Preparation method of natural cyclic peptide petrichorin C

Abstract

The present invention provides a method for preparing a natural cyclic peptide petrichorin C, comprising the following steps: converting compound 1 into compound 29 after multiple-step reactions; performing a cyclization reaction on compound 20 and then converting it into compound 25; performing a dehydration condensation reaction on compound 25 and compound 29 to generate compound 30; converting compound 14 into compound 19, and performing a coupling reaction on compound 19 and compound 30 to obtain compound 35, which is the natural cyclic peptide petrichorin C; compared with the traditional cyclic peptide synthesis method, this design not only simplifies the reaction steps and reduces the reaction difficulty, but also significantly improves the yield of the cyclic peptide and ensures the high purity of the final product. This method provides a reliable path for the synthesis of similar complex organic molecules and has a wide range of application potentials.

Description

Technical Field

[0001] The invention belongs to the field of synthetic chemistry, and in particular relates to a preparation method of natural cyclic peptide petrichorin C. Background Art

[0002] The natural cyclic peptide petrichorin C is a new cyclic peptide natural product discovered by Chunshun Li's research group in 2021 from the rare actinomycete Lentzeaflaviverrucosa DSM 44664 by using a targeted metabologenomic method to identify piperazine compounds, and its structure was speculated. The natural cyclic peptide petrichorin C is a unique cyclic hexapeptide, composed of two piperazine cyclic peptides with different configurations, a 7-Cl-pyrroloindoline tryptophan derivative, N-methylalanine, threonine and alanine links. Studies have shown that the natural cyclic peptide petrichorin C exhibits strong in vitro activity against A2780 human ovarian cancer, HT1080 male sarcoma, PC3 human prostate cancer and Jurkat human T lymphocyte cell lines, with IC50 values ​​at the nM level.

[0003] However, the absolute configuration of the natural cyclic peptide petrichorin C has not been determined, and the process of preparing the natural cyclic peptide petrichorin C through bacterial culture is complicated and difficult. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing a natural cyclic peptide petrichorin C, aiming to solve the problem that the natural cyclic peptide petrichorin C has an uncertain configuration and is difficult to synthesize.

[0005] To solve the above technical problems, the present invention is implemented as follows: a method for preparing a natural cyclic peptide petrichorin C, comprising the steps of:

[0006] S1, converting compound 1 into compound 29 through multiple steps of reaction;

[0007] S2, compound 20 undergoes a cyclization reaction and is then converted into compound 25;

[0008] S3, the compound 25 and the compound 29 undergo a dehydration condensation reaction to generate a compound 30;

[0009] S4, converting compound 14 into compound 19, and subjecting compound 19 and compound 30 to coupling reaction to obtain compound 35, wherein compound 35 is a natural cyclic peptide petrichorin C;

[0010] Wherein, the structural formula of the above compound is as follows:

[0011] , , , , , , , .

[0012] In some embodiments of the present invention, step S1 comprises:

[0013] S1.1, subjecting the compound 1 to an internal ring closure reaction to obtain a compound 6;

[0014] S1.2, removing the protecting group in the compound 6, and then introducing an allyl group to obtain compound 13;

[0015] S1.3, performing a peptide grafting reaction on the compound 13 and the compound 26 to obtain the compound 27;

[0016] S1.4, removing the allyl ester and the protecting group from the compound 27 to obtain the compound 29;

[0017] Wherein, the structural formula of the above compound is as follows:

[0018] , , , .

[0019] In some embodiments of the present invention, step S1.1 comprises:

[0020] The compound 1 is subjected to a bromination reaction to obtain a compound 2;

[0021] Placing the compound 2 in an alkaline environment to perform an oxidation reaction to obtain a compound 3;

[0022] The compound 3 undergoes an asymmetric nucleophilic addition reaction with azobenzoyloxymethylphenyl chloroformate, and then the aldehyde group in the compound 3 is reduced to a hydroxyl group to obtain compound 4;

[0023] The hydroxyl group in the compound 4 is converted into tert-butyl dimethylsilyl ether to obtain compound 5;

[0024] The compound 5 is placed in an alkaline environment to undergo an internal cyclization reaction to obtain the compound 6;

[0025] Wherein, the structural formula of the above compound is as follows:

[0026] , , , .

[0027] In some embodiments of the present invention, step S1.2 comprises:

[0028] Tetrabutylammonium fluoride is added to the compound 6 to remove the tert-butyldimethylsilyl group to obtain compound 7;

[0029] An oxidant is added to the compound 7 to perform an oxidation reaction to obtain a compound 8, wherein the oxidant comprises at least one of 2,2,6,6-tetramethylpiperidinyl oxide, sodium hypochlorite, and sodium chlorite;

[0030] Placing the compound 8 in an acidic environment to convert it into compound 9;

[0031] The bis-benzyloxycarbonyl group in the compound 9 is removed, and a single benzyloxycarbonyl group is introduced to obtain compound 11;

[0032] The compound 11 is placed in an alkaline environment, the methyl ester in the compound 11 undergoes a hydrolysis reaction, and then the hydrolyzed carboxylic acid is converted into an allyl ester to obtain a compound 13;

[0033] Wherein, the structural formula of the above compound is as follows:

[0034] , , , , .

[0035] In some embodiments of the present invention, step S1 comprises:

[0036] The compound 1 is dissolved and then pyridine chlorochromate is added to generate compound 36;

[0037] The compound 36 is mixed with imidazole, and tert-butyldimethylsilyl chloride is added dropwise to react to generate compound 37;

[0038] L-alanine and methyl iodide were mixed and reacted, and then basic 9-fluorenylmethoxycarbonyl chloride was added to obtain compound 38;

[0039] After the compound 38 is dissolved, 1-hydroxybenzotriazole and N,N-diisopropylethylamine are added, and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and the compound 37 are added to carry out a coupling reaction to obtain compound 39;

[0040] The compound 39 is dissolved in an acidic environment, tetrabutylammonium fluoride is added, and hydrazine hydrate is then added dropwise to carry out a cyclization reaction to generate the compound 29;

[0041] Wherein, the structural formula of the above compound is as follows:

[0042] , , , .

[0043] In some embodiments of the present invention, step S2 includes:

[0044] S2.1, adding N-phenylselenophthalamide and pyridine p-toluenesulfonate to the compound 20 to carry out a cyclization reaction to generate a compound 21;

[0045] S2.2, adding m-chloroperbenzoic acid to the compound 21 to carry out an oxidation reaction to generate a compound 22;

[0046] S2.3, placing the compound 22 in an acidic environment, adding lithium hydroxide to react, and then reacting with sodium bicarbonate and allyl bromide after the reaction is completed to obtain compound 23;

[0047] S2.4, converting the tertiary alcohol group in the compound 23 into triethylsilyl ether to obtain compound 24;

[0048] S2.5, placing the compound 24 in an acidic environment and removing the protecting group to obtain compound 25;

[0049] Wherein, the structural formula of the above compound is as follows:

[0050] , , , .

[0051] In some embodiments of the present invention, step S4 includes:

[0052] S4.1, the compound 14 is subjected to a dehydration condensation reaction with threonine allyl ester to obtain compound 15;

[0053] S4.2, the compound 15 is subjected to multi-step treatment and peptide grafting reaction with alanyl chloride to obtain the compound 19;

[0054] S4.3, adding a peptide-linking reagent to the compound 19 and the compound 30 to carry out a coupling reaction to obtain a compound 31;

[0055] S4.4, removing the protecting group in the compound 31 to prepare the compound 35;

[0056] Wherein, the structural formula of the above compound is as follows:

[0057] , .

[0058] In some embodiments of the present invention, step S4.2 includes:

[0059] The 9-fluorenylmethoxycarbonyl group in the compound 15 is removed to obtain compound 16;

[0060] The compound 16 is subjected to a peptide grafting reaction with alanyl chloride to obtain compound 17;

[0061] Tetrakistriphenylphosphine palladium and nitrogen methyl aniline are added to the compound 17 to remove the allyl ester to obtain compound 18;

[0062] The compound 18 is placed in a hydrogen atmosphere, and palladium hydroxide on carbon is added to remove the benzyloxycarbonyl group to obtain the compound 19;

[0063] Wherein, the structural formula of the above compound is as follows:

[0064] , , .

[0065] In some embodiments of the present invention, step S4.4 comprises:

[0066] The allyl group in the compound 31 is removed to obtain compound 32;

[0067] Add diethylamine to the compound 32 to remove the 9-fluorenylmethoxycarbonyl group to obtain compound 33;

[0068] The compound 33 is first subjected to a cyclization reaction, and then the protecting group is removed to obtain compound 35;

[0069] Wherein, the structural formula of the above compound is as follows:

[0070] ,

[0071] Compared with the prior art, the preparation method of the natural cyclic peptide petrichorin C in the present invention has the following beneficial effects:

[0072] Compound 29 is a linear peptide compound, and compound 25 is a cyclic peptide compound. The two are synthesized into compound 30, which is then coupled with linear compound 19 to synthesize cyclic compound 35. This method breaks down the synthesis of complex molecules into several simpler modules, which are optimized and synthesized separately, and then coupled.

[0073] Using sites with less steric hindrance for cyclization significantly reduces the steric hindrance and tension that may occur during the cyclization process, making the cyclization process more efficient. By using cyclic peptides as intermediates, the complexity of the final cyclization step can be reduced. This strategy avoids the challenge of cyclization directly from long-chain linear peptides, reduces the requirements for reaction conditions and the risk of reaction failure, ensures the successful synthesis of the target cyclic peptide, improves the overall synthesis efficiency, and increases the control of the synthesis steps, thereby reducing the occurrence of side reactions.

[0074] Compared with the traditional cyclopeptide synthesis method, this design not only simplifies the reaction steps, but also significantly improves the yield of cyclopeptides and ensures the high purity of the final product. This method provides a reliable path for the synthesis of similar complex organic molecules and has a wide range of application potential. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Figure 1 The figure is a schematic flow chart of a method for preparing the natural cyclic peptide petrichorin C in one embodiment of the present invention. DETAILED DESCRIPTION

[0076] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0077] Please refer to Figure 1 The present invention provides a method for preparing a natural cyclic peptide petrichorin C, comprising the steps of:

[0078] S1, converting compound 1 into compound 29 through multiple steps of reaction;

[0079] S2, compound 20 undergoes a cyclization reaction and is then converted into compound 25;

[0080] S3, compound 25 and compound 29 undergo a dehydration condensation reaction to generate compound 30;

[0081] S4, converting compound 14 into compound 19, and coupling reaction of compound 19 and compound 30 to obtain compound 35, wherein compound 35 is a natural cyclic peptide petrichorin C;

[0082] Wherein, the structural formula of the above compound is as follows:

[0083] , , , , , , , .

[0084] Compound 29 is a linear peptide compound, and compound 25 is a cyclic peptide compound. The two are synthesized into compound 30, which is then coupled with linear compound 19 to synthesize cyclic compound 35. This method breaks down the synthesis of complex molecules into several simpler modules, which are optimized and synthesized separately, and then coupled.

[0085] Using sites with less steric hindrance for cyclization significantly reduces the steric hindrance and tension that may occur during the cyclization process, making the cyclization process more efficient. By using cyclic peptides as intermediates, the complexity of the final cyclization step can be reduced. This strategy avoids the challenge of cyclization directly from long-chain linear peptides, reduces the requirements for reaction conditions and the risk of reaction failure, ensures the successful synthesis of the target cyclic peptide, improves the overall synthesis efficiency, and increases the control of the synthesis steps, thereby reducing the occurrence of side reactions.

[0086] In one embodiment, the retrosynthetic analysis of the natural cyclic peptide petrichorin C is as follows:

[0087]

[0088] In view of the structure of the natural cyclic peptide petrichorin C, it is judged that it is most appropriate to cut from the alanine and pyrroloindoline fragments with less steric hindrance as the final ring closure site, so as to obtain the linear hexapeptide compound 31. Next, the linear hexapeptide compound 31 can be divided into two tripeptide fragments, namely the tripeptide fragment compound 30 containing pyrroloindoline and the tripeptide fragment compound 19 containing (S)-piperazine acid. Among them, the tripeptide fragment compound 30 can be prepared by dehydration condensation of the dipeptide fragment compound 29 of (R)-piperazine acid and N-methylalanine and the 7-Cl-pyrroloindoline compound 25. Another tripeptide fragment compound 19 can be prepared by the dipeptide fragment compound 16 condensed by piperazine acid and threonine, and alanine by peptide grafting reaction.

