Method for preparing Brasilicardin A key intermediate
Patent Information
- Application Number
- CN202411368028.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-29
- Publication Date
- 2026-03-31
Smart Images
Figure CN121758486A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a novel method for preparing a key intermediate of Brasilicardin A, which possesses strong immunosuppressive activity (IC50). 50 (0.057 μg / ml), possessing potential clinical application value. This invention belongs to the field of raw material and intermediate preparation technology in organic synthesis. Background Technology
[0002] In 1998, Professor Kobayashi's research group isolated a novel terpenoid compound—Brasilicardin A—from Nocardia brasiliensis IFM 0406 obtained from patients with pulmonary nocardiac disease. This compound has a novel structure, containing a unique 8,10-dimethyl-trans-syn-trans-polyhydrophenanthrene skeleton with significant ring strain, comprising an amino acid side chain and a sugar side chain. Brasilicardin A not only exhibits superior properties compared to cyclosporine A (IC50)... 50 It has a strong immunosuppressive effect (IC50 = 0.15 μg / mL). 50 Brasilicardin A has a concentration of 0.057 μg / mL and its mechanism of action differs from existing immunosuppressants (such as cyclosporine and FK-506). It achieves its immunosuppressive effect by inhibiting the L amino acid transport system. Compared with known immunosuppressants cyclosporine and FK-506 (both of which are prone to causing nephrotoxicity and arterial hypertension), Brasilicardin A exhibits lower toxicity and higher immunosuppressive activity. Due to the extremely low content of Brasilicardin A, total synthesis is an effective means to overcome the limited source problem restricting its clinical research. However, its 8,10-dimethyl-trans-syn-trans-polyhydrophenanthrene skeleton is a key intermediate and a challenge in total synthesis. Therefore, we conducted a synthetic study on its key intermediate I (from which the synthesis of Brasilicardin A has been reported in the literature) in order to discover a simple and efficient synthetic route to complete the synthesis of this key intermediate I.
[0003] The structural formula of Brasilicardin A is:
[0004]
[0005] The structural formula of its key intermediate is:
[0006]
[0007] The preparation methods of the key intermediate of Brasilicardin A have been reported. Among them, Anada et al. reported the following synthetic route in 2017: starting from the known compound A, compound B was obtained through 16 steps of reaction including Rubottom oxidation, stereoselective reduction of carbonyl, asymmetric Diels-Alder reaction and angular methylation. Then, B was subjected to 9 steps of reaction including Johnson-Claisen rearrangement to complete the preparation of the key intermediate of Brasilicardin A.
[0008]
[0009] In 2018, Yoshimura et al. reported another synthetic route, which used commercially available neopentyl glycol as the starting material to obtain compound C through 10 steps of reaction including Sharpless dihydroxylation. Then, C underwent 12 steps of reaction including intramolecular Michael addition to obtain E. Finally, E was used to complete the preparation of Brasilicardin A, a key intermediate, through 3 steps of reaction including Corey-Fuchs olefination and intramolecular Michael addition.
[0010]
[0011] While the synthetic routes in the two aforementioned studies differ in the use of starting materials and the methods for controlling chirality, both suffer from several problems. For instance, the route by Anada et al. uses lithium naphthide, which is unavailable commercially and must be prepared in-house, a process deemed extremely dangerous and unsuitable for large-scale industrial production. Furthermore, the methylation step generates byproducts and yields low results. Yoshimura et al.'s route for preparing Weinreb amide D utilizes a highly efficient acylating agent, N-tert-butoxy-N-methylamide, which is not commercially available and requires in-house preparation, a complex and costly process, hindering industrial production. Therefore, designing and developing simple, efficient, economical, environmentally friendly, and easily industrialized synthetic routes using modern chemical synthesis methods and mature techniques is crucial for the subsequent clinical research of Brasilicardin A. Summary of the Invention
[0012] The purpose of this invention is to address the shortcomings of existing technologies by providing a novel method for preparing the key intermediate of Brasilicardin A using readily available industrial raw materials. This method offers advantages such as simplicity, efficiency, controllability, high product purity, and ease of industrial production.
[0013] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: a method for preparing a key intermediate (compound of formula I) of Brasilicardin A, a natural product with immunosuppressive activity.
[0014]
[0015] The preparation steps include: reacting the compound of formula II with an oxidizing agent, such as Dess-Martin oxidant, manganese dioxide, etc., to obtain the compound of formula III. The compound of formula III undergoes a silylation-Rubottom oxidation-deprotection reaction to obtain the compound of formula IV. The compound of formula IV reacts with a protecting agent, such as trimethylsilyl trifluoromethanesulfonate, triethylsilyltrifluoromethanesulfonate, tert-butyldimethylsilyltrifluoromethanesulfonate, triisopropylsilyltrifluoromethanesulfonate, tert-butyldiphenylsilyltrifluoromethanesulfonate, trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane, tert-butyldiphenylchlorosilane, chloromethylmethyl ether, benzyl bromide, p-methoxybenzyl chloride, acetic anhydride, etc., to obtain the compound of formula V. The compound of formula V reacts with a reducing agent, such as sodium borohydride, tri-sec-butyllithium borohydride, tri-n-butyltin, polymethylhydrosiloxane, etc., to obtain the compound of formula VI. Compound VI reacts with protecting agents such as trimethylsilyl trifluoromethanesulfonate, triethylsilyltrifluoromethanesulfonate, tert-butyldimethylsilyltrifluoromethanesulfonate, triisopropylsilyltrifluoromethanesulfonate, tert-butyldiphenylsilyltrifluoromethanesulfonate, trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane, tert-butyldiphenylchlorosilane, chloromethylmethyl ether, benzyl bromide, p-methoxybenzyl chloride, acetic anhydride, etc., to give compound VII. Compound VII undergoes a formylation reaction with N,N-dimethylformamide, followed by a reaction with a reducing agent such as sodium borohydride, lithium borohydride, etc., to give compound VIII. Compound VIII undergoes the Eschenmoser-Claisen rearrangement with N,N-dimethylacetamide dimethylacetal and reacts with the reducing agent triethyllithium borohydride to give compound X. Compound X undergoes a hydroxyl protection reaction with p-methoxybenzyl chloride to give compound XI. Compound XI undergoes hydroboration oxidation, cyanation, and stereoselective methylation to yield compound XIV. Compound XIV undergoes reduction, Wittig, and deprotection reactions to yield compound XVII. Compound XVII undergoes Swern oxidation and Grignard reaction to yield compound XIX. Compound XIX undergoes olefin metathesis and Johnson-Claisen rearrangement to prepare the key intermediate Brasilicardin A.
[0016]
[0017] In addition, the present invention also proposes the following supplementary technical solutions:
[0018] (1) The compound of formula II reacts with an oxidant in dichloromethane at a reaction temperature of 0℃-25℃ for a reaction time of 3h-10h to obtain the compound of formula III; the oxidant is Dess-Martin oxidant, manganese dioxide.
[0019]
[0020] (2) The compound of formula III undergoes a silyl etherification-Rubottom oxidation-deprotection reaction. In the silyl etherification reaction, the silyl etherification reagent is trimethylchlorosilane, the base is diisopropylaminolithium, the reaction solvent is tetrahydrofuran, the reaction temperature is -78℃ to 0℃, and the reaction time is 2 to 6 h. In the Rubottom oxidation reaction, the oxidant is m-chloroperoxybenzoic acid, the base is sodium bicarbonate, the reaction solvent is dichloromethane, the reaction temperature is -20℃ to 0℃, and the reaction time is 0.5 to 2 h. In the deprotection reaction, the deprotection reagent is potassium carbonate or oxalic acid, the reaction solvent is ethanol / tetrahydrofuran, the reaction temperature is 0℃ to 25℃, and the reaction time is 0.5 h to 1 h, to obtain the compound of formula IV.
