A compound and its synthesis method and its application in the synthesis method of actin stabilizer

Abstract

The present invention discloses a compound and a synthesis method thereof and an application of the compound in a synthesis method of an actin stabilizer. The compound is a side chain compound, and the structural formula of the side chain compound is shown in the following formula: The present invention designs a new side chain compound structure, and synthesizing a stabilizer through the compound structure only requires three steps, thereby simplifying the operation process and improving the operation efficiency; further, when the side chain compound is used to prepare the stabilizer rhizopodin, the parent compound can be synthesized using the route designed by the present invention, and the yield is better.

Description

Technical Field

[0001] The present invention relates to the technical field related to pharmaceutical chemistry, and in particular to a compound and a synthesis method thereof and an application of the compound in a synthesis method of an actin stabilizer. Background Art

[0002] Rhizopodin is a novel actin stabilizer that can affect the actin cytoskeleton at nanomolar concentrations and exhibits potent antiproliferative activity against a range of tumor cell lines. 50 The value is in the low nanomolar range. Due to its remarkable biological activity and fascinating molecular structure, rhizopodin is an attractive synthetic target. In 2011, Nicolaou completed the total synthesis of monomeric rhizopodin for the first time, and found that the monomer compound was not active. In 2012, Menche and his collaborators reported the first total synthesis of rhizopodin based on the Suzuki macrocyclization synthesis strategy. Soon after, in 2013, Paterson reported the total synthesis of rhizopodin based on the Yamaguchi esterification strategy to construct a macrolactonization.

[0003] In the synthesis method of rhizopodin reported in the related art, the method of introducing the side chain fragment C23-C31 into compound 2 requires 5 transformations to achieve the HWE (Horner-Wadsworth-Emmons) method. The aldol method requires 4 steps (i.e., aldol reaction, elimination of hydroxyl group, selective reduction of the double bond of enone, and deprotection), and the synthesis efficiency is slightly improved compared with the former. However, its synthesis efficiency is still low, so it is of great significance to develop a new synthesis route.

[0004] Summary of the invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention provides a synthetic precursor compound, which provides a new direction for the synthesis of actin stabilizers such as rhizopodin.

[0006] According to one aspect of the present invention, a side chain compound is provided, and the structural formula of the side chain compound is shown as follows:

[0007]

[0008] According to a preferred embodiment of the present invention, at least the following beneficial effects are achieved: the present invention designs a new side chain compound structure, and the synthesis of a stabilizer through the compound structure only requires three steps, thereby simplifying the operation process and improving the operation efficiency; further, when the side chain compound is used to prepare a stabilizer, the parent compound can be synthesized using the route designed by the present invention, with a better yield.

[0009] According to another aspect of the present invention, the present invention also provides a precursor compound of the above-mentioned side chain compound, and the structural formula of the precursor compound of the side chain compound is shown in one of the following formulas I to V:

[0010] In the formula, R1, R2, and R3 are independently selected from H or a hydroxyl protecting group, and are the same or different.

[0011] In some preferred embodiments of the present invention, R1 is TBS (tert-butyldimethylsilyl), R2 is PMB (para-methoxybenzyl), and R3 is Ac (acetyl).

[0012] According to another aspect of the present invention, the present invention also provides a precursor compound of a parent compound, wherein the structural formula of the precursor compound of the parent compound is shown in one of the following formulas VII to XXIV:

[0013]

[0014]

[0015] In the formula, R1, R2, R4, and R5 are independently selected from H or hydroxyl protecting groups, and are the same or different; R6 is selected from H or a carboxyl protecting group, and R7 is selected from H or an amino protecting group, and the amino protecting group can be used to protect the hydroxyl group; the substituent X is a halogen selected from F, Cl, Br or I.

[0016] In some embodiments of the present invention, the parent compound can react with the above-mentioned side chain compound to synthesize rhizopodin.

[0017] In some embodiments of the present invention, the hydroxyl protecting group includes at least one of TBS (tert-butyldimethylsilyl), PMB (para-methoxybenzyl), Ac (acetyl), Piv (pivaloyl), and TES (triethylsilyl).

[0018] In some embodiments of the present invention, the carboxyl protecting group includes at least one of Tce (trichloroethyl) or t-Bu (tert-butyl).

[0019] In some embodiments of the present invention, the amino protecting group includes at least one of Troc (trichloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyloxy) or Boc (tert-butyloxycarbonyl, tert-butyloxycarbonyl) or Trt (Triphenylmethyl, trityl).

[0020] In some preferred embodiments of the present invention, R1 is TBS (tert-butyldimethylsilyl), R2 is PMB (para-methoxybenzyl), R4 is Piv (pivaloyl), R5 is TES (triethylsilyl), R6 is Tce (trichloroethyl), and R7 is Troc (trichloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyloxy).

[0021] According to another aspect of the present invention, a method for synthesizing the above-mentioned side chain compound is provided, comprising the following steps:

[0022] by Compound I is prepared as a raw material, compound II is prepared using compound I as a raw material, compound III is prepared using compound II as a raw material, compound IV is prepared using compound III as a raw material, compound V is prepared using compound IV as a raw material, and the side chain compound is prepared using compound V as a raw material; wherein the structures of compounds I, II, III, IV and V are shown in the following formula: In the formula, R1, R2, and R3 are independently selected from H or a hydroxyl protecting group, and are the same or different.

[0023] According to a preferred embodiment of the preparation method of the present invention, at least the following beneficial effects are achieved: the side chain compound can be efficiently prepared through the synthetic route of the scheme of the present invention, the operation is simple, and the method has good industrial application prospects.

[0024] In some preferred embodiments of the present invention, the synthesis route of the side chain compound is as follows:

[0025]

[0026] In some preferred embodiments of the present invention, the pore size of the molecular sieve is

[0027] According to another aspect of the present invention, a method for synthesizing the above-mentioned parent compound is provided, comprising the following steps:

[0028] S1. preparing compound XXI;

[0029] S2, reacting compound XVII and XXI to generate compound XXII;

[0030] S3, using compound XXII as a raw material to prepare compound XXIII;

[0031] S4, using compound XXIII as a raw material to prepare compound XXIV;

[0032] Wherein, the structural formula of the parent compound is as follows:

[0033]

[0034] The structural formulas of compounds XVII, XXI, XXII, XXIII and XXIV are as follows:

[0035]

[0036] In the formula, R1 and R5 are independently selected from H or hydroxyl protecting groups, which are the same or different; R6 is selected from H or carboxyl protecting groups, and R7 is selected from H or amino protecting groups, wherein the amino protecting groups can be used to protect hydroxyl groups; and the substituent X is a halogen selected from F, Cl, Br or I.

[0037] The preparation method according to a preferred embodiment of the present invention has at least the following beneficial effects: the scheme of the present invention provides a new synthesis route of rhizopodin parent compound, which is simple to operate, has a high synthesis yield, and has good prospects for industrial application.

[0038] In some embodiments of the present invention, the synthetic route of the parent compound is as follows:

[0039]

[0040] According to another aspect of the present invention, the present invention also provides a method for synthesizing an actin stabilizer, comprising the following steps:

[0041] The above side chain compound is reacted with the parent compound to obtain the parent compound, the structural formula of which is as follows:

[0042] R1 and R5 are independently selected from H or a hydroxyl protecting group and are the same or different.

[0043] According to a preferred embodiment of the synthesis method of the present invention, at least the following beneficial effects are achieved: the synthesis of the actin stabilizer can be achieved within three steps through the side chain compound of the structure of the scheme of the present invention and the parent compound, the operation is simpler, and at the same time, the yield of the actin stabilizer can be further improved.

[0044] In some preferred embodiments of the present invention, the side chain compound is hydrogen-extracted to react with the parent compound to generate the actin stabilizer.

[0045] In some preferred embodiments of the present invention, the hydrogenation is carried out under the action of a hydrogenation reagent, and the hydrogenation reagent is selected from at least one of Ba(OH)2, NaH, LiHMDS (lithium hexamethyldisilazide), KHMDS (potassium hexamethyldisilazide), LDA (lithium isopropyldisilazide), NaOH or potassium tert-butoxide.

[0046] In some preferred embodiments of the present invention, the hydrogen extraction agent is selected from Ba(OH) 2. Using barium hydroxide as the hydrogen extraction agent has a higher yield.

[0047] In some preferred embodiments of the present invention, R1 is TBS, R5 is TES, and the synthesis method further comprises a step of deprotecting the side chain compound after reacting with the parent compound.

[0048] In some preferred embodiments of the present invention, the synthetic route of the actin stabilizer is as follows:

[0049]

[0050] Other features and advantages of the present invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the present invention. DETAILED DESCRIPTION

[0051] The following will be combined with the embodiments to clearly and completely describe the concept of the present invention and the technical effects produced, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of them. Based on the embodiments of the present invention, other embodiments obtained by technicians in this field without creative work are all within the scope of protection of the present invention. The test methods used in the embodiments are conventional methods unless otherwise specified; the materials, reagents, etc. used, unless otherwise specified, can be reagents and materials obtained from commercial channels. Unless otherwise specified, the same parameter in each embodiment has the same value. The embodiments described below are exemplary and are only used to explain the present invention, and cannot be understood as limitations on the present invention.

[0052] The "room temperature" referred to in the present invention refers to 25±5°C, and is specifically 25°C in the embodiments.

[0053] Example

[0054] In this example, an actin stabilizer, rhizopodin, was prepared. The specific process was as follows:

[0055] 1) Preparation of the side chain compound (as shown in Formula 6), the preparation process is as follows:

[0056]

[0057] 2) Preparation of the parent compound (as shown in Formula 2):

[0058] 2.1 The preparation route of the raw material compound i (as shown in formula 28) of the parent compound is as follows:

[0059] 2.2 Using raw material i to prepare raw material compound ii (as shown in formula 34), the specific preparation route is as follows:

[0060]

[0061] 2.3 The parent compound is prepared using the raw material compound ii. The specific preparation route is as follows:

[0062]

[0063] 3) The steps of preparing an actin stabilizer using a side chain compound and a parent compound are as follows:

[0064]

[0065] Specifically, the synthesis process and characterization data are as follows:

[0066] 1. Synthesis of Compound 6

[0067] 1. Synthesis of compound S1:

[0068]

[0069] The olefin substrate 7 (650 mg, 2.46 mmol) was dissolved in a mixed solvent of dioxane-H2O (10 mL-10 mL), and 2,6-lutidine (0.43 mL, 3.69 mmol), NaIO4 (2.10 g, 9.84 mmol), and OsO4 (25.0 mg, 0.098 mmol) were added in sequence at room temperature. After stirring for 8 hours at room temperature, the reaction was complete as determined by TLC. After filtering the solid, Na2S2O3 (2.0 g) solid was added to the filtrate and stirring was continued for 3 hours. After dilution with ethyl acetate, the mixture was washed with saturated Na2S2O3 and saturated brine in sequence and dried with solid sodium sulfate. After the organic phase was concentrated under reduced pressure, the aldehyde was redissolved in a THF-H2O solution (10 mL-2 mL), and NaBH4 (372 mg, 9.84 mmol) solid was carefully added at room temperature. After stirring for 4 hours, the reaction was complete as determined by TLC, and the reaction was quenched with saturated ammonium chloride at 0°C. After diluting with ethyl acetate, the mixture was washed with saturated ammonium chloride and saturated brine in sequence and dried over solid sodium sulfate. The organic phase was concentrated under reduced pressure and separated by a silica gel column to obtain substrate S1 (613 mg, 93%).

