Method for synthesizing carex A ring fragment key intermediate and method for synthesizing A ring C1-C14 fragments

Abstract

The invention discloses a method for synthesizing a carex A-ring fragment key intermediate and a method for synthesizing A-ring C1-C14 fragments, and belongs to the field of chemical synthesis, and the method for synthesizing the carex A-ring fragment key intermediate comprises the following steps: dissolving a compound (V) and a compound (VI with a solvent, adding 2, 4-dichloro-2, 4-diphenyl-1, 3, 4-triazole-1, 3, 4-triazole-1, 3-diphenyl-1, 3, 4-triazole-1, 3-diphenyl-1, 3- The preparation method comprises the following steps: adding 2, 6-di-tert-butyl-4-methylpyridine, an activating agent and metal particles or powder, then adding substituted bipyridine-metal nickel halide as a catalyst, and carrying out a coupling reaction, thereby obtaining the 2, 6-di-tert-butyl-4-methylpyridine. The invention also discloses a method for synthesizing the C1-C14 fragment of the A ring. According to the invention, an asymmetric [2 + 2] cyclization method is used for diastereoselective construction at C3 / C5 position and asymmetric reduction at C7 position for the first time, so that the diastereoselectivity of C3 / C5 / C7, i.e., the dr value greater than or equal to 95: 5, is higher than that reported in the prior art, the existence of a large number of grass moss isomers in the synthetic route is avoided, high performance liquid phase separation in the later period is not needed, and the method is suitable for industrial production. Therefore, the separation cost is obviously reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing a key intermediate of a bruceastatin A ring fragment and a method for synthesizing an A ring C1-C14 fragment. Background Art

[0002] Bryostatins (1968) are a class of marine macrolide compounds extracted from the marine bryozoan bryozoan, which have been shown to have anti-cancer, anti-AIDS and anti-Alzheimer's effects. So far, the number of members of this class of natural products has increased to 21 through extraction and separation studies.

[0003] The skeleton structure of the natural product bryostatin includes: three ABC polysubstituted tetrahydropyran rings with different oxidation states, a large sterically hindered C16-C17 E-double bond linking the BC ring, a geminal dimethyl group (Bryostatins 1-20) or a chiral monomethyl group (Bryostatins 21) at C18, and two acid-base unstable exocyclic unsaturated esters at C13\C17 (except for C9 and C19 of Bryostatins 16 and 17, which are ketal structures). Due to the challenging unique structural skeleton of this type of molecule, as well as their high biological activity in vitro and in vivo, and the extremely low yield of extraction and separation from nature, their total synthesis is an urgent problem to be solved. Among them, the key to the efficiency of the total synthesis lies in how to efficiently construct the three polysubstituted pyran rings of Bryostatins A, B, and C, especially the construction of the highly oxidized, polysubstituted A and C rings, which determines the specific type of Bryostatin molecules synthesized and the length and efficiency of the synthetic route.

[0004] Among them, the synthesis of the A ring C1-C14 fragment has been reported less. Among them, Chinese patent application CN109923110 A discloses a synthesis method, which has at least the following problems: (1) The stereoselectivity of the synthesis method is low, and the dr value of the C5 position is only 2:1; (2) A large amount of equivalent expensive chiral auxiliary agents are used in the synthesis of key intermediates, which is costly and not easy to industrialize; (3) The hydrolysis of the ethyl ester group in the synthesis route uses highly toxic and expensive trimethyltin hydroxide, which is costly and difficult to operate, and is easy to pollute the environment; (4) The overall synthesis route has 10 steps, but there are 7 separation steps, the post-reaction treatment is cumbersome, and the total yield is only 13%, and there is still room for further improvement to make it more suitable for industrialization. Summary of the invention

[0005] One of the purposes of the present invention is to provide a method for synthesizing a key intermediate of bruceastatin A ring fragment to solve the above-mentioned problem.

[0006] In order to achieve the above-mentioned object, the technical solution adopted by the present invention is as follows: a method for synthesizing a key intermediate of the A ring fragment of bruceastatin, wherein compound (V) and compound (VI) are dissolved in a solvent, and then 2,6-di-tert-butyl-4-methylpyridine, an activator and metal particles or powder are added, and then a substituted bipyridine-metal nickel halide is added as a catalyst to carry out a coupling reaction to obtain compound (VII), and the reaction formula thereof is shown below:

[0007]

[0008] In the above reaction formula, R 1 R is selected from H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, aromatic or aromatic substituted by heteroatoms; 2 , R 3 is selected from H, alkyl, substituted alkyl, alkenyl, alkynyl, halogen, amino, phenyl, substituted phenyl, R 2 , R 3 Same or different; R 4 Selected from 1,3-dihydroxy protecting groups or their chemical synthesis equivalents; R 5 Representative groups are halogen, alkoxy, substituted alkoxy, acyloxy, substituted acyloxy, phenoxy, substituted phenoxy, substituted heterocyclic aromatic oxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, substituted heterocyclic aromatic thio; R 6 is selected from alkyl or substituted alkyl; P and P 1 is selected from H, various hydroxyl protecting groups; X is selected from chlorine, bromine, iodine, boron, and substituted boron.

[0009] As a preferred technical solution, the R 4 is selected from one of an alkyl group, a substituted alkyl group, and a cyclic alkyl group; said R 5 is selected from various alkylthiols, substituted alkylthiols, substituted or unsubstituted arylthiols, aromatic esters, substituted aromatic esters, phentin esters, aromatic heterocyclic thiols, halogens, preferably 5-methylpyridylthio, 4-methylpyridylthio, 3-methylpyridylthio, 5-methoxypyridylthio, 5-chloropyridylthio, 4-chloropyridylthio; the P 1 One selected from the group consisting of alkyl, substituted alkyl, amino, phenyl, and substituted phenyl.

