A total synthesis method of valerine and antofen

Abstract

This invention discloses a total synthetic method for valerine and antofen. The method involves using 3,4-dimethoxyphenylacetylpyrrolidineacetic acid and 4-methoxyphenylacetylpyrrolidineacetic acid as starting materials, reacting them in the presence of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine to generate a Weinreb amide intermediate. This intermediate then reacts with the Grignard reagent 3,4-dimethoxyphenyl magnesium bromide to form a Weinreb ketone, generating valerine and antofen intermediates. Further, photocyclization and dehydrogenation reactions occur under light irradiation, followed by reduction reactions in the presence of lithium aluminum hydride to obtain valerine and antofen. This method for synthesizing valerine and antofen has advantages such as simple operation, short route, mild reaction conditions, and low production cost. Furthermore, the total synthetic route does not use metal catalysts, making it environmentally friendly. The yield of each step is above 70%, resulting in a high product yield.

Description

Technical Field

[0001] This invention belongs to the field of heterocyclic compound synthesis technology, specifically relating to a total synthesis method for phenanthrene-indolizidine alkaloids. Background Technology

[0002] Phenantheroindolithidine alkaloids are an important class of alkaloids widely distributed in plants of the Asclepiadaceae, Moraceae, Acanthaceae, and Lauraceae families. These alkaloids not only possess significant antitumor activity but also exhibit excellent biological activities such as antiviral, anti-inflammatory, and inhibition of biological protein synthesis. Valerianine and antofen are representative compounds of the phenantheroindolithidine class.

[0003] The alkaloid *Cephalotaxus fortunei* is mainly found in plants of the *Cephalotaxus* genus, including *Cephalotaxus fortunei* var. *ovoidea*, *Cephalotaxus fortunei* var. *dense-flowering*, and *Cephalotaxus fortunei* var. *tancas*. It was first isolated from *Cephalotaxus fortunei* var. *ovoidea* and was initially used primarily to treat asthma and diarrhea. *Cephalotaxus fortunei* alkaloids possess excellent physiological effects, exhibiting significant antitumor activity, as well as anti-inflammatory, anti-leukemic, antimicrobial, and anti-insect / antibacterial activities. Antofen, an alkaloid widely found in *Cephalotaxus fortunei* var. *forestry* in arid and sandy desert areas of Northwest my country, shows significant inhibitory concentration (IC50) against common cancer cells (breast cancer, lung cancer, nasopharyngeal carcinoma, etc.). 50 At concentrations in the nanomolar range (p<0.05), it maintains high inhibitory activity against drug-sensitive nasopharyngeal carcinoma cells KB-3-1 and multidrug-resistant nasopharyngeal carcinoma cells KBV1. Antofen not only exhibits good anticancer effects but also demonstrates good antiviral activity against tobacco mosaic virus (TMV), with a concentration of 1 ppm showing an inhibition rate of up to 60% against TMV. Furthermore, R-antofen possesses good water solubility and antibacterial activity, showing promising potential applications in postharvest preservation of fruits and vegetables.

[0004] Currently, the main methods for obtaining valerian and antofen are isolation from natural plants and total synthesis. The total synthetic routes and methods for valerian and antofen can be broadly classified into two categories. One category involves constructing the phenanthrene ring first, which means first constructing the phenanthrene ring portion of the phenanthrene-indolizine alkaloid, then extending the carbon chain, connecting it to a five-membered nitrogen-containing heterocycle, and finally closing the ring to form the target compound. The other category involves constructing the indole ring first, which means first constructing the indole ring from the nitrogen-containing heterocycle, then connecting it to a polysubstituted benzene, and finally closing the ring to form the target compound. Both synthetic routes have their advantages and disadvantages. The phenanthrene-based route is currently the mainstream method for synthesizing these compounds, as its raw materials are relatively economical and readily available, but the synthetic route is generally longer and more cumbersome. While the indole-based route generally has fewer steps, it usually requires expensive transition metal catalysts and difficult-to-store VOF3 to achieve the phenanthrene ring construction, resulting in poorer economic and environmental performance. In recent years, phytochemists have been dedicated to the total synthesis of phenanthrene-indolizidine alkaloids and their derivatives and the study of their bioactivity. How to efficiently construct phenanthrene-indolizidine ring systems has always been a common goal. Summary of the Invention

[0005] The purpose of this invention is to provide a total synthesis method for valerine and antofen that is simple to operate, has a short route, operates under mild reaction conditions, has low production costs, and yields high product yields.

