A method for synthesizing chiral gamma-keto acid ester compounds

Abstract

The application discloses a synthesis method of chiral gamma-keto acid ester compounds and belongs to the field of organic synthesis. Under a nitrogen atmosphere, a mixture of alpha-keto oxime ester 1, trans-cinnamaldehyde 2, azacyclic carbene catalyst NHC, potassium carbonate and a solvent is stirred at room temperature, then dry methanol is added to continue the stirring reaction, after the reaction is completed by monitoring by TLC point plate, the organic solvent is removed by rotary evaporation to obtain a crude product, and the target product 3 is obtained after separation and purification. The method has mild reaction conditions, excellent stereoselectivity, provides a practical method for obtaining a gamma-keto acid ester skeleton, and has potential value for the synthesis of natural products and bioactive molecules.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing chiral γ-keto ester compounds. Background Technology

[0002] Optically active γ-keto esters and their derivatives are indispensable core skeletal molecules in the field of organic synthesis. These structures are abundant in natural products, pharmaceuticals, and agrochemicals, such as the anti-inflammatory drug flubufen, the immunomodulatory lipid-lowering lead molecule esonarimod, and the natural product chizhine from Ganoderma lucidum. This structure is also a key building block in organic synthesis, possessing both ketone carbonyl and ester dicarbonyl functional groups. It can serve as a general modular building block for the rapid derivatization of various complex chiral molecules, and also has irreplaceable application value in the synthesis of intermediates in fine chemicals and agrochemicals. Currently, the retrosynthetic cleavage of γ-keto esters faces severe polarity mismatch problems, and the selection of substrates and catalysts is subject to many limitations. Furthermore, when catalysts need to simultaneously control multiple chiralities, the requirements for selectivity and reaction conditions are stringent; therefore, most methods can only construct a single type of chirality (central chirality or axial chirality), making it difficult to simultaneously control multiple chiralities.

[0003] γ-keto esters can serve as intermediates for the further construction of 5H-furan-2-one derivatives, and also for the construction of axially chiral phosphine ligands. The natural product (-)-Incrustoporin possesses inhibitory activity against human pathogenic fungi; the 5H-furan-2-one skeleton is the key pharmacodynamic group for its antibacterial and antiviral activities, and γ-keto esters are key intermediates in the synthesis of this active skeleton. On the other hand, axially chiral phosphine ligands play a crucial role in palladium-catalyzed asymmetric allylic alkylation reactions and are widely used in the asymmetric synthesis of pharmaceutical intermediates and natural products. Summary of the Invention

[0004] In light of the aforementioned research background, this invention provides a simple and efficient method for synthesizing chiral γ-keto esters. This method uses α-ketooxime esters as starting materials to obtain chiral γ-keto esters in a short time with a yield of 39-80%, an ee value of 94-99%, and a dr value >20:1.

[0005] The present invention discloses a method for synthesizing chiral γ-keto ester compounds. Under a nitrogen atmosphere, a mixture of α-ketooxime ester 1, trans-cinnamaldehyde 2, nitrogen heterocyclic carbene catalyst NHC, potassium carbonate, and solvent is stirred at room temperature for 12 hours. Dry methanol is then added, and stirring continues for another 12 hours. After the reaction is complete as monitored by TLC, the organic solvent is removed by rotary evaporation to obtain a crude product, which is then separated and purified to obtain the target product 3.

[0006] The nitrogen heterocyclic carbene catalyst NHC is (5AS,10BR)-2-(2,4,6-triisopropylphenyl)-4,5A,6,10B-tetrahydroindo[2,1-B][1,2,4]triazolo[4,3-D][1,4]oxazine-2-onium tetrafluoroborate.

[0007] The solvent is redistilled toluene.

[0008] Furthermore, the molar ratio of α-ketooxime ester 1 to trans-cinnamaldehyde 2 is 1:2; the molar ratio of α-ketooxime ester 1 to nitrogen heterocyclic carbene catalyst NHC is 1:0.05; and the molar ratio of α-ketooxime ester 1 to potassium carbonate is 1:3.