[0010] As a preferred technical solution, the substituted bipyridine in the catalyst is selected from 4,4'-di-tert-butyl-2.2'-bipyridine, 4,4'-di-tert-butyl-6-methyl-2.2'-bipyridine, 4,4'-di-tert-butyl-6,6'-dimethyl-2.2'-bipyridine, 3,3'-dimethyl-2.2'-bipyridine, 4,4'-dimethyl-2.2'-bipyridine , 4,4'-dimethoxy-2.2'-bipyridine, 2,3,4,7,8,9-hexamethyl-1,10-phenanthroline, 4,7-dimethoxy-2,9-dimethyl-1,10-phenanthroline, 2,9-diisopropyl-1,10-phenanthroline; the metal nickel halide in the catalyst is selected from one of nickel dibromide, nickel dichloride and nickel diiodide;

[0011] The solvent is selected from one of N,N-dimethylformamide, N,N-dimethylaniline, N,N-dimethylpropylene urea, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, dichloroethane, ether, ethyl acetate, 1,4-dioxane, acetonitrile, benzene, toluene, ethylene glycol dimethyl ether, hexafluoroisopropanol, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, or a mixed solvent of 1,3-dimethyl-2-imidazolidinone / ethyl acetate, 1,3-dimethyl-2-imidazolidinone / acetonitrile, 1,3-dimethyl-2-imidazolidinone / tetrahydrofuran, 1,3-dimethyl-2-imidazolidinone / ethylene glycol dimethyl ether; preferably, the volume ratio of 1,3-dimethyl-2-imidazolidinone / ethyl acetate is 10 / 1, 8 / 1, 5 / 1, 3 / 1, 1 / 1, 1 / 2, 1 / 4, 1 / 10, 1 / 20;

[0012] The activator is selected from one of dichlorozirconocene, triethylchlorosilane, trimethylchlorosilane, chromium dichloride, cobalt phthalocyanine, lithium iodide, magnesium chloride, 4-fluoro-styrene, and 4-trifluoromethyl-styrene.

[0013] As a preferred technical solution, the molar ratio of the raw materials is compound (VI): compound (VII): 2,6-di-tert-butyl-4-methylpyridine: activator: metal particles or powder: catalyst = 1:1.2:4.0:3.0:6.0:0.3, and the reaction is carried out under stirring. The preferred stirring speed is 400-4000r / min. The appropriate stirring speed effectively ensures that the contact between the substances is more complete. Different feed amounts have different required speeds. However, the overall trend is that the larger the feed amount, the greater the speed, which can improve the reaction quality and efficiency.

[0014] The second object of the present invention is to provide a method for synthesizing the C1-C14 fragment of bruceastatin A ring, the technical scheme adopted is comprising the following steps:

[0015] (1)-(3), three-step continuous reaction: the aldehyde represented by compound (I) undergoes asymmetric [2+2] cyclization at the C5 aldehyde group in the presence of a catalyst to obtain compound (II), followed by ester condensation at the C7 position to obtain compound (III), and finally, the carbonyl group at the C7 position undergoes asymmetric reduction to obtain the cyclization product;

[0016] The above-mentioned synthesis method of the present invention achieves a three-step yield of up to 45% and dr≥95:5, and only one step of purification is required for the three-step reaction, and the asymmetric selectivity of the C5 and C7 positions of the method is much higher than that reported previously;

[0017] (4)-(6), the cyclization product obtained in step (3) is subjected to protection of the hydroxyl groups at C5 and C7, selective removal of the ester group at C9, and thioesterification at C9 to obtain a thioester product;

[0018] The above-mentioned synthesis method of the present invention achieves a three-step yield of up to 86% and only requires one purification and separation; and the originality of the synthesis of thioester is used in the synthesis of bruceastatin;

[0019] (7), the thioester product (V) and the compound (VI) are subjected to a nickel-catalyzed coupling reaction to construct the C1-C14 fragment of the straight-chain skeleton of the bruceidin A ring;

[0020] The skeleton construction method of this step is completely different from the existing reports, making the yield of this step stable and as high as 76%;

[0021] (8) Under the catalytic action of pyridine p-toluenesulfonate, the linear skeleton C1-C14 fragment of bryozostatin A ring obtained in step (7) is ring-closed to form a cyclic product;

[0022] The yield of this step reached 86%;

[0023] (9), after bromination reaction of the silicon protecting group and deprotection reaction of the terminal ester group;

[0024] (10), chemoselective protection of the hydroxyl group to obtain the carboxylic acid product;

[0025] (9)-(10) The two-step yield reached 63%;

[0026] (11), using a geminal bissilyl reagent to carry out a Kumada coupling reaction to obtain a brucein A ring C1-C14 fragment of formula (VII),

[0027] The synthesis method of this step can synthesize the C1-C14 fragment of the A ring of brucein at a gram scale with a yield of 90%;

[0028] in,

[0029] Wherein, the reaction formula of step (1) is:

[0030]

[0031] The reaction formula of step (2) is:

[0032]

[0033] The reaction formula of step (3) is:

[0034]

[0035] The reaction formula of steps (4)-(6) is:

[0036]

[0037] The chemical starting reagent used for synthesizing the A ring C1-C14 fragment of bruceastatin in the present invention is commercially available (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester; the total number of steps for finally synthesizing the A ring C1-C14 fragment from this reagent is 11 steps, of which only 6 steps are required for separation steps, the total yield is as high as 14.3%, and the selectivity dr value of C5 is ≥95:5.

[0038] The present invention is the first to use the asymmetric [2+2] cyclization method to construct the diastereoselective construction of the C3 / C5 position and the asymmetric reduction of the C7 position, ultimately making the diastereoselectivity of C3 / C5 / C7 of bruceastatin, i.e., the dr value ≥ 95:5, higher than that in existing reports, ensuring the absence of a large number of bruceastatin isomers in the synthetic route, and eliminating the need for subsequent high-performance liquid phase separation, thereby significantly reducing the separation cost.

[0039] As a preferred technical solution, during the reaction of step (1), one of 9-O-benzylquinidine, unsubstituted quinidine, 9-O-alkyl substituted quinidine, 9-O-benzene substituted quinidine, 9-O-aromatic heterocyclic substituted quinidine, 9-O-amino substituted quinidine or other substituted quinidine is added.

[0040] 9-O-benzylquinidine is further preferred, which can achieve higher yield and diastereoselectivity.

[0041] As a preferred technical solution, during the reaction of step (1), the solvent used is a dichloromethane / ether mixed solvent, or one of dichloroethane, ether, and tetrahydrofuran, and the water content of the solvent is preferably less than 10 ppm.

[0042] As a preferred technical solution, the reaction temperature of step (1) is -78°C to -25°C.

[0043] Further preferably, -45°C can achieve higher yield and diastereoselectivity.

