Preparation method of tunicamycin-V and analogues thereof

Abstract

The invention discloses a preparation method of tunicamycin-V and analogues thereof, and belongs to the field of medicine synthesis. According to the preparation method disclosed by the invention, 6-bromo-galactose and uracil uronic acid selenide which are easy to obtain are taken as raw materials, and a nickel-promoted reduction coupling reaction is adopted, so that the chlamydoamine ketone compound is efficiently prepared; 2-deoxy-2-azido glucose N-phenyl imine ester is used as a donor, perchloric acid is used as a catalyst, construction of an alphaglc betaga (1, 1)-type glucosidic bond is efficiently achieved, and a framework of the chlamymycin is built; and finally, the gram-scale preparation of the tunicamycin-V and the analogues thereof is realized through an efficient functional group conversion and water washing post-treatment purification method. The core undecane disaccharide structure can be efficiently constructed at the scale of more than 10g and the yield of 72% in one time; construction of a challenging seaweed type alphaglc betaga (1, 1) glucosidic bond is completed with high stereoselectivity on the reaction scale of 8.3 g; finally, the longest route is 15 steps, the yield reaches 13.7%, and 1.33 g of the chlamymycin V and the analogues thereof are obtained on the gram-level scale.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and more specifically, relates to a method for preparing tunicamycin-V and its analogs. Background Art

[0002] Since the 1940s, the discovery and use of antibiotics have saved countless lives, but with the abuse of antibiotics, the emergence of drug-resistant bacteria and superbugs has posed a serious threat to human health. Nucleoside compounds derived from microbial secondary metabolites have multiple biological activities (J. Antibiot. 1988, 41, 1711-1739; Biotechnology Advances 2021, 46, 107673) and have been widely used as antiviral and anticancer drugs (Chem. Rev. 2021, 121, 3464–3694), but their antibacterial activity has not been studied in depth, and most of them remain at the cellular level.

[0003] Tunicamycins are nucleoside antibiotics with unique structures produced by Streptomyces Lysosuperficus nov.sp. They are highly effective inhibitors of MraY (phosphoryl-MurNAc-pentapeptide transferase), a key enzyme in bacterial cell wall synthesis, and can inhibit Gram-positive bacteria, fungi and viruses (Eur. J. Med. Chem. 2015, 97, 582-611; J. Antimicrob. Chemother. 2004, 54, 755–760). Since the human glycosyltransferase (polyphenol phosphate-N-acetylglucosamine phosphotransferase) has partial homology with MraY, tunicamycins not only show good inhibitory effects on prokaryotic cells, but also inhibit eukaryotic cells (Trends Biochem. Sci. 1981, 6, 219). In the evaluation of the antibacterial activity of tunicamycins with different amide side chains, tunicamycin-V (Tunicamycin V) showed the best inhibitory activity against bacteria (IC 50:0.35μM)(Bioorg.Med.Chem.Lett.2019,27,1714–1719). Currently, the main way to obtain tunicamycin is still strain fermentation (Journal of Biological Chemistry,2002,277,35289–35296), but because the structures of different subtypes differ only at the amide side chain, its separation and purification are difficult (Journal of the Agricultural Chemical Society of Japan,2006,52,859–861;ACS Chem.Biol.2020,15,2885–2895).

[0004]

[0005] In order to solve the two major problems of tunicamycin being difficult to separate and purify and having poor antibacterial selectivity, it is crucial to obtain tunicamycin-V and its analogs, which have the best activity in the tunicamycin family, by chemical synthesis to study the structure-activity relationship between structure and activity, and then obtain antibacterial drugs that specifically inhibit MraY targets. The skeleton of tunicamycin-V is mainly composed of a core 11-carbon disaccharide, glucosamine, uracil, and side chains with different amide structures (J. Antibiot. 1971, 24, 215–223). The difficulty in synthesis lies in the construction of the 11-carbon disaccharide structure and the trehalose-type α-D-pyranosyl-β-D-pyranosylgalactose α glc β gal (1,1) Disaccharide glycosidic bond. Currently, five research groups have achieved the total synthesis of tunicamycin-V.

[0006] In 1984, the Suami group completed the first total synthesis of tunicamycin-V (Tetrahedron Lett. 1984, 25, 4533–4536). First, the authors used aminogalactose 12 and ribose 13 as raw materials to construct the core 11-carbon disaccharide skeleton through the Henry reaction, and obtained the o-nitro alcohol 14 with a yield of 51%; secondly, 14 was subjected to 9 steps of reactions including removal of the 6′ hydroxyl group, conversion of the 5′ nitro group to a hydroxyl group, introduction of a uracil group, and conversion of the methoxy group to a chloroglycoside, to obtain the key glycosylation donor 15 with a yield of 1.4%; subsequently, the chloroglycoside donor 15 reacted with the glucosamine receptor 16 under the promotion of silver salt to obtain the glycosylation donor 15 with a yield of 33% and a ratio of α glc β gal / β glc β gal =1.2 / 1 to obtain the glycosylation product 17, completing the skeleton construction of tunicamycin; finally, the authors introduced side chains and removed protecting groups, with the longest linear step of 22 and a yield of 0.042%, to obtain 21 mg of tunicamycin-V.

[0007]

[0008] In 1994, Myers's group completed the second synthesis of tunicamycin-V (J.Am.Chem.Soc.1994,116,4697–4718). This synthesis strategy is different from that of Professor Suami. The authors first applied free radical coupling reaction to the C5′-C6′ skeleton construction process. First, the authors used phthaloyl (Phth) protected aminogalactose 18 and trichloroimide donor 19 to carry out glycosylation reaction in toluene solution at -20°C catalyzed by trifluoromethanesulfonic acid (TfOH), and obtained 88% yield and α glc β gal / α glc α gal =7 / 1 stereoselectivity to obtain trehalose-type disaccharide 20; secondly, 20 was subjected to 7 functional group transformations including conversion of azide to acetamide, conversion of NPhth to NHCbz, oxidation and elimination of phenylselenoyl to obtain free radical coupling precursor 21 with a yield of 53%; subsequently, the authors used silyl protecting groups to connect sugar ene 21 with ribouridine 22, mediating intramolecular free radical coupling reaction of the alkenyl functional group, achieving C5′-C6′ bond coupling, and stereoselectively introducing chiral hydroxyl group at C5′ position to obtain 24 with a yield of 60%; finally, after the steps of introducing side chains and removing protecting groups, 88 mg of tunicamycin-V was obtained in 24 steps with a yield of 2.1%.

