Valactamide A and method for synthesizing diastereomers

Abstract

The present application belongs to the field of chemical synthesis technology, and in particular, relates to a method for synthesizing Valactamide A and diastereomers. The method comprises the steps of preparing compound 16 and compound ent-16; oxidizing the compound 16 or the compound ent-16 in turn, introducing two chiral methyl groups by a classic asymmetric methylation reaction controlled by an Evans auxiliary group, and then performing a Wittig reaction with a phosphorus ylide reagent, performing an activation treatment with L-valine tert-butyl ester trifluoroacetate, removing the protecting group, and performing a coupling reaction with L-isoleucine containing a protecting group, and performing a ring closure to obtain Valactamide A or its diastereomers. The present application completes the first total synthesis and structural identification of Valactamide A and diastereomers, laying a foundation for the identification of its absolute stereochemical structure and the study of its biological activity.

Description

Technical Field

[0001] The present application belongs to the technical field of chemical synthesis, and in particular relates to a method for synthesizing Valactamide A and diastereoisomers. Background Art

[0002] Valactamide A is a 20-membered macrocyclic lipopeptide natural product isolated from the fungus Aspergillus nidulans reported by NL Kelleher's research group in 2017 (the fungus is not the original mother fungus with the corresponding genetic information of Valactamide A, the original mother fungus is Aspergillus terreu):

[0003] The original one-dimensional structure of Valactamide A. The structure is a twenty-membered macrocyclic ester peptide with eight chiral centers, consisting of two natural amino acid units and one unsaturated fatty hydroxy acid unit, of which five chiral centers have undetermined absolute configurations and are located in the polyketide part, and the remaining chiral centers are located on two natural amino acids.

[0004] There are 5 chiral centers in the Valactamide A molecular structure whose absolute configurations are undetermined, which means that Valactamide A has up to 32 potential possible structures. Therefore, it is a huge challenge to reveal the true stereostructure of Valactamide A through chemical synthesis. In addition, Valactamide A is not naturally expressed in its original mother bacteria, and the sample amount of Valactamide A obtained by the separation team through heterologous expression is only about 0.2 mg. Therefore, the identification of the absolute stereochemical structure of Valactamide A and the study of its biological activity have been seriously hindered. Up to now, there has been no report on the absolute stereochemical structure and biological activity of Valactamide A. Summary of the invention

[0005] The purpose of the present application is to provide a method for synthesizing Valactamide A and its diastereomers, aiming to solve the problem that the prior art lacks a method for synthesizing the absolute stereochemical structure of Valactamide A to a certain extent.

[0006] In order to achieve the above application purpose, the technical solution adopted in this application is as follows:

[0007] In a first aspect, the present application provides a method for synthesizing Valactamide A and diastereomers, comprising the following steps:

[0008] Preparation of compound 16, and compound ent-16,

[0009] The compound 16 and the compound ent-16 are subjected to oxidation treatment respectively to obtain compound 8, and compound ent-8,

[0010] The compound 8 or the compound ent-8 is subjected to Horner-Wordsworth-Emmons olefination reaction and asymmetric methylation reaction with a HWE reagent, and then subjected to reduction treatment and oxidation treatment to obtain compound 20;

[0011] The compound 20 is subjected to Horner-Wordsworth-Emmons olefination reaction and asymmetric methylation reaction with a HWE reagent, and then subjected to reduction treatment and oxidation treatment to obtain compound 6;

[0012] The compound 6 is subjected to a Wittig reaction with a phosphorus ylide reagent to obtain a compound 5;

[0013] The compound 5 is activated with L-valine tert-butyl ester trifluoroacetate to obtain compound 24;

[0014] After removing the protecting group from the compound 24, a coupling reaction is carried out with L-isoleucine containing a protecting group to obtain compound 2;

[0015] Performing a ring-closing treatment on the compound 2 to obtain Valactamide A or a diastereomer of Valactamide A;

[0016] Wherein, the HWE reagent comprises: compound 9, or compound ent-9,

[0017] The compound 20 comprises 20-1, 20-2 or 20-3;

[0018] The compound 6 comprises 6-1, 6-2, or, 6-3;

[0019] The structural formula of the Valactamide A is: RSSSS-1; the diastereomers of Valactamide A include: RSSRR-1 and / or RRRSS-1.

[0020] The Valactamide A and diastereomers provided in the first aspect of the present application are used to prepare compound 16 or ent-16, and then oxidized to obtain compound 8 or ent-8, and then subjected to Horner-Wadsworth-Emmons olefination reaction and asymmetric methylation reaction with HWE reagent, introduce chiral methyl, reduce and remove auxiliary groups, and oxidize the corresponding alcohol to aldehyde to obtain compound 20. Then, compound 20 is treated in the same way to introduce another chiral methyl, reduce and remove auxiliary groups, and oxidize the alcohol to aldehyde to obtain compound 6. Compound 6 and phosphorus ylide reagent are used to construct E-type trisubstituted double bonds through Wittig reaction, and ester groups are introduced to complete the construction of polyketone skeleton to obtain compound 5. Compound 5 and L-valine tert-butyl ester trifluoroacetate are activated and connected to peptide to obtain compound 24. After removing the protecting group, it is coupled with L-isoleucine containing the protecting group to obtain the ring-closing precursor compound 2, and then the product RSSSS-1, RRRSS-1 or RSSRR-1 can be obtained through ring-closing treatment. Through verification, it can be seen that the NMR data of RSSSS-1 is almost completely consistent with the NMR data of natural Valactamide A, indicating that the structure RSSSS-1 is the true stereostructure of the natural product Valactamide A. RRRSS-1 or RSSRR-1 is a diastereomer of Valactamide A. This application completes the first total synthesis and structural identification of Valactamide A and its diastereomers, unveiling the true stereostructure of Valactamide A and laying the foundation for the identification of the absolute stereochemical structure of Valactamide A and the study of its biological activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0022] Figure 1 The synthetic route of RSSSS-1 is provided in Example 1 of the present application;

[0023] Figure 2 Example 2 of the present application provides a synthetic route for RSSRR-1;

[0024] Figure 3 Example 3 of the present application provides a synthetic route of RRRSS-1;

[0025] Figure 4 The present application example 1 provides RSSSS-1 and natural Valactamide A13 C NMR data comparison chart;

[0026] Figure 5 The present application Example 2 provides RSSRR-1 and natural Valactamide A 13 C NMR data comparison chart;

[0027] Figure 6 Example 3 of the present application provides RRRSS-1 and natural Valactamide A 13 C NMR data comparison. DETAILED DESCRIPTION

[0028] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0029] In this application, the term "and / or" describes the association relationship of associated objects, indicating that there may be three relationships. For example, A and / or B can mean: A exists alone, A and B exist at the same time, and B exists alone. A and B can be singular or plural. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0030] In this application, "at least one" means one or more, and "plurality" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single items or plural items. For example, "at least one of a, b or c", or "at least one of a, b and c", can all represent: a, b, c, ab (i.e. a and b), ac, bc, or abc, where a, b, c can be single or multiple, respectively.

[0031] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution, some or all of the steps can be executed in parallel or sequentially, and the execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0032] The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "an" and "the" used in the embodiments of the present application and the appended claims are also intended to include plural forms, unless the context clearly indicates other meanings.

[0033] The weight of the relevant components mentioned in the embodiment description of the present application can not only refer to the specific content of each component, but also represent the proportional relationship between the weights of the components. Therefore, as long as the content of the relevant components is proportionally enlarged or reduced according to the embodiment description of the present application, it is within the scope disclosed in the embodiment description of the present application. Specifically, the mass in the embodiment description of the present application can be μg, mg, g, kg and other mass units known in the chemical industry.

[0034] The terms "first" and "second" are used only for descriptive purposes to distinguish objects such as substances from each other, and should not be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. For example, without departing from the scope of the embodiments of the present application, the first XX may also be referred to as the second XX, and similarly, the second XX may also be referred to as the first XX. Thus, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features.

[0035] The first aspect of the embodiment of the present application provides a method for synthesizing Valactamide A and diastereomers, comprising the following steps:

[0036] S10. Preparation of compound 16, and compound ent-16,

[0037] S20. Compound 16 and compound ent-16 are oxidized to obtain compound 8, and compound ent-8,

[0038] S30. Compound 8 or compound ent-8 is subjected to Horner-Wordsworth-Emmons olefination reaction and asymmetric methylation reaction with HWE reagent, followed by reduction treatment and oxidation treatment to obtain compound 20; wherein the HWE reagent comprises: compound 9, or compound ent-9, Compound 20 includes 20-1, 20-2 or 20-3;

[0039] S40. Compound 20 is subjected to Horner-Wordsworth-Emmons olefination reaction and asymmetric methylation reaction with HWE reagent, and then subjected to reduction treatment and oxidation treatment to obtain compound 6; compound 6 includes 6-1, 6-2, or, 6-3;

[0040] S50. Compound 6 is subjected to a Wittig reaction with a phosphorus ylide reagent to obtain compound 5;

[0041] S60. Activating compound 5 with L-valine tert-butyl ester trifluoroacetate to obtain compound 24;

[0042] S70. After removing the protecting group from compound 24, coupling reaction is carried out with L-isoleucine containing a protecting group to obtain compound 2;

[0043] S80. Performing a ring-closing treatment on compound 2 to obtain Valactamide A or a diastereomer of Valactamide A;

[0044] Among them, the structural formula of Valactamide A is: RSSSS-1; Diastereoisomers of Valactamide A include: RSSRR-1 and / or RRRSS-1.

[0045] Valactamide A and diastereomers provided in the first aspect of the embodiment of the present application are used to prepare compound 16 or ent-16, and then oxidized to obtain compound 8 or ent-8, and then subjected to Horner-Wadsworth-Emmons olefination reaction and asymmetric methylation reaction with HWE reagent, introduce chiral methyl, reduce and remove auxiliary groups, and oxidize the corresponding alcohol to aldehyde to obtain compound 20. Then, compound 20 is treated in the same way to introduce another chiral methyl, reduce and remove auxiliary groups, and oxidize the alcohol to aldehyde to obtain compound 6. Compound 6 and phosphorus ylide reagent are used to construct E-type trisubstituted double bonds through Wittig reaction, and ester groups are introduced to complete the construction of polyketone skeleton to obtain compound 5. Compound 5 and L-valine tert-butyl ester trifluoroacetate are activated and connected to peptide to obtain compound 24. After removing the protecting group, it is coupled with L-isoleucine containing the protecting group to obtain the ring-closing precursor compound 2, and then the product RSSSS-1, RRRSS-1 or RSSRR-1 can be obtained through ring-closing treatment. Through verification, it can be seen that the NMR data of RSSSS-1 is almost completely consistent with the NMR data of natural Valactamide A, indicating that the structure RSSSS-1 is the true stereostructure of the natural product Valactamide A. RRRSS-1 or RSSRR-1 is a diastereomer of Valactamide A. This application completes the first total synthesis and structural identification of Valactamide A and its diastereomers, unveiling the true stereostructure of Valactamide A and laying the foundation for the identification of the absolute stereochemical structure of Valactamide A and the study of its biological activity.

[0046] Based on the reported structure of Valactamide A, the examples of this application narrowed down the possible three-dimensional structures of Valactamide A from thirty-two to one. RSSSS-1. And speculate the possible stereostructure of Valactamide A, narrowed down to RSSRR-1 or RRRSS-1. The present invention uses a retrosynthetic analysis method to determine Valactamide A and its diastereoisomers. The macrocyclic structure contains ester bonds and amide bonds. These two chemical bonds are common ring-closing sites for the synthesis of macrocyclic compounds. Therefore, sites ①, ②, and ③ are usually the preferred ring-closing sites. Because the macrocyclic lactonization of secondary hydroxyl groups usually has a greater risk due to the limited nucleophilicity of hydroxyl groups, we first discard site ①. Choosing site ③ for ring closure can make the synthesis route more convergent, but considering the relative position of this site to the cyclic lactone group (site ①) and the activity of the C-terminus, we believe that there is a higher risk of diketopiperazine side reactions in the ring closure here, so site ③ was also ruled out. Finally, we decided to perform cyclization at site ②. Cyclization precursor 2 It can be obtained from polyketone intermediate 5 Firstly by amidation and then by Yamaguchi esterification (Yamaguchi Esterification) with valine fragment 4 Isoleucine fragment 3 The polyketide intermediate 5 can be reversed to aldehyde 6 through the Wittig reaction. and Wittig reagent The linear skeleton of aldehyde 6 can be composed of aldehyde 8 With HWE reagent The three chiral centers of aldehyde 8 were all introduced by the raw materials, and its skeleton can be constructed by combining two HWE reactions (Horner-Wadsworth-Emmons Olefination) with hydrogenation reactions, and two chiral methyl groups can be introduced by a classic Evans auxiliary group-controlled asymmetric methylation reaction. and sulfone 10 The sulfone 10 can be reversed to the known compound 12 by Kocienski-Julia olefination and hydrogenation.

[0047] In some embodiments, in the above step S10, compound 16 is prepared, and compound ent-16, Compound 16 or ent-16 is used as a raw material component for preparing Valactamide A and its diastereomers.

[0048] In some embodiments, in the above step S11, the step of preparing compound 16 comprises:

[0049] S111. Obtaining compound 12-1, After that, compound 12-1 is subjected to Mitsunobu reaction to convert the hydroxyl group into thioether to obtain compound 13-1.

[0050] S112. Compound 13-1 is oxidized with m-chloroperbenzoic acid to oxidize TPS to sulfone to obtain compound 14-1.

[0051] S113. Compound 14-1 and TIPS-protected lactaldehyde compound 11, The Kochinsky-Julia olefination reaction produces a pair of olefin mixtures 15-1 The purified product is then hydrolyzed and subjected to a hydrogenation reduction reaction to obtain the target monoprotected diol compound 16. In some specific embodiments, the mixture 15 This symbol represents the cis-trans isomers Z / E of the olefin, indicating that the product obtained here is a pair of cis-trans isomers; the cis-trans isomers Z / E of the olefin in the mixture 15 is 1.3:1.

[0052] In other embodiments, in the above step S12, the step of preparing compound ent-16 comprises:

[0053] S121. Obtaining compound 12-2, Then, compound 12-1 is subjected to Mitsunobu reaction to convert the hydroxyl group into thioether to obtain compound 13-2.

[0054] S122. Compound 13-2 is oxidized with m-chloroperbenzoic acid to oxidize TPS to sulfone to obtain compound 14-2.

[0055] S123. Compound 14-2 and TIPS-protected lactaldehyde compound 11, The Kochinsky-Julia olefination reaction produces a pair of olefin mixtures 15-2 The purified product is then hydrolyzed and subjected to a hydrogenation reduction reaction to obtain the target monoprotected diol compound ent-16. In some specific embodiments, the cis-trans isomerism of the olefin in the mixture 15 is Z / E=1.3:1.