[0006] To achieve the above objectives, this invention uses 4-methoxyphenylacetylpyrrolidineacetic acid and 3,4-dimethoxyphenylacetylpyrrolidineacetic acid (compound 1) as starting materials, and synthesizes valerine and antofen via a Weinreb ketone reaction, photocyclization dehydrogenation reaction, aldol condensation reaction, and reduction reaction. Compound 1 is reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine to generate intermediate 2; intermediate 2 reacts with 3,4-dimethoxyphenyl magnesium bromide via a Weinreb ketone reaction to generate intermediate 3; intermediate 3 undergoes an aldol condensation reaction in the presence of NaOH to generate intermediate 4; intermediate 4 is dehydrogenated under argon protection and ultraviolet radiation to generate intermediate 5; intermediate 5 undergoes a reduction reaction in the presence of lithium aluminum hydride to obtain compound 6; the total synthetic route is as follows:

[0007]

[0008] In the formula, R is a methoxy group or a hydrogen atom; when R is a methoxy group, compound 6 is cinnabarine; when R is a hydrogen atom, compound 6 is antophenone.

[0009] In the above total synthesis method, preferably under argon protection and at -20 to -5°C, compound 1, N,O-dimethylhydroxylamine hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine are added to dichloromethane, stirred at room temperature for 1 to 3 hours, the reaction solution is acidified with a 10% hydrochloric acid aqueous solution, and then purified by extraction and column chromatography to obtain intermediate 2.

[0010] In the above total synthesis method, the preferred molar ratio of compound 1, N,O-dimethylhydroxylamine hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine is 1:1.5-2.5:1.5-2.5.

[0011] In the above total synthesis method, it is preferred to add intermediate 2 and 3,4-dimethoxyphenyl magnesium bromide to tetrahydrofuran under argon protection and at -10 to 0°C, stir the reaction at 0 to 5°C for 12 to 20 hours, quench the reaction solution with saturated ammonium chloride aqueous solution, and then separate and purify it by extraction and column chromatography to obtain intermediate 3.

[0012] In the above total synthesis method, the preferred molar ratio of intermediate 2 and 3,4-dimethoxyphenyl magnesium bromide is 1:1.5 to 2.

[0013] In the above total synthesis method, intermediate 4 is preferably dissolved in an organic solvent and reacted for 15 to 20 hours under argon protection and ultraviolet light radiation of 300 to 365 nm. After the reaction is completed, the reaction solution is distilled under reduced pressure and then purified by column chromatography to obtain intermediate 5.

[0014] In the above total synthesis method, the organic solvent is preferably any one of dichloromethane and dioxane, or a mixture of dichloromethane and methanol.

[0015] The beneficial effects of this invention are as follows:

[0016] This invention uses commercially available 4-methoxyphenylacetylpyrrolidineacetic acid and 3,4-dimethoxyphenylacetylpyrrolidineacetic acid as starting materials to synthesize valerian alkaloids and antofen alkaloids through a Weinreb ketone reaction, photocyclization dehydrogenation reaction, aldol condensation reaction, and reduction reaction. No metal catalysts are used in the total synthesis. Compared with existing methods for synthesizing valerian alkaloids and antofen alkaloids, this method involves the construction of both indolithidine and phenanthrene rings, with each step achieving a yield of over 70%. It offers advantages such as a short synthetic route, simple process, mild reaction conditions, low production cost, environmental friendliness without the need for any transition metal catalysts, and high product yield. Attached Figure Description

[0017] Figure 1 This is the retention time of the hydrogen standard sample.