[0044] As a preferred technical solution, the reaction equivalents of (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester, 9-O-benzylquinidine, lithium perchlorate, and N,N-diisopropylethylamine can also be changed accordingly, but in order to ensure high yield and diastereoselectivity, the optimal equivalents are 1.0 molar equivalent of (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester, 10% molar equivalent of 9-O-benzylquinidine, 1.0 molar equivalent of lithium perchlorate, and 2.5 molar equivalents of N,N-diisopropylethylamine.

[0045] Furthermore, the reaction product of general formula (I) has a diastereoselectivity at C3\C5, that is, a diastereomeric excess ratio dr value ranging from 90:10 to 95:5.

[0046] As a preferred technical solution, during the reaction in step (2), one of potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium diisopropylamide, and n-butyl lithium is added, and one of magnesium bromide etherate and boron trifluoride etherate is also added, and allyl isobutyrate is also added, and the solvent is tetrahydrofuran.

[0047] As a preferred technical solution, during the reaction in step (2), the concentration of the reaction system is 0.01 mol / L to 0.1 mol / L; more preferably 0.05 mol / L, which can achieve a higher yield;

[0048] The temperature of the reaction system in step (2) is between -45°C and -80°C; preferably -78°C to achieve a higher yield;

[0049] The reaction time of step (2) is 6 to 24 hours; generally speaking, extending the reaction time can increase the reaction yield;

[0050] 20 h is further preferred, as it can achieve a higher yield.

[0051] Compared with the prior art, the advantages of the present invention are: the total yield of the synthetic route is increased to 14.3% compared with all the existing reports, the starting materials are commercially available and low in cost, in the specific synthetic method, the stereoselective construction of the C5 position uses the asymmetric [2+2] cyclization strategy of aldehyde for the first time, the stereoselectivity of the C5 position, i.e., the dr value, is increased to ≥95:5, the carbon-carbon bond connection mode of the C9 and C10 positions innovatively uses the coupling method of thioester and iodoalkane catalyzed by metal nickel, and the skeleton construction of the C1-C14 fragment of the A ring of bruceastatin is realized in one step, which greatly improves the synthetic efficiency, and the reaction of this step is The conditions are mild, and no low temperature or heating or hazardous reagents are required. Under the reaction conditions of the present invention, the yield of the original substrate is increased from 43% to 76%, and the problem of slow reaction rate of complex thioester coupling is solved, and the original reaction time is shortened from at least 2 days to 24 hours. The C1-C14 fragment of the bruceastatin A ring obtained by the present invention is a geminal disilicon. Compared with the single silicon bond in the prior art, the compound obtained by the geminal disilicon is more stable and easier to store for a long time. When the subsequent Prince cyclization reaction is used to construct the B ring, the stereoselectivity of the C13 exocyclic double bond is significantly improved, and Z / E≥95:5 (CN 109923110 A reports that the stereoselectivity of the C13 enoate double bond is obtained by an asymmetric HWE reaction, and Z / E is only 11:1), thereby avoiding the difficulty of separating its isomers. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 This is the hydrogen spectrum of compound 2 synthesized in step 1) of Example 1 of the present invention;

[0053] Figure 2 The carbon spectrum of compound 2 synthesized in step 1) of Example 1 of the present invention;

[0054] Figure 3 is the hydrogen spectrum of compound 4 obtained in step 3) of Example 1 of the present invention;

[0055] Figure 4 The carbon spectrum of compound 4 obtained in step 3) of Example 1 of the present invention;

[0056] Figure 5 is the hydrogen spectrum of compound 10 obtained in step 11) of Example 1 of the present invention;

[0057] Figure 6 This is the carbon spectrum of compound 10 obtained in step 11) of Example 1 of the present invention. DETAILED DESCRIPTION

[0058] The present invention will be further described below in conjunction with the accompanying drawings.

[0059] Embodiment 1:

[0060] A method for synthesizing the C1-C14 fragment of bruceascin A ring, the reaction formula of which is as follows:

[0061]

[0062] The specific synthesis steps are:

[0063] 1) At -45°C, under argon protection, lithium perchlorate (10.67 g, 100 mmol, 1.0 equivalent) was weighed into a 2L round-bottom flask, 1L of dichloromethane and 660 mL of ether were added as a mixed solvent, 9-O-benzylquinidine (4.16 g, 10.0 mmol, 10 mol%) and diisopropylethylamine (32.4 g, 250 mmol, 2.5 equivalent), (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester (40 g, 100 m mol, 1.0 equivalent) was dissolved in 200 mL and added to the system. After stirring for 10 minutes, 120 mL of dichloromethane solution of acetyl chloride (14.2 mL, 200 mmol, 2.0 equivalent) was added dropwise to the reaction system at 15 mL / h by means of a syringe pump, and the reaction was continued for 24 hours. After the reaction was completed as detected by TLC, brine was added to quench, and dichloromethane was extracted 3-4 times. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a concentrate of a quaternary lactone compound, namely compound 2, which was used in the next step without purification.

[0064] The H-NMR and C-NMR spectra of compound 2 are shown in Figure 1 and Figure 2 , the results showed that dr≥95:5; 1 H NMR (400MHz, CDCl3) δ7.75–7.63(m,4H),7.48–7.35(m,6H),4.57–4.47(m,1 H),4.37–4.26(m,1H),4.02(qd,J=7.2,2.4Hz,2H),3.41(dd,J=16.0,6.0Hz ,1H),2.88(dd,J=16.0,4.4Hz,1H),2.49(dd,J=14.8,5.6Hz,1H),2.42(dd, J=14.8,6.8Hz,1H),2.13–1.92(m,2H),1.17(t,J=7.2Hz,3H),1.04(s,9H); 13 C NMR (150MHz, CDCl3) δ170.5,167.8,135.8,135.8,133.3,133.1,130.0,129.9, 127.8,127.7,68.0,67.5,60.5,43.4,42.3,42.2,26.8,19.3,14.0;IR(neat)cm -12963,2940,2863,1836,1733,1470,1113,1090,823,701; HRMS(MALDI,m / z)calcdfor C 25 H 32 O5Si(M+Na) + 463.1911, found 463.1916; [α] D 25 =+0.34°(c=1.0in CHCl3);

