass ratio of the glycine derivative to the fatty acid NHPI ester in the step (2) is 1:1.5-1: 3.

9. The method of claim 8 for the synthesis of chiral alpha-unnatural amino acid derivatives catalyzed by copper complexes under visible light drive, wherein: in the step (3), the visible light is purple light, blue light or white light.

10. The method of synthesizing the chiral α -unnatural amino acid derivative catalyzed by copper complexes under visible light drive as claimed in claim 9, wherein: the structural formula of the chiral alpha-unnatural amino acid derivative in the step (4) is shown in the specificationIn the formula, R¹Is AQ or MQ, R²Selected from alkoxy, alkylamino, amino acid amino or polypeptide amino, R is selected from primary, secondary or tertiary alkyl.

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing a chiral alpha-unnatural amino acid derivative catalyzed by a copper compound under the drive of visible light.

Background

The unnatural amino acid is a very important compound, and has important application value in the fields of biology, biochemistry, pharmaceutical science, material science and the like. Among the reported strategies for synthesizing unnatural amino acids, chemical synthesis is a very important route for preparing unnatural amino acids. For example, chemical modifications of 20 natural amino acids can yield a variety of unnatural amino acids including the main structure of natural amino acids, including phenylalanine derivatives, tyrosine derivatives, glutamine derivatives, alanine derivatives, serine derivatives, lysine derivatives, and cysteine derivatives. However, general synthetic strategies directed to chiral α -unnatural amino acids have not been developed.

Among the 20 natural amino acids, glycine is a very specific occurrence and can be considered as a basic building block for most a-unnatural amino acids. Thus, based on the glycine host structure C (sp)³) Asymmetric alkylation of the-H bond is a very straightforward and simple strategy for the synthesis of alpha-unnatural amino acids. It is noteworthy that alkylation based on a glycine fragment of a polypeptide molecule is also an important strategy for achieving selective modification of a glycine fragment of a polypeptide. The application of electrophilic alkylation strategies of glycine derivatives with various phase transfer catalysts to the synthesis of chiral alpha-unnatural amino acids was described in detail in a review written by Ooi in 2003 (Ooi, t.; Maruoka, K).Chem. Rev. 2003, 103, 3013). However, these strategiesAll have the defects of narrow range of alkylating reagents (such as allyl and benzyl), poor ee value of products and the like, and the strategy cannot be applied to the field of polypeptide modification. In addition, in previous studies, we developed two visible light-driven methods of alpha-unnatural amino acid synthesis using glycine derivatives as starting materials and fatty acid-derived NHPI esters and primary fatty amine-derived Katritzky salts as alkylating agents, and successfully achieved alkylated modifications of the glycine fragments of the polypeptide molecules (Wang, C.; Guo, M.; Qi, R.; Shang, Q.; Liu, Q.; Wang, S.; ZHao, L.; Wang, R.; Xu, Z.).Angew. Chem. Int. Ed.2018, 5715841 and Wang, C.; Qi, R.; Xue, H.; Shen, Y.; Chang, M.; Chen, Y.; Wang, R.; Xu, Z).Angew. Chem. Int. Ed.2020, 59, 7461). The two methods can synthesize a plurality of alpha-unnatural amino acids and polypeptide molecules with structural specificity, however, the obtained non-stereoselective products have the application prospect of the two strategies to the maximum extent, namely, if chiral amino acids or polypeptide molecules are obtained, the chiral resolution is required.

Disclosure of Invention

The invention aims to provide a method for synthesizing a chiral alpha-unnatural amino acid derivative catalyzed by a copper compound under the drive of visible light, so as to solve the problems.

In order to achieve the purpose, the invention adopts the technical scheme that:

a method for synthesizing chiral alpha-unnatural amino acid derivatives under the drive of visible light comprises the steps of taking glycine derivatives as raw materials, reacting the glycine derivatives with metal copper salts and chiral phosphine ligands to form copper compounds, and reacting the copper compounds with fatty acid NHPI ester, alkali and a solvent under the irradiation of visible light to obtain the chiral alpha-unnatural amino acid derivatives.

To further realize the invention, the structural formula of the glycine derivative is as follows:in the formula, R¹Is AQ or MQ, and has the following structural formula:，R²selected from alkoxy, alkylamino, amino acid amino or polypeptide amino.

In order to further realize the invention, the synthesis method comprises the following steps:

(1) adding a glycine derivative into a dry reaction container with a stirrer, adding a metal copper salt and a chiral phosphine ligand, adding a solvent in an argon atmosphere, and stirring to obtain a solution containing a copper compound;

(2) adding a mixed solution of a solvent, fatty acid NHPI ester and alkali into the solution containing the copper compound obtained in the step (1) in an argon atmosphere;

(3) transferring the reaction vessel into a visible light reactor, and irradiating the reaction vessel with visible light at-10-10 ℃ for 36-60 h;

(4) after the reaction is finished, the chiral alpha-unnatural amino acid derivative is obtained by carrying out separation, purification and elution through silica gel column chromatography after quenching, ethyl acetate extraction, saturated saline solution washing, anhydrous sodium sulfate drying and reduced pressure concentration.

In order to further realize the invention, the concentration of the glycine derivative in the step (1) is 0.033 to 0.067 mmol/L.

In order to further realize the invention, the metal copper salt in the step (1) is tetraacetonitrileconium hexafluorophosphate, tetraacetonitrileconium tetrafluoroborate or copper trifluoromethanesulfonate, and the amount ratio of the metal copper salt to the substance of the glycine derivative is 0.05:1 to 0.2: 1; the chiral phosphine ligand is (S) -binaphthyl (3, 5-xylyl) phosphine or (R) -binaphthyl (3, 5-xylyl) phosphine, and the mass ratio of the metal copper salt to the chiral phosphine ligand is 1:1.1-1: 2.

