CN101029049B - Use of recovered and reutilized quinine derivative derivative ligand in synthesizing paclitaxel and polyene paclitaxel sided chain - Google Patents

Abstract

The invention relates to the application of recyclable and reusable cinchona alkaloid derivative ligands in the synthesis of side chains of anticancer drugs paclitaxel and docetaxel. The recyclable and reusable cinchona alkaloid derivative ligand represented by the general structural formula (I) can be used to synthesize the side chains of anticancer drugs paclitaxel and docetaxel, using the cheap and easy-to-obtain cinchona alkaloid quinine as a raw material , to prepare recyclable and reusable chiral ligands through reactions such as substitution and oxidation of alkenes, which significantly reduces the cost of synthesizing _C13 side chains. At the same time, the activity and stereoselectivity of the recovered ligands did not change significantly when they were reused.

Description

Application of recyclable and reusable cinchona alkaloid derivative ligands in the synthesis of paclitaxel and docetaxel side chains

technical field

The invention relates to the application of recyclable and reusable cinchona alkaloid derivative ligands in the synthesis of side chains of anticancer drugs paclitaxel and docetaxel, belonging to the field of medicinal chemistry.

Background technique

Paclitaxel and docetaxel are high-efficiency, low-toxic and broad-spectrum anticancer drugs, especially for gynecological tumors, so they are currently the fastest growing chemotherapy drugs in clinical use. The total sales in 2004 have reached 27% of all other chemotherapy drugs. Simultaneously, the side chain of docetaxel is obtained after slightly modifying the _C13 side chain of paclitaxel (that is, changing the benzoyl group of the side chain to a tert-butoxycarbonyl group). The obtained paclitaxel and docetaxel _C13 side chains are then coupled with baccatin III to obtain the anticancer drugs paclitaxel and docetaxel respectively. The activity of docetaxel is higher, twice that of paclitaxel. But it is not extracted from yew like paclitaxel, it can only be synthesized artificially.

Paclitaxel can be directly extracted from the bark and root of Taxus chinensis, but due to the very low content (only 0.6 per ten thousand), the extraction is very difficult. In addition, yew is a rare tree species, and massive felling of yew will not only destroy resources, but also have a catastrophic impact on the ecological environment. More importantly, the extraction method cannot meet people's demand for paclitaxel. Therefore, artificially synthesizing paclitaxel is the fundamental way to solve this problem.

There are two ways to artificially synthesize paclitaxel:

1. Artificial Total Synthesis 367:630.]: Because the structure of paclitaxel is extremely complex, the synthetic route is too long, and the total yield is low, so the artificial synthesis of paclitaxel has no practical significance at least at present.

2. Artificial semi-synthesis: through asymmetric epoxidation of alkenes [aJOrg.Chem., 1991, 56(8), 2869-2875.bJOrg.Chem., 1992, 57(1), 4320-4323.], Dihydroxylation [J.Org.Chem., 1994, 59 (17), 5104-5104.] or ammonia hydroxylation [Tetrahedron: Asym-metry, 1999 (10), 671-674.] reaction to synthesize paclitaxel and polyene The _C13 side chain of paclitaxel is then condensed with baccatin extracted from yew leaves to give paclitaxel or docetaxel. However, asymmetric catalytic methods generally use catalysts containing precious metals and expensive ligands, so the cost is high.

Contents of the invention

One of the purposes of the present invention is to provide a new recyclable cinchona alkaloid derivative ligand, which effectively reduces the production cost and has a good industrialization prospect because the ligand can be reused;

Another object of the present invention is to provide the application of the above-mentioned ligand in the asymmetric dihydroxylation or aminohydroxylation of alkenes and in the synthesis of side chains of anticancer drugs paclitaxel and docetaxel.

Content of the present invention is as follows:

The recyclable and reusable cinchona alkaloid derivative ligand with following general structural formula (I):

R ₁ is C ₁ -C ₅ alkyl, halogen, nitro, amino or C ₁ -C ₃ alkyl substituted phenyl;

R_2A为-OH、-S(CH₂)_nOH(n＝1-5整数)或-SO₂(CH₂)_nOH(n＝1-5整数)，R_2B为-H或-OH； _R2 is

R _2A is -OH, -S(CH ₂ ) _n OH (n=1-5 integer) or -SO ₂ (CH ₂ ) _n OH (n=1-5 integer), R _2B is -H or -OH;

_R3 is H or methoxy.