[0056] In some embodiments, in the above step S20, the steps of respectively oxidizing compound 16 and compound ent-16 include: mixing compound 16 with 2,2,6,6-tetramethylpiperidinoxide, trichloroisocyanuric acid and sodium bicarbonate and dissolving them in an organic solvent, conducting an ice bath reaction, oxidizing the hydroxyl group to an aldehyde group, and obtaining compound 8.

[0057] In other embodiments, compound ENT-16 is mixed with 2,2,6,6-tetramethylpiperidinyl oxide, trichloroisocyanuric acid and sodium bicarbonate, dissolved in an organic solvent, and reacted in an ice bath to oxidize the hydroxyl group to an aldehyde group to obtain compound ENT-8.

[0058] In some embodiments, in the above step S30, compound 8 or ent-8 is subjected to Horner-Wordsworth-Emmons olefination reaction and asymmetric methylation reaction with HWE reagent, a chiral methyl group is introduced, the auxiliary group is reduced and removed, and the corresponding alcohol is oxidized to an aldehyde to obtain compound 20. The prepared compound 20 includes three structures: compound 20-1, compound 20-2 and compound 20-3.

[0059] In some embodiments, the steps of preparing compound 20-1 include:

[0060] S311. Compound 8, With HWE reagent compound ent-9, Dissolve in an organic solvent, add lithium chloride, N, N-diisopropylethylamine and hexamethylphosphoramide, and carry out a mixed reaction to obtain a carbon extension product compound 17-1.

[0061] S312. Compound 17-1 is subjected to hydrogenation reduction reaction and methylation reaction in sequence to introduce a third chiral methyl group to obtain compound 18-1.

[0062] S313. Compound 18-1 is subjected to reduction treatment to remove the auxiliary group to obtain compound 19-1, In some specific embodiments, compound 18-1 is reduced to remove the auxiliary group in the presence of sodium borohydride, tetrahydrofuran and water as a mixed solvent.

[0063] S314. Compound 19-1 is oxidized using 2,2,6,6-tetramethylpiperidinyl oxide, trichloroisocyanuric acid and sodium bicarbonate to oxidize the hydroxyl group to an aldehyde group to obtain compound 20-1.

[0064] In some embodiments, the steps of preparing compound 20-2 include:

[0065] S321. Compound 8, With HWE reagent compound 9, Dissolve in an organic solvent, add lithium chloride, N, N-diisopropylethylamine and hexamethylphosphoramide, and react to obtain the carbon extension product compound 17-2.

[0066] S322. Compound 17-2 is subjected to hydrogenation reduction reaction and methylation reaction in sequence to introduce a third chiral methyl group to obtain compound 18-2.

[0067] S323. Compound 18-2 is subjected to reduction treatment to remove the auxiliary group to obtain compound 19-2, In some specific embodiments, compound 18-2 is reduced to remove the auxiliary group in the presence of sodium borohydride, tetrahydrofuran and water as a mixed solvent.

[0068] S324. Compound 19-2 is oxidized using 2,2,6,6-tetramethylpiperidinoxide, trichloroisocyanuric acid and sodium bicarbonate to oxidize the hydroxyl group to an aldehyde group to obtain compound 20-2.

[0069] In some embodiments, the steps of preparing compound 20-3 include:

[0070] S331. Compound ent-8, With HWE reagent compound ent-9, Dissolve in an organic solvent, add lithium chloride, N, N-diisopropylethylamine and hexamethylphosphoramide, and carry out a mixed reaction to obtain the carbon extension product compound 17-3

[0071] S332. Compound 17-3 is subjected to hydrogenation reduction reaction and methylation reaction in sequence to introduce a third chiral methyl group to obtain compound 18-3.

[0072] S333. Compound 18-3 is subjected to reduction treatment to remove the auxiliary group to obtain compound 19-3, In some specific embodiments, compound 18-3 is reduced to remove the auxiliary group in the presence of sodium borohydride, tetrahydrofuran and water as a mixed solvent.

[0073] S334. Compound 19-3 is oxidized using 2,2,6,6-tetramethylpiperidinoxide, trichloroisocyanuric acid and sodium bicarbonate to oxidize the hydroxyl group to an aldehyde group to obtain compound 20-3.

[0074] In some embodiments, in the above step S40, the same treatment method as step S30 is used to treat compound 20 in the same way to introduce another chiral methyl group, reduce and remove the auxiliary group, oxidize the alcohol to aldehyde, and obtain compound 6 including three structures of compound 6-1, compound 6-2, and compound 6-3.

[0075] In some embodiments, the steps of preparing compound 6-1 include:

[0076] S411. Compound 20-1 and HWE reagent compound ent-9, Dissolve in an organic solvent, add lithium chloride, N, N-diisopropylethylamine and hexamethylphosphoramide, and carry out a mixed reaction to obtain the carbon extension product compound 21-1

[0077] S412. Compound 21-1 is subjected to hydrogenation reduction reaction and methylation reaction in sequence to introduce a fourth chiral methyl group to obtain compound 22-1.

[0078] S413. Compound 22-1 is subjected to reduction treatment to remove the auxiliary group to obtain compound 23-1, In some specific embodiments, compound 22-1 is reduced to remove the auxiliary group in the presence of sodium borohydride, tetrahydrofuran and water as a mixed solvent.

[0079] S414. Compound 23-1 is treated with 2,2,6,6-tetramethylpiperidinoxide, trichloroisocyanuric acid and sodium bicarbonate to oxidize the hydroxyl group to an aldehyde group to obtain compound 6-1.

[0080] In some embodiments, the steps of preparing compound 6-2 include:

[0081] S421. Compound 20-2, With HWE reagent compound 9, Dissolve in an organic solvent, add lithium chloride, N, N-diisopropylethylamine and hexamethylphosphoramide, and carry out a mixed reaction to obtain the carbon extension product compound 21-2

[0082] S422. Compound 21-2 is subjected to hydrogenation reduction reaction and methylation reaction in sequence to introduce a fourth chiral methyl group to obtain compound 22-2.

[0083] S423. Compound 22-2 is subjected to reduction treatment to remove the auxiliary group to obtain compound 23-2, In some specific embodiments, compound 22-2 is reduced to remove the auxiliary group in the presence of sodium borohydride, tetrahydrofuran and water as a mixed solvent.

[0084] S424. Compound 22-2 is oxidized using 2,2,6,6-tetramethylpiperidinoxide, trichloroisocyanuric acid and sodium bicarbonate to oxidize the hydroxyl group to an aldehyde group to obtain compound 6-2.

[0085] In some embodiments, the steps of preparing compound 6-3 include:

[0086] S431. Compound 20-3, With HWE reagent compound ent-9, Dissolve in an organic solvent, add lithium chloride, N, N-diisopropylethylamine and hexamethylphosphoramide, and carry out a mixed reaction to obtain the carbon extension product compound 21-3

[0087] S432. Compound 21-3 is subjected to hydrogenation reduction reaction and methylation reaction in sequence to introduce a fourth chiral methyl group to obtain compound 22-3.

[0088] S433. Compound 22-3 is subjected to reduction treatment to remove the auxiliary group to obtain compound 23-3, In some specific embodiments, compound 22-3 is reduced to remove the auxiliary group in the presence of sodium borohydride, tetrahydrofuran and water as a mixed solvent.

[0089] S434. Compound 23-3 is oxidized using 2,2,6,6-tetramethylpiperidinyl oxide, trichloroisocyanuric acid and sodium bicarbonate to oxidize the hydroxyl group to an aldehyde group to obtain compound 6-3.

[0090] In some embodiments, in the above step S50, compound 6 is subjected to a Wittig reaction with a phosphorus ylide reagent to construct an E-type trisubstituted double bond, and an ester group is introduced to complete the construction of a polyketone skeleton to obtain compound 5. Compound 5 includes compound 5-1, compound 5-2, and compound 5-3.

[0091] In some embodiments, the steps of preparing compound 5-1 include:

[0092] S51. Compound 6-1 With phosphorus ylide reagent compound 7, Dissolve in an organic solvent, react at a temperature of 60 to 100°C, construct an E-type trisubstituted double bond through the Wittig reaction, and introduce an ester group to complete the construction of the polyketone skeleton to obtain compound 5-1

[0093] In some embodiments, the steps of preparing compound 5-2 include:

[0094] S52. Compound 6-2 With phosphorus ylide reagent compound 7, Dissolve in an organic solvent, react at a temperature of 60-100°C, construct an E-type trisubstituted double bond through Wittig reaction, and introduce an ester group to complete the construction of the polyketone skeleton to obtain compound 5-2

[0095] In some embodiments, the steps of preparing compound 5-3 include:

[0096] S53. Compound 6-3 With phosphorus ylide reagent compound 7, Dissolve in an organic solvent, react at a temperature of 60 to 100°C, construct an E-type trisubstituted double bond through the Wittig reaction, and introduce an ester group to complete the construction of the polyketone skeleton to obtain compound 5-3

[0097] In some embodiments, in the above step S60, compound 5 is activated with L-valine tert-butyl ester trifluoroacetate and then connected to a peptide to obtain compound 24; including compound 24-1, compound 24-2, and compound 24-3.

[0098] In some embodiments, the steps of preparing compound 24-1 include:

[0099] S61. After the compound 5-1 is hydrolyzed in a potassium hydroxide solution at a temperature of 60 to 100°C, it is reacted with N-hydroxy-7-azabenzotriazole HOAt, L-valine tert-butyl ester trifluoroacetate 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) was mixed and dissolved, and N,N-diisopropylethylamine DIPEA was added under ice bath conditions for mixed reaction to obtain compound 24-1

[0100] In some embodiments, the steps of preparing compound 24-2 include:

[0101] S62. After the compound 5-2 is hydrolyzed in a potassium hydroxide solution at a temperature of 60 to 100°C, it is reacted with N-hydroxy-7-azabenzotriazole and L-valine tert-butyl ester trifluoroacetate. 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) was mixed and dissolved, and N,N-diisopropylethylamine was added under ice bath conditions for mixed reaction to obtain compound 24-2

[0102] In some embodiments, the steps of preparing compound 24-3 include:

[0103] S63. After the compound 5-3 is hydrolyzed in a potassium hydroxide solution at a temperature of 60 to 100°C, it is reacted with N-hydroxy-7-azabenzotriazole and L-valine tert-butyl ester trifluoroacetate. 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) was mixed and dissolved, and N,N-diisopropylethylamine was added under ice bath conditions for mixed reaction to obtain compound 24-3

[0104] In some embodiments, in the above step S70, after removing the protecting group in compound 24, a coupling reaction is carried out with L-isoleucine containing a protecting group to obtain a ring-closed precursor compound 2; including compound 2-1, compound 2-2, and compound 2-3.

[0105] In some embodiments, the steps of preparing compound 2-1 include:

[0106] S71. The triisopropylsilyl protecting group on the secondary hydroxyl group at the terminal of compound 24-1 was removed under the action of hydrogen fluoride to obtain compound 25-1

[0107] S72. Compound 25-1 and tert-butyloxycarbonyl-protected L-isoleucine are dissolved in an organic solvent, cooled to 5-0°C, N,N-diisopropylethylamine and 2,4,6-trichlorobenzoyl chloride are added, the temperature is raised to 20-40°C for mixed reaction, cooled again to 5-0°C, 4-dimethylaminopyridine is added for reaction, and compound 2-1 is obtained.

[0108] In some embodiments, the steps of preparing compound 2-2 include:

[0109] S73. The triisopropylsilyl protecting group on the secondary hydroxyl group at the terminal of compound 24-2 was removed under the action of hydrogen fluoride to obtain compound 25-2

[0110] S74. Compound 25-2 and tert-butyloxycarbonyl-protected L-isoleucine are dissolved in an organic solvent, cooled to 5-0°C, N,N-diisopropylethylamine and 2,4,6-trichlorobenzoyl chloride are added, the temperature is raised to 20-40°C for mixed reaction, cooled again to 5-0°C, 4-dimethylaminopyridine is added for reaction, and compound 2-2 is obtained.

[0111] In some embodiments, the steps of preparing compound 2-3 include:

[0112] S75. The triisopropylsilyl protecting group on the secondary hydroxyl group at the terminal of compound 24-3 was removed under the action of hydrogen fluoride to obtain compound 25-3

[0113] S76. Compound 25-3 and tert-butyloxycarbonyl-protected L-isoleucine were dissolved in an organic solvent, cooled to 5-0°C, N,N-diisopropylethylamine and 2,4,6-trichlorobenzoyl chloride were added, the temperature was raised to 20-40°C for mixed reaction, cooled to 5-0°C again, 4-dimethylaminopyridine was added for reaction, and compound 2-3 was obtained.

[0114] In some embodiments, in the above step S80, compound 2 is subjected to ring-closing treatment to obtain Valactamide A or a diastereomer of Valactamide A. In some embodiments, the tert-butyloxycarbonyl (Boc) protecting group and tert-butyl ester in compound 2 are removed in the next step under the action of trifluoroacetic acid TFA, and then cyclized under the activation of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) to obtain Valactamide A or a diastereomer of Valactamide A.

[0115] In some embodiments, the step of performing ring-closing treatment on compound 2-1 comprises:

[0116] S81. The tert-butyloxycarbonyl protecting group and tert-butyl ester in compound 2-1 are removed under the action of trifluoroacetic acid TFA.

[0117] S82. Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU, N,N-diisopropylethylamine DIPEA and N-hydroxy-7-azabenzotriazole HOAt and other coupling activators to carry out cyclization reaction to obtain Valactamide A. RSSSS-1.

[0118] In some embodiments, the step of performing ring-closing treatment on compound 2-2 or 2-3 comprises:

[0119] S83. The tert-butyloxycarbonyl protecting group and tert-butyl ester in compound 2-2 or 2-3 are removed under the action of trifluoroacetic acid TFA.

[0120] S84. Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU, N,N-diisopropylethylamine DIPEA and N-hydroxy-7-azabenzotriazole HOAt and other coupling activators to carry out cyclization reaction to obtain the diastereomer of Valactamide A RSSRR-1 or RRRSS-1.

[0121] In order to make the above implementation details and operations of the present application clearly understood by those skilled in the art, as well as to demonstrate the significant improvement in the performance of the synthesis method of Valactamide A and its diastereoisomers in the embodiment of the present application, the above technical scheme is illustrated by multiple embodiments below.

[0122] Example 1

[0123] A synthetic method of Valactamide A, the synthetic route is as shown in the attached Figure 1 As shown, the steps include:

[0124] 1. Add 1-phenyl-5-thiotetrazolyl PTSH (716.00 mg, 4.02 mmol, 1.4 eq.) and triphenylphosphine PPh3 (1.13 g, 4.30 mmol, 1.5 eq.) to a tetrahydrofuran THF (10 mL) solution of compound 12-1 (500.00 mg, 2.87 mmol, 1.0 eq.) at 0 °C and stir. After stirring evenly, slowly add diisopropyl azodicarboxylate DIAD (0.54 mL, 3.72 mmol, 3.0 eq.) at the same temperature. Return to 25 °C and react for 11 hours. Directly add about 1 g of silica gel to the reaction system, stir evenly, and concentrate under reduced pressure. The crude product is separated by silica gel column chromatography (petroleum ether PE / ethyl acetate EtOAc = 20:1–10:1) to obtain a light yellow oil product compound 13-1 (912 mg, 95%).

