Asymmetric total synthesis of vinca alkaloids

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to an asymmetric total synthesis method of catharanthine. Commercially available oxazolidinone 1 is used as a starting material, and is condensed with bromoacrylic acid to obtain compound 2. Then, asymmetric DA reaction of compound 2 and compound 3 occurs under the catalysis of scandium triflate to obtain compound 4. Compound 4 is hydrolyzed into a carboxylic acid under the condition of lithium hydroxide and hydrogen peroxide, and is treated by trimethylsilane diazomethane to obtain compound 6. Compound 6 is selectively reacted with sodium methoxide, and after the protective group is removed by treatment of iodo-trimethylsilane, compound 6 is condensed with an acid to obtain compound 9. Compound 9 is subjected to radical annulation under the catalysis of a photocatalyst Ir(ppy)3 to obtain compound 10. Finally, selective reduction of the amide obtains natural product (+) - catharanthine. The asymmetric total synthesis route of the application has a total step of 8 or 9, and a total yield of 17.8% - 23.5%, which is shorter than that of the prior art, and the total yield is significantly improved.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to an asymmetric total synthesis method for vincristine. Background Technology

[0002] Iboga alkaloids are monoterpenoid indole alkaloids isolated from plants of the Apocynaceae family. These alkaloids possess significant anti-addictive and anticancer biological activities. Among them, ibogaine (-)-ibogaine (1) and its derivative 18-MC (2) have entered clinical trials for the treatment of drug addiction. Vincristine (+)-Catharanthine (3) is not only a potent TRPM8 antagonist, but more importantly, this natural product can serve as a synthetic precursor for the anticancer drugs vinblastine (+)-vinblastine (5) and vincristine (+)-vincristine (6). The content of these two drugs in periwinkle plants is very low, with only 5-10 grams obtainable from each ton of dried periwinkle leaves. Therefore, industrially, they are mainly prepared through oxidative coupling between the monomeric vinblastine (3) and vindoline (-)-vindoline (4). However, due to the complex chemical structure and high synthesis difficulty of its important intermediate, vincristine (3), it can only be extracted industrially from the leaves of Madagascar periwinkle. Its content in dried leaves is only 0.0009%, making its natural source scarce and limiting the industrial manufacturing of the two drugs mentioned above. In 2019-2020, these two drugs were listed on the FDA's shortage drug list. Therefore, developing efficient and concise asymmetric synthetic routes can not only provide a material basis for in-depth research on the pharmacological activity of (+)-catharanthine, but more importantly, it can provide the possibility for the industrial synthesis of the antitumor drugs vincristine and vinblastine.

[0003]

[0004] Vincristine alkaloids have three stereocenters: C14, C16, and C21, with C16 being an all-carbon quaternary carbon center. The indoleethyl and isoquinine moieties are linked via a seven-membered C-ring, making their synthesis challenging. Since their isolation in 1959, several research groups, including Büch's, have conducted total synthesis studies on this natural product. However, only six asymmetric synthesis studies have been performed, involving 15-30 steps and yields below 1%, indicating a lack of prospects for industrial application. Therefore, developing novel synthetic strategies to achieve efficient asymmetric total synthesis is of significant practical importance for the application of vinca alkaloids in pharmaceuticals. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide an asymmetric total synthesis method for vincristine.

[0006] The objective of this invention is achieved through the following technical solution: an asymmetric total synthesis method for vincristine, comprising the following steps:

[0007]

[0008] S1. Compound 1 is reacted with haloacrylic acid in a condensation reaction to obtain intermediate compound 2; wherein, R1 is one of methyl, phenyl, tert-butyl, isopropyl, benzyl, diphenylmethyl, and triphenylmethyl; R2 is one of hydrogen, methyl, phenyl, tert-butyl, isopropyl, and benzyl; R3 is one of hydrogen, methyl, phenyl, tert-butyl, isopropyl, and benzyl; and X is one of chlorine, bromine, and iodine.

[0009]

[0010] S2, intermediate compound 2 and compound 3 undergo an asymmetric DA reaction under the action of a catalyst to obtain intermediate compound 4; wherein, R4 is one of methyl, phenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, p-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl.

[0011]

[0012] S3. The intermediate compound 4 is hydrolyzed under the conditions of lithium hydroxide and hydrogen peroxide to obtain the intermediate compound 5.

[0013]

[0014] S4. Methylation of intermediate compound 5 yields intermediate compound 6;

[0015]

[0016] S5. React intermediate compound 6 with sodium methoxide to obtain intermediate compound 7; when R4 is methyl, skip step S5 and proceed directly to step S6.

[0017]

[0018] S6. The intermediate compound 7 is subjected to a deprotection reaction to obtain the intermediate compound 8;

[0019]

[0020] S7. Intermediate compound 8 is condensed with 3-indoleacetic acid to obtain intermediate compound 9;

[0021]

[0022] S8. Compound 10 was obtained by radical cyclization reaction of intermediate compound 9 under the catalysis of a photocatalyst.

[0023]

[0024] S9. The intermediate compound 10 is subjected to a selective reduction amide reaction to obtain the (+)-catharanthine vincristine base. Further, in step S1, the molar ratio of compound 1 to haloacrylic acid is 1:1.1–5;

[0025] And / or, the base used in the condensation reaction includes one or more of n-butyllithium, potassium tert-butoxide, sodium hydride, sodium bicarbonate, potassium carbonate, triethylamine, and diisopropylethylamine;

[0026] And / or, the solvent used in the condensation reaction includes one or more of DMF, tetrahydrofuran, dichloromethane, and 1,2-dichloroethane;

[0027] And / or, the solvent condensing agent used in the condensation reaction includes one of PivCl (tervapotranolol chloride), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), and EDCI (1-ethyl-carbodiimide hydrochloride).