[0065] 2) At -78°C, under argon protection, potassium hexamethyldisilazide (452mL, 452mmol, 5.0 equivalents. 1M in THF) was drawn into a round-bottom flask by syringe, and 400mL of anhydrous tetrahydrofuran was added and mixed and precooled; allyl isobutyrate (61.34g, 478.6mmol, 5.3 equivalents) was dissolved in 300mL of tetrahydrofuran and added dropwise through a dropping funnel. After the addition was complete, stirring was continued for 1 hour; the reaction solution was then transferred to a tetrahydrofuran (800mL) solution of magnesium bromide ether complex (141g, 541.8mmol, 6.0 equivalents) precooled at -78°C, and stirring was continued for 1 hour; at the same time, the step Step 1) The obtained quaternary lactone compound 2 (90.3 mmol, 1.0 equivalent) was dissolved in 200 mL of tetrahydrofuran in a 500 mL round-bottom flask, precooled at -78°C for 30 minutes, and the precooled tetrahydrofuran solution of the quaternary lactone compound 2 was quickly transferred to the above reaction system, and the reaction was continued at -78°C for 20 hours; after the reaction was completed, a saturated aqueous solution of ammonium chloride was added to quench, extracted with ether, dried over anhydrous sodium sulfate, and concentrated to obtain a concentrate of compound 3, which was directly used for asymmetric reduction without purification;

[0066] 3) At room temperature, under argon protection, tetramethylammonium triacetoxyborohydride (114 g, 433.3 mmol, 8.0 equivalents) was weighed into a 1L round-bottom flask, and 540 mL of acetonitrile and 540 mL of glacial acetic acid were added in sequence, and stirred until the solid was completely dissolved; the compound 3 concentrate obtained in step 2) (54.2 mmol, 1.0 equivalent) was dissolved in 270 mL of acetonitrile, and the tetramethylammonium triacetoxyborohydride solution prepared above was transferred thereto in an ice bath, stirred for half an hour, and then moved to room temperature to react for 12 hours to complete the reaction; saturated potassium sodium tartrate and sodium bicarbonate were added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 8:1→4:1) to obtain the reduction product compound 4 (25.7 g), and the NMR hydrogen spectrum and carbon spectrum of compound 4 were shown in Figure 3 and Figure 4 , the results showed that dr≥95:5; 1H NMR (400MHz, CDCl3) δ7.68–7.59(m,4H),7.49–7.34(m,6H),6.01–5.79(m,1H),5.31(dd,J=17.2,1.6Hz ,1H),5.24(dd,J=10.4,1.6Hz,1H),4.59(d,J=5.2Hz,2H),4.41–4.30(m,1H),4.23–4.12(m,1H),4.00( d,J=10.0Hz,1H),2.78(s,1H),2.66(dd,J=17.2,6.0Hz,1H),2.49(dd,J=17.2,7.2Hz,1H),2.15–2.02( m,1H),1.83–1.65(m,2H),1.49(ddd,J=14.4,10.8,2.4Hz,1H),1.21(s,3H),1.17(s,3H),1.05(s,9H); 13 C NMR (100MHz, CDCl3) δ177.2,170.6,135.6,135.6,133.3,133.1,131.8,130.0,129.9,127.8,12 7.8,118.5,73.5,71.7,65.3,65.2,46.6,39.7,38.8,37.6,26.8,22.6,19.8,19.0;IR(neat)cm -1 3448,2925,2855,2031,1729,1466,1426,1388,1256,1108,1084,1012,934,887,820,747,703; HRMS(MALDI,m / z)calcd for C 30 H 40 O6Si(M+Na) + 547.2492,foun 547.2488; [α] D 25 =-63.70°(c=0.27in CHCl3);

[0067] So far, the yield of steps 1)-3) is 45%;

[0068] 4) Compound 4 (25.36 g, 44.4 mmol, 1.0 equivalent) obtained in step 3 was concentrated in a 250 mL round-bottom flask. Under argon protection, 88 mL of diethoxypropane was added and stirred until completely dissolved. D-camphorsulfonic acid (1.03 g, 4.44 mmol, 0.1 equivalent) was added under an ice bath and the mixture was moved to room temperature and continued to react for 12 hours. After the reaction was complete, 100 mL of saturated sodium bicarbonate aqueous solution was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and simply purified by concentration column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain intermediate a (24.63 g), which was directly used in the next step.

[0069] 5) In the glove box, weigh tetrakistriphenylphosphine palladium (2.32 g, 2.02 mmol, 5 mol%) into a 500 mL round-bottom flask, remove it and protect it with argon. At room temperature, the propylidene-protected intermediate product a (24.63 g, 40.32 mmol, 1.0 equivalent) is dissolved in 160 mL of tetrahydrofuran and transferred to the round-bottom flask, and the remaining raw materials are rinsed with 4×10 mL; after adding morpholine (7.05 mL, 80.64 mmol, 2.0 equivalent), continue to react at room temperature for 16 hours; add 1 M hydrochloric acid to quench, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the intermediate product b concentrate, which is directly used in the next step without purification;

[0070] 6) At room temperature, under argon protection, the intermediate product b concentrate (38.3 mmol, 1.0 equivalent) was dissolved in 38 mL of toluene in a 100 mL round-bottom flask, and triphenylphosphine (12.05 g, 45.96 mmol, 1.2 equivalent) and 2,2'-disulfide-5,5'-dimethylbipyridine (11.41 g, 45.96 mmol, 1.2 equivalent) were added in sequence, and the mixture was reacted in an oil bath at 30°C for 24 hours; after the reaction of the raw materials was complete, the toluene was directly removed by vacuum concentration, and then appropriate amounts of silica gel and dichloromethane were added, and the sample was mixed with silica gel by a rotary evaporator, and used for dry loading, and column chromatography purification (eluent: petroleum ether / ethyl acetate = 1000:66) to obtain thioester compound 5 (25.63 g); the yield of steps 4)-6) was 86%;