[0125] [α] D 24 =-2.8 (c 1.0, CHCl3).

[0126] 1H NMR(400MHz,Chloroform-d)δ7.57–7.47(m,5H),3.89(dd,J=10.8,5.6Hz,1H),3. 82(dd,J=10.8,6.5Hz,1H),3.48(dd,J=12.7,5.1Hz,1H),3.16(dd,J=12.8,7.7Hz ,1H),2.07–2.01(m,1H),1.99(s,3H),1.96–1.89(m,1H),1.49(dt,J=13.7,6.8Hz ,1H),1.12(dt,J=14.3,7.4Hz,1H),1.04(d,J=6.7Hz,3H),0.95(d,J=6.7Hz,3H).

[0127] 13 C NMR (101MHz, Chloroform-d) δ171.21,154.60,133.73,130.16,129.84,123.91,68.98,40.23,40.13,30.48,30.02,20.94,19.82,17.61.

[0128] HRMS(ESI,m / z):for C 16 H 23 N4O2S + [M+H] + :Calcd.335.1537; Found 335.1539.

[0129] 2. Add m-chloroperbenzoic acid mCPBA (85wt%, 1.82g, 8.97mmol, 2.5eq.) to a solution of compound 13-1 (1.20g, 3.58mmol, 1.0eq.) in dichloromethane (DCM) (10mL) at 0°C and heat to 25°C. After stirring for 17 hours, slowly add saturated sodium thiosulfate Na2S2O3 aqueous solution to the reaction system and stir for about 30 minutes to remove the remaining mCPBA. The resulting mixture was extracted with DCM (10mL×2), and the organic phase was washed with saturated sodium bicarbonate NaHCO3 aqueous solution and saturated brine in turn, then dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated by vacuum rotary evaporation with a vacuum water pump. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc=20:1–2:1) to obtain a colorless to slightly yellow oily product compound 14-1 (1.20g, 91%).

[0130] [α] D 20 = +1.5 (c 1.0, CHCl3).

[0131] 1 H NMR (400MHz, Chloroform-d) δ7.71–7.64(m,2H),7.64–7.55(m,3H),3.89(d,J=5. 9Hz, 2H), 3.79 (dd, J=14.5, 4.4Hz, 1H), 3.56 (dd, J=14.5, 8.0Hz, 1H), 2.42 (ddd, J= 14.2,9.3,5.6Hz,1H),2.03(s,3H),1.91(h,J=6.6Hz,1H),1.63(dt,J=13.8,6.9H z,1H),1.25(dt,J=13.8,6.6Hz,1H),1.19(d,J=6.7Hz,3H),0.96(d,J=6.6Hz,3H).

[0132] 13 C NMR (101MHz, Chloroform-d) δ171.23,154.08,133.14,131.58,129.79,125.23,68.52,61.76,40.86,29.88,26.13,20.98,20.57,17.56.

[0133] HRMS(ESI,m / z):for C 16 H 22 N4O4SNa + [M+Na] + :389.1254:Calcd.389.1254; Found389.1251.

[0134] 3. Slowly add sodium bis(trimethylsilyl)amide NaHMDS (solution in THF, 2.0N, 0.20mL, 0.40mmol, 1.5eq.) to a solution of compound 14-1 (0.10g, 0.27mmol, 1.0eq.) in THF (1mL) at -78°C via a syringe, stir at the same temperature for about 15 minutes, then slowly add a solution of compound 11 (187.00mg, 0.81mmol, 3.0eq.) in THF (3mL) via a syringe to the above reaction system, and then continue to stir at -78°C for about 4 hours. At the same temperature, add saturated ammonium chloride NH4Cl aqueous solution to the reaction system to quench the reaction, return to room temperature and separate the liquids, and use methyl tert-butyl ether to separate the aqueous phase. tThe mixture was extracted with BuOMe (5 mL×3), and the combined organic phases were washed with saturated NaHCO3 aqueous solution and saturated brine in sequence, then dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated by rotary evaporation under reduced pressure using a vacuum water pump. The crude product was crudely separated by silica gel column chromatography (petroleum ether / EtOAc=100:1-20:1) to obtain a colorless oily crude product containing 11, compound 15-1 (77.00 mg).

[0135] 4. Dissolve the crude product 15-1 (77.00 mg) in methanol MeOH (1 mL), add potassium carbonate K2CO3 solid (144.00 mg, 1.04 mmol, 5.0 eq.) in an ice bath, stir for 20 minutes, remove the ice bath, slowly return to room temperature and stir for 3 hours until TLC shows that the raw material is completely reacted. Saturated NH4Cl aqueous solution is slowly added dropwise to the reaction system in an ice bath, and the resulting mixture is washed with water. t The organic phase was extracted with BuOMe (5 mL × 3), and then washed with water and saturated brine, and then dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated by vacuum rotary evaporation with a vacuum water pump. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc = 100: 1-10: 1) to obtain a colorless oily product (43.00 mg, Z / E = 1 / 1.3). The above product (43.00 mg), 5% Pd / C (13.00 mg) and a stirrer were placed in a round-bottom flask, evacuated and protected with argon, and ethyl acetate (2 mL) and triethylamine Et3N (0.02 mL, 0.14 mmol) were added in sequence with a syringe. After stirring evenly, the mixture was ventilated with a hydrogen balloon for 3 times, and the reaction system was stirred in a hydrogen atmosphere at 25°C for about 8 hours. The solid in the reaction system was removed by filtration using diatomaceous earth, the filter cake was washed with ethyl acetate, and the filtrate was concentrated by rotary evaporation under reduced pressure using a vacuum water pump. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc=100:1-10:1) to give a colorless oily product compound 16 (40.00 mg, total yield of 45% in 3 steps).

[0136] [α] D 25 =-2.48 (c 2.0, CHCl3).

[0137] 1H NMR(400MHz,Chloroform-d)δ3.92(tq,J=8.5,5.9Hz,1H),3.54(dd,J=10.5,5.1Hz,1H),3.39(dd,J=10.5,6.8Hz,1H),1.81–1.66 (m,2H),1.65–1.46(m,2H),1.44–1.28(m,4H),1.17(d,J=6.0Hz,3H),1.08(s,21H),0.94(d,J=6.7Hz,3H),0.90(d,J=6.6Hz,3H).

[0138] 13 C NMR (101MHz, Chloroform-d) δ69.02,68.55,41.09,37.18,33.26,31.97,30.42,23.63,20.52,18.30,18.28,17.40,12.62.

[0139] HRMS(ESI,m / z):for C 19 H 42 O2SiNa + [M+Na] + :Calcd.353.2847; Found 353.2851.

[0140] 5. Dissolve compound 16 (2.47 g, 7.48 mmol, 1.0 eq.) in DCM (75 mL), and add NaHCO3 (1.89 g, 22.44 mmol, 3.0 eq.), trichloroisocyanuric acid TCCA (1.91 g, 8.23 ​​mmol, 1.1 eq.) and 2,2,6,6-tetramethylpiperidinoxide TEMPO (0.12 g, 0.75 mmol, 0.1 eq.) in ice bath. React for 3 minutes in ice bath, and TLC monitoring shows that the raw materials are completely reacted. The reaction solution is filtered under reduced pressure through a thin layer of diatomaceous earth (lower layer) and a thin layer of silica gel (upper layer), and the filter cake is washed with DCM. The filtrate is collected by a separatory funnel containing saturated Na2S2O3 aqueous solution (50 mL) and saturated NaHCO3 aqueous solution (50 mL). The liquids were separated and the organic phase was retained. The aqueous phase was extracted with DCM (50 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The filtrate was concentrated by rotary evaporation under reduced pressure using a vacuum water pump. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc=500:1) to give a colorless oily product, compound 8 (2.01 g, 82%).

[0141] 6. Dissolve compound ent-9 (2.31 g, 6.50 mmol, 2.5 eq.) and anhydrous lithium chloride LiCl (0.38 g, 9.10 mmol, 3.5 eq.) in anhydrous acetonitrile CH3CN (7.5 mL), then add N,N-diisopropylethylamine DIPEA (1.36 mL, 7.80 mmol, 3.0 eq.) dropwise, and stir at room temperature for about 30 minutes. Add hexamethylphosphoric acid triamide HMPA (1.85 mL, 10.40 mmol, 4.0 eq.) dropwise to the reaction system, stir for about 20 minutes, then add substrate compound 8 (0.87 g, 2.60 mmol, 1.0 eq.) in anhydrous acetonitrile solution (7.5 mL) dropwise, and then react at room temperature for about 24 hours until compound 8 is almost completely consumed. Filter the reaction mixture through a thin layer of diatomaceous earth, and wash the filter cake with ethyl acetate. The obtained filtrate was concentrated by rotary evaporation under reduced pressure using a vacuum water pump, and the obtained crude product was separated by silica gel column chromatography (petroleum ether / EtOAc=50:1-20:1) to obtain a light yellow oily product compound 17-1 (2.01 g, 82%, E:Z>20:1).

[0142] [α] D 23 = +22.70 (c 1.0, CHCl3).

[0143] 1 H NMR(400MHz,Chloroform-d)δ7.34(dd,J=8.0,6.4Hz,2H),7.32–7.23(m,1H),7.26–7.20(m,3H),7.06(d d,J=15.4,8.5Hz,1H),4.72(ddt,J=10.3,6.8,3.2Hz,1H),4.25–4.11(m,2H),3.88(h,J=6.1Hz,1H),3.3 6(dd,J=13.4,3.3Hz,1H),2.78(dd,J=13.3,9.7Hz,1H),2.55(hept,J=6.9,6.3Hz,1H),1.55–1.25(m,6H ),1.21–1.14(m,1H),1.14(d,J=6.0Hz,3H),1.09(d,J=6.6Hz,3H),1.06(s,21H),0.87(d,J=6.4Hz,3H).

[0144] 13C NMR(101MHz,Chloroform-d)δ165.35,157.28,153.55,135.61,129.59,129.09,127.43,118.88,68.9 5,66.23,55.55,43.92,38.08,37.23,34.89,32.89,30.78,23.67,20.48,19.54,18.31,18.29,12.62.

[0145] HRMS(ESI,m / z):for C 31 H 52 NO4Si + [M+H] + :Calcd.530.3661; Found 530.3661.

[0146] 7. Evacuate the round-bottom flask containing compound 17-1 (166.00 mg, 0.31 mmol, 1.0 eq.), 5% Pd / C (0.05 g, 30 wt%) and a magnetic particle, and then protect it with argon. Add anhydrous ethyl acetate (12 mL) with a syringe, and then ventilate it three times with a hydrogen balloon. Stir the reaction solution in a hydrogen atmosphere for about 3.5 hours at room temperature. Filter the reaction mixture through a thin layer of diatomaceous earth, and wash the filter cake with ethyl acetate. The filtrate is concentrated by vacuum rotary evaporation with a vacuum water pump, and dehydrated by azeotropic decompression with toluene. The product is directly used in the next reaction after being drained by an oil pump. The above product was dissolved in anhydrous THF (3 mL), cooled to -78 ° C, NaHMDS (solution in THF, 2.0 N, 0.37 mmol, 1.2 eq.) was added dropwise, and then stirred at -78 ° C for about 30 minutes, and then iodomethane MeI (23.00 μL, 0.37 mmol, 1.2 eq.) was added dropwise, and then continued to stir at -78 ° C for about 7 hours. The reaction solution was quickly poured into a saturated NH4Cl aqueous solution (10 mL), and the aqueous phase was extracted with ethyl acetate (5 mL × 3) after separation. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The filtrate was concentrated by vacuum water pump under reduced pressure rotary evaporation, and the crude product was separated by silica gel column chromatography (petroleum ether / EtOAc = 100: 1-50: 1) to obtain a colorless to light yellow oily product compound 18-1 (0.127 g, 75% for two steps).

[0147] [α] D 24 = +22.30 (c 1.0, CHCl3).

[0148] 1H NMR(400MHz,Chloroform-d)δ7.35–7.31(m,2H),7.29–7.24(m,1H),7.22(dd,J=6.9,1.9Hz,2H),4.68(ddt,J=10.2,6.9,3.2Hz,1H),4.24–4.13(m,2H),3.99–3.82(m,2H),3.25(dd,J=13.4,3.3Hz,1H),2.77(dd,J=13.4,9.6Hz,1H),1.90(ddd,J=13.7,9.1,4.9Hz,1H),1.62–1.40(m,4H),1.42–1.26(m,3H),1.22(d,J=6.8Hz,3H),1.15(d,J=6.1Hz,3H),1.13–1.06(m,1H),1.06(s,21H),1.01–0.89(m,1H),0.86(t,J=6.4Hz,6H).

[0149] 13 C NMR(101MHz,Chloroform-d)δ177.45,153.15,135.42,129.62,129.05,127.47,69.01,66.07,55.40,45.23,40.59,37.96,37.31,35.41,32.25,30.23,28.17,23.67,20.75,20.34,18.72,18.32,18.30,12.62.

[0150] HRMS(ESI,m / z)for C 32 H 55 NO4SiNa + [M+Na] + :Calcd.568.3793;Found 568.3790.

[0151] 8. Compound 18-1 (0.42 g, 0.77 mmol, 1.0 eq.) was dissolved in a mixture of THF (7 mL) and H2O (3.5 mL). Sodium borohydride NaBH4 (0.29 g, 7.70 mmol, 10.0 eq.) was added in two portions under ice bath, and the reaction system was slowly warmed to room temperature and stirred for about 24 hours. Saturated NH4Cl aqueous solution was slowly added dropwise under ice bath to quench the reaction (note that the system violently produces gas). After separation, the aqueous phase was extracted with dichloromethane (5 mL×2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated by vacuum rotary evaporation with a vacuum water pump under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc=20:1) to obtain a colorless oily product compound 19-1 (0.50 g, 90%).

[0152] [α] D 25 = -3.20 (c1.0, CHCl3);

[0153] 1 H NMR(400MHz,Chloroform-d)δ3.90(h,J=5.7Hz,1H),3.53(dd,J=10.5,5.0Hz,1H),3.35(dd,J=10.5,6.9Hz,1H),1.76–1.67(m ,1H),1.61–1.41(m,4H),1.40–1.18(m,5H),1.14(d,J=6.1Hz,3H),1.05(s,22H),0.92(d,J=6.8Hz,3H),0.85(t,J=7.0Hz,6H).

[0154] 13 C NMR (101MHz, Chloroform-d) δ69.04,68.38,45.13,41.38,37.17,33.20,31.79,30.34,27.64,23.68,21.03,20.66,18.31,18.29,17.65,12.63.