[0028] Furthermore, in step S2, the molar ratio of intermediate compound 2, compound 3, and catalyst is 1:1.1-5.0:0.5-3.5;

[0029] And / or, the solvent used in the asymmetric DA reaction includes one or more of 1,2-dichloroethane, acetonitrile, toluene, and dichloroethane;

[0030] And / or, the catalyst used in the asymmetric DA reaction includes one or more of the following: Sc(OTf)3 (scandium trifluoromethanesulfonate), EtAlCl2 (dichloroethylaluminum), AlCl3 (aluminum trichloride), BF3·Et2O (boron trifluoride diethyl ether), TMSOTf (trimethylsilyl trifluoromethanesulfonate), TiCl4 (titanium tetrachloride), In(OTf)3 (indium trifluoromethanesulfonate), Sm(OTf)3 (samarium trifluoromethanesulfonate), Yb(OTf)3 (ytterbium trifluoromethanesulfonate), La(OTf)3 (lanthanum trifluoromethanesulfonate), AgOTf (silver trifluoromethanesulfonate), Ca(OTf)2 (calcium trifluoromethanesulfonate), Zn(OTf)2 (zinc trifluoromethanesulfonate), Mg(OTf)2 (magnesium trifluoromethanesulfonate), Ni(OTf)2 (nickel trifluoromethanesulfonate), SnCl4 (tin tetrachloride), and InBr3 (indium tribromide).

[0031] Furthermore, in step S3, the molar ratio of intermediate compound 4, lithium hydroxide and hydrogen peroxide is 1:1 to 3:5 to 10;

[0032] And / or, the solvent in the hydrolysis reaction is tetrahydrofuran and water.

[0033] Furthermore, in step S4, the methylating agent for the methylation reaction is trimethylsilyldiazomethane, methyl methanesulfonate, methyl p-toluenesulfonate, or iodomethane; the molar ratio of the methylating agent to compound 5 is 1:10 to 20.

[0034] And / or, the solvent for the methylation reaction is methanol.

[0035] Furthermore, in step S5, the molar ratio of the intermediate compound 6 to sodium methoxide is 1:3 to 10.

[0036] And / or, the solvent used in the reaction with sodium methoxide is methanol.

[0037] Furthermore, in step S6, the reagent used for the deprotection reaction is methyliodotrimethylsilane, the solvent is dichloromethane, and the reaction is carried out at room temperature; or the reagent is methyllithium, the solvent is tetrahydrofuran, and the reaction is carried out at -78°C; the molar ratio of the intermediate compound 7 and the deprotection reaction reagent is 1:2 to 10.

[0038] Furthermore, in step S7, the molar ratio of the intermediate compound 8 to 3-indoleacetic acid is 1:1.2 to 2;

[0039] And / or, the condensing agent of the condensation reaction includes one of PivCl (tervapotranolol chloride), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), and EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride);

[0040] And / or, the base of the condensation reaction includes DIPEA (diisopropylethylamine) or triethylamine;

[0041] And / or, the solvent for the condensation reaction includes DMF (dimethylformamide) or THF (tetrahydrofuran);

[0042] Furthermore, in step S8, the photocatalyst comprises Ir(ppy)3 (tris(2-phenylpyridine)iridium),

[0043] [Ir(dtbbpy)(ppy)2]PF6 ((4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III)hexafluorophosphate), Ru(bpy)3(PF6)2 (ruthenium-tris(2,2′-bipyridine)dihexafluorophosphate), Ru(bpy)3Cl2·6H2O (tripyridineruthenium chloride hexahydrate), or one or more of the organic photocatalysts Eosin and Rose Bengal;

[0044] And / or, the light source for the free radical cyclization reaction is blue light or other visible light;

[0045] And / or, the base for the free radical cyclization reaction is one or more of sodium bicarbonate, potassium carbonate, disodium hydrogen phosphate, cesium carbonate, 4-MeOC6H4NPh2 (4-methoxytriphenylamine), 4-methoxypridine (4-methoxypyridine), triethylamine, and DIPEA (N,N-diisopropylethylamine);

[0046] And / or, the solvent for the free radical cyclization reaction is one or more of 1,4-dioxane, toluene, acetonitrile, tetrahydrofuran, dichloromethane, and 1,2-dichloroethane.

[0047] Furthermore, in step S9, the reducing agent for the selective reduction reaction of the amide is one or more of the following: tris(triphenylphosphine)carbonyl rhodium hydride, carbon bis(triphenylphosphine)iridium chloride (Vaska's catalyst), lithium borohydride, sodium borohydride, and triacetyl sodium borohydride.

[0048] The additives for the selective reduction amide reaction are one or more of the following: benzylsilane, glacial acetic acid, formic acid, trifluoroacetic acid, triethylsilane, and tetramethyldisilazane;

[0049] The solvent for the selective reduction amide reaction is one or more of methanol, tetrahydrofuran, dichloromethane, and toluene.

[0050] The beneficial effects of this invention are as follows: This invention uses commercially available compound 1 (oxazolidinone) as a starting material, which is condensed with bromoacrylic acid to obtain compound 2. Then, compound 2 and compound 3 undergo an asymmetric DA reaction under scandium trifluoromethanesulfonate catalysis to obtain endo compound 4. Compound 4 is hydrolyzed to a carboxylic acid under lithium hydroxide and hydrogen peroxide conditions, and then treated with trimethylsilyldiazomethane to obtain compound 6. Compound 6 can optionally react with sodium methoxide, and after deprotection with trimethyliodosilane, it is condensed with an acid to obtain compound 9. Compound 9 undergoes free radical cyclization under the catalysis of photosensitizer Ir(ppy)3 to obtain compound 10. Finally, the amide is selectively reduced to obtain the natural product (+)-catharanthine. This asymmetric total synthetic route has a total of 8 or 9 steps, with an overall yield of 17.8%-23.5%, which is shorter than the prior art and significantly improves the overall yield. Detailed Implementation

[0051] The technical solution of the present invention will be described in further detail below, but the scope of protection of the present invention is not limited to the following description.