[0018] Figure 2 It is the retention time of the photo-cyclization reaction gas sample. Detailed Implementation

[0019] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0020] Example 1

[0021] Synthetic valerian alkaloid

[0022]

[0023] Step 1: Add 30.7 g (0.1 mol) of 3,4-dimethoxyphenylacetylpyrrolidineacetic acid (compound 1-1) and 1.0 L of dichloromethane to the reactor. Cool to -15°C under argon protection. Then add 19.5 g (0.2 mol) of N,O-dimethylhydroxylamine hydrochloride, 38.3 g (0.2 mol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 19.5 g (0.2 mol) of N-methylmorpholine to the reactor. After reacting at room temperature for 2 hours, the reactor was cooled to 0°C. The reaction solution was acidified to pH 6-7 with a 10% hydrochloric acid aqueous solution, and then 1.0 L of distilled water was added for three extractions. The organic layer of the extract was dried with anhydrous sodium sulfate. The dried organic phase was subjected to vacuum distillation to remove the solvent, and then purified by silica gel column chromatography using a mixed solvent with a volume ratio of dichloromethane:methanol = 150:1 to 50:1 as the eluent. After elution and separation, a white solid intermediate 2-1 was obtained with a yield of 98%.

[0024] The structural characterization data of intermediate 2-1 are as follows: 1 H NMR (400MHz, CDCl3) δ6.92-6.68(m,3H),4.57-4.34(m,1H),3.83(d,J=4.2Hz,6H),3.65(s,3H),3.5 6(d,J=11.6Hz,2H),3.51-3.37(m,2H),3.13(d,J=9.1Hz,3H),2.67-2.27(m,1H),2.18-1.71(m,5H); 13CNMR(400MHz, CDCl3)δ169.8(s),169.7(s),149.0(s),147.9(s),127.4(s),121.1(s),112.0(s),111.2(s), 61.2(s),55.9(s),54.6(s),54.3(s),47.3(s),42.1(s),32.0(s),31.3(s),23.9(s),21.5(s); HRMS(ESI)m / z C 18 H 21 The theoretical value of N2O5 is 351.1514, and the measured value is 351.1912.

[0025] Step 2: Add 33.6 g (0.1 mol) of intermediate 2-1 and 1.0 L of anhydrous tetrahydrofuran to a dry reaction vessel, ensuring complete dissolution of intermediate 2-1, and lower the reaction temperature to -5°C. Simultaneously, add 1.0 L of a tetrahydrofuran solution containing 48.0 g (0.2 mol) of 3,4-dimethoxyphenyl magnesium bromide, lowered to -5°C, to the reaction vessel slowly. After stirring at 0°C for 12 hours, quench the reaction with 50 mL of saturated ammonium chloride aqueous solution. Recover the tetrahydrofuran by vacuum distillation. Add 1 L of distilled water to the concentrated product and extract three times with 1 L of ethyl acetate. Combine the organic phases and remove the ethyl acetate by vacuum distillation. Finally, purify the product by silica gel column chromatography using a mixed solvent of petroleum ether:ethyl acetate (v / v) = 2.5:1 as the eluent to obtain a colorless oily liquid intermediate 3-1 in 76% yield.

[0026] The structural characterization data of intermediate 3-1 are as follows: 1 H NMR (400MHz, CDCl3) δ7.91-7.80(m,1H),7.65-7.56(m,1H),6.90(d,J=8.3Hz,1H),6.85-6.74(m,3H),4.54(td,J=7.6,3.8Hz,1H),3.93(d,J=6.8 Hz, 6H), 3.86 (d, J=3.6Hz, 6H), 3.61 (s, 2H), 3.52 (dt, J=7.4, 4.6Hz, 1H), 3.45(t,J=7.7Hz,1H),2.59(dd,J=13.8,10.4Hz,1H),2.07-1.81(m,5H); 13CNMR(400MHz, CDCl3)δ170.1(s),153.5(s),149.2(s),149.1(s),148.0(s),129.9(s),127.2(s),123.9(s),121.2(s),112.2( s),111.3(s),110.4(s),110.3(s),56.1(s),56.0(s),55.5(s),47.6(s),42.1(s),29.8(s),29.3(s),24.0(s); HRMS(ESI)m / z C 16 H 21 NO5[M+H] + Theoretical value: 428.2068; measured value: 428.2075.

