Preparation method of cyclic lipopeptide natural product Dysoxylactam A and its analogues

Abstract

The present invention provides a method for preparing natural product dysoxylactam A and its analogues, which relates to the technical field of organic synthesis. The synthetic route starts from aldehydes with different substitutions, constructs four consecutive chiral centers through two aldol condensation reactions, and then through sulfonylation reaction, borohydride reduction, deprotection, protection of hydroxyl protecting groups, and esterification reaction with amino acids, all chiral centers of the target molecule are constructed. Finally, through amide reaction, ring-closing metathesis reaction and hydrogenation reduction reaction, natural product dysoxylactam A and its analogues are successfully obtained. This synthetic method has a high overall yield, simple steps, easy derivatization, low operation requirements, can be prepared in large quantities, and has broad application and development prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing a cyclic lipopeptide natural product Dysoxylactam A and its analogs. Background Art

[0002] Currently, chemotherapy is one of the important methods for treating malignant tumors, aiming to eradicate primary tumors and metastatic malignant tumors. However, during the clinical treatment process, most patients develop multi-drug resistance (MDR) to targeted chemotherapy, resulting in a significant reduction in the efficacy of anti-cancer drugs and becoming one of the main reasons for the failure of cancer chemotherapy. The latest research shows that there are many potential mechanisms for MDR, and the main mechanism is the increased drug efflux mediated by the upregulation of ATP-binding cassette (ABC) transporters. Among them, P-glycoprotein (P-gp), as a member of the ABC transporter family, is responsible for enhancing the efflux of chemotherapy drugs and reducing the concentration of chemotherapy drugs in tumor cells. Therefore, regulating the drug transport function of P-gp is considered an effective way to restore the sensitivity of tumors to anti-cancer drugs. Unfortunately, so far, no P-gp specific inhibitor has been successful in clinical trials.

[0003] Natural products are an important source of drugs and lead compounds. In 2019, our research group isolated a 17-membered macrocyclic lipopeptide natural product dysoxylactam A with the ability to reverse MDR in tumor cells from the bark of Dysoxylum hongkongense. It did not significantly reduce the expression of P-gp, but inhibited the transport function of P-gp in tumor cells. Through in vitro cell experiments, it was found that after multi-drug resistant tumor cells were treated with 10 μM of dysoxylactam A, the reversal coefficients for adriamycin, vincristine, and paclitaxel reached 28.4 - 1039.7 times. More importantly, at this concentration, dysoxylactam A did not show cytotoxicity. The unique chemical structure and excellent MDR reversal activity of Dysoxylactam A make it have potential drug development potential. Once this molecule was discovered, it attracted the interest of many scholars around the world, and the total synthesis work was carried out on it.

[0004] However, the current total preparation methods still have problems such as cumbersome synthesis steps, low yields, and inconvenience for derivatization.

[0005] In view of this, the present invention is specifically proposed. Summary of the Invention

[0006] The object of the present invention is to provide a general, simple and effective total preparation method for the natural active product Dysoxylactam A and its analogues. Among them, the total preparation method includes the racemic total synthesis and chiral total preparation methods of the above compounds.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] The present invention provides a total preparation method for the natural active product Dysoxylactam A and its analogues shown in formula (I).

[0009]

[0010] Among them, R1 is selected from hydrogen, C1-C 10 alkoxy, C1-C 10 substituted or unsubstituted alkyl; substituted or unsubstituted aryl or substituted or unsubstituted benzyl;

[0011] R2 is selected from hydrogen, C1-C 10 substituted or unsubstituted alkyl; substituted or unsubstituted aryl or substituted or unsubstituted benzyl;

[0012] R3 is selected from hydrogen, C1-C 10 substituted or unsubstituted fatty acyl; substituted or unsubstituted aromatic acyl or substituted or unsubstituted benzoyl;

[0013] The natural active product Dysoxylactam A and its analogue compounds are racemates or R / S configurations;

[0014] The synthesis of the natural active product Dysoxylactam A and its analogue compounds includes the following steps:

[0015] (a1) Compound 1 and propionaldehyde carry out an asymmetric aldol condensation reaction in the presence of a solvent and a catalyst, and then a silyl ether protecting group is added in the presence of a base and a salt to protect the hydroxyl group to obtain compound 2; or,

[0016] (a2) Compound 1 and E-form or Z-form allyl alcohol protected by silyl ether carry out an asymmetric aldol condensation reaction in the presence of a solvent and a catalyst to obtain compound 2;

[0017] (b) Compound 2 and a chiral auxiliary carry out an Evans aldol reaction in the presence of a solvent and a base to obtain compound 3;

[0018] (c) Compound 3 carries out a sulfonylation reaction in the presence of a solvent and a base to obtain compound 4;

[0019] (d) Compound 4 carries out a borohydride reduction reaction in the presence of a solvent to obtain compound 5;

[0020] (e) Compound 5 undergoes an asymmetric allylation reaction in the presence of a solvent and a catalyst to obtain Compound 6;

[0021] (f) Compound 6 undergoes benzyl protection of the hydroxyl group in the presence of a base and a catalyst, and then the silyl ether protecting group is removed in the presence of a solvent and a deprotecting agent to obtain Compound 7;

[0022] (g) Compound 7 undergoes an esterification reaction with an amino-protected amino acid in the presence of a solvent, a base, and a reaction auxiliary to obtain Compound 8;

[0023] (h) Compound 8 removes the protecting group in the presence of an acid, and then undergoes an amidation reaction in the presence of a solvent, a base, and a condensing agent to obtain Compound 9;

[0024] (i) Compound 9 undergoes ring-closing metathesis of the olefin and hydrogenation reduction reactions in the presence of a solvent and a catalyst to remove the protecting group to obtain Compound 10;

[0025] (j) Compound 10 undergoes an esterification reaction with a carboxylic acid or an acyl chloride in the presence of a solvent, a base, and an optional condensing agent to obtain the compound of Formula I;

[0026] The synthetic route is as follows:

[0027]

[0028] Wherein, A is selected from one of TMS, TES, TBDMS, TBDPS, TIPS, Si(TMS)3;

[0029] R’ is selected from an alkylsulfonyl group or an arylsulfonyl group, preferably methanesulfonyl group, p-toluenesulfonyl group, ethylsulfonyl group;

[0030] The definitions of R1, R2, and R3 are as described above.

[0031] Next, the new preparation method of the present invention will be described in more detail. However, the equivalents and ratios of the reactants, solvents, bases, catalysts, etc. used in this method, the reaction temperature, the reaction time required, etc. can be adjusted according to the specific reaction, and are not limited to the following explanations.