[0089] The examples of synthesizing each compound are as follows:

[0090] (1) Synthesis of compound 13.

[0091] Specifically, step S1 includes:

[0092] S1.1. Compound 1 is subjected to an internal ring closure reaction to obtain compound 6.

[0093] Compound 1 is subjected to bromination reaction to obtain compound 2. Through the bromination reaction, a bromine atom is introduced into a hydroxyl group or a hydrogen atom position of compound 1. The technical effect of this step is to introduce a highly reactive halogen group, so that compound 2 can more easily undergo nucleophilic substitution or elimination reaction in the subsequent step.

[0094] Compound 2 is placed in an alkaline environment and subjected to an oxidation reaction to obtain compound 3. The oxidation reaction carried out under alkaline conditions converts the bromine group in compound 2 into a more functional carbonyl group to generate compound 3. The key to this step is efficient conversion while keeping other functional groups in the compound structure unaffected, providing a suitable carbonyl site for the subsequent asymmetric nucleophilic addition reaction.

[0095] Compound 3 undergoes an asymmetric nucleophilic addition reaction with azobenzoyloxymethylphenyl chloroformate, and then the aldehyde group in compound 3 is reduced to a hydroxyl group to obtain compound 4. The asymmetric nucleophilic addition reaction introduces a new chiral center in compound 3, producing a stereoselective intermediate. Subsequently, a stable hydroxyl compound (compound 4) is obtained by reducing the aldehyde group. This step significantly increases the structural complexity and functionality of the molecule, laying the foundation for stereochemical control in subsequent reactions. This step ensures the formation of the key chiral center in the target molecule while retaining the reactivity of the molecule.

[0096] The hydroxyl group in compound 4 was converted to tert-butyldimethylsilyl (TBS) ether to obtain compound 5. Silicon protection of the hydroxyl group (such as TBS) can prevent unnecessary side reactions in subsequent reactions. By introducing the TBS protecting group, the hydroxyl group of compound 5 was temporarily "shielded" to avoid interference in subsequent steps. This protection strategy makes the molecular structure more stable and provides favorable conditions for the subsequent internal cyclization reaction.

[0097] Compound 5 is placed in an alkaline environment and undergoes an internal cyclization reaction to obtain compound 6. Under alkaline conditions, compound 5 undergoes an internal cyclization reaction to form a cyclic compound 6. This step enables the functional groups within the molecule to interact with each other, and ultimately forms a stable cyclic product through cyclization. The cyclization reaction not only increases the structural complexity of the molecule, but also significantly improves the stability and functionality of the molecule. This cyclization step is the key in the entire synthetic route and directly affects the properties and yield of the final product.

[0098] S1.2, removing the protecting group in compound 6, and then introducing an allyl group to obtain compound 13;

[0099] Tetrabutylammonium fluoride was added to compound 6 to remove the tert-butyldimethylsilyl group to obtain compound 7. Tetrabutylammonium fluoride (TBAF) was used to efficiently remove the TBS protecting group, exposing the hydroxyl group in compound 6, thereby generating compound 7. The technical effect of this step is to restore the active hydroxyl group in the molecule, facilitating subsequent oxidation or other modification reactions, while ensuring the integrity of the molecular skeleton.

[0100] An oxidant is added to compound 7 to perform an oxidation reaction to obtain compound 8, wherein the oxidant includes at least one of 2,2,6,6-tetramethylpiperidinyl oxide (TEMPO), sodium hypochlorite, and sodium chlorite. The hydroxyl group in compound 7 is oxidized to a carbonyl group by using an oxidant. This reaction increases the functional group diversity of the molecule, making compound 8 have higher reactivity and potential for further derivatization. The selection of an appropriate oxidant ensures the selectivity and high yield of the oxidation.

[0101] Compound 8 is placed in an acidic environment and converted into compound 9. Under acidic conditions, compound 8 undergoes structural transformation or functional group adjustment to generate compound 9. This process may involve the rearrangement or removal of groups such as hydroxyl, ether or ester. The selection of acidic conditions helps to achieve efficient and directional reactions, ensuring the purity of the final product and the controllability of the reaction.

[0102] The bis-benzyloxycarbonyl group in compound 9 was removed, and a single benzyloxycarbonyl group was introduced to obtain compound 11. By removing the two benzyloxycarbonyl protecting groups, the originally protected amino group or other active groups can be exposed, and then a benzyloxycarbonyl group can be reintroduced for selective protection. The technical effect of this step is to precisely control the number and position of the protecting groups to facilitate subsequent chemical modification, while avoiding unnecessary side reactions in multi-step synthesis.

[0103] Compound 11 is placed in an alkaline environment, the methyl ester in compound 11 undergoes a hydrolysis reaction, and the hydrolyzed carboxylic acid is converted into an allyl ester to obtain compound 13. Under alkaline conditions, the methyl ester group in compound 11 is hydrolyzed into a carboxylic acid, which is a standard reaction step used to increase the reactivity of the compound. Subsequently, the obtained carboxylic acid is reacted with an allylation agent and converted into an allyl ester. The effect of this step is to make the compound easier to participate in subsequent coupling or cyclization reactions, and to provide additional reaction sites by introducing an allyl group, thereby increasing the flexibility of the synthesis.

[0104]

[0105] (2) Synthesis of compound 29.

[0106] S1.3, Compound 13 and Compound 26 are subjected to a peptide grafting reaction to obtain Compound 27. Through the peptide grafting reaction, Compound 13 is effectively coupled with the amino acid fragment in Compound 26 to generate Compound 27. The technical effect of this step is to efficiently and selectively form a new peptide bond, thereby splicing the two fragments into a larger polypeptide molecule. Since Compound 26 contains an Fmoc protecting group, this step also ensures the effective protection of sensitive groups during the reaction, thereby avoiding the occurrence of side reactions and ensuring the high purity and high yield of the final product.

[0107] S1.4. Remove the allyl ester and protecting group from compound 27 to obtain compound 29. By removing the allyl ester and protecting group (such as Fmoc) in compound 27, the previously protected carboxylic acid and amino groups are exposed. This deprotection step is crucial to achieving the final structure because it restores all active functional groups in the molecule and is ready to participate in the next chemical reaction. The process of removing the allyl ester and protecting group ensures the structural integrity and functionality of compound 29, while improving the reaction efficiency and yield, and provides a basis for further synthesis steps.

[0108]

[0109] In another embodiment, step S1 of synthesizing compound 29 comprises:

[0110] Compound 1 is dissolved and then pyridine chlorochromate is added to generate compound 36; pyridine chlorochromate (PCC) is a chromium (VI)-based oxidant. In this step, PCC oxidizes the hydroxyl group in compound 1 to an aldehyde or ketone group to generate compound 36. The reaction conditions are mild and highly selective, which helps to achieve efficient oxidation without causing side reactions of other functional groups.

[0111] Compound 36 was mixed with imidazole, and then tert-butyldimethylsilyl chloride was added dropwise to react to generate compound 37. TBSCl (tert-butyldimethylsilyl chloride) is a commonly used silicon-based protecting agent used to convert alcohols into silyl ethers. As a base, imidazole can not only neutralize the hydrogen chloride generated in the reaction, but also promote the effective transfer of the TBS group. Imidazole and TBSCl together protected the hydroxyl group in compound 36 as TBS ether to generate compound 37. This step protects the hydroxyl group and prevents it from participating in unnecessary side reactions in subsequent steps, thereby improving the selectivity and efficiency of the reaction.

[0112] L-alanine was mixed with methyl iodide for reaction, and then basic 9-fluorenylmethoxycarbonyl chloride was added to obtain compound 38. Fmoc-Cl (9-fluorenylmethoxycarbonyl chloride) is a reagent used to protect the amino group in amino acids. It reacts with the amino group in an alkaline environment to form an Fmoc protecting group, which provides efficient protection and can be easily removed in subsequent reactions.

[0113] Methyl iodide reacts with L-alanine to generate N-methylated amino acids, which then react with Fmoc-Cl under alkaline conditions to form Fmoc-protected amino acid derivatives (compound 38). This step introduces a protected amino acid unit for the subsequent coupling reaction and controls the reactivity of the amino acid.

[0114] After compound 38 is dissolved, 1-hydroxybenzotriazole and N,N-diisopropylethylamine are added, and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and compound 37 are added for coupling reaction to obtain compound 39.

[0115] HOBt (1-hydroxybenzotriazole) and EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) work synergistically to activate carboxylic acid and enable efficient coupling with amino groups. DIPEA (N,N-diisopropylethylamine) acts as a non-nucleophilic base to maintain the alkalinity of the reaction environment and promote the coupling reaction. This coupling reaction connects compound 38 and compound 37 through an amide bond to generate compound 39. The use of HOBt and EDC improves the efficiency and selectivity of the coupling reaction and reduces the formation of by-products. DIPEA acts as a base to maintain the alkaline environment of the reaction and ensure the smooth formation of the amide bond.

[0116] Compound 39 was dissolved in an acidic environment, tetrabutylammonium fluoride was added, and hydrazine hydrate was then added dropwise for cyclization reaction to generate compound 29. TBAF (tetrabutylammonium fluoride) is a deprotection agent that can effectively remove silicon-based protecting groups. Hydrazine hydrate is a strong reducing agent that can remove various protecting groups and promote cyclization reactions within the molecule. TBAF was first used to remove the TBS protecting group in compound 39 to expose the hydroxyl group. Subsequently, compound 39 was deprotected and cyclized by treatment with hydrazine hydrate to form compound 29. The acidic environment helps to remove protecting groups such as Fmoc, while promoting the cyclization reaction, and finally generates a compound 29 with a specific ring structure.

[0117]

[0118] (3) Synthesis of compound 25.

[0119] Specifically, step S2 includes:

[0120] S2.1. Add N-phenylselenophthalamide and pyridine toluenesulfonate to compound 20 for cyclization reaction to generate compound 21. N-phenylselenophthalamide reacts with compound 20 to introduce a phenylselenyl group into the molecule, and a new ring structure is formed through cyclization reaction to generate compound 21. Pyridine toluenesulfonate (PPTS) is used as an acid catalyst to promote the smooth progress of the cyclization reaction. This step makes compound 21 have higher reactivity and structural complexity by forming a new ring system and functional group modification.

[0121] S2.2, m-chloroperbenzoic acid is added to compound 21 to carry out oxidation reaction to generate compound 22. m-Chloroperbenzoic acid (mCPBA) is a strong oxidant, which is used to oxidize the phenylselenide group in compound 21 to the corresponding phenylselenide group. This step improves the reactivity of the molecule through oxidation reaction, so that compound 22 has new functional groups and provides more reaction sites for subsequent chemical reactions.

[0122] S2.3, compound 22 is placed in an acidic environment, lithium hydroxide is added for reaction, and after the reaction is completed, it is reacted with sodium bicarbonate and allyl bromide to obtain compound 23. This step first uses lithium hydroxide to carry out a deprotection reaction under acidic conditions to remove certain protecting groups. Subsequently, the compound is reacted with sodium bicarbonate and allyl bromide to form compound 23 through allylation. This step further enhances the chemical diversity of the molecule through selective deprotection and allylation reactions, and introduces a more active allyl functional group.

[0123] S2.4, converting the tertiary alcohol group in compound 23 into triethylsilyl ether to obtain compound 24. By converting the tertiary alcohol group in compound 23 into triethylsilyl ether (TES), the hydroxyl group is protected to prevent it from participating in unnecessary side reactions in subsequent reactions. This step protects the reactive sites of the molecule, making it more controllable in subsequent synthesis and enhancing the stability of the molecule.

[0124] S2.5, Compound 24 is placed in an acidic environment and the protecting group is removed to obtain Compound 25. Under acidic conditions, the triethylsilyl ether protecting group in Compound 24 is removed to restore the hydroxyl group of Compound 25. This deprotection step is to remove the protection of the functional group in the final stage of the synthesis and restore its reactivity, thereby ensuring the functionality and structural integrity of Compound 25.