[0070] 1 H NMR (400MHz, CDCl3) δ7.30–7.22(m,2H),6.93–6.83(m,2H),4.48–4.39(m,2H),3.79(s,3H),3.66–3.58(m,1H),3.58–3. 50(m,3H),3.36(s,3H),3.35–3.31(m,1H),2.93(brs,1H),1.93–1.83(m,1H),1.83–1.70(m,1H),0.91(d,J=7.0Hz,3H).

[0071] 13 C NMR (100MHz, CDCl3) δ159.18,130.39,129.31,113.78,82.90,72.75,66.47,66.23,57.96,55.26,38.21,31.23,13.44.

[0072] 2. Synthesis of compound 8:

[0073]

[0074] The primary alcohol compound S1 (876 mg, 3.27 mmol) was dissolved in anhydrous dichloromethane (30 mL), and imidazole (334 mg, 4.90 mmol) and TBSCl (641 mg, 4.25 mmol) were added at 0°C, and the mixture was allowed to react for 12 hours after warming to room temperature. The reaction was complete when detected by TLC plate. After diluting with ethyl acetate, the mixture was washed with saturated ammonium chloride solution and saturated brine in sequence, dried with sodium sulfate, and the organic phase was concentrated under reduced pressure. The residue was separated by silica gel column to obtain compound 8 (1.19 g, 95%).

[0075] 1 H NMR (400MHz, CDCl3) δ7.30–7.23(m,2H),6.91–6.85(m,2H),4.51–4.39(m,2H),3.80(s,3H),3.61–3.51(m,4H),3.38–3.34(m,1H) ,3.33(s,3H),1.97–1.87(m,1H),1.85–1.74(m,1H),1.72–1.60(m,1H),0.90(s,9H),0.88(d,J=6.9Hz,3H),0.05(d,J=2.8Hz,6H).

[0076] 13 C NMR (100MHz, CDCl3) δ159.10,130.74,129.23,113.72,79.13,72.61,67.0 6,64.96,57.63,55.23,38.41,30.69,25.93,18.27,12.28,-5.42,-5.43.

[0077] 3. Synthesis of Compound 10

[0078]

[0079] Substrate 8 (926 mg, 2.42 mmol) was dissolved in DCM (analytical grade, 15 mL), DDQ (926 mg, 2.42 mmol) was added at room temperature, and the reaction was detected by TLC until the reaction was complete. The reaction solution was concentrated to about 2 mL under reduced pressure and directly purified by silica gel column to obtain primary alcohol substrate S2 (526 mg, 83%).

[0080] 1H NMR (400MHz, CDCl3) δ3.80–3.73(m,2H),3.59–3.52(m,1H),3.50–3.44(m,2H),3.36(s,3H),2. 10–1.98(m,1H),1.76–1.61(m,2H),0.88(s,9H),0.84(d,J=7.0Hz,3H),0.03(d,J=2.8Hz,6H).

[0081] 13 C NMR (101MHz, CDCl3) δ82.11,64.96,61.42,57.04,37.22,31.37,25.86,18.23,11.53,-5.45,-5.50.

[0082]

[0083] Dissolve primary alcohol S2 (467 mg, 1.78 mmol) in a solution of dichloromethane (20 mL)-NaHCO3 (10 mL, 50 mg / mL), and add TEMPO (10 mg, 0.064 mmol) and NaClO solution (2 mL) in turn at room temperature. After about half an hour of reaction, TLC detection shows that the reaction is complete. Dilute with ethyl acetate, wash with saturated sodium thiosulfate and saturated brine in turn, and dry with anhydrous sodium sulfate. After the organic phase is concentrated under reduced pressure, the residue is separated with a silica gel column to obtain aldehyde S3 (about 421 mg).

[0084] Dissolve Wittig salt 9 (1.12 g, 3.06 mmol) in anhydrous THF, add LiHMDS (2.7 mL, 1 M) at 0°C, and react at 0°C for half an hour. Add the anhydrous THF solution of the above aldehyde S3 to the reaction solution at 0°C. Continue the reaction at 0°C for 2 hours, and the reaction is complete when detected by TLC. Quench the reaction with saturated ammonium chloride, dilute with ethyl acetate, wash with saturated ammonium chloride and saturated brine in turn, and dry with anhydrous sodium sulfate. After the organic phase is concentrated under reduced pressure, the residue is separated and purified by silica gel column to obtain product 10 (two-step yield 437 mg, 78%, Z:E=4.6:1)

[0085] 1H NMR (400MHz, CDCl3) δ8.28 (s, 0.14H), 8.20 (s, 0.65H), 8.06 (s, 0.14H), 7.18 (d, J = 14.7Hz, 0.06H), 6.51 (d, J = 14.0Hz, 0. 14H),6.22(d,J=9.2Hz,0.09H),5.99(d,J=8.6Hz,0.66H),5.42–5.31(m,0.74H),5.20–5.07(m,0.19H),3.63–3.55(m,1. 18H),3.55–3.49(m,0.81H),3.38–3.30(m,3H),3.28–3.19(m,0.79H),3.17(s,0.27H),3.06(s,0.21H),3.02(s,2.31H), 2.45–2.31(m,1H),2.31–2.12(m,1H),1.95–1.78(m,1H),0.92–0.87(m,9H),0.84(d,J=6.9Hz,3H),0.04(d,J=2.1Hz,6H).

[0086] 13 C NMR (100MHz, CDCl3) δ162.96,162.10,129.67,128.65,120.58,108.82,107.24,81.91,81.31,81.15,64.65,57 .51,38.40,38.08,36.06,31.42,30.57,28.49,27.48,27.17,25.86,18.23,12.72,12.55,12.38,-5.49,-5.51.

[0087] 4. Synthesis of Compound 12

[0088]

[0089] Substrate 10 (300 mg, 0.96 mmol) was dissolved in THF (10 mL), TBAF (2 mL, 1 M) was added, and the reaction was detected by TLC to be complete. The reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated brine in sequence, and dried with anhydrous sodium sulfate to obtain the primary alcohol, which was directly used in the next step.

[0090] The primary alcohol obtained in the previous step was dissolved in dichloromethane (10 mL), and TEA (0.40 mL, 2.88 mmol), DMAP (35.0 mg, 0.29 mmol), and Ac2O (0.18 mL, 1.92 mmol) were added at room temperature. The reaction was complete after 4 hours of reaction. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate, and diluted with 1M hydrochloric acid in turn, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and separated and purified with a silica gel column, and the residue was directly used for the next reaction.

[0091] The product of the previous step was dissolved in dichloromethane (10 mL), and I2 (7.2 mg, 0.028 mmol) was added at room temperature. After stirring for 24 hours, the reaction was quenched with thiosulfate. Diluted with ethyl acetate, washed with saturated sodium thiosulfate and saturated brine, and dried over anhydrous sodium sulfate. After the organic phase was concentrated under reduced pressure, the residue was separated and purified by silica gel column to obtain product 12 (141 mg, 62%).

[0092] 1 H NMR (500MHz, CDCl3) δ8.20 (s, 0.65H), 7.97 (s, 0.29H), 7.09 (d, J = 14.6Hz, 0.29H) ,6.46(d,J=14.0Hz,0.66H),5.11–4.95(m,1H),4.12–4.03(m,1H),3.95–3.86(m,1 H),3.27(s,2H),3.26(s,1H),3.07–3.01(m,1H),2.98(s,1H),2.93(s,2H),2.38–2 .25(m,1H),2.21–2.09(m,1H),1.97(s,3H),1.95–1.86(m,1H),0.87–0.83(m,3H).

[0093] 13 C NMR (125MHz, CDCl3) δ170.99,162.06,160.70,130.16,126.10,108.52,107.93,106.77,106.26,82.20,81.62,66.5 6,66.49,66.31,66.24,57.64,57.46,43.50,35.37,32.90,31.58,30.67,27.42,20.84,13.35,13.30,11.31,11.16.

[0094] 5. Synthesis of compound S4

[0095]

[0096] Substrate 12 (136 mg, 0.56 mmol) was dissolved in anhydrous methanol (10 mL), and anhydrous potassium carbonate (237 mg, 2.24 mmol) was added at room temperature. After stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column to obtain product S4 (109 mg, 97%).

[0097] 1 H NMR (400MHz, CDCl3) δ8.25 (s, 0.66H), 8.03 (s, 0.32H), 7.15 (d, J = 14.5Hz, 0.32H), 6.50 (d, J=14.0Hz, 0.67H), 5.16–4.98 (m, 1H), 3.68–3.50 (m, 2H), 3.37(s,2H),3.37(s,1H),3.22–3.16(m,1H),3.04(s,1H),2.99(s,2H),2. 54–2.38(m,1H),2.31–2.16(m,1H),1.89–1.78(m,1H),0.91–0.83(m,3H).

[0098] 13 C NMR (100MHz, CDCl3) δ162.11,160.76,130.10,126.10,107.52,105.90,85.84,85.54, 66.76,66.47,57.51,57.28,37.57,37.50,32.99,30.69,30.60,27.46,13.67,13.63.

[0099] 6. Synthesis of Compound 13

[0100]

[0101] The substrate S4 (368 mg, 1.83 mmol) was dissolved in DCM (7 mL), and NaHCO3 (461 mg, 5.49 mmol) and Dess-Martin reagent (1.16 g, 2.74 mmol) were added in sequence at room temperature. After stirring at room temperature for half an hour, the reaction solution was poured into 200 mL of n-hexane, filtered, concentrated under reduced pressure, and separated and purified on a silica gel column to obtain aldehyde (about 0.9 g).

