Process for the preparation of alpha-pyrone-polyketides

Abstract

The application relates to the technical field of synthetic chemistry, and provides a preparation method of alpha-pyrone-polyketone, which comprises the following steps: coupling reaction of compound 3 and compound 2 to obtain compound 26; secondary alcohol group of the compound 26 is removed to obtain compound 27; the compound 27 is removed from a protection group to obtain the alpha-pyrone-polyketone shown in compound 1; wherein the structural formula of the compound is as follows: the preparation method of the alpha-pyrone-polyketone provided in the application is based on the instability of the bis-bisolefin, and is constructed by using an alkenyl tin intermediate and an alkenyl iodine intermediate through a coupling reaction, so that the operation is simple, the yield of each step is high, and the method can be widely popularized and applied.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of synthetic chemistry, and particularly relates to a preparation method of an alpha-pyrone-polyketide. BACKGROUND

[0002] Polyketide compounds containing alpha-pyrone structural units are a class of natural products with a wide range of biological activities. Among them, alpha-pyrone-polyketide (alternapyrone) was first discovered by Professor Fuji's team of Tokyo University (Fujii, I.; et al., Chem. Biol. 2005, 12, 1301) in 2005. In order to identify the function of polyketide synthase, the alt5 gene was introduced into the fungal host Aspergillus oryzae, and alternapyrone was first biosynthesized by highly reduced polyketide synthase. In terms of structure, alternapyrone contains alpha-pyrone, conjugated diene and three methyl groups, but the chiral configuration of the methyl group is unknown.

[0003] Since the discovery of alternapyrone in 2005, research by Chooi's group (Chooi, Y.; et al., Org. Lett., 2018, 20, 6148) has shown that alternapyrone has cytotoxic activity (MIC = 3.1 μg / mL) on mouse myeloma cells, but the cytotoxic activity (MIC = 25 μg / mL) on non-tumor cells of newborn foreskin fibroblasts is eight times lower than that on mouse myeloma cells. MIC refers to the minimum drug concentration that inhibits the growth of pathogenic microorganisms. The lower the value of MIC, the stronger the inhibitory ability of the drug on pathogenic microorganisms. Therefore, it shows that alternapyrone has a certain specificity for tumor cells.

[0004] In view of the excellent biological activity of alternapyrone and in order to determine the absolute configuration of alternapyrone, it is of great significance to obtain alternapyrone by total synthesis for biological activity research. SUMMARY

[0005] The purpose of the present application is to provide a preparation method of alpha-pyrone-polyketide, aiming to solve the problem of the lack of chemical synthesis method of existing alpha-pyrone-polyketide.

[0006] In order to achieve the above application purpose, the technical scheme adopted by the present application is as follows:

[0007] The present application provides a preparation method of alpha-pyrone-polyketide, comprising the following steps:

[0008] Coupling reaction of compound 3 with compound 2 to obtain compound 26;

[0009] Reduction of the secondary alcohol group of compound 26 to remove to obtain compound 27;

[0010] Compound 27 is deprotected to obtain the alpha-pyrone-polyketone shown in compound 1;

[0011] The structure of the above compound is as follows:

[0012]

[0013] The preparation method of the alpha-pyrone-polyketone provided in the application is based on the instability of the bi-diene, and is constructed by coupling reaction of the alkenyl tin intermediate and the alkenyl iodine intermediate, which fills the gap of the existing chemical synthesis method of the alpha-pyrone-polyketone, and the preparation method is simple in application operation, high in yield of each step, and can be widely applied. DETAILED DESCRIPTION

[0014] In order to make the technical problems, technical solutions and beneficial effects to be solved in the application more clear and obvious, the application will be further described in detail below in combination with embodiments. It should be understood that the specific embodiments described herein are only used to explain the application, and are not used to limit the application.

[0015] In the application, the term "and / or" describes the association relationship of the associated objects, which means that there can be three kinds of relationships, for example, A and / or B can mean that A exists alone, A and B exist together, and B exists alone. Wherein A and B can be singular or plural. The character " / " generally represents an "or" relationship between the associated objects before and after it.

[0016] It should be understood that in various embodiments of the application, the size of the serial number of the above processes does not mean the order of execution, and part or all of the steps can be executed in parallel or in sequence, and the execution order of the processes should be determined according to its function and inherent logic, and should not constitute any limitation on the implementation process of the embodiments of the application.

[0017] The terms used in the embodiments of the application are only for the purpose of describing specific embodiments, and are not intended to limit the application. The singular forms "a", "said" and "the" used in the embodiments of the application and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0018] The weight of the related components mentioned in the embodiment specification 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 each component. Therefore, as long as the content of the related components in the embodiment specification of the present application is scaled up or down in proportion, it is within the scope disclosed in the embodiment specification of the present application. Specifically, the mass mentioned in the embodiment specification of the present application can be μg, mg, g, kg, and other mass units commonly known in the chemical industry.

[0019] The terms "first", "second" are only for descriptive purposes, to distinguish objects such as substances from each other, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. For example, without departing from the scope of the present application, the first XX can also be referred to as the second XX, and similarly, the second XX can also be referred to as the first XX. Therefore, the features defined with "first", "second" can explicitly or implicitly include one or more of the features.

[0020] The embodiment of the present application provides a preparation method of alpha-pyrone-polyketone, comprising the following steps:

[0021] S01: coupling reaction of compound 3 and compound 2 to obtain compound 26;

[0022] S02: reducing and removing the secondary alcohol group of compound 26 to obtain compound 27;

[0023] S03: removing the protecting group of compound 27 to obtain compound 1, which is alpha-pyrone-polyketone;

[0024] Among them, the structural formula of the above compound is as follows:

[0025]

[0026] The preparation method of alpha-pyrone-polyketone provided by the embodiment of the present application is based on the instability of bis-diene, and is constructed by coupling reaction of alkenyl tin intermediate and alkenyl iodine intermediate, which fills the gap of the existing chemical synthesis method of alpha-pyrone-polyketone, and the preparation method is simple to operate, the yield of each step is high, and can be widely applied.

[0027] Specifically, the coupling reaction of compound 3 with compound 2 is a Stille coupling reaction, which is a cross-coupling reaction of organotin compounds and halogenated hydrocarbons (or triflate) without β-hydrogen under palladium catalysis. The Stille coupling reaction generally undergoes three steps of oxidative addition, transmetalation and reductive elimination. In the Stille coupling reaction of compound 3 with compound 2, palladium and alkenyl iodide compound 2 undergo oxidative addition to form a first intermediate, the halogen atom in the first intermediate exchanges with R in compound 3 to form a second intermediate, the tributylstannyl group (Bu3Sn-) in compound 3 forms a reductive elimination product with iodine in compound 2, and the second intermediate undergoes a reduction reaction, thereby constructing a carbon-carbon bond between compound 2 and compound 3 to obtain compound 26.

[0028] The MOM protecting group (Methoxymethyl, abbreviated as MOM) is a chemical group commonly used to protect the hydroxyl group of alcohol compounds. The MOM protecting group can be added and removed through different chemical reactions, thereby achieving the protection and deprotection of the hydroxyl group. In the series of reactions of compound 2 with compound 3 to obtain compound 26 and compound 26 to obtain compound 27, the exposed alcohol group is prone to react, and the temporary protection of the alcohol group by the MOM protecting group can reduce its activity and achieve selective reaction.

[0029] In addition, based on the rule discovered by Professor Oikawa's team (Oikawa, H.; et al., Angew. Chem. Int. Ed. 2021, 60, 23403) for predicting the absolute configuration of polyketide compounds, the configurations of the three chiral methyl groups were deduced, and the full synthesis process of α-pyrone-polyketide was completed through the preparation method of α-pyrone-polyketide provided in the embodiments of the present application, and the first synthesis of α-pyrone-polyketide was successfully completed. It is proved that the compound prepared based on the Oikawa rule is α-pyrone-polyketide, the chiral configuration of the three methyl groups in α-pyrone-polyketide is determined, and the absolute configuration of α-pyrone-polyketide is determined, which can efficiently prepare the active natural product α-pyrone-polyketide.

[0030] In order to complete the full synthesis of α-pyrone-polyketide, the embodiments of the present application have carried out in-depth research, and a lot of creative labor has been paid to realize the present application.