[0009]

[0010]

[0011] In 2015, Yu Biao's research group completed the third synthesis of tunicamycin-V (Angew. Chem., Int. Ed. 2015, 54, 6618–6621). First, in order to efficiently construct the 11-carbon disaccharide structure 28, the authors used the open-chain sugar enol 26 and the aldehyde ribose 27 to carry out the Mukaiyama-Aldol reaction, and at the same time stereoselectively introduced the C5′ chiral hydroxyl group with a yield of 89%, dr = 13:1, of which 26 needed to be converted from pyranosamine galactose 25 in 12 steps; secondly, in order to obtain α glc β galFor the seaweed-type disaccharide 31, the authors transformed 28 into a hemiacetal acceptor 29 with a yield of 54%, and then reacted it with the glucosamine o-alkynyl benzoate donor 30 under the catalysis of a gold promoter for glycosylation to construct a single-configuration disaccharide 31 with a yield of 61%. Subsequently, 31 underwent five steps of reactions, including removal of the PMP protecting group at the anomeric position, preparation of an alkynyl ester donor, and introduction of a uracil group, to obtain the key intermediate 32 with a yield of 50%, completing the skeleton construction. Finally, the authors removed the deprotecting group and obtained 12 mg of the target product with a yield of 1.79% through 33 steps with the longest linear step.

[0012]

[0013] In 2018, the Ichikawa group completed the fourth total synthesis of tunicamycin-V (Org. Lett. 2018, 20, 256–259). First, the authors used furanol 33 and ribouridine 34 as raw materials, and also used the Mukaiyama-Aldol reaction to construct the C5′-C6′ bond, and completed the stereoselective introduction of the chiral hydroxyl group at the C5′ position, and obtained 35 with a yield of 64% and a stereoselectivity of dr=98 / 2; secondly, in order to convert the furanyl group of intermediate 35 into pyranosylgalactose, it involved 14 steps of reactions such as the Achmatowicz reaction to form pyranose ene and the conversion of the oxazoline intermediate into amino sugars, and obtained the hemiacetal acceptor 36 with a yield of 17%; then, the authors glycosylated 36 with the β-configuration trichloroimide donor 37 under the catalysis of trifluoromethanesulfonic acid (TfOH), and obtained 35 with a yield of 84% and a stereoselectivity of α=2. glc β gal / β glc β gal =14 / 1 stereoselectivity to construct the seaweed disaccharide 38 to obtain the basic skeleton of tunicamycin; finally, 38 was subjected to the process of introducing side chains and deprotection, with the longest linear step of 23 and a yield of 3.89% to obtain 1.1 mg of tunicamycin-V.

[0014]

[0015] In 2022, Kurosu's group completed the fifth total synthesis of tunicamycin-V (Angew. Chem., Int. Ed. 2022, 61, e202203225). The synthesis strategy of this work is different from that of previous studies in that the authors used the Büchner–Curtius–Schlotterbeck (BCS) reaction to construct the core C5′-C6′ bond, and then used Noyori catalyst to reduce the C5′ carbonyl group to introduce a chiral hydroxyl group. First, the authors used aminogalactose 39 and glucose 40 as raw materials, and carried out glycosylation reaction under the promotion of N-iodosuccinimide (NIS) and silver borofluoride (AgBF4), and constructed seaweed-type disaccharide 41 with 85% yield stereoselectively. Secondly, 41 removed 2,4-dinitrobenzenesulfonyl (DNs) and underwent nitration reaction to obtain N-nitrosoacetamide intermediate 42. 42 was reacted with 40% KOH / Et2O / MeOH to generate The diazomethylene disaccharide 43 present in the solution was coupled with the aldehyde group of uridine 44 to obtain 45 with a yield of 90%, constructing the C5′-C6′ bond and introducing the keto carbonyl group at the C5′ position; subsequently, the keto carbonyl group at the C5′ position of compound 45 was subjected to Noyori asymmetric hydrogenation to obtain a single-configuration product 46 with an almost quantitative yield; finally, 46 was subjected to the process of introducing a side chain and deprotection to obtain 4.4 mg of the target product with a total yield of 21% in 15 steps.

[0016]

[0017] In summary, the efficient construction of tunicamycin undecaned disaccharide and the stereoselective formation of the unique α glc β gal The (1,1)-type glycosidic bond is the key to obtaining tunicamycin-V. Although the above five synthetic strategies all eventually completed the synthesis of tunicamycin-V, they also have some shortcomings: (1) The route used to prepare tunicamycin-V undecyl disaccharide is complicated, the reagents used are not easy to obtain, and the reaction conditions used are not mild enough; (2) The construction of α glc β gal The glycosylation method used for (1,1)-type trehalose glycosidic bonds has poor stereoselectivity and expensive catalysts; (3) it is not suitable for the synthesis of tunicamycin-V on a gram scale. None of the above routes have achieved the synthesis of tunicamycin-V on a gram scale, and only samples of milligrams to hundreds of milligrams have been obtained. Summary of the invention

[0018] Based on the above problems, the purpose of the present invention is to provide a method for preparing tunicamycin-V and its analogs on a large scale with easy-to-obtain raw materials, high stereoselectivity and high yield, so as to solve the problem that tunicamycin-V and its analogs are difficult to obtain in large quantities and provide a material basis for the activity research of tunicamycin-V and its analogs.

[0019] The invention uses easily available 6-bromogalactose and uracil selenoester as raw materials, adopts nickel-promoted reduction coupling reaction, and efficiently prepares tunicamidone compound; then uses 2-deoxy-2-azidoglucose N-phenylimine ester as donor, and uses perchloric acid as catalyst, and efficiently realizes α glc β gal The (1,1)-type glycosidic bond was constructed to build the skeleton of tunicamycin; finally, the gram-scale preparation of tunicamycin-V was achieved through efficient functional group transformation and water-washing post-treatment purification methods.