In order to further realize the invention, in the step (1), the copper compound is a copper compound I or a copper compound II, and the structural formula of the copper compound I is as follows:the structural formula of the copper compound II is as follows:wherein X is selected from hydrogen orA methoxy group; ar is 3, 5-xylyl.

In order to further realize the present invention, the solvent in the step (2) is N, N-dimethylformamide or N, N-dimethylacetamide.

In order to further realize the invention, the ratio of the amount of the substances of glycine derivative and fatty acid NHPI ester in the step (2) is 1:1.5-1: 3.

In order to further realize the invention, the visible light in the step (3) is purple light, blue light or white light.

In order to further realize the invention, the structural formula of the chiral alpha-unnatural amino acid derivative in the step (4) is shown in the specificationIn the formula, R¹Is AQ or MQ, R²Selected from alkoxy, alkylamino, amino acid amino or polypeptide amino, R is selected from primary, secondary or tertiary alkyl, R is selected from alkyl¹The structural formula of (A) is:or。

To further realize the invention, the ratio of the amount of the glycine derivative to the amount of the base is 1:1 to 1: 2.

In order to further realize the present invention, the copper salt of a metal in the step (1) is preferably copper trifluoromethanesulfonate.

To further realize the present invention, the chiral phosphine ligand in step (1) is preferably (S) -binaphthyl (3, 5-xylyl) phosphine.

In order to further realize the present invention, the solvent in step (1) is preferably N, N-dimethylformamide.

In order to further realize the present invention, the base in the step (2) is preferably triethylenediamine.

In order to further realize the present invention, the visible light in step (3) is preferably blue light.

To further carry out the invention, the temperature in step (3) is preferably-10 ℃.

In order to further realize the present invention, the irradiation time in step (3) is preferably 60 hours.

To further realize the invention, the ratio of the amount of substance of the glycine derivative to the fatty acid NHPI ester is preferably 1: 2.

To further realize the present invention, the ratio of the amount of the copper metal salt to the substance of the glycine derivative is preferably 0.1: 1.

To further realize the invention, the ratio of the amount of the substance of the copper metal salt to the chiral phosphine ligand is preferably 1: 1.1.

To further realize the present invention, the ratio of the amount of the glycine derivative to the base substance is preferably 1:1.

To further carry out the present invention, the glycine derivative is preferably 0.033 mmol/L.

To further implement the present invention, said R²Preferred are tert-butoxy, tert-butylamino and amino acid amino.

Compared with the prior art, the invention has the beneficial effects that:

1. the invention adopts a synthesis strategy driven by visible light, the conditions are mild and green, and the tolerance of functional groups in the conversion process is excellent;

2. the invention adopts fatty acid which is ubiquitous in the nature as an alkylating reagent, the raw materials are cheap and easy to obtain, and the obtained product chiral alpha-unnatural amino acid or polypeptide modified molecular structure is rich;

3. the invention has high yield and excellent stereoselectivity, can selectively synthesize D-type or L-type amino acid by using chiral phosphine ligands with different configurations, and efficiently realize stereoselective modification of polypeptide molecules;

4. the invention establishes a brand new catalysis mode, namely a copper compound is formed by a metal copper salt, a chiral phosphine ligand and a raw material glycine derivative;

5. the product obtained by the method is a chiral alpha-unnatural amino acid derivative completely different from the method, so that the chiral resolution step of racemic alpha-unnatural amino acid before use is avoided, and the method has more obvious application value in the field of chemical synthesis.

Detailed Description

The present invention will be further described with reference to the following embodiments.

The structural formula of the glycine derivatives used in the following examples is as follows:

the fatty acid NHPI esters used in the following examples have the following structural formula:

example 1: 2a Synthesis

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.005 mmol,1.8 mg) and chiral phosphine ligand L1 (0.006 mmol,4.4 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI-n-pentanoate (0.2 mmol,49.4 mg) and triethylene diamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2a is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data for 2a are as follows:

yellow liquid, yield 83% (26.0 mg), ee value 93% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 50/1).

HRMS (ESI): C₁₉H₂₇N₂O₂ [M+H]⁺Theoretical value: 315.2067, measurement: 315.2076.

¹H NMR (300 MHz, CDCl₃) δ 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.04 (dd, J= 8.3, 1.7 Hz, 1H), 7.40 – 7.29 (m, 2H), 7.07 (dd, J = 8.2, 0.8 Hz, 1H), 6.64 (d, J = 7.4 Hz, 1H), 6.58 (d, J = 8.6 Hz, 1H), 4.18 – 4.07 (m, 1H), 2.07 – 1.83 (m, 2H), 1.58 – 1.34 (m, 13H), 0.93 (t, J = 7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 173.13, 147.07, 143.88, 138.36, 135.84, 128.63, 127.45, 121.37, 114.61, 105.27, 81.24, 56.92, 32.51, 28.00, 27.85, 22.52, 13.93。

example 2: 2b Synthesis

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI ester of 3, 3-dimethylbutyric acid (0.2 mmol,52.2 mg) and triethylenediamine (0.2 mmol,22.4 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2b is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, 84% yield (27.6 mg), 93% ee (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 50/1).

HRMS (ESI): C₂₀H₂₉N₂O₂ [M+H]⁺Theoretical value: 329.2224, measurement: 329.2227.