[0032] Step (a1)

[0033] Compound 1 undergoes an asymmetric aldol condensation reaction with propionaldehyde in the presence of a solvent and a catalyst, and then a silyl ether protecting group is added to protect the hydroxyl group in the presence of a base and a salt to obtain Compound 2.

[0034] Preferably, the catalyst in step (a1) is a chiral ligand, preferably D / L-proline;

[0035] Preferably, the solvent in step (a1) is one or more selected from N,N-dimethylformamide and dimethyl sulfoxide;

[0036] Preferably, the reaction temperature of the asymmetric aldol condensation reaction in step (a1) is -10 to 10 °C (such as -10, -5, 0, 5, 10 °C), and the reaction time is 12 to 48 hours (such as 12, 24, 36, 48 hours);

[0037] Preferably, the base in step (a1) is an organic base, preferably one or more selected from pyridine, 4-dimethylaminopyridine, and N,N-diisopropylethylamine;

[0038] Preferably, the salt in step (a1) is an inorganic salt, preferably silver nitrate;

[0039] Preferably, the reaction temperature of the hydroxyl protection in step (a1) is 0 to 30 °C (such as 0, 5, 10, 15, 20, 25, 30 °C), and the reaction time is 2 to 10 hours (such as 2, 5, 6, 8, 10 hours);

[0040] Preferably, the silyl ether protecting group is added stepwise or by the "one-pot" method.

[0041] Step (a2)

[0042] Compound 1 undergoes an asymmetric aldol condensation reaction with E- or Z-propenol protected by silyl ethers in the presence of a solvent and a catalyst to obtain compound 2.

[0043] Preferably, the catalyst in step (a2) is one or more selected from trifluoromethanesulfonimide (HNTf2), boron trifluoride diethyl etherate, and titanium tetrachloride;

[0044] Preferably, the reaction temperature in step (a2) is -80 to 0 °C, and the reaction time is 3 to 12 hours;

[0045] Preferably, the solvent in step (a2) is one or more selected from dichloromethane, acetonitrile, and water.

[0046] Step (b)

[0047] Compound 2 undergoes an Evans aldol reaction with a chiral auxiliary in the presence of a solvent and a base to obtain compound 3.

[0048] Preferably, the chiral auxiliary in step (b) is one or more selected from (±)-4-benzyl-3-propionyl-2-oxazolidinone and dibutylboron trifluoromethanesulfonate (Bu2BOTf), preferably (±)-4-benzyl-3-propionyl-2-oxazolidinone and dibutylboron trifluoromethanesulfonate;

[0049] Preferably, the base in step (b) is one or more selected from triethylamine and N,N - diisopropylethylamine (DIPEA);

[0050] Preferably, the reaction temperature in step (b) is -78 to 0 °C (such as -70, -60, -50, -40, -30, -20, -10, -5 °C), and the reaction time is 10 - 24 hours;

[0051] Preferably, the solvent in step (b) is one or more selected from dichloromethane, tetrahydrofuran, toluene, acetonitrile, and ethyl acetate;

[0052] Preferably, the molar ratio of the base, (±)-4 - benzyl - 3 - propionyl - 2 - oxazolidinone, and dibutylboron trifluoromethanesulfonate is (1.3 - 2.0):(0.8 - 1.2):(1.2:1.8).

[0053] Step (c)

[0054] Compound 3 undergoes a sulfonylation reaction in the presence of a solvent and a base to obtain compound 4.

[0055] Preferably, the sulfonylation reagent used in the sulfonylation reaction in step (c) is an alkylsulfonyl chloride or an arylsulfonyl chloride, preferably one or more selected from methanesulfonyl chloride (MsCl) and benzenesulfonyl chloride (TsCl);

[0056] Preferably, the base in step (c) is one or more selected from triethylamine, pyridine, imidazole, and N,N - diisopropylethylamine.

[0057] Preferably, the reaction temperature in step (c) is 0 to 60 °C (such as 0, 10, 20, 30, 40, 50, 60 °C);

[0058] Preferably, the solvent in step (c) is one or more selected from dichloromethane, tetrahydrofuran, toluene, acetonitrile, ethyl acetate, and pyridine.

[0059] Step (d)

[0060] Compound 4 undergoes a borohydride reduction reaction in the presence of a solvent to obtain compound 5.

[0061] Preferably, the reducing reagent used in the borohydride reduction reaction in step (d) is lithium borohydride;

[0062] Preferably, the reaction temperature in step (d) is 0 to 40 °C (such as 0, 10, 20, 30, 40 °C);

[0063] Preferably, the solvent in step (d) is one or more selected from diethyl ether and tetrahydrofuran;

[0064] Preferably, the molar ratio of the reducing agent to Compound 4 is (1.0 - 10.0):(0.5 - 2.0).

[0065] Step (e)

[0066] Compound 5 undergoes an asymmetric allylation reaction in the presence of a solvent and a catalyst to obtain Compound 6.

[0067] Preferably, the catalyst in step (e) is an iridium catalyst;

[0068] Preferably, the reaction raw materials in step (e) further include 4-chloro-3-nitrobenzoic acid, cesium carbonate, and allyl acetate;

[0069] Preferably, the reaction temperature in step (e) is 80 - 120 °C (e.g., 80, 90, 100, 110, 120 °C), and the reaction time is 24 - 72 hours (24, 36, 48, 56, 72 hours);

[0070] Preferably, the solvent in step (e) is one selected from degassed tetrahydrofuran, water, and ether. Maintain an inert, airtight environment.

[0071] Step (f)

[0072] Compound 6 undergoes benzyl protection of the hydroxyl group in the presence of a base and a catalyst, and then the silyl ether protecting group is removed in the presence of a solvent and a deprotecting agent assistant to obtain Compound 7.

[0073] Preferably, the benzyl reagent used for benzyl protection in step (f) is one or more selected from benzyl bromide and benzyl chloride;

[0074] Preferably, the base in step (f) is an inorganic base, preferably sodium hydride;

[0075] Preferably, the catalyst in step (f) is preferably tetrabutylammonium iodide;

[0076] Preferably, the deprotecting agent assistant in step (f) is one or more selected from pyridine hydrofluoride and tetrabutylammonium fluoride;

[0077] Preferably, the solvent in step (f) is one or more selected from acetonitrile, tetrahydrofuran, dichloromethane, and N,N-dimethylformamide;

[0078] Preferably, the molar ratio of Compound 6, the benzyl reagent, the base, and the catalyst is 1.0:

[0079] (1.2 - 2.0):(1.2 - 2.0):(0 - 0.2).

[0080] Step (g)

[0081] Compound 7 undergoes an esterification reaction with an amino-protected amino acid in the presence of a solvent, a base, and a reaction auxiliary to obtain Compound 8.