R ₁ is preferably C ₁ -C ₅ alkyl or C ₁ -C ₃ alkyl substituted phenyl.

R₃是甲氧基。R ₁ can be C ₁ -C ₃ alkyl substituted phenyl, such as p-tolyl, p-ethylphenyl, R ₂ is

_R3 is methoxy.

R_2A为-SO₂(CH₂)_nOH(n＝1-5整数)，如n＝2、3或4，R_2B为-H，R₃是甲氧基。R ₁ can also be C ₁ -C ₃ alkyl substituted phenyl, such as p-tolyl, p-ethylphenyl, R ₂ is

R _2A is -SO ₂ (CH ₂ ) _n OH (n=1-5 integer), such as n=2, 3 or 4, R _2B is -H, R ₃ is methoxy.

Generally, _R2 selects a polar group, such as hydroxyl, nitro, amino, sulfonyl, etc.; if a non-polar group is selected, the obtained ligand is difficult to recover.

The ligand represented by the general structural formula (I) can be used in the asymmetric dihydroxylation or aminohydroxylation reaction of olefins. Of course, if the ligand can be used in the asymmetric dihydroxylation reaction, the asymmetric aminohydroxylation can also be carried out reaction. In particular, the ligands represented by the general structural formula (I) are used in the synthesis of paclitaxel C ₁₃ fragments, docetaxel C ₁₃ fragments, paclitaxel and docetaxel.

Using recyclable and reusable chiral ligands, using methyl cinnamate as a raw material, through the key steps of asymmetric dihydroxylation (AD, Asymmetric Dihydroxylation) and esterification, cyclization, ring-opening catalytic reduction and substitution Steps such as reaction to synthesize paclitaxel C ₁₃ side chain and docetaxel C ₁₃ side chain, and then couple with baccatin III with protected hydroxyl to produce paclitaxel and docetaxel. The cinnamate esters used were methyl cinnamate, ethyl cinnamate, propyl cinnamate, isopropyl cinnamate, n-butyl cinnamate, isobutyl cinnamate, tert-butyl cinnamate.

The reaction equation for the synthesis of paclitaxel and docetaxel _C13 side chains by AD reaction starting from methyl cinnamate is as follows:

Reaction conditions: (1) AD reaction; (2) PPTs, MeC(OMe) ₃ , AcBr; K ₂ CO ₃ , MeOH; (3) NaN ₃ , DMF; (4) C ₆ H ₅ COCl, Et ₃ N, DMAP, _H2 , Pd-C _{, CH3CO2Et} ; NaOH; (5 ₎ (Boc) _2O , _H2 , Pd-C, _CH3CO2Et ; NaOH.

The key step in the synthesis of _C13 side chains is the AD reaction of alkenes, and the core work is the synthesis of cinchona alkaloid derivative ligands that can be recovered and reused in the AD reaction.

Synthesis of Paclitaxel and Docetaxel Side Chains by AD Reaction of Methyl Cinnamate in the Presence of Recyclable and Reusable Cinchona Bio-Derivative Ligands. Advantages of the present invention are: (1) use cheap and easy-to-get cinchona alkaloid quinine as raw material, prepare recyclable and reusable chiral ligands by reactions such as substitution and oxidation of olefins, significantly reduce the synthesis C ₁₃ The cost of the side chain; (2) Since R in the ligand is a polar group, it can be dissolved in the system of the AD reaction, so _the activity is high (the chiral tertiary amine ligand in the AD reaction can catalyze the reaction), and the three-dimensional Good choice. After the reaction, the ligand can be precipitated by adding a non-polar solvent, and the ligand can be recovered by simple filtration, achieving "homogeneous reaction, two-phase separation", and the recovery rate of the ligand is ≥92%. At the same time, the activity and stereoselectivity of the recovered ligands did not change significantly when they were reused.

Detailed ways

Example 1:

The structural formula of ligand 7 is shown in the figure.

The synthetic route of ligand 7 is shown below.

Reagents and reaction conditions:

(1) MsCl, Et ₃ N, THF, 90%; (2) NaN, DMF, 85-90°C; H ₂ , Pd-C, 82%;

(3) TsCl, K ₂ CO ₃ , PEG-400, CH ₂ Cl ₂ , rt, 80%, (4) NMO, OsO ₄ , CH ₂ Cl ₂ , 83%.