[0031] Specifically, the synthesis of the polyketide natural product α-pyrone-polyketide is analyzed by using classical retrosynthetic analysis, and the natural product α-pyrone-polyketide is successfully synthesized. The retrosynthetic analysis of α-pyrone-polyketide is as follows:

[0032]

[0033] Due to the instability of the conjugated diene group in the a-pyrone-polyketide, the present embodiment chooses to build this structure at the end by Stille coupling, thus one can trace back to the alkenyl iodide compound 2 and the alkenyl tin compound 3. The alkenyl tin compound 3 can be prepared from the nucleophilic addition reaction of the alkynyl aldehyde compound and the allyl bromide compound and the subsequent series of chemical transformations. The alkenyl iodide compound 2 can be converted from the compound 4 by the retro-Diels-Alder reaction. Finally, the compound 4 can be prepared by the nucleophilic addition reaction of the compound 7 and the compound 8.

[0034] The specific synthesis route is as follows:

[0035] (1) Synthesis of the chiral aldehyde compound 7: the compound 12 is subjected to methylalumination, iodination and oxidation in sequence to obtain the compound 13; the compound 13 is connected with the first chiral auxiliary to obtain the compound 14; the compound 14 is subjected to methylation, and then the first chiral auxiliary is removed and oxidized to obtain the compound 7. In an embodiment, the specific reaction process is as follows:

[0036]

[0037] Starting from the commercially available compound 12 (4-pentyn-1-ol), the Wipf-optimized Negishi conditions are adopted to subject the compound 12 to methylalumination (in the presence of AlMe3 (TMA, Trimethyl Aluminum), Cp2ZrCl2 (dichlorobis-cyclopentadienylzirconium)) and the subsequent iodination to obtain the alkenyl iodide alcohol intermediate. The alkenyl iodide alcohol intermediate is subjected to TEMPO (2,2,6,6-tetramethylpiperidine-N-oxide) oxidation under the condition of DIPA (diacetic acid iodobenzene) to obtain the alkenyl iodide carboxylic acid compound 13. The carboxyl group in the alkenyl iodide carboxylic acid compound 13 is connected with the first chiral auxiliary in the presence of PivCl (Pivaloyl chloride), Et3N (triethylamine) and LiCl (lithium chloride) to obtain the compound 14. The compound 14 is subjected to methylation, and then the first chiral auxiliary is removed by reaction with sodium borohydride to obtain the alcohol compound 15 with a chiral methyl group. Finally, the primary alcohol group in the compound 15 is oxidized to aldehyde by Swern oxidation (in the presence of DMSO (dimethyl sulfoxide), (COCl)2 (oxalyl chloride) and Et3N) to obtain the chiral aldehyde compound 7, which can be used for the subsequent synthesis of the alkenyl iodide fragment of the alkenyl iodide compound 2.

[0038] (2) Synthesis of the six-membered ring compound 8: the ester condensation reaction of the tert-butyl propionate and the phenyl propionate is carried out to obtain the β-keto ester compound; the β-keto ester compound is subjected to tert-butyl removal and condensation reaction with acetone to obtain the compound 8. In an embodiment, the specific reaction process is as follows:

[0039]

[0040] First, Claisen ester condensation of compound 9 (tert-butyl propionate) and compound 10 (phenyl propionate) in the presence of LDA (lithium diisopropylamide) and LiHMDS (lithium bis(trimethylsilyl)amide) generates compound 11 (β-keto ester). Next, compound 11 is deprotected from tert-butyl ester and condensed with acetone in the presence of concentrated sulfuric acid, acetic anhydride and acetone to obtain six-membered ring compound 8.

[0041] (3) Synthesis of alkenyl iodide compound 2 (α-pyrone fragment): nucleophilic addition of compound 7 and compound 8, followed by oxidation to obtain compound 4; inverse Diels-Alder reaction of compound 4 to generate α-pyrone fragment, and protection of the hydroxyl group on the α-pyrone fragment to obtain compound 2. In one embodiment, the specific reaction process is as follows:

[0042]

[0043] First, chiral aldehyde compound 7 and six-membered ring compound 8 undergo nucleophilic addition similar to aldol condensation in the presence of LDA (lithium diisopropylamide) to obtain an alcohol intermediate. The alcohol intermediate is directly oxidized by DMP (Dess-Martin periodinane) to obtain ketone compound 4. The ketone compound 4 itself undergoes inverse Diels-Alder reaction under heating reflux of toluene to generate α-pyrone fragment. Finally, the exposed hydroxyl group on the α-pyrone fragment is reacted with MOMCl ((chloromethyl)methyl ether) in the presence of triethylamine to obtain hydroxyl-protected alkenyl iodide compound 2, which can be used in the subsequent Stille coupling reaction.

[0044] (4) Synthesis of alkyne aldehyde compound 5: conversion of the carboxyl group of 4-benzyloxybutyric acid to aldehyde group and introduction of methyl group to obtain chiral aldehyde; conversion of the aldehyde group of chiral aldehyde to alkyne group, and then removal of the benzyl group to obtain compound 5. The step of converting the carboxyl group of 4-benzyloxybutyric acid to aldehyde group and introducing methyl group to obtain chiral aldehyde includes: connecting the second chiral auxiliary to 4-benzyloxybutyric acid, followed by asymmetric methylation reaction, then introducing methyl group at the α position of the carbonyl group, removing the second chiral auxiliary and reducing the carbonyl group to hydroxyl group, and then oxidation to obtain chiral aldehyde. In one embodiment, the specific reaction process is as follows:

[0045]

[0046] Starting from commercially available 4-benzyloxybutyric acid compound 16, compound 16 was linked to a second chiral auxiliary in the presence of pivaloyl chloride, triethylamine and lithium chloride to give chiral compound 17. Chiral compound 17 was then subjected to asymmetric methylation in the presence of NaHMDS (sodium bis(trimethylsilyl)amide) to stereoselectively introduce a methyl group at the α position of the carbonyl group. The second chiral auxiliary was then removed by reaction with sodium borohydride (NaBH4) and the carbonyl group was reduced to a hydroxyl group to give a hydroxyl intermediate. The hydroxyl intermediate was directly oxidized to chiral aldehyde compound 18 under TEMPO (2,2,6,6-tetramethylpiperidine N-oxide) catalysis. The aldehyde group in compound 18 was converted to an alkyne group under the conditions of Corey-Fuchs reaction (referring to the reaction of aldehyde with carbon tetrabromide and triphenylphosphine to give a dibromoalkene, which was then treated with n-butyllithium to give a terminal alkyne), to give compound 19. The protecting group on the benzyl group in compound 19 was removed in the presence of boron trichloride and the exposed hydroxyl group was oxidized to an aldehyde using DMP (Dess-Martin periodinane) to give alkyne aldehyde compound 5.

[0047] (5) Synthesis of allyl bromide compound 6: After compound 20 was linked to a third chiral auxiliary, an enol silyl ether was generated in the presence of sodium bis(trimethylsilyl)amide and tert-butyldimethylsilyl chloride, which was subjected to an aldol reaction with ethanol to give compound 22; the third chiral auxiliary of compound 22 was removed and reduced to form a diol, the secondary alcohol group of the diol was removed, and the primary alcohol group of the diol was substituted with a halogen to give compound 6. In one embodiment, the steps of removing the secondary alcohol group of the diol and substituting the primary alcohol group of the diol with a halogen include: first protecting the primary alcohol group of the diol, then removing the secondary alcohol group of the diol, and then substituting the primary alcohol group after removing the protection with a halogen. In one embodiment, the specific reaction process is as follows:

[0048]