[0155] HRMS (ESI, m / z) for C 22 H 49 O2Si + [M+H] + :Calcd.373.3497; Found 373.3496.

[0156] 9. Dissolve compound 19-1 (124.00 mg, 0.33 mmol, 1.0 eq.) in DCM (3.2 mL), and add NaHCO3 (83.00 mg, 0.99 mmol, 3.0 eq.), TCCA (84.00 mg, 0.36 mmol, 1.1 eq.) and TEMPO (5.20 mg, 0.03 mmol, 0.1 eq.) in ice bath. React for about 3 minutes in ice bath, and TLC monitoring shows that the raw materials are completely reacted. The reaction solution is filtered under reduced pressure through a thin layer of diatomaceous earth (lower layer) and a thin layer of silica gel (upper layer), and the filter cake is washed with DCM. The filtrate is received in a separatory funnel containing saturated Na2S2O3 aqueous solution (10 mL) and saturated NaHCO3 aqueous solution (10 mL). The liquids were separated and the organic phase was retained. The aqueous phase was extracted with DCM (20 mL×2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The filtrate was concentrated by rotary evaporation under reduced pressure using a vacuum water pump. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc=500:1) to give a colorless oily product compound 20-1 (0.11 g, 90%).

[0157] 10. Dissolve compound ent-9 (0.26 g, 0.74 mmol, 2.5 eq.) and anhydrous LiCl (48.00 mg, 1.16 mmol, 4.0 eq.) in anhydrous acetonitrile (1.5 mL), then add DIPEA (0.15 mL, 0.87 mmol, 3.0 eq.) dropwise, and stir at room temperature for about 30 minutes. Add HMPA (0.23 mL, 1.30 mmol, 4.5 eq.) dropwise to the reaction system, stir for about 20 minutes, then add anhydrous acetonitrile solution (1.5 mL) of compound 20-1 (0.11 g, 0.29 mmol, 1.0 eq.) dropwise, and then react at room temperature for about 28 hours until compound 20-1 is almost completely consumed. Filter the reaction mixture through a thin layer of diatomaceous earth, and wash the filter cake with ethyl acetate. The obtained filtrate was concentrated by rotary evaporation under reduced pressure using a vacuum water pump, and the obtained crude product was separated by silica gel column chromatography (petroleum ether / EtOAc=100:1-20:1) to obtain a light yellow oily product compound 21-1 (0.15 g, 87%).

[0158] [α] D 24 = +16.62 (c1.0, CHCl3).

[0159] 1H NMR(400MHz,Chloroform-d)δ7.38–7.29(m,2H),7.30–7.21(m,4H),7.05(dd,J=15.3,8.5Hz,1H),4.79–4.63(m,1H),4.26–4.13(m,2H),3.90(h,J=5.9Hz,1H),3.35(dd,J=13.4,3.3Hz,1H),2.78(dd,J=13.4,9.6Hz,1H),2.62–2.49(m,1H),1.56–1.40(m,4H),1.38–1.27(m,3H),1.27–1.18(m,2H),1.15(d,J=6.0Hz,3H),1.09(d,J=6.6Hz,3H),1.06(s,21H),0.99–0.90(m,1H),0.86(d,J=6.4Hz,3H),0.83(d,J=6.6Hz,3H).

[0160] 13 C NMR(101MHz,Chloroform-d)δ165.31,157.29,153.55,135.62,129.59,129.08,127.43,118.92,68.99,66.22,55.54,45.49,43.70,38.08,37.30,34.86,32.37,30.23,28.00,23.66,20.63,20.42,20.33,18.32,18.29,12.63.

[0161] HRMS(ESI,m / z)for C 34 H 57 NO4SiNa + [M+Na] + :Calcd.594.3950;Found 594.3950.

[0162] 11. After the round-bottom flask containing compound 21-1 (214.00 mg, 0.37 mmol, 1.0 eq.), 5% Pd / C (64.00 mg, 30 wt%) and a magnetic particle was evacuated and protected with argon, ethyl acetate (re-distilled, 38 mL) was added with a syringe, and then the reaction solution was stirred in a hydrogen atmosphere for about 12 hours at room temperature. The reaction mixture was filtered through a thin layer of diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated by vacuum rotary evaporation with a vacuum water pump, and dehydrated by azeotropic decompression with toluene. The product was directly used in the next reaction after being dried with an oil pump. The above product was dissolved in anhydrous THF (4 mL), cooled to -78 ° C, and NaHMDS (solution in THF, 2.0 N, 0.46 mmol, 1.2 eq.) was added dropwise, and then stirred at -78 ° C for about 30 minutes, and then iodomethane (35.00 μL, 0.57 mmol, 1.5 eq.) was added dropwise, and then continued to stir at -78 ° C for about 7 hours. The reaction solution was quickly poured into a saturated NH4Cl aqueous solution (10 mL), and the aqueous phase was extracted with ethyl acetate (5 mL × 3) after separation. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The filtrate was concentrated by vacuum water pump under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc = 100: 1-30: 1) to obtain a light yellow oil product compound 22-1 (0.18 g, 81% in two steps). [α] D 21 = +14.62 (c0.5, CHCl3).

[0163] 1 H NMR(500MHz,Chloroform-d)δ7.36–7.32(m,2H),7.30–7.26(m,1H),7.24–7.21(m,2H),4.70(ddt,J=10.4,7.0,3.1Hz,1H),4.28–4. 07(m,2H),4.02–3.80(m,2H),3.26(dd,J=13.4,3.3Hz,1H),2.78(dd,J=13.4,9.5Hz,1H),1.93(ddd,J=13.8,9.3,4.7Hz,1H),1.71–

[0164] 1.42(m,6H),1.42–1.31(m,2H),1.23(d,J=6.9Hz,3H),1.21–1.17(m,1H),1.16(d,J =6.0Hz,3H),1.07(s,21H),1.04–1.01(m,1H),0.95–0.88(m,2H),0.88–0.84(m,9H).

[0165] 13 C NMR(126MHz,Chloroform-d)δ177.44,153.17,135.45,129.63,129.06,127.48,69.10,66.09,55.40,45.48,45.25 ,40.43,37.99,37.23,35.42,32.03,30.31,28.16,27.42,23.70,20.87,20.84,20.66,18.86,18.33,18.31,12.66.

[0166] HRMS (ESI, m / z) for C 35 H 61 NO4SiNa + [M+Na] + :Calcd.610.4263; Found 610.4261.

[0167] 12. Compound 22-1 (0.17 g, 0.29 mmol, 1.0 eq.) was dissolved in a mixture of THF (3 mL) and H2O (1.5 mL). NaBH4 (0.16 g, 4.35 mmol, 15.0 eq.) was added in two portions under ice bath, and the reaction system was slowly warmed to room temperature and stirred for about 34 hours. Saturated NH4Cl aqueous solution was slowly added dropwise under ice bath to quench the reaction (note that the system violently produces gas). After separation, the aqueous phase was extracted with dichloromethane (5 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated by vacuum rotary evaporation with a vacuum water pump. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc = 40:1) to obtain a colorless to light yellow oily product compound 23-1 (0.11 g, 94%).

[0168] [α] D 25 = -1.62 (c1.0, CHCl3);

[0169] 1H NMR(400MHz,Chloroform-d)δ3.94(h,J=5.9Hz,1H),3.58(dd,J=10.5,4.9Hz,1H),3.40(dd,J=10.4,7.0Hz,1H),1.76(pd,J=6.9,4.9Hz,1H ),1.68–1.44(m,5H),1.46–1.20(m,6H),1.18(d,J=6.1Hz,3H),1.15–1.12(m,1H),1.09(s,21H),0.97(d,J=6.7Hz,3H),0.93–0.84(m,11H).

[0170] 13 C NMR(101MHz,Chloroform-d)δ69.07,68.31,45.64,45.04,41.15,37.13,33.20,31 .70,30.34,27.63,27.54,23.69,21.18,21.08,20.79,18.32,18.30,17.81,12.63.

[0171] HRMS (ESI, m / z) for C 25 H 55 O2Si + [M+H] + :Calcd.415.3966;Found 415.3965.

[0172] 13. Dissolve compound 23-1 (88.00 mg, 0.21 mmol, 1.0 eq.) in DCM (2.0 mL), and add NaHCO3 (53.00 mg, 0.63 mmol, 3.0 eq.), TCCA (54.00 mg, 0.23 mmol, 1.1 eq.) and TEMPO (3.00 mg, 0.02 mmol, 0.1 eq.) in ice bath. React for about 3 minutes in ice bath, and TLC monitoring shows that the raw materials are completely reacted. The reaction solution is filtered under reduced pressure through a thin layer of diatomaceous earth (lower layer) and a thin layer of silica gel (upper layer), and the filter cake is washed with DCM. The filtrate is received in a separatory funnel containing saturated Na2S2O3 aqueous solution (5 mL) and saturated NaHCO3 aqueous solution (5 mL). The liquids were separated and the organic phase was retained. The aqueous phase was extracted with DCM (10 mL×2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The filtrate was concentrated by rotary evaporation under reduced pressure using a vacuum water pump. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc=500:1) to give a colorless oily product compound 6-1 (74.00 mg, 85%).

[0173] 14. Dissolve compound 6-1 (74.00 mg, 0.17 mmol, 1.0 eq.) in anhydrous toluene (0.56 mL), add compound 7 (0.23 g, 0.68 mmol, 4.0 eq.), react at 80 °C for about 5 hours, return to room temperature, take a small amount of reaction solution, concentrate and pass 1 H NMR determined that the raw material was completely reacted. The reaction solution was concentrated by vacuum evaporation with a vacuum pump, and the obtained crude product was separated by silica gel column chromatography (petroleum ether / EtOAc=300:1) to obtain a colorless oil product compound 5-1 (85.00 mg, quantitative).

[0174] [α] D 25 = +8.20 (c1.0, CHCl3);

[0175] 1 H NMR(500MHz,Chloroform-d)δ6.50(dq,J=10.0,1.5Hz,1H),4.25–4.11(m,2H),3.90(h,J=5.6Hz,1H ),2.61(ddt,J=10.1,5.6,2.3Hz,1H),1.85(d,J=1.4Hz,3H),1.63–1.29(m,8H),1.28(t,J=7.1Hz,3H ),1.21–1.17(m,1H),1.15(d,J=6.0Hz,3H),1.12–1.08(m,1H),1.06(s,21H),1.03(s,1H),0.98(d,J =6.7Hz,3H),0.94–0.85(m,2H),0.84(d,J=6.6Hz,3H),0.82(d,J=6.4Hz,3H),0.79(d,J=6.5Hz,3H).

[0176] 13 C NMR(126MHz,Chloroform-d)δ168.52,148.29,126.38,69.03,60.45,45.78,45.46,44.11,37.16,3 1.94,31.00,30.24,28.17,27.36,23.67,20.81,20.59,20.56,18.31,18.29,14.41,12.64,12.60.

[0177] HRMS (ESI, m / z) for C 30 H 60 O3SiNa + [M+Na] +:Calcd.519.4204; Found 519.4207.

[0178] 15. Dissolve compound 5-1 (47.00 mg, 0.094 mmol, 1.0 eq) in a sealed tube with MeOH (0.90 mL) and THF (0.45 mL), then add potassium hydroxide aqueous solution (1N, 1.35 mL), seal after argon replacement, and stir at 60-100°C until TLC shows that raw material 5-1 is basically completely reacted. Cool to room temperature, dilute the reaction solution with ethanol EtOH (5 mL), and then adjust the system pH to 4 with 10% citric acid aqueous solution at 0°C. Extract the reaction solution with ethyl acetate (10 mL×3), wash the combined organic phase with water (2 mL×3), dry with anhydrous sodium sulfate, filter under reduced pressure, and concentrate the filtrate with a vacuum water pump under reduced pressure rotary evaporation. The crude product is used directly in the next step after fully removing the residual low boiling substances with an oil pump. The above crude product was dissolved in anhydrous N,N-dimethylformamide DMF (1 mL), and N-hydroxy-7-azabenzotriazole HOAt (51 mg, 0.38 mmol, 4.0 eq.), compound 4 (solution in anhydrous DMF, 0.56N, 0.56 mmol, 6.0 eq.), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU (143.00 mg, 0.38 mmol, 4.0 eq.) were added in sequence. After full dissolution, N,N-diisopropylethylamine DIPEA (0.2 mL, 1.13 mmol, 12.0 eq.) was slowly added in an ice bath and stirred for about 30 minutes, and then the temperature was slowly raised to room temperature for reaction for about 12 hours. The reaction solution was diluted with dichloromethane (5 mL), and then a saturated NH4Cl aqueous solution (5 mL) was added dropwise. The organic phase was separated and retained. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with 5% citric acid aqueous solution, water (2 mL × 4) and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated by vacuum water pump under reduced pressure rotary evaporation. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc = 100:1–20:1) to obtain a colorless oil product compound 24-1 (55.00 mg, 94% in two steps). [α] D 23 = +14.53 (c1.0, CHCl3);

[0179] 1H NMR(400MHz,Chloroform-d)δ6.22(d,J=8.6Hz,1H),6.08(dd,J=9.9,1.6Hz,1H),4.53(dd,J=8.6,4.3Hz,1H),3.89(p,J=5.8Hz,1H),2.59(tdd,J=10.0,6.9,4.3Hz,1H),2.18(pd,J=6.9,4.3Hz,1H),1.88(d,J=1.4Hz,3H),1.61–1.48(m,2H),1.46(s,9H),1.45–1.22(m,6H),1.20–1.09(m,2H),1.13(d,J=6.1Hz,3H),1.04(s,21H),1.10–1.00(m,2H),0.97(d,J=6.6Hz,3H),0.93(d,J=6.9Hz,3H),0.90(d,J=6.9Hz,3H),0.88–0.85(m,1H),0.82(d,J=5.2Hz,3H),0.81(d,J=5.0Hz,3H),0.77(d,J=6.5Hz,3H).

[0180] 13 C NMR(101MHz,Chloroform-d)δ171.66,169.25,142.46,129.61,82.06,69.02,57.30,45.60,45.41,44.11,37.16,31.98,31.86,30.67,30.18,28.18,28.05,27.25,23.66,21.07,20.86,20.53,19.02,18.30,18.28,17.78,12.94,12.60.

[0181] HRMS(ESI,m / z)for C 37 H 73 NO4SiNa + [M+Na] + :Calcd.646.5202;Found 646.5197.