[0009] Furthermore, the separation and purification are carried out by silica gel column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1.

[0010] The above-mentioned reaction of the present invention is carried out in a nitrogen atmosphere.

[0011] The reaction route of this invention is shown below:

[0012] ;

[0013] R and R′ are each independently selected from one or more of H, C1-C6 alkyl, alkynyl, halogen, aryl, and trifluoromethyl.

[0014] Furthermore, the starting material α-ketooxime ester 1 is selected from one of the following structures:

[0015] .

[0016] The starting material, trans-cinnamaldehyde 2, is selected from one of the following structures:

[0017] .

[0018] The starting material of this invention, trans-cinnamaldehyde, is readily available. Chiral γ-keto esters are synthesized via an asymmetric ring-opening reaction. The reaction conditions are mild, no transition metals or organometallic reagents are used, and the reaction exhibits excellent stereoselectivity. This reaction can yield a series of chiral γ-keto esters.

[0019] The target product 4 of this invention can be used as an intermediate to further synthesize 5H-furan-2-one derivatives. This carbon core structure is present in the natural product (-)-Incrustoporin. Product 4 can also be further synthesized into axially chiral phosphine ligand 5, which has wide applications in asymmetric allylation reactions. The conditions and procedures for the asymmetric allylation reaction are those conventional in the art.

[0020] Detailed Implementation

[0021]

[0022] Example 1:

[0023] Under nitrogen protection, α-ketooxime ester 1a (21.6 mg, 0.05 mmol, 1.0 equivalent), p-methylcinnamaldehyde 2a (14.6 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 3a (13.9 mg, 70% yield, 98% ee, >20:1 dr, yellow liquid).

[0024] 1 ¹H NMR (600 MHz, deuterated chloroform) δ 7.84 – 7.80 (m, 1H), 7.60 – 7.55 (m, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.34 – 7.29 (m, 2H), 7.03 (d, J = 7.9 Hz, 2H), 6.99 – 6.94 (m, 2H), 4.89 (dd, J = 9.0, 5.7 Hz, 1H), 3.58 (s, 3H), 3.09 (dd, J = 16.9, 9.0 Hz, 1H), 2.56 (dd, J = 16.9, 5.7Hz, 1H). 2.28 (s, 3H), 1.90 (s, 3H), 1.38 (s, 3H). 13C10 NMR (151 MHz, deuterated chloroform) δ 200.5, 172.1, 143.2, 137.32, 137.28, 137.2, 136.7, 134.0, 133.9, 133.8, 129.8, 129.7, 128.31, 128.28, 127.5, 127.1, 118.2, 113.7, 51.8, 51.3, 37.8, 21.0, 19.7, 19.0. HRMS (ESI) m / z: Calcd for C10 NMR. 27 H 25 NO3Na [M+Na] + : 434.1727; Found 434.1733. HPLC conditions: Chiral column (Shanghai Daicel) ID, isopropanol / hexane = 10:90, flow rate: 1.0 mL / min, λ = 254 nm; t R = 20.9 min (main peak), 28.0 min (secondary peak). = +184.6 (c 1.0,CH2Cl2).

[0025] Example 2:

[0026] Under nitrogen protection, α-ketooxime ester 1a (21.6 mg, 0.05 mmol, 1.0 equivalent), p-chlorocinnamaldehyde 2b (16.6 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 3b (14.9 mg, 69% yield, 96% ee, >20:1 dr, yellow liquid).