[0102] The above aldehyde was dissolved in anhydrous THF (20 mL), and the base S5 (2.74 mmol, 1.5 equivalents) (obtained by hydrogenation of methylphosphite with n-butyl lithium in the presence of 4A molecular sieve) was added in three portions at -78°C. After reacting for 1 hour, the reaction was quenched with saturated ammonium chloride. The reaction solution was diluted with ethyl acetate, washed with saturated ammonium chloride and saturated brine in sequence, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel column to obtain 13 (171 mg, two-step yield 29%).

[0103] 1 H NMR(400MHz, CDCl3) δ8.28(d,J=7.4Hz,0.67H),8.05(s,0.33H),7.18(d,J=14.5Hz,0.33H),6.5 9–6.49(m,0.67H),5.20–4.98(m,1H),4.43–4.22(m,0.4H),4.12–3.88(m,0.6H),3.80–3.71(m,6 H),3.42–3.39(m,1.5H),3.37–3.34(s,1.5H),3.34–3.24(m,1H),3.06(s,1H),3.02(s,2H),2.5 2–2.38(m,1H),2.38–2.13(m,1H),2.13–1.96(m,1.5H),1.96–1.77(m,1.5H),0.97–0.79(m,3H).

[0104] 13 C NMR (100MHz, CDCl3) δ162.19,162.12,160.74,130.54,130.00,126.31,12 6.06,107.85,107.42,106.44,105.61,84.20,82.80,68.34,65.72,58.10, 57.81,57.16,56.98,52.58,52.55,52.42,52.35,41.15,40.99,40.52,40. 38,33.00,31.00,30.58,30.20,29.76,29.20,27.48,27.46,11.26,10.24.

[0105] 7. Synthesis of compound 6:

[0106]

[0107] Substrate 13 (49.0 mg, 0.15 mmol) was dissolved in dichloromethane, and sodium bicarbonate (50.0 mg, 0.60 mmol) and Dess-Martin reagent (127 mg, 0.30 mmol) were added thereto at room temperature. After stirring for 1 hour at room temperature, the reaction solution was poured into n-hexane, the solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column to obtain the target compound ketone 6 (31.0 mg, 65%).

[0108] 1 H NMR(500MHz,Methanol-d4)exists as rotational conformers: δ8.34(s,0.67H),8.10(s,0.33H),7.15(d,J=14.5Hz,0.33H),6.75(d,J=14.1Hz,0. 67H),5.29(ddd,J=14.7,8.3,6.5Hz,0.33H),5.21(ddd,J=14.4,8.2,6.5Hz,0.67H),3.80(s,3H) ,3.78(s,3H),3.48–3.44(m,1H),3.44–3.37(m,1H),3.33(s,3H),3.13(s,1H),3.04(s,2H),3.03 –2.98(m,1H),2.59–2.47(m,1H),2.35–2.18(m,1H),1.06(d,J=6.9Hz,2H),1.04(d,J=6.9Hz,1H).

[0109] 13 C NMR(125MHz,Methanol-d4)exists as rotational conformers:δ205.5,205.5,163.2,161.8,130.6,126.0,107.8,105.7,82.7,82 .7,56.4,56.4,52.3,52.2,52.2,52.2,49.6,49.6,32.0,30.0,29.8,26.2,11.1.

[0110] 2. Synthesis of Compound 2

[0111] 1. Synthesis of Compound 16

[0112]

[0113] Compound 15 (15.12 g, 33.6 mmol) was dissolved in CH2Cl2 / MeOH (50 mL:50 mL) and cooled to 0°C. (-)-CSA (0.78 g, 3.4 mmol) was added to the reaction solution at once. The mixture was warmed to room temperature within about 30 minutes and stirred at room temperature for 4 hours. Et3N (0.94 mL, 6.8 mmol) was added and the residue was purified by rapid silica gel column (ethyl acetate / n-hexane = 1 / 3) to obtain primary alcohol compound S5 (about 11.06 g).

[0114] Compound alcohol S5 (11.06 g) was dissolved in CH2Cl2 (200 mL) and cooled to 0°C, and then Et3N (11.5 mL, 82.66 mmol), DMAP (40.0 mg, 0.33 mmol) and PivCl (6.0 mL, 49.10 mmol) were added in sequence. The reaction was stirred overnight at room temperature. After the raw material disappeared by thin layer column chromatography, the reaction was quenched with saturated ammonium chloride (30 mL). After separation of the organic phase, the aqueous phase was extracted with CH2Cl2 (100 mL × 2), and the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by rapid silica gel column (ethyl acetate / n-hexane = 1 / 8) to obtain a colorless oily liquid compound 16 (13.40 g, two-step yield 95%).

[0115] 1 H NMR (500MHz, CDCl3) δ7.33–7.21(m,2H),6.91–6.85(m,2H),5.84(ddd,J=17.3,10.7,6.9Hz ,1H),5.11–4.98(m,2H),4.54(d,J=2.1Hz,2H),3.98(d,J=10.8Hz,1H),3.92(d,J=10.7Hz,1 H),3.81(s,3H),3.63–3.50(m,1H),3.37(s,3H),3.36–3.29(m,1H),2.71–2.57(m,1H),1.52 (ddt,J=5.8,4.1,2.0Hz,2H),1.23(s,9H),1.01(d,J=7.0Hz,3H),0.95(s,3H),0.94(s,3H).

[0116] 13C NMR (125MHz, CDCl3) δ178.4,159.1,139.8,131.3,128.9,114.8,113.8,81.4, 80.4,74.8,70.3,56.3,55.3,39.4,39.0,38.7,32.0,27.3,22.1,20.3,15.4.

[0117] 2. Synthesis of Compound 17

[0118]

[0119] Compound 16 (14.70 g, 35.00 mmol) was dissolved in dioxane / H2O (150 mL:50 mL), and 2,6-lutidine (14.3 mL, 122.50 mmol), NaIO4 (18.72 g, 87.50 mmol) and OsO4 (5.0 mL, 0.20 mmol, 0.04 M in t-BuOH) were added in sequence at room temperature. The reaction was stirred for 5.5 hours, and then unsaturated Na2S2O3 solution (50 mL) was added, stirred for another 3 hours, and extracted with CH2Cl2 (100 mL×3). The combined organic phase was washed with saturated brine and dried over anhydrous Na2SO4. The aldehyde S6 (about 14.10 g) obtained after filtration and concentration under reduced pressure was directly used in the next transformation without further purification.

[0120] The aldehyde compound S6 (about 14.10 g) was dissolved in MeOH (150 mL) and cooled to 0°C. NaBH4 (1.99 g, 52.50 mmol) was added to the reaction system three times, and the stirring was continued at 0°C for 1 hour. Saturated ammonium chloride solution (30 mL) was slowly added to quench the reaction. After separation of the organic phase, it was extracted with CH2Cl2 (100 mL×3); the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by rapid silica gel column (ethyl acetate / n-hexane=1 / 3) to obtain a colorless oily liquid compound 17 (13.52 g, two-step yield 91%).

[0121] 1H NMR (500MHz, CDCl3) δ7.31–7.22(m,2H),6.93–6.84(m,2H),4.56(d,J=10.8Hz,1H),4.48(d,J=10.8Hz,1H),3.9 8(d,J=10.9Hz,1H),3.94(d,J=10.8Hz,1H),3.80(s,3H),3.69(t,J=9.8Hz,1H),3.56(dd,J=10.0,1.9Hz,1H),3. 53–3.47(m,1H),3.43(dt,J=10.6,2.7Hz,1H),3.40(s,3H),2.87(d,J=6.9Hz,1H),2.36–2.25(m,1H),1.66(ddd, J=14.4,10.3,1.9Hz,1H),1.55(ddd,J=14.4,10.0,2.2Hz,1H),1.24(s,9H),0.97(s,6H),0.81(d,J=7.1Hz,3H).

[0122] 13 C NMR (125MHz, CDCl3) δ178.3,159.1,131.0,128.9,113.8,82.3,80.7,74.9,70.3,65.5,57.1,55.3,39.5,39.0,35.3,31.0,27.3,22.0,20.4,13.0.

[0123] 3. Synthesis of Compound 18

[0124]

[0125] Compound 17 (11.50 g, 27.1 mmol) was dissolved in CH2Cl2 (100 mL) and cooled to 0°C, and Et3N (8.23 mL, 59.20 mmol), DMAP (0.007 g, 0.05 mmol) and TBSCl (5.72 g, 37.94 mmol) were added in sequence. The mixture was stirred at room temperature overnight, and the reaction was quenched with saturated NH4Cl solution (30 mL). After separation of the organic phase, the aqueous phase was extracted with CH2Cl2 (60 mL × 3), and the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, intermediate S7 (about 11.50 g) was obtained.

[0126] The intermediate S7 (11.50 g) was dissolved in THF (100 mL), cooled to -78 °C, and DIBAL (59.6 mL, 59.60 mmol, 1.0 M in hexane) was slowly added dropwise along the inner wall of the flask. The reaction was stirred at -78 °C for 3 hours, and then slowly heated to -50 °C and reacted for 2.5 hours; MeOH (3.0 mL) was carefully added to quench the reaction, and then a saturated sodium potassium solution (100 mL) was poured into the solution. After rapid stirring overnight, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by rapid silica gel column (ethyl acetate / n-hexane = 1 / 3) to obtain compound 18 as a colorless oily liquid (10.60 g, two-step yield 86%).

[0127] 1 H NMR (500MHz, CDCl3) δ7.32–7.24(m,2H),6.91–6.84(m,2H),4.57(s,2H),3.79(s,3H),3. 62(dd,J=9.9,5.9Hz,1H),3.54(dd,J=11.1,5.1Hz,1H),3.53–3.44(m,3H),3.38(s,3H),3 .36–3.32(m,1H),3.05(t,J=5.7Hz,1H),2.01–1.90(m,1H),1.70(ddd,J=14.8,10.2,2.2H z,1H),1.59(ddd,J=14.8,8.8,2.7Hz,1H),1.00(s,3H),0.93–0.86(m,15H),0.05(s,6H).

[0128] 13 C NMR (125MHz, CDCl3) δ159.2,130.8,129.1,113.8,83.6,80.3,74.4,70.5,6 4.1,57.5,55.2,39.9,38.3,33.3,25.9,22.2,21.5,18.2,12.4,-5.4,-5.4.

[0129] 4. Synthesis of Compound 20

[0130]

[0131] Compound 18 (4.00 g, 8.80 mmol) was dissolved in CH2Cl2 (35 mL), and NaHCO3 (2.96 g, 35.24 mmol) and Dess-Martin periodinane (5.61 g, 13.22 mmol) were added in sequence at 0°C. The reaction was returned to room temperature and stirred for another hour, and then quenched with unsaturated Na2S2O3 solution (25 mL). After stirring for 20 minutes, the reaction was extracted with CH2Cl2 (40 mL×3), and the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by rapid silica gel column (ethyl acetate / n-hexane=1:6) to obtain aldehyde S8 as a colorless liquid (about 3.63 g, 91%).