[0020] In order to achieve the above object, the specific technical solution adopted by the present invention is:

[0021] The preparation method of tunicamycin-V and its analogs comprises the following steps:

[0022]

[0023] in,

[0024] R 1 : is pyridylthio (PyS), ethylthio (EtS), phenylthio (PhS) or phenylselenyl (PhSe), preferably: PhSe;

[0025] R 2 :is a hydrogen atom (H) or benzyl (Bn), substituted benzyl, phthaloyl (Phth), alkyl or ester group, silicon group, benzaldehyde dimethyl acetal or isopropylidene acetal protecting group, R in the same molecule 2 can be the same or different groups, preferably: isopropylidene;

[0026] R 3 : tert-butyldimethylsilyloxy (TBSO), triisopropylsilyloxy (TIPSO), p-methoxyphenoxy (MPO), p-tolylthio (TolS), ethylthio (EtS) or phenylthio (PhS), preferably TBSO;

[0027] R 4 : is a halogen atom selected from Br or I, preferably Br;

[0028] R 5 :H or benzyl, substituted benzyl, alkyl or ester, silicon, benzaldehyde dimethyl acetal and other acetal protecting groups. 5 can be the same or different groups, preferably: benzaldehyde dimethyl acetal group;

[0029] R 6 : is the activated leaving group (LG) of donor 6, selected from the following groups, preferably: LG3;

[0030]

[0031] R: is a fatty chain branch structure, selected from any of the following structures:

[0032]

[0033] Step 1: dissolving compounds 2 and 3, a nickel catalyst, a ligand, a zirconium promoter, a reducing agent and an additive in a first solvent, and reacting at room temperature for 15-180 minutes to obtain compound 4;

[0034] Step 2: dissolving compound 4 in a second solvent, adding the first catalyst, and reacting at 0°C-60°C for 6-24 hours to obtain compound 5;

[0035] Step 3: Compound 5 and compound 6 are dissolved in a third solvent, a second catalyst is added, and a glycosylation reaction is carried out at -40°C-0°C for 3-6 hours to obtain compound 7;

[0036] Step 4: dissolving compound 7 in a fourth solvent, adding a third catalyst, and reacting at room temperature for 6-24 hours to obtain compound 8;

[0037] Step 5: dissolving compound 8 in a fifth solvent, adding a fourth catalyst, and reacting at 0°C to room temperature for 10 to 48 hours to obtain compound 9;

[0038] Step 6: dissolving compound 9 in a sixth solvent, adding a fifth catalyst, reacting at 25°C-100°C for 10-48 hours, dissolving the obtained amino intermediate and aliphatic chain carboxylic acid 10 in a seventh solvent, adding a sixth catalyst, reacting at room temperature for 6-24 hours, and obtaining compound 11;

[0039] Step 7: Dissolve compound 11 in the eighth solvent, add the seventh catalyst, and react at -80°C-0°C for 1-3 hours to obtain tunicamycin-V and its analogue 1.

[0040] In step 1, the nickel catalyst is: Ni(BF4)2, Ni(ClO4)2, NiCl2, NiBr2, NiI2, Ni(NTf)2, Ni(OAc)2 or Ni(OTf)2, preferably: Ni(BF4)2; the ligand is selected from any one of compounds L1-L13, preferably: ligand L6; the zirconium catalyst is: Cp2ZrCl2, Cp2ZrI2 or Cp2Zr(OTf)2, preferably: Cp2ZrCl2; the reducing agent is Zn, Mn or In, preferably: Zn; the additives include: ZnCl2, acetone, NaH2PO4 and Molecular sieve; the molar ratio of compound 2, 3, nickel catalyst, ligand, zirconium promoter, reducing agent and additive is: 1:1.0:0.1:0.1:1.0:1.0:1.0-1:5.0:1.0:1.0:5.0:5.0:5.0; the first solvent is: 1,3-dimethyl-2-imidazolidinone (DMI), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dioxane, 1,2-dichloroethane (DCE) or tetrahydrofuran, preferably: DMI or DMF; the concentration of compound 2 in the first solvent is: 0.1-0.5 mmol / mL;

[0041] The structure of the ligand compound is shown below:

[0042]

[0043] In step 2, the first catalyst is: pyridinium hydrofluoride (HF·Pyridine) or tetrabutylammonium fluoride (TBAF), preferably: HF·Pyridine; the molar ratio of compound 4 to the first catalyst is: 1:1.5 to 1:20; the second solvent is: pyridine or tetrahydrofuran, preferably: pyridine; the concentration of compound 4 in the second solvent is: 0.01 to 0.1 mmol / mL.

[0044] In step 3, the second catalyst is HClO4 or TMSClO4; the preferred second catalyst is HClO4; the molar ratio of compound 5, compound 6 and the second catalyst is 1:1.0:0.1 to 1:5.0:0.5; the third solvent is ether, dioxane or a mixed solvent of ether and dioxane; preferably, a mixed solvent of ether and dioxane, with a volume ratio of 9:1; the concentration of compound 5 in the third solvent is 0.01 to 0.1 mmol / mL.

[0045] In step 4, the third catalyst is: NaBH4, NaBH4+Et3B, NaBH4+Zn(OTf)2, Zn(BH4)2, lithium tri-sec-butyl borohydride, (S)-B-Me-CBS-BH·THF, (R)-B-Me-CBS-BH·THF, (S)-B-Me-CBS, BH·SMe2, (R)-B-Me-CBS, BH·SMe2, Al(OiPr)3 or (R,R)-N-(p-methyl)- Benzenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (CAS No.: 192139-92-7), preferably: (S)-B-Me-CBS, BH·SMe2; the molar ratio of compound 7 to the third catalyst is: 1:0.1~1:0.5; the fourth solvent is a mixed solvent of iPrOH+Et3N+HCO2H, with a volume ratio of 6:3:1; the concentration of compound 7 in the fourth solvent is: 0.01~0.1mmol / mL.

[0046] In step 5, the fourth catalyst is thioacetic acid (AcSH); the molar ratio of compound 8 to the fourth catalyst is 1:20 to 1:100; the fifth solvent is pyridine; and the concentration of compound 8 in the fifth solvent is 0.01 to 0.1 mmol / mL.

[0047] In step 6, the fifth catalyst is ethylenediamine or hydrazine hydrate; the molar ratio of compound 9 to the fifth catalyst is 1:5 to 1:50; the sixth solvent is EtOH; the concentration of compound 9 in the sixth solvent is 0.01 to 0.1 mmol / mL; the sixth catalyst is DMTMM·BF4 and DIPEA; the molar ratio of compound 9, fatty chain carboxylic acid 10, DMTMM·BF4 and DIPEA is 1:1.5:1.5:1.5 to 1:5.0:5.0:5.0; the seventh solvent is MeOH; the concentration of fatty chain carboxylic acid 10 in the seventh solvent is 0.01 to 0.1 mmol / mL.

[0048] In step 7, the seventh catalyst is BCl3 or BBr3; the molar ratio of compound 11 to the seventh catalyst is 1:10 to 1:50; the eighth solvent is dichloromethane (DCM); the concentration of compound 11 in the eighth solvent is 0.01 to 0.1 mmol / mL.