¹H NMR (300 MHz, CDCl₃) δ 8.73 (dd, J = 4.1, 1.6 Hz, 1H), 8.04 (dd, J= 8.2, 1.5 Hz, 1H), 7.40 – 7.30 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H), 6.68 (d, J= 7.5 Hz, 1H), 6.39 (d, J = 8.9 Hz, 1H), 4.18 – 4.07 (m, 1H), 1.93 (dd, J = 14.2, 4.6 Hz, 1H), 1.80 (dd, J = 14.2, 7.4 Hz, 1H), 1.37 (s, 9H), 1.04 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 173.89, 147.03, 143.72, 138.38, 135.81, 128.61, 127.47, 121.34, 114.61, 105.40, 81.03, 54.90, 46.85, 30.72, 29.85, 27.90。

example 3: synthesis of 2c

Mixing glycine derivative 1-AQ (0.1 mmol, 25)8 mg) was added to a 10mL dry reaction flask with a stirrer, and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (1 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI ester of 5-oxo-5-phenylpentanoic acid (0.2 mmol,67.4 mg) and triethylenediamine (0.12 mmol,13.4 mg) in dimethylformamide (1 mL). The mixture was transferred to a blue light photoreactor and irradiated at-10 ℃ for 48 h. After the reaction is finished, the target product 2c is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, 84% yield (34.0 mg), 93% ee (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 3/2).

HRMS (ESI): C₂₅H₂₉N₂O₃ [M+H]⁺Theoretical value: 405.2173, measurement: 405.2185.

¹H NMR (300 MHz, CDCl₃) δ 8.74 (dd, J = 4.2, 1.6 Hz, 1H), 8.04 (dd, J= 8.3, 1.6 Hz, 1H), 7.96 – 7.88 (m, 2H), 7.54 (dd, J = 8.4, 6.2 Hz, 1H), 7.47 – 7.30 (m, 4H), 7.08 (d, J = 7.5 Hz, 1H), 6.65 (dd, J = 8.0, 3.5 Hz, 2H), 4.24 – 4.14 (m, 1H), 3.06 (t, J = 6.7 Hz, 2H), 2.17 – 1.92 (m, 4H), 1.42 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 199.60, 172.74, 147.11, 143.65, 138.35, 136.82, 135.83, 132.94, 128.61, 128.53, 127.99, 127.42, 121.40, 114.77, 105.30, 81.56, 56.75, 38.07, 32.11, 27.98, 20.50。

example 4: synthesis of 2d

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with stirrer and copper trifluoromethanesulfonate (0.02 mmol,7.2 mg) and chiral phosphine ligand L1 (0.022 mmol,16.2 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI levulinate (0.3 mmol,78.3 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). Transferring the mixed solution into a white light photoreactor, and irradiating for 60h at-10 ℃. After the reaction is finished, the target product 2d is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, 88% yield (29.0 mg), 96% ee (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/ethanol = 100/1).

HRMS (ESI): C₁₉H₂₄N₂O₃Na [M+Na]⁺Theoretical value: 351.1679, measurement: 351.1681.

¹H NMR (300 MHz, CDCl₃) δ 8.76 (dd, J = 4.2, 1.6 Hz, 1H), 8.06 (dd, J= 8.2, 1.6 Hz, 1H), 7.42 – 7.30 (m, 2H), 7.09 (d, J = 8.1 Hz, 1H), 6.69 – 6.59 (m, 2H), 4.20 (dd, J = 13.7, 7.4 Hz, 1H), 2.69 (t, J = 7.4 Hz, 2H), 2.38 – 2.16 (m, 2H), 2.15 (s, 3H), 1.42 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 207.81, 172.41, 147.22, 143.59, 138.37, 135.90, 128.62, 127.44, 121.46, 115.00, 105.45, 81.77, 55.88, 39.39, 30.11, 29.69, 27.98, 26.31。

example 5: synthesis of 2e

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,N-in dimethylformamide (1 mL)NBoc- γ -aminobutyric acid NHPI ester (0.2 mmol,69.6 mg) and triethylenediamine (0.1 mmol,11.2 mg). Transferring the mixed solutionIrradiating in a purple light photoreactor at-10 deg.C for 60 hr. After the reaction is finished, the target product 2e is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, yield 85% (35.3 mg), ee value 93% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 9/1).

HRMS (ESI): C₂₃H₃₄N₃O₄ [M+H]⁺Theoretical value: 416.2544, measurement: 416.2554.

¹H NMR (300 MHz, CDCl₃) δ 8.74 (dd, J = 4.2, 1.6 Hz, 1H), 8.05 (dd, J= 8.3, 1.6 Hz, 1H), 7.41 – 7.30 (m, 2H), 7.08 (d, J = 7.9 Hz, 1H), 6.62 (dd, J = 13.7, 8.1 Hz, 2H), 4.58 (br, 1H), 4.16 (dd, J = 14.8, 6.6 Hz, 1H), 3.19 (dd, J = 12.6, 6.3 Hz, 2H), 2.11 – 1.85 (m, 2H), 1.78 – 1.61 (m, 2H), 1.43 (d, J = 3.6 Hz, 18H). ¹³C NMR (75 MHz, CDCl₃) δ 172.68, 155.90, 147.14, 143.61, 138.33, 135.86, 128.60, 127.41, 121.42, 114.86, 105.35, 81.59, 79.11, 56.51, 40.20, 29.91, 28.36, 27.97, 26.32。

example 6: synthesis of 2f

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI cyclobutylformate (0.2 mmol,49.0 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the mixture is quenched by water, extracted by ethyl acetate, washed by saturated saline solution, dried by anhydrous sodium sulfate and concentrated under reduced pressure, and then passes through a silica gel column layerAnd (5) separating, separating and purifying to obtain the target product 2f, wherein the eluent is n-hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, yield 80% (25.0 mg), ee value 96% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 9/1).

HRMS (ESI): C₁₉H₂₅N₂O₂ [M+H]⁺Theoretical value: 313.1911, measurement: 313.1914.