[0082] Preferably, the amino protecting group in step (g) is one selected from a 9-fluorenylmethoxycarbonyl protecting group and a tert-butoxycarbonyl (Boc) protecting group;

[0083] Preferably, the base in step (g) is one or more selected from triethylamine, N,N-diisopropylethylamine (DIPEA), and 4-dimethylaminopyridine (DMAP);

[0084] Preferably, the reaction auxiliary in step (g) is preferably 2,4,6-trichlorobenzoyl chloride (TCBC);

[0085] Preferably, the reaction temperature in step (g) is 0 to 40 °C (such as 0, 10, 20, 30, 40 °C), and the reaction time is 8 to 24 hours (such as 8, 10, 12, 18, 24 hours);

[0086] Preferably, the solvent in step (g) is one or more selected from dichloromethane, toluene, acetonitrile, and N,N-dimethylformamide.

[0087] Step (h)

[0088] Compound 8 removes the protecting group in the presence of an acid, and then undergoes an amidation reaction in the presence of a solvent, a base, and a condensing agent to obtain Compound 9.

[0089] Preferably, the acid in step (h) is an organic acid, preferably trifluoroacetic acid;

[0090] Preferably, the base in step (h) is one or more selected from triethylamine, N,N-diisopropylethylamine (DIPEA), and 4-dimethylaminopyridine (DMAP);

[0091] Preferably, the condensing agent in step (h) is one or more selected from N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) and 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBop);

[0092] Preferably, the solvent in step (h) is selected from one or more of dichloromethane, toluene, acetonitrile, and N,N-dimethylformamide;

[0093] Preferably, the volume ratio of dichloromethane to trifluoroacetic acid can be (1.0 to 5.0):(0.5 to 3.0).

[0094] Step (i)

[0095] Compound 9 undergoes ring-closing metathesis of olefins and hydrogenation reduction reactions in the presence of a solvent and a catalyst to remove the protecting group, obtaining Compound 10.

[0096] Preferably, the catalyst used in the ring-closing metathesis reaction of step (i) is one or more selected from Grubbs second-generation catalyst, palladium dichloride, palladium on carbon, and palladium hydroxide, and the molar content is 1-10 mmol%.

[0097] Preferably, the reaction temperature of the ring-closing metathesis reaction of step (i) is 25-100 °C, and the reaction time is 15-30 hours.

[0098] Preferably, the catalyst used in the hydrogenation reduction reaction of step (i) is one or more selected from palladium dichloride, palladium on carbon, and palladium hydroxide on carbon.

[0099] Preferably, the solvent in step (i) is one or more selected from dichloromethane, toluene, methanol, and tetrahydrofuran.

[0100] Step (j)

[0101] Compound 10 undergoes an esterification reaction with a carboxylic acid or an acyl chloride in the presence of a solvent, a base, and an optional condensing agent to obtain the compound of formula I.

[0102] When the reaction raw material R3 is a carboxylic acid, Compound 10 undergoes an esterification reaction in the presence of a solvent, a condensing agent, and a base to obtain the compound of formula I; when the reaction raw material R3 is an acyl chloride, Compound 10 undergoes an esterification reaction in the presence of a solvent and a base to obtain the compound of formula I.

[0103] Preferably, the base in step (j) is one or more selected from triethylamine, N,N-diisopropylethylamine (DIPEA), and 4-dimethylaminopyridine (DMAP).

[0104] Preferably, the solvent in step (j) is one or more selected from dichloromethane, tetrahydrofuran, toluene, acetonitrile, and ethyl acetate.

[0105] Preferably, the condensing agent in step (j) is one or more selected from dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and diethyl azodicarboxylate.

[0106] Preferably, the above synthetic methods a-j are all carried out under the protection of an inert gas, and the protective gas includes at least one of nitrogen, argon, and helium.

[0107] The preparation method of Dysoxylactam A and its analogs of the present invention uses differently substituted aldehydes and readily available propionaldehyde as starting materials. Through two aldol condensation reactions, four consecutive chiral centers are constructed. Then, through sulfonylation reaction, borohydride reduction, deprotection, protection of hydroxyl protecting groups, and esterification reaction with amino acids, all chiral centers of the target molecule are constructed. Finally, through amide reaction, ring-closing metathesis reaction, and hydrogenation reduction reaction, the natural product dysoxylactam A and its analogs are successfully obtained. This preparation method has good generality, high total yield, concise steps, easy derivatization, low operation requirements, can be prepared in large quantities, and has broad application and development prospects, laying a solid foundation for the subsequent in-depth structure-activity relationship and activity research of this type of compound.

[0108] The present invention has been described in detail above, but the above embodiments are essentially only illustrative and are not intended to limit the present invention. In addition, the present invention is not limited by any theory described in the foregoing prior art, invention content, or the following examples. BRIEF DESCRIPTION OF THE DRAWINGS

[0109] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the specific embodiments or the prior art. Obviously, the following drawings are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0110] Figure 1 It is a schematic diagram of the synthetic route of the natural product dysoxylactam A and its analogs provided by the embodiments of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0111] The present invention will be further described below in conjunction with the embodiments. It should be noted that the following embodiments are provided for illustrative purposes only and do not constitute a limitation on the scope of protection required by the present invention.

[0112] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the embodiments are all conventional raw materials, reagents, methods in the art.

[0113] According to Figure 1 The specific examples shown in the synthetic route are described.

[0114] Example 1

[0115] Prepare compound 2:

[0116] Method 1: Aldehydes substituted with different R1 groups (1.0 eq.) were dissolved in anhydrous DMF, and L-proline (0.2 eq.) was added. The mixture was cooled to 0 - 4 °C under argon or nitrogen protection. Then, a DMF solution of propionaldehyde (2 equiv.) was added dropwise to the reaction solution at a rate of 5 - 15 μL / min using a syringe pump. After the addition was complete, the mixture was stirred at the same temperature for another 24 - 48 hours. Subsequently, silver nitrate (1.5 eq.) was added to the reaction solution, and then chlorosilane (2.0 eq.) and pyridine (2.0 eq.) were added dropwise simultaneously. The reaction was stirred for 3 hours. After the reaction was completed, it was quenched with water (10 mL), and extracted with ether (3 × 20 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (n-hexane / dichloromethane = 100:1 - 20:1) to obtain compound 2 and its diastereoisomers. When the aldehyde substituted with R1 was propionaldehyde, the yield was 65%, anti: syn = 5:1, 1 H NMR (400 MHz, Chloroform-d) δ 9.74 (d, J = 2.4 Hz, 1H), 3.86 (q, J = 5.5 Hz, 1H), 2.51 (qdd, J = 7.2, 5.3, 2.5 Hz, 1H), 1.59–1.47 (m, 2H), 1.06 (d, J = 7.1 Hz, 3H), 0.93–0.87 (m, 12H), 0.06 (d, J = 5.5 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 205.43, 74.66, 50.73, 27.61, 25.91 (3C), 18.19, 10.65, 9.05, -4.13, -4.65.