[0027] Step 3: Following the method reported in the literature [Bioorganic & Medicinal Chemistry Letters 2003, 13: 1679-1682.], 42.8 g (0.1 mol) of intermediate 3-1 and 8.0 g (0.2 mol) of sodium hydroxide were added to a dry reaction vessel, followed by 1 L of anhydrous ethanol. The reaction was carried out at 78 °C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, excess sodium hydroxide was removed by filtration, and the solvent was removed by vacuum distillation. The product was then dissolved in 1 L of dichloromethane and extracted three times with 1 L of distilled water. The organic phase was dried over anhydrous sodium sulfate to remove water, and dichloromethane was recovered by vacuum distillation. The product was separated and purified by silica gel column chromatography using a mixed solvent with a volume ratio of ethyl acetate:petroleum ether = 1.5:1 to 1:1 as the eluent to obtain a white solid intermediate 4-1 with a yield of 93%.

[0028] The structural characterization data of intermediate 4-1 are as follows: 1 H NMR (400MHz, CDCl3) δ6.73-6.69(m,3H),6.68(s,1H),6.65(dd,J=8.2,1.8Hz,1H),6.47(d,J= 1.8Hz,1H),3.94(ddt,J=14.5,10.1,5.1Hz,1H),3.81(d,J=4.7Hz,6H),3.69(s,3H),3.60(m, J=12.1,9.9,7.4Hz,1H),3.51(s,3H),2.86(dd,J=16.4,4.5Hz,1H),2.70(dd,J=16.4,13.8Hz ,1H),2.33-2.25(m,1H),2.13-2.04(m,1H),1.91-1.83(m,1H),1.72(dd,J=11.8,5.8Hz,2H); 13C NMR (400MHz, CDCl3) δ 164.2(s), 148.4(s), 148.3(s), 148.1(s), 147.9(s), 144.4(s), 132.7(s), 131.9(s), 129.1(s), 123.7(s), 120.9(s), 114.6(s), 112.5(s), 110.7(s), 110.5(s), 77.4(s), 77.1(s), 76.8(s), 55.8(s), 55.8(s), 55.6(s), 44.8(s), 37.3(s), 33.8(s), 23.2(s); HRMS (ESI) m / z theoretical value C 16 H 21 NO5[M+H] + 410.1962, measured value 410.1963.

[0029] Step 4: Add 40.9 g (0.1 mol) of intermediate 4-1 and 5 L of a mixed solvent of dichloromethane and methanol in a volume ratio of 1:9 to a photoreaction tube. Under argon protection and stirring, irradiate with 365 nm ultraviolet light for 15 hours. After the reaction is completed, the reaction solution is distilled under reduced pressure and purified by column chromatography. Using a mixed solvent of dichloromethane:methanol = 200:1 as the eluent, a white solid intermediate 5-1 is obtained in pure form with a yield of 82%.

[0030] The structural characterization data of intermediate 5-1 are as follows: 1 H NMR (400MHz, CDCl3) δ9.04(s,1H),7.82(s,1H),7.78(s,1H),7.34(s,1H),4.14(s,3H),4.12(s,3H),4.09(s,3H),4.06(s ,3H),3.79-4.01(m,3H),3.56-3.63(m,1H),2.70-2.99(m,1H),2.37-2.46(m,1H),2.12-2.22(m,1H),1.87-2.01(m,2H); 13C NMR (400MHz, CDCl3) δ164.8(s),150.4(s),149.0(s),148.9(s),148.8(s),133.2(s),126.8(s),124.5(s),124.4(s),123.3(s),122.6(s) ,108.1(s),104.9(s),103.2(s),102.4(s),76.7(s),56.0(s),55.9(s),55.3(s),45.4(s),33.9(s),32.7(s),23.6(s); HRMS(ESI)m / z C 24 H 25 NO5[M+H] + Theoretical value: 408.1805; measured value: 408.1803.