[0132] The chiral auxiliary 19 (2.65 g, 10.54 mmol) was dissolved in CH2Cl2 (25 mL) and cooled to 0°C. TiCl4 (5.75 mL, 11.50 mmol, 2.0 M in DCM) was slowly added and stirred for 10 minutes, and then cooled to -78°C. DIPEA (2.90 mL, 17.62 mmol) was added dropwise to the reaction. The mixture was stirred at -78°C for 1.5 hours. The newly prepared aldehyde (3.63 g) was dissolved in CH2Cl2 (10 mL) and slowly added along the inner wall of the reaction bottle. After reacting at -78°C for 2 hours, the reaction was quenched with saturated NH4Cl (20 mL). After separation of the organic phase, the aqueous phase was extracted with CH2Cl2 (100 mL x 3), the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by flash silica gel column (ethyl acetate / n-hexane = 1 / 5) to give 20 as a colorless liquid (4.83 g, total yield of two steps 78%, dr = 10:1).

[0133] 1H NMR (500MHz, CDCl3) δ7.41–7.21(m,7H),6.86(dd,J=9.2,2.9Hz,2H),5.35(ddd,J=10.7,7.1,3.6Hz,1H),4.63(s, 2H),4.40(d,J=10.3Hz,1H),4.22(s,1H),3.79(s,3H),3.65(dd,J=9.9,6.0Hz,1H),3.62–3.57(m,1H),3.56–3.47 (m,3H),3.42(s,3H),3.41–3.34(m,1H),3.31–3.20(m,2H),3.05(dd,J=13.2,10.7Hz,1H),2.87(d,J=11.5Hz,1H) ,2.03–1.93(m,1H),1.78–1.67(m,2H),1.11(s,3H),0.94(d,J=6.9Hz,3H),0.91(s,9H),0.89(s,3H),0.07(s,6H).

[0134] 13 C NMR (125MHz, CDCl3) δ201.4,173.3,159.3,136.7,130.4,129.5,129.1,128.9,127.2,113.9,86.3,79.6,75. 1,72.4,69.0,64.4,57.7,55.3,41.6,41.2,38.7,36.7,33.4,32.2,26.0,22.4,20.7,18.3,12.3,-5.3,-5.4.

[0135] 5. Synthesis of Compound 22

[0136]

[0137] Compound 20 (1.53 g, 2.17 mmol) was dissolved in CH2Cl2 (15 mL) and cooled to -78°C. 2,6-lutidine (0.76 mL, 6.51 mmol) and TESOTf (0.94 mL, 4.34 mmol) were slowly added in sequence. The reaction was stirred at -78°C for 2 hours, quenched with saturated NH4Cl solution (15 mL), and CH2Cl2 (50 mL) was added to dilute the reaction solution. After separation of the organic phase, the aqueous phase was extracted with CH2Cl2 (100 mL × 3). The combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by rapid silica gel column (ethyl acetate / n-hexane = 1 / 10) to obtain a light yellow liquid compound S9 (1.70 g, 95%).

[0138] 1 H NMR(500MHz,CDCl3)δ7.41–7.34(m,2H),7.34–7.28(m,5H),6.93–6.84(m,2H),5.33(ddd,J=10.7,7.0,3.7Hz,1H),4.65–4.58(m,2H),4.40(t,J=5.2Hz,1H),3.82(s,3H),3.65(dd,J=9.8,5.9Hz,1H),3.56–3.41(m,5H),3.37(s,3H),3.35–3.30(m,1H),3.24(dd,J=13.2,3.6Hz,1H),3.05(dd,J=13.2,10.8Hz,1H),2.90(d,J=11.5Hz,1H),2.00–1.88(m,1H),1.63–1.53(m,2H),1.01(s,3H),0.97(t,J=8.0Hz,9H),0.96(s,3H),0.93–0.88(m,12H),0.68–0.58(m,6H),0.06(s,3H),0.05(s,3H).

[0139] 13 C NMR(125MHz,CDCl3)δ200.9,172.9,159.0,136.7,131.6,129.5,128.9,128.8,127.2,113.7,82.1,80.0,74.6,73.6,68.7,64.6,57.6,55.3,43.9,43.3,38.8,36.4,33.7,32.0,26.0,20.8,20.3,18.3,12.4,7.1,5.6,-5.4,-5.4.

[0140] S9 (1.69 g, 2.07 mmol) was dissolved in CH2Cl2 (15 mL), and Et3N (1.8 mL, 12.95 mmol) and DMAP (2.4 mg, 0.02 mmol) were added in sequence, and then cooled to 0°C. Hydroxylamine hydrochloride 21 was dissolved in CH2Cl2 (15 mL) and slowly added to the above reaction solution, and then heated to room temperature and stirred for 14 hours. The reaction was quenched with saturated ammonium chloride (15 mL), and CH2Cl2 (50 mL) was added to dilute the reaction solution. After separation of the organic phase, the aqueous phase was extracted with CH2Cl2 (50 mL × 3), and the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by rapid silica gel column (ethyl acetate / n-hexane = 1 / 3) to obtain colorless liquid compound 22 (1.34 g, 86%).

[0141] 1 H NMR(500MHz, CDCl3)δ7.32–7.23(m,2H),6.93–6.81(m,2H),6.50(d,J=7.7H z,1H),5.91–5.72(m,1H),5.20–5.05(m,2H),4.59(d,J=10.7Hz,1H),4.55(d ,J=10.8Hz,1H),4.16–4.06(m,1H),3.99(dd,J=7.6,3.7Hz,1H),3.90(dd,J =11.5,3.8Hz,1H),3.80(s,3H),3.64(dd,J=9.8,6.0Hz,2H),3.52–3.41(m,4 H),3.38(s,3H),3.38(s,3H),3.17(s,1H),2.65(dd,J=15.3,3.7Hz,1H),2. 47(dddd,J=14.2,7.7,4.6,1.4Hz,1H),2.30(dd,J=15.3,6.5Hz,1H),2.28–2 .20(m,1H),1.98–1.87(m,1H),1.62–1.48(m,2H),0.99(s,3H),0.97(t,J=7 .3Hz,9H),0.93(s,3H),0.91–0.87(m,12H),0.70–0.60(m,6H),0.04(s,6H).

[0142] 13C NMR (125MHz, CDCl3) δ172.1,159.0,133.7,131.5,128.8,118.0,113.7,83.0,82.3,80.0,74.7,74.6,64.5,6 2.1,58.0,57.7,55.3,52.4,44.2,40.6,38.8,35.1,33.8,25.9,21.0,20.4,18.3,12.4,7.1,5.3,-5.4,-5.4.

[0143] 6. Synthesis of Compound 24

[0144]

[0145] Compound 22 (1.14 g, 1.51 mmol) was dissolved in CH2Cl2 (15 mL), cooled to 0°C, and NaHCO3 (0.51 g, 6.06 mmol) and Dess-Martin periodinane (0.96 g, 2.27 mmol) were added in sequence. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction was quenched with an unsaturated Na2S2O3 solution (15 mL), stirred for another 30 minutes, and CH2Cl2 (50 mL) was added to dilute the reaction solution. After separation of the organic phase, the aqueous phase was extracted with CH2Cl2 (50 mL × 3), and the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by rapid silica gel column (ethyl acetate / n-hexane = 1 / 5) to obtain a colorless liquid aldehyde compound S10 (about 1.06 g).

[0146] The obtained aldehyde S10 (1.06 g, 1.41 mmol) was dissolved in CH2Cl2 (15 mL) and cooled to 0°C. 23 (2.33 g, 11.3 mmol), PPh3 (1.49 g, 5.67 mmol) and Br2C2Cl4 (1.85 g, 5.67 mmol) were carefully added in sequence. The reaction was heated to room temperature and stirred for 1.5 hours. DBU (1.7 mL, 11.3 mmol) was dissolved in CH3CN (3.0 mL) and slowly added to the reaction within 25 minutes. After stirring at room temperature for 3 hours, the reaction was quenched with saturated NH4Cl solution (15 mL), and CH2Cl2 (50 mL) was added to dilute the reaction solution. After separation of the organic phase, the aqueous phase was extracted with CH2Cl2 (50 mL x 3), and the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by flash silica gel column (ethyl acetate / n-hexane = 1 / 7) to give a colorless liquid compound 24 (0.90 g, total yield of two steps 81%).

[0147] 1H NMR (400MHz, CDCl3) δ7.49(s,1H),7.34–7.27(m,2H),6.99–6.82(m,2H),5.96–5.74(m,1H),5.21–5.00(m,2H),4.62(d,J=10 .8Hz,1H),4.58(d,J=10.7Hz,1H),4.29–4.19(m,2H),3.83(s,3H),3.68(dd,J=9.8,5.9Hz,1H),3.58–3.52(m,1H),3.51–3.46 (m,1H),3.47–3.43(m,1H),3.39(s,3H),3.36(s,3H),3.07(dd,J=15.4,2.8Hz,1H),2.92(dd,J=15.4,9.0Hz,1H),2.65–2.55 (m,2H),2.04–1.92(m,1H),1.68–1.59(m,2H),0.97(s,6H),0.95–0.91(m,12H),0.90(t,9H),0.50–0.35(m,6H),0.07(s,6H).

[0148] 13 C NMR (100MHz, CDCl3) δ164.0,158.9,140.8,134.8,134.4,131.4,128.7,117.1,113.7,81.8,79.7,76.4,76.0, 74.5,64.5,57.4,56.9,55.3,44.0,39.2,38.5,33.2,32.8,25.9,20.8,20.0,18.3,12.4,7.0,5.1,-5.4,-5.4.

[0149] 7. Synthesis of Compound 27

[0150]

[0151] Under Ar protection, compound 24 (0.286 g, 0.39 mmol), vinylboronic acid pinacol ester 25 (0.20 mL, 1.19 mmol), 2,6-dichlorobenzoquinone 26 (0.021 g, 0.12 mmol) were dissolved in toluene (15.0 mL), heated to 80°C, and Hoveyda-Grubbs II (0.025 g, 0.04 mmol) was dissolved in toluene (6.0 mL) and added to the reaction system. After stirring at 85°C for 12 hours, the mixture was concentrated under vacuum, and the residue was purified by rapid silica gel column (ethyl acetate / n-hexane = 1 / 6) to obtain colorless liquid compound 27 (191.0 mg, 67%).