[0021]
[0022] (3) The compound of formula IV undergoes a hydroxyl protection reaction. When the protecting reagent is a silicon-based reagent, the base is 2,6-dimethylpyridine, the reaction solvent is dichloromethane, the reaction temperature is -25℃ to 25℃, and the reaction time is 1.5h to 2h; when the protecting reagent is chloromethyl methyl ether, the base is N,N-diisopropylethylamine, the reaction solvent is dichloromethane, the reaction temperature is 0℃ to 25℃, and the reaction time is 12h to 24h; when the protecting reagent is benzyl bromide or p-methoxybenzyl chloride, the base is sodium hydride, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 0℃ to 25℃, and the reaction time is 12h to 20h; when the protecting reagent is acetic anhydride, the base is pyridine, the reaction solvent is dichloromethane, the reaction temperature is 0℃ to 25℃, and the reaction time is 10h to 20h.
[0023]
[0024] (4) The compound of formula V is reacted with a reducing agent in tetrahydrofuran at a reaction temperature of -78℃ to 0℃ and a reaction time of 2-8h to obtain the compound of formula VI; the reducing agent is sodium borohydride, trisec-butyl borohydride, tri-n-butyltin, and polymethylhydrosiloxane.
[0025]
[0026] (5) The compound of formula VI undergoes a hydroxyl protection reaction. When the protecting reagent is a silicon-based reagent, the base is 2,6-dimethylpyridine, the reaction solvent is dichloromethane, the reaction temperature is -25℃ to 25℃, and the reaction time is 1.5h to 2h; when the protecting reagent is chloromethyl methyl ether, the base is N,N-diisopropylethylamine, the reaction solvent is dichloromethane, the reaction temperature is 0℃ to 50℃, and the reaction time is 12h to 24h; when the protecting reagent is benzyl bromide or p-methoxybenzyl chloride, the base is sodium hydride, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 0℃ to 25℃, and the reaction time is 12h to 20h; when the protecting reagent is acetic anhydride, the base is pyridine, the reaction solvent is dichloromethane, the reaction temperature is 0℃ to 25℃, and the reaction time is 10h to 20h.
[0027]
[0028] (6) The compound of formula VII undergoes a formylation reaction with N,N-dimethylformamide in tetrahydrofuran, with lithium tert-butyl as the base, at a reaction temperature of -78℃ to 25℃ and a reaction time of 10h to 20h; subsequently, it reacts with a reducing agent in methanol or tetrahydrofuran / methanol at a reaction temperature of 0℃ to 25℃ and a reaction time of 0.5h to 5h to obtain the compound of formula VIII; the reducing agent is sodium borohydride or lithium borohydride;
[0029]
[0030] (7) The compound of formula VIII undergoes an Eschenmoser-Claisen rearrangement reaction with N,N-dimethylacetamide dimethylacetal in m-xylene at a reaction temperature of 110℃-150℃ and a reaction time of 3h-6h to obtain the compound of formula IX.
[0031]
[0032] (8) The compound of formula IX is reacted with a reducing agent in tetrahydrofuran at a reaction temperature of 0℃-25℃ for a reaction time of 5h-12h to obtain compound of formula X; the reducing agent is triethyllithium borohydride.
[0033]
[0034] (9) The compound of formula X undergoes a hydroxyl protection reaction in N,N-dimethylformamide, the protecting agent is p-methoxybenzyl chloride, the base is sodium hydride, the reaction temperature is 0℃-25℃, and the reaction time is 6h-12h to obtain the compound of formula XI.
[0035]
[0036] (10) The compound of formula XI undergoes a borohydride oxidation reaction in tetrahydrofuran at a reaction temperature of 0℃-25℃ and a reaction time of 12h-20h to obtain the compound of formula XII.
[0037]
[0038] (11) The compound of formula XII undergoes a cyanidation reaction in acetonitrile / water at a reaction temperature of 0℃-25℃ and a reaction time of 5h-20h to obtain the compound of formula XIII;
[0039]
[0040] (12) The compound of formula XIII undergoes a stereoselective methylation reaction with iodomethane in tetrahydrofuran, with lithium diisopropylamino as the base, at a reaction temperature of -78℃ to 25℃ and a reaction time of 12 to 20 h, to obtain the compound of formula XIV.
[0041]
[0042] (13) The XIV compound is reacted with a reducing agent in dichloromethane at a reaction temperature of -78℃ to 40℃ for 5h to 10h to obtain the XV compound; the reducing agent is diisobutylaluminum hydride.
[0043]
[0044] (14) The XV compound undergoes a Wittig reaction in tetrahydrofuran at a temperature of 0℃-25℃ and a reaction time of 3h-6h to obtain the XVI compound;
[0045]
[0046] (15) The compound of formula XVI undergoes a deprotection reaction, the deprotection reagent is 2,3-dichloro-5,6-dicyanobenzoquinone, the reaction solvent is dichloromethane / phosphate buffer, the reaction temperature is 0℃-25℃, the reaction time is 2h-5h, and the compound of formula XVII is obtained.
[0047]
[0048] (16) The compound of formula XVII undergoes a Swern oxidation reaction in dichloromethane at a reaction temperature of -78℃ to 0℃ and a reaction time of 2h to 6h to obtain the compound of formula XVIII; the oxidant is dimethyl sulfoxide.
[0049]
[0050] (17) The compound of formula XVIII undergoes a Grignard reaction in tetrahydrofuran, with the Grignard reagent being isopropenyl magnesium bromide, the reaction temperature being 0℃-25℃, and the reaction time being 5h-10h, to obtain the compound of formula XIX.
[0051]
[0052] (18) The compound of formula XIX undergoes an olefin metathesis reaction in dichloromethane, the reaction reagent is a second-generation Grubbs catalyst, the reaction temperature is 25℃-50℃, and the reaction time is 12h-24h to obtain the compound of formula XX.
[0053]
[0054] (19) The compound of formula XX undergoes a Johnson-Claisen rearrangement reaction in triethyl orthoacetate, with p-nitrophenol as the catalyst, a reaction temperature of 120℃-150℃, and a reaction time of 12h-20h to obtain compound of formula I.
[0055]
[0056] Advantages of the present invention
[0057] This invention provides a method for synthesizing a key intermediate of Brasilicardin A. The method is characterized by first preparing a C-ring precursor compound XIX through reactions such as cationic carbocyclization, Rubottom oxidation, Eschenmoser-Claisen rearrangement, and Wittig. Then, the key intermediate of Brasilicardin A is synthesized through olefin metathesis and Johnson-Claisen rearrangement. This method uses readily available raw materials, is simple to operate, and achieves higher product yields and fewer steps than previously reported methods, making it suitable for large-scale industrial production. Detailed Implementation
[0058] The following examples are used to further illustrate the present invention, but they do not imply any limitation on the present invention.
[0059] The following examples are used to explain the present invention, but are not intended to limit the invention in any way.