[0027] 1¹H NMR (500 MHz, deuterated chloroform) δ 7.82 – 7.76 (m, 1H), 7.61 – 7.56 (m, 1H), 7.46 – 7.43 (m, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.36 – 7.31 (m, 2H), 7.23– 7.17 (m, 2H), 7.06 – 7.01 (m, 2H), 4.90 (dd, J = 8.6, 6.1 Hz, 1H), 3.59 (s, 3H), 3.06 (dd, J = 16.9, 8.6 Hz, 1H), 2.57 (dd, J = 16.9, 6.1 Hz, 1H). 1.91 (s, 3H), 1.41 (s, 3H). 13 C10 NMR (151 MHz, deuterated chloroform) δ 200.2, 171.7, 143.0, 137.5, 137.12, 137.06, 136.7, 135.6, 134.0, 133.9, 133.6, 129.9, 129.8, 129.2, 128.4, 127.6, 126.9, 118.2, 113.7, 51.9, 51.0, 37.6, 19.7, 19.0. HRMS(ESI) m / z: Calcd for C10 NMR. 26 H 22 ClNO3Na [M+Na] + : 454.1181; Found 454.1188. HPLC conditions: chiral column (Shanghai Daicel) ID, isopropanol / hexane = 10:90, flow rate: 1.0 mL / min, λ = 254 nm; t R =20.7 min (main peak), 24.5 min (secondary peak). = +140.0 (c 1.0, CH2Cl2).

[0028] Example 3:

[0029] Under nitrogen protection, α-ketooxime ester 1a (21.6 mg, 0.05 mmol, 1.0 equivalent), p-bromocinnamaldehyde 2c (21.0 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 3c (15.0 mg, 63% yield, 96% ee, >20:1 dr, yellow liquid).

[0030] 1 ¹H NMR (600 MHz, deuterated chloroform) δ 7.79 (d, J = 7.7 Hz, 1H), 7.61 – 7.55 (m, 1H), 7.46 – 7.43 (m, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.37 – 7.31 (m, 4H), 6.98 (d, 2H), 4.89 (dd, J = 8.6, 6.1 Hz, 1H), 3.59 (s, 3H), 3.06 (dd, J = 17.0, 8.6 Hz, 1H), 2.57 (dd, J = 17.0, 6.1 Hz, 1H), 1.91 (s, 3H), 1.41 (s, 3H). 13 C10 NMR (151 MHz, deuterated chloroform) δ 200.1, 171.7, 143.0, 137.5, 137.1, 137.0, 136.7, 136.1, 134.04, 133.94, 132.1, 130.2, 129.9, 128.4, 127.6, 126.9, 121.7, 118.2, 113.7, 51.9, 51.1, 37.5, 19.7, 19.0. HRMS (ESI) m / z: Calcd for C10 NMR. 26 H 22 BrNO3Na [M+Na] + : 498.0676; Found 498.0685. HPLC conditions: chiral column (Shanghai Daicel) ID, isopropanol / hexane = 10:90, flow rate: 1.0 mL / min, λ = 254 nm; tR = 22.1 min (main peak), 26.6 min (secondary peak). = +166.3 (c 1.0, CH2Cl2).

[0031] Example 4:

[0032] Under nitrogen protection, α-ketooxime ester 1a (21.6 mg, 0.05 mmol, 1.0 equivalent), p-trifluoromethylcinnamaldehyde 2d (20.0 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 3d (13.0 mg, 56% yield, 96% ee, >20:1 dr, yellow liquid).

[0033] 1 ¹H NMR (500 MHz, deuterated chloroform) δ 7.81 (d, J = 7.6 Hz, 1H), 7.61 – 7.57 (m, 1H), 7.52 – 7.44 (m, 3H), 7.44 – 7.39 (m, 1H), 7.36 – 7.31 (m, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.01 (dd, J = 8.6, 6.1 Hz, 1H), 3.60 (s, 3H), 3.12 (dd, J = 17.0, 8.6 Hz, 1H), 2.61 (dd, J = 17.0, 6.1 Hz, 1H), 1.91 (s, 3H), 1.35 (s, 3H). 13C NMR (126 MHz, deuterated chloroform) δ 199.9, 171.6, 142.8, 141.1, 137.6, 137.1, 137.0, 136.7, 134.2, 133.9, 123.0 (q, J = 32.8 Hz), 129.9, 128.9, 127.69, 127.67 (q, J = 220.9 Hz), 125.9 (q, J = 3.7 Hz), 118.2, 113.7, 52.0, 51.5, 37.5, 19.7, 18.9. 19 F NMR (471 MHz, deuterated chloroform) δ -62.66. HRMS (ESI) m / z:Calcd for C 27 H 22 F3NO3Na [M+Na] + : 488.1444; Found 488.1448. HPLC conditions: Chiral column (Shanghai Daicel) IB, isopropanol / hexane = 10:90, flow rate: 1.0 mL / min, λ = 254 nm; t R = 10.4 min (secondary peak), 11.4 min (main peak). = +119.1 (c 1.0, CH2Cl2).