[0152] 1 H NMR (400MHz, Methanol-d4) δ7.78(s,1H),7.34–7.24(m,2H),6.98–6.83(m,2H),6.57(dt,J=17.9,6.6Hz,1H),5.47(dt,J=17.9,1. 5Hz,1H),4.63(d,J=2.7Hz,2H),4.35–4.24(m,2H),3.80(s,3H),3.68(dd,J=9.8,5.9Hz,1H),3.60(dd,J=8.6,2.8Hz,1H),3.57–3. 47(m,2H),3.40(s,3H),3.31(s,3H),3.13(dd,J=15.5,2.7Hz,1H),2.91(dd,J=15.5,9.1Hz,1H),2.79–2.60(m,2H),2.07–1.91(m, 1H),1.75–1.59(m,2H),1.25(s,12H),1.00(s,3H),1.00(s,3H),0.95(s,3H),0.94–0.89(m,18H),0.56–0.35(m,6H),0.08(s,6H).

[0153] 13 C NMR(100MHz,Methanol-d4)δ164.5,159.2,149.3,139.9,136.2,131.1,128.5,113.3,83.0,81.8,79.7,76.0,75.0, 74.3,64.1,56.5,55.5,54.3,43.8,40.4,38.3,33.2,32.3,25.1,23.7,19.9,19.2,17.7,11.4,6.1,4.8,-6.6,-6.7.

[0154] 8. Synthesis of Compound 28

[0155]

[0156] Compound 27 (0.95 g, 1.1 mmol) was dissolved in CH2Cl2 / pH=6.8 buffer (24 mL:3 mL) and cooled to 0°C; DDQ (0.376 g, 1.66 mmol) was carefully added, and the mixture was heated to room temperature and stirred for 1 hour. The mixture was cooled to 0°C, saturated NaHCO3 solution (15 mL) was added to quench the reaction, and the reaction solution was diluted with ethyl acetate (50 mL). After separation of the organic phase, ethyl acetate (50 mL×3) was used for extraction. The combined organic phase was washed with saturated brine (20 mL), dried by adding Na2SO4, filtered, and concentrated in vacuo. The residue was purified by rapid silica gel column (ethyl acetate / n-hexane=1 / 4) to obtain compound 28 as a colorless oily liquid (676.0 mg, 83%).

[0157] 1 H NMR(300MHz, Methanol-d4)δ7.81(s,1H),6.56(dt,J=17.9,6.6Hz,1H),5.47(dt,J=17.9,1.5Hz,1H),4.37(dd,J=9.1,2.7Hz,1H) ,4.28(t,J=6.5Hz,1H),3.77(dd,J=10.3,1.7Hz,1H),3.67(dd,J=9.8,5.8Hz,1H),3.62–3.50(m,2H),3.44(s,3H),3.30(s,3H),3. 09(dd,J=15.4,2.7Hz,1H),2.89(dd,J=15.3,9.2Hz,1H),2.80–2.58(m,2H),1.92(dt,J=10.6,6.3Hz,1H),1.65–1.53(m,1H),1.53 –1.40(m,1H),1.25(s,12H),0.96(d,J=2.0Hz,3H),0.95–0.92(m,18H),0.91(s,3H),0.88(s,3H),0.60–0.37(m,6H),0.09(s,6H).

[0158] 13 C NMR (75MHz, Methanol-d4) δ164.5,149.3,139.9,136.4,83.0,79.5,77.2,74.9,71.7,64.3,57. 6,55.5,41.8,40.4,38.9,33.6,32.0,25.0,23.7,19.1,17.9,17.7,11.3,6.0,4.6,-6.6,-6.7.

[0159] 9. Synthesis of Compound 29

[0160]

[0161] Compound 20 (1.05 g, 1.42 mmol) was dissolved in THF / H2O (20.0 mL:5.0 mL) and cooled to 0°C. NaBH4 (107.0 mg, 2.84 mmol) was slowly added to the reaction solution. After warming to room temperature, the mixture was vigorously stirred for 3 hours. Saturated NH4Cl solution (20 mL) was added to quench the reaction. Ethyl acetate (50 mL) was added to dilute the reaction solution. After separation of the organic phase, the aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine (25 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, diol compound S12 (about 0.67 g) was obtained as a colorless liquid.

[0162] The obtained diol compound S12 (about 0.67 g) was dissolved in CH2Cl2 (20 mL) and cooled to -78°C. Et3N (0.78 mL, 5.60 mmol) and TESOTf (0.64 mL, 2.84 mmol) were added slowly in sequence. After stirring for 0.5 hours, the temperature was raised to 0°C and stirred for another 4 hours. Saturated NH4Cl solution (15 mL) was added to quench the mixture, and CH2Cl2 (50 mL) was added to dilute the reaction solution. After separation of the organic phase, the aqueous phase was extracted with CH2Cl2 (50 mL×3). The combined organic phase was washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by rapid silica gel column (ethyl acetate / n-hexane=1 / 10) to obtain a light yellow liquid compound S11 (0.908 g, total yield of two steps 88%).

[0163] 1 H NMR (400MHz, CDCl3) δ7.33–7.26(m,2H),6.93–6.85(m,2H),4.61(d,J=10.8Hz,1H),4.56(d ,J=10.7Hz,1H),3.82(s,3H),3.78–3.69(m,2H),3.69–3.61(m,2H),3.55–3.46(m,2H),3.46 –3.39(m,1H),3.37(s,3H),2.02–1.92(m,1H),1.88–1.78(m,1H),1.65–1.55(m,1H),1.54–1 .44(m,2H),1.02–0.96(m,24H),0.91(s,9H),0.89(s,3H),0.67–0.60(m,12H),0.06(s,6H).

[0164] 13C NMR (100MHz, CDCl3) δ158.9,131.7,128.8,113.6,81.5,79.6,74.6,74.3,64.5,60.7,57.2 ,55.3,44.1,38.6,35.8,33.0,25.9,20.2,19.6,18.3,12.4,7.2,6.8,5.7,4.4,-5.4,-5.4.

[0165]

[0166] Compound S11 (500.0 mg, 0.69 mmol) was dissolved in CH2Cl2 / pH=6.8 buffer (8 mL:1 mL) and cooled to 0℃; DDQ (204.0 mg, 0.90 mmol) was carefully added, and the mixture was heated to room temperature and stirred for 1 hour. The mixture was cooled to 0℃ again, saturated NaHCO3 solution (10 mL) was added to quench the reaction, and the reaction solution was diluted with ethyl acetate (30 mL). After separation of the organic phase, ethyl acetate (60 mL×3) was used for extraction. The combined organic phase was washed with saturated brine (20 mL), dried by adding Na2SO4, filtered and concentrated in vacuo, and the residue was purified by rapid silica gel column (ethyl acetate / n-hexane=1 / 4) to obtain colorless oily liquid compound 29 (356.0 mg, 85%).

[0167] 1 H NMR (500MHz, CDCl3) δ4.17(s,1H),3.93–3.87(m,1H),3.79–3.73(m,1H),3.73–3.70(m,1 H),3.68–3.61(m,2H),3.55–3.49(m,1H),3.46(dd,J=9.8,7.2Hz,1H),3.43(s,3H),1.96– 1.81(m,2H),1.77–1.67(m,1H),1.44–1.36(m,2H),1.01–0.94(m,21H),0.92(d,J=6.9Hz, 3H),0.90(s,9H),0.75(s,3H),0.68(q,J=8.2Hz,6H),0.60(q,J=7.9Hz,6H),0.05(s,6H).

[0168] 13 C NMR (125MHz, CDCl3) δ80.2,79.4,72.1,65.0,60.2,58.9,40.5,39.7,35.9,34.4,26.0,22.9,20.1,18.3,12.3,7.0,6.7,5.3,4.5,-5.4,-5.4.

[0169] 10. Synthesis of Compound 31

[0170]

[0171] Fragment alcohol 29 (70.0 mg, 0.12 mmol) and fragment acid 30 (70.0 mg, 0.17 mmol) were dissolved in toluene (10 mL) solvent, and Et3N (0.07 mL, 0.46 mmol) and Yamaguchi reagent TCBC (0.04 mL, 0.23 mmol) were added in sequence. After stirring at room temperature for 3 hours, DMAP (42.0 mg, 0.35 mmol) was dissolved in toluene (3.0 mL) and added to the reaction system, and stirred at room temperature for 12 hours. Saturated NH4Cl solution (15 mL) was added to quench the reaction, ethyl acetate (15 mL) was added to dilute the reaction solution, and ethyl acetate (50 mL×3) was used for extraction. The combined organic phase was washed with saturated brine (20 mL), dried by adding Na2SO4, filtered and concentrated in vacuo, and the residue was purified by rapid silica gel column (ethyl acetate / n-hexane=1 / 8) to obtain compound 31 as a light yellow oily liquid (105.0 mg, 91%).

[0172] 1 H NMR (500MHz, CDCl3) δ6.41(dd,J=14.6,7.6Hz,1H),6.31(d,J=14.5Hz,1H),5.15(dd,J=9.0,2.9Hz,1H),4.28–4.16(m,1H),3 .80–3.73(m,1H),3.73–3.67(m,1H),3.65–3.59(m,3H),3.43–3.39(m,1H),3.32(s,3H),3.25(s,3H),3.02(dt,J=7.6,3.4Hz, 1H),2.60–2.49(m,2H),1.90–1.78(m,3H),1.78–1.69(m,1H),1.58–1.54(m,1H),1.54–1.47(m,2H),0.97(t,J=7.9Hz,9H),0. 97(t,J=7.9Hz,9H)0.92–0.89(m,12H),0.88(s,9H),0.87(s,3H),0.83(s,3H),0.67–0.56(m,12H),0.07(s,6H),0.05(s,6H).

[0173] 13C NMR (125MHz, CDCl3) δ170.8,146.5,80.6,79.2,78.1,75.7,74.4,66.1,64.5,60.1,58.3,56.3,42.5,42.5, 42.0,39.1,35.8,32.5,26.0,25.9,20.8,19.8,18.3,18.0,12.4,7.1,6.8,5.6,4.5,-4.4,-4.6,-5.4,-5.4.

[0174] 11. Synthesis of compound 33

[0175]

[0176] Dissolve fragment alcohol 31 (140.0 mg, 0.14 mmol) in ethyl acetate (10.0 mL) solvent, add 1M HCl (2.8 mL, 2.8 mmol), and stir at room temperature for half an hour. Add ethyl acetate (100 mL) to dilute the reaction solution, separate the aqueous phase, wash the organic phase with saturated brine (10 mL), add anhydrous Na2SO4 to dry, and concentrate the organic phase under reduced pressure. The residue is purified by rapid silica gel column (ethyl acetate / n-hexane = 1 / 5) to obtain light yellow oily liquid compound 32 (102.0 mg, 82%).