[0117] Method 2: Different aldehydes substituted with R1 (1.0 eq.) and allyl alcohols in E or Z form protected with different silyl ethers (1.0 eq.) were dissolved in anhydrous dichloromethane (3 mL) at -78 °C and stirred continuously. Then, a solution of bis(trifluoromethanesulfonyl)imide (HNTf2) (0.001 eq, 0.01 M) was added dropwise slowly, and the mixture was stirred at the same temperature for 90 min. After thin-layer chromatography analysis showed the consumption of the silyl enol ether, the reaction was heated to -40 °C and quenched by adding a pH = 7.0 phosphate buffer solution (3 mL). The reaction was heated to ambient temperature and stirred vigorously for 5 min. The mixture was diluted with 20 mL of hexane and washed with water (2 times) and brine. The organic phases were combined, dried over sodium sulfate, filtered through cotton, concentrated under reduced pressure, and then purified by column chromatography (n-hexane:dichloromethane = 100:1 - 5:1). When the aldehyde substituted with R1 was S-2-methylbutyraldehyde, the yield was 80% (dr = 76:21:3), 11H NMR (500 MHz, C6D6) δ 9.73 (d, J = 1.8 Hz, 1H), 3.53 (t, J = 3.9 Hz, 1H), 2.36 (ddd, J = 7.1, 3.4, 2.0 Hz, 1H), 1.43 - 1.55 (m, 2H), 1.00 (d, J = 7.1 Hz, 3H), 0.84 - 0.95 (m, 1H), 0.82 (t, J = 7.1 Hz, 3H), 0.77 (d, J = 7.0 Hz, 3H), 0.25 (s, 27H); 13 13C NMR (500 MHz, C6D6) δ = 202.5, 83.6, 49.7, 40.5, 26.8, 15.6, 12.3, 12.1, 0.9.

[0118] Example 2

[0119] Preparation of Compound 3:

[0120] Dissolve dibutylboron trifluoromethanesulfonate (1.5 eq.) in dichloromethane, then slowly add a solution of (S)-(-)-benzyl-3-propionyl-2-oxazolidinone (1.2 eq.) (1 g / 20 mL) at 0 °C. Then add N,N-diisopropylethylamine (1.5 eq.). After stirring the solution at 0 °C for 1 hour, cool it to -78 °C and stir for 30 minutes. Add the aldehyde from the previous step (1.0 eq.) dropwise via syringe. Continue stirring the reaction for 2 hours, then gradually warm it to room temperature overnight. Add a mixture of methanol and hydrogen peroxide (10:30 mL) dropwise and stir at room temperature for 3 hours. After adding water, extract with dichloromethane. Combine the organic phases and dry over anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure and purify by column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain the target product. If the structure of the aldehyde is then the yield is 84%, 11H NMR (500 MHz, Chloroform-d) δ 7.39–7.21 (m, 5H), 4.68 (ddt, J = 10.1, 7.3, 2.7 Hz, 1H), 4.17 (dtd, J = 16.4, 9.1, 2.6 Hz, 2H), 3.94–3.85 (m, 2H), 3.67 (dt, J = 5.6, 2.8 Hz, 1H), 3.62–3.57 (m, 1H), 3.41 (dt, J = 13.3, 2.9 Hz, 1H), 2.78 (ddd, J = 13.0, 10.0, 2.8 Hz, 1H), 1.83 (tdq, J = 10.7, 7.2, 4.8, 3.7 Hz, 1H), 1.67 (d, J = 6.3 Hz, 1H), 1.59–1.39 (m, 2H), 1.28–1.15 (m, 4H), 0.98–0.89 (m, 18H), 0.12–0.10 (m, 6H). 13 13C NMR (126 MHz, Chloroform-d) δ 176.26, 153.40, 135.67, 129.60 (2C), 129.07 (2C), 127.42, 80.15, 73.14, 66.38, 56.23, 40.60, 40.23, 39.90, 37.91, 26.78, 26.07 (3C), 18.37, 14.97, 14.42, 12.31, 8.30, -4.21, -4.27. MS (ESI-LTQ) m / z: 492.1 [M+H] + . HRMS (ESI) m / z calcd for C 27 H 46 N2O5Si: 492.3140 [(M+H) + , measured: 492.3151.

[0121] Example 3

[0122] Preparation of Compound 4:

[0123] At 0 °C, dissolve the compound 3 (1.0 eq.) obtained in the previous step in dichloromethane solution, then add MsCl or TsCl (1.3 eq.) and pyridine (1.5 eq.), and then heat the reaction solution to reflux at 40 °C for 1 day. After the reaction is completed, quench the reaction solution with saturated solution NH4Cl, extract with Et2O, collect the organic phase, dry it with Na2SO4, concentrate it under reduced pressure, and obtain Compound 4 by column chromatography (petroleum ether / ethyl acetate = 25 / 1). If the R1 group is When using MsCl for the reaction, the reaction yield is 90%, 11H NMR (400 MHz, Chloroform-d) δ 7.36–7.19 (m, 5H), 5.08 (dd, J=10.2, 1.7 Hz, 1H), 4.66–4.56 (m, 1H), 4.26 (t, J=8.2 Hz, 1H), 4.18–4.04 (m, 2H), 3.78 (t, J=3.3 Hz, 1H), 3.28 (dd, J=13.4, 3.4 Hz, 1H), 3.06 (s, 3H), 2.79 (dd, J=13.4, 9.8 Hz, 1H), 2.05 (ddp, J=10.8, 7.3, 3.6 Hz, 1H), 1.53 (ddq, J=10.0, 6.7, 3.3 Hz, 1H), 1.51–1.36 (m, 1H), 1.23 (d, J=6.8 Hz, 3H), 1.08 (d, J=7.4 Hz, 3H), 0.93–0.84 (m, 15H), 0.05 (s, 6H). 13 13C NMR (101 MHz, Chloroform-d) δ 174.00, 153.81, 135.53, 129.52 (2C), 129.05 (2C), 127.44, 83.09, 75.10, 66.69, 56.22, 42.32, 40.28, 39.08, 37.95, 36.61, 28.77, 26.05 (3C), 18.32, 14.24, 12.13, 10.98, 8.42, -4.10, -4.46. MS (ESI-LTQ) m / z: 570.9 [M+H] + . HRMS (ESI) m / z calcd for C 28 H 47 NNaO7SSi: 592.2735 [(M+Na) + , measured: 592.2738.