[0034] Example 5:

[0035] Under nitrogen protection, α-ketooxime ester 1a (21.6 mg, 0.05 mmol, 1.0 equivalent), p-phenylcinnamaldehyde 2e (20.8 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 3e (13.0 mg, 55% yield, 99% ee, >20:1 dr, white solid).

[0036] 1¹H NMR (600 MHz, deuterated chloroform) δ 7.89 (dd, J = 7.3, 1.8 Hz, 1H), 7.59 (dd, J = 7.0, 2.0 Hz, 1H), 7.54 – 7.51 (m, 2H), 7.46 – 7.40 (m, 6H), 7.37 – 7.29 (m, 3H), 7.17 – 7.12 (m, 2H), 4.99 (dd, J = 9.0, 5.6 Hz, 1H), 3.61 (s, 3H), 3.17 (dd, J = 17.0, 9.1 Hz, 1H), 2.64 (dd, J = 17.0, 5.6 Hz, 1H), 1.91 (s, 3H). 1.34 (s, 3H). 13 C10 NMR (151 MHz, deuterated chloroform) δ 200.3, 172.0, 143.0, 140.5, 140.4, 137.38, 137.35, 137.2, 136.7, 136.0, 133.9, 129.8, 128.9, 128.8, 128.4, 127.7, 127.53, 127.46, 127.0, 126.9, 118.3, 113.9, 51.9, 51.4, 37.6, 19.7, 18.9. HRMS (ESI) m / z: Calcd for C10 32 H 28 NO3 [M+H] + : 474.2064; Found474.2066. HPLC conditions: chiral column (Shanghai Daicel) ID, isopropanol / hexane = 20:80, flow rate: 1.0 mL / min, λ = 254 nm; t R = 23.2 min (main peak), 29.4 min (secondary peak). = +230.2 (c 1.0, CH2Cl2).

[0037] Example 6:

[0038] Under nitrogen protection, α-ketooxime ester 1a (21.6 mg, 0.05 mmol, 1.0 equivalent), p-acetylenecinnamaldehyde 2f (15.6 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 3f (16.8 mg, 80% yield, 96% ee, >20:1 dr, yellow liquid).

[0039] 1 H NMR (400 MHz, deuterated chloroform) δ 7.83 – 7.77 (m, 1H), 7.61 – 7.56 (m,1H), 7.46 – 7.43 (m, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.36 – 7.30 (m, 4H), 7.06(d, J = 8.3 Hz, 2H), 4.93 (dd, J = 8.7, 6.0 Hz, 1H), 3.59 (s, 3H), 3.09 (dd,J = 16.9, 8.7 Hz, 1H), 3.06 (s, 1H), 2.58 (dd, J = 16.9, 6.0 Hz, 1H), 1.91(s, 3H), 1.39 (d, J = 0.8 Hz, 3H). 13 C10 NMR (151 MHz, deuterated chloroform) δ 200.0, 171.7, 143.0, 137.9, 137.5, 137.11, 137.08, 136.7, 134.0, 133.9, 132.7, 129.8, 128.5, 128.4, 127.6, 127.0, 121.5, 118.2, 113.7, 83.0, 77.8, 51.9, 51.6, 37.5, 19.7, 19.0. HRMS (ESI) m / z: Calcd for C10 28 H 23 NO3Na [M+Na] +: 444.1571; Found 444.1584. HPLC conditions: chiral column (Shanghai Daicel) ID, isopropanol / hexane = 15:85, flow rate: 1.0 mL / min, λ = 254 nm; t R = 16.8 min (main peak), 19.8 min (secondary peak). = +118.7 (c 1.0,CH2Cl2).