[0049] Starting from commercially available compound 20 ((E)-2-methyl-2-pentenoic acid), compound 20 was attached to a third chiral auxiliary in the presence of pivaloyl chloride, triethylamine and lithium chloride to give chiral intermediate compound 21. Chiral intermediate compound 21 generated enol silyl ether intermediate in the presence of NaHMDS and TBSCl (tert-butyldimethylsilyl chloride). Mukaiyama aldol reaction (aldol reaction of an enol silyl ether with an aldehyde or ketone in the presence of a Lewis acid such as titanium tetrachloride, which generates an enol silyl ether from a carbonyl compound, and the product is a β-hydroxy aldehyde or ketone) of the enol silyl ether intermediate with acetaldehyde in the presence of TiCl4 (titanium tetrachloride) gave chiral alcohol compound 22. Chiral alcohol compound 22 was deprotected from the third chiral auxiliary and reduced the carbonyl group to a hydroxyl group by reaction with sodium borohydride to give diol intermediate. The primary alcohol group of the diol intermediate reacted selectively with TBDPSCl (tert-butyldiphenylsilyl chloride) in the presence of triethylamine, DMAP (4-dimethylaminopyridine) and TBDPSCl (tert-butyldiphenylsilyl chloride) to give hydroxyl-protected silyl ether compound 23. The free secondary alcohol group of silyl ether compound 23 reacted with TsCl (p-toluenesulfonyl chloride) in the presence of DMAP to give p-toluenesulfonate intermediate. The p-toluenesulfonate group of the p-toluenesulfonate intermediate was removed in the presence of lithium triethylborohydride and generated methylene in situ to give compound 24. Finally, the TBDPS protecting group of compound 24 was removed in the presence of TBAF (tetra-n-butylammonium fluoride) to give primary alcohol group, which underwent Appel reaction (refers to the conversion of an alcohol to a chlorohydrin using triphenylphosphine and carbon tetrabromide) with triphenylphosphine and carbon tetrabromide to give allyl bromide compound 6.

[0050] (6) Synthesis of allyl stannane compound 3: nucleophilic addition of compound 5 with compound 6 gave compound 25; reaction of compound 25 with tributyltin hydride gave compound 3. In one example, the specific reaction process is as follows:

[0051]

[0052] Nucleophilic addition of alkynyl aldehyde compound 5 with allyl bromide compound 6 in the presence of SmI2 (samarium diiodide) gave homoallyl alcohol compound 25. Homoallyl alcohol compound 25 reacted with tributyltin hydride in the presence of Pd(OAc)2 (palladium acetate) to give allyl stannane compound 3.

[0053] (7) Synthesis of α-alternapyrone:

[0054]

[0055] Stille coupling of alkenyl stannane 3 with alkenyl iodide 2 catalyzed by Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium) and CuTC (copper thiophene-2-carboxylate) in the presence of CsF (cesium fluoride) as base to give diene compound 26. The exposed hydroxyl group of diene compound 26 reacted with Mel (iodomethane) and CS2 (carbon disulfide) in the presence of NaHMDS (sodium bis(trimethylsilyl)amide) as base to give thioester derivative intermediate. Barton-McCombie deoxygenation of thioester derivative intermediate with Bu3SnH (tributyltin hydride) in the presence of Et3B (triethylborane) as radical initiator to give compound 27. Removal of MOM protecting group of compound 27 under acidic condition to give final product compound 1, an α-pyrone-polyketone.

[0056] The present application has undergone multiple tests, now a part of the test results as a reference to further describe the invention in detail, the following specific examples are described in detail.

[0057] Example 1

[0058]

[0059] Compound 13 (3.68 g, 15.34 mmol, 1.0 equiv.) was dissolved in THF (80 mL, 0.19 M) and cooled to -10 °C, to which was added triethylamine (5.3 mL, 38.35 mmol, 2.5 equiv.) and pivaloyl chloride (1.9 mL, 15.34 mmol, 1.0 equiv.). The reaction was stirred at -10 °C for 1 h, then lithium chloride (976 mg, 23.01 mmol, 1.5 equiv.) and (S)-4-benzyl-2-oxazolidinone (2.66 g, 15.03 mmol, 0.98 equiv.) were added. The reaction was allowed to warm to room temperature and monitored by TLC (thin layer chromatography) to confirm complete conversion, then saturated ammonium chloride solution (20 mL) was added slowly at 0 °C, followed by extraction with ethyl acetate (3 x 50 mL), the combined organic phase was washed with saturated brine solution (20 mL) and dried over anhydrous sodium sulfate. After drying, the mixture was filtered through a Buchner funnel and the filtrate was concentrated under reduced pressure using a vacuum pump to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate / n-hexane = 1 / 5) to give compound 14 (5.26 g, 13.19 mmol) as colorless oil in 86% yield.

[0060] TLC: Rf = 0.40 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 5). UV fluorescence & molybdenum blue. (c 0.50, CHCl3). 1 H NMR (400 MHz, CDC13) δ 7.37 - 7.24 (m, 3H), 7.23 - 7.17 (m, 2H), 6.03 (q, J = 1.1 Hz, 1H), 4.67 (ddt, J = 12.8, 7.1, 3.3 Hz, 1H), 4.26 - 4.14 (m, 2H), 3.28 (dd, J = 13.4, 3.4 Hz, 1H), 3.22 - 2.98 (m, 2H), 2.77 (dd, J = 13.4, 9.6 Hz, 1H), 2.68 - 2.52 (m, 2H), 1.90 (d, J = 1.0 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 172.1, 153.5, 146.2, 135.3, 129.5, 129.1, 127.5, 76.4, 66.4, 55.3, 38.0, 33.9, 33.8, 24.1. HRMS (ESI, m / z) for C 16 H 18 INO3Na + [M+Na] + : Calcd. 422.0224; Found: 422.0225.

[0061] Example 2

[0062]

[0063] Compound 14 (3.30 g, 8.27 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (80 mL, 0.10 M) and cooled to -78 °C, to which was added dropwise sodium bis(trimethylsilyl)amide (5.4 mL, 10.75 mmol, 2.0 M in tetrahydrofuran, 1.3 equiv.), after continued stirring at -78 °C for 30 min, iodomethane (0.77 mL, 12.41 mmol, 1.5 equiv.) was added dropwise. The reaction system was stirred at -78 °C for 1 h, then slowly warmed to -40 °C, and continued stirring at this temperature for 3 h. After TLC monitoring confirmed that the starting material was completely converted, the reaction was quenched by adding saturated ammonium chloride solution (20 mL). The reaction liquid was extracted with methyl tert-butyl ether (50 mL x 3), the combined organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, after drying was completed, filtered through a sand funnel, and the filtrate was concentrated under reduced pressure by a vacuum pump to obtain the crude product, which was separated by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 8) to obtain the intermediate compound (2.22 g, 5.38 mmol, 65%) as colorless oil.

[0064] TLC: Rf = 0.50 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 5). UV fluorescence & molybdenum blue. (c 0.50, CHCl3). 1 H NMR (500 MHz, CDC13) δ 7.36 - 7.25 (m, 3H), 7.23 - 7.18 (m, 2H), 5.97 (s, 1H), 4.64 (tt, J = 10.5, 3.1 Hz, 1H), 4.26 - 4.14 (m, 2H), 4.05-3.95 (m, 1H), 3.25 (dd, J = 13.4, 3.3 Hz, 1H), 2.77 (dd, J = 13.4, 9.6 Hz, 1H), 2.66 (dd, J = 13.5, 7.2 Hz, 1H), 2.29 (dd, J = 13.6, 7.4 Hz, 1H), 1.86 (s, 3H), 1.19 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 176.2, 153.2, 145.3, 135.3, 129.6, 129.1, 127.5, 77.3, 66.3, 55.5, 43.2, 38.0, 36.0, 23.9, 17.1. HRMS (ESI, m / z) for C 17 H 20 INO3Na + [M+Na] + : Calcd. 436.0380; Found: 436.0380.

[0065] Intermediate compound (1.11 g, 2.69 mmol, 1.0 equiv.) was dissolved in a mixture solvent of tetrahydrofuran (20 mL) / water (10 mL) and cooled to 0 °C, then sodium borohydride (508 mg, 13.44 mmol, 5.0 equiv.) was added. The reaction system was raised to room temperature and continuously stirred for 3 hours, after TLC monitoring confirmed the complete conversion, the reaction was quenched by slowly adding saturated ammonium chloride solution (5 mL) at 0 °C. Extraction was performed by adding methyl tert-butyl ether (3 x 20 mL), the combined organic phase was washed with saturated brine solution (10 mL), then dried over anhydrous sodium sulfate solid. After drying, the filtrate was filtered through a Buchner funnel, then concentrated under reduced pressure by a vacuum pump to obtain the crude product, which was separated by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 4) to obtain compound 15 (607 mg, 2.53 mmol) as a colorless oil in 94% yield.