[0071] The method for the parallel synthesis of iodine hydrocarbon 5B is as follows: (1) Preparation of Grignard reagent: Weigh magnesium chips (15.4 g, 640 mmol, 2.4 eq.) into a 1000 mL three-necked round-bottom flask, evacuate, bake for 10-15 minutes until uniformly dispersed, replace with argon gas for cooling, add a stirrer and 350 mL of redistilled tetrahydrofuran, add about 0.5 mL of 1,2-dibromoethane and a small amount of bromine at room temperature, blow the outer wall with a hair dryer, and when a large amount of foam appears on the liquid surface, it indicates that the initiation is successful. Transfer to a 60°C oil bath for reflux, then mix the raw material (1-bromovinyl)trimethylsilane (57.3 g, 320 mmol, 1.2 eq.) and 50 mL of anhydrous tetrahydrofuran, and then add dropwise through a dropping funnel, slowly at first and then quickly, keeping a slightly boiling state, stir for about 2 hours after the addition, let it stand and cool, and set aside for the next step. (2) Epoxy opening: At -45°C, under argon protection, the Grignard reagent prepared in the previous step was added dropwise to a 500 mL tetrahydrofuran solution of (S)-2-(chloromethyl)oxirane (24.67 g, 267 mmol, 1.0 eq.) and cuprous cyanide (2.39 g, 26.67 mmol, 0.1 eq.), and stirring was continued after the addition. After the reaction was completed, saturated ammonium chloride solution was added at this temperature to quench the reaction, and the mixture was moved to room temperature and stirred for 30 minutes, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The reaction system was clean and purified by simple column chromatography (eluent polarity: petroleum ether / ethyl acetate = 20:1→10:1) to obtain the product (S)-1-chloro-4-(trimethylsilyl)pent-4-en-2-ol (47.35 g) with a yield of 92%. (3) At room temperature, under argon protection, sodium iodide (180 g, 1.2 mol, 5.0 eq.) was added to a 2 L round-bottom flask, and the argon was replaced three times. 250 mL of acetone was added to dissolve the sodium iodide, and then a 250 mL acetone solution of (S)-1-chloro-4-(trimethylsilyl)pent-4-en-2-ol (46.26 g, 240 mmol, 1.0 eq.) was added. After reflux reaction at 80°C for 48 hours, the reaction of the raw materials was detected to be complete, and the mixture was cooled to room temperature. Then, 600 mL of dichloromethane was added to the mixture in an ice bath. Imidazole (32.68 g, 480 mmol, 2.0 eq.) and triethylsilyl chloride (48.3 mL, 288 mmol, 1.2 eq.) were added to the reaction system in sequence. With the addition of triethylsilyl chloride, the solution changed from colorless and clear to turbid. Stirring was continued after the addition was completed. After the reaction was completed by TLC detection, ice water was added for quenching, and the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent polarity: petroleum ether / ethyl acetate = 1000:1→200:1) to give iodoalkane 5B (87.03 g). The two-step yield was 91%. 1H NMR(400MHz,CDCl3)δ5.72(dd,J=2.8,1.6Hz,1H),5.47(d,J=2.8Hz,1H),3.72–3.56(m,1H),3.25(dd,J=10.0,4.8Hz,1H),3.15(dd,J=10.0,4.8Hz,1H),2.45(ddd,J=14.0,7.6,1.2Hz,1H),2.38(ddt,J=14.0,5.6,1.2Hz,1H),0.98(t,J=8.0Hz,9H),0.63(q,J=8.0Hz,6H),0.11(s,9H). 13 C NMR(150MHz,CDCl3)δ147.8,128.3,70.2,43.9,14.5,6.9,5.1,-1.3;IR(neat)cm -1 2954,2911,2878,1246,1091,1042,1005,934,834,729,690;HRMS(MALDI,m / z)calcd for C 14 H 31 IOSi2(M+Na) + :421.0850,found 421.0849;[α] D 25 =+0.99°(c=1.0in CHCl3);

[0072] 7) At room temperature, under argon protection, weigh the thioester compound 5 (12 g, 17.7 mmol, 1.0 eq.) and the iodide compound 5B (8.46 g, 21.24 mmol, 1.2 eq.) in 36 mL 1,3-Dimethyl-2-imidazolidinone was dissolved in a 500 mL round-bottom flask, and 2,6-di-tert-butyl-4-methylpyridine (14.53 g, 70.8 mmol, 4.0 equiv.) was added. Zirconocene dichloride (15.52 g, 53.1 mmol, 3.0 equiv.) and zinc powder (6.95 g, 106.2 mmol, 6.0 equiv.) were weighed in the glove box, and then NiBr2·dtbbpy (2.59 g, 5.31 mmol, 30 mol%) was added in the glove box. After the addition was completed, the color of the solution changed from green to brown after 5-10 minutes. The glove box was removed to room temperature and argon was replaced. The mixture was stirred 2-3 times and stirred vigorously for 32 hours. The solution continued to darken and turned from dark red brown to black. After the reaction, 2 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction. A few milliliters of ethyl acetate were added and the salt produced after quenching was simply filtered off through diatomaceous earth and washed with ethyl acetate. 20 mL of saturated sodium bicarbonate aqueous solution was added to the collected filtrate, and the mixture was extracted with ethyl acetate for 3-4 times, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 500:1 → 200:1 → 100:1) to obtain the coupling product compound 6 (11.10 g) with a yield of 76%. The structural data of compound 6 are as follows: 1 H NMR (400MHz, CDCl3) δ7.75–7.61(m,4H),7.46–7.33(m,6H),5.58(d,J=2.8Hz,1H),5.40(d,J=2.8Hz,1H),4.39–4.32(m,1H),4 .28–4.20(m,1H),4.09–3.95(m,2H),3.80(dd,J=9.2,6.4Hz,1H),3.56–3.37(m,1H),2.64–2.44(m,4H),2.34(dd,J=13.6,5.6H z,1H),2.22(dd,J=13.6,7.6Hz,1H),1.70(dd,J=14.4,6.4Hz,1H),1.56(dt,J=14.4,4.4Hz,1H),1.41–1.30(m,1H),1.19(t,J= 7.2Hz,3H),1.15(s,3H),1.12–1.06(m,1H),1.02(s,6H),1.01(s,9H),0.96–0.86(m,12H),0.58(q,J=8.0Hz,6H),0.09(s,9H); 13C NMR (150MHz, CDCl3) δ212.9,171.4,148.7,135.9,135.9,134.0,133.8,129.6,129.6,127.6,127.5,127.5,100.1,70.5,68. 9,67.2,64.2,60.2,50.3,46.1,44.6,43.7,43.2,33.1,26.8,24.6,24.2,20.2,19.2,18.7,14.1,6.9,5.0,-1.4; IR(neat)cm - 1 2953,1738,1706,1464,1376,1220,1170,1104,1011,839,772,704; HRMS(MALDI,m / z)calcd for C 46 H 76 O7Si3(M+Na) + 847.4797, found 847.4800; [α] D 25 =-42.14°(c=0.28inCHCl3);