[0182] 16. Dissolve compound 24-1 (55.00 mg, 0.09 mmol, 1.0 eq.) in anhydrous THF (4.4 mL) in a PP tube, cool to 0°C, and add 70% HF·pyridine (3.3 mL) dropwise to the reaction system. Keep the reaction at 0°C for about 30 minutes until TLC shows that the substrate is basically completely reacted, then slowly add H2O (5 mL) and saturated NaHCO3 aqueous solution (15 mL) at 0°C, and then slowly warm to room temperature. Pour the reaction solution into saturated NaHCO3 aqueous solution, extract with ethyl acetate (25 mL×2), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter under reduced pressure, and concentrate the filtrate with a vacuum pump under reduced pressure. The crude product is separated by silica gel column chromatography (petroleum ether / EtOAc=20:1) to obtain a light yellow oil product compound 25-1 (36.00 mg, 88%). [α] D 24 = +15.65 (c 1.0, CHCl3);

[0183] 1 H NMR(500MHz,Chloroform-d)δ6.24(d,J=8.5Hz,1H),6.10(dd,J=9.8,1.7Hz,1H),4.53(dd,J=8.6,4.3Hz,1H),3.74(h,J=5.8H z,1H),2.59(dtt,J=10.5,6.9,4.2Hz,1H),2.18(pd,J=7.0,4.5Hz,1H),1.88(d,J=1.4Hz,3H),1.60–1.43(m,2H),1.47(s,9H), 1.43–1.22(m,5H),1.17(d,J=6.3Hz,3H),1.15–1.09(m,2H),1.04(ddd,J=13.6,9.5,4.1Hz,2H),0.98(d,J=6.6Hz,3H),0.93( d,J=6.9Hz,3H),0.90(d,J=6.9Hz,3H),0.83(d,J=6.5Hz,3H),0.89–0.75(m,2H),0.82(d,J=6.4Hz,3H),0.78(d,J=6.5Hz,3H).

[0184] 13C NMR (126MHz, Chloroform-d) δ171.73,169.25,142.64,129.53,82.14,68.52,57.33,45.86,45.37,44.45,36. 68,32.63,31.87,30.78,30.21,28.26,28.19,27.51,23.65,21.12,20.85,20.81,20.46,19.03,17.80,12.95.

[0185] HRMS (ESI, m / z) for C 28 H 53 NO4Na + [M+Na] + :Calcd.490.3867;Found 490.3864.

[0186] 17. Dissolve compound 25-1 (36.00 mg, 0.08 mmol, 1.0 eq.) and compound 3 (53.00 mg, 0.23 mmol, 3.0 eq.) in anhydrous toluene (4.0 mL) and cool to 0°C. Add DIPEA (0.13 mL, 0.96 mmol, 12.5 eq.) and 2,4,6-trichlorobenzoyl chloride TCBC (70.00 μL, 0.46 mmol, 6.0 eq.) to the reaction system in sequence, then warm to room temperature and stir for about 30 minutes. Cool to 0°C again, and add 4-dimethylaminopyridine DMAP (56.00 mg, 0.46 mmol, 6.0 eq.) to the reaction system. The resulting white turbid solution is stirred at room temperature for about 15 hours. MeOH (1 mL) was added to the reaction solution, which was then diluted with ethyl acetate (10 mL), washed successively with saturated aqueous NH4Cl solution and saturated brine, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The filtrate was concentrated by rotary evaporation under reduced pressure using a vacuum water pump. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc=10:1) to give a colorless oily product, compound 2-1 (49.00 mg, 93%).

[0187] [α] D 24 = +14.83 (c 1.0, CHCl3);

[0188] 1H NMR 1H NMR(400MHz,Chloroform-d)δ6.22(d,J=8.6Hz,1H),6.12–6.04(m,1H),5.06(d,J=8.8Hz,1H),4.90(h,J=6.2Hz,1H),4.53(dd,J=8.6,4.3Hz,1H),4.21(dd,J=8.9,4.5Hz,1H),2.58(ddt,J=14.9,11.0,6.5Hz,1H),2.18(pd,J=6.9,4.4Hz,1H),1.88(d,J=1.3Hz,3H),1.58(ddt,J=27.7,13.7,7.1Hz,2H),1.46(s,9H),1.42(s,9H),1.43–1.21(m,7H),1.20(d,J=6.2Hz,3H),1.20–1.00(m,5H),0.97(d,J=6.6Hz,3H),0.95–0.87(m,12H),0.88–0.85(m,2H),0.81(t,J=6.2Hz,6H),0.77(d,J=6.5Hz,3H).

[0189] 13 C NMR(101MHz,Chloroform-d)δ172.00,171.66,169.22,155.63,142.52,129.54,82.08,79.66,72.61,57.94,57.28,45.34,45.21,44.10,38.30,33.32,32.20,31.85,30.67,29.88,28.45,28.17,28.04,27.20,25.18,21.07,20.84,20.66,20.21,20.06,19.02,17.77,15.54,12.94,11.84.

[0190] HRMS(ESI,m / z)for C 39 H 73 N2O7 + [M+H] + :Calcd.681.5413;Found 681.5414.

[0191] 18. Dissolve compound 2-1 (10.00 mg, 0.015 mmol, 1.0 eq.) in anhydrous DCM (1.5 mL) and cool to 0°C. Add trifluoroacetic acid TFA (0.38 mL) dropwise to the reaction system, then warm to room temperature and stir for about 4 hours. Dilute the reaction solution with DCM (3.0 mL), and concentrate it by vacuum water pump under reduced pressure rotary evaporation. The crude product is directly used in the next reaction after the low boiling point is fully removed by oil pump. Dissolve the above crude product in anhydrous DCM (15 mL), then add HOAt (16.00 mg, 0.12 mmol, 8.0 eq.) and HATU (45.00 mg, 0.12 mmol, 8.0 eq.) in sequence at 0°C, and then slowly add DIPEA (50.00 μL, 0.30 mmol, 20.0 eq.). Warm to room temperature and stir for about 14 hours. The reaction solution was diluted with ethyl acetate (20 mL), then washed with saturated aqueous NH4Cl solution and saturated brine, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The filtrate was concentrated by rotary evaporation under reduced pressure using a vacuum water pump. The crude product was separated by silica gel column chromatography (petroleum ether / EtOAc=5:1–2:1) to give a white solid product RSSSS-1, i.e., Valactamide A (6.00 mg, 79% for two steps).

[0192] [α] D 22 = -9.32 (c 1.0, CHCl3);

[0193] 11H NMR (500 MHz, Chloroform-d) δ 6.59 (d, J = 6.4 Hz, 1H), 6.34 (dd, 1H), 6.19 (d, J = 7.8 Hz, 1H), 4.93 (qd, J = 6.7, 3.7 Hz, 1H), 4.34 (dd, J = 7.8, 5.0 Hz, 1H), 4.28 (t, J = 5.8 Hz, 1H), 2.57 (tdd, J = 10.2, 6.6, 3.3 Hz, 1H), 2.34 (m, 1H), 1.93 (d, J = 1.3 Hz, 3H), 1.89 (m, 1H), 1.62 (m, 1H), 1.51 (m, 1H), 1.49 (m, 1H), 1.48 (m, 1H), 1.44 (m, 1H), 1.43 (m, 1H), 1.38 (td, J = 12.4, 11.3, 2.4 Hz, 1H), 1.28 (m, 1H), 1.26 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H), 1.20 (m, 1H), 1.12 (ddd, J = 14.0, 11.3, 3.2 Hz, 1H), 1.02 (d, J = 6.8 Hz, 3H), 0.99 (m, 2H), 0.96 (d, J = 5.8 Hz, 3H), 0.94 (m, 1H), 0.94 (dd, J = 7.5, 4.2 Hz, 3H), 0.92 (d, 3H), 0.87 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H), 0.82 (m, 1H), 0.81 (d, J = 6.6 Hz, 6H).

[0194] 13 13C NMR (126 MHz, Chloroform-d) δ 171.22, 170.98, 169.44, 144.46, 128.31, 72.45, 58.81, 57.24, 47.96, 46.06, 44.86, 37.33, 32.53, 30.74, 30.46, 30.23, 29.91, 28.97, 28.42, 25.85, 21.13, 20.88, 20.80, 20.28, 19.59, 19.51, 17.48, 15.03, 12.57, 11.45.

[0195] HRMS (ESI, m / z) for C 30 H 55 N2O4 + [M + H] + : Calcd. 507.4157; Found 507.4160。

[0196] As attached Figure 4As shown, by comparing the NMR data of the prepared RSSSS-1, it is almost completely consistent with the NMR data of the natural Valactamide A. The structure RSSSS-1 predicted based on the biogenic synthesis pathway in the present application example is the true three-dimensional structure of the natural product Valactamide A. The present application example completes the first total synthesis and structural identification of Valactamide A.

[0197] Example 2

[0198] A method for synthesizing the diastereomer RSSRR-1 of Valactamide A, wherein the synthetic route is as shown in the attached Figure 2 As shown, the steps include:

[0199] 1. Compound 8 was prepared according to steps 1-5 of Example 1.

[0200] 2. The synthesis process is similar to that of step 6 in Example 1, except that compound ent-9 is replaced by compound 9 to obtain a slightly yellow oily liquid compound 17-2 (500 mg, 84%, E:Z>10:1).

[0201] [α] D 21 =-10.65 (c1.0, CHCl3).

[0202] 1 H NMR(400MHz,Chloroform-d)δ7.37–7.25(m,3H),7.23(dd,J=6.5,2.2Hz,3H),7.07(dd,J=15.3,8.3Hz,1H ),4.73(ddt,J=10.3,6.8,3.2Hz,1H),4.29–4.13(m,2H),3.90(h,J=4.8,4.0Hz,1H),3.35(dd,J=13.4,3.4 Hz,1H),2.79(dd,J=13.3,9.7Hz,1H),2.55(dt,J=14.8,8.1Hz,1H),1.61–1.23(m,5H),1.19(dd,J=9.8,4 .9Hz,1H),1.15(d,J=6.0Hz,3H),1.09(s,1H),1.08(d,J=6.7Hz,3H),1.06(s,21H),0.89(d,J=6.2Hz,3H).

[0203] 13C NMR(101MHz,Chloroform-d)δ165.37,157.30,153.56,135.59,129.58,129.08,127.43,118.86,68.9 6,66.24,55.51,43.91,38.09,37.22,34.83,32.87,30.77,23.68,20.47,19.60,18.29,18.27,12.61.

[0204] HRMS(ESI,m / z):for C 31 H 52 NO4Si + [M+H] + :Calcd.530.3661;Found 530.3659.

[0205] 3. The synthesis procedure is similar to that of step 7 in Example 1, except that compound 17-1 is replaced by 17-2 to obtain a light yellow oily liquid compound 18-2 (0.34 g, 67% in two steps, dr>10:1).

[0206] [α] D 21 =-12.50 (c1.0, CHCl3).

[0207] 1 H NMR(400MHz,Chloroform-d)δ7.37–7.27(m,3H),7.24–7.19(m,2H),4.65(ddt,J=10.3,7.2,3 .0Hz,1H),4.26–4.11(m,2H),3.94–3.77(m,2H),3.28(dd,J=13.3,3.3Hz,1H),2.76(dd,J=13. 3,9.6Hz,1H),1.67–1.40(m,5H),1.40–1.22(m,4H),1.19(d,J=6.8Hz,3H),1.13(d,J=6.1Hz, 3H), 1.05 (s, 21H), 0.97 (dd, J = 13.8, 7.0Hz, 1H), 0.87 (d, J = 6.4Hz, 3H), 0.84 (d, J = 6.5Hz, 3H).

[0208] 13C NMR(101MHz,Chloroform-d)δ177.95,153.13,135.51,129.59,129.07,127.47,68.98,66.12,55.61 ,45.59,40.41,38.05,37.25,35.49,32.15,30.28,27.80,23.62,20.29,19.91,18.30,16.88,12.61.

[0209] HRMS (ESI, m / z) for C 32 H 56 NO4Si + [M+H] + :Calcd.546.3974; Found 546.3972.

[0210] 4. The synthesis process is similar to that of step 8 in Example 1, except that compound 18-1 is replaced by 18-2 to obtain a colorless to light yellow oily liquid compound 19-2 (0.38 g, 87%).

[0211] [α] D 21 = +51.98 (c1.0, CHCl3);

[0212] 1 H NMR (400MHz, Chloroform-d) δ3.89 (td, J=6.3, 5.1Hz, 1H), 3.47 (dd, J=10.4, 5.8Hz, 1H), 3.40 (dd, J=10.4,6.6Hz,1H),1.72(dq,J=13.4,6.6Hz,1H),1.53(dddd,J=34.7,21.5,11.0,4.4Hz,5H),1.42 –1.22(m,3H),1.20(dd,J=13.5,6.8Hz,1H),1.15(d,J=6.1Hz,3H),1.10–1.07(m,1H),1.06(s,21H) ,0.98(dt,J=13.9,7.2Hz,1H),0.89(d,J=6.6Hz,3H),0.85(d,J=3.4Hz,3H),0.83(d,J=3.3Hz,3H).

[0213] 13C NMR (101MHz, Chloroform-d) δ69.41,69.04,46.06,40.46,37.25,33.37,32.37,30.21,27.26,23.68,20.26,20.13,18.33,18.31,16.26,12.64.

[0214] HRMS (ESI, m / z) for C 22 H 48 O2SiNa + [M+Na] + :Calcd.395.3316; Found 395.3311.

[0215] 5. The synthesis process is similar to that of step 9 in Example 1, except that compound 19-1 is replaced by 19-2 to obtain a colorless to light yellow oily liquid compound 20-2 (0.51 g, 90%).

[0216] 6. The synthesis step is similar to step 10 in Example 1, except that compound 20-1 is replaced by 20-2, and compound ent-9 is replaced by compound 9 to obtain a light yellow oily liquid compound 21-2 (0.73 g, 92%).

[0217] [α] D 22 =-14.52 (c1.0, CHCl3).

[0218] 1 H NMR(500MHz,Chloroform-d)δ7.34(dd,J=8.2,6.7Hz,2H),7.28(d,J=7.2Hz,1H),7.25–7.20(m,3H),7.13(dd,J=15.4,7. 6Hz,1H),4.72(ddt,J=10.3,6.8,3.2Hz,1H),4.28–4.13(m,2H),3.89(h,J=6.0Hz,1H),3.35(dd,J=13.4,3.3Hz,1H),2.7 8(dd,J=13.3,9.7Hz,1H),2.52(hept,J=6.9Hz,1H),1.55–1.43(m,2H),1.39–1.28(m,3H),1.25–1.17(m,2H),1.13(d,J= 6.0Hz,3H),1.11–1.09(m,1H),1.05(s,25H),0.97(dt,J=13.9,7.2Hz,1H),0.86(d,J=3.6Hz,3H),0.85(d,J=3.6Hz,3H).

[0219] 13 C NMR(101MHz,Chloroform-d)δ165.48,158.06,153.55,135.62,129.60,129.10,127.44,118.21,69.00,66.22,5 5.55,45.58,43.48,38.08,37.25,34.67,32.06,30.32,27.80,23.60,20.40,20.26,18.91,18.32,18.30,12.62.

[0220] HRMS (ESI, m / z) for C 34 H 58 NO4Si + [M+H] + :Calcd.572.4130; Found 572.4133.