[0066] TLC: Rf = 0.40 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 4). UV fluorescence & molybdenum blue. 1HNMR (400 MHz, CDC13) δ 5.89 (q, J = 1.1 Hz, 1H), 3.52 - 3.38 (m, 2H), 2.35 (ddd, J = 13.5, 6.1, 1.2 Hz, 1H), 2.01 (ddd, J = 13.5, 8.4, 0.9 Hz, 1H), 1.93 - 1.77 (m, 1H), 1.83 (d, J = 1.1 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H).

[0067] Example 3

[0068]

[0069] Dissolve oxalyl chloride (0.18 mL, 2.13 mmol, 5.0 equiv.) in dichloromethane (12 mL) and cool to -78 °C, then add dimethyl sulfoxide (0.30 mL, 4.25 mmol, 10.0 equiv.) dropwise. After 10 min, dissolve compound 15 (102 mg, 0.43 mmol, 1.0 equiv.) in dichloromethane (1 mL) and then add dropwise to the reaction. Continue stirring the reaction at -78 °C for 20 min, then allow to warm to -40 °C and continue stirring for 20 min. Cool the reaction to -78 °C, add triethylamine (1.1 mL, 7.65 mmol, 18.0 equiv.) dropwise, allow the reaction to warm to room temperature and continue stirring for 2 h. Once TLC monitoring confirms complete conversion of compound 15, quench the reaction by slowly adding saturated ammonium chloride solution (3 mL) at 0 °C. Extract with additional ethyl acetate (3 x 10 mL), combine the organic layers and wash with saturated brine solution (5 mL), then dry over anhydrous sodium sulfate. Once dry, filter through a fritted funnel and concentrate the filtrate under reduced pressure using a vacuum pump to obtain the crude product. Isolate compound 7 (88 mg, 0.37 mmol) as a colorless oil in 87% yield using silica gel column chromatography (ethyl acetate / n-hexane = 1 / 5).

[0070] TLC: Rf = 0.50 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 5). UV fluorescence & molybdenum blue. 1 HNMR (500 MHz, CDC13) δ 9.62 (d, J = 1.5 Hz, 1H), 5.99 - 5.95 (m, 1H), 2.64 (ddd, J = 13.9, 6.0, 1.3 Hz, 1H), 2.59 - 2.48 (m, 1H), 2.19 (ddd, J = 13.9, 8.4, 0.8 Hz, 1H), 1.82 (d, J = 1.1 Hz, 3H), 1.06 (d, J = 7.0 Hz, 3H).

[0071] Example 4

[0072]

[0073] To a solution of compound 8 (400 mg, 2.35 mmol, 7.0 equiv.) in tetrahydrofuran (2 mL) was added dropwise at -78 °C. After 30 min, compound 7 (80 mg, 0.336 mmol, 1.0 equiv.) in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred at -78 °C overnight. After TLC monitoring, the reaction was quenched by the addition of saturated ammonium chloride solution (3 mL). The pH value was adjusted to 1-2 with 1 M hydrochloric acid. The reaction mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered through a fritted funnel and concentrated under reduced pressure to give the crude product. The intermediate compound was obtained as a colorless oil by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3) and used directly in the next step.

[0074] To a solution of the intermediate compound (113 mg, 0.277 mmol, 1.0 equiv.) in dichloromethane (6 mL, 0.05 M) was added Dess-Martin reagent (590 mg, 1.39 mmol, 5.0 equiv.) at 0 °C. The reaction mixture was slowly warmed to room temperature. After TLC monitoring, the reaction was quenched by the addition of saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) at 0 °C. The reaction mixture was extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered through a fritted funnel and concentrated under reduced pressure to give the crude product. Compound 4 (95 mg, 0.235 mmol, dr = 1 : 1.5) was obtained as a colorless oil by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 5) in 70% yield over two steps.

[0075] TLC: Rf = 0.40 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 5). UV fluorescence & molybdenum blue. 1HNMR (400 MHz, CDC13) δ 5.95 - 5.90 (m, 2.5H), 3.76 (q, J = 6.9 Hz, 1H), 3.54 (q, J = 6.9 Hz, 1.5H), 2.94 - 2.78 (m, 2.5H), 2.56 (ddd, J = 14.0, 6.4, 1.1 Hz, 1H), 2.47 (ddd, J = 13.4, 7.8, 1.0 Hz, 1.5H), 2.23 - 2.13 (m, 2.5H), 1.91 (s, 3H), 1.90 (s, 4.5H), 1.82 (d, J = 1.1 Hz, 4.5H), 1.76 (d, J = 1.1 Hz, 3H), 1.64 (s, 3H), 1.63 (s, 4.5H), 1.62 - 1.59 (m, 7.5H), 1.26 (d, J = 6.9 Hz, 3H), 1.23 (d, J = 6.9 Hz, 4.5H), 1.05 (d, J = 7.1 Hz, 3H), 1.02 (d, J = 6.7 Hz, 4.5H). 13 CNMR (101 MHz, CDC13) δ 209.1, 208.2, 162.7, 162.6, 162.4, 144.7, 144.7, 105.6, 105.5, 102.5, 102.3, 77.9, 77.6, 48.8, 46.8, 44.2, 42.8, 42.3, 41.9, 26.3, 26.0, 24.0, 24.0, 23.9, 23.8, 17.4, 16.7, 12.4, 12.3, 10.4, 10.4. HRMS (ESI, m / z) for C 16 H 23 IO4Na + [M+Na] + : Calcd. 429.0533; Found: 429.0521.

[0076] Example 5

[0077]

[0078] Compound 4 (23 mg, 0.0566 mmol, 1.0 equiv.) was dissolved in toluene (2 mL) and added dropwise to refluxing toluene (54 mL), the reaction system was heated under reflux for 65 hours, after the room temperature was recovered, the vacuum pump was concentrated under reduced pressure to obtain the crude product, and the silica gel column chromatography was separated (ethyl acetate / n-hexane = 1 / 1) to obtain the white solid intermediate compound (18 mg, 0.0517 mmol, 91%).

[0079] TLC: Rf = 0.50 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 1). Ultraviolet fluorescence & molybdenum phosphoric acid coloration. (c 0.50, CHCl3). 1 H NMR (400 MHz, CDC13) δ 5.90 (q, J = 1.1 Hz, 1H), 3.16 - 3.01 (m, 1H), 2.57 (ddd, J = 13.7, 8.4, 1.0 Hz, 1H), 2.37 (ddd, J = 13.7, 6.7, 1.0 Hz, 1H), 2.01 (s, 3H), 1.96 (s, 3H), 1.79 (d, J = 1.1 Hz, 3H), 1.17 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 166.3, 165.0, 160.5, 145.1, 106.9, 98.5, 77.5, 43.9, 33.2, 24.1, 18.1, 9.7, 8.8. HRMS (ESI, m / z) for C 13 H 17 IO3Na + [M+Na] + : Calcd. 371.0115; Found: 371.0109.

[0080] Intermediate compound (128 mg, 0.368 mmol, 1.0 equiv.) was dissolved in dry dichloromethane (30 mL, 0.012 M) and cooled to 0 °C, then triethylamine (0.26 mL, 1.84 mmol, 5.0 equiv.) was added dropwise, stirred at 0 °C for 10 min. Then chloromethyl methyl ether (0.14 mL, 1.84 mmol, 5.0 equiv.) was added dropwise, the reaction system was raised to room temperature and continuously stirred for 12 h, TLC monitoring confirmed the complete conversion, then quenched with water slowly at 0 °C, dichloromethane (3 x 30 mL) was added to extract, the combined organic phase was washed with saturated brine solution (10 mL), then dried over anhydrous sodium sulfate solid. After drying, it was filtered through a Buchner funnel, the filtrate was concentrated under reduced pressure with a vacuum pump to obtain the crude product, which was separated by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3) to obtain compound 2 (110 mg, 0.280 mmol) as a white solid in 76% yield.