[0040] Example 7:

[0041] Under nitrogen protection, α-ketooxime ester 1a (21.6 mg, 0.05 mmol, 1.0 equivalent), 3-fluorocinnamaldehyde 2 g (15.0 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give 3 g of the target product (12.5 mg, 60% yield, 99% ee, >20:1 dr, yellow liquid).

[0042] 1 ¹H NMR (600 MHz, deuterated chloroform) δ 7.83 (dd, J = 7.7, 1.4 Hz, 1H), 7.60 –7.56 (m, 1H), 7.46 – 7.44 (m, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.35 – 7.31 (m, 2H), 7.23 – 7.18 (m, 1H), 6.94 – 6.88 (m, 2H), 6.76 – 6.72 (m, 1H), 4.93 (dd, J = 8.9, 5.8 Hz, 1H), 3.60 (s, 3H), 3.09 (dd, J = 17.0, 8.9 Hz, 1H), 2.58 (dd, J = 17.0, 8.9 Hz, 1H) J = 17.0, 5.8 Hz, 1H), 1.92 (s, 3H), 1.39 (s, 3H). 13C NMR (151 MHz, deuterated chloroform) δ 199.9, 171.7, 162.9 (d, J = 247.2 Hz), 142.9, 139.5 (d, J = 7.3 Hz), 137.5, 137.1, 137.0, 136.7, 134.1, 133.9, 130.5 (d, J = 8.2 Hz), 129.8, 128.4, 127.6, 126.9, 124.4 (d, J = 2.9 Hz), 118.2, 115.3 (d, J = 22.1 Hz), 114.7 (d, J = 20.9 Hz), 113.8, 51.9, 51.3, 37.7, 19.7, 18.9. 19 F NMR (565 MHz, deuterated chloroform) δ -111.63. HRMS (ESI) m / z: Calcd for C 26 H 22 FNO3Na [M+Na] + : 438.1476; Found 438.1484. HPLC conditions: Chiral column (Shanghai Daicel) ID, isopropanol / hexane = 10:90, flow rate: 1.0 mL / min, λ = 254 nm; t R = 10.4 min (secondary peak), 13.1 min (main peak). = +130.9 (c 1.0,CH2Cl2).

[0043] Example 8:

[0044] Under nitrogen protection, α-ketooxime ester 1a (21.6 mg, 0.05 mmol, 1.0 equivalent), 3-chlorocinnamaldehyde 2h (16.6 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 3h (15.5 mg, 72% yield, 98% ee, >20:1 dr, brown solid).

[0045] 1¹H NMR (600 MHz, deuterated chloroform) δ 7.85 (d, J = 7.5 Hz, 1H), 7.62 – 7.56 (m, 1H), 7.43 (dt, J = 15.2, 7.6 Hz, 2H), 7.37 – 7.30 (m, 2H), 7.22 – 7.19 (m, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.03 – 6.98 (m, 2H), 4.92 (dd, J = 9.0, 5.7 Hz, 1H), 3.61 (d, J = 1.1 Hz, 3H), 3.11 (dd, J = 17.2, 9.1 Hz, 1H), 2.56 (dd, J = 17.0, 5.6 Hz, 1H), 1.91 (s, 3H), 1.36 (s, 3H). 13 C10 NMR (151 MHz, deuterated chloroform) δ 199.8, 171.7, 142.8, 139.0, 137.5, 137.1, 136.9, 136.7, 134.8, 134.1, 134.0, 130.3, 129.8, 128.4, 128.2, 127.9, 127.6, 127.0, 126.9, 118.2, 113.9, 51.9, 51.2, 37.7, 19.7, 18.8. HRMS (ESI) m / z: Calcd for C10 NMR. 26 H 22 ClNO3Na [M+Na] + :454.1181; Found 454.1189. HPLC conditions: Chiral column (Shanghai Daicel) IB, isopropanol / hexane = 10:90, flow rate: 1.0 mL / min, λ = 254 nm; t R = 10.2 min (secondary peak), 11.0 min (main peak). = +115.4(c 1.0, CH2Cl2).