[0221] 7. The synthesis process is similar to that of step 11 in Example 1, except that compound 21-1 is replaced by 21-2 to obtain light yellow oily liquid compound 22-2 (0.56 g, 73% in two steps).

[0222] [α] D 21 =-23.55 (c1.0, CHCl3).

[0223] 1 H NMR(400MHz,Chloroform-d)δ7.37–7.29(m,2H),7.32–7.25(m,1H),7.25–7.18(m,2H),4.68(ddt,J=10.2,6.9,3.2Hz, 1H),4.27–4.12(m,2H),3.88(tp,J=13.2,6.9,6.4Hz,2H),3.26(dd,J=13.4,3.3Hz,1H),2.77(dd,J=13.4,9.6Hz,1H), 1.75(ddd,J=13.9,8.1,6.3Hz,1H),1.63–1.41(m,5H),1.42–1.26(m,2H),1.26–1.18(m,1H),1.21(d,J=6.8Hz,3H),1. 15(d,J=6.0Hz,3H),1.13–1.06(m,1H),1.06(s,21H),1.04–0.91(m,3H),0.83(d,J=6.5Hz,6H),0.81(d,J=6.5Hz,3H).

[0224] 13 C NMR(101MHz,Chloroform-d)δ177.57,153.14,135.47,129.60,129.05,127.46,69.08,66.10,55.46,46.17,44.28 ,41.91,38.01,37.25,35.41,32.39,30.18,28.06,27.40,23.67,20.24,20.01,19.63,18.32,18.30,18.23,12.63.

[0225] HRMS (ESI, m / z) for C 35 H 61 NO4SiNa + [M+Na] + :Calcd.610.4263; Found 610.4267.

[0226] 8. The synthesis process is similar to that of step 12 in Example 1, except that compound 22-1 is replaced by 22-2 to obtain a colorless to light yellow oily liquid compound 23-2 (0.31 g, 89%).

[0227] [α] D 22 = +9.7 (c1.0, CHCl3);

[0228] 1 H NMR(500MHz,Chloroform-d)δ3.89(dt,J=12.3,5.8Hz,1H),3.51(dd,J=10.4,5.3H z,1H),3.38(dd,J=10.4,6.8Hz,1H),1.73(dq,J=14.9,6.6Hz,1H),1.63–1.43(m,5 H),1.40–1.20(m,4H),1.15(d,J=6.1Hz,3H),1.13–1.08(m,1H),1.06(s,21H),1.0 1–0.94(m,4H),0.91(d,J=6.6Hz,3H),0.84(t,J=6.2Hz,6H),0.81(d,J=6.5Hz,3H).

[0229] 13 C NMR (126MHz, Chloroform-d) δ69.1,68.8,46.2,44.1,42.2,37.3,33.2,32.5,30.2,27.4,23.7,20.3,20.3,20.2,18.3,18.3,17.2,12.7.

[0230] HRMS (ESI, m / z) for C 25 H 54 O2SiNa + [M+Na] + :Calcd.437.3786;Found 437.3783.

[0231] 9. The synthesis process is similar to that of step 13 in Example 1, except that compound 23-1 is replaced by 23-2 to obtain a light yellow oily liquid compound 6-2 (0.26 g, 87%).

[0232] 10. The synthesis process is similar to step 14 in Example 1, except that compound 6-1 is replaced by 6-2 to obtain light yellow oily liquid compound 5-2 (0.28 g, 91%).

[0233] [α] D 23 = -2.1 (c1.0, CHCl3);

[0234] HRMS (ESI, m / z) for C 30 H 61 O3Si + [M+H] + :Calcd.497.4385; Found 497.4387.

[0235] 11. The synthesis process is similar to that of step 15 in Example 1, except that compound 5-1 is replaced by 5-2 to obtain a light yellow oily liquid compound 24-2 (0.27 g, 83% in two steps).

[0236] [α] D 21 = +3.1 (c1.0, CHCl3);

[0237] 1H NMR(400MHz,Chloroform-d)δ6.21(d,J=8.5Hz,1H),6.15(d,J=9.7Hz,1H),4.52(dd,J=8.5,4.4Hz, 1H),3.89(q,J=5.9Hz,1H),2.67–2.52(m,1H),2.19(dq,J=11.4,6.8Hz,1H),1.89(d,J=1.5Hz,3H), 1.61–1.49(m,3H),1.47(s,9H),1.45–1.41(m,2H),1.38–1.19(m,6H),1.14(d,J=6.1Hz,3H),1.05( s,21H),1.01(s,0H),1.00(s,0H),1.00–0.89(m,11H),0.82(d,J=6.5Hz,3H),0.79(t,J=6.2Hz,6H).

[0238] 13 C NMR(101MHz,Chloroform-d)δ171.6,169.3,142.9,129.1,82.1,69.0,57.4,46.2,45.8,44.8,37.3, 32.4,31.9,30.5,30.2,28.2,28.0,27.4,23.7,20.6,20.2,20.1,19.4,19.0,18.3,17.9,13.0,12.6.

[0239] HRMS (ESI, m / z) for C 37 H 74 NO4Si + [M+H] + :Calcd.624.5382; Found 624.5380.

[0240] 12. The synthesis process is similar to that of step 16 in Example 1, except that compound 24-1 is replaced by 24-2 to obtain a light yellow oily liquid compound 25-2 (74.50 mg, 95%).

[0241] [α] D 21 = -2.38 (c1.0, CHCl3);

[0242] 1H NMR(400MHz,Chloroform-d)δ6.24(d,J=8.8Hz,1H),6.21(dd,J=10.0,1.5Hz,1H),4.53(dd,J=8.5,4.3Hz,1H),3.76( h,J=6.0Hz,1H),2.58(td,J=9.7,4.7Hz,1H),2.36–2.11(m,2H),1.89(d,J=1.3Hz,3H),1.54(q,J=6.9Hz,1H),1.46(s, 9H),1.44–1.35(m,2H),1.39–1.21(m,4H),1.18(d,J=6.0Hz,3H),1.19–1.05(m,3H),1.04–0.97(m,1H),0.97(d,J=6.6 Hz,3H),0.94(d,J=6.7Hz,3H),0.92(d,J=7.0Hz,3H),0.90–0.82(m,2H),0.82(t,J=5.7Hz,6H),0.79(d,J=4.8Hz,3H).

[0243] 13 C NMR(101MHz,Chloroform-d)δ171.7,168.9,143.6,128.6,82.2,68.6,57.4,45.6,45.4,36. 9,32.9,31.9,30.7,30.3,28.2,28.1,27.5,23.6,20.9,20.7,20.4,20.1,19.1,17.9,12.9.

[0244] HRMS (ESI, m / z) for C 28 H 54 NO4 + [M+H] + :Calcd.468.4047; Found 468.4048.

[0245] 13. The synthesis process is similar to that of step 17 in Example 1, except that compound 25-1 is replaced by 25-2 to obtain a light yellow oily liquid compound 2-2 (56.80 mg, 70%).

[0246] [α] D 21 = +3.6 (c1.0, CHCl3);

[0247] 1H NMR(400MHz,Chloroform-d)δ6.21(d,J=8.5Hz,1H),6.14(dd,J=9.8,1.6Hz,1H),5.07(d,J=8.8Hz,1H),4.91(h,J=6.1Hz,1H),4 .51(dd,J=8.5,4.4Hz,1H),4.22(dd,J=9.0,4.6Hz,1H),2.58(ddd,J=15.5,8.8,6.2Hz,1H),2.18(pd,J=6.9,4.4Hz,1H),1.88(d, J=1.3Hz,3H),1.70–1.47(m,4H),1.47(s,9H),1.43(s,9H),1.45–1.36(m,3H),1.31–1.20(m,3H),1.21(dd,J=6.5,2.3Hz,3H),1 .20–0.96(m,6H),0.96(d,J=6.5Hz,3H),0.97–0.87(m,12H),0.82(d,J=6.5Hz,3H),0.80(d,J=6.4Hz,3H),0.78(d,J=6.5Hz,3H).

[0248] 13 C NMR(101MHz,Chloroform-d)δ172.0,171.6,169.2,155.6,142.8,128.9,82.0,79.6,72.6,57.9,57.4,45.8(d,J=19.9Hz),44 .6,38.3,33.3,32.5,31.8,30.5,29.8,28.4,28.1,27.9,27.2,25.1,20.5,20.2–19.7(m),19.4,18.9,17.9,15.5,12.9,11.8.

[0249] HRMS (ESI, m / z) for C 39 H 73 N2O7 + [M+H] + :Calcd.681.5413; Found 681.5415.

[0250] 14. The synthetic procedure is similar to step 18 in Example 1, except that compound 2-1 is replaced by 2-2 to obtain a white solid, which is the diastereomer RSSRR-1 of Valactamide A (14.00 mg, 61% in two steps).

[0251] [α] D 21= -1.42 (c1.0, CHCl3);

[0252] 1 H NMR(400MHz,Chloroform-d)δ6.61(d,J=6.4Hz,1H),6.11(d,J=8.0Hz,1H),5.89(dd,J=9.7,1.7Hz,1H),5.05–4.93(m ,1H),4.32(dd,J=8.1,5.3Hz,1H),4.27(t,J=6.1Hz,1H),2.62–2.51(m,1H),2.35(dq,J=13.3,6.8Hz,1H),1.95–1.87 (m,1H),1.85(d,J=1.4Hz,3H),1.62–1.32(m,6H),1.29–1.27(m,1H),1.26–1.24(m,1H),1.23(d,J=6.3Hz,3H),1.16– 1.14(m,0H),1.08–1.01(m,3H),1.01(d,J=2.2Hz,3H),0.99(d,J=2.4Hz,3H),0.98–0.88(m,9H),0.87–0.78(m,10H).

[0253] 13 C NMR(101MHz,Chloroform-d)δ171.4,171.3,171.3,141.6,131.3,72.2,58.8,57.6,46.4,45.8,45.1,37.2, 33.6,31.7,31.4,30.7,29.9,29.8,28.5,25.9,22.0,21.6,21.4,20.5,20.3,19.6,17.6,15.4,13.4,11.6.

[0254] HRMS (ESI, m / z) for C 30 H 55 N2O4 + [M+H] + :Calcd.507.4157;Found 507.4156.

[0255] RSSRR-1 and natural Valactamide A 13 The C NMR data comparison results are shown in the attached Figure 5 As shown, the horizontal axis is the number of carbon atoms.

[0256] Example 3

[0257] A method for synthesizing the diastereomer RRRSS-1 of Valactamide A, wherein the synthetic route is as shown in the attached Figure 3 As shown, the steps include:

[0258] 1. The synthetic procedure is similar to that of step 1 in Example 1, except that compound 12 is replaced by known compound 12-2. The crude product is separated by silica gel column chromatography (petroleum ether / EtOAc=50:1-20:1) to obtain a light yellow oily product compound 13-2 (3.63 g, 90%).

[0259] [α] D 23 = +2.6 (c 5.0, CHCl3).

[0260] 1 H NMR(400MHz,Chloroform-d)δ7.60–7.46(m,5H),3.48(dd,J=12.6,5.3Hz,1H),3. 37(dd,J=5.7,1.6Hz,2H),3.20(dd,J=12.6,7.5Hz,1H),2.12–1.99(m,1H),1.79– 1.66(m,1H),1.54(dt,J=13.6,6.8Hz,1H),1.03(d,J=6.7Hz,3H),1.08–0.98(m,1 H),0.98(s,1H),0.89(d,J=6.6Hz,3H),0.84(s,9H),-0.01(s,3H),-0.02(s,3H).

[0261] 13 C NMR (101MHz, Chloroform-d) δ154.8,133.8,130.1,129.8,123.9,67.9,40.5,40.1,33.1,30.5,26.0,20.0,18.3,17.5,-5.3,-5.4.

[0262] HRMS(ESI,m / z):for C 20 H 35 N4OSSi + [M+H] + :Calcd.407.2296; Found 407.2299.

[0263] 2. The synthesis step is similar to that of step 2 in Example 1, except that compound 13-1 is replaced by 13-2. The crude product is separated by silica gel column chromatography (petroleum ether / EtOAc=80:1-30:1) to obtain a light yellow oily product compound 14-2 (3.50 g, 85%).

[0264] [α] D 23 = -17.4 (c 1.0, CHCl3).

[0265] 1 H NMR(500MHz,Chloroform-d)δ7.68–7.63(m,2H),7.61–7.51(m,3H),3.80(dd,J=14.5 ,3.8Hz,1H),3.50(dd,J=14.4,8.7Hz,1H),3.39(d,J=5.8Hz,2H),2.53–2.36(m,1H), 1.70(dq,J=12.9,6.4Hz,1H),1.59(ddd,J=13.8,7.5,6.3Hz,1H),1.16(d,J=6.7Hz,3 H),1.16–1.09(m,1H),0.87(d,J=6.7Hz,3H),0.86(s,9H),0.01(s,3H),0.00(s,3H).

[0266] 13 C NMR (126MHz, Chloroform-d) δ154.1,133.1,131.4,129.6,125.2,67.8,61.8,41.1,32.9,26.1,25.9,20.7,18.3,17.3,-5.4,-5.4.

[0267] HRMS(ESI,m / z):for C 20 H 35 N4O3SSi + [M+H] + :Calcd.439.2194; Found 439.2191.

[0268] 3. Slowly add NaHMDS (solution in THF, 2.0N, 5.47mL, 10.94mmol, 2.0eq.) to a solution of compound 14-2 (2.40g, 5.47mmol, 1.0eq.) in THF (14mL) at -78°C via syringe and stir for 30 minutes at the same temperature. Slowly add a solution of 11 (2.50g, 10.94mol, 2.0eq.) in THF (28mL) via syringe to the above reaction system, and then continue stirring at -78°C for 12 hours. Saturated NH4Cl aqueous solution was added to the reaction system at the same temperature to quench the reaction. After returning to room temperature, the liquids were separated, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated NaHCO3 aqueous solution and saturated brine in sequence, and then dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtrate was concentrated by rotary evaporation under reduced pressure using a vacuum water pump. The crude product was crudely separated by silica gel column chromatography (pure petroleum ether-petroleum ether / EtOAc=500:1) to give a crude product 15-2 (2.00 g) containing 11.

[0269] 4. The above crude product 15-2 (1.00 g), 5% Pd / C (300.00 mg) and a stirrer were placed in a round-bottom flask, evacuated and protected with argon, anhydrous ethyl acetate (23 mL) and Et3N (0.62 mL, 4.50 mmol) were added in sequence with a syringe, stirred evenly and ventilated with a hydrogen balloon 3 times, and the reaction system was stirred in a hydrogen atmosphere at 25°C for about 8 hours. The solids in the reaction system were removed by diatomaceous earth filtration, the filter cake was washed with ethyl acetate, and the filtrate was concentrated by vacuum evaporation with a vacuum water pump. The crude product was separated by silica gel column chromatography (pure petroleum ether-petroleum ether / EtOAc=500:1) to obtain a colorless oily product 15-3 (1.04 g, 2-step total yield 85%).