¹H NMR (300 MHz, CDCl₃) δ 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.04 (dd, J= 8.3, 1.6 Hz, 1H), 7.36 (dt, J = 12.9, 6.1 Hz, 2H), 7.08 (t, J = 7.1 Hz, 1H), 6.63 (d, J = 7.4 Hz, 1H), 6.55 (t, J = 7.4 Hz, 1H), 4.04 (dd, J = 15.4, 7.0 Hz, 1H), 2.89 (h, J = 8.1 Hz, 1H), 2.25 – 1.78 (m, 6H), 1.40 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 172.21, 147.09, 144.29, 138.38, 135.84, 128.62, 127.43, 121.37, 114.69, 105.39, 81.24, 61.42, 38.42, 28.05, 25.63, 25.11, 18.19。

example 7: synthesis of 2g

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI cyclopentylcarboxylate (0.2 mmol,51.8 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the reaction product is subjected to water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and reduced pressure concentration, and then is separated and purified through silica gel column chromatography, wherein the eluent is n-hexane/ethyl acetate, and 2g of a target product is obtained. The structure and characterization data are as follows:

yellow liquid, yield 87% (28.4 mg), ee value 99% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 9/1).

HRMS (ESI): C₂₀H₂₇N₂O₂ [M+H]⁺Theoretical value: 327.2067, found 327.2078.

¹H NMR (300 MHz, CDCl₃) δ 8.74 (dd, J = 4.2, 1.7 Hz, 1H), 8.04 (dd, J= 8.3, 1.6 Hz, 1H), 7.40 – 7.29 (m, 2H), 7.06 (dd, J = 8.2, 0.8 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.61 (d, J = 8.6 Hz, 1H), 3.94 (t, J = 8.4 Hz, 1H), 2.53 – 2.36 (m, 1H), 2.02 – 1.90 (m, 1H), 1.90 – 1.76 (m, 1H), 1.76 – 1.63 (m, 4H), 1.62 – 1.49 (m, 2H), 1.40 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 173.02, 147.06, 144.27, 138.37, 135.83, 128.63, 127.45, 121.35, 114.60, 105.44, 81.14, 61.39, 43.13, 29.57, 29.24, 28.01, 25.40, 25.16。

Example 8: 2h Synthesis

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI ester of 2-indenecarboxylic acid (0.2 mmol,61.4 mg) and tetramethylethylenediamine (0.1 mmol,11.6 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product is obtained for 2 hours by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out by silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, yield 77% (28.9 mg), ee value 93% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 9/1).

HRMS (ESI): C₂₄H₂₇N₂O₂ [M+H]⁺Theoretical value: 375.2067, measurement:375.2064。

¹H NMR (300 MHz, CDCl₃) δ 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.05 (dd, J= 8.3, 1.6 Hz, 1H), 7.41 – 7.30 (m, 2H), 7.25 – 7.11 (m, 4H), 7.09 (dd, J = 8.2, 0.8 Hz, 1H), 6.72 (t, J = 9.2 Hz, 2H), 4.19 (dd, J = 8.9, 6.1 Hz, 1H), 3.28 – 3.03 (m, 5H), 1.38 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 172.36, 147.17, 143.93, 142.43, 142.33, 138.38, 135.87, 128.62, 127.41, 126.38, 124.53, 124.46, 121.43, 114.90, 105.51, 81.59, 60.64, 42.58, 36.13, 35.72, 27.95。

example 9: synthesis of 2i

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI cyclohexylcarboxylate (0.2 mmol,54.6 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2i is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, 88% yield (30.0 mg), 94% ee (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 9/1).

HRMS (ESI) C₂₁H₂₉N₂O₂ [M+H]⁺Theoretical value: 341.2224, measurement: 341.2226.

¹H NMR (300 MHz, CDCl₃) δ 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.03 (dd, J= 8.3, 1.6 Hz, 1H), 7.39 – 7.29 (m, 2H), 7.05 (dd, J = 8.2, 0.8 Hz, 1H), 6.69 – 6.62 (m, 2H), 3.95 (dd, J = 9.0, 6.1 Hz, 1H), 1.97 (d, J = 5.7 Hz, 2H), 1.83 – 1.76 (m, 3H), 1.67 (br, 1H), 1.41 (s, 9H), 1.35 – 1.16 (m, 5H). ¹³C NMR (75 MHz, CDCl₃) δ 172.46, 147.04, 144.28, 138.41, 135.82, 128.63, 127.44, 121.34, 114.40, 105.22, 81.26, 62.25, 41.16, 29.69, 29.38, 28.06, 26.24, 26.17, 26.14。

example 10: synthesis of 2j

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI ester of 1-benzyloxycarbonyl-4-piperidinecarboxylic acid (0.2 mmol,81.6 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). Transferring the mixed solution into a white light photoreactor, and irradiating for 60h at-10 ℃. After the reaction is finished, the target product 2j is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, yield 90% (42.7 mg), ee value 93% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 3/2).

HRMS (ESI): C₂₈H₃₄N₃O₄ [M+H]⁺Theoretical value: 476.2544, measurement: 476.2547.

¹H NMR (300 MHz, CDCl₃) δ 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.05 (dd, J= 8.3, 1.5 Hz, 1H), 7.41 – 7.27 (m, 7H), 7.08 (d, J = 7.7 Hz, 1H), 6.70 – 6.62 (m, 2H), 5.12 (s, 2H), 4.27 (br, 2H), 4.00 (dd, J = 9.1, 6.7 Hz, 1H), 2.82 (br, 2H), 2.19 – 2.04 (m, 1H), 1.96 (d, J = 12.8 Hz, 1H), 1.79 (d, J = 13.0 Hz, 1H), 1.53 – 1.45 (m, 2H), 1.40 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 171.78, 155.15, 147.20, 143.86, 138.37, 136.78, 135.88, 128.62, 128.44, 127.92, 127.82, 127.33, 121.46, 114.94, 105.37, 81.86, 67.01, 61.40, 44.02, 43.87, 39.53, 28.03。

example 11: synthesis of 2k

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI ester of tetrahydropyran-4-carboxylic acid (0.15 mmol,41.3 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixture was transferred to a blue light photoreactor and irradiated at zero degrees for 36 h. After the reaction is finished, the target product 2k is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification by silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, 91% yield (31.5 mg), 94% ee (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 4/1).