[0073] 8) At room temperature, under argon protection, the compound 6 (25.93 g, 31.42 mmol, 1.0 equivalent) obtained in step 7) was dissolved in 1260 mL of methanol in a 2 L round-bottom flask, 315 mL of trimethyl orthoformate was added, and pyridine p-toluenesulfonate (39.48 g, 0.157 mol, 5.0 equivalent) was added in three batches under ice bath. After the addition, it was moved to a 30 ° C oil bath to react for 24 hours. After TLC detection, the reaction was complete, and saturated sodium bicarbonate aqueous solution was added under ice bath to quench, and stirring was continued for half an hour until the quenching was sufficient; the aqueous phase was extracted with petroleum ether / ethyl acetate (1:1) 4-5 times, the organic phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20:1→10:1) to obtain compound 7 (18.51 g), yield: 86%;

[0074] 9) Under argon protection, compound 7 (17.07 g, 24.92 mmol, 1.0 equivalent) was weighed and dissolved in 250 mL of dichloromethane in a dried 1000 mL round-bottom flask. In an ice bath, triethylamine (4.16 mL, 29.9 mmol, 1.2 equivalent) and tribromopyridine (9.56 g, 29.9 mmol, 1.2 equivalent) were added in sequence, and triethylamine and tribromopyridine were added until the reaction of the raw materials was complete; 250 mL of methanol and 1N sodium hydroxide aqueous solution (250 mL) were added at room temperature, and the mixture was moved into an 80°C oil bath and continued to react for 12 hours; after the raw materials were completely converted, 1 M hydrochloric acid aqueous solution was added in an ice bath to acidify to pH 6-7, extracted with ethyl acetate, combined the organic phases, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain compound 8, which was directly used in the next step without purification;

[0075] 10) Under argon protection, the concentrate of compound 8 obtained in step 9) (step 9) with a yield of 88% was dissolved in 220 mL of dichloromethane in a 500 mL round-bottom flask taken out of the oven, and ice-bathed for 10 minutes. 4-dimethylaminopyridine (5.36 g, 43.86 mmol, 2.0 equiv.) and acetic anhydride (2.47 mL, 26.32 mmol, 1.2 equiv.) were added in sequence, and the reaction was continued at this temperature for 0.5 hours. After the reaction was complete, argon was still used for protection, and imidazole (17.92 g, 263.16 mmol, 12.0 equiv.) was added under ice-bath, and triethylsilyl chloride (22.08 mL, 131.58 mmol, 6.0 equiv.) was slowly added, and the reaction solution changed from clear to turbid. After the addition, the mixture was moved to room temperature and the reaction was continued for 30 minutes. After the reaction was complete as detected by TLC, 200 mL of saturated aqueous ammonium chloride solution was added to quench the mixture. After stirring for 5-10 minutes, the mixture was extracted with dichloromethane 3-4 times, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 15:1→5:1) to obtain compound 9 (12.87 g), with a yield of 63%;

[0076] 11) Under argon protection, the product compound 9 (6.1 g, 7.44 mmol, 1.0 equiv.) of step 10) and 1,3-bis(diphenylphosphinopropane)nickel dichloride (403 mg, 0.744 mmol, 10 mol%) were dissolved in 298 mL of ether in a 500 mL round-bottom flask. In an ice bath, freshly prepared (bis(trimethylsilyl)methyl)magnesium chloride (51 mL, titrated to 0.59 M) was slowly added. 29.76mmol, 4.0 equivalents.); after the addition, a spherical condenser was installed, argon was replaced 2-3 times, and the mixture was moved to a 45°C oil bath for reaction for 2 hours; after the reaction, a saturated aqueous solution of ammonium chloride was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 15:1→6:1) to obtain a light yellow viscous liquid compound 10 (6.02g) with a yield of 90%; the hydrogen and carbon spectra of compound 10 are shown in Figure 5 and Figure 6 ; 1 H NMR (600MHz, CDCl3) δ7.77–7.62(m,4H),7.50–7.32(m,6H),4.97(dd,J=11.4,4.8Hz,1H),4.66(s,1H),4.55(s,1H),4.29–4.21(m, 1H),4.18–4.10(m,1H),3.29–3.19(m,1H),2.96(s,3H),2.68(dd,J=15.0,3.6Hz,1H),2.52(dd,J=15.0,7.2Hz,1H),2.19(dd,J=16. 2,3.6Hz,1H),2.05(dd,J=15.6,7.2Hz,1H),2.01(s,3H),1.94–1.79(m,2H),1.73(dd,J=15.6,7.8Hz,1H),1.55(ddd,J=13.8,6.0, 3.6Hz,1H),1.32(ddd,J=12.6,4.8,3.0Hz,1H),1.02(s,9H),0.99–0.85(m,16H),0.79(s,1H),0.57(q,J=7.9Hz,6H),0.06(s,18H). 13C NMR (150MHz, CDCl3) δ176.2,170.6,146.6,135.9,135.8,133.7,133.1,129.8,129.8,127.6,127.6,107.6,104.4,74.0,68 .8,67.4,65.5,50.8,48.2,43.3,42.5,41.7,39.9,32.5,29.7,26.8,21.2,20.8,19.2,17.2,7.1,5.5,0.5,0.3; IR(neat)cm -1 3078,3051,2956,2877,2861,1744,1709,1618,1470,1428,1390,1367,1246,1105,1075,1025,968,865,839,740,702; HRMS(MALDI,m / z)calcd for C 48 H 82 O8Si4(M+Na) + 921.4979, found 921.4977; [α] D 25 =+25.04°(c=1.97in CHCl3);

[0077] The comprehensive yield of all the above steps is 14.3%.

[0078] Embodiment 2-6:

[0079] Compared with Example 1, in step 1), the 9-O-benzylquinidine added during the reaction was replaced by 9-O-trimethylsilyl substituted quinidine, 9-O-triethylsilyl substituted quinidine, 9-O-triisopropylsilyl substituted quinidine, 9-O-(4-trifluoromethyl-benzyl) substituted quinidine, and 9-O-(2-methyl-benzyl) substituted quinidine, respectively, and the rest remained unchanged. The corresponding yields and dr values ​​were 38% and 5:1, 21% and 11:1, 27% and 4:1, 24% and 4:1, and 36% and 15:1, respectively.