[0270] [α] D 25 = +1.6 (c 2.0, CHCl3).

[0271] 1H NMR(500MHz,Chloroform-d)δ3.88(h,J=6.0Hz,1H),3.44(dd,J=9.7,5.3Hz,1H),3.32(dd,J=9.5,6.8Hz,1H),1.73–1.62(m,1H),1.51–1.42(m,3H) ,1.41–1.26(m,2H),1.15(d,J=6.0Hz,3H),1.06(s,21H),1.08–0.98(m,2H ),0.90(s,9H),0.88(d,J=2.8Hz,3H),0.87(d,J=2.9Hz,3H),0.04(s,6H).

[0272] 13 C NMR (126MHz, Chloroform-d) δ69.1,68.5,41.3,37.4,33.3,32.4,30.4,26.1,23.7,20.6,18.5,18.3,18.3,17.7,12.7,-5.2.

[0273] HRMS(ESI,m / z):for C 25 H 57 O2Si2 + [M+H] + :Calcd.445.3892;Found 445.3890.

[0274] 5. Dissolve compound 15-3 (1.40 g, 3.15 mmol, 1.0 eq.) in methanol (31 mL), add ammonium fluoride (1.70 g, 47.29 mmol, 15.0 eq.), stir at 40°C for about 20 hours until TLC shows that the reaction is complete, and concentrate the reaction solution by rotary evaporation under reduced pressure with a vacuum water pump. The crude product is separated by silica gel column chromatography (petroleum ether / EtOAc=30:1-10:1) to give a colorless oily product compound ent-16 (0.84 g, 81%).

[0275] [α] D 25 = +3.6 (c 5.0, CHCl3).

[0276] 1H NMR(500MHz,Chloroform-d)δ3.87(h,J=5.9Hz,1H),3.50(dd,J=10.5,5.1Hz, 1H),3.35(dd,J=10.4,6.8Hz,1H),1.76–1.65(m,1H),1.51–1.41(m,3H),1.43– 1.33(m,1H),1.29(dt,J=13.6,6.8Hz,1H),1.14(d,J=6.0Hz,3H),1.07(s,1H), 1.05(s,21H),0.99–0.91(m,1H),0.91(d,J=6.6Hz,3H),0.88(d,J=6.5Hz,3H).

[0277] 13 C NMR (126MHz, Chloroform-d) δ69.0,68.5,41.2,37.3,33.2,32.2,30.4,23.6,20.5,18.3,18.3,17.3,12.6.

[0278] HRMS(ESI,m / z):for C 19 H 43 O2Si+[M+H]+:Calcd.331.3027; Found 331.3029.

[0279] 6. The synthesis step is similar to that of step 5 in Example 1, except that compound 16 is replaced by compound ent-16, and the crude product is separated by silica gel column chromatography (petroleum ether / EtOAc=500:1) to obtain a colorless to slightly yellow oily product compound ent-8 (0.53 g, 87%).

[0280] 7. The synthesis process is similar to that of step 6 in Example 1, except that compound 8 is replaced with ent-8 to obtain a slightly yellow oily liquid compound 17-3 (0.69 g, 88%).

[0281] [α] D 24 = +10.9 (c 1.0, CHCl3).

[0282] 1H NMR(500MHz,Chloroform-d)δ7.33(dd,J=8.0,6.5Hz,2H),7.31–7.20(m,4H),7.07(dd,J=15.4,8. 3Hz,1H),4.77–4.68(m,1H),4.19(qd,J=9.0,5.2Hz,2H),3.89(h,J=6.0Hz,1H),3.36(dd,J=13.4,3 .3Hz,1H),2.79(dd,J=13.4,9.6Hz,1H),2.54(p,J=7.8Hz,1H),1.53–1.31(m,5H),1.24–1.16(m,1 H),1.15(d,J=6.0Hz,3H),1.12(s,1H),1.08(d,J=6.8Hz,3H),1.06(s,21H),0.89(d,J=6.1Hz,3H).

[0283] 13 C NMR(126MHz,Chloroform-d)δ165.4,157.3,153.5,135.6,129.6,129.1,127.4,118.9,6 9.0,66.2,55.5,44.0,38.1,37.3,34.8,32.9,30.8,23.7,20.4,19.6,18.3,18.3,12.6.

[0284] HRMS(ESI,m / z):for C 31 H 52 NO4Si + [M+H] + :Calcd.530.3661; Found 530.3662.

[0285] 8. The synthesis process is similar to that of step 7 in Example 1, except that compound 17-1 is replaced by 17-3 to obtain a slightly yellow oily product compound 18-3 (0.69 g, 88%).

[0286] [α] D 24 = +14.38 (c 1.0, CHCl3).

[0287] 1H NMR(400MHz,Chloroform-d)δ7.37–7.31(m,2H),7.30–7.26(m,1H),7.24–7.19(m,2H),4.66(ddt,J=10.2 ,7.2,3.1Hz,1H),4.29–4.13(m,2H),3.95–3.73(m,2H),3.27(dd,J=13.3,3.3Hz,1H),2.77(dd,J=13.3,9 .6Hz,1H),1.70–1.53(m,2H),1.52–1.40(m,4H),1.39–1.27(m,1H),1.20(d,J=6.7Hz,3H),1.23–1.14(m, 1H),1.14(d,J=6.0Hz,3H),1.05(s,21H),1.03–0.94(m,2H),0.87(d,J=6.5Hz,3H),0.85(d,J=6.5Hz,3H).

[0288] 13 C NMR(101MHz,Chloroform-d)δ177.9,153.1,135.5,129.6,129.1,127.5,69.1,66.1,55.6 ,45.6,40.4,38.0,37.3,35.5,32.4,30.2,27.7,23.7,20.2,19.8,18.3,18.3,16.9,12.6.

[0289] HRMS (ESI, m / z) for C 32 H 56 NO4Si + [M+H] + :Calcd.546.3974; Found 546.3978.

[0290] 9. The synthesis process is similar to that of step 8 in Example 1, except that compound 18-1 is replaced by 18-3 to obtain yellow oily liquid compound 19-3 (0.16 g, 93%).

[0291] [α] D 24 = -10.55 (c1.0, CHCl3);

[0292] 1H NMR (400MHz, Chloroform-d) δ3.87 (h, J=5.9Hz, 1H), 3.46 (dd, J=10.4, 5.9Hz, 1H), 3.39 (dd, J= 10.4,6.6Hz,1H),1.71(dq,J=13.3,6.6Hz,1H),1.59(dq,J=13.7,6.5Hz,1H),1.51–1.40(m,4H) ,1.35(dtd,J=12.8,9.1,8.2,4.7Hz,1H),1.19(d,J=6.9Hz,1H),1.14(d,J=6.0Hz,3H),1.08(s ,1H),1.05(s,21H),0.99(dt,J=14.1,7.3Hz,2H),0.88(d,J=6.6Hz,3H),0.83(t,J=6.5Hz,6H).

[0293] 13 C NMR (101MHz, Chloroform-d) δ69.3,69.1,46.2,40.5,37.5,33.3,32.7,30.2,27.2,23.7,20.2,20.0,18.3,18.3,16.3,12.6.

[0294] HRMS (ESI, m / z) for C 22 H 49 O2Si + [M+H] + :Calcd.373.3497; Found 373.3495.

[0295] 10. The synthesis process is similar to that of step 9 in Example 1, except that compound 19-1 is replaced by 19-3 to obtain a colorless oily liquid compound 20-3 (0.38 g, 90%).

[0296] 11. The synthesis process is similar to that of step 10 in Example 1, except that compound 20-1 is replaced by 20-3 to obtain a colorless to light yellow oily liquid compound 21-3 (0.52 g, 89%).

[0297] [α] D 21 = +19.5 (c1.0, CHCl3);

[0298] 1H NMR(400MHz,Chloroform-d)δ7.43–7.35(m,2H),7.35–7.24(m,4H),7.22–7.12(m,1H),4.76(ddt,J=10.2, 7.0,3.5Hz,1H),4.30–4.17(m,2H),3.91(h,J=6.0Hz,1H),3.39(dd,J=13.4,3.3Hz,1H),2.82(dd,J=13.4, 9.7Hz,1H),2.56(hept,J=6.8Hz,1H),1.70–1.57(m,2H),1.56–1.43(m,2H),1.46–1.29(m,2H),1.30–1.18 (m,2H),1.18(d,J=6.1Hz,3H),1.12(s,3H),1.10–1.07(m,21H),1.09–0.96(m,2H),0.90(d,J=6.5Hz,6H).

[0299] 13 C NMR(101MHz,Chloroform-d)δ165.5,158.0,153.5,135.6,129.6,129.1,127.4,118.2,69.1,66. 2,55.5,45.7,43.5,38.1,37.5,34.6,32.4,30.3,27.8,23.7,20.4,20.1,18.9,18.3,18.3,12.6.

[0300] HRMS (ESI, m / z) for C 34 H 57 NO4SiNa + [M+Na] + :Calcd.594.3950; Found 594.3954.

[0301] 12. The synthesis procedure is similar to step 11 in Example 1, except that compound 21-1 is replaced by 21-3 to obtain colorless oily liquid compound 22-3 (0.25 g, 83% in two steps).

[0302] [α] D 21 = +12.13 (c1.0, CHCl3).

[0303] 1H NMR(500MHz,Chloroform-d)δ7.36–7.31(m,2H),7.30–7.27(m,1H),7.24–7.19(m,2H),4.68(ddt,J=10.3,7. 5,3.1Hz,1H),4.31–4.13(m,2H),3.97–3.80(m,2H),3.26(dd,J=13.4,3.3Hz,1H),2.77(dd,J=13.3,9.6Hz,1H ),1.75(ddd,J=13.9,8.1,6.3Hz,1H),1.62–1.32(m,6H),1.21(d,J=6.8Hz,3H),1.15(d,J=6.0Hz,3H),1.06( s,21H),0.97(ddd,J=16.5,10.0,5.0Hz,4H),0.91–0.85(m,2H),0.84(d,J=6.4Hz,6H),0.81(d,J=6.5Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ177.6,153.2,135.5,129.6,129.1,127.5,69.2,66.1,55.5,46.3,44 .4,41.9,38.0,37.5,35.4,32.7,30.2,29.8,28.1,27.4,23.8,20.3,20.0,19.7,18.3,18.3,12.7.

[0304] HRMS (ESI, m / z) for C 35 H 61 NO4SiNa + [M+Na] + :Calcd.610.4263; Found 610.4266.

[0305] 13. The synthesis process is similar to that of step 12 in Example 1, except that compound 22-1 is replaced by 22-3 to obtain a light yellow oily liquid compound 23-2 (0.15 g, 91%).

[0306] [α] D 25 = -9.1 (c1.0, CHCl3);

[0307] 1H NMR(400MHz,Chloroform-d)δ3.87(h,J=6.0Hz,1H),3.51(dd,J=10.4,5.3Hz,1H),3.38(dd,J =10.4,6.7Hz,1H),1.73(h,J=6.5Hz,1H),1.63–1.51(m,3H),1.45(dt,J=8.9,6.5Hz,3H),1.43 –1.30(m,2H),1.30–1.19(m,2H),1.15(d,J=5.9Hz,3H),1.11(d,J=7.1Hz,1H),1.06(s,21H), 0.99(m,3.7Hz,3H),0.91(d,J=6.7Hz,3H),0.84(dd,J=6.6,3.8Hz,6H),0.81(d,J=6.5Hz,3H).

[0308] 13 C NMR (101MHz, Chloroform-d) δ69.2,68.7,46.3,44.2,42.1,37.5,33.1,32.7,30.2,27.4,27.4,23.7,20.4,20.2,20.1,18.3,18.3,17.2,12.6.

[0309] HRMS (ESI, m / z) for C 25 H 55 O2Si + [M+H] + :Calcd.415.3966;Found 415.3969.

[0310] 14. The synthesis process is similar to that of step 13 in Example 1, except that compound 23-1 is replaced by 23-3 to obtain a colorless oily liquid compound 6-3 (0.11 g, 85%).

[0311] 15. The synthesis step is similar to step 14 in Example 1, except that compound 6-1 is replaced by 6-3 to obtain a milky white oily liquid compound 5-3 (0.11 g, 78%, E:Z>12:1).

[0312] [α] D 25 = +2.58 (c1.0, CHCl3);

[0313] 1H NMR(400MHz,Chloroform-d)δ6.51(d,J=10.1Hz,1H),4.18(ddd,J=8.8,7.1,5.8Hz,2H),3.87 (q,J=6.0Hz,1H),2.60(q,J=8.3,7.5Hz,1H),1.84(s,3H),1.62–1.52(m,2H),1.51–1.38(m,4H ),1.34–1.23(m,2H),1.29(t,J=7.2Hz,3H),1.15(d,J=5.6Hz,3H),1.19–1.09(m,2H),1.06(s ,21H),0.97(d,J=5.8Hz,3H),1.02–0.87(m,3H),0.83(d,J=6.3Hz,3H),0.79(t,J=5.8Hz,6H).

[0314] 13 C NMR (101MHz, Chloroform-d) δ168.6,148.4,126.2,69.2,60.5,46.2,45.5,45.1,37. 6,32.6,30.9,30.2,28.1,27.3,23.8,20.5,20.3,20.1,19.5,18.3,18.3,14.5,12.6.

[0315] HRMS (ESI, m / z) for C 30 H 61 O3Si + [M+H] + :Calcd.497.4385; Found 497.4389.

[0316] 16. The synthesis procedure is similar to that of step 15 in Example 1, except that compound 5-1 is replaced by 5-3 to obtain a colorless to light yellow oily liquid compound 24-3 (75.00 mg, 80% in two steps).

[0317] [α] D 25 = +9.8 (c1.0, CHCl3);

[0318] 1H NMR(400MHz,Chloroform-d)δ6.22(d,J=8.5Hz,1H),6.13(d,J=9.8Hz,1H),4.54(dd,J=8.5,4.3Hz,1H),3.87(h,J= 5.8Hz,1H),2.59(tt,J=8.6,6.1Hz,1H),2.19(pd,J=7.0,4.4Hz,1H),1.89(s,3H),1.61–1.50(m,1H),1.47(s,9H), 1.48–1.15(m,8H),1.14(d,J=6.0Hz,3H),1.13–1.07(m,2H),1.06(s,21H),1.03–0.99(m,2H),0.97(d,J=6.4Hz,3H ),0.94(d,J=6.8Hz,3H),0.92(d,J=6.9Hz,3H),0.82(d,J=6.4Hz,3H),0.79(d,J=6.4Hz,3H),0.77(d,J=6.5Hz,3H).