[0060] Example 1: Preparation of Compound III
[0061] Compound II (30 g, 110 mmol) and 500 mL of CH2Cl2 were added to a 1000 mL single-necked flask. Dess-Martin oxidant (70 g, 165 mmol) was added at 0 °C. After reacting at 0 °C for 10 min, the mixture was raised to room temperature and reacted for 2 h. A mixture of saturated NaHCO3 solution and saturated Na2S2O4 solution (1:1) was added to the reaction solution. After stirring for 10 min, the mixture was separated. The organic phase was washed successively with a mixture of saturated NaHCO3 solution and saturated Na2S2O4 solution, and saturated NaCl. The mixture was dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. The solution was purified by column chromatography (PE:EA = 30:1) to obtain 26.8 g of colorless oily substance with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ5.77(t,J=2.4,1.2Hz,1H),2.59-2.45(m,4H),1.78-1.72(m,2H),1.71-1.69(m,3H),1.11(s,4H),1.08(s,3H),1.03(s,3H); 13 C NMR (100MHz, CDCl3) δ216.4,139.1,121.3,48.9,47.0,38.3,36.7,36.2,34.3,26.7,21.9,20.9,20.7.
[0062] Example 2: Preparation of Formula IV compound
[0063] Add 16.8 mL (120 mmol) of diisopropylamine and 100 mL of THF to a 1000 mL single-necked flask. Add n-BuLi (68.8 mL, 1.6 M in hexane, 110 mmol) at -78 °C and react for 30 min at -78 °C. Then add a 200 mL THF solution of compound III (25 g, 92 mmol) and react for 1 h at -78 °C. Add 17.5 mL (138 mmol) of TMSCl and react for 2 h at 0 °C. Add a saturated NH4HCO3 solution, 200 mL of n-hexane, 200 mL of EtOAc, and 150 mL of H2O to the reaction mixture. Separate the solutions. Wash the organic phase sequentially with H2O and saturated NaCl, and dry with anhydrous Na2SO4. Filter and remove the solvent under reduced pressure. The crude product is not purified.
[0064] The above residue, NaHCO3 (23.2 g, 276 mmol), and CH2Cl2 (300 mL) were added to a 1000 mL single-necked flask. m-CPBA (85%, 24.3 g, 120 mmol) was added at -15 °C. After reacting for 1 h, 100 mL of a 10% Na2S2O3 and saturated NaHCO3 (1:1) mixture was added to the reaction solution. The mixture was separated, and the aqueous phase was extracted with EtOAc. The extract was washed successively with 10% Na2S2O3 solution, H2O, and saturated NaCl, and dried over anhydrous Na2SO4. After filtration, the solvent was removed by vacuum distillation; the residue was not purified.
[0065] The above residue, 100 mL of EtOH, 20 mL of THF, and (COOH)₂ (24.9 g, 276 mmol) were added to a 500 mL single-necked flask. After reacting at room temperature for 30 min, a saturated NaHCO₃ solution was added to the reaction solution. The reaction solution was filtered through diatomaceous earth, washed with EtOAc, and the filtrate was washed successively with saturated NaHCO₃, H₂O, and saturated NaCl. The solution was dried over anhydrous Na₂SO₄. After filtration, the solvent was removed under reduced pressure, and the solution was purified by column chromatography (PE:EA = 20:1) to give 18 g of white solid, with a yield of 68%. 1 H NMR (400MHz, CDCl3) δ5.82(t,J=1.8Hz,1H),4.55(dd,J=12.8,6.5Hz,1H),2.61-2.45(m,2H),2.25(d d,J=12.5,6.5Hz,1H),1.89-1.70(m,2H),1.60-1.46(m,2H),1.32(s,3H),1.18(s,3H),1.11(s,3H); 13 CNMR(100MHz, CDCl3)δ215.2,139.1,121.4,69.4,50.8,47.4,46.9,38.7,36.0,24.7,21.7,21.3,21.1.
[0066] Example 3: Preparation of Compound V
[0067] Compound IV (17 g, 59.2 mmol), N,N-diisopropylethylamine (29.4 mL, 177.6 mmol), and 300 mL of CH₂Cl₂ were added to a 1000 mL single-necked flask. MOMCl (11.8 mL, 148 mmol) was added at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 20 h. A saturated NaHCO₃ solution, 200 mL of EtOAc, and 100 mL of H₂O were added to the reaction mixture. The mixture was separated, and the organic phase was washed successively with H₂O, then with saturated NaCl, and dried over anhydrous Na₂SO₄. The mixture was filtered, and the solvent was removed under reduced pressure. The solution was purified by column chromatography (PE:EA = 30:1) to give 18.3 g of a colorless oily substance, with a yield of 86%. 1 H NMR (400MHz, CDCl3) δ5.80(t,J=1.7Hz,1H),4.75-4.68(m,2H),4.52(dd,J=12.6,6.3Hz,1H),3.38(s,3H),2.60-2.39(m,2 H),2.10(dd,J=12.6,6.3Hz,1H),1.85-1.65(m,3H),1.59(dd,J=12.2,2.5Hz,1H),1.28(s,3H),1.13(s,3H),1.06(s,3H); 13 CNMR (100MHz, CDCl3) δ211.9,139.0,121.6,95.9,73.4,55.8,49.9,48.2,45.1,38.8,36.0,25.2,22.0,21.8,21.4,21.1.
[0068] Example 4: Preparation of Compound VI
[0069] Compound V (18 g, 54.3 mmol), PMHS (4.9 g, 1.5 mol equiv of hydrogen atom), and 300 mL of THF were added to a 1000 mL two-necked flask. TBAF (2.7 mL, 1 M in THF, 2.7 mmol) was added at -78 °C, and the reaction was continued at -78 °C for 30 min. Then, TBAF (54.3 mL, 1 M in THF, 54.3 mmol) was added, and the reaction was continued at -78 °C for 1 h. The temperature was then raised to 0 °C and reacted for 30 min. The reaction solution was poured into a mixed solution of MTBE and saturated NaCl. The pH was adjusted to approximately 2 with 1 M (mol / L) HCl. The mixture was separated, and the organic phase was washed with saturated NaHCO3 solution and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure, and the solution was purified by column chromatography (PE:EA = 15:1) to obtain 16.2 g of a colorless oily substance, with a yield of 90%. 1H NMR (400MHz, CDCl3) δ5.73(t,J=1.7Hz,1H),4.73(q,J=6.8Hz,2H),3.60-3.53( m,1H),3.41(s,3H),3.14(brs,1H),3.11(d,J=9.3Hz,1H),2.51-2.45(m,2H),1. 88(dd,J=12.6,4.5Hz,1H),1.80-1.74(m,1H),1.70-1.59(m,1H),1.36(t,J=12 .1Hz,1H),1.25(dd,J=12.5,2.3Hz,1H),1.08(s,3H),1.05(s,3H),0.84(s,3H); 13 CNMR (100MHz, CDCl3) δ140.3,121.1,96.9,81.4,78.3,55.8,48.7,43.1,39.4,38.8,36.7,28.6,22.2,20.5,16.7.