[0081] TLC: Rf = 0.40 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 3). UV fluorescence & molybdenum blue. (c 0.50, CHCl3). 1H NMR (500 MHz, CDC13) δ 5.88 (q, J = 1.1 Hz, 1H), 5.04 (s, 2H), 3.56 (s, 3H), 3.11 - 2.98 (m, 1H), 2.58 (ddd, J = 13.7, 8.3, 1.0 Hz, 1H), 2.39 (ddd, J = 13.7, 6.7, 1.0 Hz, 1H), 2.01 (s, 3H), 1.92 (s, 3H), 1.80 (d, J = 1.1 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 166.3, 165.7, 160.2, 145.2, 110.1, 109.1, 99.2, 77.4, 58.1, 44.0, 33.5, 24.1, 17.9, 11.0, 10.5. HRMS (ESI, m / z) for C 15 H 21 IO4Na + [M+Na] + : Calcd. 415.0377; Found: 415.0370.

[0082] Example 6

[0083]

[0084] Compound 19 (1.53 g, 7.57 mmol, 1.0 equiv.) was dissolved in dry dichloromethane (76 mL, 0.1 M) and cooled to -78 °C, then boron trichloride (23 mL, 22.71 mmol, 1.0 M in dichloromethane, 3.0 equiv.) was added dropwise. The reaction was stirred at -78 °C for 1 h, then quenched by the slow addition of methanol (20 mL) and saturated sodium bicarbonate solution (20 mL) in succession, and extracted with diethyl ether (3 x 50 mL), the combined organic phases were washed with saturated brine solution (10 mL) and dried over anhydrous sodium sulfate solid. After drying was completed, the mixture was filtered through a Buchner funnel and the filtrate was concentrated under reduced pressure using a vacuum pump to obtain the crude product, which was purified by column chromatography on silica gel (diethyl ether / n-pentane = 1 / 3) to give the intermediate compound (798 mg, 7.12 mmol) as a colorless oil in 94% yield.

[0085] TLC: Rf = 0.30 (thin layer silica gel plate, diethyl ether / n-pentane = 1 / 3). Molybdenum phospohate visualization. (c 0.50, CHCl3). 1H NMR (500 MHz, CDC13) δ 3.83 - 3.71 (m, 2H), 2.61-2.48 (m, 1H), 1.85 (s, 1H), 1.77 (d, J = 2.4 Hz, 3H), 1.72 - 1.54 (m, 2H), 1.15 (dd, J = 6.9, 3H). 13 C NMR (101 MHz, CDC13) δ 83.3, 76.7, 61.5, 39.8, 23.1, 21.7, 3.6. HRMS (ESI, m / z) for C7H 12 ONa + [M+Na] + : Calcd. 135.0780; Found: 135.0783.

[0086] Intermediate compound (300 mg, 2.68 mmol, 1.0 equiv.) was dissolved in dry dichloromethane (27 mL, 0.1 M) and cooled to 0 °C, then Dess-Martin reagent (2.27 g, 5.36 mmol, 2.0 equiv.) was added. The reaction was allowed to warm to room temperature and stirred for 3 h, then TLC monitoring confirmed complete conversion, n-pentane (27 mL) was added and the mixture was cooled to -50 °C, then filtered rapidly through a short column packed with silica gel (diethyl ether / n-pentane = 1 / 4, -50 °C), the resulting organic phases were combined and washed with saturated sodium thiosulfate solution (2 x 30 mL), saturated sodium bicarbonate (2 x 30 mL) and saturated brine (10 mL), then dried over anhydrous sodium sulfate. After drying was completed, the mixture was filtered through a Buchner funnel and the filtrate was concentrated under reduced pressure using a vacuum pump to give the crude product, which was purified by column chromatography on silica gel (diethyl ether / n-pentane = 1 / 4) to give compound 5 (251 mg, 2.28 mmol) as a colorless oil in 85% yield.

[0087] TLC: Rf = 0.50 (thin layer silica gel plate, diethyl ether / n-pentane = 1 / 4). Phosphomolybdic acid visualization. (c 0.50, CHCI3). 1 H NMR (500 MHz, CDC13) δ 9.77 (t, J = 2.1 Hz, 1H), 2.97 - 2.85 (m, 1H), 2.52 (ddd, J = 16.5, 7.6, 2.2 Hz, 1H), 2.44 (ddd, J = 16.5, 6.3, 2.0 Hz, 1H), 1.76 (d, J = 2.4 Hz, 3H), 1.19 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 201.8, 81.7, 77.2, 50.4, 21.4, 20.9, 3.6. HRMS (ESI, m / z) for C7H 10ONa + [M+Na] + : Calcd. 133.0624; Found: 133.0624.

[0088] Example 7

[0089]

[0090] Compound 22 (4.30 g, 15.98 mmol, 1.0 equiv.) was dissolved in a mixture solvent of tetrahydrofuran (80 mL) / water (40 mL) and cooled to 0 °C, then sodium borohydride (2.42 g, 63.92 mmol, 4.0 equiv.) was added. The reaction system was raised to room temperature and continuously stirred for 2 hours, TLC monitoring confirmed that compound 22 was completely converted, then the reaction was quenched by slowly adding saturated ammonium chloride solution (20 mL) at 0 °C. Methyl tert-butyl ether (3 x 80 mL) was added for extraction, the obtained organic phase was combined and washed with saturated brine solution (20 mL), then dried with anhydrous sodium sulfate solid. After drying, it was filtered through a Buchner funnel, and the filtrate was concentrated under reduced pressure with a vacuum pump to obtain the crude product, which was separated by silica gel column chromatography (ethyl acetate / n-hexane = 2 / 1) to obtain the intermediate compound (2.10 g, 14.54 mmol) as a colorless oil in 91% yield.

[0091] TLC: Rf = 0.50 (thin layer silica gel plate, ethyl acetate / n-hexane = 2 / 1). Molybdenum phosphoric acid coloration. (c 0.50, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 5.32-5.23 (m, 1H), 4.02 (d, J = 1.5 Hz, 2H), 3.59-3.48 (m, 1H), 2.45-2.31 (m, 1H), 2.03-1.82 (m, 2H), 1.69 (d, J = 1.5 Hz, 3H), 1.18 (d, J = 6.2 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 137.1, 127.9, 72.1, 68.6, 40.3, 20.5, 17.1, 14.3. HRMS (ESI, m / z) for C8H 16 O2Na + [M+Na] + : Calcd. 167.1043; Found: 167.1043.

[0092] Intermediate compound (2.14 g, 14.87 mmol, 1.0 equiv.) was dissolved in dichloromethane (100 mL) and cooled to 0 °C, then 4-dimethylaminopyridine (363 mg, 2.97 mmol, 0.2 equiv.), triethylamine (3.1 mL, 22.31 mmol, 1.5 equiv.) and tert-butyldiphenylsilyl chloride (4.6 mL, 17.84 mmol, 1.2 equiv.) were added. The reaction was allowed to warm to room temperature and stirred for 2 h, then quenched by the slow addition of water (20 mL) at 0 °C. The reaction was extracted with ethyl acetate (3 x 40 mL), the combined organic phases were washed with saturated aqueous brine solution (20 mL) and dried over anhydrous sodium sulfate. After drying, the mixture was filtered through a fritted funnel and the filtrate was concentrated under reduced pressure using a vacuum pump to give the crude product. Purification by column chromatography on silica gel (ethyl acetate / n-hexane = 1 / 8) gave compound 23 (5.46 g, 14.28 mmol) as a colorless oil in 96% yield.

[0093] TLC: Rf = 0.40 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 8). UV fluorescence & molybdenum blue. 1 HNMR (400 MHz, CDC13) δ 7.71 - 7.63 (m, 4H), 7.44 - 7.33 (m, 6H), 5.27 (dq, J = 10.0, 1.5 Hz, 1H), 4.08 (d, J = 1.5 Hz, 2H), 3.53 - 3.42 (m, 1H), 2.45 - 2.31 (m, 1H), 1.64 (d, J = 1.4 Hz, 3H), 1.17 (d, J = 6.2 Hz, 3H), 1.06 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H).