[0125]

[0126] (4) Synthesis of compound 30.

[0127] S3, compound 25 and compound 29 were subjected to dehydration condensation reaction to generate compound 30. The dehydration condensation reaction connected compound 25 and compound 29 by forming an amide bond to generate compound 30. The technical effect of this step is that a stable and complex peptide molecule is efficiently constructed, ensuring the high yield and high purity of the target compound. The design of this reaction fully utilizes the chemical activity of the two reaction sites to achieve precise molecular assembly. In addition, the optimization of the reaction conditions ensures the minimization of by-products, improves the overall efficiency of the synthesis and the simplicity of the steps. Ultimately, the generated compound 30 provides an ideal basis for further cyclization or modification. By using HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) and HOAt (1-hydroxy-7-azabenzotriazole) as peptide grafting reagents, the efficient formation of the amide bond is ensured. This reagent combination can effectively activate the carboxylic acid and undergo coupling reaction with the amino group to generate a stable amide bond while reducing the generation of by-products.

[0128]

[0129] (5) Synthesis of compound 35.

[0130] Specifically, step S4 includes:

[0131] S4.1, compound 14 and threonine allyl ester undergo dehydration condensation reaction to obtain compound 15. The dehydration condensation reaction connects compound 14 and threonine allyl ester by forming an amide bond to obtain compound 15. The key to this step is to achieve efficient amide bond formation to ensure high yield and high purity of compound 15. This reaction uses an allyl ester protecting group, making the selective deprotection operation in the subsequent reaction more flexible, thus laying the foundation for the subsequent steps.

[0132] S4.2, compound 15 is subjected to a multi-step treatment and alanyl chloride for peptide grafting reaction to obtain compound 19. Compound 15 is subjected to a multi-step treatment, which may include the removal of protecting groups and the activation of functional groups, in preparation for the peptide grafting reaction with alanyl chloride. The introduction of alanyl chloride is to introduce a new amide bond into compound 19. The technical effect of this step is that a linear peptide compound 19 with a complex structure and specific functional groups is obtained through an effective peptide grafting reaction, which ensures the yield and stereochemical purity of the synthesis.

[0133] The specific reaction steps are as follows:

[0134] The 9-fluorenylmethoxycarbonyl group in compound 15 was removed to obtain compound 16. In this step, the Fmoc protecting group was efficiently removed by using an appropriate deprotection reagent (such as piperidine) to generate compound 16 and expose the amino site. This prepared for the subsequent peptide bond formation and ensured the smooth progress of the subsequent reaction.

[0135] Compound 16 is subjected to a peptide grafting reaction with alanyl chloride to obtain compound 17. The peptide grafting reaction forms a new amide bond through the reaction of alanyl chloride with the amino group of compound 16 to obtain compound 17. The technical effect of this step is to ensure the efficient formation of the peptide bond while maintaining stereochemical purity. This reaction provides a new functional group, so that compound 17 can be further modified in the subsequent steps.

[0136] Tetrakistriphenylphosphine palladium and nitrogen methyl aniline were added to compound 17 to remove the allyl ester to obtain compound 18. Tetrakistriphenylphosphine palladium and nitrogen methyl aniline were used to selectively remove the allyl ester protecting group to generate compound 18. The technical effect of this step is to efficiently remove the allyl ester protecting group while avoiding the influence on other sensitive functional groups. This creates conditions for subsequent deprotection operations and coupling reactions.

[0137] Compound 18 is placed in a hydrogen atmosphere, and palladium hydroxide on carbon is added to remove the benzyloxycarbonyl group to obtain compound 19. In a hydrogen atmosphere, palladium hydroxide on carbon catalyst is used to efficiently remove the benzyloxycarbonyl (Cbz) protecting group to generate compound 19. This process needs to be carried out under mild conditions to ensure the protection of other sensitive functional groups. The technical effect of this step is that the target peptide compound 19 is finally obtained through efficient and mild deprotection operation, and is ready for further coupling or cyclization reactions.

[0138] S4.3, adding a peptide-linking reagent to compound 19 and compound 30 to carry out a coupling reaction to obtain compound 31. This step promotes an efficient coupling reaction between compound 19 and compound 30 by introducing a peptide-linking reagent to form an amide bond. Compound 31 is thus generated, which contains the connection of two key peptide segments. The technical effect of this step is to ensure the efficiency and selectivity of the coupling reaction, minimize the generation of by-products, and maintain the high yield and structural integrity of compound 31.

[0139] S4.4, removing the protecting groups in compound 31 to prepare compound 35. By selectively removing the protecting groups in compound 31, the final compound 35, i.e., the natural cyclic peptide petrichorin C, is generated. In this step, the removal of the protecting groups requires strict control of the reaction conditions to ensure that the integrity of the peptide chain or cyclic peptide is not affected. The technical effect of this step is to successfully remove all protecting groups to form the target cyclic peptide, while ensuring the high purity and biological activity of compound 35.

[0140] The specific reaction steps are as follows:

[0141] The allyl group in compound 31 is removed to obtain compound 32. By using an appropriate catalyst, the allyl protecting group in compound 31 is selectively removed to generate compound 32. The technical effect of this step is to accurately remove the allyl group, expose the carboxylic acid group without affecting other functional groups, thereby preparing for the next step of deprotection operation.

[0142] Diethylamine was added to compound 32 to remove the 9-fluorenylmethoxycarbonyl group to obtain compound 33. Diethylamine was introduced into compound 32 to remove the Fmoc protecting group to generate compound 33. The technical effect of this step is to efficiently remove the Fmoc group, expose the key amino site, and ensure that an effective cyclization reaction can be carried out in the subsequent cyclization reaction. At the same time, the by-products are easy to remove during the Fmoc removal process, ensuring the high purity of compound 33.

[0143] Compound 33 is first subjected to a cyclization reaction, and then the protecting group is removed to obtain compound 35. Under appropriate reaction conditions, the amino group and the carboxyl group in compound 33 undergo a cyclization reaction to form a closed cyclic peptide structure, and then the protecting group is removed to finally obtain compound 35. The technical effect of this step is that a stable cyclic peptide structure is successfully constructed, and all residual protecting groups are removed at the same time, ensuring the high purity and structural integrity of compound 35. The smooth progress of the cyclization reaction and the effective removal of the protecting group are the key to the success of this synthetic route. The final product, compound 35, is the target natural product, natural cyclic peptide petrichorin C.

[0144]

[0145] The present invention has been tested for many times, and some test results are now cited as references to further describe the invention in detail, and the following is a detailed description in conjunction with specific embodiments.

[0146] Embodiment 1:

[0147]

[0148] Compound 1 (10.0 g, 0.1 mol, 1.0 equiv.) was dissolved in toluene (168 mL, 0.58 M), and then 48% hydrobromic acid (13 mL, 0.11 mol, 1.1 equiv.) was added. A condensing reflux device was set up, and the reaction bottle was placed in a 115 ℃ oil bath for stirring and reflux reaction for 4 hours. After TLC monitoring confirmed that compound 1 was completely converted, toluene (3× 100 mL) was added for extraction, and the combined organic phase was dried with anhydrous sodium sulfate solid. After drying, it was filtered with a sand core funnel, and the filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product. The yellow oil compound 2 (3.20 g, 0.02 mol) was obtained with a yield of 50% by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1).

[0149] TLC: R f = 0.30 (Thin layer silica gel plate, petroleum ether / ethyl acetate = 3 / 1). UV fluorescence & phosphomolybdic acid color development. 1 H NMR (400 MHz, CDCl3) δ 3.57 (t, J = 6.4 Hz, 2H), 3.37 (t, J = 6.7 Hz, 2H),2.62 (s, 1H), 1.83 (p, J = 6.9 Hz, 2H), 1.59 – 1.39 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 62.3, 33.8, 32.5, 31.7, 24.4.

[0150] Embodiment 2:

[0151]

[0152] Compound 2 (8.0 g, 48 mmol, 1.0 equiv.) was dissolved in dichloromethane (161 mL, 0.5 M), and then trichloroisocyanuric acid (11.2 g, 48 mmol, 1.0 equiv.), sodium bicarbonate (12.4 g, 144 mmol, 3.0 equiv.) and 2,2,6,6-tetramethylpiperidinoxide (0.19 g, 1.0 mmol, 0.02 equiv.) were added in turn under ice bath, and stirred for 15 minutes. After TLC monitoring confirmed that compound 2 was completely converted, the reaction solution was poured into a sand core funnel filled with diatomaceous earth for filtration, and an appropriate amount of saturated sodium thiosulfate solution was added to the filtrate until the starch potassium iodide test paper was colorless, and then an appropriate amount of saturated sodium bicarbonate solution was added to adjust the filtrate to neutral. Dichloromethane (3 × 100 mL) was added for extraction, and the combined organic phases were dried over anhydrous sodium sulfate solid. After drying, the product was filtered through a sand core funnel, and the filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a light yellow liquid compound 3 (5.26 g, 32 mmol) with a yield of 68%.

[0153] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 5 / 1), UV fluorescence & phosphomolybdic acid color development. 1 HNMR(400 MHz, CDCl3) δ 9.75 – 9.66 (m, 1H), 3.34 (ddd, J = 10.9, 7.1, 4.2 Hz,2H), 2.49 – 2.37 (m, 2H), 1.90 – 1.75 (m, 2H), 1.70 (dt, J = 14.5, 6.9 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 201.8, 42.7, 33.2, 31.8, 20.6.

[0154] Embodiment 3:

[0155]

[0156] Dissolve dibenzyl azodicarboxylate (4.17 g, 14 mmol, 1.0 equiv.) in acetonitrile (68 mL, 0.14M), place the reaction bottle at -15℃ and fully cool and stir for 30 minutes, then add compound 3 (2.6 g, 18.2 mmol, 1.3 equiv.) and L-proline (0.55 g, 4.2 mmol, 0.3 equiv.) in turn and stir to react for 15 hours. After TLC monitoring confirms that compound 3 is completely converted, add sodium borohydride (0.60 g, 14 mmol, 1.0equiv.) and ethanol (2.61 mL, 0.1 M) to the reaction solution and stir to react for 1 hour. After TLC monitoring confirms that the raw material is completely converted, add an appropriate amount of 10% citric acid to the reaction solution to quench until no bubbles are generated. Add ethyl acetate (3 × 100 mL) for extraction, and the combined organic phases are dried over anhydrous sodium sulfate solid. After drying, the mixture was filtered using a sand core funnel, and the filtrate was concentrated under reduced pressure using a vacuum pump to obtain a light yellow viscous liquid compound 4 (12.00 g, 25.9 mmol) with a yield of 74%.

[0157] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 3 / 1), UV fluorescence & phosphomolybdic acid color development. 1 HNMR(400 MHz, CDCl3) δ 7.41 – 7.26 (m, 10H), 6.87 (d, J = 16.4 Hz, 1H), 5.29 –5.07 (m, 4H), 4.36 (d, J = 59.1 Hz, 2H), 3.63 – 3.14 (m, 4H), 1.78 (d, J = 38.9Hz, 2H), 1.57 – 1.31 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.1, 157.0, 156.2,135.7, 135.6, 135.0, 128.7, 128.6, 128.6, 128.5, 128.4, 128.3, 128.1, 127.8,68.7, 68.6, 68.4, 62.0, 60.4, 60.3, 33.6, 33.0, 29.1, 26.3.

[0158] Embodiment 4:

[0159]

[0160] Compound 4 (12.00 g, 26.58 mmol, 1.0 equiv.) was dissolved in N,N -Dimethylformamide (64 mL, 0.4 M) was added with tert-butyldimethylsilyl chloride (9.74 g, 49 mmol, 1.9 equiv.), imidazole (8.81 g, 129 mmol, 5.0 equiv.) and 4,-dimethylaminopyridine (0.32 g, 2.66 mmol, 0.1 equiv.) in an ice bath and stirred overnight. After the conversion of compound 4 was confirmed by TLC monitoring, an appropriate amount of saturated sodium bicarbonate was added to the reaction solution to dissolve and quench until no bubbles were generated, indicating that the quenching was complete, and ethyl acetate (2 × 100 mL) was added for extraction, and the organic phases were combined, washed with saturated lithium chloride solution (100 mL), and then dried over anhydrous sodium sulfate solid. After drying, the product was filtered and the filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain white solid compound 5 (7.60 g, 13.78 mmol) with a yield of 45%.