[0049] Advantages of the present invention: The present invention uses a nickel-catalyzed reduction coupling strategy to form a ketone, using uridine uronic acid selenoester and aminogalactose bromide as raw materials, and can efficiently construct a core 11-carbon disaccharide structure at a scale of more than 10 grams and a yield of 72% in a single step; subsequently, by comprehensively utilizing substrate control, solvent effect and other means, the challenging seaweed-type α-hydroxylation reaction is completed with high stereoselectivity at a reaction scale of 8.3 grams. glc βgal (1,1) Construction of glycosidic bond; then Noyori asymmetric hydrogenation reduction reaction, introduction of side chain and deprotection process, finally after the longest route of 15 steps, the yield reached 13.7%, and 1.33 grams of tunicamycin-V was obtained on a gram scale. DETAILED DESCRIPTION

[0050] The present invention can be better understood according to the following embodiments. However, it is easy for those skilled in the art to understand that the contents described in the specific embodiments are only used to illustrate the present invention, and should not and will not limit the scope of protection claimed in the claims of the present invention.

[0051] Embodiment 1:

[0052] Step 1: Preparation of compound 4:

[0053]

[0054] Under argon atmosphere, compound 2 (10.01 g, 17.94 mmol, 1.0 equiv), compound 3 (11.40 g, 21.65 mmol, 1.2 equiv), Cp2ZrCl2 (5.24 g, 17.94 mmol, 1.0 equiv), ZnCl2 (5.38 g, 35.89 mmol, 2.0 equiv), Na2HPO4 (5.09 g, 35.86 mmol, 2.0 equiv), zinc powder (3.52 g, 53.83 mmol, 3.0 equiv), Ni(BF4)2·6H2O (1.83 g, 5.38 mmol, 0.3 equiv), ligand L6 (2.17 g, 8.09 mmol, 0.45 equiv) were added to the reaction tube for activation. Molecular sieves, acetone (4.0mL, 54.41mmol, 3equiv) and DMI (70.0mL), react at room temperature for 2 hours. TLC detection reaction conversion is complete, then add solvent ethyl acetate to the system to dilute, then add an equal amount of distilled water, pad diatomaceous earth for suction filtration, the filtrate is washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in turn, and dried over anhydrous sodium sulfate, the filtrate is concentrated and silica gel column chromatography (1:1, petroleum ether / ethyl acetate, v / v) to obtain compound 4 (10.90g, 12.85mmol, 72%) as white foam.

[0055] Compound 4: 1H NMR (400MHz, CDCl3) δ7.82–7.80(m,2H),7.73–7.67(m,2H),7.39–7.26(m,6H),5.79(d,J=8.0Hz,1H),5.51 (s,1H),5.42(d,J=9.8Hz,1H),5.39–5.32(m,2H),5.19(d,J=8.3Hz,1H),5.09(d,J=6.1Hz,1H),4.76(dd,J =9.5,5.0Hz,1H),4.66(s,2H),4.61(d,J=2.5Hz,1H),4.40–4.32(m,1H),3.08(dd,J=16.9,8.1Hz,1H),2.8 5(dd,J=17.0,5.0Hz,1H),1.61(s,3H),1.55(s,3H),1.39(s,3H),1.29(s,3H),0.60(s,9H),-0.12(s,3H); 13 C NMR (100MHz, CDCl3) δ203.1,169.1,162.4,151.3,142.2,137.8,134.0,131.8,128.3,127.8,127.7,123.4,122.9,113.8,110.1,102.5,98.5,94 .6,92.8,84.4,82.6,77.3,77.0,76.7,74.7,73.7,72.2,70.2,68.9,56. 9,39.8,28.0,26.7,26.5,25.2,25.0,17.3,-4.2,-5.8.HRMS(ESI)calcd for C 43 H 57 N4O 13 Si[M+NH4] + 865.3686, found 865.3705.

[0056] Step 2: Preparation of compound 5:

[0057]

[0058] Under argon atmosphere, compound 4 (10.90 g, 12.85 mmol, 1.0 equiv) was dissolved in dry pyridine (64.0 mL), HF·Pyridine (11.6 mL, 128.75 mmol, 10.0 equiv) was added under ice-water bath, and then the temperature was gradually raised to 45°C for reaction for 10 h. After TLC detection of the reaction of the raw material, the reaction was placed in an ice-water bath, saturated sodium bicarbonate solution was added dropwise to quench the reaction, the organic phase was separated and spin-dried, diluted with ethyl acetate, extracted three times with 1 M hydrochloric acid and then extracted three times with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and chromatographed on a silica gel column (1:1, petroleum ether / ethyl acetate, v / v) to obtain compound 5 (6.68 g, 9.10 mmol, 71%) as a white foam.

[0059] Compound 5: 1 H NMR (400MHz, CDCl3) δ7.86–7.78(m,2H),7.76–7.67(m,2H),7.36–7.30(m,4H),7.26–7.19(m,2H),5.77 (d,J=8.0Hz,1H),5.51(s,1H),5.46–5.29(m,4H),5.22–5.11(m,1H),5.10–5.02(m,1H),4.76(dd,J=9. 2,5.0Hz,1H),4.69–4.58(m,4H),4.40–4.33(m,1H),4.15–4.06(m,2H),3.60(d,J=6.6Hz,1H),3.07(dd ,J=17.4,7.2Hz,1H),2.89(dd,J=17.4,5.8Hz,1H),1.57(s,3H),1.55(s,3H),1.38(s,3H),1.27(s,3H); 13C NMR (100MHz, CDCl3) δ204.2,203.9,168.2,162.5,151.3,142.3,142.2,137.8,134.4,134.0,131. 8,131.5,128.3,128.2,127.8,127.74,127.71,127.6,123.6,123.3,113.7,112.4,110.1,109.4, 102.5,98.9,98.8,94.5,94.2,92.5,92.2,84.4,82.8,77.3,77.0,76.7,74.5,74.2,73.5,72.4,7 2.1,70.3,69.2,68.7,63.3,56.2,54.5,39.7,39.0,29.6,28.0,26.6,26.4,24.9.HRMS(ESI)calcd for C 37 H 43 N4O 13 [M+NH4] + 751.2821, found751.2842.