Synthesis of Ligand 7

1, the synthesis of quinine mesylate 9

In a 250mL three-necked flask, add 3.89g (12mmol) of quinine, 70mL of tetrahydrofuran (refluxing with sodium and benzophenone) and 7mL of triethylamine. The above reaction mixture was cooled to 0°C, and a solution of 0.93 mL (12 mmol) methanesulfonyl chloride in 10 mL tetrahydrofuran was slowly added dropwise. After the dropwise addition, react at 0°C for 2.5h, and then react at room temperature for about 4h until the reaction is complete (TLC tracking). Suction filtration, tetrahydrofuran was evaporated under reduced pressure, the residue was acidified with 1mol·L ^-1 HCl to pH = 5, the aqueous phase was extracted three times with ethyl acetate, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off to obtain an oily crude product. The latter was subjected to flash column chromatography (Et ₂ O/MeOH=9:1) to obtain 4.35 g of white crystals with a yield of 90%. IR (KBr) ν (cm ^-1 ): 2490, 1595, 1510, 1420, 1346, 1170, 945, 922, 868, 855, 834, 780.

2. Synthesis of 9-amino-(9-deoxy)epiquinine 10

Quinine mesylate 9 (4.26mmol, 1.71g) was dissolved in 27mL of DMF, sodium azide (420mg, 6.4mmol, excess) was added, and stirred at 85-90°C for 2h. 20 mL of water was added to the reaction liquid, and extracted three times with 30 mL of ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a red gum. The above crude product was dissolved in absolute methanol (0.1 mmol/mL), added with a catalytic amount of 10% Pd/C, and hydrogenated with high-purity H2 at room temperature until the reaction was complete (monitored by TLC). The reaction solution was filtered through a neutral Al ₂ O ₃ packed column, the insoluble matter was filtered off, and the solvent was removed by rotary evaporation. The residue was separated by flash column chromatography (EtOAc/MeOH=10:1) to obtain 10 as a pale yellow liquid. The yield was 82%. [α] D = +83° (c = 1.0, CHCl ₃ ). IR(KBr)ν(cm ^-1 ): 3380, 3290, 2080, 2940, 2860, 1625, 1600, 1515. ¹ H NMR (CDCl ₃ ): 0.80(m, 1H), 1.26～1.63(m, 4H), 2.08(s, 2H), 2.27(m, 1H), 2.77(m, 2H), 3.02～3.34(m , 3H), 3.97(s, 3H), 4.57(d, J=10.4Hz, 1H), 4.97(m, 2H), 5.79(m, 1H), 7.36～8.05(m, 4H), 8.75(d, J=4.6Hz, 1H). MS: m/z=323 (M ⁺ ), 207, 188, 136.

3. Synthesis of 9-p-toluenesulfonamide-(9-deoxy)epiquinine 11

9-Amino-(9-deoxy)epiquinine 10 (0.92g, 2.85mmol), p-toluenesulfonyl chloride (3.42mmol, 651.5mg), anhydrous potassium carbonate (19.95mmol, 2.76 g) Add a few drops of PEG 400 and 15mL CH ₂ Cl ₂ into a 50mL round bottom flask, and react at room temperature for 24h (monitored by TLC). After the reaction, the filtrate was washed with saturated sodium carbonate solution (25 mL×3), and dried over anhydrous sodium carbonate. The solvent was rotary evaporated to obtain 1.62 g of crude product, which was purified by flash column chromatography (EtOAc/MeOH=9:1) to obtain white crystals with a yield of 80%. mp65～67℃. [α] D = +45° (c = 0.55, CHCl ₃ ). IR (KBr) ν (cm ^-1 ): 3435, 2941, 1392, 1332, 1175. ¹ H NMR (400 MHz, CDCl ₃ ): 0.87～0.92(m, 1H), 1.24～1.30(m, 2H), 1.53～1.68(m, 5H), 2.13(s, 2H), 2.28(s, 3H) ), 2.65～2.90(m, 4H), 3.21～3.27(m, 2H), 3.84(s, 0.9H), 3.98(s, 2.1H), 4.33(d, J=11.2 Hz, 0.3H), 4.85 ～4.98(m, 2.7H), 5.61～5.65(m, 1H), 6.70(d, J=8.4Hz, 1H), 6.92(d, J=8.0 Hz, 1H), 7.17～7.54(m, 7H) , 7.82(d, J=9.2 Hz, 0.3H), 7.97(d, J=9.2Hz, 0.7H), 8.50(d, J=4.8 Hz, 0.7H), 8.60(d, J=4.0 Hz, 0.3 h).