[0046] Example 9:

[0047] Under nitrogen protection, α-ketooxime ester 1a (21.6 mg, 0.05 mmol, 1.0 equivalent), 3,4-dichlorocinnamaldehyde 2i (20.1 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 3i (16.3 mg, 70% yield, 96% ee, >20:1 dr, yellow liquid).

[0048] 1 H NMR (600 MHz, deuterated chloroform) δ 7.80 (dd, J = 7.7, 1.4 Hz, 1H), 7.59 (dd, J = 7.4, 1.5 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.39 – 7.33 (m, 2H), 7.31 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.3, 2.1 Hz, 1H), 4.89 (dd, J = 8.4, 6.2 Hz, 1H), 3.60 (s, 3H),3.05 (dd, J = 17.1, 8.4 Hz, 1H), 2.57 (dd, J = 17.0, 6.2 Hz, 1H), 1.92 (s,3H), 1.44 (s, 3H). 13 C10 NMR (151 MHz, deuterated chloroform) δ 199.6, 171.5, 142.8, 137.7, 137.3, 136.91, 136.89, 136.7, 134.3, 134.0, 133.0, 132.0, 130.9, 130.1, 129.9, 128.5, 128.1, 127.7, 126.8, 118.2, 113.8, 52.0, 50.7, 37.6, 19.7, 19.0. HRMS (ESI) m / z: Calcd for C10 26 H 21Cl2NO3Na [M+Na] + : 488.0791; Found 488.0796. HPLC conditions: Chiral column (Shanghai Daicel) IB, isopropanol / hexane = 10:90, flow rate: 0.8 mL / min, λ = 254 nm; t R = 14.9 min (secondary peak), 15.8 min (main peak). = +142.0 (c 1.0,CH2Cl2).

[0049] Example 10:

[0050] Under nitrogen protection, α-ketooxime ester 1a (21.6 mg, 0.05 mmol, 1.0 equivalent), 3-(naphthyl-2-yl)propenal 2j (18.2 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 3j (14.1 mg, 63% yield, 97% ee, >20:1 dr, yellow liquid).

[0051] 1 ¹H NMR (500 MHz, deuterated chloroform) δ 7.90 – 7.86 (m, 1H), 7.80 – 7.75 (m, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.69 – 7.64 (m, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.51 – 7.48 (m, 1H), 7.48 – 7.43 (m, 2H), 7.42 – 7.36 (m, 2H), 7.32 (t, J = 7.7 Hz, 1H), 7.25 – 7.18 (m, 2H), 5.10 (dd, J = 8.9, 5.7 Hz, 1H), 3.60 (s, 3H), 3.21 (dd, J = 17.0, 8.9 Hz, 1H), 2.68 (dd, J = 17.0, 5.7 Hz, 1H), 1.88 (s, 3H), 1.14 (s, 3H). 13C NMR (126 MHz, deuterated chloroform) δ 200.2, 172.0, 143.0, 137.4, 137.3, 137.1, 136.7, 134.4, 133.79, 133.78, 133.5, 132.6, 129.8, 128.9, 128.3, 127.8, 127.6, 127.49, 127.47, 127.0, 126.29, 126.27, 126.2, 118.3, 113.9, 51.9, 51.8, 37.9, 19.6, 18.8. HRMS (ESI) m / z: Calcd for C 30 H 25 NO3Na [M+Na] + : 470.1727; Found 470.1733. HPLC conditions: Chiral column (Shanghai Daicel) IB, isopropanol / hexane = 10:90, flow rate: 1.0 mL / min, λ = 254 nm; t R = 14.2 min (main peak), 17.0 min (secondary peak). = +187.8 (c 1.0, CH2Cl2).

[0052] Example 11:

[0053] Under nitrogen protection, α-ketooxime ester 1b (23.0 mg, 0.05 mmol, 1.0 equivalent), trans-cinnamaldehyde (13.2 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 3k (9.8 mg, 46% yield, 96% ee, >20:1 dr, yellow liquid).