[0080] Embodiment 7-11:

[0081] Compared with Example 1, in step 1), the reaction temperature was replaced with -78°C, -60°C, -50°C, -30°C and -25°C, respectively, and the other conditions remained unchanged. The corresponding yields and dr values ​​were 20% and 5:1, 25% and 5:1, 80% and 18:1, 40% and 4:1, and 40% and 2:1, respectively.

[0082] Examples 12-15

[0083] Compared with Example 1, during the reaction in step 2), the concentrations of the reaction system were replaced with 0.01 mol / L, 0.03 mol / L, 0.07 mol / L and 0.1 mol / L, respectively, and the other conditions remained unchanged. The corresponding yields were 50%, 70%, 35% and 27%, respectively.

[0084] Examples 16-18

[0085] Compared with Example 1, during the reaction in step 2), the temperature of the reaction system was replaced with -45°C, -60°C, and -80°C, respectively; the other conditions remained unchanged, and the corresponding yields were 10%, 30%, and 70%, respectively.

[0086] Examples 19-20

[0087] Compared with Example 1, in step 2), the reaction time was replaced with 6 h and 24 h respectively; the other conditions remained unchanged, and the corresponding yields were 30% and 70% respectively.

[0088] Examples 21-24

[0089] Compared with Example 1, during the reaction in step 2), the allyl isobutyrate in the reaction was replaced with allyl 2-ethylhexanoate, allyl 2-ethylphenylacetate, allyl valerate, and allyl 2-fluoroacetate, while the rest remained unchanged. The corresponding yields were 10%, 50%, 5%, and 5%, respectively.

[0090] Examples 25-31

[0091] Compared with Example 1, in step 7), the 5-methylpyridine-2-thioester in the reaction was replaced with pyridine-2-thioester, 3-methylpyridine-2-thioester, 4-methylpyridine-2-thioester, 6-methylpyridine-2-thioester, 3-chloropyridine-2-thioester, 4-chloropyridine-2-thioester, 5-chloropyridine-2-thioester, and 2-quinoline-2-thioester, while the rest remained unchanged. The corresponding yields were 49%, 44%, 56%, 47%, 55%, 46%, 45%, and 30%.

[0092] Embodiment 32

[0093] Compared with Example 1, in step 7), 2,6-di-tert-butyl-4-methylpyridine in the reaction was replaced by 2,6-lutidine, and the rest remained unchanged. The corresponding yield was 62%.

[0094] Examples 33-34

[0095] Compared with Example 1, during the reaction in step 7), the single solvent of 1,3-dimethyl-2-imidazolidinone in the reaction was replaced with 1,3-dimethyl-2-imidazolidinone / ethyl acetate (5 / 1) and 1,3-dimethyl-2-imidazolidinone / ethyl acetate (1 / 1), and the rest remained unchanged. The corresponding yields were 26% and 17%.

[0096] Examples 35-37

[0097] Compared with Example 1, in step 7), the NiBr2·dtbbpy single catalyst in the reaction is replaced by (Me)3tPy·NiI / Py - (Me)imid·NiCl2(5 / 20mol%),

[0098] (Me)3tPy·NiI / Py - (Me)imid·NiCl2 (2 / 20mol%), Ni(cod)2 / dtbbpy (30 / 30mol%), and the rest remained unchanged. The corresponding yields were 17%, 16%, and 3%.

[0099] Examples 38-41

[0100] Compared with Example 1, during the reaction in step 7), the reaction system concentration of 0.5 mol / L was replaced by 0.1 mol / L, 0.2 mol / L, 0.7 mol / L, and 1 mol / L, while the rest remained unchanged. The corresponding yields were 41%, 43%, 30%, and 17%.

[0101] Examples 42-44

[0102] Compared with Example 1, during the reaction in step 7), the reaction system temperature of 25°C was replaced with 30°C, 35°C, and 40°C, while the rest remained unchanged. The corresponding yields were 70%, 68%, and 50%.

[0103] Examples 45-47

[0104] Compared with Example 1, in step 7), the reaction time of 32 hours was replaced by 12 hours, 24 hours, and 48 hours, and the rest remained unchanged. The corresponding yields were 20%, 50%, and 73%.

[0105] Examples 48-51

[0106] Compared with Example 1, in step 7), R 1 The ethyl group was replaced by methyl, phenyl, benzyl, and 3-picolinoyl, while the rest remained unchanged. The corresponding yields were 65%, 56%, 52%, and 49%.

[0107] Examples 52-56

[0108] Compared with Example 1, in step 7), R 2 and R 3 The methyl group was replaced by ethyl and ethyl, ethyl and hexyl, ethyl and phenethyl, pentyl and hydrogen, fluorine and ethyl, while the rest remained unchanged. The corresponding yields were 65%, 68%, 59%, 51%, and 29%.

[0109] Examples 57-58

[0110] Compared with Example 1, in step 7), R 4 The methyl group was replaced by hydrogen and ethyl, while the rest remained unchanged, and the corresponding yields were 71% and 72%.

[0111] Embodiment 58

[0112] Compared with Example 1, in step 7), R 6 The trimethyl group was replaced by triethyl group, while the rest remained unchanged, and the corresponding yield was 61%.

[0113] Examples 59-60

[0114] Compared with Example 1, during the reaction in step 7), X in the general formula (V) was replaced by chlorine or bromine instead of iodine, while the rest remained unchanged. The corresponding yields were 10% and 12%.

[0115] Examples 61-64

[0116] Compared with Example 1, in step 7), P in the general formula (V) is 1 The triethylsilyl group was replaced by trimethylsilyl, tert-butyldiphenylsilyl, tert-butyldiethylsilyl, and acetyl groups, while the rest remained unchanged. The corresponding yields were 59%, 69%, 72%, and 59%.

[0117] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a key intermediate of bruceastatin A ring fragment, characterized in that: The method comprises the following steps: dissolving compound (V) and compound (VI) in a solvent, adding 2,6-di-tert-butyl-4-methylpyridine, an activator and metal particles or powder, and then adding substituted bipyridine-metal nickel halide as a catalyst to carry out a coupling reaction to obtain compound (VII). The reaction formula is as follows: In the above reaction formula, R 1 R is selected from H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, aromatic or aromatic substituted by heteroatoms; 2 , R 3 is selected from H, alkyl, substituted alkyl, alkenyl, alkynyl, halogen, amino, phenyl, substituted phenyl, R 2 , R 3 Same or different; R 4 Selected from 1,3-dihydroxy protecting groups or their chemical synthesis equivalents; R 5 Representative groups are halogen, alkoxy, substituted alkoxy, acyloxy, substituted acyloxy, phenoxy, substituted phenoxy, substituted heterocyclic aromatic oxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, substituted heterocyclic aromatic thio; R 6 is selected from alkyl or substituted alkyl; P and P 1 is selected from H, various hydroxyl protecting groups; X is selected from chlorine, bromine, iodine, boron, and substituted boron.