[0070] Example 5: Preparation of Compound VII
[0071] Compound VI (14 g, 42.2 mmol), N,N-diisopropylethylamine (21.0 mL, 126.6 mmol), and CH₂Cl₂ (300 mL) were added to a 1000 mL single-necked flask. MOMCl (8.4 mL, 105.5 mmol) was added at 0 °C. After the addition was complete, the mixture was heated to 50 °C and reacted for 20 h. A saturated NaHCO₃ solution, EtOAc (200 mL), and H₂O (100 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was washed successively with H₂O, then with saturated NaCl, and dried over anhydrous Na₂SO₄. The mixture was filtered, and the solvent was removed under reduced pressure. The solution was purified by column chromatography (PE:EA = 10:1) to give 15.3 g of a colorless oily substance, with a yield of 96%. 1H NMR (400MHz, CDCl3) δ5.73(t,J=1.8Hz,1H),4.90(dd,J=6.5,1.4Hz,1H),4.73(dd,J=6.4,1 .3Hz,2H),4.69(dd,J=6.7,1.3Hz,1H),3.77-3.67(m,1H),3.42(s,3H),3.37(s,3H),3.02(d d,J=9.5,1.4Hz,1H),2.55-2.45(m,2H),1.89(dd,J=12.7,4.5Hz,1H),1.83-1.73(m,1H),1 .73-1.59(m,1H),1.33(t,J=12.2Hz,1H),1.23(d,J=12.7Hz,1H),1.05(s,6H),0.84(s,3H); 13 C NMR (100MHz, CDCl3) δ140.2,120.9,99.3,96.4,89.4,75.9,56.2,55.4,49.0,43.7,39.2,39.1,36.6,28.5,22.1,20.8,17.3.
[0072] Example 6 Preparation of compound VIII
[0073] Add compound VII (15 g, 39.8 mmol) and 200 mL of THF to a 500 mL two-necked flask. Add t-BuLi (91.9 mL, 1.3 M in hexane, 119.4 mmol) dropwise at -78 °C. After the addition is complete, react at -78 °C for 1 h. Add DMF (30.7 mL, 398.0 mmol) to the reaction mixture, slowly raise the temperature to room temperature, and react for 12 h. Add H₂O to the reaction mixture, separate the layers, and extract the aqueous phase with EtOAc. Wash the extract successively with H₂O, then with saturated NaCl, and dry with anhydrous Na₂SO₄. Filter, remove the solvent under reduced pressure, and use the crude product directly in the next step without purification.
[0074] The unpurified compound was added to a 500 mL two-necked flask along with 100 mL of CH3OH and 100 mL of THF. NaBH4 (2.3 g, 59.7 mmol) was added at 0 °C, and the reaction was carried out for 2 h at 0 °C. A saturated NaHCO3 solution was then added to the reaction mixture. The mixture was separated, and the aqueous phase was extracted with EtOAc. The extract was washed with saturated NaCl and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EA = 3:1) to obtain 12.2 g of a colorless oily substance, with a yield of 93%. 1H NMR (400MHz, CDCl3) δ5.35(s,1H),4.90(d,J=6.5Hz,1H),4.74(d,J=4.6Hz,2H),4.70(d,J=6.7Hz,1H),3. 94(s,2H),3.79-3.72(m,1H),3.43(s,3H),3.38(s,3H),3.01(d,J=9.6Hz,1H),2.14(dd,J=17.7,6.4Hz,1 H),2.07-1.98(m,1H),1.89(dd,J=12.6,4.5Hz,1H),1.78(dd,J=13.3,7.0Hz,1H),1.71(brs,1H),1.55-1 .41(m,2H),1.25(t,J=12.1Hz,1H),1.14(dd,J=12.5,2.0Hz,1H),1.05(s,3H),1.00(s,3H),0.86(s,3H); 13 C NMR (100MHz, CDCl3) δ135.0,134.1,99.3,96.3,89.8,76.3,66.9,56.2,55.4,50.2,44.2,39.4,35.5,28.6,27.2,22.4,18.5,17.4.
[0075] Example 7 Preparation of Compound IX
[0076] Compound VIII (11 g, 33.50 mmol), N,N-dimethylacetamide dimethylacetal (39.2 mL, 268.0 mmol), and 150 mL of m-xylene were added to a 100 mL single-necked flask. The mixture was heated under reflux for 3 h, and the solvent was removed under reduced pressure. The residue was diluted with EtOAc, washed successively with H2O and saturated NaCl, and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure, and the product was purified by column chromatography (PE:EA = 1:1) to give 12.6 g of a colorless oily substance in 95% yield. 1H NMR (400MHz, CDCl3) δ4.91 (d, J=6.5Hz, 1H), 4.72-4.68 (m, 3H), 4.66 (d, J=6.6Hz, 1H), 4.62 (t, J= 2.0Hz,1H),3.78-3.72(m,1H),3.41(s,3H),3.35(s,3H),2.98(s,3H),2.96(s,1H),2.88(s,3H), 2.51(dd,J=13.2,3.8Hz,1H),2.44-2.32(m,2H),2.28-2.21(m,1H),2.21-2.11(m,1H),1.68-1.5 9(m,2H),1.43-1.29(m,2H),1.24(dd,J=12.5,2.9Hz,1H),1.04(s,3H),1.01(s,3H),0.82(s,3H); 13 C NMR (100MHz, CDCl3) δ172.1,147.6,110.9,99.2,96.0,89.4,75.4,56.3,55.5 ,52.9,45.6,41.5,39.7,38.2,37.6,35.6,32.5,31.6,29.0,23.0,22.9,17.7.
[0077] Example 8: Preparation of Compound X
[0078] Compound IX (12 g, 30.2 mmol) and 150 mL of THF were added to a 25 mL two-necked flask. Triethyllithium borohydride (90.6 mL, 1.0 M in THF, 90.6 mmol) was added dropwise at 0 °C. After reacting for 5 h at 0 °C, saturated NH₄Cl solution was added to the reaction mixture. The mixture was separated, and the aqueous phase was extracted with EtOAc. The extract was washed with saturated NaCl and dried over anhydrous Na₂SO₄. After filtration, the solvent was removed under reduced pressure, and the solution was purified by column chromatography (PE:EA = 3:1) to give 10.2 g of a colorless oily substance, with a yield of 95%. 1H NMR(400MHz, CDCl3)4.92(d,J=6.6Hz,1H),4.77-4.71(m,3H),4.68(dd,J=6.7,1.2Hz,1H),4.64(t,J =2.0Hz,1H),3.80-3.74(m,1H),3.64-3.47(m,2H),3.42(s,3H),3.37(s,3H),2.98(d,J=9.6Hz,1H), 2.22(dd,J=13.7,3.9Hz,1H),2.10(dd,J=15.0,10.2Hz,1H),1.85-1.72(m,2H),1.69-1.56(m,3H),1 .55-1.51(m,1H),1.48(d,J=12.4Hz,1H),1.40-1.35(m,2H),1.04(s,3H),0.98(s,3H),0.83(s,3H); 13 C NMR (100MHz, CDCl3) δ148.7,110.4,99.2,96.1,89.5,75.8,61.9,56.3,55.4,54.4,45.1,41.5,39.6,38.2,31.1,29.4,29.0,23.2,23.0,17.7.