[0124] Example 4

[0125] Preparation of Compound 5:

[0126] At 0 °C, Compound 4 (1.0 eq.) obtained in the previous step was added to a mixed solvent of diethyl ether or tetrahydrofuran (50 mL) and methanol (5.0 eq.), and then LiBH4 (5.0 eq.) was added. After 30 minutes, the mixture was stirred overnight at room temperature. After the reaction was completed, 1N aq. NaOH aqueous solution (10 mL) was added, and the reaction mixture was stirred at room temperature for 30 min, and then extracted with diethyl ether multiple times. The organic phase was collected, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (n-hexane / ethyl ether = 3 / 1) to obtain Compound 5. If the R1 group is A is TBS, the yield is 88%, 1 1H NMR (600 MHz, Chloroform-d) δ 3.48 (dd, J = 10.4, 5.9 Hz, 1H), 3.42 (dd, J = 10.4, 6.6 Hz, 1H), 3.33 (dd, J = 5.1, 3.3 Hz, 1H), 1.74–1.63 (m, 1H), 1.52–1.33 (m, 3H), 1.27–1.09 (m, 3H), 0.91–0.83 (m, 21H), 0.03 (d, J = 3.0 Hz, 6H). 13 13C NMR (151 MHz, Chloroform-d) δ 80.12, 69.63, 38.03, 36.20, 34.90, 33.54, 28.01, 26.32 (3C), 18.62, 16.45, 15.98, 14.70, 12.37, -3.56, -3.68. HRMS (ESI) m / z calcd for C 17 H 38 O2NaSSi: 325.2539 [(M+Na) + , measured: 325.2527.

[0127] Example 5

[0128] Preparation of Compound 6:

[0129] The compound 5 (1.0 eq.) obtained in the previous step, iridium catalyst (0.05 eq.), 4-cyano-3-nitrobenzoic acid (1.0 eq.) and cesium carbonate (1.2 eq.) were added to a sealed tube. The air in the pressure tube was carefully replaced with argon, and then degassed tetrahydrofuran (0.03 M) was added. Then, distilled water (2 v%) and allyl acetate (10.0 eq.) were added. The sealed tube was sealed to avoid air pollution and then heated to 100 °C in an oil bath for 72 hours. After the reaction was completed, the reaction mixture was slowly cooled to room temperature, then diluted with dichloromethane (20 mL), and the mixture was filtered through diatomaceous earth and then rinsed several times with dichloromethane. The filtrate was concentrated into a brown oily liquid and then purified by column chromatography (ethyl acetate / petroleum ether = 1 / 10 - 1 / 6) to obtain Compound 6. If the R1 group is Si is TBS, the yield is 80%, 11H NMR (400 MHz, Chloroform-d) δ 5.91–5.78 (m, 1H), 5.19–5.09 (m, 2H), 3.47 (dt, J = 8.6, 4.1 Hz, 1H), 3.32 (dd, J = 5.3, 3.3 Hz, 1H), 2.35–2.26 (m, 1H), 2.15 (dt, J = 14.1, 8.4 Hz, 1H), 1.78–1.52 (m, 3H), 1.52–1.30 (m, 2H), 1.21–1.07 (m, 2H), 0.96–0.82 (m, 21H), 0.03 (d, J = 3.7 Hz, 6H). 13 13C NMR (101 MHz, Chloroform-d) δ 135.67, 118.03, 80.16, 75.35, 39.16, 38.05, 36.08, 35.55, 35.00, 28.01, 26.32 (3C), 18.62, 16.36, 14.64, 13.71, 12.39, -3.52, -3.64. MS (ESI-LTQ) m / z: 365.1 [M+Na] + . HRMS (ESI) m / z calcd for C 20 H 42 NaO2Si: 365.2846 [(M+Na) + , measured: 365.2848.

[0130] Example 6

[0131] Preparation of Compound 7:

[0132] At 0 °C, NaH (60% dispersed in oil, 1.5 eq.) dissolved in DMF was added to a DMF solution of the compound 6 (1.0 eq.) obtained in the previous step. The mixed solution was stirred at 0 °C for 20 min, then tetrabutylammonium iodide (0.1 eq.) and benzyl bromide (1.5 eq.) were added. After removing the ice bath, the resulting mixture was stirred at room temperature for 5 h. After monitoring the completion of the reaction, it was quenched with a saturated aqueous solution of NH4Cl, then extracted with ether multiple times, washed with saturated brine, the organic phase was collected, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a colorless oily product, which was continued to be used in the next step. The oily product was dissolved in anhydrous acetonitrile in an ice bath at 0 °C, and HF·pyridine (∼70% HF) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was cooled to 0 °C and quenched by dropwise addition of sodium bicarbonate solution (1 mL), and then restored to room temperature. The reaction mixture was extracted with dichloromethane multiple times, washed with saturated brine multiple times, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 - 5 / 1) to obtain compound 7. If the R1 group is the yield is 90%, 1 H NMR (500 MHz, Chloroform-d) δ 7.36–7.31 (m, 4H), 7.30–7.23 (m, 1H), 5.88 (ddt, J = 17.2, 10.2, 7.0 Hz, 1H), 5.12–5.02 (m, 2H), 4.57 (d, J = 11.6 Hz, 1H), 4.50 (d, J = 11.6 Hz, 1H), 3.28 (dt, J = 6.4, 5.0 Hz, 1H), 3.16 (dd, J = 7.3, 4.2 Hz, 1H), 2.33 (ddt, J = 8.4, 5.5, 1.4 Hz, 2H), 1.89–1.77 (m, 1H), 1.63 (dtd, J = 10.1, 6.8, 3.0 Hz, 1H), 1.53–1.46 (m, 1H), 1.46–1.36 (m, 1H), 1.23 (dddd, J = 26.8, 13.4, 11.2, 5.2 Hz, 3H), 0.95–0.79 (m, 12H). 13 C NMR (126 MHz, Chloroform-d) δ 139.14, 136.00, 128.41 (2C), 127.92 (2C), 127.56, 116.65, 84.09, 79.37, 72.07, 36.75, 35.44, 34.82, 33.58, 33.17, 26.99, 16.02, 14.99, 12.86, 11.85. MS (ESI-LTQ) m / z: 319.2 [M + H] +.HRMS(ESI) m / z calcd for C 21 H 34 NaO2: 341.2451 [(M+Na) + , measured: 341.2456.