HRMS (ESI): C₂₀H₂₇N₂O₃ [M+H]⁺Theoretical value: 343.2016, measurement: 343.2019.

¹H NMR (300 MHz, CDCl₃) δ 8.74 (dd, J = 4.2, 1.7 Hz, 1H), 8.04 (dd, J= 8.3, 1.6 Hz, 1H), 7.40 – 7.30 (m, 2H), 7.08 (dd, J = 8.2, 0.8 Hz, 1H), 6.67 (d, J = 7.5 Hz, 2H), 4.07 – 3.94 (m, 3H), 3.50 – 3.36 (m, 2H), 2.27 – 2.11 (m, 1H), 1.88 (dd, J = 13.1, 1.9 Hz, 1H), 1.75 – 1.57 (m, 3H), 1.41 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 171.82, 147.12, 143.88, 138.35, 135.84, 128.59, 127.34, 121.41, 114.82, 105.34, 81.70, 67.87, 67.65, 61.71, 38.50, 29.53, 29.45, 28.02。

example 12: synthesis of 2l

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (1 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI 4, 4-Difluorocyclohexanecarboxylic acid ester (0.2 mmol,61.8 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (0.5 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the reaction product is subjected to water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and reduced pressure concentration, and then is separated and purified by silica gel column chromatography, wherein the eluent is n-hexane/ethyl acetate, and 2l of the target product is obtained. The structure and characterization data are as follows:

yellow liquid, 88% yield (33.2 mg), 94% ee (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 9/1).

HRMS (ESI): C₂₁H₂₇F₂N₂O₂ [M+H]⁺Theoretical value: 377.2035, measurement: 377.2039.

¹H NMR (300 MHz, CDCl₃) δ 8.76 (dd, J = 4.2, 1.7 Hz, 1H), 8.06 (dd, J= 8.3, 1.6 Hz, 1H), 7.42 – 7.30 (m, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.67 (t, J= 9.2 Hz, 2H), 4.02 (dd, J = 9.2, 6.3 Hz, 1H), 2.23 – 1.61 (m, 9H), 1.42 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 171.82, 147.24, 143.77, 138.39, 135.92, 128.65, 127.36, 121.50, 114.97, 105.38, 81.94, 60.94, 39.14, 33.27, 33.06, 32.96, 28.04, 25.71, 25.58, 25.48, 25.35. ¹⁹F NMR (282 MHz, CDCl₃) δ -91.95 (d, J = 235.6 Hz), -102.28 (d, J = 235.5 Hz)。

example 13: synthesis of 2m

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a solution with a stirring bar10mL dry reaction flask and adding four acetonitrile copper hexafluorophosphate (0.01 mmol,3.7 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg). Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI-1-adamantanecarboxylic acid ester (0.2 mmol,65.0 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixture was transferred to a blue light photoreactor and irradiated at 10 ℃ for 60 h. After the reaction is finished, the target product 2m is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification by silica gel column chromatography, wherein the eluent is n-hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, 74% yield (29.2 mg), 81% ee (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 9/1).

HRMS (ESI): C₂₅H₃₃N₂O₂ [M+H]⁺Theoretical value: 393.2537, measurement: 393.2547.

¹H NMR (300 MHz, CDCl₃) δ 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.03 (dd, J= 8.3, 1.7 Hz, 1H), 7.40 – 7.28 (m, 2H), 7.04 (dd, J = 8.1, 0.8 Hz, 1H), 6.84 (d, J = 10.0 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 3.76 (d, J = 9.9 Hz, 1H), 2.05 (d, J = 2.6 Hz, 3H), 1.91 (d, J = 12.5 Hz, 3H), 1.76 (d, J = 18.0 Hz, 9H), 1.39 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 171.54, 147.08, 144.72, 138.60, 135.78, 128.63, 127.44, 121.33, 114.27, 105.29, 81.21, 66.70, 39.25, 36.94, 36.57, 28.48, 28.15。

example 14: synthesis of 2n

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,NDimethylformamide (2 mL), stirring at room temperatureAdding into the above mixed solution with a syringe for 40min, and dissolvingN,NBicyclo [2.2.2 ] in dimethylformamide (1 mL)]Octane-1, 4-cyclohexanedicarboxylic acid monomethyl ester NHPI ester (0.3 mmol,107.1 mg) and triethylenediamine (0.1 mmol,11.2 mg). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2n is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, yield 81% (34.4 mg), ee value 84% (high performance liquid chromatography, CHIRALCEL OD-H column separation, n-hexane/isopropanol = 9/1).

HRMS (ESI): C₂₅H₃₃N₂O₄ [M+H]⁺Theoretical value: 425.2435, measurement: 425.2454.

¹H NMR (300 MHz, CDCl₃) δ 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.04 (dd, J= 8.3, 1.6 Hz, 1H), 7.41 – 7.28 (m, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.71 (d, J= 10.1 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 3.84 (d, J = 10.1 Hz, 1H), 3.65 (s, 3H), 1.91 – 1.75 (m, 9H), 1.76 – 1.66 (m, 3H), 1.37 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 178.19, 171.54, 171.16, 147.16, 144.30, 138.52, 135.84, 128.60, 127.36, 121.40, 114.69, 105.37, 81.47, 64.32, 60.39, 58.45, 53.41, 51.69, 38.64, 35.04, 28.15, 28.08, 27.41, 21.04, 18.42, 14.17。

example 15: synthesis of 2o

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI ester of 2, 2-dimethylbutyric acid (0.2 mmol, 52) in dimethylformamide (1 mL)2 mg) and triethylenediamine (0.1 mmol,11.2 mg). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2o is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification by silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, yield 81% (26.7 mg), ee value 97% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 50/1).

HRMS (ESI): C₂₀H₂₉N₂O₂ [M+H]⁺Theoretical value: 329.2224, measured value of f: 329.2224.