[0052] Example 1

[0053] Taking X as bromine, R1 as benzyl, and R2 and R3 as hydrogen as an example, intermediate compound 2 was synthesized. The reaction formula and experimental method are as follows:

[0054]

[0055] 2-Bromoacrylic acid (936 mg, 6.20 mmol, 1.1 equiv.) was dissolved in dry tetrahydrofuran (9.4 mL), and triethylamine (1.18 mL, 8.46 mmol, 1.5 equiv.) and tervapotranol chloride (832 μL, 6.77 mmol, 1.2 equiv.) were added sequentially at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred for 2 hours to obtain the acid anhydride intermediate. Simultaneously, compound 1 (1.00 g, 5.64 mmol, 1.0 equiv.) was dissolved in dry tetrahydrofuran (0.8 mL), and t-BuOK (1.0 M in THF, 6.77 mL, 6.77 mmol, 1.2 equiv.) and lithium chloride (287 mg, 6.77 mmol, 1.2 equiv.) were added dropwise at -78 °C. The pre-prepared acid anhydride was added dropwise to the reaction system, and after reacting at this temperature for 1 hour, the reaction was quenched with saturated ammonium chloride aqueous solution (5 mL), extracted with ethyl acetate (5 mL × 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain compound 2 (white solid, 1.54 g, 88%).

[0056] TLC: Petroleum ether / ethyl acetate = 3:1, v / v, R f =0.30;

[0057] 1 H NMR (400MHz, CDCl3): δ7.44–7.28(m,3H),7.22(d,J=6.8Hz,2H),6.24(d,J=2.8Hz,1H),6.07(d,J=2.8Hz,1H),4.80–4.6 6(m,1H),4.30(t,J=8.5Hz,1H),4.22(dd,J=9.1,4.2Hz,1H),3.35(dd,J=13.5,3.1Hz,1H),2.87(dd,J=13.4,9.3Hz,1H).

[0058] 13 C NMR (100MHz, CDCl3): δ164.42,151.73,134.55,129.42,129.01,127.52,124.76,119.60,66.51,55.35,37.22.

[0059] IR(neat):ν max =3112,3087,3062,3028,1781,1685,1384,1355,1198cm -1 ;

[0060] HRMS(ESI):m / z calcd.for C 13 H 12 BrNO3[M+H] + 310.0073,312.0053,found310.0078,312.0058.

[0061] Example 2

[0062] The difference between Example 2 and Example 1 is that R1 is diphenylmethyl, while the other reaction conditions are the same, and the yield is 56%.

[0063] 1 H NMR(400MHz, CDCl3):7.38–7.30(m,4H),7.30–7.26(m,3H),7.26–7.22(m,3H),5.04(s,1H) ,4.68–4.55(m,1H),4.44–4.37(m,1H),4.10(dd,J=9.0,5.8Hz,1H),3.97(d,J=10.6Hz,1H).

[0064] Example 3

[0065] The difference between Example 3 and Example 1 is that R2 and R3 are phenyl, while the other reaction conditions are the same, with a yield of 54%.

[0066] 1 H NMR (400MHz, CDCl3): δ7.49–7.43(m,2H),7.40–7.31(m,3H),7.31–7.23(m,5H),7.18–7.09(m,3H),6.90–6.79(m,2 H), 5.91 (q, J = 2.9Hz, 2H), 5.58 (dd, J = 7.3, 5.8Hz, 1H), 2.90 (dd, J = 14.2, 5.8Hz, 1H), 2.79 (dd, J = 14.2, 5.8Hz, 1H).

[0067] Example 4

[0068] Intermediate compound 2 was synthesized using Example 1, and intermediate compound 4 was synthesized using R4 as a p-nitrophenyl group. The reaction formula and experimental method are as follows:

[0069]

[0070] To a DCE (1.0 mL) solution of compound 2 (110 mg, 0.355 mmol, 1.0 equiv.), scandium trifluoromethanesulfonate (262 mg, 0.532 mmol, 1.5 equiv.) was added sequentially. Molecular sieve (110 mg). At 0 °C, a DCE solution (2 mL) of compound 3 (166 mg, 0.605 mmol, 1.7 equiv.) was added dropwise. The mixture was maintained at this temperature and stirred for approximately 2 hours. The reaction solution was filtered through a thin silica gel filter, washed three times with dichloromethane / methanol (100:1), and the crude product was concentrated and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1-6:1-4:1, v / v) to give compound 4 (white vesicle, 143 mg, yield 77%).

[0071] TLC: Petroleum ether / ethyl acetate = 3:1, v / v, R f =0.25;

[0072] 1H NMR (400MHz, CDCl3): δ8.30–8.15(m,2H),7.42–7.29(m,5H),7.16–7.03(m,2H),6.17(d d,J=11.2,6.7Hz,1H),5.37(d,J=13.3Hz,1H),4.96–4.57(m,1H),4.37(t,J=8.8Hz,1H) ,4.28–4.08(m,1H),3.85–3.47(m,1H),3.29–3.09(m,1H),3.02(dt,J=13.5,3.7Hz,1H) ,2.94–2.80(m,2H),2.78–2.63(m,1H),2.51–2.33(m,3H),1.11(dt,J=14.7,7.4Hz,3H).

[0073] 13 C NMR (100MHz, CDCl3): δ168.86,168.59,156.28,152.54,151.82,151.07,150.99,147.86, 146.89,144.90,144.74,134.55,134.48,129.49,129.45,128.98,128.95,127.64,127.59 ,126.97,126.16,125.13,125.06,122.39,122.22,66.47,62.84,62.62,58.90,58.21,55.88,55.82,46.77,46.65,42.02,41.89,37.78,31.36,31.02,26.24,26.14,11.59,11.44.

[0074] IR(neat):ν max =2965,2940,2875,1791,1726,1679,1522,1396,1344,1212,1043cm -1 ;

[0075] HRMS:m / z calcd.for C 27 H 26 BrN3O7[M+H] + 584.1027,586.1006,found 584.1092,586.1014.

[0076] Example 5

[0077] The difference between Example 5 and Example 4 is that R1 is diphenylmethyl, while the other reaction conditions are the same, and the yield is 86%.