[0161] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 10 / 1), UV fluorescence & phosphomolybdic acid color development. 1 H NMR (400 MHz, CDCl3) δ 7.34 (dq, J = 18.8, 11.5, 8.6 Hz, 10H), 6.47 (s, 1H), 5.26 – 5.03 (m, 4H), 4.22 (d, J = 55.4 Hz, 1H), 3.80 – 3.09 (m, 2H), 1.76 (s, 2H), 1.46 – 1.22 (m, 3H), 0.85 (s, 9H), 0.29 – -0.06 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 157.0, 156.4, 135.9, 135.7, 128.6, 128.5, 128.5, 128.5, 128.4,128.2, 128.1, 127.9, 127.7, 68.4, 68.0, 67.7, 67.6, 62.9, 59.6, 58.4, 45.2,29.7, 29.0, 25.7, 25.5, 18.0, -5.5.

[0162] Embodiment 5:

[0163]

[0164] Compound 5 (12.00 g, 26.58 mmol, 1.0 equiv.) was dissolved in N , N -dimethylformamide (240mL, 0.1 M), sodium hydride (1.73 g, 57.44 mmol, 1.8 equiv.) was added under ice bath and stirred for 30 minutes. After TLC monitoring confirmed that compound 5 was completely converted, an appropriate amount of water was added to the reaction solution to quench the sodium hydride until no bubbles were generated, and then an appropriate amount of 10% citric acid was added to adjust the solution pH to 5-6, and then the reaction solution was added to ethyl acetate (2 × 100 mL) for extraction, the organic phases were combined, washed with saturated lithium chloride solution (100 mL), and then dried with anhydrous sodium sulfate solid and filtered. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain yellow liquid compound 6 (15.90 g, 31.91 mmol) with a yield of 84%.

[0165] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate / dichloromethane = 10 / 1 / 2), UV fluorescence & phosphomolybdic acid color development. 1 H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 11.3 Hz, 10H), 5.32 – 4.89(m, 4H), 4.50 – 3.98 (m, 2H), 3.92 – 3.48 (m, 2H), 3.01 (d, J = 12.2 Hz, 1H),1.94 – 1.59 (m, 3H), 1.53 – 1.40 (m, 1H), 0.89 (d, J = 11.3 Hz, 9H), 0.07 (d, J =48.2 Hz, 6H). 13 C NMR(101 MHz, CDCl3) δ 155.5, 155.3, 155.0, 136.3, 136.1,128.5, 128.5, 128.5, 128.2, 128.1, 127.9, 127.8, 127.7, 127.5, 67.7, 67.6,60.9, 54.3, 44.4, 25.9, 25.8, 22.4, 19.3, 18.9, 18.2, -5.3, -5.4, -5.5, -5.5.

[0166] Embodiment 6:

[0167]

[0168] Compound 6 (15.90 g, 31.91 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (260 mL, 0.16M), and tetrabutylammonium fluoride trihydrate (10.80 g, 63.82 mmol, 2.0 equiv.) was added under ice bath, and stirred for 40 minutes. After TLC monitoring confirmed that compound 6 was completely converted, an appropriate amount of saturated ammonium chloride solution was added to the reaction solution to quench until a white solid precipitated and no bubbles were generated. The reaction solution was then extracted with ethyl acetate (2 × 100 mL), the organic phases were combined, washed with saturated ammonium chloride solution (100 mL), dried with anhydrous sodium sulfate solid and filtered, and the filtrate was concentrated under reduced pressure by a vacuum pump to obtain a light yellow liquid compound 7 (7.00 g, 18.21 mmol) with a yield of 75%.

[0169] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 1 / 1), UV fluorescence & phosphomolybdic acid color development. 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 12.0 Hz, 10H), 5.18 (d, J = 18.9 Hz, 4H),4.49 (d, J = 33.0 Hz, 1H), 4.12 (dd, J = 40.1, 12.5 Hz, 1H), 3.75 – 3.39 (m, 3H), 3.08 (d, J = 47.3 Hz, 1H), 1.86 – 1.60 (m, 2H), 1.51 (d, J = 17.9 Hz, 2H). 13 C NMR(101 MHz, CDCl3) δ 156.8, 156.1, 155.7, 154.9, 136.1, 135.9, 135.7, 135.5,128.7, 128.6, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.8, 68.5, 68.3,68.3, 68.1, 60.5, 59.9, 56.2, 55.0, 45.8, 44.1, 22.9, 22.5, 19.7, 19.3.

[0170] Embodiment 7:

[0171]

[0172] Compound 7 (7.00 g, 18.21 mmol, 1.0 equiv.) was dissolved in acetonitrile: phosphate buffer = 1:1 (182 mL, 0.1 M) and stirred in an ice bath. Subsequently, 2,2,6,6-tetramethylpiperidinyl oxide (0.45 g, 4.73 mmol, 0.26 equiv.) was added, and the solution turned orange-red. Then, sodium chlorite (3.30 g, 29.14 mmol, 1.6 equiv.) and sodium hypochlorite (0.62 mL, 1.1 mmol, 0.06 equiv.) were added in sequence, and the solution turned from orange-red to purple-black. The reaction was stirred overnight. After TLC monitoring confirmed that compound 6 was completely converted, the reaction bottle was stirred in an ice bath, and about 1 mol / L sodium hydroxide solution (27 mL) was added to the reaction solution, and the solution changed from purple-black to purple-red. Then, about saturated sodium thiosulfate solution (5.4 mL) was added, and the solution changed from purple-red to light red, then to yellow, and finally to turbidity. Finally, 1 mol / L hydrochloric acid solution (49 mL) was added to adjust the pH of the solution to 2-3, and the solution turned back to clear yellow. All the reaction solutions were concentrated under reduced pressure by a vacuum pump, extracted with ethyl acetate (3 × 100 mL), dried with anhydrous sodium sulfate solid and filtered, and the filtrate was concentrated under reduced pressure by a vacuum pump to obtain brown viscous liquid compound 8 (6.70 g, 16.82 mmol) with a yield of 90%.

[0173] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 1 / 3), UV fluorescence & phosphomolybdic acid color development.

[0174] Embodiment 8:

[0175]

[0176] Compound 8 (6.70 g, 16.82 mmol, 1.0 equiv.) was dissolved in methanol (168 mL, 0.07 M) and stirred in an ice bath, followed by dropwise addition of thionyl chloride (3.00 mL, 42.05 mmol, 2.5 equiv.) and stirred overnight. After TLC monitoring confirmed that compound 8 was completely converted, a saturated sodium bicarbonate solution was added to the reaction solution to quench, all the reaction solutions were concentrated under reduced pressure by a vacuum pump, ethyl acetate (3 × 100 mL) was added for extraction, and then dried with anhydrous sodium sulfate solid and filtered. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a yellow oily liquid compound 9 (5.20 g, 12.62 mmol) with a yield of 71%.

[0177] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 2 / 1), UV fluorescence & phosphomolybdic acid color development. 1 H NMR (400 MHz, CDCl3) δ 7.28 (s, 10H), 5.10 (d, J = 28.3 Hz, 5H), 4.17 (dd, J =45.5, 10.0 Hz, 1H), 3.59 (d, J = 76.9 Hz, 3H), 3.20 – 2.81 (m, 1H), 2.12 (dd, J =13.3, 3.4 Hz, 1H), 1.78 (d, J = 89.2 Hz, 3H), 1.63 – 1.49 (m, 1H). 13 C NMR(101MHz, CDCl3) δ 170.0, 155.5, 155.2, 136.2, 135.7, 128.5, 128.4, 128.2, 127.8,127.7, 77.5, 77.2, 76.8, 68.4, 67.7, 55.0, 52.1, 44.0, 24.5, 19.9, 1.0.

[0178] Embodiment 9:

[0179]

[0180] Compound 9 (10.70 g, 25.94 mmol, 1.0 equiv.) was dissolved in methanol (130 mL, 0.17 M), palladium carbon (1.00 g, 0.52 mmol, 0.02 equiv.) was added, and a hydrogen balloon was inserted for ultrasonic exhaust for 15 minutes, and then stirred for 2 hours. After TLC monitoring confirmed that compound 9 was completely converted, a sand core funnel of appropriate size was taken, covered with diatomaceous earth, and the reaction solution was poured into it for suction filtration. During the period, the diatomaceous earth was rinsed with MeOH until no product remained in it. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain a colorless viscous liquid compound 10 (3.80 g, 26.37 mmol) with a yield of 88%.

[0181] TLC: R f = 0.1 (thin layer silica gel plate, petroleum ether / ethyl acetate = 1 / 2), UV fluorescence & phosphomolybdic acid color development.

[0182] Embodiment 10:

[0183]

[0184] Compound 10 (3.80 g, 26.37 mmol, 1.0 equiv.) was dissolved in methanol (240 mL, 0.13 M) and stirred in an ice bath, followed by the addition of triethylamine (11.00 mL, 79.11 mmol, 3.0 equiv.) and benzyl chloroformate (4.00 mL, 29.0 mmol, 1.1 equiv.) and the reaction mixture was stirred for 1.5 hours. After the complete conversion of compound 10 was confirmed by TLC monitoring, a saturated ammonium chloride solution was added to the reaction solution to adjust the pH to neutral, and a white solid was produced. The reaction solution was concentrated under reduced pressure by a vacuum pump, extracted with ethyl acetate (3 × 100 mL), dried with anhydrous sodium sulfate solid and filtered, and the filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain a colorless oily liquid compound 11 (5.50 g, 19.77 mmol) with a yield of 80%.

[0185] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 2 / 1), UV fluorescence & phosphomolybdic acid color development. 1 H NMR (400 MHz, CDCl3) δ 7.38 – 7.28 (m, 5H), 5.16 (d, J = 6.9 Hz, 2H), 4.14 –3.94 (m, 1H), 3.75 (d, J= 28.8 Hz, 3H), 3.59 – 3.48 (m, 1H), 2.12 – 1.98 (m,1H), 1.84 – 1.50 (m, 3H). 13 C NMR(101 MHz, CDCl3) δ 171.4, 155.3, 136.4, 128.5,128.1, 127.9, 67.5, 58.3, 52.0, 44.7, 27.8,27.4, 25.7, 23.2.

[0186] Embodiment 11:

[0187]

[0188] Compound 11 (7.30 g, 26.25 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran: methanol: water = 1:1:1 (198 mL, 0.1 M) and stirred in an ice bath, followed by the addition of lithium hydroxide (2.49 g, 78.75 mmol, 3.0 equiv.) and stirred for 1.5 hours. After TLC monitoring confirmed that compound 11 was completely converted, concentrated hydrochloric acid was added to the reaction solution to adjust the pH to neutral, and then 1M hydrochloric acid was added to adjust the pH of the solution to 2-3, and a white solid was produced. The reaction solution was concentrated under reduced pressure by a vacuum pump, and ethyl acetate (3 × 100 mL) was added for extraction, and then dried with anhydrous sodium sulfate solid and filtered. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain a white solid compound 12 (4.70 g, 17.80 mmol) with a yield of 86%.

[0189] TLC: R f = 0.1 (thin layer silica gel plate, petroleum ether / ethyl acetate = 1 / 3), UV fluorescence & phosphomolybdic acid color development. 1 H NMR(400 MHz, CDCl3) δ 7.39 – 7.23 (m, 5H), 5.15 (s, 2H), 4.14 – 3.83 (m,1H), 3.68 (s, 3H), 3.56 – 3.47 (m, 1H), 2.02 (d, J = 13.7 Hz, 1H), 1.79 – 1.46(m, 3H). 13 C NMR (101 MHz, MeOD) δ 173.0, 156.0, 136.5, 128.1, 127.7, 126.6, 67.3, 57.9, 44.3, 27.0, 22.8.HRMS (ESI, m / z ) for C 13H 16 N2O4 + [M + H] + : Calcd.265.11; Found: 265.1184.