[0031] Step 5: Following the method reported in the literature [Org. Lett., 2013, 15(20): 5334-5337.], 40 g (0.1 mol) of intermediate 5-1 was weighed and added to a dry reaction vessel, followed by 1 L of dry tetrahydrofuran. Under argon protection and stirring at 0 °C, 0.8 L of 0.25 mol / L lithium aluminum hydride tetrahydrofuran solution was added, and the reaction was refluxed in an oil bath at 68 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and 10 mL of 6 mol / L sodium hydroxide aqueous solution was slowly added dropwise to quench the reaction. The solvent was removed by vacuum distillation, and the reaction product was dissolved in 1 L of diethyl ether and extracted three times with 1 L of distilled water. The organic phase was dried over anhydrous sodium sulfate to remove water, and the diethyl ether was recovered by vacuum distillation. The reaction product was separated and purified by silica gel column chromatography using a mixed solvent with a volume ratio of dichloromethane:methanol = 200:1 as the eluent to obtain a white solid valerine with a yield of 95%.

[0032] The structural characterization data of valerianine are as follows: 1 H NMR (400MHz, CDCl3) δ7.82(d,J=2.3Hz,2H),7.30(s,1H),7.14(s,1H),4.63(d,J=14.7Hz,1H),4.15-4.09(m,6H),4.05(d,J=2.4Hz,6H),3.6 9(d,J=15.0Hz,1H),3.55-3.44(m,1H),3.40-3.32(m,1H),2.51(s,2H),2.38-2.15(m,1H),2.11-1.99(m,1H),1.95(m,1H),1.79(m,1H); 13C NMR (400MHz, CDCl3) δ148.7(s),148.5(s),148.4(s),126.2(s),125.8(s),124.3(s),123.6(s),123.4(s),103.9(s),103.4( s),103.3(s),103.1(s),60.2(s),56.0(s),56.0(s),55.9(s),55.9(s),55.1(s),31.2(s),29.7(s),21.6(s); HRMS(ESI)m / z C 24 H 27 NO4[M+H] + Theoretical value: 394.2013, measured value: 394.2014.

[0033] Example 2

[0034] In step 2 of this embodiment, the 1.0 L tetrahydrofuran solution containing 48 g (0.2 mol) 3,4-dimethoxyphenyl magnesium bromide in step 2 of Example 1 is replaced with 0.75 L tetrahydrofuran solution containing 36 g (0.15 mol) 3,4-dimethoxyphenyl magnesium bromide. The other steps in this step are the same as in Example 1, yielding a colorless oily liquid intermediate 3-1 with a yield of 70%. In step 4 of this embodiment, the 5 L dichloromethane and methanol mixed solvent (volume ratio 1:9) in step 4 of Example 1 is replaced with 5 L dichloromethane. The other steps in this step are the same as in Example 1, yielding a pure white solid intermediate 5-1 with a yield of 78%. Steps 1, 3, and 5 of this embodiment are the same as steps 1, 3, and 5 of Example 1.

[0035] Example 3

[0036] In step 2 of this embodiment, 1 L of tetrahydrofuran solution containing 48 g (0.2 mol) of 3,4-dimethoxyphenyl magnesium bromide was replaced with 1 L of tetrahydrofuran solution containing 43.2 g (0.18 mol) of 3,4-dimethoxyphenyl magnesium bromide. The other steps in this step were the same as in Example 1, yielding a colorless oily liquid intermediate 3-1 with a yield of 73%. In step 4 of this embodiment, 5 L of dioxane and methanol mixed solvent (volume ratio 1:9) in step 4 of Example 1 was replaced with 5 L of dioxane. The mixture was irradiated with 313 nm ultraviolet light for 20 hours under argon protection and stirring. The other steps in this step were the same as in Example 1, yielding a pure white solid intermediate 5-1 with a yield of 80%. Steps 1, 3, and 5 of this embodiment were the same as steps 1, 3, and 5 of Example 1.