4. Synthesis of recyclable ligand 9-N-TsQNC2H4OH 7

In a 100mL round bottom flask, add 0.95g (2.0mmol) N-p-toluenesulfonamido-(9-deoxy) epiquinine 9-N-TsQN 11, 0.7g (6.0mmol)-hydrated N-oxygen- 4-Methylmorpholine (NMO), 20mL THF, 8mL ^tBuOH , 0.24mL OsO ₄ toluene solution (100mg/mL) was added dropwise with stirring, and stirred at room temperature for 12h. NaHSO ₃ 6 g (excess) was added and stirring was continued for 1 h. Filter and dry the filtrate with anhydrous MgSO ₄ . The solvent was removed under reduced pressure. The residual solid was separated by column chromatography (developing solvent: CHCl ₃ :Et ₃ N=5:1) to obtain 0.38 g of product 9-N-TsQNC ₂ H ₃ (OH) ₂ 7 with a chemical yield of 75%. ¹ H NMR (CDCl ₃ ): 0.96 (1H, br), 1.09 (1H, br), 1.29 (3H, m), 1.34 (1H, m), 1.47 (1H, m), 1.48 (1H, m), 1.54(2H,m), 1.59(2H,m), 1.64(1H,m), 2.19(3H,s), 2.29(2H,t), 3.17(1H,m), 3.39(3H,s), 6.94 ~8.64 (9H, Ar-H).

Example 2: The structural formula of Ligand 8 is as follows.

Recyclable ligand 8 was synthesized by the following reaction.

Synthesis of Ligand 9-N-TsQNC ₂ H ₄ SO ₂ C ₂ H ₄ OH 8

1. Synthesis of intermediate 9-N-TsQNC ₂ H ₄ SC ₂ H ₄ OH 12

Add 0.53g (3.2mmol) of azobisisobutyronitrile (AIBN), 0.6mL (8.4mmol) of mercaptoethanol, 3.8g (8mmol) of p-toluenesulfonamidoquinine 11 and 60mL of chloroform into a 100mL three-necked flask, nitrogen Reflux for 36 h under protection (TLC monitoring reaction), cool to room temperature, add 40 mL of water, wash with chloroform, dry over anhydrous MgSO ₄ , evaporate the solvent under reduced pressure to obtain a crude product, separate by column chromatography (CH ₃ OH:Et ₃ N= 5:1), 70.40 g of the product was obtained, and the yield was 71%. ¹ H NMR (CDCl ₃ ): 8.57 (1H, quinoline ring proton), 8.23 (1H, br, -NH), 7.76～7.04 (8H, Ar-H), 4.78 (1H, br, OH), 4.13 ( 1H, d, J=7.2Hz, C ₉ -H), 3.90 (2H, t, CH ₂ -OH), 2.85 (1H, q, C ₈ -H), 2.63 (2H, t, S-CH ₂ ) , 2.44 (2H, m, S-CH ₂ ), 2.33-2.19 (4H, 2CH ₂ ), 1.59-1.29 (10H, m).

2. Synthesis of Ligand 9-N-TsQNC ₂ H ₄ SO ₂ C ₂ H ₄ OH 8

3.0 g (5.4 mmol) of 9-N-TSQNC ₂ H ₄ SC ₂ H ₄ OH 12 , 1.0 g (9 mmol) of NMO, 20 mL of THF, and 7 mL ^of tBuOH were successively added to a round bottom flask. 0.33 mL of a 100 mg/mL OsO ₄ -toluene solution was added dropwise with stirring. Stir at room temperature for 26h. Add NaHSO ₃ 10g (excessive amount), and continue stirring for 1h. After filtration, the filtrate was dried with anhydrous Na ₂ CO ₃ , the solvent was evaporated under reduced pressure, and the remaining solid was separated by column chromatography (eluent CHCl ₃ : MeOH:Et ₃ N=8:1:0.5). 2.0 g of the product 9-N-TsQNC ₂ H ₄ SO ₂ C ₂ H ₄ OH 8 was obtained with a yield of 63%. ¹ H NMR (CDCl ₃ ): 8.23 (1H, s, NH), 7.48~8.64 (5H, quinoline ring proton), 7.38~7.68 (4H, Ar-H), 4.78 (1H, disappears with D ₂ O) , 4.13 (1H, C ₉ -H), 4.09 (2H, O-CH ₂ ), 3.6 (2H, S-CH ₂ ), 3.41 (2H, S-CH ₂ ), 2.85 (1H, C ₈ -H) , 2.33(2H), 2.29(2H), 1.59(2H), 1.54(2H), 1.48(2H), δ ¹³ C(CDCl ₃ ): 156.7, 148.3, 142.3, 141.6, 140.5, 136.7, 130.7, 129.3, 128.3, 127.2, 121.7, 60.9, 59.0, 57.8, 56.0, 55.8, 52.4, 49.6, 49.2, 40.7, 37.0, 30.8, 30.2, 24.3, 21.5.