[0078] TLC: Petroleum ether / ethyl acetate = 3:1, v / v, R f =0.25;

[0079] 1 H NMR (400MHz, CDCl3): δ8.29–8.19(m,2H),7.36–7.30(m,5H),7.30–7.21(m,3H),7.14–7.05(m,4H),6.03–5.95(m,1H) ,5.48–5.35(m,1H),5.23(s,1H),4.57(d,J=6.8Hz,1H),4.48(t,J=8.9Hz,1H),4.44–4.36(m,1H),3.62(dd,J=10.1,1 .5Hz,0.5H),3.48(dd,J=10.1,1.5Hz,0.5H),3.18(dt,J=10.0,2.5Hz,0.5H),3.05(t,J=10.0,2.5Hz,0.5H),2.80–2. 71(m,1H),2.61–2.47(m,1H),2.40–2.19(m,2H),2.06–1.83(m,1H),1.12(t,J=8.0Hz,1.5H),1.08(t,J=8.0Hz,1.5H).

[0080] Example 6

[0081] The difference between Example 6 and 4 is that R2 and R3 are phenyl, while the other reaction conditions are the same, with a yield of 84%.

[0082] TLC: Petroleum ether / ethyl acetate = 3:1, v / v, R f =0.25;

[0083] 1H NMR (400MHz, CDCl3): δ8.41–8.00(m,2H),7.49–7.42(m,2H),7.38–7.28(m,10H),7.18–7.10(m,3H),6.98 –6.86(m,2H),5.97–5.83(m,1H),5.77–5.70(m,1H),5.02(d,J=7.7Hz,1H),3.61–3.55(m,0.5H),3.44(d,J =10.3Hz,0.5H),3.14(dt,J=10.1,2.4Hz,0.5H),3.01(dt,J=10.1,2.4Hz,0.5H),2.89–2.77(m,1H),2.73– 2.53(m,3H),2.35(d,J=16.0Hz,1H),2.04–1.95(m,2H),1.00(t,J=7.3Hz,1.5H),0.95(t,J=7.3Hz,1.5H).

[0084] Example 7

[0085] The difference between Example 7 and Example 4 is that R4 is methyl, while the other reaction conditions are the same, yielding a white bubbly substance (153 mg, yield 50%).

[0086] TLC: Petroleum ether / ethyl acetate = 3:1, v / v, R f =0.30;

[0087] 1 H NMR (400MHz, CDCl3): δ7.36–7.27(m,3H),7.12–7.05(m,2H),6.19–5.94(m,1H),5.45– 5.07(m,1H),4.92–4.72(m,1H),4.34(t,J=8.8Hz,1H),4.19(ddd,J=9.0,3.9,1.9Hz,1 H),3.75(d,J=9.3Hz,3H),3.45(dd,J=10.1,1.7Hz,1H),3.15–2.93(m,2H),2.90–2.73 (m,2H),2.59(dd,J=15.7,2.5Hz,1H),2.46–2.21(m,3H),1.03(td,J=7.4,4.8Hz,3H).

[0088] 13C NMR (100MHz, CDCl3): δ169.08,168.80,156.04,155.62,150.98,150.90,134.56,134.50,129.42,129.39,128.85,128.82,126.18,12 5.55,66.24,62.87,62.80,58.18,57.80,55.72,55.68,52.56,46.27,46.02,42.01,41.93,37.69,31.35,31.11,26.06,26.04,11.31.

[0089] IR(neat):ν max =3061,2961,2933,2877,1787,1681,1448,1389,1350,1115,1097cm -1 ;

[0090] HRMS:m / z calcd.for C 22 H 25 BrN2O5[M+H] + 477.1020,479.0999, found 477.1015,479.0998.

[0091] Example 8

[0092] The difference between Example 8 and Example 4 is that R4 is phenyl, while the other reaction conditions are the same, yielding a white solid compound (white solid, 161 mg, yield 84%).

[0093] TLC: Petroleum ether / ethyl acetate = 3:1, v / v, R f =0.25;

[0094] 11H NMR (400 MHz, CDCl3): δ 7.42–7.28 (m, 5H), 7.23–7.15 (m, 3H), 7.14–7.07 (m, 2H), 6.15 (t, J = 8.1 Hz, 1H), 5.51–5.32 (m, 1H), 4.89–4.72 (m, 1H), 4.35 (t, J = 8.8 Hz, 1H), 4.28–4.11 (m, 1H), 3.78–3.50 (m, 1H), 3.32–3.10 (m, 1H), 3.01 (dt, J = 13.5, 2.9 Hz, 1H), 2.91–2.81 (m, 2H), 2.69 (ddd, J = 15.6, 9.4, 2.4 Hz, 1H), 2.49–2.33 (m, 3H), 1.11 (dt, J = 19.0, 7.4 Hz, 3H).

[0095] 13 13C NMR (100 MHz, CDCl3): δ 168.75, 168.53, 153.69, 153.07, 151.18, 150.87, 150.82, 134.42, 134.36, 129.32, 129.30, 129.05, 128.99, 128.69, 128.66, 127.33, 127.29, 126.50, 125.85, 125.11, 124.95, 121.65, 121.52, 66.19, 62.84, 62.74, 58.47, 57.83, 55.53, 55.50, 46.37, 46.35, 41.88, 41.77, 37.42, 31.22, 30.89, 26.05, 25.94, 11.43, 11.25.

[0096] IR (neat): ν max = 3056, 2964, 2933, 1788, 1712, 1679, 1393, 1332, 1350, 1271, 1200, 1065, 732,

[0097] 702 cm -1 ;

[0098] HRMS: m / z calcd. for C 27 H 27 BrN2O5 [M + H] + 539.1176, 541.1156, found 539.1175, 541.1158.

[0099] Example 9

[0100] The difference between Example 9 and Example 4 is that R4 is chlorophenyl, while the other reaction conditions are the same, yielding a white foamy substance (160 mg, yield 79%).