[0190] Embodiment 12:

[0191]

[0192] Compound 12 (4.70 g, 17.80 mmol, 1.0 equiv.) was dissolved in N,N -Dimethylformamide (90 mL, 0.1 M) was stirred in an ice bath, and potassium bicarbonate (2.00 g, 142.4 mmol, 8.0 equiv.) and allyl bromide (2.30 g, 71.2 mmol, 4.0 equiv.) were added in sequence and stirred at room temperature overnight. After TLC monitoring confirmed that compound 12 was completely converted, ethyl acetate (3 × 100 mL) was added for extraction, and then dried with anhydrous sodium sulfate solid and filtered. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a colorless viscous liquid compound 13 (4.22 g, 22.59 mmol) with a yield of 78%. That is, a white solid compound 12 (4.70 g, 22.59 mmol) was obtained with a yield of 86%.

[0193] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 4 / 1), UV fluorescence & phosphomolybdic acid color development. 1 HNMR(400 MHz, CDCl3) δ 7.39 – 7.27 (m, 5H), 5.89 (ddt, J = 17.4, 10.4, 5.8 Hz,1H), 5.31 (dd, J = 17.2, 1.5 Hz, 1H), 5.24 (dd, J = 10.4, 1.3 Hz, 1H), 5.17 (s,2H), 4.61 (d, J = 5.8 Hz, 2H), 4.00 (d, J = 13.3 Hz, 1H), 3.56 (dd, J = 10.1, 3.2Hz, 1H), 3.13 (t, J= 12.2 Hz, 1H), 2.13 – 2.04 (m, 1H), 1.77 – 1.22 (m, 4H). 13 CNMR (101 MHz, CDCl3) δ 170.7, 155.3, 136.4, 131.6, 128.5, 128.2, 128.0, 118.9, 67.6, 65.7, 58.4, 27.5, 23.3.

[0194] Embodiment 13:

[0195]

[0196] Compound 14 (2.40 g, 4.94 mmol, 1.00 equiv.) and 1-hydroxy-7-azobenzotriazole (2.00 g, 14.70 mmol, 3.00 equiv.) were dissolved in dichloromethane (100 mL, 0.06 M) and cooled to 0°C. Then, allyl- O -tert-Butyl-D-threonine (1.58 g, 7.34 mmol, 1.50 equiv.), DIPEA (5.12 mL, 29.40 mmol, 6.00 equiv.) and O -(7-nitrobenzotriazole)- N,N,N',N' -Tetramethyluronium hexafluorophosphate (2.79 g, 7.34 mmol, 1.50 equiv.) was stirred at room temperature under nitrogen protection overnight. After TLC monitoring confirmed that compound 14 was completely converted, it was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain a white solid 15 (3.20 g, 4.68 mmol) with a yield of 95%.

[0197] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 2 / 1), UV fluorescence & potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.6 Hz, 2H), 7.72 – 7.47 (m, 2H), 7.40 – 7.15 (m, 9H), 5.98 – 5.83 (m, 1H), 5.40 – 5.08 (m, 4H), 4.97 (d, J = 12.6 Hz,1H), 4.70 – 4.48 (m, 4H), 4.26 (td,J = 6.3, 2.4 Hz, 1H), 4.24 – 4.16 (m, 1H), 4.05 (d, J = 13.0 Hz, 1H), 2.83 (s, 1H), 2.34 (d, J = 14.9 Hz, 1H), 1.77 – 1.34 (m, 4H), 1.27 – 1.09 (m, 12H). 13 C NMR(101 MHz, CDCl3) δ 170.6, 169.6, 154.9,141.4, 136.6, 136.0, 131.9, 128.5, 128.3, 128.2, 128.2, 127.9, 124.9, 120.0,118.7, 74.0, 67.8, 66.8, 66.0, 65.7, 58.9, 53.5, 47.1, 28.4, 21.1, 20.5,20.1. = -7.975 ( c 1.0, CHCl3).HRMS(ESI, m / z ) for C 39 H 45 N3NaO8 + [M + Na] + : Calcd.706.3207; Found: 706.3316.

[0198] Embodiment 14:

[0199]

[0200] Compound 15 (3.20 g, 4.68 mmol, 1.00 equiv.) was dissolved in acetonitrile (370 mL, 0.02 M), and then diethylamine (18.30 mL, 177.65 mmol, 38.00 equiv.) was added and stirred at room temperature for 3 hours. After TLC monitoring confirmed that compound 15 was completely converted, the reaction solution was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a light yellow liquid compound 16 (2.00 g, yield 92%) with a yield of 92%.

[0201] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 3 / 2), potassium permanganate color development. 11H NMR (400 MHz, CDCl3) δ 7.66 (d, J J = 9.4 Hz, 1H), 7.42 – 7.28 (m, 5H), 5.90 (ddt, J J = 17.3, 10.4, 5.9 Hz, 1H), 5.33 (dd, J J = 17.2, 1.5 Hz, 1H), 5.23 (dd, J J = 10.4, 1.3 Hz, 2H), 5.14 (d, J J = 12.1 Hz, 1H), 4.63 – 4.51 (m, 3H), 4.24 (tt, J J = 6.3, 3.1 Hz, 1H), 3.58 (dd, J J = 6.8, 4.3 Hz, 3H), 2.13 – 2.03 (m, 1H), 1.88 – 1.81 (m, 1H), 1.74 – 1.67 (m, 1H), 1.60 (s, 1H), 1.17 (d, J J = 6.3 Hz, 3H), 1.13 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 171.7, 170.3, 155.5, 136.6, 131.7, 128.5, 128.1, 118.9, 74.0, 67.6, 67.2, 65.9, 58.8, 57.9, 44.8, 28.4, 27.0, 22.4, 20.9. = -20.000 ( c 1.0, CHCl3). HRMS (ESI) for C 24 18 35 H + N3NaO6 + [M + Na]

[0202] Example 15:

[0203]

[0204] Compound 16 (2.00 g, 4.34 mmol, 1.00 equiv.) was dissolved in dichloromethane (400 mL, 0.01 M), 80 mL of saturated sodium bicarbonate solution was added, and Fmoc-Me-D-alanine (8.58 g, 26.00 mmol, 6.00 equiv.) prepared as acid chloride was added under ice bath and stirred at room temperature for overnight reaction. After TLC monitoring confirmed that compound 16 was completely converted, it was extracted with ethyl acetate (3 × 50 mL), and the combined organic phases were dried and filtered with anhydrous sodium sulfate solid. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain white solid 17 (1.80 g, 2.39 mmol) with a yield of 67%.

[0205] TLC: R f = 0.3 (petroleum ether / ethyl acetate = 2 / 1), UV fluorescence & potassium permanganate color development. 1 H NMR (400MHz, CDCl3) δ 7.77 (d, J = 7.5 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 7.47 – 7.26 (m,9H), 5.87 (s, 1H), 5.35 – 5.12 (m, 4H), 4.70 – 4.16 (m, 9H), 2.81 (d, J = 259.7Hz, 2H), 1.84 (s, 3H), 1.57 (d, J = 12.5 Hz, 1H), 1.35 (t, J = 5.9 Hz, 3H), 1.14(d, J = 23.7 Hz, 12H). 13 C NMR(101 MHz, CDCl3) δ 174.9, 170.1, 169.7, 156.4,144.1, 143.9, 141.3, 141.3, 135.4, 131.8, 128.6, 128.3, 128.0, 127.7, 127.1,125.2, 120.0, 118.6, 73.9, 69.5, 66.9, 65.8, 58.7, 47.6, 47.2, 46.7, 29.7,28.3, 21.0, 20.3, 19.5. = -11.068 ( c 1.0, CHCl3).HRMS(ESI,m / z ) forC 42 H 50 N4NaO9 + [M + Na] + : Calcd. 777.3578; Found: 777.3569.

[0206] Embodiment 16:

[0207]

[0208] Compound 17 (3.20 g, 4.68 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (370 mL, 0.01 M) and added N -methylaniline (3.30 mL, 9.36 mmol, 2.00 equiv.) was added and then pierced with a nitrogen balloon for ultrasonic ventilation. At the same time, tetrakistriphenylphosphine palladium (1772.00 mg, 0.47 mmol, 0.10 equiv.) was weighed and dissolved in tetrahydrofuran (20 mL, 0.3 M) and then pierced with a nitrogen balloon for ultrasonic ventilation. The solution containing tetrakistriphenylphosphine palladium was then transferred to a reaction bottle and stirred at room temperature for 3 hours. After TLC monitoring confirmed that compound 17 was completely converted, the solution was concentrated under reduced pressure by a vacuum pump. After dilution with ethyl acetate, 1 N hydrochloric acid was added to the reaction solution to adjust the pH to neutral. Ethyl acetate (3 × 50 mL) was added for extraction, and the combined organic phases were dried over anhydrous sodium sulfate solid. After drying, the product was filtered through a sand core funnel, and the filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a white solid 18 (3.18 g, 4.45 mmol) with a yield of 98%.

[0209] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 3 / 2), potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 9.4 Hz, 1H), 7.42 – 7.28 (m, 5H), 5.90 (ddt, J =17.3, 10.4, 5.9 Hz, 1H), 5.33 (dd, J = 17.2, 1.5 Hz, 1H), 5.23 (dd, J = 10.4, 1.3Hz, 2H), 5.14 (d, J= 12.1 Hz, 1H), 4.63 – 4.51 (m, 3H), 4.24 (tt, J = 6.3, 3.1Hz, 1H), 3.58 (dd, J = 6.8, 4.3 Hz, 3H), 2.13 – 2.03 (m, 1H), 1.88 – 1.81 (m,1H), 1.74 – 1.67 (m, 1H), 1.60 (s, 1H), 1.17 (d, J = 6.3 Hz, 3H), 1.13 (s, 9H). 13 C NMR(101 MHz, CDCl3) δ 171.7, 170.3, 155.5, 136.6, 131.7, 128.5, 128.1,118.9, 74.0, 67.6, 67.2, 65.9, 58.8, 57.9, 44.8, 28.4, 27.0, 22.4, 20.9. =-20.000 ( c 1.0, CHCl3).HRMS(ESI, m / z ) for C 24 H 35 N3NaO6 + [M + Na] + : Calcd. 484.2526;Found: 484.2577.

[0210] Embodiment 17:

[0211]

[0212] Compound 27 (4.57 g, 0.03 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (150 mL, 0.02 M) and added N-methylaniline (1.63 mL, 4.62 mmol, 2.00 equiv.) was added and then pierced with a nitrogen balloon for ultrasonic ventilation. At the same time, tetrakistriphenylphosphine palladium (867.00 mg, 0.23 mmol, 0.10 equiv.) was weighed and dissolved in tetrahydrofuran (10 mL, 0.3 M) and then pierced with a nitrogen balloon for ultrasonic ventilation. The solution containing tetrakistriphenylphosphine palladium was then transferred to a reaction bottle and stirred at room temperature for 3 hours. After TLC monitoring confirmed that compound 27 was completely converted, the mixture was concentrated under reduced pressure by a vacuum pump. After dilution with ethyl acetate, 1 M hydrochloric acid was added to the reaction solution to adjust the pH to neutral. Ethyl acetate (3 × 50 mL) was added for extraction, and the combined organic phases were dried over anhydrous sodium sulfate solid. After drying, the product was filtered using a sand core funnel, and the filtrate was concentrated under reduced pressure using a vacuum pump to obtain a crude product, which was separated using silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a white solid 28 (4.10 g, 9.40 mmol) with a yield of 98%.

[0213] TLC: R f = 0.3 (thin layer silica gel plate, dichloromethane / methanol = 15 / 1), UV fluorescence & phosphomolybdic acid color development.