[0133] Example 7

[0134] Preparation of Compound 8:

[0135] At 0 °C, Compound 7 (1.0 eq.) obtained in the previous step and the R2-substituted amino acid (2.0 eq.) were dissolved in toluene (0.01 M)), N,N-diisopropylethylamine (4.0 eq.) and TCBC (3.0 eq.) were added, then the reaction mixture was stirred at room temperature for 0.5 h, and then DMAP (5.0 eq.) was added at 0 °C. The reaction mixture was slowly restored to ambient temperature and stirred for 12 h. After the reaction was complete, it was quenched with saturated aqueous ammonium chloride, extracted multiple times with ethyl acetate, washed with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 6 / 1) gave Compound 7. If the R1 group is and the amino acid is L-valine, the yield is 90%, 1 H NMR (500 MHz, Chloroform-d) δ 7.35–7.30 (m, 4H), 7.29–7.22 (m, 1H), 5.85 (ddt, J = 17.2, 10.2, 7.0 Hz, 1H), 5.13–5.00 (m, 2H), 4.95 (d, J = 9.5 Hz, 1H), 4.77 (dd, J = 7.1, 4.5 Hz, 1H), 4.56 (d, J = 11.7 Hz, 1H), 4.48 (d, J = 11.6 Hz, 1H), 4.22 (dd, J = 9.5, 4.3 Hz, 1H), 3.24 (q, J = 5.6 Hz, 1H), 2.30 (tt, J = 5.9, 1.3 Hz, 2H), 2.17 (pd, J = 6.6, 4.1 Hz, 1H), 1.78 (dddd, J = 25.8, 9.5, 6.8, 4.4 Hz, 1H), 1.68 (tt, J = 7.7, 5.4 Hz, 1H), 1.59 (s, 2H), 1.43 (s, 9H), 1.33 (ddd, J = 13.5, 7.5, 5.6 Hz, 1H), 1.22–1.10 (m, 2H), 0.99 (d, J = 6.9 Hz, 3H), 0.92–0.86 (m, 12H), 0.82 (d, J = 6.8 Hz, 3H). 1313C NMR (126 MHz, Chloroform-d) δ 172.54, 155.86, 139.18, 135.79, 128.40 (2C), 127.87 (2C), 127.52, 116.71, 83.68, 82.17, 79.70, 71.93, 59.07, 35.95, 35.37, 34.63, 33.21, 32.23, 31.01, 28.47 (3C), 26.76, 19.72, 17.35, 16.04, 14.51, 13.90, 11.73. MS (ESI-LTQ) m / z: 540.4 [M+Na] + . HRMS (ESI) m / z calcd for C 31 H 51 NNaO5: 540.3659 [(M+Na) + , measured: 540.3662.

[0136] Example 8

[0137] Preparation of Compound 9:

[0138] Dissolve the obtained Compound 8 (1.0 eq.) from the previous step in dichloromethane, then add dropwise TFA (CH2Cl2 / TFA = 3 / 1), stir the reaction for 3 hours, and evaporate under reduced pressure to obtain the crude product. Dissolve the crude product and heptenoic acid (2.0 eq.) in dichloromethane, add DIPEA (10.0 eq.), HOBT (2.0 eq.) and HATU (4.0 eq.) at 0 °C. Stir at room temperature for 10 hours. After the reaction is completed, quench with a saturated aqueous solution of ammonium chloride, then extract with dichloromethane multiple times, collect the organic phase, dry it over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Finally, purify by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain Compound 9. If the R1 group is the amino acid is L-valine, the yield is 90%, 11H NMR (400 MHz, Chloroform-d) δ 7.33 (d, J = 4.5 Hz, 4H), 7.29–7.24 (m, 1H), 5.91–5.72 (m, 3H), 5.13–4.99 (m, 2H), 4.99–4.92 (m, 2H), 4.77 (dd, J = 6.9, 4.7 Hz, 1H), 4.61 (dd, J = 9.0, 4.4 Hz, 1H), 4.55 (d, J = 11.5 Hz, 1H), 4.47 (d, J = 11.4 Hz, 1H), 3.25 (q, J = 5.7 Hz, 1H), 2.28 (ddd, J = 7.3, 4.9, 3.6 Hz, 2H), 2.23–2.17 (m, 3H), 2.09–2.02 (m, 2H), 1.87–1.69 (m, 1H), 1.73–1.57 (m, 3H), 1.45–1.27 (m, 4H), 1.21–1.15 (m, 2H), 1.15–1.05 (m, 1H), 0.97 (d, J = 6.9 Hz, 3H), 0.92–0.86 (m, 12H), 0.82 (d, J = 6.7 Hz, 3H). 13 13C NMR (126 MHz, Chloroform-d) δ 172.82, 172.42, 139.16, 138.60, 135.74, 128.41 (2C), 127.91 (2C), 127.55, 116.77, 114.81, 83.71, 82.55, 72.02, 57.15, 36.70, 35.87, 35.44, 34.61, 33.56, 33.14, 32.21, 31.27, 28.60, 26.75, 25.27, 19.69, 17.49, 16.06, 14.34, 14.05, 11.70. MS (ESI-LTQ) m / z: 528.4 [M+H] + . HRMS (ESI) m / z calcd for C 33 H 54 NO4: 528.4047 [(M+H) + , measured: 528.4058.

[0139] Example 9

[0140] Preparation of Compound 10: Add the compound 9 obtained in the previous step (1.0 eq.) to a round-bottom flask, then evacuate with argon multiple times. Then add degassed dichloromethane (0.001 M) and a dichloromethane solution of Grubbs second-generation catalyst (0.1 eq.). Then heat to 40 °C and stir for 24 hours. After judging that the reaction is complete by TLC analysis, concentrate under reduced pressure to obtain the crude product. Dissolve the crude product in methanol solution, add palladium on carbon (0.1 eq.), then charge with hydrogen and react in a 50 °C water bath for 12 hours, and replace the gas in the reaction system with hydrogen multiple times during this period. After the reaction is complete, spin-dry the reaction solution under reduced pressure and purify by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain Compound 10. If the R1 group is The amino acid is L-valine, then the product is dysoxylactam A with a yield of 75%. 1 H NMR (500 MHz, Chloroform-d) δ 6.04 (d, J = 8.7 Hz, 1H), 4.81 (d, J = 9.2 Hz, 1H), 4.66 (dt, J = 8.8, 2.9 Hz, 1H), 3.27 (t, J = 7.4 Hz, 1H), 2.40–2.32 (m, 1H), 2.23–2.15 (m, 2H), 1.87 (d, J = 9.8 Hz, 1H), 1.83–1.75 (m, 1H), 1.71 (q, J = 7.0 Hz, 1H), 1.54–1.38 (m, 8H), 1.37–1.06 (m, 8H), 0.98 (dd, J = 6.9, 2.1 Hz, 3H), 0.89 (dddd, J = 20.2, 13.8, 6.8, 2.0 Hz, 16H).

