CN107129515B

CN107129515B - Novel method for synthesizing natural product Cyanolide A analogue

Info

Publication number: CN107129515B
Application number: CN201710216147.8A
Authority: CN
Inventors: 黄双平; 王博; 冷晓; 李晓彤; 徐天祥; 梁程; 王晓季
Original assignee: Jiangxi Science and Technology Normal University
Current assignee: Jiangxi Science and Technology Normal University
Priority date: 2017-04-01
Filing date: 2017-04-01
Publication date: 2021-01-15
Anticipated expiration: 2037-04-01
Also published as: CN107129515A

Abstract

The invention takes propionaldehyde 1 and Evans chiral auxiliary 2 as initial raw materials, and the initial raw materials are subjected to the conditions of Evans Aldol and potassium monomethyl malonate，BEt₃/NaBH₄Reducing, protecting p-methoxybenzaldehyde dimethyl acetal, DIBAL-H, synthesizing segment 9 by Mukaiyama Aldol and other processes, then synthesizing segment 11 by MOMCl protection, p-methoxybenzaldehyde dimethyl acetal protection and other processes, and constructing tetrahydropyran ring with potassium carbonate to obtain compound 12, and synthesizing segments 15 and 15 by hydrolysis, Yamaguchi reaction, MOM protection removal and other processes, and glycosidating with compound 16 to obtain the product, namely the Cyanolide A analogue. The key step of the invention adopts Ti (O-i-Pr)₂Cl₂The catalytic Mukaiyama aldol reaction has high product yield and good control of stereoselectivity.

Description

Novel method for synthesizing natural product Cyanolide A analogue

Technical Field

The invention relates to a novel method for stereoselectively synthesizing a natural product, namely a Cyanolide A analogue, which takes propionaldehyde 1 and Evans auxiliary agent 2 as initial raw materials and Ti (O-i-Pr)₂Cl₂The catalytic Mukaiyama aldol reaction completes a series of reactions with key steps of constructing hydroxyl chirality and the like to synthesize the natural product Cyanolide A analogue.

Background

Cyanolide A is a natural product with molluscicidal activity extracted by the Gerwick group in 2010 from a genus of Lyophyllum in New Guinea. Cyanolide A is a dimeric glycoside macrolide possessing a C₂The structure of the axis of symmetry, the central 16-membered macrolide fused two tetrahydropyran rings and two xylose-type substrates. The synthesis of Cyanolide a has attracted the interest of many chemists, since its molluscicidal activity plays a key role in human health and has great potential as an effective and selective molluscicidal agent in eradicating endemic parasitic infectious schistosomiasis. The chemical structure of Cyanolide a is as follows:

there are many reported methods for stereoselective synthesis of natural product Cyanolide a, which are mainly represented by: jiyong Hong et al published in 2010 an academic paper entitled Total Synthesis of Cyanolide A and compliance of its absolute compliance on Organic Letters. Srinivasa Reddy et al published in 2011 as an academic paper entitled Synthesis of maleic agent Cyanolide A macrolactone from D- (-) -Pantolactone on The Journal of Organic Chemistry. ③ Srihari Pabbaraja et al published in 2011 an academic paper entitled Formal total synthesis of Cyanolide A on The Journal of Organic Chemistry. Scott D.Rychnovsky et al published an academic paper entitled Total Synthesis of the Cyanolide A aglycon in the Journal of the American Chemical Society in 2011. Junnings et al published 2011 in The Journal of Organic Chemistry an academic paper entitled A formal synthesis of (-) -Cyanolide A healing a stereoselective mukaiyamal interaction and oxobearing reduction. Michael J.Krische et al published in 2013 in academic papers titled Total Synthesis of Cyanolide A in the absence of protective groups, chiral auxiliaries, or premelated carbon nuclei. Careful analysis and comparison show that most of the reported routes design and synthesis methods for natural product Cyanolide A adopt classical conventional reactions in organic synthesis, and the synthesis routes have the problems of longer synthesis route, low reaction yield, stereoselectivity and the like during design.

Disclosure of Invention

The invention aims to overcome the problems of expensive synthesis cost, low yield and the like of the existing synthesis method and provides a brand-new synthesis method of a natural product, namely a Cyanolide A analogue.

In order to achieve the purpose, the invention designs a synthetic method of a natural product Cyanolide A analogue, which is characterized in that: by using chiral auxiliary agent Evans、BEt₃/NaBH₄、Ti(O-i-Pr)₂Cl₂The catalyzed Mukaiyama aldol reaction controls the chirality of the hydroxyl groups formed during the reaction to give a single analogue of Cyanolide a, and conventional chemical reagents are utilized in the route.