[0079] Example 9 Preparation of compound XI
[0080] Compound X (1.10 g, 3.09 mmol) and 15 mL of DMF were added to a 50 mL two-necked flask. NaH (60%, 186 mg, 4.64 mmol) was added at 0 °C, and the reaction was continued at 0 °C for 10 min. PMBCl (0.7 mL, 4.64 mmol) was added dropwise, and the reaction was continued at 0 °C for 30 min. After reacting at room temperature for 12 h, H₂O was added to the reaction solution, and the mixture was extracted with EtOAc. The extract was washed successively with H₂O and saturated NaCl, and dried over anhydrous Na₂SO₄. The mixture was filtered, the solvent was removed under reduced pressure, and the solution was purified by column chromatography (PE:EA = 15:1) to give 1.33 g of a colorless oily substance, with a yield of 90%. 1H NMR (400MHz, CDCl3) δ7.27(d,J=8.0Hz,2H),6.90(d,J=9.8Hz,2H),4.94(dd,J=6.5,1.1Hz,1 H),4.81-4.68(m,4H),4.59(s,1H),4.41(s,2H),3.87-3.76(m,4H),3.46(s,3H),3.42-3.29 (m,5H),3.00(d,J=9.5Hz,1H),2.22(d,J=12.8Hz,1H),2.09(dd,J=16.0,9.0Hz,1H),1.94-1 .80(m,2H),1.71-1.53(m,5H),1.38(d,J=4.1Hz,1H),1.07(s,3H),1.01(s,3H),0.86(s,3H); 13 C NMR (100MHz, CDCl3) δ159.1,147.6,130.7,129.3,113.8,110.4,99.3,96.1,89.6,75.8,72. 7,69.1,56.3,55.4,55.3,53.9,45.0,41.4,39.6,38.2,31.00,29.0,26.4,23.2,23.1,17.7.
[0081] Example 10 Preparation of Compound XII
[0082] Compound XI (1.27 g, 2.67 mmol), NaBH4 (127 g, 3.34 mmol), and 15 mL of tetrahydrofuran were added to a 50 mL two-necked flask. A borane tetrahydrofuran complex (10.4 mL, 1 M in THF, 10.4 mmol) was added dropwise at -20 °C. After the addition was complete, the mixture was allowed to react at room temperature for 3 h. The reaction solution was then added dropwise to 46 mL of H2O. After the addition was complete, NaBO3·4H2O (2.5 g, 16.1 mmol) was added, and the mixture was reacted at room temperature for 4 h. The mixture was then extracted with EtOAc, washed with saturated NaCl, and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EA = 3:1) to give 1.15 g of a colorless oily substance, with a yield of 88%. 1H NMR (400MHz, CDCl3) δ7.28(d,J=8.6Hz,2H),6.90(d,J=8.6Hz,2H),4.93(d,J=6.4Hz,1H),4.75(dd,J=6.6, 3.2Hz,2H),4.69(d,J=6.7Hz,1H),4.44(d,J=4.1Hz,2H),3.83(s,3H),3.81-3.74(m,2H),3.63(d,J=5.5Hz, 1H),3.46(d,J=4.8Hz,5H),3.38(s,3H),2.96(d,J=9.5Hz,1H),1.97(dd,J=8.6,5.2Hz,1H),1.74(dt,J=8.8 ,4.6Hz,3H),1.59-1.47(m,5H),1.35-1.26(m,2H),1.14(dd,J=12.0,2.7Hz,1H),1.04(s,6H),0.84(s,3H); 13 C NMR (100MHz, CDCl3) δ159.2,130.6,129.3,113.8,99.2,96.1,89.5,75.7,72.6,70.2,6 7.1,56.3,55.4,55.3,46.7,42.6,42.3,39.7,37.7,30.6,28.6,24.4,23.8,18.2,17.3.
[0083] Example 11 Preparation of Compound XIII
[0084] Compound XII (1.08 g, 2.19 mmol), 18 mL CH3CN, and 2 mL H2O were added to a 100 mL two-necked flask. TEMPO (52 mg, 0.33 mmol), NH4OAc (1.18 g, 15.33 mmol), and PIDA (2.55 g, 7.67 mmol) were added at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 24 h. A saturated Na2SO3 solution was added to the reaction mixture, and the mixture was extracted with EtOAc. The extract was washed with saturated NaCl and dried over anhydrous Na2SO4. The mixture was filtered, the solvent was removed under reduced pressure, and the solution was purified by column chromatography (PE:EA = 6:1) to give 770 mg of a yellow oily substance, with a yield of 73%. 1H NMR (400MHz, CDCl3) δ7.27(d,J=8.5Hz,2H),6.92(d,J=8.6Hz,2H),4.93(d,J=6.5Hz,1H),4.78-4.7 2(m,2H),4.69(d,J=6.7Hz,1H),4.44(d,J=2.8Hz,2H),3.84(s,4H),3.45(s,4H),3.39(s,4H),2.96 (d,J=9.6Hz,1H),2.93(d,J=4.1Hz,1H),2.02-1.89(m,2H),1.69(tdd,J=9.5,7.4,3.5Hz,4H),1.62 (dd,J=12.4,4.4Hz,1H),1.50-1.37(m,5H),1.11(dd,J=8.5,3.6Hz,1H),1.06(s,3H),0.88(s,3H); 13 C NMR (100MHz, CDCl3) δ159.3,130.1,129.3,124.1,113.9,99.2,96.2,89.2,75.3,72.8,69. 1,56.3,55.5,55.3,46.8,45.8,41.7,39.7,38.5,28.7,28.6,27.4,25.1,24.2,19.0,17.4.
[0085] Example 12 Preparation of Formula XIV compound
[0086] Add diisopropylamine (0.25 mL, 1.74 mmol) and THF 5 mL to a 100 mL two-necked flask. Add n-BuLi (1.1 mL, 1.6 M in hexane, 1.74 mmol) dropwise at -78 °C. After reacting at 0 °C for 30 min, cool to -78 °C and add a THF (8 mL) solution of compound XIII (707 mg, 1.45 mmol). After reacting at -78 °C for 1 h, add CH3I (0.27 mL, 4.35 mmol) and HMPA (0.51 mL, 2.90 mmol). After reacting for 12 h, add saturated NH4Cl solution to the reaction solution. Separate the solution and extract the aqueous phase with MTBE. Wash the extract successively with 1 M (mol / L) HCl, saturated NaHCO3 solution, H2O, and saturated NaCl. Dry with anhydrous Na2SO4. The solvent was removed by filtration under reduced pressure and purified by column chromatography (PE:EA = 8:1) to obtain 632 mg of colorless oil, with a yield of 87%. 1H NMR (400MHz, CDCl3) δ7.27(d,J=8.6Hz,2H),6.90(d,J=8.6Hz,2H),4.93(d,J=6.5Hz,1H),4.75 (dd,J=6.6,2.6Hz,2H),4.68(d,J=6.6Hz,1H),4.48-4.39(m,2H),3.83(s,4H),3.45(s,3H),3.4 2-3.29(m,5H),2.97(d,J=9.6Hz,1H),1.94(d,J=14.0Hz,1H),1.74(s,1H),1.72-1.60(m,4H), 1.53(d,J=11.8Hz,1H),1.46(s,3H),1.44(s,3H),1.41-1.32(m,2H),1.04(s,4H),0.87(s,3H); 13 C NMR (100MHz, CDCl3) δ159.2,130.2,129.3,127.1,113.8,99.2,96.3,89.00,75.6,72.8,70.9, 56.3,55.4,55.3,51.1,45.3,41.6,39.8,39.4,34.9,34.4,28.6,27.7,26.1,25.1,20.2,17.0.