[0177] 1 H NMR (500MHz, CDCl3) δ6.40(dd,J=14.6,7.6Hz,1H),6.32(d,J=14.6Hz,1H),5.16(d,J=9.4Hz,1H),4.23(p,J=5.9Hz,1H),3.84–3.72(m,3H ),3.62(brs,1H),3.56(dd,J=9.9,5.9Hz,1H),3.45(dd,J=9.9,6.5Hz,1H),3.41(s,3H),3.25(s,3H),3.16–3.11(m,1H),2.55(dd,J=6.2, 1.2Hz,2H),2.24–2.13(m,1H),1.95–1.74(m,4H),1.66(dd,J=15.0,10.9Hz,1H),1.60–1.52(m,1H),1.47–1.39(m,1H),0.98(t,J=7.9Hz, 9H),0.91(d,J=4.4Hz,3H),0.89(s,9H),0.88(s,9H),0.85(d,J=7.0Hz,3H),0.81(s,3H),0.65(q,J=7.9Hz,6H),0.07(s,6H),0.04(s,6H).

[0178] 13 C NMR (125MHz, CDCl3) δ171.1,146.8,146.4,80.6,80.1,78.1,75.6,73.9,66.1,64.3,60.0,58.9,56.3,42. 5,42.5,42.0,39.0,36.0,32.8,26.0,25.9,20.0,18.7,18.2,18.0,12.2,7.1,5.6,-4.4,-4.6,-5.4,-5.4.

[0179] Substrate 32 (987.0 mg, 1.11 mmol) was dissolved in DCM (7 mL), and NaHCO3 (373.0 mg, 4.44 mmol) and Dess-Martin reagent (708.0 mg, 1.67 mmol) were added in sequence at room temperature. After stirring at room temperature for half an hour, the mixture was extracted with CH2Cl2 (40 mL x 3), and the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by rapid silica gel column (ethyl acetate / n-hexane = 1:6) to obtain colorless liquid aldehyde S13 (about 935.0 mg).

[0180] The fragment aldehyde S13 (about 935.0 mg) was dissolved in tert-butanol (10 mL) and 2,3-dimethyl-2-butene (5 mL), and a mixed aqueous solution (5 mL) of NaClO2 (301.0 mg, 3.33 mmol) and NaH2PO4 (400.0 mg, 3.33 mmol) was added thereto. After stirring at room temperature for 1 hour, ethyl acetate (100 mL) was added to dilute the reaction solution, and ethyl acetate (20 mL x 2) was used for extraction. The combined organic phase was washed with saturated sodium thiosulfate (20 mL) and brine (20 mL), and then dried by adding Na2SO4. The organic phase was concentrated under reduced pressure, and the residue was purified by rapid silica gel column (ethyl acetate / n-hexane = 1 / 2) to obtain a light yellow oily liquid acid S14 (about 860.0 mg).

[0181] Acid S14 (about 860.0 mg) was dissolved in CH2Cl2 (10 mL), and (590.0 mg, 4.80 mmol), TceOH (300.0 μL, 3.30 mmol) and EDCI (420.0 mg, 2.20 mmol) were added in sequence, and stirred at room temperature for 12 hours. Ethyl acetate (150 mL) was added to dilute the reaction solution, and the organic phase was washed with saturated brine (20 mL), and then dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the residue was purified by rapid silica gel column (ethyl acetate / n-hexane = 1 / 6) to obtain a light yellow oily liquid compound 33 (781.0 mg, total yield of three steps 68%).

[0182] 1 1H NMR (400 MHz, CDCl3) δ 6.42 (dd, J = 14.5, 7.5 Hz, 1H), 6.33 (d, J = 14.6 Hz, 1H), 5.10 (dd, J = 8.7, 2.8 Hz, 1H), 4.83 (d, J = 11.9 Hz, 1H), 4.68 (d, J = 11.9 Hz, 1H), 4.34–4.19 (m, 1H), 4.19–4.02 (m, 1H), 3.82–3.74 (m, 1H), 3.61 (dd, J = 10.0, 5.5 Hz, 1H), 3.45 (dd, J = 9.8, 6.9 Hz, 1H), 3.34 (s, 3H), 3.27 (s, 3H), 3.10–3.02 (m, 1H), 2.86 (dd, J = 16.7, 2.9 Hz, 1H), 2.61 (d, J = 8.5 Hz, 1H), 2.59–2.53 (m, 2H), 1.91–1.81 (m, 2H), 1.80–1.72 (m, 1H), 1.61–1.52 (m, 2H), 0.97 (t, J = 7.9 Hz, 9H), 0.94–0.83 (m, 27H), 0.67–0.59 (m, 6H), 0.09 (s, 6H), 0.06 (s, 3H), 0.06 (s, 3H).

[0183] 13 13C NMR (100 MHz, CDCl3) δ 170.9, 170.9, 146.3, 94.8, 80.5, 79.2, 78.2, 75.3, 74.2, 73.9, 66.0, 64.3, 58.4, 56.3, 42.4, 41.9, 38.7, 38.2, 32.6, 25.9, 25.8, 20.5, 19.9, 18.2, 17.9, 12.4, 7.0, 5.2, 4.4, -4.4, -4.6, -5.4, -5.4.

[0184] 12. Synthesis of Compound 34

[0185]

[0186] Under Ar protection, substrate 24 (176.0 mg, 0.17 mmol), 20 (178.0 mg, 0.24 mmol), Ag2O (158.0 mg, 0.68 mmol) and Pd(PPh3)4 (39.0 mg, 0.034 mmol) were dissolved in degassed THF / H2O (12:2 mL) solvent and stirred at room temperature for 5 hours. The solid was removed by diatomaceous earth filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column (ethyl acetate / n-hexane = 1 / 6) to obtain colorless oily compound 34 (233.0 mg, 90%).

[0187] 1 H NMR(300MHz, CDCl3)δ7.50(s,1H),6.27–5.99(m,2H),5.79–5.60(m,1H),5.49–5.32 (m,1H),5.08(dd,J=7.0,4.3Hz,1H),4.82(d,J=12.0Hz,1H),4.67(d,J=12.0Hz,1H), 4.30–4.14(m,3H),4.10(dd,J=8.4,2.7Hz,1H),4.02(s,1H),3.94(dd,J=7.2,5.0Hz, 1H),3.82–3.71(m,1H),3.69–3.48(m,4H),3.46(s,3H),3.45–3.37(m,1H),3.33(s,3 H),3.32(s,3H),3.22(s,3H),3.16–2.97(m,3H),2.86(dd,J=16.7,2.7Hz,1H),2.70– 2.48(m,5H),1.96–1.77(m,3H),1.71(dt,J=13.9,5.4Hz,1H),1.62–1.51(m,2H),1.4 5(dd,J=7.1,5.0Hz,2H),1.00(s,3H),0.98(s,3H),0.96(s,6H),0.93(s,6H),0.92–0 .84(m,45H),0.67–0.56(m,6H),0.52–0.41(m,6H),0.07(s,6H),0.06–0.02(m,12H).

[0188] 13C NMR (75MHz, CDCl3) δ171.1,171.0,163.5,140.9,135.1,132.7,132.0,131.9,130.1,94.8, 80.9,79.3,79.2,78.7,76.3,75.2,74.2,74.0,71.7,66.3,64.8,64.3,59.0,58.4,56.9,5 5.9,42.9,42.3,40.8,39.4,38.6,38.2,38.1,34.0,32.5,25.9,25.9,22.4,20.6,20.0,19.7,18.3,18.2,18.0,12.5,12.4,7.0,6.9,6.8,5.2,4.7,4.4,-4.4,-4.6,-5.4,-5.4,-5.4.

[0189] 13. Synthesis of Compound 36

[0190]

[0191] Alcohol 34 (107.0 mg, 0.26 mmol) and acid 30 (107.0 mg, 0.260 mmol) were dissolved in toluene (20 mL) solvent, and DMAP (35.0 mg, 0.29 mmol) and Yamaguchi reagent TCBC (0.045 mL, 0.291 mmol) were added in sequence. After stirring at room temperature for 3 hours, saturated NH4Cl solution (15 mL) was added to quench the reaction, and ethyl acetate (150 mL) was added to dilute the reaction solution. The organic phase was washed with saturated brine (20 mL), dried by adding Na2SO4, filtered and concentrated in vacuo, and the residue was purified by flash silica gel column (ethyl acetate / n-hexane = 1 / 8) to obtain compound S15 as a light yellow oily liquid (244.0 mg, 95%).

[0192] 1H NMR(400MHz,CDCl3)δ7.49(s,1H),6.42(dd,J=14.5,7.5Hz,1H),6.33(d,J=14.6Hz,1H),6.23–6.07(m,2H),5.73(dt,J=13.9,7.0Hz,1H),5.41(dd,J=14.1,7.8Hz,1H),5.18(dd,J=9.5,2.1Hz,1H),5.13–5.03(m,1H),4.83(d,J=11.9Hz,1H),4.68(d,J=11.9Hz,1H),4.26(td,J=5.9,2.6Hz,2H),4.21(t,J=6.3Hz,1H),4.12(ddd,J=8.4,6.5,2.6Hz,2H),3.83–3.71(m,2H),3.63(ddd,J=11.1,9.8,5.5Hz,2H),3.46(td,J=10.1,6.8Hz,2H),3.36(s,3H),3.35(s,3H),3.33(s,3H),3.27(s,3H),3.23(s,3H),3.12–3.01(m,3H),2.94(dd,J=15.3,9.5Hz,1H),2.87(dd,J=16.8,2.8Hz,1H),2.70–2.45(m,7H),1.94–1.79(m,4H),1.79–1.69(m,2H),1.69–1.60(m,2H),1.60–1.49(m,2H),0.99(s,3H),0.97(s,6H),0.95(s,6H),0.93(s,3H),0.92(s,9H),0.91(s,9H),0.90–0.86(m,36H),0.67–0.58(m,6H),0.40(p,J=7.9Hz,6H),0.09(s,6H),0.08(s,3H),0.08(s,3H),0.07(s,3H),0.07(s,3H),0.06(s,3H),0.06(s,3H).

[0193] 13C NMR (100MHz, CDCl3) δ171.1,171.0,170.9,163.7,146.4,140.9,134.8,132.7,131.9,131.8,130.4,94.9, 80.5,79.3,79.2,78.7,78.2,77.2,76.5,76.2,75.5,75.2,74.2,74.0,66.3,66.0,64.4,64.3,58.5,58.4 ,57.0,56.3,55.9,42.9,42.5,42.4,42.3,41.9,38.8,38.7,38.2,38.1,32.6,32.5,25.9,25.9,25.8,21.1,20.6,20.4,19.9,18.3,18.2,18.0,12.4,12.4,7.0,5.2,5.0,-4.4,-4.4,-4.6,-4.6,-5.4,-5.4,-5.4.