[0060] Step 3: Preparation of compound 7:

[0061]

[0062] Under argon atmosphere, compound 5 (6.80 g, 9.27 mmol, 1.0 equiv), compound 6 (14.10 g, 27.73 mmol, 3.0 equiv) and activated MS (4.0 g) was dissolved in dry Et2O / 1,4-dioxane (45.0 mL, 9 / 1, v / v), stirred and dried at -20°C for 30 min, HClO4 (186.2 mg, 1.85 mmol, 0.2 equiv) was added, and the reaction was continued for 4.5 hours. After the completion of the receptor reaction by TLC detection, triethylamine was added to quench the reaction, and the mixture was filtered off with diatomaceous earth pad. The filtrate was concentrated and purified by silica gel column chromatography (1:1:1, petroleum ether / ethyl acetate / dichloromethane, v / v / v) to obtain compound 7 (8.30 g, 7.88 mmol, 85%) as a white foam.

[0063] Compound 7: 1H NMR(400MHz,CDCl3)δ7.86–7.82(m,2H),7.74–7.67(m,2H),7.45–7.41(m,2H),7.38–7.28(m,8H),7.19(d,J=8.1Hz,1H),5.74(d,J=8.0Hz,1H),5.46(s,1H),5.44(s,1H),5.40(d,J=9.9Hz,1H),5.38–5.32(m,2H),5.17(d,J=8.9Hz,1H),5.05(d,J=6.1Hz,1H),4.79(d,J=3.6Hz,1H),4.75(d,J=6.4Hz,1H),4.70(dd,J=9.3,5.0Hz,1H),4.66(s,2H),4.61(d,J=2.3Hz,1H),4.57(d,J=6.4Hz,1H),4.40–4.33(m,1H),4.27(t,J=9.1Hz,1H),4.14(dd,J=4.9,1.9Hz,1H),4.10(dd,J=10.2,4.8Hz,1H),4.04–3.97(m,1H),3.95(t,J=9.5Hz,1H),3.57(t,J=10.2Hz,1H),3.46(t,J=9.4Hz,1H),3.21(s,3H),3.14(dd,J=9.9,3.6Hz,1H),3.04(dd,J=17.2,7.4Hz,1H),2.86(dd,J=17.2,5.7Hz,1H),1.65(s,3H),1.52(s,3H),1.35(s,3H),1.30(s,3H); 13 C NMR(100MHz,CDCl3)δ203.5,162.4,151.3,142.4,138.0,137.3,134.0,129.0,128.4,128.2,127.8,127.7,126.2,113.8,110.4,102.5,101.6,100.1,99.2,98.9,97.3,94.6,84.4,82.8,81.8,77.4,77.3,77.1,76.8,74.4,74.1,73.1,72.2,70.3,69.5,68.6,63.4,63.0,60.4,55.9,54.7,39.7,28.0,26.6,26.5,25.0,14.2.HRMS(ESI)calcd for C 52 H 57 N6O 18 [M+H] +1076.3622, found 1076.3600.

[0064] Step 4: Preparation of compound 8:

[0065]

[0066] Under argon atmosphere, compound 7 (6.83 g, 6.49 mmol, 1.0 equiv) was dissolved in iPrOH / Et3N / HCO2H (65.0 mL, v / v / v, 6:3:1), and Noyori catalyst: (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (41.0 mg, 0.64 mmol, 0.1 equiv) was added at room temperature. The reaction was allowed to proceed overnight at room temperature. TLC detected that the reaction of the raw material was complete. The reaction solution was spin-dried and the crude product was purified by silica gel column chromatography (3:1, dichloromethane / ethyl acetate, v / v) to obtain compound 8 (6.57 g, 6.23 mmol, 96%) as a light yellow foam.

[0067] Compound 8: 1 H NMR (400MHz, CDCl3) δ7.93–7.78(m,2H),7.76–7.65(m,2H),7.43–7.26(m,1 0H),7.19–7.12(m,1H),5.65(d,J=8.1Hz,1H),5.48–5.42(m,2H),5.40(s,1 H),5.32(d,J=8.8Hz,1H),5.02(dd,J=6.7,3.6Hz,1H),4.97(dd,J=6.7,3.0 Hz,1H),4.93(d,J=3.7Hz,1H),4.81–4.74(m,2H),4.68(s,1H),4.58(d,J=6. 4Hz,1H),4.36(t,J=9.1Hz,1H),4.33–4.28(m,1H),4.22–4.13(m,3H),4.12 –4.06(m,2H),3.97(t,J=9.6Hz,1H),3.57(t,J=10.1Hz,1H),3.53(s,1H),3 .45(t,J=9.4Hz,1H),3.22(s,2H),3.19(dd,J=10.0,3.6Hz,1H),2.29–2.14 (m,1H),1.88–1.78(m,1H),1.75(s,1H),1.69(s,3H),1.36(d,J=8.4Hz,6H); 13C NMR (100MHz, CDCl3) δ162.3,151.1,141.5,137.8,137.0,133.9,129.1,128.3,128 .2,127.7,127.6,126.1,114.6,110.5,102.2,101.7,100.1,99.4,97.2,96.3,89. 1,83.3,81.8,78.6,77.3,77.0,76.7,75.6,74.2,72.9,72.3,70.3,70.1,68.6,67 .7,63.5,63.0,55.8,54.8,33.8,29.6,28.0,27.2,26.5,25.3.HRMS(ESI)calcdfor C 52 H 62 N7O 18 [M+NH4] + 1072.4146, found 1072.4174.

[0068] Step 5: Preparation of compound 9:

[0069]

[0070] Under argon atmosphere, compound 8 (1.11 g, 1.05 mmol, 1.0 equiv) was dissolved in dry pyridine (7.5 mL), and AcSH (2.5 mL) was added under ice bath. The temperature was naturally raised to room temperature and reacted overnight. After TLC showed that the starting material disappeared, the mixture was diluted with ethyl acetate, washed three times with 1 M hydrochloric acid, washed three times with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (1:3→1:4, dichloromethane / ethyl acetate, v / v) to obtain compound 9 (1.09 g, 1.02 mmol, 97%) as white foam.