Embodiment 3: the recovery experiment of ligand and the synthesis of paclitaxel and docetaxel C ₁₃ side chain

1. Add acetone-water (ν/ν=9:1) 100mL, OsO ₄ 51μL 0.02mmol) OsO ₄ toluene solution (100mg/mL) and ligand 7 5.2mg (0.01mmol) in a 250mL round bottom flask, stir After 10 min, 1.35 g (10 mmol) of N-oxy-4-methylmorpholine (NMO) and 1.76 g (10 mmol) of ethyl cinnamate were added, and stirred at 0° C. for 24 h. Add solid Na ₂ SO ₃ 3.5g (excess), slowly warm up to room temperature, and continue stirring for 45min. Filter, evaporate the acetone in the filtrate under reduced pressure, dissolve the residue with 30mL _CH2Cl2 , _dry over anhydrous _Na2SO4 , filter, concentrate the filtrate to one third under reduced _pressure , add ether to completely precipitate the ligand, After filtration, 0.47 g of the ligand was recovered, with a recovery rate of 92%. Diethyl ether in the filtrate was distilled off under reduced pressure to obtain the crude product of ethylene glycol 9, and the impurities were washed away with a solvent to obtain 2.00 g of the pure product with a yield of 95% and an optical purity of 99% ee. [α] _D = +6.6° (c1.0, EtOH).

^* Using 0.059g (0.01mmol) of ligand 8 to replace ligand 7, the rest of the operation was the same as above, 0.056g of ligand was recovered, the recovery rate was 93%, and 2.00g of dihydroxylated product was obtained. The optical purity of the product was ~99%ee.

^* The recovered ligand was used in the AD reaction of methyl cinnamate according to the above method, and was recovered and reused 10 times. The recovery rate of the ligand, the yield of the AD reaction and the ee value of the product are collected in Table 1.

Table 1 Recovery and reuse of ligands 7 and 8 in AD reactions

2. Synthesis of (2R, 3R)-3-phenyl-2,3-epoxypropionic acid methyl ester 5

Add 2.10g (10mmol) ethylene glycol 4, 15mL CH ₂ Cl ₂ , 20mg pyridine p-toluenesulfonate (PPTS) and 1.5mL triethyl orthoformate into a round bottom flask, and stir at room temperature for 20min. The solvent was evaporated, the residue was dissolved in CH ₂ Cl ₂ , 90 μL of acetyl bromide was added dropwise with stirring, and stirring was continued at room temperature for 30 min. The solvent was evaporated, and the remaining yellow oil was dissolved in 35 mL of MeOH, added with 1.8 g of anhydrous K ₂ CO ₃ , and stirred at room temperature for 1.5 h. The reaction solution was directly poured into 70 mL saturated NH ₄ Cl solution, then extracted with CH ₂ Cl ₂ (50 mL×3), the extracts were combined, and the solvent was evaporated to obtain 1.63 g of a yellow oil with a yield of 85%. ¹ H NMR: 3.67 (3H, s, CH ₃ ), 3.75 (1H, d, j=7.5Hz, OC ^* -H), 4.45 (1H, d,=8.5Hz, OC ^* H), 7.19-7.37( m, 5H, Ar-H).

3. Synthesis of (2R, 3S)-2-hydroxy-3-azido-3-phenylpropionic acid methyl ester 6

Add 1.92g (10mmol) epoxy compound 5, 3.23g NaN ₃ , 8mL ethyl formate and 45mL methanol-water (volume ratio 8:1) solution into a round bottom flask, and react at 50°C for 40h. Methanol was evaporated under reduced pressure, the aqueous layer was extracted with dichloromethane (50mL×3), the extracts were combined, dried over anhydrous MgSO ₄ , and the solvent was evaporated to give 2.23g of light yellow oil with a yield of 95%. ¹ H NMR: 3.80 (1H, d, j = 7.0, N ₃ C ^* H), 3.67 (3H, s, CH ₃ ), 4.14 (1H, br, OH), 4.50 (1H, d, j = 8.7, OC ^* H), 7.12-7.32 (5H, m, Ar-H). 4. Synthesis of (2R, 3S)-(-)-N-(tert-butoxycarbonyl)-3-phenylisoserine methyl ester 2 (docetaxel side chain)