[0101] TLC: Petroleum ether / ethyl acetate = 3:1, v / v, R f =0.25;

[0102] 1 H NMR (400MHz, CDCl3): δ7.35–7.28(m,5H),7.15–7.09(m,4H),6.24–6.07(m,1H) ,5.37(d,J=17.5Hz,0H),4.90–4.68(m,1H),4.36(t,J=8.8Hz,1H),4.21(dt,J= 9.1,3.3Hz,1H),3.77–3.43(m,1H),3.31–3.08(m,1H),2.95–2.80(m,2H),2.68 (ddd,J=15.6,8.8,2.4Hz,1H),2.51–2.30(m,3H),1.10(dt,J=16.4,7.4Hz,3H).

[0103] 13 C NMR (100MHz, CDCl3): δ168.94,168.67,153.49,152.85,151.02,150.94,149.86,148.03, 147.13,134.55,134.48,130.58,130.39,129.45,129.42,129.24,129.16,128.93,128.90 ,127.58,127.53,126.67,125.91,123.17,123.05,66.36,62.86,62.70,58.66,58.05,55.82,55.78,46.58,46.51,42.07,41.94,37.77,31.38,31.04,26.21,26.09,11.56,11.39.

[0104] IR(neat):ν max =3059,2964,2879,1789,1714,1679,1488,1395,1350,1203,1062,732,

[0105] 701cm -1 ;

[0106] HRMS:m / z calcd.for C 27 H 26BrClN2O5[M+H] + 573.0786,575.0766,found573.0790,575.0711.

[0107] Example 10

[0108] The difference between Example 10 and Example 4 is that R4 is p-bromophenyl, while the other reaction conditions are the same, yielding a white bubbly substance (170 mg, yield 77%).

[0109] TLC: Petroleum ether / ethyl acetate = 3:1, v / v, R f =0.22;

[0110] 1 H NMR (400MHz, CDCl3): δ7.52–7.41(m,2H),7.31(dd,J=7.6,1.7Hz,3H),7.15–7.09(m,2H),7.0 6(d,J=8.8Hz,1H),6.19–6.08(m,1H),5.46–5.29(m,1H),4.87–4.75(m,1H),4.36(t,J=8.8Hz ,1H),4.26–4.17(m,1H),3.70–3.47(m,1H),3.27–3.08(m,1H),3.02(dt,J=13.5,3.5Hz,1H), 2.93–2.80(m,2H),2.68(ddd,J=15.7,8.7,2.5Hz,1H),2.49–2.28(m,3H),1.18–1.02(m,3H).

[0111] IR(neat):ν max =3054,792,1717,1684,1486,1400,1351,1264,1155,731,702cm -1 ;

[0112] HRMS:m / z calcd.for C 27 H 26 Br2N2O5[M+H] + 617.0218,619.0261,found 617.0284,619.0260.

[0113] Example 11

[0114] The difference between Example 11 and Example 4 is that R4 is p-methoxyphenyl, while the other reaction conditions are the same, yielding a white bubbly substance (173 mg, yield 79%).

[0115] TLC: Petroleum ether / ethyl acetate = 3:1, v / v, R f =0.20;

[0116] 1 H NMR (400MHz, CDCl3): δ7.37–7.28(m,3H),7.15–7.01(m,4H),6.95–6.81(m,2H),6.17–6.07 (m,1H),5.52–5.31(m,1H),4.87–4.73(m,1H),4.36(t,J=8.8Hz,1H),4.20(dt,J=9.1,3.3Hz ,1H),3.79(d,J=3.5Hz,3H),3.73–3.43(m,1H),3.27–3.09(m,1H),3.01(dt,J=13.5,3.1Hz, 1H),2.90–2.80(m,2H),2.74–2.60(m,1H),2.51–2.30(m,3H),1.10(dt,J=18.8,7.4Hz,1H).

[0117] 13 C NMR (100MHz, CDCl3): δ169.00,168.75,156.92,156.80,154.25,153.67,151.03,150.96,14 8.13,147.31,144.93,144.91,134.58,134.52,129.46,129.44,128.92,128.89,127.56,12 7.52,126.52,125.81,122.61,122.51,114.29,114.22,66.33,62.92,62.80,58.57,58.00,55.80,55.60,46.51,46.49,42.12,41.99,37.77,31.43,31.09,26.23,26.10,11.58,11.39.

[0118] IR(neat):ν max =3054,2965,2933,1791,1712,1682,1508,1399,1351,1201,733,702,679cm -1 ;

[0119] HRMS:m / z calcd.for C 28 H 29 BrN2O6[M+H] +569.1282,571.1261,found 569.1286,571.1268.

[0120] Example 12

[0121] Intermediate compound 4 was synthesized using Example 4, and intermediate compound 6 was synthesized in two steps. The reaction formulas and experimental methods are as follows:

[0122]

[0123] Compound 4 (284 mg, 0.486 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran / water (4:1, 5 mL). An aqueous solution of lithium hydroxide (40.8 mg, 0.972 mmol, 2.0 equiv.) (1 mL) and a hydrogen peroxide solution (30%, 243 μL, 2.43 mmol) were added sequentially at 0 °C. After the addition was complete, the reaction proceeded at room temperature. After 3 hours, the organic solvent was removed by concentration under reduced pressure. The pH was adjusted to 11-12, and ethyl acetate (20 mL) was added. The mixture was extracted with an aqueous sodium hydroxide solution (20 mL × 4). The aqueous phases were combined, and the pH was adjusted again to 1-2. The mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in dry methanol (5 mL), and TMSCHN2 (2.0 M, 2.43 mL, 4.86 mmol, 10.0 equiv.) was added at 0 °C. After stirring at this temperature for 10 minutes, the organic solvent was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-8:1-5:1) to give compound 6 (colorless oil, 172 mg, 80% yield in 2 steps).