[0087] Example 13 Preparation of Compound XV
[0088] Add formula XIV (632 mg, 1.26 mmol) and 10 mL of CH2Cl2 to a 50 mL two-necked flask. Under argon protection, slowly add DIBAL-H (1.89 mL, 1 M in hexane, 1.89 mmol) dropwise at -78 °C. After the addition is complete, react at -78 °C for 8 h. Add 10 mL of EtOAc, stir at -78 °C for 15 min, then add 10% tartaric acid solution to the reaction mixture, raise the temperature to room temperature, and stir until the solution is clear. Separate the layers; extract the aqueous phase with EtOAc, wash the extract with saturated NaCl, and dry with anhydrous Na2SO4. Filter, remove the solvent under reduced pressure, and purify by column chromatography (PE:EA = 8:1) to obtain 507 mg of a colorless oily substance, with a yield of 80%. 1H NMR (400MHz, CDCl3) δ9.54(s,1H),7.29(d,J=8.2Hz,2H),6.90(s,2H),4.92(d,J=6.4Hz,1H),4.76(d,J=6.6Hz,2H),4.68(d,J =6.7Hz,1H),4.47(d,J=2.3Hz,2H),3.84(s,3H),3.80-3.71(m,1H),3.45(s,3H),3.44-3.38(m,2H),3.36(s,3H),2.98(d,J=9. 6Hz,1H),2.10(d,J=13.8Hz,1H),1.77(td,J=9.4,5.0Hz,1H),1.67(s,2H),1.60(d,J=7.6Hz,2H),1.57-1.48(m,1H),1.35(d, J=4.1Hz,1H),1.18(dd,J=14.3,5.4Hz,1H),1.10(dd,J=12.2,3.1Hz,1H),1.03(s,3H),0.93(s,3H),0.92(s,3H),0.78(s,3H); 13 C NMR (100MHz, CDCl3) δ205.1,159.2,130.4,129.2,113.8,99.2,96.3,89.2,75.7,72.7,71. 4,56.3,55.4,55.3,50.1,49.8,44.8,41.5,39.8,39.4,28.7,26.3,24.2,22.2,19.2,17.0.
[0089] Example 14 Preparation of Compound XVI
[0090] Add methyltriphenylphosphine bromide (986 mg, 2.76 mmol) and 10 mL of THF to a 50 mL two-necked flask. Add potassium tert-butoxide (289 mg, 2.58 mmol) at 0 °C. After the addition is complete, react at 0 °C for 30 min. Slowly add 8 mL of THF solution of compound XV (464 mg, 0.92 mmol). After the addition is complete, react at 0 °C for 3 h. Add saturated NH4Cl solution to the reaction mixture, separate the layers, extract the aqueous phase with MTBE, and wash the extract successively with 5% KHSO4 solution, saturated NaHCO3 solution, H2O, and saturated NaCl. Dry the extract on anhydrous Na2SO4. Filter, remove the solvent under reduced pressure, and purify by column chromatography (PE:EA = 6:1) to obtain 436 mg of colorless oil, with a yield of 94%. 1H NMR (400MHz, CDCl3) δ7.30(d,J=8.5Hz,2H),6.91(d,J=8.5Hz,2H),5.94(dd,J=17.8,10.8Hz,1H),4.96-4.90(m,2H), 4.89-4.81(m,1H),4.79-4.74(m,2H),4.69(d,J=6.6Hz,1H),4.46(s,2H),3.83(s,3H),3.77(td,J=10.2,4.9Hz,1H), 3.46(s,3H),3.37(s,5H),2.98(d,J=9.6Hz,1H),1.94-1.84(m,1H),1.75-1.66(m,3H),1.61(d,J=11.4Hz,1H),1.59- 1.47(m,3H),1.31(td,J=13.1,5.6Hz,1H),1.11(s,3H),1.04(s,3H),0.94(s,3H),0.87(d,J=8.4Hz,1H),0.81(s,3H). 13 C NMR (100MHz, CDCl3) δ159.1,151.2,130.6,129.2,113.8,107.2,99.3,96.2,89.5,76.1,72.6,72. 00,56.3,55.3,55.3,54.4,45.8,42.0,40.8,40.4,39.4,31.2,30.8,28.8,27.6,26.2,19.1,17.1.
[0091] Example 15 Preparation of Compound XVII
[0092] Compound XVI (576 mg, 1.14 mmol), 7 mL of CH₂Cl₂, 776 mg of 2,3-dichloro-5,6-dicyanobenzoquinone (3.42 mmol), and 2 mL of phosphate buffer were added to a 50 mL single-necked flask. After addition, the mixture was reacted at room temperature for 3 h. A saturated NaHCO₃ solution was added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with CH₂Cl₂, and the extract was washed successively with saturated NaHCO₃ solution and saturated NaCl. The extract was dried over anhydrous Na₂SO₄. After filtration, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EA = 4:1) to give 417 mg of a yellow oily substance, with a yield of 95%. 1H NMR (400MHz, CDCl3) δ5.96 (dd, J=17.7, 11.4Hz, 1H), 4.94-4.82 (m, 3H), 4.76 (dd, J=6.6, 2.2Hz, 2 H),4.70(d,J=6.6Hz,1H),3.79(td,J=9.7,5.8Hz,1H),3.56(t,J=8.0Hz,2H),3.45(s,3H),3.40( s,3H),2.98(d,J=9.6Hz,1H),1.90(d,J=11.5Hz,1H),1.66(m,2H),1.62-1.57(m,2H),1.49(m,3H ),1.36-1.25(m,2H),1.12(s,3H),1.05(s,3H),0.96(s,3H),0.91(q,J=3.5Hz,1H),0.81(s,3H); 13 CNMR (100MHz, CDCl3) δ151.1,107.3,99.2,96.3,89.5,76.0,64.7,56.3,55.4 ,54.1,45.9,42.2,40.7,40.3,39.4,31.2,30.9,30.7,28.8,26.2,19.0,17.1.
[0093] Example 16 Preparation of Compound XVIII
[0094] Add (COCl)₂ (0.12 mL, 1.31 mmol) and CH₂Cl₂ (5 mL) to a 50 mL two-necked flask. Under argon protection, slowly add a CH₂Cl₂ solution containing DMSO (0.19 mL, 2.62 mmol) in 2 mL at -78 °C. After reacting for 20 min, add a CH₂Cl₂ solution containing compound XVII (417 mg, 1.09 mmol) in 6 mL. After reacting at -78 °C for 1 h, add triethylamine (0.76 mL, 5.45 mmol). After reacting at -78 °C for 1 h, add H₂O to the reaction mixture. Separate the solution. Extract the aqueous phase with MTBE. Wash the extract successively with 10% KHSO₄ solution, saturated NaHCO₃ solution, and saturated NaCl. Dry the extract with anhydrous Na₂SO₄. Filter the solution, remove the solvent under reduced pressure, and purify by column chromatography (PE:EA = 10:1) to obtain 372 mg of a yellow oily substance, with a yield of 90%. 1H NMR (400MHz, CDCl3) δ9.81 (s, 1H), 6.02 (dd, J = 17.8, 10.9Hz, 1H), 5.02-4.82 (m, 3H), 4.76-4.6 9(m,2H),4.66(d,J=6.7Hz,1H),3.77(td,J=10.4,4.4Hz,1H),3.44(s,3H),3.36(s,3H),2.95(d ,J=9.6Hz,1H),2.60(m,2H),2.07(t,J=5.1Hz,1H),1.96(d,J=14.0Hz,1H),1.55(m,3H),1.29- 1.20(m,2H),1.19(s,3H),1.05(s,3H),0.99(dd,J=11.0,4.2Hz,1H),0.85(s,3H),0.82(s,3H); 13 C NMR (100MHz, CDCl3) δ201.8,150.3,108.1,99.2,96.1,89.4,75.7,56.3,55.4 ,50.3,46.5,43.1,42.5,40.0,39.6,39.5,31.8,31.7,28.9,25.7,18.9,17.2.