[0319] 13 C NMR(101MHz,Chloroform-d)δ171.7,169.3,142.7,129.2,82.1,69.2,57.3,46.3,45.8,45.1,37.6,32. 7,31.9,30.6,30.2,28.2,28.0,27.3,23.8,20.7,20.3,20.0,19.4,19.0,18.3,18.3,17.9,13.0,12.6.

[0320] HRMS (ESI, m / z) for C 37 H 73 NO4SiNa + [M+Na] + :Calcd.646.5202; Found 646.5201.

[0321] 17. The synthesis process is similar to that of step 16 in Example 1, except that compound 24-1 is replaced by 24-3 to obtain a light yellow oily liquid compound 25-3 (40.00 mg, 89%).

[0322] [α] D 25 = +11.6 (c1.0, CHCl3);

[0323] 1H NMR(400MHz,Chloroform-d)δ6.25(d,J=8.5Hz,1H),6.20(d,J=9.9Hz,1H),4.54(dd,J=8.5,4.3Hz,1H),3. 74(h,J=6.0Hz,1H),2.60(td,J=14.0,11.8,7.6Hz,1H),2.19(pd,J=6.9,4.3Hz,1H),1.90(s,3H),1.74(br s,1H),1.48(s,9H),1.59–1.27(m,7H),1.19(d,J=6.2Hz,3H),1.17–1.00(m,5H),0.98(d,J=6.7Hz,3H),0. 93(t,J=7.2Hz,6H),0.90–0.86(m,1H),0.84(d,J=6.5Hz,3H),0.80(d,J=3.6Hz,3H),0.79(d,J=3.7Hz,3H).

[0324] 13 C NMR(101MHz,Chloroform-d)δ171.7,169.0,143.3,128.8,82.2,68.6,57.4,45.6,45.6,45.5, 36.8,32.9,31.9,30.7,30.3,28.2,28.1,27.6,23.6,20.9,20.6,20.5,19.9,19.0,17.9,12.9.

[0325] HRMS (ESI, m / z) for C 28 H 54 NO4 + [M+H] + :Calcd.468.4047; Found 468.4048.

[0326] 18. The synthesis process is similar to that of step 17 in Example 1, except that compound 25-1 is replaced by 25-3 to obtain a light yellow oily liquid compound 2-3 (40.00 mg, 92%).

[0327] [α] D 25 = +7.0 (c1.0, CHCl3);

[0328] 1H NMR(400MHz,Chloroform-d)δ6.23(d,J=8.6Hz,1H),6.14(d,J=9.7Hz,1H),5.06(d,J=8.9Hz,1H),4.91(h,J=6.2Hz ,1H),4.54(dd,J=8.6,4.3Hz,1H),4.22(dd,J=9.0,4.6Hz,1H),2.59(dt,J=15.6,8.4Hz,1H),2.18(qd,J=6.9,4.3H z,1H),1.89(s,3H),1.92–1.80(m,1H),1.59–1.51(m,4H),1.47(s,9H),1.44(s,9H),1.41–1.24(m,4H),1.21(d,J= 6.2Hz,3H),1.19–1.00(m,6H),0.99–0.89(m,15H),0.89–0.85(m,1H),0.83(d,J=6.5Hz,3H),0.79(t,J=6.0Hz,6H).

[0329] 13 C NMR(101MHz,Chloroform-d)δ172.0,171.7,169.2,155.7,142.8,129.2,82.1,79.7,72.7,58.0,57.3,46.0,45.8,44.8,38 .3,33.3,32.6,31.9,30.6,29.8,28.5,28.2,28.0,27.3,25.2,20.7,20.2,20.0,19.9,19.4,19.0,17.9,15.6,13.0,11.9.

[0330] HRMS (ESI, m / z) for C 39 H 72 N2O7Na + [M+Na] + :Calcd.703.5232; Found 703.5233.

[0331] 19. The synthetic procedure is similar to step 18 in Example 1, except that compound 2-1 is replaced by 2-3 to obtain a white solid, which is the diastereomer of Valactamide A RRRSS-1 (9.00 mg, 54% in two steps).

[0332] [α] D 25 = -10.4 (c1.0, CHCl3);

[0333] 1H NMR(400MHz,Chloroform-d)δ6.78(d,J=7.5Hz,1H),6.29(dd,J=10.0,1.5Hz,1H),6.22(d,J=7.7Hz,1H),5.03–4.90(m,1H),4.32(ddd,J=10.2 ,7.6,5.5Hz,2H),2.58(ddt,J=13.4,6.8,3.2Hz,1H),2.41(pd,J=6.9,5.2Hz,1H),1.91(d,J=1.3Hz,3H),1.95–1.84(m,1H),1.59–1.45(m,4H), 1.47–1.34(m,3H),1.26(d,J=3.5Hz,2H),1.24(d,J=6.2Hz,3H),1.21–1 .15(m,1H),1.10(dq,J=6.4,3.8Hz,3H),1.03(d,J=3.7Hz,1H),1.00(d, J=6.8Hz,3H),0.97(d,J=6.8Hz,3H),0.97–0.89(m,6H),0.90(d,J=6.8Hz,3H),0.85(d,J=6.5Hz,6H),0.82(d,J=6.5Hz,3H),0.84–0.76(m,1H).

[0334] 13 C NMR(101MHz,Chloroform-d)δ170.7,170.1,169.3,143.7,127.6,72.0,58.2,57.2,46.8,44.8,44.4,36.6, 33.1,32.2,31.2,30.9,29.2,28.9,28.0,25.0,22.0,21.0,20.7,19.8,19.5,19.1,17.1,14.9,12.3,10.8.

[0335] HRMS (ESI, m / z) for C 30 H 55 N2O4 + [M+H] + :Calcd.507.4157; Found 507.4154.

[0336] RRRSS-1 and natural Valactamide A 13 The C NMR data comparison results are shown in the attached Figure 6 As shown, the horizontal axis is the number of carbon atoms.

[0337] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A method for synthesizing Valactamide A and diastereomers, characterized in that: The following steps are involved: Preparation of compound 16, and compound ent-16, ; The compound 16 and the compound ent-16 are subjected to oxidation treatment to obtain compound 8, respectively. and compound ent-8, ; The compound 8 is subjected to Horner-Wordsworth-Emmons olefination reaction and asymmetric methylation reaction with the HWE reagent compound ent-9, and then subjected to reduction treatment and oxidation treatment to obtain compound 20-1; The compound 20-1 and the HWE reagent compound ent-9 are subjected to Horner-Wordsworth-Emmons olefination reaction and asymmetric methylation reaction, and then subjected to reduction treatment and oxidation treatment to obtain compound 6-1; The compound 6-1 is subjected to a Wittig reaction with a phosphorus ylide reagent to obtain a compound 5-1; The compound 5-1 is activated with L-valine tert-butyl ester trifluoroacetate to obtain compound 24-1; After removing the protecting group from the compound 24-1, a coupling reaction is carried out with L-isoleucine containing a protecting group to obtain compound 2-1; The compound 2-1 is subjected to ring-closing treatment to obtain Valactamide A with the structural formula RSSSS-1; and / or, The compound 8 is subjected to Horner-Wordsworth-Emmons olefination reaction and asymmetric methylation reaction with the HWE reagent compound 9, and then subjected to reduction treatment and oxidation treatment to obtain compound 20-2; The compound 20-2 and the HWE reagent compound 9 are subjected to Horner-Wordsworth-Emmons olefination reaction and asymmetric methylation reaction, and then subjected to reduction treatment and oxidation treatment to obtain compound 6-2; The compound 6-2 is subjected to a Wittig reaction with a phosphorus ylide reagent to obtain a compound 5-2; The compound 5-2 is activated with L-valine tert-butyl ester trifluoroacetate to obtain compound 24-2; After removing the protecting group from the compound 24-2, a coupling reaction is carried out with L-isoleucine containing a protecting group to obtain compound 2-2; The compound 2-2 is subjected to a ring-closing treatment to obtain a diastereoisomer of Valactamide A with the structural formula RSSRR-1; and / or, The compound ent-8 and the HWE reagent compound ent-9 are subjected to Horner-Wordsworth-Emmons olefination reaction and asymmetric methylation reaction, and then subjected to reduction treatment and oxidation treatment to obtain compound 20-3; The compound 20-3 and the HWE reagent compound 9 are subjected to Horner-Wordsworth-Emmons olefination reaction and asymmetric methylation reaction, and then subjected to reduction treatment and oxidation treatment to obtain compound 6-3; The compound 6-3 is subjected to a Wittig reaction with a phosphorus ylide reagent to obtain a compound 5-3; The compound 5-3 is activated with L-valine tert-butyl ester trifluoroacetate to obtain compound 24-3; After removing the protecting group from the compound 24-3, a coupling reaction is carried out with L-isoleucine containing a protecting group to obtain compound 2-3; The compound 2-3 is subjected to a ring-closing treatment to obtain a diastereoisomer of Valactamide A having the structural formula RRRSS-1; Wherein, the HWE reagent comprises: the compound 9, or the compound ent-9, ; The structural formula of the compound 20-1 is The structural formula of the compound 20-2 is The structural formula of the compound 20-3 is ; The structural formula of the compound 6-1 is The structural formula of the compound 6-2 is The structural formula of the compound 6-3 is ; The structural formula of the Valactamide A is: , RSSSS-1; the diastereomers of Valactamide A include: , RSSRR-1 and / or ,RRRSS-1.

2. The method for synthesizing Valactamide A and diastereomers according to claim 1, characterized in that: The steps of preparing the compound 16 include: Obtain compound 12-1, Then, the compound 12-1 is subjected to a Mitsunobu reaction to obtain a compound 13-1. ; Compound 13-1 is oxidized with m-chloroperbenzoic acid to obtain compound 14-1. ; Compound 14-1 and compound 11, After the Kochinsky-Julia olefination reaction, the compound 16 is obtained by hydrolysis and hydrogenation reduction reaction; Alternatively, the steps of preparing the compound ENT-16 include: Obtain compound 12-2, Then, the compound 12-1 is subjected to a Mitsunobu reaction to obtain a compound 13-2. ; Compound 13-2 is oxidized by m-chloroperbenzoic acid to obtain compound 14-2. ; Compound 14-2 and compound 11, After the Kochinsky-Julia olefination reaction, hydrolysis and reduction reaction are carried out to obtain the compound ent-16.

3. The method for synthesizing Valactamide A and diastereomers according to claim 2, characterized in that: The steps of respectively oxidizing the compound 16 and the compound ent-16 include: The compound 16 or the compound ent-16 is mixed with 2,2,6,6-tetramethylpiperidinyl oxide, trichloroisocyanuric acid and sodium bicarbonate and dissolved in an organic solvent, and then reacted in an ice bath to obtain the compound 8 or the compound ent-8.

4. The method for synthesizing Valactamide A and diastereomers according to claim 3, characterized in that: The steps of preparing the compound 20-1, the compound 20-2 and the compound 20-3 include: The compound 8 or the compound ent-8 and the HWE reagent are dissolved in an organic solvent, lithium chloride, N,N-diisopropylethylamine and hexamethylphosphoramide are added, and a mixed reaction is carried out to obtain a compound 17; including , 17-1, , 17-2, 17-3; The compound 17 is subjected to a hydrogenation reduction reaction and a methylation reaction in sequence to obtain a compound 18; The compound 18 is subjected to reduction treatment to remove the auxiliary group to obtain compound 19; The compound 19 is oxidized using 2,2,6,6-tetramethylpiperidinyl oxide, trichloroisocyanuric acid and sodium bicarbonate to obtain the compound 20-1, the compound 20-2 or the compound 20-3.

5. The method for synthesizing Valactamide A and diastereomers according to claim 4, characterized in that: The steps of preparing the compound 6-1, the compound 6-2 and the compound 6-3 include: The compound 20-1, the compound 20-2 or the compound 20-3 and the HWE reagent are dissolved in an organic solvent, lithium chloride, N,N-diisopropylethylamine and hexamethylphosphoramide are added, and a mixed reaction is carried out to obtain a compound 21; , 21-1, , 21-2 or 21-3; The compound 21 is subjected to a hydrogenation reduction reaction and a methylation reaction in sequence to obtain a compound 22; The compound 22 is subjected to reduction treatment to remove the auxiliary group to obtain compound 23; The compound 23 is oxidized using 2,2,6,6-tetramethylpiperidinyl oxide, trichloroisocyanuric acid and sodium bicarbonate to obtain the compound 6-1, the compound 6-2 or the compound 6-3.

6. The method for synthesizing Valactamide A and diastereomers according to claim 5, characterized in that: The steps of preparing the compound 5-1, the compound 5-2 and the compound 5-3 include: Compound 6-1, compound 6-2 or compound 6-3 and compound 7, Dissolve in an organic solvent and react at a temperature of 60-100°C to obtain the compound 5-1 , the compound 5-2 , or the compound 5-3 .

7. The method for synthesizing Valactamide A and diastereomers according to claim 6, characterized in that: The steps of preparing the compound 24-1, the compound 24-2 and the compound 24-3 include: The compound 5-1, the compound 5-2 or the compound 5-3 is hydrolyzed in a potassium hydroxide solution at a temperature of 60 to 100° C., and then mixed and dissolved with N-hydroxy-7-azabenzotriazole, L-valine tert-butyl ester trifluoroacetate, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and N,N-diisopropylethylamine is added under ice bath conditions for mixed reaction to obtain the compound 24-1. , the compound 24-2 , or compound 24-3 .

8. The method for synthesizing Valactamide A and diastereomers according to claim 7, characterized in that: The step of removing the protecting groups in the compound 24-1, the compound 24-2 and the compound 24-3 comprises: The triisopropylsilyl protecting group on the secondary hydroxyl group at the terminal of the compound 24-1, the compound 24-2 or the compound 24-3 is removed under the action of hydrogen fluoride to obtain the compound 25-1, the compound 25-2 or the compound 25-3.

9. The method for synthesizing Valactamide A and diastereomers according to claim 8, characterized in that: The steps of preparing the compound 2-1, the compound 2-2 and the compound 2-3 include: Compound 25-1, the compound 25-2 or the compound 25-3 and tert-butyloxycarbonyl-protected L-isoleucine are dissolved in an organic solvent, cooled to 5-0°C, N,N-diisopropylethylamine and 2,4,6-trichlorobenzoyl chloride are added, the temperature is raised to 20-40°C for mixed reaction, cooled to 5-0°C again, 4-dimethylaminopyridine is added for reaction, and the compound 2-1 is obtained. , the compound 2-2 , or the compound 2-3 .

10. The method for synthesizing Valactamide A and diastereomers according to claim 9, characterized in that: The step of performing ring-closing treatment on the compound 2-1, the compound 2-2 and the compound 2-3 comprises: removing the tert-butyloxycarbonyl protecting group and tert-butyl ester in the compound 2-1, the compound 2-2 or the compound 2-3 under the action of trifluoroacetic acid; 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and a coupling activator are added to carry out a cyclization reaction to obtain the Valactamide A or the diastereomer of the Valactamide A.

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