[0124] TLC: Petroleum ether / ethyl acetate = 4:1, R f =0.30;

[0125] 1 H NMR (400MHz, CDCl3): δ8.37–8.12(m,2H),7.35(d,J=9.1Hz,2H),6.19–6.03(m,1H),5.34–5.12(m,1H),3.79(d,J=2.2Hz,3H),3.70 –3.51(m,1H),3.30–3.03(m,1H),2.93–2.88(m,1H),2.85(dt,J=14.6,3.1Hz,1H),2.36–2.12(m,3H),1.05(dt,J=15.4,7.4Hz,3H).

[0126] 13C NMR (100MHz, CDCl3): δ169.64,169.58,156.14,152.61,151.89,145.36,144.93,144.71,144.65,127.53,126.91,125.06,125. 01,122.42,122.09,59.81,58.06,57.18,53.26,53.17,47.63,47.42,39.20,39.08,31.09,30.72,26.38,26.30,11.38,11.22.

[0127] IR(neat):ν max =3123,2964,2847,1721,1521,1398,1343,1214,1152,1054cm -1 ;

[0128] HRMS(ESI):m / z calcd.for C 18 H 19 BrN2O6[M+H] + 439.0499,441.0479,found439.0497,441.0481.

[0129] Example 13

[0130] Intermediate compound 4 was synthesized in Example 7 using a two-step synthesis method as follows: Compound 4 (47.6 mg, 0.0997 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran / water (4:1, 1.25 mL). At 0°C, an aqueous solution (0.2 mL) of lithium hydroxide (8.37 mg, 0.199 mmol, 2.0 equiv.) and an aqueous solution of hydrogen peroxide (30%, 50.9 μL, 0.499 mmol, 5.0 equiv.) were slowly added sequentially. After the addition was complete, the reaction proceeded at room temperature. After stirring for 3 hours, the organic solvent was removed by vacuum concentration. The pH was adjusted to 11-12, and ethyl acetate (5 mL) was added. The mixture was extracted with sodium hydroxide aqueous solution (5 mL × 4). The aqueous phases were combined, and the pH was adjusted again to 1-2. The mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was dissolved in dry methanol (2 mL), and TMSCHN2 (2.0 M, 499 μL, 0.997 mmol, 10.0 equiv.) was added at 0 °C. After stirring at this temperature for 10 minutes, the organic solvent was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-8:1-5:1) to give compound 7 (colorless oil, 24.5 mg, 74% yield in two steps).

[0131] TLC: petroleum ether / ethyl acetate = 4:1, v / v, R f =0.40;

[0132] 1 H NMR (400MHz, CDCl3): δ6.06–5.92(m,1H),5.25–4.94(m,1H),3.81–3.67(m,6H),3.41(ddd,J=9.9,4.4,1.8Hz ,1H),2.96(ddt,J=18.5,9.9,2.6Hz,1H),2.83–2.72(m,2H),2.22–2.04(m,3H),0.98(td,J=7.4,2.8Hz,3H).

[0133] IR(neat):ν max =2959,2852,2879,1735,1679,1445,1388,1299,1249,1107,1080cm -1 ;

[0134] HRMS:m / z calcd.for C 13 H 18 BrNO4[M+H] + 332.0492,334.0472,found 332.0489,334.0469.

[0135] Example 14

[0136] Intermediate compound 6 was synthesized using Example 12, and intermediate compound 9 was synthesized in three steps (or intermediate compound 7 obtained in Example 13 could be directly synthesized in two steps). The reaction formula and experimental method are as follows:

[0137]

[0138] Sodium methoxide (165 mg, 3.06 mmol, 5.0 equiv.) was added to a methanol (3 mL) solution of compound 6 (269 mg, 0.612 mmol, 1.0 equiv.). After the addition was complete, the temperature was raised to 50 °C and the reaction was carried out. After stirring for 12 hours, the solvent was removed by concentration under reduced pressure. A saturated NH4Cl solution (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-8:1) to obtain a colorless oily compound.

[0139] The compound (163 mg, 0.491 mmol, 1.0 equiv.) was dissolved in dichloromethane (2.5 mL), and iodotrimethylsilane (132 μL, 0.982 mmol, 2.0 equiv.) was added at 0 °C. The reaction was carried out at room temperature for about 24 hours. The organic solvent was removed by concentration under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 80:1-60:1-30:1) to give a colorless oily compound. 3-Indoleacetic acid (129 mg, 0.734 mmol, 1.2 equiv.) was dissolved in dry DMF (2.5 mL), and DIPEA (146 μL, 1.02 mmol, 2.0 equiv.) and tervapotranolol chloride (146 μL, 1.02 mmol, 2.0 equiv.) were added sequentially at 0 °C. After the addition was complete, the reaction was carried out at room temperature for 20 minutes. Then, a DMF solution of amine (1 mL) and DIPEA (146 μL, 1.02 mmol, 2.0 equiv.) were added sequentially at 0 °C, and the reaction was carried out at room temperature for 3 hours. A saturated ammonium chloride aqueous solution (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1-3:1-2:1) to give compound 9 (colorless oil, 168 mg, 60% yield in 3 steps).

[0140] TLC: petroleum ether / ethyl acetate = 1:1, v / v, R f =0.15;

[0141] 1 H NMR (400MHz, CDCl3): δ8.41(d,J=10.5Hz,1H),7.69(d,J=7.7Hz,0.5H),7.58(d,J=7.7Hz,0.5H),7.33(dd,J=7.9,2.6H z,1H),7.21–7.03(m,3H),6.05–5.90(m,1H),5.80–5.78(m,0.5H),4.93(s,0.5H),4.20(d,J=15.6,0.5H),3.95(d,J=15 .6,0.5H),3.78(d,J=3.3Hz,1H),3.76(s,1.5H),3.73(s,1.5H),3.54(t,J=8.8Hz,1H),3.19–2.99(m,1H),2.89–2.64( m,2H),2.23–1.99(m,2H),1.68–1.52(m,0.5H),1.39–1.18(m,0.5H),0.98(t,J=7.4Hz,1.5H),0.68(t,J=7.4Hz,1.5H).