[0214] Embodiment 18:

[0215]

[0216] Compound 18 (2.53 g, 3.54 mmol, 1.00 equiv.) was dissolved in ethyl acetate (500 mL, 0.007 M), 20% palladium hydroxide on carbon (373.00 mg, 0.53 mmol, 0.15 equiv.) was added, and the mixture was pierced with a hydrogen balloon for ultrasonic ventilation and stirred at room temperature for 7 hours. After TLC monitoring confirmed that compound 18 was completely converted, the reaction solution was filtered through diatomaceous earth to remove excess palladium on carbon, and then concentrated under reduced pressure with a vacuum pump to obtain a crude product. Silica gel column chromatography (dichloromethane / methanol = 10 / 1) was used to separate the crude product, and 19 (1.60 g, 2.76 mmol) was obtained as a white solid with a yield of 80%.

[0217] TLC: R f = 0.3 (thin layer silica gel plate, dichloromethane / methanol = 10 / 1), UV fluorescence & potassium permanganate color development. 1 HNMR(400 MHz, CDCl3) δ 8.49 (s, 1H), 7.74 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 7.5Hz, 2H), 7.37 (t, J= 7.4 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.01 (d, J = 8.4 Hz,1H), 5.28 – 5.12 (m, 2H), 4.58 – 4.13 (m, 6H), 3.06 (d, J = 13.6 Hz, 1H), 2.73(t, J = 12.3 Hz, 1H), 2.33 (d, J = 10.9 Hz, 1H), 1.75 (d, J = 8.2 Hz, 2H), 1.55 (s,1H), 1.39 (d, J = 6.9 Hz, 3H), 1.12 (s, 12H). 13 C NMR(101 MHz, CDCl3) δ 175.3,171.0, 155.9, 143.9, 141.3, 127.7, 127.7, 127.1, 125.2, 119.9, 75.2, 66.9,66.6, 51.5, 50.7, 47.4, 47.3, 47.1, 28.1, 24.5, 21.1, 20.2, 18.8. = -74.840 ( c 0.5, CHCl3).HRMS(ESI, m / z ) for C 31 H 40 N4NaO7 + [M + Na] + : Calcd. 603.2897;Found: 603.2901.

[0218] Example 19:

[0219]

[0220] Peptide imide phenylselenide (7.61 g, 3.54 mmol, 6.00 equiv.), 4-methylbenzenesulfonate pyridine (1.05 g, 3.54 mmol, 1.00 equiv.) and anhydrous sodium sulfate (1.20 g, 3.54 mmol, 2.00 equiv.) were weighed into a reaction bottle, evacuated and replaced with nitrogen three times, dissolved in dry dichloromethane (300 mL, 0.04 M), and compound 20 (1.90 g, 3.54 mmol, 1.00 equiv.) was added and stirred at room temperature overnight. After TLC monitoring confirmed that compound 20 was completely converted, saturated sodium bicarbonate solution (50 mL) and ethyl acetate (3 × 100 mL) were added for extraction, and then dried over anhydrous sodium sulfate solid and filtered. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a white solid 21 (5.60 g, 9.21 mmol) with a yield of 95%.

[0221] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 5 / 1), UV fluorescence & potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.5 Hz, 2H), 7.42 – 7.22 (m, 4H), 7.00(s, 1H), 6.89 (s, 1H), 6.07 (s, 1H), 3.77 (dd, J = 9.9, 6.5 Hz, 1H), 3.61 (s,3H), 2.78 (dd, J = 12.8, 6.5 Hz, 1H), 2.28 (dd, J = 12.8, 9.9 Hz, 1H), 1.52 (d, J =45.3 Hz, 18H). 13 C NMR (101 MHz, CDCl3) δ 171.7, 153.4, 152.7, 138.0, 137.4,130.8, 129.8, 129.5, 126.7, 126.4, 121.6, 84.1, 82.3, 58.7, 52.3, 37.8, 28.4,28.2. = -66.2 (c 0.10, CHCl3).HRMS(ESI, m / z ) for C 28 H 33ClN2O6SeNa + [M + Na] + :Calcd. 631.1192; Found: 631.1201.

[0222] Embodiment 20:

[0223]

[0224] Compound 21 (5.60 g, 3.54 mmol, 1.00 equiv.) was dissolved in dichloromethane (500 mL, 0.016 M), and m-chloroperbenzoic acid (16.10 g, 3.54 mmol, 10.00 equiv.) was added under ice bath and stirred overnight at room temperature. After TLC monitoring confirmed that compound 21 was completely converted, saturated sodium thiosulfate solution (30 mL) was added to quench, saturated sodium bicarbonate solution (50 mL) and ethyl acetate (3 × 100 mL) were added to extract, the organic phase was washed once with saturated sodium chloride solution (50 mL), and then dried with anhydrous sodium sulfate solid and filtered. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 63% yellow solid 22 (2.70 g, 5.76 mmol).

[0225] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 2 / 1), UV fluorescence & potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 8.1, 1.2 Hz, 1H), 7.29 (dd, J = 7.5, 1.1Hz, 1H), 7.14 (t, J = 7.7 Hz, 1H), 5.93 (s, 1H), 3.79 (dd, J = 10.4, 6.7 Hz, 1H), 3.74 (s, 3H), 2.74 (dd, J = 12.6, 6.7 Hz, 1H), 2.39 (dd, J = 12.6, 10.4 Hz, 1H),1.49 (d, J = 24.2 Hz, 18H). 13C NMR(101 MHz, CDCl3) δ 172.3, 152.5, 140.8, 136.7,132.1, 126.8, 121.6, 84.4, 83.8, 82.5, 81.5, 58.4, 52.4, 29.7, 28.4, 28.2. = -95.9 ( c 0.60, CHCl3).HRMS(ESI, m / z ) for C 22 H 29 ClN2O7 + [M + H] + : Calcd.469.1663; Found: 469.1646.

[0226] Embodiment 21:

[0227]

[0228] Compound 22 (2.70 g, 3.54 mmol, 1.00 equiv.) was dissolved in THF:H2O=3:1 (60 mL, 0.1 M), and lithium hydroxide (1.07 g, 3.54 mmol, 5.00 equiv.) was added at 0°C and stirred overnight at room temperature. After TLC monitoring confirmed that compound 22 was completely converted, it was concentrated under reduced pressure by a vacuum pump, acidified to pH=2 with 1M HCl, extracted with ethyl acetate (3 × 100 mL), and the organic phase was washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate solid and filtered. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was directly used in the next step without purification.

[0229] The crude product obtained in the previous step (684.00 mg, 3.54 mmol, 1.00 equiv.) was dissolved in N,N-dimethylformamide (20 mL, 0.07 M), sodium bicarbonate (1.52 g, 3.54 mmol, 12.00 equiv.) and allyl bromide (0.78 mL, 3.54 mmol, 6.00 equiv.) were added at 0°C, and stirred at room temperature overnight. After TLC monitoring confirmed that the raw material was completely converted, saturated sodium bicarbonate solution (30 mL) was added to quench, and after extraction with ethyl acetate (2 × 100 mL), the organic phase was washed with saturated lithium chloride solution (2 × 100 mL), and then dried over anhydrous sodium sulfate solid and filtered. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain 77% white solid 23 (580.00 mg, 1.71 mmol).

[0230] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 4 / 1), UV fluorescence & potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 6.6 Hz, 1H),7.12 (t, J = 7.7 Hz, 1H), 5.91 (s, 1H), 5.31 (dd, J = 17.2, 1.6 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H), 4.68 – 4.54 (m, 2H), 3.78 (dd, J = 10.4, 6.7 Hz, 1H), 3.20 (s,1H), 2.74 (dd, J = 12.5, 6.7 Hz, 1H), 2.42 – 2.33 (m, 1H), 1.47 (d, J = 22.8 Hz,18H). 13 C NMR(101 MHz, CDCl3) δ 171.5, 152.6, 140.7, 136.7, 132.0, 131.7,126.8, 126.7, 121.7, 118.7, 84.3, 83.7, 82.5, 81.5, 66.0, 58.5, 28.4, 28.2. = -108.2 ( c 0.50, CHCl3).HRMS(ESI,m / z ) for C 24 H 31 ClN2O7 + [M + H] + : Calcd.495.1820; Found: 495.1825.

[0231] Embodiment 22:

[0232]

[0233] Compound 23 (580.00 mg, 3.54 mmol, 1.00 equiv.) was dissolved in N,N -dimethylformamide (50 mL, 0.02 M), triethylsilyl chloride (1.20 mL, 3.54 mmol, 6.00 equiv.) and bicyclic amidine (2.10 mL, 3.54 mmol, 12.00 equiv.) were added in sequence and heated to 50 °C for overnight reaction. After TLC monitoring confirmed that compound 23 was completely converted, saturated sodium chloride solution (50 mL) and ethyl acetate (2 × 100 mL) were added for extraction, and then saturated lithium chloride solution (2 × 100 mL) was added for washing, and then dried with anhydrous sodium sulfate solid and filtered. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to obtain 80% colorless oily liquid 24 (585.00 mg, 1.00 mmol).

[0234] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 6 / 1), UV fluorescence & potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.0 Hz, 1H), 7.25 (dd, J = 7.5, 1.1 Hz,1H), 7.12 (t, J = 7.7 Hz, 1H), 5.99 – 5.84 (m, 2H), 5.38 – 5.22 (m, 2H), 4.72 –4.58 (m, 2H), 3.77 (dd, J = 10.8, 6.5 Hz, 1H), 2.76 (dd, J = 12.2, 6.5 Hz, 1H),2.38 (t, J = 11.5 Hz, 1H), 1.51 (d, J= 19.2 Hz, 18H), 0.83 (t, J = 7.9 Hz, 9H),0.53 – 0.40 (m, 6H). 13 C NMR(101 MHz, CDCl3) δ 171.2, 153.8, 152.1, 141.1,137.2, 131.8, 126.9, 126.2, 122.0, 118.5, 85.3, 84.8, 82.0, 65.9, 58.7, 38.0,28.4, 28.1, 6.6, 5.9. = -116.4 ( c 0.30, CHCl3).HRMS(ESI, m / z ) forC 30 H 45 ClN2O7Si + [M + H] + : Calcd. 609.2685; Found: 609.2681.

[0235] Embodiment 23:

[0236]

[0237] Compound 24 (714.00 mg, 3.54 mmol, 1.00 equiv.) was dissolved in dichloromethane (30 mL, 0.035 M), and 2,3-dimethylpyridine (1.60 mL, 3.54 mmol, 12.00 equiv.) and triethylsilyl trifluoromethanesulfonate (2.12 mL, 3.54 mmol, 8.00 equiv.) were added in an ice bath, and the mixture was stirred at room temperature for 3 hours. After TLC monitoring confirmed that compound 24 was completely converted, saturated sodium bicarbonate solution (30 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3× 100 mL), dried with anhydrous sodium sulfate solid, and filtered. The filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 78% yellow oily liquid 25 (370.00 mg, 0.97 mmol).

[0238] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 5 / 1), UV fluorescence & potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.15 – 7.09 (m, 2H), 6.69 (t, J= 7.7 Hz, 1H), 5.94– 5.83 (m, 1H), 5.34 – 5.22 (m, 2H), 5.06 (s, 1H), 4.67 – 4.58 (m, 2H), 3.74(dd, J = 9.2, 6.3 Hz, 1H), 2.59 – 2.54 (m, 1H), 2.43 (dd, J = 12.3, 9.3 Hz, 1H),0.83 (t, J = 7.9 Hz, 9H), 0.49 – 0.32 (m, 6H). 13 C NMR(101 MHz, CDCl3) δ 173.0,146.8, 132.0, 131.7, 129.4, 122.8, 119.5, 118.7, 114.8, 91.9, 84.1, 65.7,59.2, 46.9, 6.8, 5.8. = -114.53 ( c 0.34, CHCl3).HRMS(ESI, m / z ) forC 20 H 29 ClN2O3SiNa + [M + Na] + : Calcd. 431.1636; Found: 431.1611.

[0239] Embodiment 24:

[0240]

[0241] Compound 13 (2.25 g, 0.03 mmol, 1.00 equiv.) and silver cyanide (2.00 g, 0.03mmol, 2.00 equiv.) were dissolved in methanol (148 mL, 0.05 M) and 26 (7.61 g, 0.03 mmol, 3.00 equiv.) was added under ice bath, and the mixture was stirred in oil bath for 2 hours. After TLC monitoring confirmed that compound 13 was completely converted, the reaction solution was filtered through diatomaceous earth, the filtrate was quenched with saturated sodium bicarbonate solution, and ethyl acetate (3 × 50 mL) was added for extraction. The organic phases were combined, dried and filtered with anhydrous sodium sulfate solid, and concentrated under reduced pressure by vacuum pump to obtain the crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 89% colorless transparent liquid 27 (4.57 g, 7.50 mmol).