[0054] 1¹H NMR (500 MHz, deuterated chloroform) δ 7.84 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.36 – 7.30 (m, 2H), 7.29 – 7.21 (m, 3H), 7.17 – 7.05 (m, 2H), 5.16 – 4.77 (m, 1H), 3.65 (s, 3H), 3.19 (dd, J = 16.9, 9.1 Hz, 1H), 2.62 (dd, J = 17.0, 5.6 Hz, 1H), 2.40 (s, 3H), 2.28 (s, 3H), 1.84 (s, 3H), 1.20 (s, 3H). 13 C10 NMR (126 MHz, deuterated chloroform) δ 200.2, 172.1, 143.4, 141.9, 141.6, 137.4, 137.3, 136.0, 135.8, 135.5, 129.6, 129.2, 128.9, 128.8, 128.5, 127.4, 126.8, 118.7, 111.7, 51.8, 51.6, 37.7, 21.0, 20.9, 15.9, 15.4. HRMS (ESI) m / z: Calcd for C10 NMR. 28 H 27 NO3Na [M+Na] + : 448.1884; Found 448.1882. HPLC conditions: chiral column (Shanghai Daicel) IB, isopropanol / hexane = 10:90, flow rate: 1.0 mL / min, λ = 254 nm; t R = 8.2 min (secondary peak), 12.7 min (main peak). = +48.5 (c 1.0, CH2Cl2).

[0055] Example 12:

[0056] Under nitrogen protection, α-ketooxime ester 1c (23.0 mg, 0.05 mmol, 1.0 equivalent), trans-cinnamaldehyde (13.2 mg, 0.10 mmol, 2.0 equivalent), NHC (1.3 mg, 5 mol%), potassium carbonate (20.7 mg, 0.15 mmol, 3.0 equivalent), and 1.0 mL of redistilled toluene were added to a Schlenk reaction tube, and the mixture was stirred at 25 °C for 12 hours. Then, dry methanol (25 μL) was added, and stirring continued for another 12 hours. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 3k (8.3 mg, 39% yield, 94% ee, >20:1 dr, yellow liquid).

[0057] 1 ¹H NMR (500 MHz, deuterated chloroform) δ 7.61 (s, 1H), 7.36 (s, 1H), 7.24 – 7.19 (m, 4H), 7.15 – 7.07 (m, 3H), 4.92 (dd, J = 8.8, 5.9 Hz, 1H), 3.59 (s, 3H), 3.11 (dd, J = 16.9, 8.8 Hz, 1H), 2.59 (dd, J = 16.9, 5.9 Hz, 1H), 2.39 (s, 3H), 2.37 (s, 3H), 1.85 (s, 3H), 1.29 (s, 3H). 13 C10 NMR (126 MHz, deuterated chloroform) δ 200.6, 172.1, 140.3, 137.8, 137.4, 137.3, 137.2, 137.1, 134.8, 134.6, 133.9, 130.2, 129.0, 128.5, 127.7, 127.5, 118.5, 113.7, 51.8, 51.6, 37.7, 21.3, 20.9, 19.6, 18.9. HRMS (ESI) m / z: Calcd for C10 NMR. 28 H 27 NO3Na [M+Na] + : 448.1884; Found 448.1888. HPLC conditions: chiral column (Shanghai Daicel) ID, isopropanol / hexane = 10:90, flow rate: 1.0 mL / min, λ = 254 nm; t R = 6.6 min (secondary peak), 9.4 min (main peak). = +124.4 (c 1.0,CH2Cl2).

[0058] Example 13:

[0059] Under nitrogen protection, γ-keto ester 3e (23.7 mg, 0.05 mmol, 1.0 equivalent), TfOH (15.0 mg, 0.1 mmol, 2.0 equivalent), and 1.0 mL of redistilled acetonitrile were added to a Schlenk reaction tube, and the mixture was stirred at 85 °C for 12 hours. The reaction was monitored by TLC until the starting material was completely reacted. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the target product 4e (15.4 mg, 70% yield, 95% ee, dr = 2.8:1, white solid).