[0071] Compound 9: 1H NMR (400MHz, CDCl3) δ7.91–7.83(m,2H),7.81–7.73(m,2H),7.55–7.48(m,1H), 7.47–7.40(m,2H),7.38–7.29(m,7H),7.28–7.26(m,1H),5.80(d,J=3.3Hz,1H), 5.73(d,J=8.1Hz,1H),5.63(d,J=7.6Hz,1H),5.52–5.41(m,3H),5.24(d,J=8.8H z,1H),5.08(d,J=3.6Hz,1H),4.91(dd,J=6.4,3.3Hz,1H),4.84–4.75(m,2H),4. 73–4.67(m,3H),4.55(d,J=6.6Hz,1H),4.34(t,J=8.8Hz,1H),4.25–4.16(m,3H) ,4.14(t,J=3.0Hz,1H),4.13–4.04(m,2H),4.00–3.92(m,1H),3.78(t,J=9.8Hz, 1H),3.72–3.61(m,2H),3.57(t,J=9.4Hz,1H),3.18(s,3H),2.28–2.16(m,1H),2 .04–1.94(m,1H),1.91(s,1H),1.67(s,3H),1.37(s,3H),1.33(d,J=1.7Hz,6H); 13 C NMR (100MHz, CDCl3) δ169.8,162.4,151.1,140.4,137.8,137.0,134.5,131.5,129.0,128. 3,128.2,127.6,127.6,126.0,123.6,114.3,110.7,102.3,101.5,99.3,98.4,97.7,94.0,8 8.0,83.6,81.3,80.9,77.3,77.0,76.7,74.8,74.4,73.5,72.4,72.2,70.3,69.9,68.5,63 .7,55.5,54.9,53.4,52.6,34.8,29.6,27.9,27.3,26.4,25.3,22.2,14.1.HRMS(ESI)calcd forC 54 H 63 N4O 19 [M+H] + 1071.4081, found 1071.4102.

[0072] Step 6: Preparation of compound 11:

[0073]

[0074] Under argon atmosphere, compound 9 (2.30 g, 2.17 mmol, 1.0 equiv) was dissolved in anhydrous ethanol (120.0 mL), ethylenediamine (12.0 mL) was added, and the temperature was raised to 85 ° C for 12 hours, cooled to room temperature, spin-dried, dried with toluene three times, and then purified by short silica gel column flash column chromatography (10:1:0.1, chloroform / methanol / triethylamine, v / v / v) to obtain the amino intermediate. The amino intermediate was dissolved in methanol (25.0 mL), and DMTMM·BF4 (1.50 g, 4.33 mmol, 2.0 equiv), DIPEA (1.2 mL, 6.89 mmol, 3.0 equiv) and fatty chain carboxylic acid 10-V (1.05 g, 4.37 mmol, 2.0 equiv) were added. The reaction was carried out at room temperature for 6 h. After TLC showed that the starting material disappeared, the reaction solution was concentrated and chromatographed on a silica gel column (25:1→20:1, CHCl3 / MeOH, v / v) to give the product 11-V (1.88 g, 1.62 mmol, 75% for 2 steps) as a white foam.

[0075] Under argon atmosphere, compound 9 (0.22 g, 0.2 mmol, 1.0 equiv) was dissolved in anhydrous ethanol (10.0 mL), ethylenediamine (1.2 mL) was added, and the temperature was raised to 85 ° C for 14 hours, cooled to room temperature, spin-dried, dried with toluene three times, and then purified by short silica gel column flash column chromatography (10:1:0.1, chloroform / methanol / triethylamine, v / v / v) to obtain the amino intermediate. The amino intermediate was dissolved in methanol (2.0 mL), and DMTMM·BF4 (146.1 mg, 0.44 mmol, 2.0 equiv), DIPEA (0.12 mL, 0.69 mmol, 3.0 equiv) and aliphatic chain carboxylic acid 10-VI (150.2 mg, 0.44 mmol, 2.0 equiv) were added. The reaction was carried out at room temperature for 10 h. After TLC showed that the starting material disappeared, the reaction solution was concentrated and subjected to silica gel column chromatography (50:1, CHCl3 / MeOH, v / v) to obtain the product 11-VI (163.4 mg, 0.14 mmol, 70% for 2 steps) as a white foam.

[0076] Compound 11-V: 11H NMR (400 MHz, CDCl3) δ 7.39–7.18 (m, 11H), 7.02 (d, J = 8.1 Hz, 1H), 6.89–6.76 (m, 1H), 6.56 (d, J = 9.3 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 5.76 (d, J = 15.2 Hz, 1H), 5.50 (d, J = 7.9 Hz, 1H), 5.48–5.43 (m, 1H), 5.39 (s, 1H), 5.38–5.27 (m, 2H), 4.96–4.88 (m, 2H), 4.78–4.72 (m, 2H), 4.67–4.54 (m, 4H), 4.22 (dd, J = 9.9, 4.5 Hz, 1H), 4.19–4.06 (m, 5H), 4.02 (t, J = 3.4 Hz, 1H), 4.00–3.83 (m, 4H), 3.64–3.52 (m, 2H), 3.25 (d, J = 2.7 Hz, 3H), 2.39 (s, 2H), 2.19–2.06 (m, 3H), 1.72–1.62 (m, 1H), 1.53 (d, J = 5.3 Hz, 6H), 1.50–1.44 (m, 1H), 1.29 (d, J = 6.8 Hz, 6H), 1.21 (s, 12H), 1.15–1.08 (m, 2H), 0.82 (d, J = 6.6 Hz, 6H); 13 13C NMR (100 MHz, CDCl3) δ 170.7, 167.0, 162.3, 151.0, 146.3, 140.9, 137.7, 137.2, 128.9, 128.2, 128.1, 127.6, 127.5, 126.1, 123.1, 114.5, 110.2, 101.9, 101.5, 100.0, 99.4, 97.3, 95.4, 89.0, 83.4, 81.8, 79.0, 77.3, 77.0, 76.7, 75.1, 74.3, 72.2, 70.3, 69.1, 68.7, 67.4, 63.8, 55.5, 54.9, 52.0, 38.9, 34.3, 32.1, 29.8, 29.6, 29.5, 29.4, 29.2, 28.2, 28.1, 27.9, 27.3, 27.1, 26.3, 25.1, 23.2, 22.6. HRMS (ESI) calcd for C 61 H 86 O 18 N4Na [M + Na] + 1185.5829, found 1185.5823。