[0242] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 2 / 1), UV fluorescence & phosphomolybdic acid color development. 1 HNMR (400 MHz, CDCl3) δ 7.78 (t, J = 7.0 Hz, 2H), 7.66 – 7.23 (m, 11H), 5.95 (d, J = 6.2 Hz, 1H), 5.39 – 5.14 (m, 4H), 4.79 – 3.95 (m, 7H), 3.25 – 1.54 (m, 9H), 1.38 – 1.21 (m, 3H). 13 C NMR(101 MHz, CDCl3) δ 172.4, 169.1, 156.2, 155.9,144.0, 141.4, 135.5, 131.9, 128.7, 128.4, 128.1, 127.7, 127.1, 125.1, 120.0,118.5, 118.4, 67.8, 67.6, 67.0, 66.0, 65.9, 50.2, 47.3, 29.3, 22.9, 15.2,14.7. = -17.945 ( c 1.0, CHCl3).HRMS(ESI, m / z ) for C 35 H 37 N3O7C 20 + [M + H] + :Calcd. 612.2632; Found: 612.2662.

[0243] Embodiment 25:

[0244]

[0245] Compound 27 (4.57 g, 0.03 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (150 mL, 0.02 M) and added N-methylaniline (1.63 mL, 4.62 mmol, 2.00 equiv.) was added and then pierced with a nitrogen balloon for ultrasonic ventilation. At the same time, tetrakistriphenylphosphine palladium (867.00 mg, 0.23 mmol, 0.10 equiv.) was weighed and dissolved in tetrahydrofuran (10 mL, 0.3 M) and then pierced with a nitrogen balloon for ultrasonic ventilation. The solution containing tetrakistriphenylphosphine palladium was then transferred to a reaction bottle and stirred at room temperature for 3 hours. After TLC monitoring confirmed that compound 27 was completely converted, the mixture was concentrated under reduced pressure by a vacuum pump. After dilution with ethyl acetate, 1 M hydrochloric acid was added to the reaction solution to adjust the pH to neutral. Ethyl acetate (3 × 50 mL) was added for extraction, and the combined organic phases were dried over anhydrous sodium sulfate solid. After drying, the product was filtered using a sand core funnel, and the filtrate was concentrated under reduced pressure using a vacuum pump to obtain a crude product, which was separated using silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a white solid 28 (4.10 g, 9.40 mmol) with a yield of 98%.

[0246] TLC: R f = 0.3 (thin layer silica gel plate, dichloromethane / methanol = 15 / 1), UV fluorescence & phosphomolybdic acid color development. 1 HNMR (400 MHz, CDCl3) δ 7.80 – 7.05 (m, 13H), 5.29 – 4.14 (m, 7H), 3.41 – 2.75 (m, 3H), 2.06 (s, 2H), 1.96 – 0.88 (m, 7H). 13 C NMR (101 MHz, CDCl3) δ 176.6,156.3, 155.0, 143.8, 141.4, 141.3, 128.7, 128.1, 127.8, 127.7, 127.2, 127.1,125.0, 120.0, 68.9, 68.0, 67.7, 67.0, 50.6, 47.2, 29.4, 20.8, 14.9, 14.2,13.7. = -8.030 ( c 1.0, CHCl3).HRMS(ESI, m / z ) for C 32 H 33 N3O7 + [M + H] + : Calcd.572.2319; Found: 572.2331.

[0247] Embodiment 26:

[0248]

[0249] Compound 28 (2.30 g, 3.54 mmol, 1.00 equiv.) was dissolved in ethyl acetate (575 mL, 0.007 M), 20% palladium hydroxide on carbon (395 mg, 0.53 mmol, 0.14 equiv.) was added, and the mixture was pierced with a hydrogen balloon for ultrasonic ventilation and stirred at room temperature for 7 hours. After TLC monitoring confirmed that compound 28 was completely converted, the reaction solution was filtered through diatomaceous earth to remove excess palladium on carbon, and then concentrated under reduced pressure with a vacuum pump to obtain a crude product. Silica gel column chromatography (dichloromethane / methanol = 10 / 1) was used to separate the crude product to obtain 29 (1.80 g, 4.11 mmol) as a colorless oily liquid with a yield of 90%.

[0250] TLC: R f = 0.3 (thin layer silica gel plate, dichloromethane / methanol = 10 / 1), UV fluorescence & phosphomolybdic acid color development. 1 HNMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 13.2 Hz, 2H), 7.36(d, J = 7.5 Hz, 2H), 7.30 (dd, J = 7.5, 1.3 Hz, 2H), 5.57–5.18 (m, 2H), 4.54–4.33(m, 2H), 4.23 (d, J = 4.2 Hz, 1H), 2.90 (d, J = 32.0 Hz, 3H), 2.77–2.56 (m, 1H), 2.24 (d, J = 5.4 Hz, 1H), 2.07 (s, 1H), 1.81 (t, J = 6.2 Hz, 1H), 1.54 (s, 2H), 1.34 (d, J = 7.1 Hz, 2H), 1.27–1.21 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 175.0,173.3, 157.0, 144.2, 143.9, 141.3, 141.2, 127.5, 127.0, 125.1, 119.8, 67.6,52.1, 47.1, 29.7, 22.1, 14.8, 14.1. = -19.526 ( c 0.5, CHCl3).HRMS(ESI, m / z )for C 24 H 27 N3O5Na + [M + Na] + : Calcd. 460.1951; Found: 460.2011.

[0251] Embodiment 27:

[0252]

[0253] Compound 25 (1.00 g, 4.94 mmol, 1.00 equiv.), 29 (1.80 g, 7.34 mmol, 1.70 equiv.) and 1-hydroxy-7-azobenzotriazole (2.06 g, 14.70 mmol, 6.20 equiv.) were dissolved in dichloromethane (60 mL, 0.04 M) and cooled to 0 °C. Then 2,4,6-trimethylpyridine (3.04 mL, 29.40 mmol, 9.40 equiv.) and O -(7-nitrobenzotriazole)- N,N,N',N' -Tetramethyluronium hexafluorophosphate (5.58 g, 7.34 mmol, 6.00 equiv.) was stirred at room temperature under nitrogen protection overnight. After TLC monitoring confirmed that compound 25 was completely converted, it was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain a colorless oily liquid 30 (1.50 g, 1.81 mmol) with a yield of 75%.

[0254] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 4 / 1), UV fluorescence & potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.77–7.03 (m, 10H), 6.65 (s, 1H), 5.91 (d, J = 5.7Hz, 1H), 5.59–4.23 (m, 12H), 3.19–2.90 (m, 2H), 2.79 (d, J = 16.8 Hz, 3H),2.44–2.18 (m, 2H), 1.63 (s, 4H), 1.27 (d, J = 11.9 Hz, 3H), 0.81 (t,J = 7.9 Hz,9H), 0.58–0.22 (m, 6H). 13 C NMR(101 MHz, CDCl3) δ 174.2, 172.7, 171.4, 144.1,144.0, 141.3, 131.7, 131.5, 129.3, 127.6, 127.0, 127.0, 125.2, 125.1, 121.4,119.9, 119.5, 118.9, 88.4, 85.1, 67.5, 66.3, 59.8, 58.9, 51.6, 47.7, 45.4,29.9, 29.7, 24.2, 19.7, 14.6, 6.7, 5.9. = -279.93 ( c 0.1, CHCl3).HRMS(ESI, m / z ) for C 44 H 54 ClN5O7SiNa + [M + Na] + : Calcd. 850.3481; Found: 850.3460.

[0255] Embodiment 28:

[0256]

[0257] Compound 30 (80.00 mg, 4.94 mmol, 1.00 equiv.), 19 (138.00 mg, 7.34 mmol, 1.80 equiv.) and 1-hydroxy-7-azobenzotriazole (54.00 mg, 14.70 mmol, 3.00 equiv.) were dissolved in dichloromethane (33 mL, 0.004 M) and cooled to 0 °C. Then 2,4,6-trimethylpyridine (0.11 mL, 29.40 mmol, 16.00 equiv.) and O -(7-nitrobenzotriazole)- N,N,N',N' -Tetramethyluronium hexafluorophosphate (100.00 mg, 7.34 mmol, 2.00 equiv.) was stirred at room temperature under nitrogen protection overnight. After TLC monitoring confirmed that compound 30 was completely converted, it was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to obtain a white solid 31 (93.00 mg, 0.08 mmol) with a yield of 64%.

[0258] TLC: R f = 0.3 (thin layer silica gel plate, petroleum ether / ethyl acetate = 6 / 1), UV fluorescence & potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 4.5 Hz, 2H),7.41 – 7.27 (m, 4H), 7.08 (d, J = 12.4 Hz, 2H), 6.93 – 6.78 (m, 1H), 6.71 –6.60 (m, 1H), 5.91 (dd, J = 11.2, 5.8 Hz, 1H), 5.69 – 5.52 (m, 2H), 5.38 – 4.84(m, 8H), 4.71 – 4.53 (m, 3H), 4.50 – 4.25 (m, 3H), 4.25 – 4.16 (m, 1H), 3.08(d, J = 14.2 Hz, 3H), 2.82 (d, J = 26.0 Hz, 6H), 2.66 – 1.93 (m, 8H), 1.24 (s,12H), 1.01 (d, J = 30.5 Hz, 6H), 0.80 (t, J = 7.8 Hz, 9H), 0.48 – 0.33 (m, 6H). 13 CNMR(101 MHz, CDCl3) δ 172.4, 171.4, 171.3, 170.7, 169.5, 155.4, 144.2, 144.0,141.3, 141.3, 131.5, 129.3, 127.6, 127.0, 125.3, 121.3, 119.9, 119.1, 119.0,114.8, 114.8, 88.4, 85.0, 74.4, 70.5, 67.7, 66.4, 59.8, 55.4, 54.4, 51.9,47.2, 45.4, 38.6, 31.9, 29.7, 28.0, 22.7, 20.6, 19.5, 17.1, 15.0, 14.1, 6.7,5.9. = -50.475 ( c0.2, CHCl3).HRMS(ESI, m / z ) for C 60 H 82 ClN9O 11 NaSi + [M + Na] + :Calcd. 1190.5592; Found: 1190.5721.

[0259] Embodiment 29:

[0260]

[0261] Compound 31 (60.00 mg, 0.03 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (5 mL, 0.02 M) and added N -methylaniline (0.02 mL, 4.62 mmol, 2.00 equiv.) was added and then pierced with a nitrogen balloon for ultrasonic ventilation. At the same time, tetrakistriphenylphosphine palladium (14.40 mg, 0.23 mmol, 0.15 equiv.) was weighed and dissolved in tetrahydrofuran (1 mL, 0.1 M) and then pierced with a nitrogen balloon for ultrasonic ventilation. The solution containing tetrakistriphenylphosphine palladium was then transferred to a reaction bottle and stirred for reaction at room temperature for 3 hours. After TLC monitoring confirmed that compound 31 was completely converted, the solution was concentrated under reduced pressure by a vacuum pump. After dilution with ethyl acetate, 1 M hydrochloric acid was added to the reaction solution to adjust the pH to neutral. Ethyl acetate (3 × 50 mL) was added for extraction, and the combined organic phases were dried over anhydrous sodium sulfate solid. After drying, the product was filtered through a sand core funnel, and the filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 40) to obtain a colorless liquid 32 (41.00 mg, 0.04 mmol) with a yield of 71%.