219mg of Pd-C with a mass fraction of 10% was dissolved in 4.4mL of ethyl acetate, and then 2.35g (10mmol) of azide 6 and 2.62g (12mmol) of di-tert-butyldi Carbonate [(Boc) ₂ O] was added into the reaction flask under the protection of H ₂ , and reacted at room temperature under H ₂ atmosphere for 48h. After filtration, the solvent was distilled off under reduced pressure to obtain a white solid, which was recrystallized to obtain 2.87 g of white needle-like crystals, with a yield of 90%. mp128.0-129.0°C, [α]D=+6.9°(c 1.0, CHCl ₃ ), mp 124°C, [α] _D =+6.3°(c1.0, CHCl ₃ )]. ¹ H NMR (300 MHz, CDCl ₃ ): ¹ H NMR 1.32(t, 3H), 1.40(s, 9H), 3.15(s, 1H), 3.82(s, 1H), 4.30(q, 2H), 4.42 (s, 1H), 5.22 (d, 1H, J=9.0Hz), 5.39 (d, 1H, J=8.5Hz), 7.28~7.37 (m, 5H).

5. Synthesis of (2R, 3S)-(-)-N-benzoyl-3-phenylisoserine methyl ester 1 (paclitaxel side chain)

Use benzoyl chloride instead of (Boc) ₂ O, and the rest are the same as the operation steps of Synthesis 2. Yield 95%, mp 184～185°C[α] _D =-48°(c 1.0, MeOH), ¹ HNMR (CDCl ₃ ): 8.87 (1H, br, -NH), 7.86～7.12 (10H, m, Ar -H), 5.59 (1H, d, J=9.4 Hz, N- ^* CH), 5.06 (1H, d, J=8.5Hz, O- ^* CH), 4.14 (1H, br, OH), 3.67 (3H , s, CH ₃ ).

Claims (9)

1. have the recyclable and reusable cinchona alkaloid derivative part of following structural general formula (I):

R ₁ is C ₁ -C ₅ alkyl, halogen, nitro, amino or C ₁ -C ₃ alkyl substituted phenyl; _R2 is

R _2A is -OH, -S(CH ₂ ) _n OH or -SO ₂ (CH ₂ ) _n OH, n=1-5 integer, R _2B is -H or -OH; _R3 is H or methoxy. 2. The recoverable and reusable cinchona alkaloid derivative ligand according to claim 1, characterized in that: R is _{C 1 -C 5} alkyl or C ₁ -C ₃ alkyl substituted benzene base. 3. The recyclable and reusable cinchona alkaloid derivative part according to claim 1 or 2, characterized in that: R ₁ is C ₁ -C ₃ alkyl substituted phenyl; R ₂ is

_R3 is methoxy. 4. The recyclable and reusable cinchona alkaloid derivative part according to claim 1 or 2, characterized in that: R ₁ is C ₁ -C ₃ alkyl substituted phenyl; R ₂ is R _2A is -SO ₂ (CH ₂ ) _n OH, n=1-5 integer, R _2B is -H; R ₃ is methoxy. 5. The application of the ligand represented by the general structural formula (I) of claim 1 in the asymmetric dihydroxylation or ammonia hydroxylation of olefins. 6. The application of the ligand represented by the general structural formula (I) of claim 1 in the synthesis of paclitaxel C ₁₃ fragments, docetaxel C ₁₃ fragments and paclitaxel and docetaxel. 7. purposes according to claim 6, it is characterized in that: take cinnamate as raw material, in the presence of the part represented by general structural formula (I) synthetic paclitaxel _C13 segment or docetaxel _C13 segment. 8. purposes according to claim 7, it is characterized in that: used cinnamate is methyl cinnamate, ethyl cinnamate, propyl cinnamate, isopropyl cinnamate, n-butyl cinnamate, isobutyl cinnamate Esters, tert-butyl cinnamate. 9. The use according to claim 7 or 8, characterized in that: the obtained paclitaxel C ₁₃ fragment or docetaxel C ₁₃ fragment is coupled with the natural product baccatin to further obtain paclitaxel or docetaxel.