[0141] 13 C NMR (126 MHz, Chloroform-d) δ 173.10, 173.04, 81.91, 77.28, 56.86, 36.68, 36.31, 35.89, 34.09, 32.18, 31.88, 31.63, 28.06, 27.74, 27.37, 27.32, 25.06, 25.03, 19.54, 17.20, 15.86, 15.37, 13.20, 12.04. HRMS (ESI) m / z calcd for C 24 H 46 NO4: 412.3427 [(M + H) + , measured: 412.3427.

[0142] If the R1 group is ethyl and the amino acid is L-valine, the yield is 76%. 11H NMR (500 MHz, Chloroform-d) δ 5.97 (d, J = 8.8 Hz, 1H), 4.78 (ddd, J = 9.0, 5.9, 3.1 Hz, 1H), 4.59 (dd, J = 8.8, 4.4 Hz, 1H), 3.38 (dt, J = 6.6, 4.5 Hz, 1H), 2.34 (ddd, J = 14.3, 7.9, 3.9 Hz, 1H), 2.27–2.15 (m, 2H), 1.84 (dddd, J = 17.5, 9.1, 6.8, 4.1 Hz, 1H), 1.71–1.44 (m, 6H), 1.43–1.17 (m, 11H), 0.98 (d, J = 6.8 Hz, 3H), 0.93–0.86 (m, 12H). 13 13C NMR (126 MHz, Chloroform-d) δ 173.37, 172.99, 80.59, 75.16, 57.08, 36.45, 35.61, 35.49, 34.81, 33.25, 31.31, 28.06, 27.81 (2C), 25.46, 24.79, 23.30, 19.38, 17.46, 15.74, 15.19, 10.36. MS (ESI-LTQ) m / z: 384.3 [M+H] + . HRMS (ESI) m / z calcd for C 22 H 42 NO4: 384.3108 [(M+H) + , measured: 384.3118.

[0143] Example 10

[0144] Preparation of the compound of formula I:

[0145] Method 1: Dissolve the compound 10 obtained in the previous step in dichloromethane solution, add the R3-substituted acid (1.2 eq.), then add EDCI or DCC (1.5 eq.) and DMAP (1.0 eq.). React under stirring at room temperature for 5 hours. After monitoring the completion of the reaction by TLC, extract with dichloromethane multiple times, wash with saturated brine, collect the organic phase, dry it with anhydrous sodium sulfate, filter, and then concentrate under reduced pressure. Purify by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain the compound of formula I.

[0146] Method 2: Dissolve the compound 10 obtained in the previous step in anhydrous dichloromethane solution at 0 °C, add R3-substituted acyl chloride (3.0 eq.), triethylamine (3.0 eq.) or DMAP (3.0 eq.) respectively, stir the reaction at room temperature for 3 hours. After monitoring the completion of the reaction by TLC, add water to quench the reaction, then extract with dichloromethane multiple times, wash with saturated brine, collect the organic phase, dry it over anhydrous sodium sulfate, filter, and then concentrate under reduced pressure. Purify by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain the compound of formula I. If the R1 group is the amino acid is L-valine, R3 is a p-bromobenzoyl substituent, the yield is 90%, 1 H NMR (C5D5N, 500 MHz) δ: 8.83 (1H, d, J = 9.1 Hz), 8.11 (2H, d, J = 8.5 Hz), 7.70 (2H, d, J = 8.5 Hz), 5.22 (m, H-9), 5.13 (1H, dd, J = 9.1, 4.7 Hz), 5.07 (1H, dd, J = 8.8, 2.9 Hz), 2.53 (1H, m), 2.34 (1H, m), 1.09 (3H, d, J = 6.8 Hz), 1.07 (3H, d, J = 6.8 Hz), 1.01 (3H, d, J = 6.8 Hz), 0.97 (3H, d, J = 6.7 Hz), 0.93 (3H, t, J = 7.4 Hz), 0.85 (3H, d, J = 6.6 Hz); 13 C NMR (C5D5N, 125 MHz) δ: 173.9, 35.7, 25.0, 28.5, 27.8, 27.9, 25.4, 30.0, 80.6, 35.1, 35.2, 33.4, 81.2, 36.4, 27.8, 12.4, 16.6, 16.2, 13.8, 174.0, 58.1, 31.6, 18.2, 20.3, 165.9, 130.8, 132.0 (2C), 132.6 (2C), 128.5. ESIMS m / z: 594.6 [M + H] + ; HRESIMS m / z: 628.2412 [M + Cl] - (calcd for C 31 H 48 NO5ClBr, 628.2404).