[0095] Example 17 Preparation of Compound XIX
[0096] Compound XVIII (372 mg, 0.98 mmol) and 6 mL of THF were added to a 50 mL two-necked flask. Under argon protection, magnesium isopropenyl magnesium bromide (2.94 mL, 1 M in THF, 2.94 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the reaction mixture was reacted at 0 °C for 6 h. Saturated NH4Cl solution was added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with EtOAc, and the extract was washed successively with H2O and saturated NaCl, and dried over anhydrous Na2SO4. The mixture was filtered, the solvent was removed under reduced pressure, and the solution was purified by column chromatography (PE:EA = 10:1) to give 405 mg of a colorless oily substance, with a yield of 97%. 1 HNMR (400MHz, CDCl3) δ6.00 (dd, J=17.8, 10.8Hz, 1H), 4.97-4.88 (m, 3H), 4.87-
[0097] 4.82(m,2H),4.78-4.74(m,2H),4.71(d,J=6.7Hz,1H),3.97(t,J=6.5Hz,1H), 3.80(m,1H),3.45(s,3H),3.40(s,3H),2.99(d,J=9.6Hz,1H),1.88(m,1H),1. 81-1.78(m,3H),1.70-1.65(m,2H),1.58(dd,J=6.7,4.0Hz,3H),1.51-1.44(m ,3H),1.37-1.27(m,4H),1.16(s,3H),1.04(s,3H),0.91(s,4H),0.81(s,3H); 13 C NMR (100MHz, CDCl3) δ151.3,148.0,110.8,107.2,99.2,96.2,89.4,77.5,76.1,56.3,5 5.4,54.4,46.1,42.8,41.1,40.,39.5,33.1,31.2,31.0,28.7,26.2,19.1,17.9,17.1.
[0098] Example 18 Preparation of Compound XX
[0099] Add 300 mg (0.71 mmol) of formula XIX and 8 mL of CH2Cl2 to a 25 mL two-necked flask. Under argon protection, add 34 mg (0.04 mmol) of Grubbs second-generation catalyst at room temperature. After the addition is complete, react at 50 °C for 20 h. Remove the solvent under reduced pressure, and purify by column chromatography (PE:EA = 10:1) to obtain 225 mg of a yellow oily substance, with a yield of 80%. 1 H NMR (400MHz, CDCl3) δ5.19 (s, 1H), 4.93 (d, J = 6.5Hz, 1H), 4.79-4.70 (m, 4H), 4.08 (t, J = 8.2Hz, 1H), 3 .82(m,1H),3.45(s,3H),3.41(s,4H),3.04(d,J=9.4Hz,1H),2.05(dd,J=12.5,6.8Hz,1H),1.89(dd,J =12.5,5.0Hz,1H),1.73(d,J=4.1Hz,1H),1.64(d,J=11.4Hz,1H),1.60-1.51(m,2H),1.48-1.41(m,1H ),1.37(t,J=11.5Hz,3H),1.29(d,J=8.4Hz,3H),1.20(s,3H),1.06(s,3H),0.99(s,3H),0.86(s,3H); 13C NMR (100MHz, CDCl3) δ139.2,129.9,99.3,96.4,90.3,77.8,72.7,56.2,55.6,48 .5,46.4,39.7,39.3,37.3,36.3,34.8,29.8,29.7,27.0,22.7,18.8,17.9,17.4.
[0100] Example 19 Preparation of Compound I
[0101] Compound XXII (200 mg, 0.51 mmol), p-nitrophenol (7 mg, 0.05 mmol), and 10 mL of triethyl orthoacetate were added to a 50 mL single-necked flask. The mixture was heated under reflux for 12 minutes. The solvent was then removed under reduced pressure. The residue was diluted with EtOAc and washed successively with saturated NaHCO3 solution, H2O, and saturated NaCl solution. The residue was dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure, and the product was purified by column chromatography (PE:EA = 15:1) to give 214 mg of a colorless oily substance, with a yield of 90%. 1 H NMR(400MHz, CDCl3)δ5.38(d,J=4.8Hz,1H),4.90(d,J=6.5Hz,1H),4.74-4.67(m,3H),4.14(qd,J=7.1,1.9Hz,2H), 3.72(ddd,J=11.6,9.6,4.3Hz,1H),3.42(s,3H),3.38(s,3H),2.96(d,J=9.6Hz,1H),2.37(dd,J=16.6,8.0Hz,1H), 2.20(dd,J=16.6,3.3Hz,1H),2.10(d,J=8.3Hz,1H),1.96-1.87(m,1H),1.86-1.79(m,1H),1.76(dd,J=12.6,4.3Hz ,1H),1.69-1.61(m,4H),1.61-1.44(m,4H),1.36-1.18(m,6H),1.08(s,3H),1.00(s,3H),0.98(s,3H),0.91(s,3H); 13 C NMR (100MHz, CDCl3) δ174.2,135.8,123.9,99.2,96.3,89.4,76.4,60.5,56.3,55.5,51.2,46 .1,43.3,42.3,40.2,36.6,36.4,35.3,29.4,28.9,28.6,25.9,22.6,22.3,17.7,17.6,14.3.
Claims
1. A method for preparing the key intermediate Brasilicardin A as shown in Formula I, Its preparation steps include: Step (1): Compound II undergoes an oxidation reaction to yield compound III. Step (2): Compound III undergoes a silanization-Rubottom oxidation-deprotection reaction to yield compound IV. Step (3): Compound IV undergoes a hydroxyl protection reaction to yield compound V. Step (4): Compound V undergoes a selective reduction reaction of its carbonyl group to yield compound VI. Step (5): Compound VI undergoes a hydroxyl group protection reaction to yield compound VII. Step (6): Compound VII undergoes formylation and reduction reactions to yield compound VIII. Step (7): Compound VIII undergoes the Eschenmoser-Claisen rearrangement reaction to yield compound IX. Step (8): Compound IX is reduced to obtain compound X. Step (9): Compound X undergoes a hydroxyl protection reaction to yield compound XI. Step (10): Compound XI is subjected to a hydroboration oxidation reaction to obtain compound XII. Step (11): Compound XII is cyanided to obtain compound XIII. Step (12): Compound XIII is subjected to a stereoselective methylation reaction to obtain compound XIV. Step (13): Compound XIV is reduced to obtain compound XV. Step (14): Compound XV is reacted with a Wittig reaction to yield compound XVI. Step (15): Compound XVI is reacted with a protecting group to yield compound XVII. Step (16): Compound XVII is subjected to a Swern oxidation reaction to obtain compound XVIII. Step (17): Compound XVIII undergoes a Grignard reaction to yield compound XIX. Step (18): Compound XIX undergoes an olefin metathesis reaction to yield compound XX. Step (19): Compound XX undergoes a Johnson-Claisen rearrangement reaction to yield compound XXI. in, R1 is selected from trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, methoxymethylene, benzyl, p-methoxybenzyl, acetyl, and tetrahydropyranyl. R2 is selected from trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, methoxymethylene, benzyl, p-methoxybenzyl, and acetyl.