[0262] TLC: R f = 0.3 (petroleum ether / ethyl acetate = 1 / 40), UV fluorescence & potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J= 7.4 Hz, 2H), 7.70 – 7.51 (m, 3H), 7.42 – 7.33(m, 2H), 7.33 – 7.24 (m, 2H), 7.23 – 7.03 (m, 2H), 6.83 – 6.64 (m, 1H), 5.29(s, 1H), 5.26 – 4.85 (m, 5H), 4.84 – 4.25 (m, 5H), 4.25 – 3.90 (m, 2H), 3.29– 3.01 (m, 3H), 2.94 – 2.58 (m, 4H), 2.57 – 2.25 (m, 2H), 2.23 – 1.40 (m,8H), 1.36 – 1.23 (m, 6H), 1.24 – 0.90 (m, 12H), 0.78 (qd, J = 8.0, 2.0 Hz, 9H),0.61 – 0.11 (m, 6H). 13 C NMR(101 MHz, CDCl3) δ 156.0, 144.2, 144.0, 141.3,135.4, 135.3, 135.3, 133.9, 133.8, 133.7, 133. 6, 130.6, 130.5, 130.2, 127.6,127.1, 125.3, 122.5, 121.6, 119.9, 90.2, 82.1, 74.9, 74.6, 67.0, 53.5, 47.5,47.2, 32.0, 31.5, 30.2, 29.7, 28.2, 22.7, 21.2, 19.3, 19.1, 14.4, 14.2, 6.7,1.0.HRMS(ESI, m / z ) for C 57 H 78 ClN9O 11 NaSi + [M + Na] + : Calcd. 1150.5279; Found:1150.5265.

[0263] Example 30:

[0264]

[0265] Compound 32 (48.00 mg, 0.04 mmol, 1.00 equiv.) was dissolved in acetonitrile (2 mL, 0.005M) and cooled to 0 °C, and diethylamine (0.09 mL, 177.65 mmol, 20.00 equiv.) was added, and the reaction was stirred at room temperature for 3 hours. After TLC monitoring confirmed that compound 32 was completely converted, it was concentrated under reduced pressure by a vacuum pump to obtain a crude product, and separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain colorless liquid 33 (34.00 mg, 0.04 mmol) with a yield of 89%.

[0266] TLC: R f = 0.3 (thin layer silica gel plate, dichloromethane / methanol = 10 / 1), UV fluorescence & potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.24 – 7.13 (m, 2H), 6.83 (d, J 0.81 (td, J = 7.9, 4.6 Hz, 9H), 0.40 – 0.25 (m, 6H). 13 C NMR(101 MHz, CDCl3) δ 130.1, 123.5, 122.7, 121.5, 74.6, 74.4, 53.5, 52.8,47.4, 46.9, 31.9, 31.5, 30.1, 29.7, 28.6, 28.2, 28.1, 22.7, 21.3, 19.6, 16.7, 15.0, 14.4, 6.8, 6.7, 5.7, 1.0.HRMS(ESI, m / z ) for C 42 H 68 ClN9O9NaSi + [M + Na] + :Calcd. 928.4598; Found: 928.4588.

[0267] Embodiment 31:

[0268]

[0269] Compound 33 (34.00 mg, 4.94 mmol, 1.00 equiv.) and 1-hydroxy-7-azobenzotriazole (41.70 mg, 14.70 mmol, 8.00 equiv.) were dissolved in dichloromethane (10 mL, 0.005 M) and cooled to 0°C, followed by the addition of 2,4,6-trimethylpyridine (0.11 mL, 29.40 mmol, 16.00 equiv.) and O -(7-nitrobenzotriazole)- N,N,N',N' -Tetramethyluronium hexafluorophosphate (58.30 mg, 7.34 mmol, 4.00 equiv.) was stirred at room temperature under nitrogen protection overnight. After TLC monitoring confirmed that compound 33 was completely converted, it was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (pure ethyl acetate) to obtain colorless liquid 34 (22.00 mg, 0.02 mmol) with a yield of 66%.

[0270] TLC: R f = 0.3 (thin layer silica gel plate, dichloromethane / methanol = 20 / 1), potassium permanganate color development. 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.7 Hz, 1H), 7.16 (dd, J = 8.0, 0.9 Hz, 1H), 7.10(d, J = 7.4 Hz, 1H), 6.70 (t, J = 7.7 Hz, 2H), 6.22 – 6.10 (m, 1H), 5.78 – 5.69(m, 1H), 5.47 (d, J = 4.8 Hz, 1H), 5.36 – 5.28 (m, 1H), 5.19 (d, J = 2.1 Hz, 1H), 5.08 – 5.02 (m, 1H), 4.53 – 4.14 (m, 3H), 3.96 (dd, J = 6.4, 4.2 Hz, 1H), 3.63(s, 1H), 3.09 (s, 3H), 2.98 – 2.89 (m, 1H), 2.79 (d, J = 2.7 Hz, 2H), 2.53 –2.27 (m, 3H), 2.16 – 1.46 (m, 8H), 1.38 – 1.26 (m, 6H), 1.20 (d,J = 17.5 Hz,12H), 0.75 (t, J = 7.9 Hz, 9H), 0.44 – 0.18 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ175.3, 173.6, 172.3, 170.2, 145.9, 130.3, 129.8, 122.3, 119.8, 116.0, 89.0,83.2, 74.7, 66.0, 62.1, 56.1, 54.8, 53.0, 48.2, 48.2, 47.0, 44.9, 39.0, 30.2,29.7, 28.3, 25.9, 25.8, 22.7, 21.8, 20.8, 20.4, 16.8, 14.5, 14.1, 6.7, 5.9. = -31.667 ( c 0.1, MeOH).HRMS(ESI, m / z ) for C 42 H 66 ClN9O8NaSi + [M + Na] + : Calcd.910.4492; Found: 910.4463.

[0271] Embodiment 32:

[0272]

[0273] Synthesis of natural cyclic peptide petrichorin C: Compound 34 (20.00 mg, 4.94 mmol, 1.00 equiv.) was dissolved in HCl in 1,4-dioxane (2 mL, 1 M) and stirred at room temperature under nitrogen protection for 3 hours. After TLC monitoring confirmed that compound 34 was completely converted, it was concentrated under reduced pressure by a vacuum pump to obtain a crude product, which was separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain a colorless liquid compound 35 with a yield of 58%, namely natural cyclic peptide petrichorin C (8 mg, 0.01 mmol). TLC: R f = 0.3 (DCM / MeOH = 10 / 1), color development with potassium permanganate. 1 H NMR (400 MHz, MeOD) δ 7.90 (dd, J = 27.8, 8.9 Hz, 1H), 7.24 (dd, J= 7.6, 5.1 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.56 – 6.27 (m, 1H), 5.51 (t, J = 5.6 Hz, 1H), 5.39 (t, J = 4.7Hz, 1H), 5.22 – 4.49 (m, 4H), 4.20 – 3.52 (m, 3H), 2.86 (s, 3H), 2.35 – 2.04(m, 6H), 1.88 – 1.36 (m, 7H), 1.35 – 1.29 (m, 6H), 1.13 (dd, J = 48.2, 6.6 Hz,3H), 0.92 (t, J = 6.6 Hz, 1H). 13 C NMR(101 MHz, MeOD) δ 173.4, 172.4, 172.2,170.8, 144.5, 133.8, 129.7, 128.7, 121.4, 120.7, 115.4, 90.2, 85.6, 67.0,61.3, 51.2, 51.2, 47.3, 46.8, 45.8, 39.8, 35.3, 22.4, 20.9, 18.3, 16.7, 14.0,13.5. = -71.250 ( c 0.1, MeOH).HRMS(ESI, m / z ) for C 32 H 44 ClN9NaO8 + [M + Na] + :Calcd.740.3001; Found: 740.2994.

[0274] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a natural cyclic peptide petrichorin C, characterized in that the steps include: S1, converting compound 1 into compound 29 through multiple steps of reaction; The step S1 comprises: S1.1, introducing a bromine group and a benzyloxycarbonylamino group into the compound 1, and then performing an internal ring closure reaction to obtain a compound 6; S1.2, removing the protecting group in the compound 6, and then introducing an allyl group to obtain compound 13; S1.3, performing a peptide grafting reaction on the compound 13 and the compound 26 to obtain the compound 27; S1.4, removing the allyl ester and the protecting group from the compound 27 to obtain the compound 29; S2, compound 20 undergoes a cyclization reaction and is then converted into compound 25; The step S2 comprises: S2.1, adding N-phenylselenophthalamide and pyridine p-toluenesulfonate to the compound 20 to carry out a cyclization reaction to generate a compound 21; S2.2, adding m-chloroperbenzoic acid to the compound 21 to carry out an oxidation reaction to generate a compound 22; S2.3, placing the compound 22 in an acidic environment, adding lithium hydroxide to react, and then reacting with sodium bicarbonate and allyl bromide after the reaction is completed to obtain compound 23; S2.4, converting the tertiary alcohol group in the compound 23 into triethylsilyl ether to obtain compound 24; S2.5, placing the compound 24 in an acidic environment and removing the protecting group to obtain compound 25; S3, the compound 25 and the compound 29 undergo a dehydration condensation reaction to generate a compound 30; S4, converting compound 14 into compound 19, and subjecting compound 19 and compound 30 to coupling reaction to obtain compound 35, wherein compound 35 is a natural cyclic peptide petrichorin C; The step S4 comprises: S4.1, the compound 14 is subjected to a dehydration condensation reaction with threonine allyl ester to obtain compound 15; S4.2, the compound 15 is subjected to multi-step treatment and peptide grafting reaction with alanyl chloride to obtain the compound 19; S4.3, adding a peptide-linking reagent to the compound 19 and the compound 30 to carry out a coupling reaction to obtain a compound 31; S4.4, removing the protecting group in the compound 31 to prepare the compound 35; Wherein, the structural formula of the above compound is as follows: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. The preparation method according to claim 1, characterized in that: The step S1.1 comprises: The compound 1 is subjected to a bromination reaction to obtain a compound 2; Placing the compound 2 in an alkaline environment to perform an oxidation reaction to obtain a compound 3; The compound 3 undergoes an asymmetric nucleophilic addition reaction with azobenzoyloxymethylphenyl chloroformate, and then the aldehyde group in the compound 3 is reduced to a hydroxyl group to obtain compound 4; The hydroxyl group in the compound 4 is converted into tert-butyl dimethylsilyl ether to obtain compound 5; The compound 5 is placed in an alkaline environment to undergo an internal cyclization reaction to obtain the compound 6; Wherein, the structural formula of the above compound is as follows: 、 、 、 。 3. The preparation method according to claim 1, characterized in that: The step S1.2 comprises: Tetrabutylammonium fluoride is added to the compound 6 to remove the tert-butyldimethylsilyl group to obtain compound 7; An oxidant is added to the compound 7 to perform an oxidation reaction to obtain a compound 8, wherein the oxidant comprises at least one of 2,2,6,6-tetramethylpiperidinyl oxide, sodium hypochlorite, and sodium chlorite; Placing the compound 8 in an acidic environment to convert it into compound 9; The bis-benzyloxycarbonyl group in the compound 9 is removed, and a single benzyloxycarbonyl group is introduced to obtain compound 11; The compound 11 is placed in an alkaline environment, the methyl ester in the compound 11 undergoes a hydrolysis reaction, and then the hydrolyzed carboxylic acid is converted into an allyl ester to obtain a compound 13; Wherein, the structural formula of the above compound is as follows: 、 、 、 、 。 4. The preparation method according to claim 1, characterized in that: The step S4.2 comprises: The 9-fluorenylmethoxycarbonyl group in the compound 15 is removed to obtain compound 16; The compound 16 is subjected to a peptide grafting reaction with alanyl chloride to obtain compound 17; Tetrakistriphenylphosphine palladium and nitrogen methyl aniline are added to the compound 17 to remove the allyl ester to obtain compound 18; The compound 18 is placed in a hydrogen atmosphere, and palladium hydroxide on carbon is added to remove the benzyloxycarbonyl group to obtain the compound 19; Wherein, the structural formula of the above compound is as follows: 、 、 。 5. The preparation method according to claim 1, characterized in that: The step S4.4 comprises: The allyl group in the compound 31 is removed to obtain compound 32; Add diethylamine to the compound 32 to remove the 9-fluorenylmethoxycarbonyl group to obtain compound 33; The compound 33 is first subjected to a cyclization reaction, and then the protecting group is removed to obtain compound 35; Wherein, the structural formula of the above compound is as follows: 、 。

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