[0037] Example 4

[0038] Synthetic Antofen

[0039]

[0040] Step 1: Replace 3,4-dimethoxyphenylacetylpyrrolidineacetic acid in Step 1 of Example 1 with equimolar 4-methoxyphenylacetylpyrrolidineacetic acid, and follow the same steps as Step 1 of Example 1 to obtain colorless oily liquid intermediate 2-2 in 95% yield.

[0041] The structural characterization data of intermediate 2-2 are as follows: 1 H NMR (400MHz, CDCl3) δ7.22-7.07(m,2H),6.82(m,2H),4.55-4.34(m,1H),3.75(d,J=5.6Hz,3H),3.66(s,3H) ,3.60(d,J=8.7Hz,1H),3.54(s,2H),3.51-3.35(m,2H),3.13(s,2H),2.64-2.25(m,1H),2.20-1.78(m,5H); 13 C NMR(400MHz, CDCl3)δ172.5(s),170.0(s),158.5(s),130.1(s),114.1(s),77.4(s),61.3(s) ,55.4(s),54.4(s),47.4(s),41.7(s),32.1(s),30.1(s),24.0(s),21.7(s); HRMS(ESI)m / zC 17 H 24 N₂O₄[M+H] + Theoretical value: 321.1809, measured value: 321.1815.

[0042] Step 2: Replace intermediate 2-1 in step 2 of Example 1 with equimolar intermediate 2-2, and follow the same steps as step 2 of Example 1 to obtain colorless oily liquid intermediate 3-2 with a yield of 80%.

[0043] The structural characterization data of intermediate 3-2 are as follows: 1 H NMR (400MHz, CDCl3) δ7.88(dd,J=8.4,2.1Hz,1H),7.63(d,J=2.0Hz,1H),7.20(d,J=8.6Hz,2H),6.89(dd,J=14.3,8.5Hz,3H), 4.54(m,1H),3.94(d,J=7.0Hz,6H),3.80(s,3H),3.61(s,2H),3.52(m,1H),3.44(m,1H),2.60-2.52(m,1H),2.18-1.72(m,2H); 13C NMR (400MHz, CDCl3) δ197.7(s),170.1(s),158.5(s),153.4(s),149.0(s),130.0(s),129.9(s),126.8(s),123.8(s),114.1( s),110.4(s),110.3(s),56.1(s),55.4(s),55.3(s),47.4(s),42.1(s),41.6(s),29.7(s),29.2(s),24.0(s); HRMS(ESI)m / z C 23 H 27 NO5[M+H] + Theoretical value: 398.1962, measured value: 398.1960.

[0044] Step 3: Replace intermediate 3-1 in step 3 of Example 1 with equimolar intermediate 3-2, and follow the same steps as step 3 of Example 1 to obtain white solid intermediate 4-2 with a yield of 90%.

[0045] The structural characterization data of intermediate 4-2 are as follows: 1 H NMR (400MHz, CDCl3) δ7.03 (d, J = 8.7Hz, 2H), 6.80-6.64 (m, 4H), 6.42 (d, J = 1.8Hz, 1H),3.97-3.62(m,1H),3.82(s,3H),3.73(s,3H),3.70-3.65(m,1H),3.59-3.57(m ,1H),3.48(s,3H),2.84(dd,J=16.3,4.5Hz,1H),2.70(dd,J=16.3,13.7Hz,1H),2. 35-2.22(m,1H),2.07(q,J=6.7,6.0Hz,1H),1.95-1.78(m,1H),1.75-1.65(m,1H); 13 C NMR (400MHz, CDCl3) δ164.4(s),158.4(s),148.3(s),147.9(s),144.1(s),132.7(s),132.2(s),131.9(s),128.9(s),120.8( s),113.3(s),112.8(s),110.4(s),55.8(s),55.6(s),55.5(s),55.2(s),44.8(s),37.3(s),33.8(s),23.2(s); HRMS(ESI)m / z C 23 H 25 NO4[M+H] +Theoretical value: 380.1856, measured value: 380.1856.