[0142] 13 C NMR (100MHz, CDCl3): δ171.00,170.70,169.96,169.65,145.75,144.16,136.16,13 6.11,127.28,127.10,126.56,123.12,122.94,121.89,121.77,119.31,119.19,11 8.67,118.43,111.28,108.84,108.01,61.08,59.65,59.43,54.40,53.08,53.00,47.74,47.18,39.17,38.96,31.64,31.38,31.34,30.54,26.33,24.99,11.37,10.49.

[0143] IR(neat):ν max =3409,3275,3053,2964,2931,1736,1627,1456,1417,1261cm -1 ;

[0144] HRMS(ESI):m / z calcd.for C 21 H 23 BrN2O3[M+H] + 431.0965,433.0944,found431.0967,433.0967.

[0145] Example 15

[0146] Intermediate compound 9 was synthesized in Example 14, and intermediate compound 10 was synthesized. The reaction formulas and experimental methods are as follows:

[0147]

[0148] In a 23 mL solution of 1,4-dioxane (100 mg, 0.232 mmol, 1.0 equiv.) of compound 9, Ir(ppy)3 (3.04 mg, 0.00464 mmol, 0.02 equiv.) and sodium bicarbonate (38.9 mg, 0.464 mmol, 2.0 equiv.) were added sequentially. After three freeze-drying cycles to remove oxygen, the reaction was placed under a blue LED lamp. After 3 hours, the light source was removed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1–2:1) to give compound 10 (white solid, 61.9 mg, yield 76%).

[0149] TLC: Petroleum ether / ethyl acetate = 1:1, v / v, R f =0.25;

[0150] 1 H NMR (400MHz, CDCl3): δ8.22(s,1H),7.54(d,J=7.7Hz,1H),7.31–7.23(m,1H),7.16(t,J=7 .6Hz,1H),7.14–7.10(m,1H),6.26(d,J=6.1Hz,1H),5.12(s,1H),4.21(d,J=15.5Hz,1H),3 .79(d,J=15.5Hz,1H),3.66(s,3H),3.56–3.49(m,1H),2.94(d,J=10.4Hz,1H),2.87(s,1H) ,2.68(d,J=13.1Hz,1H),2.36–2.10(m,2H),1.72(d,J=13.1Hz,1H),1.11(t,J=7.4Hz,3H).

[0151] 13 C NMR (100MHz, CDCl3): δ174.62,173.10,143.85,135.17,128.78,127.50,122.44,119.93, 118.55,110.68,103.84,55.81,53.22,52.63,50.87,33.61,32.65,31.41,26.86,11.34.

[0152] IR(neat):ν max =3242,3055,2961,2931,1740,1630,1457,1442,1426,1251,1197cm -1 ;

[0153] HRMS(ESI):m / z calcd.for C 21 H 22 N₂O₃[M+H] + 351.1708, found 351.1703.

[0154] Example 16

[0155] In Example 15, intermediate compound 10 was synthesized, yielding (+)-catharanthine. The reaction formula and experimental method are as follows:

[0156]

[0157] Compound 10 (15.0 mg, 0.0428 mmol, 1.0 equiv.) was dissolved in THF (1.0 mL), and Rh(H)(CO)(PPh3)3 (5.89 mg, 0.00642 mmol, 0.15 equiv.) and phenylsilane (210 μL, 0.171 mmol, 4.0 equiv.) were added sequentially. The reaction was carried out at room temperature for 3 hours. The reaction was quenched with saturated tetrabutylammonium fluoride aqueous solution (1.0 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous MgSO4, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1-1:1) to give product (+)-catharanthine (colorless oil, 13.7 mg, yield 95%).

[0158] TLC: petroleum ether / ethyl acetate = 1:1, v / v, R f =0.20;

[0159] Optical rotation: =+24.017(c=0.230,CHCl3);

[0160] 1 H NMR (400MHz, CDCl3): δ7.66(s,1H),7.49(d,J=8.1Hz,1H),7.24(d,J=8.1Hz,1H),7.15(t,J=7.2Hz,1H),7.10( t,J=7.2Hz,1H),5.93(d,J=5.0Hz,1H),4.18(s,1H),3.74(s,3H),3.57(ddd,J=13.9,10.5,3.8Hz,1H),3.38(dt ,J=13.7,4.6Hz,1H),3.30(ddd,J=15.0,10.4,4.4Hz,1H),2.92(dt,J=16.5,4.3Hz,1H),2.86(m,J=6.2Hz,2H) ,2.77–2.66(m,2H),2.43–2.24(m,1H),2.20–2.03(m,1H),1.78(dd,J=13.7,3.2Hz,1H),1.07(t,J=7.3Hz,3H).

[0161] 13C NMR (101MHz, CDCl3): δ174.15,149.41,136.41,134.92,129.00,123.55,121.85,119.43,118 .20,110.73,110.41,61.87,55.41,53.02,52.33,49.27,38.69,30.73,26.15,21.36,10.63.

[0162] IR(neat):ν max =3373,2959,2875,1711,1459,1433,1264,1076,732cm -1 ;

[0163] HRMS(ESI):m / z calcd.for C 21 H 24 N₂O₂[M+H] + 337.1911, found 337.1913.

[0164] The above description is merely a preferred embodiment of the present invention. It should be understood that the present invention is not limited to the forms disclosed herein and should not be construed as excluding other embodiments. It can be used in various other combinations, modifications, and environments, and can be altered within the scope of the concept described herein through the above teachings or related technologies or knowledge. Modifications and variations made by those skilled in the art that do not depart from the spirit and scope of the present invention should be within the protection scope of the appended claims.