¹H NMR (300 MHz, CDCl₃) δ 8.74 (dd, J = 4.2, 1.6 Hz, 1H), 8.03 (dd, J= 8.3, 1.6 Hz, 1H), 7.40 – 7.29 (m, 2H), 7.05 (d, J = 8.1 Hz, 1H), 6.79 (d, J= 10.0 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 3.96 (d, J = 10.1 Hz, 1H), 1.55 (dd, J = 15.9, 7.4 Hz, 2H), 1.37 (s, 9H), 1.14 (d, J = 7.0 Hz, 6H), 0.94 (t, J = 7.5 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 172.20, 147.09, 144.53, 138.58, 135.76, 128.62, 127.45, 121.34, 114.41 105.23, 81.13, 63.94, 37.14, 32.44, 28.04, 23.78, 23.45, 8.30。

example 16: synthesis of 2p

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylacetamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI ester (0.2 mmol,71.8 mg) of 4-chlorophenoxyisobutyric acid in dimethylacetamide (1 mL) and triethylenediamine (0.1 mmol,11.2 mg). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, quenching with water, extracting with ethyl acetate, washing with saturated salt waterWashing, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating and purifying by silica gel column chromatography, wherein the eluent is n-hexane/ethyl acetate to obtain the target product 2 p. The structure and characterization data are as follows:

a colorless liquid, yield 84% (36.0 mg), ee value 86% (high performance liquid chromatography, CHIRALCEL OD-H column separation, n-hexane/isopropanol = 9/1).

HRMS (ESI): C₂₄H₂₈ClN₂O₃ [M+H]⁺Theoretical value: 427.1783, measurement: 427.1796.

¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 4.2, 1.6 Hz, 1H), 8.05 (dd, J= 8.3, 1.6 Hz, 1H), 7.43 – 7.30 (m, 2H), 7.26 – 7.14 (m, 3H), 7.13 – 7.06 (m, 1H), 7.05 – 6.96 (m, 2H), 6.71 (d, J = 7.5 Hz, 1H), 4.25 (d, J = 9.4 Hz, 1H), 1.52 (d, J = 6.8 Hz, 6H), 1.41 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 170.71, 153.07, 147.30, 143.95, 138.58, 135.76, 129.11, 129.00, 128.60, 127.34, 125.66, 121.45, 115.04, 105.52, 81.81, 81.72, 64.96, 27.98, 24.44, 24.41。

example 17: synthesis of 2q

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper tetrakisacetonitrile tetrafluoroborate (0.01 mmol,3.1 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NGemfibrozil NHPI ester (0.2 mmol,79.0 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2q is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, yield 75% (34.8 mg), ee value 94% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 95/5).

HRMS (ESI): C₂₉H₃₉N₂O₃ [M+H]⁺Theoretical value: 463.2955, measurement: 463.2966.

¹H NMR (300 MHz, CDCl₃) δ 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.04 (dd, J= 8.3, 1.6 Hz, 1H), 7.40 – 7.29 (m, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.98 (d, J= 7.4 Hz, 1H), 6.83 (d, J = 10.1 Hz, 1H), 6.66 (dd, J = 17.0, 7.6 Hz, 2H), 6.59 (s, 1H), 4.00 (d, J = 10.1 Hz, 1H), 3.92 (t, J = 6.4 Hz, 2H), 2.28 (s, 3H), 2.14 (s, 3H), 2.02 – 1.63 (m, 4H), 1.37 (s, 9H), 1.21 (d, J = 6.1 Hz, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 172.00, 156.97, 147.11, 144.44, 138.60, 136.40, 135.76, 130.21, 128.62, 127.43, 123.56, 121.36, 120.56, 114.56, 111.92, 105.29, 81.29, 68.27, 64.23, 36.92, 36.35, 31.58, 28.05, 24.37, 24.14, 23.93, 22.65, 21.37, 15.75, 14.12。

example 18: synthesis of 2r

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.02 mmol,14.7 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NOxaprozin NHPI ester (0.2 mmol,87.6 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2r is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, yield 85% (43.0 mg), ee value 90% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 4/1).

HRMS (ESI): C₃₂H₃₂N₃O₃ [M+H]⁺Theoretical value: 506.2438, measurement: 506.2453.

¹H NMR (300 MHz, CDCl₃) δ 8.71 (dd, J = 4.1, 1.5 Hz, 1H), 8.03 (dd, J= 8.2, 1.4 Hz, 1H), 7.66 – 7.59 (m, 2H), 7.55 (dd, J = 7.6, 1.7 Hz, 2H), 7.41 – 7.30 (m, 8H), 7.08 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 4.35 (dt, J = 13.0, 6.4 Hz, 1H), 3.11 (t, J = 7.8 Hz, 2H), 2.67 – 2.41 (m, 2H), 1.45 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 172.20, 162.47, 147.16, 145.25, 143.54, 138.38, 135.81, 135.08 132.52, 128.98, 128.57, 128.51, 128.32, 127.97, 127.89, 127.38, 126.40, 121.42, 114.96, 105.40, 81.92, 56.24, 29.78, 28.19, 28.01, 24.76。

example 19: synthesis of 2s

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NArtesunate NHPI ester (0.2 mmol,105.8 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product is obtained for 2s by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

brown green solid, melting point 60-61^oC, yield 80% (47.8 mg),>20:1d.r.（¹H NMR）。

HRMS (ESI): C₃₃H₄₅N₂O₈ [M+H]⁺theoretical value: 597.3170, fixed value: 597.3185.