[0077] Compound 11-VI: 1 H NMR(400MHz,CDCl3)δ7.37–7.28(m,9H),7.27–7.23(m,1H),6.98(d,J=8.1Hz,1H),6.48(d,J=9.0Hz,1H),5.83(d,J=8.2Hz,1H),5.52(d,J=8.0Hz,1H),5.46–5.29(m,4H),4.96(dd,J=6.7,3.5Hz,2H),4.87(dd,J=6.7,3.1Hz,1H),4.79(d,J=6.8Hz,1H),4.71(d,J=8.7Hz,1H),4.65(s,2H),4.59(d,J=6.7Hz,1H),4.30–4.13(m,6H),4.07–4.05(m,1H),4.03(d,J=4.6Hz,1H),3.95–3.92(m,1H),3.85(s,1H),3.77–3.74(m,1H),3.61–3.59(m,2H),3.29(s,3H),2.21–2.12(m,3H),2.05(s,3H),1.74–1.67(m,1H),1.65–1.63(m,2H),1.56(d,J=3.2Hz,6H),1.53–1.47(m,1H),1.34(d,J=4.9Hz,6H),1.25(s,14H),1.17–1.12(m,2H),0.86(d,J=6.5Hz,6H). 13 C NMR(100MHz,CDCl3)δ174.5,170.9,162.4,151.2,141.2,137.9,137.5,129.1,128.4,128.2,127.8,127.7,126.4,114.7,110.4,102.2,101.8,99.5,99.0,97.5,96.2,89.3,83.4,81.9,79.1,75.4,74.5,72.4,70.4,69.4,68.8,67.6,64.1,55.7,55.5,52.3,39.2,37.1,34.3,30.1,29.8,29.7,29.6,29.4,28.3,28.1,27.5,27.3,26.5,25.7,25.3,23.3,22.8.HRMS(ESI)calcd for C 61 H 89 O 18 N4[M+H] + 1165.6166,found 1165.6161。

[0078] Step 7: Preparation of compound 1:

[0079]

[0080] Compound 11-V (1.88 g, 1.62 mmol, 1.0 equiv) was dissolved in dry DCM (100.0 mL), and BCl3 (1 M in hexanes, 55.0 mL, 55.0 mmol, 34 equiv) was added at -78 °C and stirred for 50 minutes, then moved to an ice-water bath and stirred for 50 minutes. After adding NaOMe (5.4 M in MeOH, 51.0 mL, 275.4 mmol, 170 equiv) solution to quench the reaction, IR120 (H + ) The resin was neutralized to neutrality and then filtered. After gel column chromatography (5:1→2:1, methanol / water, v / v), tunicamycin-V (1-V) (1.33 g, 1.6 mmol, 99%) was obtained as a white solid.

[0081] Compound 11-VI (103.4 mg, 0.09 mmol, 1.0 equiv) was dissolved in dry DCM (9.0 mL), and BCl3 (1 M in hexanes, 3.0 mL, 3.0 mmol, 34 equiv) was added at -78 °C and stirred for 10 minutes, then moved to an ice-water bath and stirred for 1 hour. After adding NaOMe (5.4 M in MeOH, 2.7 mL, 14.6 mmol, 170 equiv) solution to quench the reaction, IR120 (H + ) The resin was neutralized to neutrality and then filtered. After gel column chromatography (4:1→2:1, methanol / water, v / v), tunicamycin-VI (1-VI) (67.2 mg, 0.08 mmol, 91%) was obtained as a white solid.

[0082] Compound 1-V: 11H NMR (400 MHz, CD3OD) δ 7.91 (d, J = 8.1 Hz, 1H), 6.87–6.77 (m, 1H), 5.98–5.90 (m, 2H), 5.75 (d, J = 8.0 Hz, 1H), 4.93 (d, J = 3.5 Hz, 1H), 4.59 (d, J = 8.5 Hz, 1H), 4.24–4.17 (m, 2H), 4.12–4.05 (m, 1H), 4.05–3.97 (m, 2H), 3.89–3.85 (m, 2H), 3.82–3.75 (m, 2H), 3.73–3.70 (m, 1H), 3.69–3.67 (m, 1H), 3.67–3.58 (m, 3H), 3.38–3.34 (m, 1H), 2.24–2.19 (m, 2H), 2.16–2.06 (m, 1H), 1.94 (s, 3H), 1.55–1.50 (m, 2H), 1.48–1.44 (m, 2H), 1.31–1.24 (m, 13H), 1.20–1.17 (m, 2H), 0.89 (s, 3H), 0.87 (s, 3H); 13 13C NMR (100 MHz, CD3OD) δ 173.6, 169.7, 166.2, 152.6, 146.6, 142.8, 124.9, 103.1, 101.9, 100.2, 89.8, 89.6, 74.3, 73.3, 72.7, 72.6, 72.4, 72.0, 70.8, 68.3, 63.1, 54.9, 54.4, 40.2, 35.9, 33.1, 31.0, 30.8, 30.7, 30.6, 30.5, 30.4, 29.5, 29.2, 28.5, 23.2, 23.0, 14.4. HRMS (ESI) calcd for C 38 H 63 O 16 N4 [M + H] + 831.4234, found 831.4248。

[0083] Compound 1-VI: 1H NMR (400MHz, CD3OD) δ7.91(d,J=8.1Hz,1H),6.87–6.77(m,1H),5.98–5.90(m,2H),5.75(d,J=8.0Hz,1H),4.93(d,J=3.5 Hz,1H),4.59(d,J=8.5Hz,1H),4.24–4.17(m,2H),4.12–4.05(m,1H),4.05–3.97(m,2H),3.89–3.85(m,2H),3.82–3.75( m,2H),3.73–3.70(m,1H),3.69–3.67(m,1H),3.67–3.58(m,3H),3.38–3.34(m,1H),2.24–2.19(m,2H),2.16–2.06(m,1H ),1.94(s,3H),1.55–1.50(m,2H),1.48–1.44(m,2H),1.31–1.25(m,13H),1.20–1.17(m,2H),0.89(s,3H),0.87(s,3H); 13 C NMR (126MHz, CD3OD) δ175.9,172.2,164.7,151.2,141.4,141.3,129.5,129.4,101.7 ,99.8,98.4,88.3,88.2,74.3,74.1,72.9,71.6,71.1,70.7,69.5,67.0,61.8,60.9,5 3.5,53.1,44.1,38.9,36.4,35.1,34.5,31.7,30.4,29.7,29.6,29.4,29.3,29.2,29 .1,29.0,28.9,27.8,27.1,26.7,25.6,25.5,22.3,21.7,21.6,13.0.HRMS(ESI)calcd for C 38 H 65 O 16 N4[M+H] + 833.4390, found 833.4414.

[0084] Although the content of the present invention has been described in detail through the above preferred embodiments, it should be appreciated that the above description should not be considered as a limitation of the present invention. After reading the above content, it will be apparent to those skilled in the art that various modifications and substitutions of the present invention will occur. Therefore, the protection scope of the present invention should be limited by the appended claims.