Claims

1. An asymmetric total synthesis method for vincristine, characterized in that, Includes the following steps: S1. Compound 1 is reacted with haloacrylic acid in a condensation reaction to obtain intermediate compound 2; wherein, R1 is one of methyl, phenyl, tert-butyl, isopropyl, benzyl, diphenylmethyl, and triphenylmethyl; R2 is one of hydrogen, methyl, phenyl, tert-butyl, isopropyl, and benzyl; R3 is one of hydrogen, methyl, phenyl, tert-butyl, isopropyl, and benzyl; and X is one of chlorine, bromine, and iodine. S2, intermediate compound 2 and compound 3 undergo an asymmetric DA reaction under the action of a catalyst to obtain intermediate compound 4; wherein, R4 is one of methyl, phenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, p-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl. S3. The intermediate compound 4 is hydrolyzed under the conditions of lithium hydroxide and hydrogen peroxide to obtain the intermediate compound 5. S4. Methylation of intermediate compound 5 yields intermediate compound 6; S5. React intermediate compound 6 with sodium methoxide to obtain intermediate compound 7; when R4 is methyl, skip step S5 and proceed directly to step S6. S6. The intermediate compound 7 is subjected to a deprotection reaction to obtain the intermediate compound 8; S7. Intermediate compound 8 is condensed with 3-indoleacetic acid to obtain intermediate compound 9; S8. Compound 10 was obtained by radical cyclization reaction of intermediate compound 9 under the catalysis of a photocatalyst. S9. The vincristine base is obtained by selectively reducing amide reaction of intermediate compound 10. In step S2, the catalyst used in the asymmetric DA reaction is one or more of the following: scandium trifluoromethanesulfonate, dichloroethylaluminum, aluminum oxide, boron trifluoride ether, trimethylsilyl trifluoromethanesulfonate, titanium chloride, indium trifluoromethanesulfonate, samarium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, silver trifluoromethanesulfonate, calcium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, nickel trifluoromethanesulfonate, tin chloride, and indium tribromide. In step S9, the reducing agent for the selective reduction reaction of the amide is one or more of tris(triphenylphosphine)carbonyl rhodium hydride, carbon bis(triphenylphosphine)iridium chloride, lithium borohydride, sodium borohydride, and triacetyl sodium borohydride.

2. The asymmetric total synthesis method of vincristine according to claim 1, characterized in that, In step S1, the molar ratio of compound 1 to haloacrylic acid is 1:1.1 to 5; And / or, the base used in the condensation reaction is one or more of the following: n-butyllithium, potassium tert-butoxide, sodium hydride, sodium bicarbonate, potassium carbonate, triethylamine, and diisopropylethylamine; And / or, the solvent used in the condensation reaction is one or more of DMF, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, and toluene; And / or, the solvent condensing agent used in the condensation reaction is one of trimethylacetyl chloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

3. The asymmetric total synthesis method of vincristine according to claim 1, characterized in that, In step S2, the molar ratio of intermediate compound 2, compound 3 and catalyst is 1:1.1~5.0:0.5~3.5; And / or, the solvent used in the asymmetric DA reaction is one or more of 1,2-dichloroethane, acetonitrile, toluene, and dichloroethane.

4. The asymmetric total synthesis method of vincristine according to claim 1, characterized in that, In step S3, the molar ratio of intermediate compound 4, lithium hydroxide and hydrogen peroxide is 1:1 to 3:5 to 10; And / or, the solvent in the hydrolysis reaction is tetrahydrofuran and water.

5. The asymmetric total synthesis method of vincristine according to claim 1, characterized in that, In step S4, the methylating agent for the methylation reaction is trimethylsilyldiazomethane, methyl methanesulfonate, methyl p-toluenesulfonate, or iodomethane; the molar ratio of the methylating agent to compound 5 is 1:10 to 20. And / or, the solvent for the methylation reaction is methanol.

6. The asymmetric total synthesis method of vincristine according to claim 1, characterized in that, In step S5, the molar ratio of intermediate compound 6 to sodium methoxide is 1:3 to 10; And / or, the solvent used in the reaction with sodium methoxide is methanol.

7. The asymmetric total synthesis method of vincristine according to claim 1, characterized in that, In step S6, the reagent used for the deprotection reaction is trimethyliodosilane, and the solvent is dichloromethane; or the reagent is lithium methyl, the solvent is tetrahydrofuran, and the reaction is carried out at -78°C; the molar ratio of the intermediate compound 7 to the deprotection reaction reagent is 1:2 to 10.

8. The asymmetric total synthesis method of vincristine according to claim 1, characterized in that, In step S7, the molar ratio of the intermediate compound 8 to 3-indoleacetic acid is 1:1.2 to 2; And / or, the condensing agent of the condensation reaction is one of pentanoyl chloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; And / or, the base of the condensation reaction is diisopropylethylamine or triethylamine; And / or, the solvent for the condensation reaction is dimethylformamide or tetrahydrofuran.

9. The asymmetric total synthesis method of vincristine according to claim 1, characterized in that, In step S8, the photocatalyst is one or more of the following: tris(2-phenylpyridine)iridium, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III)hexafluorophosphate, ruthenium-tris(2,2′-bipyridine)dihexafluorophosphate, tripyridine ruthenium chloride hexahydrate, or organic photocatalysts Eosin and Rose Bengal. And / or, the light source for the free radical cyclization reaction is blue light or other visible light; And / or, the base for the free radical cyclization reaction is one or more of sodium bicarbonate, potassium carbonate, disodium hydrogen phosphate, cesium carbonate, tripropylene glycol methyl ether acetate, 4-methoxytriphenylamine, 4-methoxypyridine, triethylamine, and N,N-diisopropylethylamine. And / or, the solvent for the free radical cyclization reaction is one or more of 1,4-dioxane, toluene, acetonitrile, tetrahydrofuran, dichloromethane, and 1,2-dichloroethane.

10. The asymmetric total synthesis method of vincristine according to claim 1, characterized in that, In step S9, the additive for the selective reduction amide reaction is one or more of benzylsilane, glacial acetic acid, formic acid, trifluoroacetic acid, triethylsilane, and tetramethyldisilazane. The solvent for the selective reduction amide reaction is one or more of methanol, tetrahydrofuran, dichloromethane, and toluene.

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