¹H NMR (300 MHz, CDCl₃) δ 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.05 (dd, J= 8.3, 1.5 Hz, 1H), 7.41 – 7.31 (m, 2H), 7.09 (d, J = 7.7 Hz, 1H), 6.69 (d, J= 7.6 Hz, 1H), 6.63 (d, J = 9.0 Hz, 1H), 5.80 (d, J = 9.9 Hz, 1H), 5.45 (s, 1H), 4.22 (dd, J = 15.5, 6.7 Hz, 1H), 2.71 – 2.26 (m, 6H), 2.08 – 1.97 (m, 1H), 1.94 – 1.68 (m, 7H), 1.43 (s, 11H), 0.99 (dd, J = 15.0, 6.5 Hz, 6H), 0.80 (d, J = 7.1 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 172.20, 171.77, 147.15, 143.51, 138.37, 135.82, 128.58, 127.46, 121.39, 114.99, 108.06, 105.54, 104.42, 96.88, 96.07, 95.68, 91.95, 91.44, 82.40, 81.85, 80.08, 55.99, 51.50, 45.92, 45.56, 45.17, 41.24, 40.94, 37.22, 36.16, 35.28, 34.64, 34.50, 34.18, 34.03, 33.94, 31.68, 30.61, 27.98, 27.57, 25.92. 25.02, 24.53, 24.36, 22.72, 21.98, 21.94, 20.19, 18.77, 14.92, 12.05。

example 20: synthesis of 2t

Glycine derivative 1-AQ (0.1 mmol,25.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NDehydrocholic acid NHPI ester (0.2 mmol,109.4 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2t is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow solid, melting point 104-^oC, yield 85% (52.3 mg), 15.7:1d.r & (¹H NMR）。

HRMS (ESI): C₃₈H₅₁N₂O₅ [M+H]⁺Theoretical value: 615.3792, measurement: 615.3795.

¹H NMR (300 MHz, CDCl₃) δ 8.77 – 8.71 (m, 1H), 8.07 – 8.00 (m, 1H), 7.34 (dt, J = 14.4, 5.4 Hz, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.62 (t, J = 7.1 Hz, 2H), 4.10 (dd, J = 14.0, 6.3 Hz, 1H), 2.94 – 2.76 (m, 3H), 2.39 – 1.75 (m, 17H), 1.74 – 1.51 (m, 2H), 1.43 (s, 9H), 1.36 (s, 3H), 1.25 – 1.15 (m, 2H), 1.03 (s, 3H), 0.88 (d, J = 6.0 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 211.89, 209.00, 208.67, 172.90, 146.97, 143.66, 138.21, 135.68, 128.47, 127.32, 121.28, 114.48, 105.13, 81.19, 57.01, 56.71, 51.59 48.80, 46.64, 45.47, 45.34, 44.81, 42.63, 38.48, 36.34, 35.81, 35.67, 35.06, 31.01, 29.50, 27.91, 27.53, 24.98, 21.70, 18.83, 11.66。

example 21: synthesis of 2u

Glycine derivative 1-MQ (0.1 mmol,28.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L2 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI-isobutyrate (0.2 mmol,46.6 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2u is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, 88% yield (29.2 mg), 90% ee (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 2/1).

HRMS (ESI) C₁₉H₂₇N₂O₃ [M+H]⁺Theoretical value: 331.2016, measurement: 331.2030.

¹H NMR (300 MHz, CDCl₃) δ 8.79 (dd, J = 4.2, 1.7 Hz, 1H), 8.48 (dd, J= 8.4, 1.7 Hz, 1H), 7.38 (dd, J = 8.4, 4.2 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.27 (d, J = 8.9 Hz, 1H), 3.93 – 3.83 (m, 4H), 2.35 – 2.20 (m, 1H), 1.38 (s, 9H), 1.16 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 172.86, 147.76, 145.92, 139.06, 138.52, 130.61, 121.14, 120.57, 105.29, 104.99, 81.00, 63.50, 55.88, 31.46, 28.03, 19.32, 19.07。

example 22: 2v Synthesis

Glycine derivative 1-MQ (0.1 mmol,28.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L2 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI cyclobutylformate (0.2 mmol,49.0 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2v is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification by silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, 84% yield (28.6 mg), 90% ee (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 2/1).

HRMS (ESI) C₂₀H₂₇N₂O₃ [M+H]⁺Theoretical value: 343.2016, measurement: 343.2031.

¹H NMR (300 MHz, CDCl₃) δ 8.79 (dd, J = 4.2, 1.7 Hz, 1H), 8.48 (dd, J= 8.4, 1.6 Hz, 1H), 7.38 (dd, J = 8.4, 4.2 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 8.3 Hz, 1H), 6.13 (s, 1H), 4.00 (d, J = 8.5 Hz, 1H), 3.91 (s, 3H), 2.84 (dt, J = 16.7, 8.3 Hz, 1H), 2.26 – 1.83 (m, 6H), 1.37 (s, 9H). ¹³C NMR (75 MHz, CDCl3) δ 172.65, 147.76, 146.08, 138.99, 138.49, 130.65, 121.14, 120.56, 105.27, 105.09, 80.98, 62.25, 55.87, 38.44, 28.04, 25.83, 25.11, 18.22。

example 23: synthesis of 2w

Glycine derivative 1-MQ (0.1 mmol,28.8 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI ester of tetrahydropyran-4-carboxylic acid (0.2 mmol,55.0 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2w is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is n-hexane/ethyl acetate. The structure and characterization data are as follows:

yellow solid, melting point 77-78^oC, yield 85% (31.5 mg), ee value 85% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane/isopropanol = 2/1).

HRMS (ESI) C₂₁H₂₉N₂O₄ [M+H]⁺Theoretical value: 373.2125, measurement: 373.2125.