[0046] Step 4: Replace intermediate 4-1 in step 4 of Example 1 with equimolar intermediate 4-2, and follow the same steps as step 4 of Example 1 to obtain white solid intermediate 5-2 with a yield of 85%.

[0047] The structural characterization data of intermediate 5-2 are as follows: 1 H NMR (400MHz, CDCl3) δ9.29(d,J=9.3Hz,1H),7.98-7.81(m,2H),7.33(s,1H),7.21(dd,J=22.9,2.5Hz,1H),4.12(s,3H),4.06(s,3H),4.01(s ,3H),3.97-3.70(m,2H),3.55(dd,J=15.5,4.1Hz,1H),2.91(t,J=14.4Hz,1H),2.50-2.38(m,1H),2.16(d,J=7.4Hz,1H),2.06-1.82(m,2H); 13 C NMR(400MHz, CDCl3)δ164.4(s),157.7(s),150.2(s),149.3(s),132.6(s),131.0(s),129.7(s),126.5(s),124.4(s),123.7(s),123.6( s),115.2(s),104.9(s),104.2(s),103.9(s),56.0(s),56.0(s),55.5(s),55.3(s),45.6(s),33.9(s),32.7(s),23.6(s); HRMS(ESI)m / z C 23 H 23 NO4[M+H] + Theoretical value: 378.1700, measured value: 378.1708.

[0048] Step 5: Replace intermediate 5-1 in step 5 of Example 1 with equimolar intermediate 5-2, and follow the same steps as step 5 of Example 1 to obtain white solid antofen with a yield of 90%.

[0049] Antofen's structural characterization data are as follows: 1H NMR (400MHz, CDCl3) δ8.00-7.87(m,2H),7.79(d,J=9.0Hz,1H),7.31(s,1H),7.2 1(dd,J=9.0,2.6Hz,1H),4.77(d,J=15.1Hz,1H),4.11(s,3H),4.06(s,3H),4 .02(s,3H),3.64(s,3H),3.39(d,J=15.7Hz,1H),3.04(s,1H),2.50(dt,J=9. 8,7.5Hz,2H),2.30(s,1H),2.12(d,J=6.3Hz,1H),2.01(q,J=7.1,6.4Hz,2H); 13 CNMR(400MHz, CDCl3)δ157.6(s),149.5(s),148.5(s),130.3(s),127.0(s),125.5(s),124.3(s),124.1(s),123.7(s),115.0( s),104.8(s),104.0(s),103.9(s),60.4(s),56.1(s),56.0(s),55.6(s),55.0(s),31.2(s),29.8(s),21.6(s); HRMS(ESI)m / z C 23 H 23 NO4[M+H] + Theoretical value: 364.1907, measured value: 364.1903.

[0050] Example 5

[0051] In step 2 of this embodiment, the 1.0 L tetrahydrofuran solution containing 48 g (0.2 mol) 3,4-dimethoxyphenyl magnesium bromide in step 2 of Example 4 is replaced with 0.75 L tetrahydrofuran solution containing 36 g (0.15 mol) 3,4-dimethoxyphenyl magnesium bromide. The other steps in this step are the same as in Example 4, yielding a colorless oily liquid intermediate 3-2 with a yield of 75%. In step 4 of this embodiment, the 5 L dichloromethane and methanol mixed solvent (volume ratio 1:9) in step 4 of Example 4 is replaced with 5 L dichloromethane. The other steps in this step are the same as in Example 4, yielding a pure white solid intermediate 5-2 with a yield of 80%. Steps 1, 3, and 5 of this embodiment are the same as steps 1, 3, and 5 of Example 4.

[0052] Example 6

[0053] In step 2 of this embodiment, 1 L of tetrahydrofuran solution containing 48 g (0.2 mol) of 3,4-dimethoxyphenyl magnesium bromide was replaced with 1 L of tetrahydrofuran solution containing 43.2 g (0.18 mol) of 3,4-dimethoxyphenyl magnesium bromide. The other steps in this step were the same as in Example 4, yielding a colorless oily liquid intermediate 3-2 with a yield of 76%. In step 4 of this embodiment, 50 L of a 1:9 volume ratio mixed solvent of dichloromethane and methanol was replaced with 50 L of dioxane in step 4 of Example 4. The mixture was irradiated with 313 nm ultraviolet light for 20 hours under argon protection and stirring. The other steps in this step were the same as in Example 4, yielding a pure white solid intermediate 5-2 with a yield of 89%. Steps 1, 3, and 5 of this embodiment were the same as steps 1, 3, and 5 of Example 4.