[0194]

[0195] Under Ar protection, substrate S15 (288.0 mg, 0.15 mmol, 35 (137.0 mg, 0.220 mmol), Ag2O (105.0 mg, 0.45 mmol) and Pd(PPh3)4 (25.0 mg, 0.022 mmol) were dissolved in degassed THF / H2O (12 mL:2 mL) solvent and stirred at room temperature for 5 hours. The solid was removed by diatomaceous earth filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column (ethyl acetate / n-hexane = 1 / 6) to give colorless oily compound 36 (230.0 mg, 67%).

[0196] 1H NMR(400MHz,CDCl3)δ7.48(s,1H),6.24–6.08(m,4H),5.81–5.61(m,2H),5.51–5.36(m,3H),5.17(dd,J=9.1,2.5Hz,1H),5.12–5.05(m,1H),4.87–4.65(m,6H),4.47(dd,J=11.3,6.4Hz,1H),4.39(dd,J=11.3,3.8Hz,1H),4.31–4.21(m,2H),4.20(t,J=6.4Hz,1H),4.17–4.02(m,3H),3.77(ddd,J=13.4,7.6,5.6Hz,2H),3.65(dd,J=8.7,4.4Hz,1H),3.61(dd,J=8.8,4.4Hz,1H),3.50–3.42(m,3H),3.42(s,3H),3.36(s,3H),3.35(s,3H),3.33(s,3H),3.24(s,3H),3.23(s,3H),3.11–3.01(m,3H),2.94(dd,J=15.3,9.5Hz,1H),2.87(dd,J=16.7,2.8Hz,1H),2.65–2.53(m,7H),2.54–2.44(m,1H),2.45–2.33(m,1H),1.94–1.79(m,4H),1.77–1.70(m,2H),1.68–1.61(m,2H),1.60–1.53(m,2H),1.00–0.85(m,72H),0.67–0.57(m,6H),0.45–0.35(m,6H),0.10–0.04(m,24H).

[0197] 13C NMR (100MHz, CDCl3) δ171.1,171.1,171.0,163.7,154.1,153.9,141.0,134.8,133.0,132.8,132.7,132.1,131.9, 131.8,130.4,128.3,95.4,94.9,94.3,80.2,79.3,78.7,78.6,76.5,76.3,75.4,75.2,74.6,74.2,74.0,67.1,66.3 ,64.4,64.3,58.5,58.4,58.2,57.0,56.0,55.9,52.6,42.9,42.9,42.5,42.4,38.8,38.7,38.2,33.5,32.6,32.6,32.5,26.0,25.9,21.1,20.6,20.4,20.0,18.3,18.2,18.0,12.5,12.5,7.0,5.2,5.0,-4.4,-4.6,-5.4,-5.4,-5.4.

[0198] 14. Synthesis of Compound 37

[0199]

[0200] Compound 36 (75.0 mg, 0.033 mmol) was dissolved in THF (8 mL) solvent, KH2PO4 (8 mL, 1 M) was added, Zn (360.0 mg, 5.5 mmol) and Zn (10% Pb) (360.0 mg, 5.0 mmol) were added, and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with EA, and the solid was separated by layers, washed with brine (15 mL), dried by adding anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain intermediate S17 (about 53 mg), which was directly used for the next step.

[0201] The obtained intermediate S17 (about 53 mg) and DAMP (40.0 mg, 0.33 mmol) were dissolved in DCM (66.0 mL), and BEP (22.0 mg, 0.083 mmol) was added. After reacting for 12 hours, BEP (22.0 mg, 0.083 mmol) was added again. The reaction was continued for 12 hours and then concentrated under reduced pressure. The obtained residue was purified by flash silica gel column (ethyl acetate / n-hexane = 1 / 2) to obtain colorless oily compound S16 (30.0 mg, total yield of two-step reaction 51%).

[0202] 1H NMR(500MHz,CDCl3)δ7.47(s,1H),6.36(d,J=6.8Hz,1H),6.22–6.07(m,4H),5.77–5.67(m,2H),5.43(dd,J=14.5,8.3Hz,1H),5.38(dd,J=14.8,8.3Hz,1H),5.20–5.14(m,1H),5.16–5.11(m,1H),4.23–4.16(m,2H),4.16–4.05(m,2H),4.05–3.99(m,1H),3.99–3.94(m,1H),3.85(d,J=10.0Hz,1H),3.73(d,J=7.3Hz,2H),3.68–3.55(m,4H),3.50–3.42(m,3H),3.40(s,3H),3.36(s,3H),3.34(s,6H),3.23(s,3H),3.23(s,3H),3.11–2.97(m,3H),2.65–2.49(m,7H),2.45–2.37(m,1H),2.37–2.23(m,3H),1.91–1.79(m,4H),1.79–1.72(m,2H),1.66–1.61(m,2H),1.61–1.51(m,2H),1.01–0.82(m,72H),0.68–0.58(m,6H),0.49–0.33(m,6H),0.11–0.02(m,24H).

[0203] 13 C NMR(125MHz,CDCl3)δ172.0,170.8,170.6,163.6,140.7,134.8,133.2,132.7,132.3,132.2,131.8,131.6,130.0,129.7,82.3,79.6,79.3,79.1,79.1,76.4,75.6,75.0,74.8,66.4,66.4,64.4,64.3,62.3,58.6,58.4,58.1,56.7,55.8,55.8,53.6,43.1,43.0,42.7,42.5,42.5,40.5,38.9,38.9,37.9,34.0,33.0,32.8,25.9,25.8,21.6,21.1,20.8,19.9,18.2,18.2,17.9,12.4,12.4,7.0,6.9,5.2,5.0,-4.3,-4.3,-4.6,-5.4,-5.5,-5.5.

[0204]

[0205] Compound S16 (25.0 mg, 0.014 mmol) was dissolved in CH2Cl2 (4 mL), cooled to 0°C, and NaHCO3 (50.0 mg, 0.59 mmol) and Dess-Martin periodinane (25.0 mg, 0.059 mmol) were added in sequence. The reaction was heated to room temperature and stirred for 1 hour. After being concentrated to 1 mL under reduced pressure, the residue was purified by rapid silica gel column (ethyl acetate / n-hexane = 1 / 5) to obtain intermediate aldehyde S18 (19.0 mg) as a colorless liquid.

[0206] The intermediate aldehyde S18 (19.0 mg 0.01 mmol) was dissolved in CH2Cl2 (1.5 mL) and cooled to 0°C. 2.6-di-tert-butyl-4-methyl pyridine (20.0 mg, 0.095 mmol), PPh3 (15.0 mg, 0.057 mmol) and Br2C2Cl4 (17.0 mg, 0.052 mmol) were carefully added in sequence. The reaction was heated to room temperature and stirred for 1.5 hours until the aldehyde was completely reacted. The DCM solvent was dried under reduced pressure and redissolved in CH3CN (1.5 mL). DBU (8 μL, 11.3 mmol) was added and continued to stir at room temperature for 3 hours. The reaction was quenched with saturated NH4Cl solution (5 mL), and ethyl acetate (150 mL) was added to dilute the reaction solution. The organic phase was washed with saturated brine (10 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the residue was purified by flash silica gel column (ethyl acetate / n-hexane = 1 / 6) to give the cyclized product 37 as a colorless liquid (13.0 mg, total yield of two steps 54%).

[0207] 1H NMR(500MHz, CDCl3)δ7.45(s,2H),6.22–5.97(m,4H),5.67(dt,J=14.3,7.1Hz,2H),5.37(dd,J=14.7,8.2Hz,2H),5.14(dd,J=9.6,2.1Hz,2H), 4.19(t,J=6.1Hz,2H), 4.14(q,J=6.0Hz,2H), 4.07(dd,J=9.2,2.8Hz,2H), 3.69(q,J=7.0Hz,2H), 3.62(dd,J=9.8,5.5Hz,2H), 3.42(dd,J=9.9, 7.1Hz,2H),3.32(s,6H),3.31(s,6H),3.20(s,6H),3.08–3.00(m,4H),2.95(dd,J=15.3,9.2Hz,2H),2.61(t,J=6.7Hz,4H),2.52(d,J=6.2Hz,4 H),1.89–1.80(m,4H),1.77–1.71(m,2H),1.69–1.64(m,4H),0.92–0.8 3(m,72H),0.47–0.30(m,12H),0.05(s,12H),0.05(s,6H),0.05(s,6H).

[0208] 13 C NMR (125MHz, CDCl3) δ170.6,163.7,140.7,135.0,133.1,131.9,131.8,130.0,79.3,79.1,76.6,76.4,75.7,66.5,64.5,58.5,56. 8,55.9,43.2,42.7,42.5,39.0,37.7,33.1,33.0,29.7,26.0,25.9,21.6,21.0,18.3,18.0,12.4,7.0,5.0,-4.3,-4.5,-5.4,-5.4.

[0209] 15. Synthesis of the Precursor Compound S18 of Compound 2

[0210]

[0211] HF·Py-Py-THF (0.4mL:0.6mL:2mL) solution was added to a stirred solution of 37 (18.0mg, 10.0μmol) in THF (4mL). The reaction mixture was stirred for 17 hours, then diluted with CH2Cl2 (10mL) and quenched with NaHCO3 (aq.) (10mL). The organic phase was separated, the aqueous phase was extracted with CH2Cl2 (10mL×2), and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in air. Concentrated in vacuo. The residue was purified by flash column chromatography to obtain compound S18 (8.3mg, 54%) as a colorless oil.

[0212] 1 H NMR(500MHz,C6D6)δ7.18(s,2H),6.31(dd,J=15.2,10.4Hz,2H),6.19(dd,J=15.2,10.5 Hz,2H),5.90(dt,J=14.7,7.2Hz,2H),5.57(d,J=9.9Hz,2H),5.56–5.51(m,2H),4.53–4 .43(m,2H),4.40(dd,J=8.6,2.3Hz,2H),4.24(t,J=5.8Hz,2H),3.88(dd,J=7.2,6.6Hz, 2H),3.81–3.70(m,2H),3.64–3.56(m,2H),3.41(s,6H),3.39–3.35(m,2H),3.18(s,6H) ,3.14(s,6H),3.13–3.09(m,2H),2.89(dd,J=15.7,8.5Hz,2H),2.81–2.74(m,6H),2.71 (dd,J=15.5,5.2Hz,2H),2.20–2.13(m,2H),2.13–2.04(m,4H),1.99(dt,J=13.9,6.0Hz ,2H),1.76(ddd,J=14.9,9.9,2.3Hz,2H),1.09(s,6H),1.04(s,6H),1.01(t,J=8.1Hz,1 8H),0.99(s,18H),0.90(d,J=7.1Hz,6H),0.63–0.50(m,12H),0.15(s,6H),0.14(s,6H).