[0147] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a compound represented by Formula I, The preparation method comprises the following steps: (a1) Compound 1 undergoes an asymmetric aldol condensation reaction with propionaldehyde in the presence of a solvent and a catalyst, and then a silyl ether protecting group is added in the presence of a base and a salt to protect the hydroxyl group, obtaining Compound 2; or, (a2) Compound 1 undergoes an asymmetric aldol condensation reaction with E-form or Z-form allyl alcohol protected by a silyl ether in the presence of a solvent and a catalyst, obtaining Compound 2; (b) Compound 2 undergoes an Evans aldol reaction with a chiral auxiliary in the presence of a solvent and a base, obtaining Compound 3; (c) Compound 3 undergoes a sulfonylation reaction in the presence of a solvent and a base to obtain Compound 4; (d) Compound 4 undergoes a borohydride reduction reaction in the presence of a solvent to obtain Compound 5; (e) Compound 5 undergoes an asymmetric allylation reaction in the presence of a solvent and a catalyst to obtain Compound 6; (f) Compound 6 undergoes benzyl protection of the hydroxyl group in the presence of a base and a catalyst, and then the silyl ether protecting group is removed in the presence of a solvent and a deprotecting auxiliary to obtain Compound 7; (g) Compound 7 undergoes an esterification reaction with an amino-protected amino acid in the presence of a solvent, a base and a reaction auxiliary to obtain Compound 8; (h) Compound 8 removes the protecting group in the presence of an acid, and then undergoes an amidation reaction in the presence of a solvent, a base and a condensing agent to obtain Compound 9; (i) Compound 9 undergoes olefin ring-closing metathesis reaction and hydrogenation reduction reaction in the presence of a solvent and a catalyst to remove the protecting group to obtain Compound 10; (j) Compound 10 undergoes an esterification reaction with a carboxylic acid or an acyl chloride in the presence of a solvent, a base and an optional condensing agent to obtain the compound of Formula I; Among them, R1 is selected from hydrogen, C1-C 10 alkoxy, C1-C 10 alkyl,; R2 is selected from hydrogen, C1-C 10 alkyl,; R3 is a halogen-substituted benzoyl group; R’ is selected from mesyl group, p-toluenesulfonyl group, ethylsulfonyl group; A is selected from one of TMS, TES, TBDMS, TBDPS, TIPS, Si(TMS)3; The catalyst in step (a1) is a chiral ligand; The base in step (a1) is an organic base; The salt in step (a1) is an inorganic salt; The reaction temperature of the asymmetric aldol condensation reaction in step (a1) is -10 to 10 °C, and the reaction time is 12 to 48 hours; The reaction temperature of the hydroxyl protection in step (a1) is 0 to 30 °C, and the reaction time is 2 to 10 hours; The solvent in step (a1) is one or more of N,N-dimethylformamide, dimethyl sulfoxide; The catalyst in step (a2) is selected from one or more of trifluoromethanesulfonimide, boron trifluoride diethyl etherate, titanium tetrachloride; The reaction temperature in step (a2) is -80 to 0 °C, and the reaction time is 3 to 12 hours; The solvent in step (a2) is selected from one or more of dichloromethane, acetonitrile, water; The chiral auxiliary in step (b) is selected from one or more of (±)-4-benzyl-3-propionyl-2-oxazolidinone, dibutylboron trifluoromethanesulfonate; The base in step (b) is selected from one or more of triethylamine, N,N-diisopropylethylamine; The reaction temperature in step (b) is -78 to 0 °C, and the reaction time is 10 to 24 hours; The solvent in step (b) is selected from one or more of dichloromethane, tetrahydrofuran, toluene, acetonitrile, ethyl acetate; The sulfonylation reagent used in the sulfonylation reaction of step (c) is an alkylsulfonyl chloride or an arylsulfonyl chloride; The base in step (c) is selected from one or more of triethylamine, pyridine, imidazole, and N,N-diisopropylethylamine; The reaction temperature of step (c) is 0 to 60 °C; The solvent in step (c) is selected from one or more of dichloromethane, tetrahydrofuran, toluene, acetonitrile, ethyl acetate, and pyridine; The reducing reagent used in the borohydride reduction reaction of step (d) is one or more of lithium borohydride, sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride, lithium triethylborohydride, and diisobutylaluminum hydride; The reaction temperature of step (d) is 0 to 40 °C; The solvent in step (d) is selected from one or more of diethyl ether and tetrahydrofuran; The catalyst in step (e) is an iridium catalyst; The reaction raw materials in step (e) further include 4-chloro-3-nitrobenzoic acid, cesium carbonate, and allyl acetate; The reaction temperature of step (e) is 80 to 120 °C, and the reaction time is 24 to 72 hours; The solvent in step (e) is selected from one of degassed tetrahydrofuran, water, and diethyl ether; The benzyl reagent used for benzyl protection in step (f) is selected from one or more of benzyl bromide and benzyl chloride; The base in step (f) is an inorganic base; The catalyst in step (f) is selected from tetrabutylammonium iodide, silver oxide, and sodium iodide; The deprotecting group auxiliary in step (f) is selected from one or more of pyridine hydrofluoride and tetrabutylammonium fluoride; The solvent in step (f) is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, and N,N-dimethylformamide; The amino acid protecting group in step (g) is selected from one of 9-fluorenylmethoxycarbonyl protecting group and tert-butoxycarbonyl protecting group; The base in step (g) is selected from one or more of triethylamine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine; The reaction auxiliary in step (g) is 2,4,6-trichlorobenzoyl chloride; The reaction temperature of step (g) is 0 to 40 °C, and the reaction time is 8 to 24 hours; The solvent in step (g) is selected from one or more of dichloromethane, toluene, acetonitrile, and N,N-dimethylformamide; The acid in step (h) is an organic acid; The base in step (h) is selected from one or more of triethylamine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine; The condensing agent in step (h) is selected from one or more of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate and 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate; The solvent in step (h) is selected from one or more of dichloromethane, toluene, acetonitrile, and N,N-dimethylformamide; The catalyst used in the olefin metathesis reaction of step (i) is selected from one or more of Grubbs second-generation catalyst, palladium dichloride, palladium on carbon, and palladium hydroxide, and the molar content is 1 to 10 mmol%; The reaction temperature of the olefin metathesis reaction in step (i) is 25 to 100 °C, and the reaction time is 15 to 30 hours; The catalyst used in the hydrogenation reduction reaction of step (i) is selected from one or more of palladium dichloride, palladium on carbon, and palladium hydroxide on carbon; The solvent in step (i) is selected from one or more of dichloromethane, toluene, methanol, and tetrahydrofuran; The base in step (j) is selected from one or more of triethylamine, N,N - diisopropylethylamine, and 4 - dimethylaminopyridine; The condensing agent in step (j) is selected from one or more of dicyclohexylcarbodiimide, 1 - (3 - dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride, and diethyl azodicarboxylate; The solvent in step (j) is selected from one or more of dichloromethane, tetrahydrofuran, toluene, acetonitrile, and ethyl acetate.

2. The preparation method according to claim 1, wherein Wherein, R1 is a C1 - C6 alkyl group; R2 is a C1 - C6 alkyl group; R3 is a p - bromobenzoyl group.

3. The preparation method according to claim 1, characterized in that, Wherein, R1 is 2 - methylbutyl; R2 is isopropyl.

4. The preparation method according to claim 1, characterized in that, The catalyst in step (a1) is D / L - proline; The base in step (a1) is selected from one or more of pyridine, 4 - dimethylaminopyridine, and N,N - diisopropylethylamine; The salt in step (a1) is silver nitrate.

5. The preparation method according to claim 1, wherein The chiral auxiliary in step (b) is (±)-4 - benzyl - 3 - propionyl - 2 - oxazolidinone and dibutylboron trifluoromethanesulfonate; The molar ratio of the base, (±)-4 - benzyl - 3 - propionyl - 2 - oxazolidinone to dibutylboron trifluoromethanesulfonate in step (b) is (1.3 - 2.0):(0.8 - 1.2):(1.2:1.8).

6. The preparation method according to claim 1, characterized in that, The molar ratio of the reducing agent in step (d) to compound 4 is (1.0 - 10.0):(0.5 - 2.0).

7. According to the preparation method described in claim 1, characterized in that, The base in step (f) is sodium hydride.

8. The preparation method according to claim 1, wherein The acid in step (h) is trifluoroacetic acid; The volume ratio of the solvent to the acid in step (h) is (1.0 - 5.0):(0.5 - 3.0).

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