[0094] Example 8

[0095]

[0096] Compound 23 (5.34 g, 13.97 mmol, 1.0 equiv.) was dissolved in pyridine (140 mL, 0.1 M) and cooled to 0 °C, to which was added 4-dimethylaminopyridine (171 mg, 1.4 mmol, 0.10 equiv.) and p-toluenesulfonyl chloride (13.32 g, 69.85 mmol, 5.0 equiv.). The reaction was allowed to warm to room temperature and stirred for 6 h, after which TLC monitoring confirmed complete conversion of starting material. The reaction was quenched by slow addition of saturated ammonium chloride solution (40 mL) at 0 °C. The reaction was extracted with dichloromethane (3 x 80 mL), and the combined organic phases were washed with saturated sodium bicarbonate solution (2 x 40 mL) and saturated brine solution (40 mL), and dried over anhydrous sodium sulfate. After drying, the mixture was filtered through a fritted funnel, and the filtrate was concentrated under reduced pressure to give the crude product, which was used in the next step without further purification.

[0097] The crude product from the previous step was dissolved in anhydrous tetrahydrofuran (140 mL, 0.1 M) and cooled to 0 °C, then lithium triethylborohydride (84 mL, 83.82 mmol, 6.0 equiv.) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 10 h, after which TLC monitoring confirmed complete conversion of starting material. The reaction was quenched by slow addition of saturated aqueous ammonium chloride solution (20 mL) at 0 °C and extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with saturated brine solution (10 mL) and dried over anhydrous sodium sulfate. After drying, the mixture was filtered through a fritted funnel, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (n-hexane) to give compound 24 (3.73 g, 10.20 mmol) as a colorless oil in 73% yield over two steps.

[0098] TLC: Rf = 0.80 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 10). UV fluorescence & molybdenum blue. (c 0.10, CHCl3). 1 H NMR (500 MHz, CDC13) δ 7.74 - 7.66 (m, 4H), 7.45 - 7.33 (m, 6H), 5.22-5.15 (m, 1H), 4.06 (d, J = 1.5 Hz, 2H), 2.36 - 2.24 (m, 1H), 1.62 (d, J = 1.4 Hz, 3H), 1.39 - 1.17 (m, 2H), 1.06 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDC13) δ 135.7, 134.2, 132.8, 131.3, 129.6, 127.7, 69.4, 33.7, 30.5, 27.0, 20.9, 19.5, 13.9, 12.1. HRMS (ESI, m / z) for C 24 H 34 OSiNa + [M+Na] + : Calcd. 389.2271 ; Found: 389.2273.

[0099] Example 9

[0100]

[0101] Compound 24 (304 mg, 0.83 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (3 mL) and cooled to 0 °C, then tetrabutylammonium fluoride (1.2 mL, 1.23 mmol, 1 M in tetrahydrofuran, 1.5 equiv.) was added. The reaction was allowed to warm to room temperature and stirred for 2 hours, then quenched by the slow addition of water (1 mL) at 0 °C after TLC monitoring confirmed complete conversion of compound 24. The reaction was extracted with diethyl ether (3 x 5 mL), the combined organic phases were washed with a saturated aqueous solution of sodium chloride (2 mL) and dried over anhydrous sodium sulfate. After drying was complete, the mixture was filtered through a fritted funnel and the filtrate was concentrated under reduced pressure using a vacuum pump to give the crude product, which was purified by column chromatography on silica gel (diethyl ether / n-pentane = 1 / 5) to give the intermediate compound (87 mg, 0.68 mmol) as a colorless oil in 82% yield.

[0102] TLC: Rf= 0.40 (thin layer silica gel plate, diethyl ether / n-pentane = 1 / 5). Phosphomolybdic acid visualization. 1 H NMR (500 MHz, CDC13) δ 5.16 (dq, J = 9.5, 1.3 Hz, 1H), 3.99 (s, 2H), 2.34 - 2.22 (m, 1H), 1.66 (d, J = 1.4 Hz, 3H), 1.39 - 1.15 (m, 2H), 0.93 (d, J = 6.7 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H).

[0103] Intermediate compound (434 mg, 3.39 mmol, 1.0 equiv.) was dissolved in dry dichloromethane (26 mL, 0.13 M) and cooled to 0 °C, then carbon tetrabromide (1.46 g, 4.41 mmol, 1.3 equiv.) and triphenylphosphine (1.33 g, 5.09 mmol, 1.5 equiv.) were added sequentially. The reaction was allowed to warm to room temperature and stirred for a further 0.5 h. The reaction was concentrated under reduced pressure using a vacuum pump to give a crude product which was purified by silica gel column chromatography (n-pentane) to give compound 6 (548 mg, 2.88 mmol) as a colourless oil in 85% yield.

[0104] TLC: Rf = 0.90 (thin layer silica gel plate, n-hexane). UV fluorescence & molybdenum blue. 0.50, CHCl3). 1 H NMR (400 MHz, CDC13) δ 5.39 - 5.32 (m, 1H), 3.99-3.95 (m, 2H), 2.32-2.17 (m, 1H), 1.76 (d, J = 1.4 Hz, 3H), 1.43 - 1.15 (m, 2H), 0.93 (d, J = 6.6 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 137.9, 130.9, 42.3, 34.6, 30.2, 20.3, 15.0, 12.0.

[0105] Example 10

[0106]

[0107] Compound 5 (280 mg, 2.54 mmol, 1.0 equiv.) and compound 6 (483 mg, 2.54 mmol, 1.0 equiv.) were dissolved in tetrahydrofuran (25 mL, 0.1 M) solvent, degassed three times in succession and cooled to 0 °C. To the reaction system was added dropwise samarium diiodide (76 mL, 7.62 mmol, 0.1 M dissolved in tetrahydrofuran, 3.0 equiv.) and the reaction system was stirred at 0 °C for 0.5 h. To the reaction system was added dropwise samarium diiodide (51 mL, 5.08 mmol, 0.1 M dissolved in tetrahydrofuran, 2.0 equiv.) and the reaction system was stirred at 0 °C for 12 h. The reaction was quenched by slowly adding saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed successively with saturated sodium thiosulfate solution (40 mL) and saturated brine (20 mL) and dried over anhydrous sodium sulfate solid. After drying was completed, the filtrate was concentrated under reduced pressure with a vacuum pump to obtain the crude product, which was separated by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 12) to obtain compound 25 (237 mg, 1.07 mmol, dr = 1:1.4) as colorless oil in 42% yield.

[0108] TLC: Rf = 0.50 and 0.40 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 10). Phosphomolybdic acid visualization.

[0109] P1: (c 0.10, CHCl3). 1 H NMR (500 MHz, CDC13) δ 5.04 - 4.97 (m, 1H), 3.84 (ddt, J = 8.9, 8.0, 4.4 Hz, 1H), 2.60 - 2.49 (m, 1H), 2.35 - 2.22 (m, 1H), 2.19 (ddd, J = 13.4, 4.1, 1.2 Hz, 1H), 2.02 (ddd, J = 13.3, 8.8, 0.9 Hz, 1H), 1.79 (d, J = 2.4 Hz, 3H), 1.65 (d, J = 1.4 Hz, 3H), 1.68 - 1.58 (m, 1H), 1.49 (ddd, J = 13.6, 6.5, 4.7 Hz, 1H), 1.39 - 1.28 (m, 1H), 1.26 - 1.15 (m, 1H), 1.17 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDC13) δ 135.5, 130.6, 83.8, 76.6, 67.5, 48.0, 44.0, 34.4, 30.5, 23.3, 21.6, 20.9, 16.5, 12.3, 3.6. HRMS (ESI, m / z) for C 15 H 26 ONa + [M+Na] + : Calcd. 245.1876; Found: 245.1876.

[0110] P2: (c 0.10, CHCl3). 1 H NMR (500 MHz, CDC13) δ 5.04 - 4.98 (m, 1H), 3.94 (tt, J = 8.6, 4.1 Hz, 1H), 2.76 - 2.65 (m, 1H), 2.33 - 2.23 (m, 1H), 2.18 (ddd, J = 13.2, 4.4, 1.1 Hz, 1H), 2.06 (ddd, J = 13.2, 9.0, 0.9 Hz, 1H), 1.91 (s, 1H), 1.80 (d, J = 2.4 Hz, 3H), 1.66 (d, J = 1.4 Hz, 3H), 1.51 - 1.39 (m, 2H), 1.40 - 1.28 (m, 1H), 1.28 - 1.16 (m, 1H), 1.16 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H).