[0060]

[0061] 1 ¹H NMR (500 MHz, deuterated chloroform) δ 7.69 (d, J = 7.7 Hz, 1H), 7.65 – 7.60 (m, 3H), 7.60 – 7.55 (m, 4H), 7.47 (d, J = 7.7 Hz, 1H), 7.45 – 7.39 (m, 3H), 7.39 – 7.37 (m, 1H), 7.30 – 7.25 (m, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.58 (d, J = 1.6 Hz, 1H), 5.90 (d, J = 1.6 Hz, 1H), 2.19 (s, 3H), 2.07 (s, 3H). 13 C10 NMR (126 MHz, deuterated chloroform) δ 172.5, 165.1, 144.1, 141.7, 140.4, 139.6, 138.2, 137.1, 135.4, 133.5, 131.9, 130.7, 129.5, 128.9, 128.7, 128.5, 128.1, 128.0, 127.6, 127.1, 125.6, 118.5, 114.7, 112.6, 81.4, 20.3, 20.1. HRMS (ESI) m / z: Calcd for C10 NMR 31 H 23 NO3Na [M+Na] +: 464.1621; Found 464.1626. HPLC conditions: chiral column (Shanghai Daicel) AD, isopropanol / hexane = 20:80, flow rate: 1.0 mL / min, λ = 254 nm; t R = 17.2 min (secondary peak), 21.5 min (main peak). = +38.1 (c 1.0, CH2Cl2).

[0062] Example 14:

[0063] Under nitrogen protection, compound 4e, tetraphenyldiphosphine, nickel dichlorotriphenylphosphine, potassium tert-butoxide, and 1,4-dioxane were added to a Schlenk reaction tube, and the reaction was carried out at 90 °C. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain the target product 5e.

[0064] Under nitrogen protection, benzyl acetone, benzylamine, allyl palladium chloride dimer [Pd(C3H5)Cl]2, compound 5e, cesium carbonate, and tetrahydrofuran were added to a Schlenk reaction tube, and the reaction was carried out at 0°C. The reaction was monitored by TLC until complete. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain the target allyl alkylated product (yield 91%, 86% ee). The synthesis method of HDAC inhibitors is described in the Journal of American Chemical Society (2024) 146 (43): 29857–29864. The allyl alkylated product obtained in this example can be used as a starting material for the synthesis of HDAC inhibitors.

[0065]

[0066]

Claims

1. A method for synthesizing chiral γ-keto ester compounds, characterized in that: Under a nitrogen atmosphere, a mixture of α-ketooxime ester 1, trans-cinnamaldehyde 2, nitrogen heterocyclic carbene catalyst NHC, potassium carbonate, and solvent was stirred at room temperature. Dry methanol was then added, and the reaction was continued with stirring. After the reaction was completed by TLC, the organic solvent was removed by rotary evaporation to obtain the crude product. After separation and purification, the target product 3 was obtained. The synthesis route is shown below: ； The starting material α-ketooxime ester 1 is selected from one of the compounds shown in the following structures: ； The starting material, trans-cinnamaldehyde 2, is selected from one of the compounds shown in the following structures: ； The nitrogen heterocyclic carbene catalyst NHC is (5AS,10BR)-2-(2,4,6-triisopropylphenyl)-4,5A,6,10B-tetrahydroindo[2,1-B][1,2,4]triazolo[4,3-D][1,4]oxazine-2-onium tetrafluoroborate.

2. The method according to claim 1, characterized in that: The solvent is redistilled toluene.

3. The method according to claim 1, characterized in that: The molar ratio of α-ketooxime ester 1 to trans-cinnamaldehyde 2 is 1:

2.

4. The method according to claim 1, characterized in that: The molar ratio of α-ketooxime ester 1 to nitrogen-containing heterocyclic carbene catalyst NHC is 1:0.

05.

5. The method according to claim 1, characterized in that: The molar ratio of α-ketooxime ester 1 to potassium carbonate is 1:

3.

6. The method according to claim 1, characterized in that: The separation and purification were carried out by silica gel column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1.

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