2. The method for preparing the key intermediate Brasilicardin A according to claim 1, characterized in that, (1) The oxidizing agent in the oxidation reaction in step (1) is selected from: Dess-Martin oxidant and manganese dioxide; (2) The protecting reagent for the hydroxyl protection reaction in step (3) is selected from: trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldiphenylsilyl trifluoromethanesulfonate, trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane, tert-butyldiphenylchlorosilane, chloromethyl methyl ether, benzyl bromide, p-methoxybenzyl chloride, acetic anhydride; (3) The reducing agent for the selective reaction of carbonyl in step (4) is selected from: sodium borohydride, trisec-butyl borohydride, tri-n-butyltin, polymethylhydrosiloxane; (4) The protecting reagent for the hydroxyl protection reaction in step (5) is selected from: trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldiphenylsilyl trifluoromethanesulfonate, trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane, tert-butyldiphenylchlorosilane, chloromethyl methyl ether, benzyl bromide, p-methoxybenzyl chloride, acetic anhydride; (5) The reducing agent in the reduction reaction in step (6) is selected from: sodium borohydride and lithium borohydride; (6) The reducing agent in the reduction reaction in step (8) is selected from: lithium triethylborohydride; (7) The reducing agent in the reduction reaction in step (13) is selected from diisobutylaluminum hydride.
3. The method for preparing the key intermediate Brasilicardin A according to claim 1, characterized in that: (1) The oxidation reaction in step (1) is as follows: the oxidant is Dess-Martin oxidant or manganese dioxide, the reaction solvent is dichloromethane, the reaction temperature is 0℃-25℃, and the reaction time is 3h-10h. (2) The silyl etherification-Rubottom oxidation-deprotection reaction in step (2): the silyl etherification reagent is trimethylchlorosilane, the organic base is diisopropylaminolithium, the reaction solvent is tetrahydrofuran, the reaction temperature is -78℃ to 0℃, and the reaction time is 2-6h; the oxidant is m-chloroperoxybenzoic acid, the base is sodium bicarbonate, the reaction solvent is dichloromethane, the reaction temperature is -20℃ to 0℃, and the reaction time is 0.5-2h; the deprotection reagent is potassium carbonate or oxalic acid, the reaction solvent is ethanol / tetrahydrofuran, the reaction temperature is 0℃ to 25℃, and the reaction time is 0.5h to 1h; (3) The protection reaction of the hydroxyl group in step (3): When the protecting reagent is a silicon-based reagent, the base is 2,6-dimethylpyridine, the reaction solvent is dichloromethane, the reaction temperature is -25℃ to 25℃, and the reaction time is 1.5h to 2h; when the protecting reagent is chloromethyl methyl ether, the base is N,N-diisopropylethylamine, the reaction solvent is dichloromethane, the reaction temperature is 0℃ to 25℃, and the reaction time is 12h to 24h; when the protecting reagent is benzyl bromide or p-methoxybenzyl chloride, the base is sodium hydride, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 0℃ to 25℃, and the reaction time is 12h to 20h; when the protecting reagent is acetic anhydride, the base is pyridine, the reaction solvent is dichloromethane, the reaction temperature is 0℃ to 25℃, and the reaction time is 10h to 20h. (4) Selective reduction reaction of carbonyl group in step (4): The reducing agent is sodium borohydride, trisec-butyllithium borohydride, tri-n-butyltin or polymethylhydrosiloxane, the reaction solvent is tetrahydrofuran, the reaction temperature is -78℃-0℃, and the reaction time is 2-8h. (5) The hydroxyl protection reaction in step (5): When the protecting reagent is a silicon-based reagent, the base is 2,6-dimethylpyridine, the reaction solvent is dichloromethane, the reaction temperature is -25℃ to 25℃, and the reaction time is 1.5h to 2h; when the protecting reagent is chloromethyl methyl ether, the base is N,N-diisopropylethylamine, the reaction solvent is dichloromethane, the reaction temperature is 0℃ to 50℃, and the reaction time is 12h to 24h; when the protecting reagent is benzyl bromide or p-methoxybenzyl chloride, the base is sodium hydride, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 0℃ to 25℃, and the reaction time is 12h to 20h; when the protecting reagent is acetic anhydride, the base is pyridine, the reaction solvent is dichloromethane, the reaction temperature is 0℃ to 25℃, and the reaction time is 10h to 20h. (6) The formylation and reduction reactions in step (6): the reaction solvent is dichloromethane, the organic base is tert-butyllithium, the formylation reagent is N,N-dimethylformamide, the reaction temperature is -78℃ to 25℃, and the reaction time is 10h to 20h; the reducing agent is sodium borohydride or lithium borohydride, the reaction solvent is methanol or tetrahydrofuran / methanol, the reaction temperature is 0℃ to 25℃, and the reaction time is 0.5h to 5h; (7) The Eschenmoser-Claisen rearrangement reaction in step (7) is as follows: the reaction reagent is N,N-dimethylacetamide dimethylacetal, the reaction solvent is m-xylene, the reaction temperature is 110℃-150℃, and the reaction time is 3h-6h. (8) The reduction reaction in step (8) is as follows: the reducing agent is triethyl borohydride, the reaction solvent is tetrahydrofuran, the reaction temperature is 0℃-25℃, and the reaction time is 5h-12h. (9) The hydroxyl protection reaction in step (9): the protecting agent is p-methoxybenzyl chloride, the base is sodium hydride, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 0℃-25℃, and the reaction time is 6h-12h. (10) In step (10), the borohydride oxidation reaction is as follows: the boranizing agent is a boran tetrahydrofuran complex, the oxidant is hydrogen peroxide, the base is sodium hydroxide, the reaction reagent is tetrahydrofuran, the reaction temperature is 0℃-25℃, and the reaction time is 12h-20h. (11) In step (11), the cyanation reaction is as follows: the oxidant is iodophenyl diacetic acid, the cyanation reagent is ammonium acetate, the catalyst is 2,2,6,6-tetramethylpiperidine oxide, the solvent is acetonitrile / water, the reaction temperature is 0℃-25℃, and the reaction time is 5h-20h. (12) Stereoselective methylation reaction in step (12): The methylating agent is iodomethane, the organic base is lithium diisopropylamino, the reaction solvent is tetrahydrofuran, the reaction temperature is -78℃-25℃, and the reaction time is 12h-20h. (13) The reduction reaction in step (13) is as follows: the reducing agent is diisobutylaluminum hydride, the reaction solvent is dichloromethane, the reaction temperature is -78℃ to 40℃, and the reaction time is 5h to 10h. (14) The Wittig reaction in step (14) is as follows: the Wittig reagent is methyltriphenylphosphine bromide, the base is potassium tert-butoxide, the reaction solvent is tetrahydrofuran, the reaction temperature is 0℃-25℃, and the reaction time is 3h-6h. (15) The deprotection reaction in step (15): the deprotection reagent is 2,3-dichloro-5,6-dicyanobenzoquinone, the reaction solvent is dichloromethane / phosphate buffer, the reaction temperature is 0℃-25℃, and the reaction time is 2h-5h; (16) The Swern oxidation reaction in step (16) is as follows: the reaction reagents are dimethyl sulfoxide and oxalyl chloride, the base is triethylamine, the reaction solvent is dichloromethane, the reaction temperature is -78℃ to 0℃, and the reaction time is 2h to 6h. (17) Grignard reaction in step (17): Grignard reagent is isopropenyl magnesium bromide, reaction solvent is tetrahydrofuran, reaction temperature is 0℃-25℃, reaction time is 5h-10h; (18) The olefin metathesis reaction in step (18) is as follows: the reaction reagent is Grubbs second generation catalyst, the reaction solvent is dichloromethane, the reaction temperature is 25℃-50℃, and the reaction time is 12h-24h. (19) In step (19), the Johnson-Claisen rearrangement reaction is carried out with the following conditions: the catalyst is p-nitrophenol, the reaction solvent is triethyl orthoacetate, the reaction temperature is 120℃-150℃, and the reaction time is 12h-20h.