[0111] 13 C NMR (101 MHz, CDC13) δ 135.5, 130.6, 83.8, 76.6, 67.5, 48.0, 44.0, 34.4, 30.5, 23.3, 21.6, 20.9, 16.5, 12.3, 3.6. HRMS (ESI, m / z) for C 15 H 26 ONa + [M+Na] + : Calcd. 245.1876; Found: 245.1876.

[0112] Example 11

[0113]

[0114] A flask containing palladium acetate (17.3 mg, 0.077 mmol, 0.1 equiv.) and tricyclohexylphosphine (53.9 mg, 0.19 mmol, 0.25 equiv.) was purged with argon for 2 minutes, the gas in the reaction system was replaced by argon, then dissolved in anhydrous n-hexane (9 mL) and purged for 5 minutes, the reaction system was stirred for 1 hour. Compound 25 (171 mg, 0.77 mmol, 1.0 equiv.) was dissolved in n-hexane (1 mL) and added to the reaction system, and purged for 1 minute. Then tri-n-butyltin hydride (2.1 mL, 7.7 mmol, 10.0 equiv.) was added to the reaction system for 1 hour, and stirred for 72 hours. The reaction solution was concentrated under reduced pressure by vacuum pump to obtain the crude product, which was separated by neutral alumina column chromatography (ethyl acetate / n-hexane = 1 / 25) to obtain compound 3 (150 mg, 0.293 mmol, 38%) as colorless oil.

[0115] TLC: Rf = 0.70 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 10). UV fluorescence & molybdenum phosphoric acid coloration. (c 0.10, CHCl3). 1 H NMR (400 MHz, CDC13) δ 5.21 (dq, J = 9.1, 1.9 Hz, 1H), 5.03 - 4.96 (m, 1H), 3.67 - 3.56 (m, 1H), 2.99 - 2.85 (m, 1H), 2.32 - 2.20 (m, 1H), 2.13 (dd, J = 13.1, 4.4 Hz, 1H), 2.07-1.97 (m, 1H), 1.87 (d, J = 1.8 Hz, 3H), 1.66-1.55 (m, 2H), 1.60 (d, J = 1.4 Hz, 3H), 1.54 - 1.38 (m, 7H), 1.37 - 1.16 (m, 10H), 0.98 - 0.75 (m, 21H). 13 C NMR (101 MHz, CDC13) δ 147.2, 136.6, 135.6, 130.7, 67.0, 48.9, 44.9, 34.3, 30.5, 29.3, 29.1, 27.5, 21.9, 21.3, 19.4, 16.4, 13.9, 12.1, 9.2. HRMS (ESI, m / z) for C 27 H 54 OSnNa + [M+Na] + : Calcd. 537.3089; Found: 537.3093.

[0116] Example 12

[0117]

[0118] Compound 2 (33 mg, 0.084 mmol, 1.0 equiv.) and compound 3 (54 mg, 0.105 mmol, 1.25 equiv.) were dissolved in N,N-dimethylformamide (1.7 mL, 0.05 M) and the gas in the reaction system was replaced with argon for 10 minutes. Then, tetrakis(triphenylphosphine)palladium (9.7 mg, 0.0084 mmol, 0.1 equiv.), copper(I) thiophene-2-carboxylate (32 mg, 0.165 mmol, 1.97 equiv.) and cesium fluoride (26 mg, 0.171 mmol, 2.03 equiv.) were added, and the gas in the reaction system was replaced with argon for 10 minutes. The reaction system was continuously stirred for 48 hours, and saturated aqueous ammonium chloride solution (1 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (3 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (0.5 mL) in turn, dried over anhydrous sodium sulfate, filtered through a sand funnel after drying was completed, and the filtrate was concentrated under reduced pressure with a vacuum pump to obtain a crude product. Silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3) was used to separate the crude product to obtain compound 26 (32 mg, 0.066 mmol, 79%) as a colorless oil.

[0119] TLC: Rf = 0.40 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 3). UV fluorescence & molybdenum phosphoric acid coloration. (c 0.50, CHCl3). 1 H NMR (400 MHz, CDC13) δ 5.56 (s, 1H), 5.02 (s, 2H), 5.01 - 4.95 (m, 1H), 4.90 - 4.82 (m, 1H), 3.65-3.55 (m, 1H), 3.56 (s, 3H), 3.13 - 3.00 (m, 1H), 2.79 - 2.63 (m, 1H), 2.42 - 2.32 (m, 1H), 2.32 - 2.15 (m, 2H), 2.12 (dd, J = 13.1, 4.1 Hz, 1H), 2.03-1.95 (m, 1H), 2.01 (s, 3H), 1.94 (s, 3H), 1.70 (d, J = 1.4 Hz, 3H), 1.65 (d, J = 1.4 Hz, 3H), 1.59 (d, J = 1.4 Hz, 3H), 1.49 - 1.16 (m, 4H), 1.20 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDC13) δ 166.5, 166.0, 161.7, 135.7, 135.4, 132.2, 131.9, 131.7, 130.6, 109.8, 108.7, 99.1, 66.8, 57.9, 48.9, 45.2, 45.1, 34.3, 33.8, 30.5, 29.6, 21.9, 21.3, 17.9, 17.2, 16.5, 12.1, 11.0, 10.5. HRMS (ESI, m / z) for C 30 H 48 O5Na + [M+Na] + : Calcd. 511.3394; Found: 511.3379.

[0120] Example 13

[0121]

[0122] Compound 26 (40 mg, 0.0819 mmol, 1.0 equiv.) was dissolved in dry carbon disulfide (8.0 mL, 0.01 M) and cooled to -78 °C, then sodium bis(trimethylsilyl)amide (61 μL mg, 0.123 mmol, 2.0 M in tetrahydrofuran, 1.5 equiv.) was added dropwise to the reaction system and stirred for 1 hour. Iodomethane (77 μL, 1.23 mmol, 15.0 equiv.) was added, the reaction system was slowly raised to 0 °C and stirred for 3 hours, after TLC monitoring confirmed that compound 26 was completely converted, saturated sodium bicarbonate solution (2 mL) was added to quench and extracted with ethyl acetate (3 x 5 mL), the combined organic phase was washed with saturated brine solution (1 mL), and dried with anhydrous sodium sulfate solid. After drying, it was filtered through a Buchner funnel, and the filtrate was concentrated under reduced pressure with a vacuum pump to obtain the crude product, which was separated by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 4) to obtain the intermediate compound as colorless oil.

[0123] TLC: Rf = 0.50 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 4). UV fluorescence & phosphomolybdic acid visualization. (c 0.50, CHCl3). 1H NMR (400 MHz, CDC13) δ 5.74 - 5.63 (m, 1H), 5.52 (s, 1H), 5.02 (s, 2H), 4.92 (d, J = 9.3 Hz, 1H), 4.82 - 4.74 (m, 1H), 3.56 (s, 3H), 3.12 - 2.98 (m, 1H), 2.61-2.43 (m, 2H), 2.51 (s, 3H), 2.35 (dd, J = 13.3, 8.0 Hz, 1H), 2.28 - 2.11 (m, 3H), 2.01 (s, 3H), 1.93 (s, 3H), 1.81 - 1.66 (m, 1H), 1.69 (d, J = 1.4 Hz, 3H), 1.62 - 1.49 (m, 1H), 1.61 (d, J = 1.4 Hz, 3H), 1.54 (d, J = 1.4 Hz, 3H), 1.40 - 1.09 (m, 2H), 1.18 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H), 0.81 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 215.2, 166.5, 166.0, 161.7, 135.6, 134.2, 132.4, 132.4, 131.5, 129.2, 109.8, 108.7, 99.1, 82.1, 57.9, 45.2, 44.5, 41.1, 34.3, 33.8, 30.5, 29.5, 21.6, 20.7, 18.9, 18.0, 17.9, 17.2, 16.7, 12.2, 11.0, 10.5. HRMS (ESI, m / z) for C 32 H 50 O5S2Na + [M+Na] + : Calcd. 601.2992; Found: 601.2990.