Claims

1. A method for preparing tunicamycin-V and its analogs, characterized in that: The following steps are involved: Among them, R 1 : is pyridylthio, ethylthio, phenylthio or phenylseleno; R 2 : is a hydrogen atom or a benzyl group, a substituted benzyl group, a phthaloyl group, an alkyl group, an ester group, a silicon group, a benzaldehyde dimethyl acetal or an isopropylidene group; R 3 : is tert-butyldimethylsilyloxy, triisopropylsilyloxy, p-methoxyphenoxy, p-tolylthio, ethylthio or phenylthio; R 4 : is Br or I; R 5 : is a hydrogen atom or a benzyl group, a substituted benzyl group, an alkyl group or an ester group, a silicon group, or a benzaldehyde dimethyl acetal group; R 6 : is one of the following groups: R: is a fatty chain branch structure, selected from any of the following structures: Step 1: dissolving compounds 2 and 3, a nickel catalyst, a ligand, a zirconium promoter, a reducing agent and an additive in a first solvent, and reacting at room temperature for 15-180 minutes to obtain compound 4; Step 2: dissolving compound 4 in a second solvent, adding the first catalyst, and reacting at 0°C-60°C for 6-24 hours to obtain compound 5; Step 3: Compound 5 and compound 6 are dissolved in a third solvent, a second catalyst is added, and a glycosylation reaction is carried out at -40°C-0°C for 3-6 hours to obtain compound 7; Step 4: dissolving compound 7 in a fourth solvent, adding a third catalyst, and reacting at room temperature for 6-24 hours to obtain compound 8; Step 5: dissolving compound 8 in a fifth solvent, adding a fourth catalyst, and reacting at 0°C to room temperature for 10 to 48 hours to obtain compound 9; Step 6: dissolving compound 9 in a sixth solvent, adding a fifth catalyst, reacting at 25°C-100°C for 10-48 hours, dissolving the obtained crude product and aliphatic chain carboxylic acid 10 in a seventh solvent, adding a sixth catalyst, reacting at room temperature for 6-24 hours, and obtaining compound 11; Step 7: Dissolve compound 11 in the eighth solvent, add the seventh catalyst, and react at -80°C-0°C for 1-3 hours to obtain tunicamycin-V and its analogue 1.

2. The method for preparing tunicamycin-V and its analogs as claimed in claim 1, characterized in that: R 1 is phenylselenyl; R 2 isopropylidene; R 3 is tert-butyldimethylsilyloxy; R 4 Br; R 5 is benzaldehyde dimethyl acetal; R 6 It is LG3.

3. The method for preparing tunicamycin-V and its analogs as claimed in claim 1, characterized in that: In step 1, the nickel catalyst is: Ni(BF4)2, Ni(ClO4)2, NiCl2, NiBr2, NiI2, Ni(NTf)2, Ni(OAc)2 or Ni(OTf)2; the ligand is selected from any one of compounds L1-L13; the zirconium catalyst is: Cp2ZrCl2, Cp2ZrI2 or Cp2Zr(OTf)2; the reducing agent is Zn, Mn or In; the additives include: ZnCl2, acetone, NaH2PO4 and Molecular sieve; the molar ratio of compound 2, 3, nickel catalyst, ligand, zirconium promoter, reducing agent and additive is: 1:1.0:0.1:0.1:1.0:1.0:1.0-1:5.0:1.0:1.0:5.0:5.0:5.0; the first solvent is: 1,3-dimethyl-2-imidazolidinone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dioxane, 1,2-dichloroethane or tetrahydrofuran; the concentration of compound 2 in the first solvent is: 0.1-0.5 mmol / mL; The structure of the ligand compound is shown below:

4. The method for preparing tunicamycin-V and its analogs as claimed in claim 1, characterized in that: In step 2, the first catalyst is: pyridinium hydrofluoride or tetrabutylammonium fluoride; the molar ratio of compound 4 to the first catalyst is: 1:1.5 to 1:20; the second solvent is: pyridine or tetrahydrofuran; the concentration of compound 4 in the second solvent is: 0.01 to 0.1 mmol / mL.

5. The method for preparing tunicamycin-V and its analogs as claimed in claim 1, characterized in that: In step 3, the second catalyst is HClO4 or TMSClO4; the molar ratio of compound 5, compound 6 and the second catalyst is 1:1.0:0.1 to 1:5.0:0.5; the third solvent is ether, dioxane or a mixed solvent of ether and dioxane; the concentration of compound 5 in the third solvent is 0.01 to 0.1 mmol / mL.

6. The method for preparing tunicamycin-V and its analogs as claimed in claim 1, characterized in that: In step 4, the third catalyst is: NaBH4, NaBH4+Et3B, NaBH4+Zn(OTf)2, Zn(BH4)2, lithium tri-sec-butylborohydride, (S)-B-Me-CBS-BH·THF, (R)-B-Me-CBS-BH·THF, (S)-B-Me-CBS, BH·SMe2, (R)-B-Me-CBS, BH·SMe2, Al(OiPr)3 or (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride; the molar ratio of compound 7 to the third catalyst is: 1:0.1~1:0.5; the fourth solvent is a mixed solvent of iPrOH+Et3N+HCO2H, with a volume ratio of 6:3:1; the concentration of compound 7 in the fourth solvent is: 0.01~0.1mmol / mL.

7. The method for preparing tunicamycin-V and its analogs as claimed in claim 1, characterized in that: In step 5, the fourth catalyst is thioacetic acid; the molar ratio of compound 8 to the fourth catalyst is 1:20 to 1:100; the fifth solvent is pyridine; and the concentration of compound 8 in the fifth solvent is 0.01 to 0.1 mmol / mL.

8. The method for preparing tunicamycin-V and its analogs as claimed in claim 1, characterized in that: In step 6, the fifth catalyst is ethylenediamine or hydrazine hydrate; the molar ratio of compound 9 to the fifth catalyst is 1:5 to 1:50; the sixth solvent is EtOH; the concentration of compound 9 in the sixth solvent is 0.01 to 0.1 mmol / mL; the sixth catalyst is DMTMM·BF4 and DIPEA; the molar ratio of compound 9, fatty chain carboxylic acid 10, DMTMM·BF4 and DIPEA is 1:1.5:1.5:1.5 to 1:5.0:5.0:5.0; the seventh solvent is MeOH; the concentration of fatty chain carboxylic acid 10 in the seventh solvent is 0.01 to 0.1 mmol / mL.

9. The method for preparing tunicamycin-V and its analogs as claimed in claim 1, characterized in that: In step 7, the seventh catalyst is BCl3 or BBr3; the molar ratio of compound 11 to the seventh catalyst is 1:10 to 1:50; the eighth solvent is dichloromethane; the concentration of compound 11 in the eighth solvent is 0.01 to 0.1 mmol / mL.

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