¹H NMR (300 MHz, CDCl₃) δ 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.49 (dd, J= 8.4, 1.5 Hz, 1H), 7.39 (dd, J = 8.4, 4.2 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.24 (s, 1H), 4.03 (d, J = 11.2 Hz, 2H), 3.92 (s, 4H), 3.51 – 3.37 (m, 2H), 2.16 (td, J = 15.7, 9.4 Hz, 1H), 1.92 (d, J = 13.2 Hz, 1H), 1.71 – 1.60 (m, 3H), 1.37 (s, 9H). ¹³C NMR (75 MHz, CDCl3) δ 172.33, 147.83, 146.19, 138.12, 130.72, 121.17, 120.65, 105.24, 105.15, 81.45, 67.97, 67.73, 62.62, 55.87, 38.54, 29.78, 29.58, 28.04。

example 24: synthesis of 2 ×

Glycine derivative 1-N-AQ (0.1 mmol,25.7 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI cyclopentylcarboxylate (0.2 mmol,51.8 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2x is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification by silica gel column chromatography, wherein the eluent is n-hexane/ethyl acetate. The structure and characterization data are as follows:

white solid, melting point 126-^oC, yield 82% (26.8 mg), ee value 94% (high performance liquid chromatography, CHIRALCEL OD-H column separation, n-hexane/isopropanol = 6/1).

HRMS (ESI) C₂₀H₂₈N₃O [M+H]⁺Theoretical value: 326.2227, measurement: 326.2243.

¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 4.2, 1.7 Hz, 1H), 8.11 (dd, J= 8.3, 1.6 Hz, 1H), 7.46 – 7.33 (m, 2H), 7.17 (dd, J = 8.2, 0.8 Hz, 1H), 6.65 (d, J = 7.2 Hz, 2H), 6.49 (d, J = 2.8 Hz, 1H), 3.57 (dd, J = 6.6, 3.3 Hz, 1H), 2.52 (dt, J = 15.7, 8.0 Hz, 1H), 1.99 – 1.88 (m, 1H), 1.88 – 1.69 (m, 3H), 1.69 – 1.46 (m, 4H), 1.29 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 172.53, 147.38, 144.08, 138.31, 136.16, 128.38, 127.65, 121.55, 115.92, 107.12, 64.39, 50.62, 43.21, 29.28, 28.89, 28.57, 25.43, 25.32。

example 25: synthesis of 2y

The glycine derivative 1-AQ-Leu (0.1 mmol,32.9 mg) was added to a 10mL dry reaction flask with a stirrer and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI cyclopentylcarboxylate (0.2 mmol,51.8 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2y is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification are carried out through silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, 84% yield (33.3 mg), 9:1d.r (¹H NMR）。

HRMS (ESI) C₂₃H₃₂N₃O₃ [M+H]⁺Theoretical value: 398.2438, measurement: 398.2456.

¹H NMR (300 MHz, CDCl₃) δ 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.10 (dd, J= 8.3, 1.5 Hz, 1H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 9.0 Hz, 0.09H), 7.01 (d, J = 8.6 Hz, 0.89H), 6.71 (d, J = 7.6 Hz, 0.09H), 6.59 (dd, J = 13.3, 5.5 Hz, 2H), 4.70 – 4.58 (m, 1H), 3.79 (dd, J = 6.5, 3.7 Hz, 1H), 3.73 (s, 0.25H), 3.70 (s, 2.74H), 2.57 (dd, J = 15.4, 7.9 Hz, 1H), 1.99 (dd, J = 10.2, 6.3 Hz, 1H), 1.90 – 1.54 (m, 8H), 1.42 – 1.24 (m, 2H), 0.79 (d, J = 6.5 Hz, 3H), 0.67 (d, J = 6.5 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 173.25, 173.17, 147.43, 143.69, 138.22, 136.10, 128.38, 127.38, 121.60, 116.03, 106.87, 63.29, 52.14, 50.09, 45.54, 43.03, 40.87, 29.27, 28.87, 25.87, 25.38, 24.50, 22.71, 21.46, 21.25。

example 26: synthesis of 2z

The glycine derivative 1-AQ-Phe (0.1 mmol,36.3 mg) was added to a 10mL dry reaction flask with a stirrer, and copper trifluoromethanesulfonate (0.01 mmol,3.6 mg) and chiral phosphine ligand L1 (0.011 mmol,8.1 mg) were added. Adding into an argon atmosphereN,N-dimethylformamide (2 mL), stirred at room temperature for 40min, and then dissolved in water by syringeN,NNHPI cyclopentylcarboxylate (0.2 mmol,51.8 mg) and triethylenediamine (0.1 mmol,11.2 mg) in dimethylformamide (1 mL). The mixed solution is transferred to a blue light photoreactor and irradiated for 60 hours at the temperature of minus 10 ℃. After the reaction is finished, the target product 2z is obtained by water quenching, ethyl acetate extraction, saturated saline washing, anhydrous sodium sulfate drying and decompression concentration, and then separation and purification by silica gel column chromatography, wherein the eluent is normal hexane/ethyl acetate. The structure and characterization data are as follows:

yellow liquid, yield 80% (34.6 mg),>20:1d.r.（¹H NMR）。

HRMS (ESI) C₂₆H₃₀N₃O₃ [M+H]⁺theoretical value: 432.2282, measurement: 432.2291.

¹H NMR (300 MHz, CDCl₃) δ 8.76 (dd, J = 4.2, 1.6 Hz, 1H), 8.13 (dd, J= 8.3, 1.5 Hz, 1H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.91 (t, J = 7.3 Hz, 1H), 6.67 (t, J = 7.6 Hz, 2H), 6.59 (d, J = 7.2 Hz, 2H), 6.49 (d, J = 7.8 Hz, 2H), 4.95 (dt, J = 8.8, 6.0 Hz, 1H), 3.75 (dt, J = 6.8, 3.2 Hz, 1H), 3.69 (s, 3H), 2.94 (qd, J = 13.8, 5.9 Hz, 2H), 2.59 – 2.44 (m, 1H), 1.98 – 1.43 (m, 8H). ¹³C NMR (75 MHz, CDCl₃) δ 173.00, 171.66, 147.25, 143.41, 138.09, 135.98, 135.19, 128.83, 128.38, 128.11, 127.62, 126.70, 121.57, 115.72, 106.39, 62.86, 52.14, 52.03, 42.87, 37.77, 29.21, 28.91, 25.32。