[0124] The product from previous step was dissolved in dry toluene (3 mL, 0.027 M) and then tri-n-butyltin hydride (0.15 mL, 0.573 mmol, 7.0 equiv.) and triethylboron (98 μL, 0.0983 mmol, 1 M in tetrahydrofuran, 1.2 equiv.) were added sequentially. The reaction was stirred for 12 h and then quenched by the addition of water (0.5 mL) and potassium fluoride (71 mg, 1.23 mmol, 15.0 equiv.) and extracted with ethyl acetate (3 x 3 mL). The combined organic phases were washed with saturated aqueous brine solution (0.5 mL) and dried over anhydrous sodium sulfate. After drying was complete, the mixture was filtered through a fritted funnel and the filtrate was concentrated under reduced pressure using a vacuum pump to give the crude product. Purification of the crude product by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 5) gave compound 27 (19 mg, 0.0401 mmol) as a colorless oil in 49% yield over two steps.

[0125] TLC: Rf = 0.30 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 8). UV fluorescence & molybdenum blue. (c 0.10, CHCl3). 1 H NMR (400 MHz, CDC13) δ 5.56 (s, 1H), 5.03 (s, 2H), 4.93 - 4.80 (m, 2H), 3.56 (s, 3H), 3.15 - 2.97 (m, 1H), 2.42 - 2.30 (m, 2H), 2.28 - 2.12 (m, 2H), 2.01 (s, 3H), 1.97 - 1.87 (m, 2H), 1.94 (s, 3H), 1.70 (d, J = 1.4 Hz, 3H), 1.61 (d, J = 1.4 Hz, 3H), 1.56 (d, J = 1.4 Hz, 3H), 1.42 - 1.08 (m, 6H), 1.20 (d, J = 6.8 Hz, 3H), 0.97 - 0.85 (m, 6H), 0.82 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 166.5, 166.0, 161.8, 136.3, 133.8, 132.0, 131.8, 131.4, 130.9, 109.8, 108.8, 99.1, 57.9, 45.3, 40.0, 37.2, 34.1, 33.8, 32.5, 30.7, 26.0, 21.3, 21.2, 17.9, 17.3, 16.2, 12.1, 11.0, 10.5. HRMS (ESI, m / z) for C 30 H 48 O4Na + [M+Na] +Calcd. 495.3445; Found: 495.3456.

[0126] Example 14

[0127]

[0128] Compound 27 (10 mg, 0.0212 mmol, 1.0 equiv.) was dissolved in 0.015 M hydrochloric acid in methanol solution (21 mL, 0.001 M, 0 °C) and stirred at 0 °C for 12 h. After TLC monitoring confirmed that the starting material compound 27 was completely converted, the reaction solution was concentrated under reduced pressure by vacuum pump to obtain the crude product, which was separated by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 2) to obtain compound 1, i.e. a-pyrone-polyketone (6 mg, 0.0142 mmol) as colorless oil in 67% yield.

[0129] TLC: Rf = 0.40 (thin layer silica gel plate, ethyl acetate / n-hexane = 1 / 2). UV fluorescence & molybdenum blue. (c 0.10, CHCl3). 1 H NMR (400 MHz, Acetone-d6) δ 5.58 (s, 1H), 4.94 - 4.83 (m, 2H), 3.28 - 3.15 (m, 1H), 2.46 - 2.37 (m, 1H), 2.33 (ddd, J = 13.2, 8.6, 1.0 Hz, 1H), 2.29 - 2.23 (m, 1H), 2.19 (dd, J = 12.9, 6.5 Hz, 1H), 1.96 (s, 3H), 1.92-1.99 (m, 2H), 1.91 (s, 3H), 1.74 (d, J = 1.4 Hz, 3H), 1.63 (d, J = 1.4 Hz, 3H), 1.57 (d, J = 1.4 Hz, 3H), 1.44 - 1.10 (m, 6H), 1.17 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, Acetone-d6) δ 165.3, 165.1, 161.5, 136.6, 134.5, 133.3, 132.2, 132.1, 131.9, 106.9, 98.4, 45.9, 40.5, 37.9, 34.8, 34.0, 33.1, 31.3, 26.6, 21.6, 21.4, 18.3, 18.0, 17.4, 16.3, 12.4, 10.0, 9.2. HRMS (ESI, m / z) for C 28 H 44 O3Na+ [M+Na] + : Calcd. 451.3183; Found: 451.3182.

[0130] The above description is only the preferred embodiment of the present application, and is not used to limit the present application, any modification, equivalent replacement and improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing α-pyranone-polyketone, characterized in that, Includes the following steps: Compound 3 was coupled with compound 2 to obtain compound 26; The secondary alcohol group of compound 26 was reduced to obtain compound 27; Deprotecting compound 27 yields the α-pyranone-polyketide shown in compound 1; The structural formula of the above-mentioned compound is as follows:

2. The method for preparing α-pyranone-polyketone according to claim 1, characterized in that, The preparation method of compound 2 includes the following steps: Compound 4 was subjected to a reverse Diels-Alder reaction to generate an α-pyranone fragment, and the hydroxyl groups on the α-pyranone fragment were protected to obtain compound 2; The structural formula of compound 4 is as follows:

3. The method for preparing α-pyranone-polyketone according to claim 2, characterized in that, The preparation method of compound 4 includes the following steps: Compound 7 and compound 8 were subjected to a nucleophilic addition reaction, followed by oxidation to obtain compound 4; The structural formula of the above-mentioned compound is as follows:

4. The method for preparing α-pyranone-polyketone according to claim 3, characterized in that, The preparation method of compound 7 includes the following steps: Compound 12 was subjected to methylalumination, iodation and oxidation reactions in sequence to obtain compound 13; Compound 13 was connected to a first chiral prosthetic group to obtain compound 14; Compound 14 was methylated, and then the first chiral prosthetic group was removed and oxidized to give compound 7. The structural formula of the above-mentioned compound is as follows:

5. The method for preparing α-pyranone-polyketone according to claim 3, characterized in that, The preparation method of compound 8 includes the following steps: β-keto ester compounds are obtained by ester condensation reaction of tert-butyl propionate and phenyl propionate. The β-keto ester compound was de-tert-butylened and condensed with acetone to obtain compound 8.

6. The method for preparing α-pyranone-polyketone according to any one of claims 1-5, characterized in that, The preparation method of compound 3 includes the following steps: Compound 5 was subjected to a nucleophilic addition reaction with compound 6 to give compound 25; Compound 25 was reacted with tributyltin hydride to give compound 3; The structural formula of the above-mentioned compound is as follows:

7. The method for preparing α-pyranone-polyketide according to claim 6, characterized in that, The preparation method of compound 5 includes the following steps: The carboxyl group of 4-benzyloxybutyric acid is converted into an aldehyde group and a methyl group is introduced to obtain a chiral aldehyde; The aldehyde group of the chiral aldehyde was converted to an alkynyl group, and then the benzyl group was removed to obtain compound 5.

8. The method for preparing α-pyranone-polyketide according to claim 7, characterized in that, The steps for converting the carboxyl group of 4-benzyloxybutyric acid to an aldehyde group and introducing a methyl group to obtain a chiral aldehyde include: After attaching a second chiral cofactor to 4-benzyloxybutyric acid, an asymmetric methylation reaction is carried out. Then, a methyl group is introduced at the α-position of the carbonyl group, the second chiral cofactor is removed, and the carbonyl group is reduced to a hydroxyl group. Finally, the carbonyl group is oxidized to obtain a chiral aldehyde.

9. The method for preparing α-pyranone-polyketone according to claim 6, characterized in that, The preparation method of compound 6 includes the following steps: After attaching a third chiral prosthetic group to compound 20, an enol silyl ether is generated in the presence of sodium di(trimethylsilyl)amino and tert-butyldimethylchlorosilane. The enol silyl ether reacts with ethanol to react with astragalal to give compound 22. The third chiral prosthetic group of compound 22 was removed and reduced to form a diol. The secondary alcohol group of the diol was removed, and the primary alcohol group of the diol was replaced with a halogen to obtain compound 6. The structural formula of the above-mentioned compound is as follows:

10. The method for preparing α-pyranone-polyketone according to claim 9, characterized in that, The steps of removing the secondary alcohol group of the diol compound and replacing the primary alcohol group of the diol compound with a halogen include: first protecting the primary alcohol group of the diol compound, then removing the secondary alcohol group of the diol compound, and finally replacing the protected primary alcohol group with a halogen.

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