2. The method according to claim 1, characterized in that: The R 4 is selected from one of an alkyl group, a substituted alkyl group, and a cyclic alkyl group; said R 5 is selected from various alkylthiols, substituted alkylthiols, substituted or unsubstituted arylthiols, aromatic esters, substituted aromatic esters, phenyltin esters, aromatic heterocyclic thiols, halogens, preferably 5-methylpyridylthio, 4-methylpyridylthio, 5-methoxypyridylthio, 3-fluoro-phenylthio, ethanethiol, trifluoroethanethiol; the P 1 One selected from the group consisting of an alkyl group, a substituted alkyl group, a phenyl group, and a substituted phenyl group.

3. The method according to claim 1, characterized in that The substituted bipyridine in the catalyst is selected from 4,4'-di-tert-butyl-2.2'-bipyridine, 4,4'-di-tert-butyl-6-methyl-2.2'-bipyridine, 4,4'-di-tert-butyl-6,6'-dimethyl-2.2'-bipyridine, 3,3'-dimethyl-2.2'-bipyridine, 4,4'-dimethyl-2.2'-bipyridine, 4,4'-dimethyl-2.2'-bipyridine, -dimethoxy-2.2'-bipyridine, 2,3,4,7,8,9-hexamethyl-1,10-phenanthroline, 4,7-dimethoxy-2,9-dimethyl-1,10-phenanthroline, 2,9-diisopropyl-1,10-phenanthroline; the metal nickel halide in the catalyst is selected from one of nickel dibromide, nickel dichloride and nickel diiodide; The solvent is selected from one of N,N-dimethylformamide, N,N-dimethylaniline, N,N-dimethylpropylene urea, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, dichloroethane, ether, ethyl acetate, 1,4-dioxane, acetonitrile, benzene, toluene, ethylene glycol dimethyl ether, hexafluoroisopropanol, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, or a mixed solvent of 1,3-dimethyl-2-imidazolidinone / ethyl acetate, 1,3-dimethyl-2-imidazolidinone / acetonitrile, 1,3-dimethyl-2-imidazolidinone / tetrahydrofuran, 1,3-dimethyl-2-imidazolidinone / ethylene glycol dimethyl ether; preferably, the volume ratio of 1,3-dimethyl-2-imidazolidinone / ethyl acetate is 10 / 1, 8 / 1, 5 / 1, 3 / 1, 1 / 1, 1 / 2, 1 / 4, 1 / 10, 1 / 20; The activator is selected from one of dichlorozirconocene, triethylchlorosilane, trimethylchlorosilane, chromium dichloride, cobalt phthalocyanine, lithium iodide, magnesium chloride, 4-fluoro-styrene, and 4-trifluoromethyl-styrene.

4. The method according to claim 1, characterized in that: The molar ratio of the raw materials is compound (V): compound (VI): 2,6-di-tert-butyl-4-methylpyridine: activator: metal particles or powder: catalyst = 1:1.2:4.0:3.0:6.0:0.3; the reaction is carried out under stirring, and the preferred stirring speed is 400-4000r / min.

5. A method for synthesizing the C1-C14 fragment of bruceastatin A ring, characterized in that: The steps include: (1)-(3), three-step continuous reaction: the aldehyde represented by compound (I) undergoes asymmetric [2+2] cyclization at the C5 aldehyde group in the presence of a catalyst to obtain compound (II), followed by ester condensation at the C7 position to obtain compound (III), and finally, the carbonyl group at the C7 position undergoes asymmetric reduction to obtain the cyclization product (IV); (4)-(6), the cyclization product (IV) is subjected to protection of the hydroxyl groups at C5 and C7, selective removal of the ester group at C9, and thioesterification at C9 to obtain the thioester product (V); (7), the thioester product (V) and the compound (VI) are subjected to a nickel-catalyzed coupling reaction to construct the C1-C14 fragment of the straight-chain skeleton of the bruceidin A ring; (8) Under the catalytic action of pyridine p-toluenesulfonate, the linear skeleton C1-C14 fragment of bryozostatin A ring obtained in step (7) is ring-closed to form a cyclic product; (9), after removal and bromination of the silicon protecting group and deprotection of the terminal ester group; (10), chemoselective protection of the hydroxyl group to obtain the carboxylic acid product; (11), using geminal bis-silicon Grignard reagent to carry out Kumada coupling reaction to obtain the brucein A ring C1-C14 fragment of formula (VII), Wherein, the reaction formula of step (1) is: The reaction formula of step (2) is: The reaction formula of step (3) is: The reaction formula of steps (4)-(6) is:

6. The method according to claim 5, characterized in that During the reaction of step (1), one of 9-O-benzylquinidine, unsubstituted quinidine, 9-O-alkyl substituted quinidine, 9-O-benzene substituted quinidine, 9-O-aromatic heterocyclic substituted quinidine, 9-O-amino substituted quinidine or other substituted quinidine is added, preferably 9-O-benzylquinidine.

7. The method according to claim 5, characterized in that During the reaction of step (1), the solvent used is a dichloromethane / ether mixed solvent, or one of dichloroethane, ether, and tetrahydrofuran, and the water content of the solvent is preferably less than 10 ppm.

8. The method according to claim 5, characterized in that The reaction temperature of step (1) is -78°C to -25°C, preferably -45°C.

9. The method according to claim 5, characterized in that During the reaction of step (2), one of potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium diisopropylamide, and n-butyl lithium is added, and one of magnesium bromide etherate and boron trifluoride etherate is also added, and allyl isobutyrate is also added, and the solvent is tetrahydrofuran.

10. The method according to claim 5, characterized in that During the reaction of step (2), the concentration of the reaction system is 0.01 mol / L to 0.1 mol / L, preferably 0.05 mol / L; the temperature of the reaction system of step (2) is between -45°C and -80°C, preferably -78°C; the reaction time of step (2) is 6 to 24 h, preferably 20 h.

Images