[0213] 13C NMR (125MHz, C6D6) δ171.0,164.0,141.8,135.1,133.5,132.4,132.2,130.6,80.9,79.6,77.1,77.0,75.4,67.2 ,64.9,58.1,56.6,55.8,43.7,43.0,38.1,37.6,33.0,32.0,26.1,21.0,19.9,18.2,12.7,7.3,5.5,-4.2,-4.4.

[0214]

[0215] The substrate S18 (20.0 mg, 13.0 μmol) was dissolved in dichloromethane, and sodium bicarbonate (44.0 mg, 52.0 μmol) and Dess-Martin reagent (11.0 mg, 26.0 μmol) were added at room temperature. After stirring for 1 hour at room temperature, the mixture was concentrated under reduced pressure to 2 mL and separated and purified by silica gel column to obtain the aldehyde substrate 2 (about 15 mg).

[0216] 3. Synthesis of the actin stabilizer rhizopodin

[0217]

[0218] Ba(OH)2·8H2O (15.0 mg, 49.0 μmol) was placed in a 10 mL round-bottom flask and burned with an alcohol burner for 3-5 min, followed by the addition of an anhydrous THF solution (1 mL) of ketone 6 (31.0 mg, 98.0 μmol). After stirring at room temperature for half an hour, aldehyde 2 (about 15 mg) in THF-H2O (3 mL: 0.1 mL) was added to the above reaction system. After stirring at room temperature for 10 hours, the reaction solution was diluted with ethyl acetate, washed with saturated ammonium chloride and saturated brine in turn, and dried over anhydrous sodium sulfate. The organic phase was separated and purified by silica gel column to obtain compound 38 (17.2 mg, total yield of two steps 69%).

[0219] 1H NMR(500MHz,C6D6)δ7.90(s,1.3H),7.57(s,0.7H),7.42(d,J=14.5Hz,1H),7.27(s,0.7H),7.25(s,1.3H),7.20(s,1H),7.19(s,1H),6.37–6.22(m,4H),6.15(dd,J=15.2,10.5Hz,2H),5.96–5.83(m,3.3H),5.57–5.48(m,3.7H),4.93(dt,J=14.5,7.3Hz,0.7H),4.79(dt,J=14.3,7.3Hz,1.3H),4.55–4.45(m,2H),4.31(dd,J=8.4,3.2Hz,2H),4.26–4.17(m,2H),3.87(q,J=7.4Hz,2H),3.53–3.45(m,2H),3.35(s,3.9H),3.35(s,2.1H),3.22(4H,m),3.20(s,2.1H),3.19(s,3.9H),3.18–3.13(m,12H),3.07–3.00(m,4H),2.84–2.77(m,4H),2.77–2.71(m,4H),2.66(s,4H),2.62–2.58(m,2H),2.32–2.27(m,0.7H),2.24–2.20(m,1.3H),2.16(s,2H),2.19–2.11(2H,m),2.07–1.93(m,4H),1.87–1.82(m,2H),1.80–1.75(m,2H),1.09–0.90(m,60H),0.65–0.49(m,12H),0.18(s,6H),0.16(s,6H).

[0220] 13C NMR(125MHz,C6D6)δ201.0,200.9,170.9,163.7,161.5,160.2,148.0,147.8,141.6,135.4,133.5 ,132.4,132.4,132.3,130.7,130.7,130.2,128.3,126.8,106.8,104.8,82.9,82.9,81.8,79.5,77 .1,76.9,75.5,67.1,58.1,57.8,57.6,56.6,55.9,47.5,47.2,43.8,42.9,42.7,39.0,38.9,38.0,33.5,33.4,33.2,31.9,31.4,31.2,26.9,26.2,21.7,18.3,14.8,12.9,12.7,7.4,5.5,-4.1,-4.3.

[0221]

[0222] In an argon atmosphere, [(PPh3)CuH]6 (9.4 mg, 4.8 μmol) was added to a round-bottom flask containing substrate 38 (9.2 mg, 4.8 μmol), and a mixed solution of toluene-H2O (5 mL, 99:1) that had been strictly treated with oxygen was added. After stirring at room temperature for 10 hours, the mixture was directly concentrated under reduced pressure, and the residue was quickly filtered through a silica gel column to obtain the crude product S19 (about 7 mg) of enone reduction product, which was directly used in the next step reaction.

[0223] HF·Py (200 μL) was added to a stirred solution of S19 (about 7 mg) in THF (4 mL). The reaction mixture was stirred for 18 hours, then diluted with CH2Cl2 (10 mL) and quenched with NaHCO3 (aq.) (5 mL). The organic phase was separated, the aqueous phase was extracted with CH2Cl2 (10 mL×2), and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in air. Concentrated in vacuo. The residue was purified by flash column chromatography to obtain rhizopodin (1) (4.2 mg, 60% total yield for two steps) as a colorless oil.

[0224] 13C NMR(125MHz,Methanol-d4)exists as rotational conformers:δ8.32(s,1.3H),8.08(s,0.7H),7.70(s,2H),7.13(d,J=14.6Hz,0.7H),6.73(d,J=14.1Hz,1.3H),6.20(dd,J=15.1,10.5Hz,2H),6.11(dd,J=14.9,10.5Hz,2H),5.64(dt,J=14.8,7.3Hz,2H),5.39(dd,J=15.1,8.3Hz,2H),5.31(dd,J=9.0,2.0Hz,2H),5.27–5.24(m,0.7H),5.19(ddd,J=14.3,8.1,6.5Hz,1.3H),4.22(t,J=6.6Hz,2H),4.13–4.02(m,2H),3.94(dd,J=10.3,2.7Hz,2H),3.81(q,J=7.3Hz,2H),3.51–3.45(m,2H),3.33(s,6H),3.31(s,3H),3.27(s,6H),3.22(s,6H),3.11(s,2H),3.09–3.03(m,2H),3.02(s,4H),2.97(dd,J=15.2,2.7Hz,2H),2.87–2.83(m,2H),2.83–2.78(m,2H),2.65–2.60(m,4H),2.60–2.54(m,6H),2.53–2.47(m,4H),2.24–2.17(m,1H),1.87–1.80(m,2H),1.80–1.78(m,2H),1.78–1.74(m,2H),1.68–1.63(m,2H),1.63–1.58(m,4H),1.28–1.20(m,2H),1.00(d,J=6.9Hz,6H),0.93(s,12H),0.85(d,J=6.6Hz,6H).

[0225] 13C NMR(125MHz,Methanol-d4)exists as rotational conformers:δ216.3,174.0,166.5,164.8,163.4,141.0,138.0,135.2,133.5,132.6,132.1,131.6,127.4,109.5,107.4,84.1,83.3,81.5,76.9 ,76.6,74.5,67.4,58.4,58.1,56.9,56.5,50.4,44.1,44.0,42.8,42.1 ,38.7,35.6,33.7,32.2,32.2,31.3,27.8,26.0,19.5,19.1,16.1,13.2.

[0226] In summary, the present invention innovatively synthesizes a compound containing a phosphate fragment and having a complete C23-C31 in the side chain of the anticancer natural product rhizopodin. The compound can be subjected to HWE condensation with a macrocyclic lactone structure (the structural formula is shown in Compound 2 above), and then the newly generated unsaturated double bond is selectively reduced with Stryker reagent ([(PPh3)CuH]6), so that the side chain fragment can be introduced into the macrocyclic lactone structure. The scheme of the present invention is shorter than the existing synthesis steps for introducing side chains, and the synthesis efficiency is relatively high. At the same time, the method of introducing side chain fragments in the present invention can provide a certain reference and reference for the total synthesis of other natural products containing similar Z-enamine aldehyde structures. Furthermore, the present invention has also successfully developed a new route for synthesizing compound 2 (the total yield of the synthesis is 0.69%, the highest total yield of the related art synthesis route is 0.42%, and the total yield of the present invention is more than 1.6 times that of the related art), and the above strategy is used to react with compounds of phosphate fragments to successfully prepare the actin stabilizer rhizopodin. The overall total yield in the embodiment scheme reaches 0.36%, which is the highest yield among the reported routes (more than 1.9 times that of the related art (the total yield of the synthesis route described in the background technology section is up to about 0.19%)).

[0227] The embodiments of the present invention are described in detail above, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge scope of ordinary technicians in the relevant technical field without departing from the purpose of the present invention.

Claims

1. A side chain compound, characterized in that: The structural formula of the side chain compound is shown below:

2. The precursor compound of the side chain compound according to claim 1, characterized in that: The structural formula of the precursor compound of the side chain compound is shown in one of the following formulas V:

3. The method for synthesizing the side chain compound according to claim 1, characterized in that: The steps include: by Compound I is prepared as a raw material, compound II is prepared using compound I as a raw material, compound III is prepared using compound II as a raw material, compound IV is prepared using compound III as a raw material, compound V is prepared using compound IV as a raw material, and the side chain compound is prepared using compound V as a raw material; wherein the structures of compounds I, II, III, IV and V are shown in the following formula: In the formula, R1, R2, and R3 are independently selected from H or a hydroxyl protecting group, and are the same or different.

4. The preparation method according to claim 3, characterized in that: The synthetic route of the side chain compound is as follows:

5. A method for synthesizing an actin stabilizer, characterized in that: The steps include: The side chain compound as claimed in claim 1 is reacted with a parent compound to obtain a parent compound having the structural formula as shown below: R1 and R5 are independently selected from H or a hydroxyl protecting group and are the same or different.

6. The method for synthesizing an actin stabilizer according to claim 5, characterized in that: The side chain compound is hydrogenated and reacts with the parent compound to generate the actin stabilizer.

7. The method for synthesizing an actin stabilizer according to claim 6, characterized in that: The hydrogenation is carried out under the action of a hydrogenation reagent, and the hydrogenation reagent is selected from at least one of Ba(OH)2, NaH, LiHMDS, KHMDS, LDA, NaOH or potassium tert-butoxide.

8. The method for synthesizing an actin stabilizer according to claim 5, characterized in that: R1 is TBS, R5 is TES, and the synthesis method further comprises a step of deprotecting the side chain compound after reacting with the parent compound.

9. The method for synthesizing an actin stabilizer according to claim 8, characterized in that: The synthetic route of the actin stabilizer is as follows:

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