[0054] To verify that the reaction in step 4 of the above embodiment is a photocyclization dehydrogenation reaction, the gas in the light-illuminating tube was collected and detected by gas chromatography to verify whether hydrogen was generated. GC conditions: argon was used as the carrier gas, and gas chromatography analysis was performed using a stainless steel column (2m long, 80℃) and a thermal conductivity detector (TCD, 100℃). At a gas flow rate of 0.3MPa and 75mL / min, 1mL of gas was injected at room temperature for analysis. First, the hydrogen standard sample was detected by gas chromatography, and the retention time of its signal peak was found to be 2.543min (see...). Figure 1 Hydrogen gas is less dense than argon gas. If hydrogen gas is produced by the reaction, it will concentrate in the upper layer of the gas phase in the light tube. Therefore, the upper gas layer in the light tube was collected and analyzed by gas chromatography, as shown in the following results. Figure 2 The results showed that the upper gas in the illumination tube exhibited a distinct single signal peak with a retention time of 2.583 min, which was consistent with the retention time of the hydrogen standard sample. Therefore, gas chromatography confirmed the generation of hydrogen gas in the reaction, thus confirming the reaction as a photocyclization dehydrogenation reaction.

Claims

1. A method for the total synthesis of valerine or antophen, characterized in that: Compound 1 was reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine to generate intermediate 2; intermediate 2 reacted with 3,4-dimethoxyphenyl magnesium bromide in a Weinreb ketone reaction to generate intermediate 3; intermediate 3 underwent an aldol condensation reaction in the presence of NaOH to generate intermediate 4; intermediate 4 was dehydrogenated under argon protection and ultraviolet light irradiation to generate intermediate 5; intermediate 5 underwent a reduction reaction in the presence of lithium aluminum hydride to give compound 6; the specific synthetic route is as follows: In the formula, R is a methoxy group or a hydrogen atom. When R is a methoxy group, compound 6 is valerine; when R is a hydrogen atom, compound 6 is antophenone.

2. The total synthesis method of valerine or antofen according to claim 1, characterized in that: Compound 1, N,O-dimethylhydroxylamine hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine were added to dichloromethane under argon protection and at -20 to -5°C. The mixture was stirred at room temperature for 1 to 3 hours. The reaction solution was acidified with a 10% hydrochloric acid aqueous solution and then purified by extraction and column chromatography to obtain intermediate 2.

3. The total synthesis method of valerine or antofen according to claim 2, characterized in that: The molar ratio of compound 1, N,O-dimethylhydroxylamine hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine is 1:1.5-2.5:1.5-2.

5.

4. The total synthesis method of valerine or antofen according to claim 1, characterized in that: Under argon protection and at -10 to 0°C, intermediates 2 and 3,4-dimethoxyphenyl magnesium bromide were added to tetrahydrofuran and stirred at 0 to 5°C for 12 to 20 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution and then purified by extraction and column chromatography to obtain intermediate 3.

5. The total synthesis method of valerine or antofen according to claim 4, characterized in that: The molar ratio of intermediate 2 and 3,4-dimethoxyphenyl magnesium bromide is 1:1.5 to 2.

6. The total synthesis method of valerine or antofen according to claim 1, characterized in that: Intermediate 4 was dissolved in an organic solvent and reacted for 15–20 hours under argon protection and ultraviolet light irradiation of 300–365 nm. After the reaction was completed, the reaction solution was distilled under reduced pressure and purified by column chromatography to obtain intermediate 5.

7. The total synthesis method of valerine or antofen according to claim 6, characterized in that: The organic solvent is any one of dichloromethane and dioxane, or a mixture of dichloromethane and methanol.

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