The method for synthesizing the natural product Cyanolide A analogue is characterized by comprising the following steps:

1) after a compound of a formula 3 is obtained by a compound of a formula 1 and a compound of a formula 2 through an Evans Aldol reaction, an Evans precursor is removed under the condition of potassium salt to obtain a compound of a formula 4;

2) the compound of formula 4 is in BEt₃/NaBH₄Stereoselective reduction under the conditions to give a compound of formula 5, 1, 3-dihydroxy protection of a compound of formula 5 to give a compound of formula 7, reduction of a compound of formula 7 under DIBAL-H conditions to give a compound of formula 8;

3) carrying out Mukaiyama aldol reaction on the compound of the formula 8 to obtain a compound of a formula 9, protecting the compound of the formula 9 with MOM to obtain a compound of a formula 10, and removing 1, 3-dihydroxy protection from the compound of the formula 10 under the condition of p-toluenesulfonic acid to obtain a compound of a formula 11;

4) compounds of formula 11 at K₂CO₃Constructing a tetrahydropyran ring under a catalytic condition to obtain a compound of a formula 12, and hydrolyzing the compound of the formula 12 under a lithium hydroxide condition to obtain a compound of a formula 13;

5) the compound shown in the formula 13 is subjected to Yamaguchi lactonization reaction to obtain a compound shown in the formula 14, the compound shown in the formula 14 is subjected to MOM protection removal under the condition of lithium tetrafluoroborate to obtain a compound shown in the formula 15, and the compound shown in the formula 15 and a compound shown in the formula 16 are subjected to glycosylation to obtain a natural product, namely a Cyanolide A analogue.

The reaction formula is as follows:

the invention has the beneficial effects that:

1. compared with the known method, the synthesis method has the advantages of novel synthesis route, single selective synthesis of the analogue of the Cyanolide A theoretically obtained, simple and convenient operation, high product yield, cheap and easily obtained raw materials and reagents and the like.

2. Compared with the existing method, the synthesis method of the invention has the advantages of obviously improved yield and greatly reduced production cost.

3. The synthesis route of the invention has simple and reasonable design, simple and convenient operation process and mild reaction conditions.

Detailed Description

In order that the invention may be more clearly understood, reference will now be made in detail to the following examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Example 1: synthesis of Compounds of formula 3

Under the protection of nitrogen, the chiral auxiliary 2(1.19g,4.75mmol) is dissolved in 31ml of dry dichloromethane, then the reaction system is placed in an ice-water mixture to be cooled to 0 ℃, and 1.04ml of titanium tetrachloride is slowly added dropwise. After stirring at 0 ℃ for 5min, 1.65ml of DIPEA (diisopropylethylamine) was dissolved in 3ml of dry dichloromethane and added to the reaction system. The reaction was then brought to-78 ℃ and after 30min of reaction, a solution of propionaldehyde formula 1(1ml,14.25mmol) in dry dichloromethane (9ml) was added dropwise and the reaction continued at-78 ℃ for 3 h. After completion of the reaction, TLC (thin layer chromatography) detection was carried out using saturated NH₄And (3) after the Cl solution is quenched, moving the reaction system to room temperature, after the temperature of the solution is raised to the room temperature, extracting with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 0.94g of a yellow viscous compound of the formula 3 with the yield of 67%.

Example 2: synthesis of Compound of formula 4

Under the protection of nitrogen, the raw material formula 3(2.8297g,9.14mmol) is dissolved in 36.56ml of dry tetrahydrofuran, the reaction system is placed in an ice-water mixture and cooled to 0 ℃, then monomethyl malonate potassium salt (2.85g,18.28mmol), imidazole (1.24g,18.28mmol) and anhydrous magnesium chloride (1.74g,18.28mmol) are added, the reaction system reacts at room temperature for 44h, and saturated NH is added₄Quenching with Cl solution, extracting with ethyl acetate, combining organic phases, and using anhydrousDrying sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 1.2106g of a yellow viscous compound of formula 4 with a yield of 76%;¹H NMR(400MHz,CDCl₃):δ3.99(s,1H),3.72(s,3H),3.48(s,2H),2.78-2.75(m,1H),2.74-2.59(m,2H),1.57-1.40(m,2H),0.93(t,J＝7.4Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ203.48, 167.42,68.87,52.35,49.63,49.25,29.40,9.70；HRMS(ESI):m/z calcd for C₈H₁₄O₄Na[M+Na]⁺197.0784,found 197.0784。

example 3: synthesis of Compounds of formula 5

Under the protection of nitrogen, the raw material formula 4(414.4mg,2.38mmol) is dissolved in 14ml of dry tetrahydrofuran, the reaction system is placed in an ice-water mixture, the temperature is reduced to 0 ℃, then 7.14ml of triethylboron is dropwise added, 7.2ml of refined methanol is dropwise added after the dropwise addition of the triethylboron is finished, and the reaction is continued for 1 h. The reaction was then moved to-78 ℃ and 269.99mg NaBH was added₄After stirring at this temperature for 1 hour, the reaction was completed by TLC detection. With saturated NH₄And (3) quenching the Cl solution, extracting with ethyl acetate, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain a crude product. Then 15mL of ethyl acetate was added to dissolve the mixture, 20mL of 3% hydrogen peroxide solution was added dropwise, and after completion of the TLC detection reaction, saturated NaHCO was used₃Quenching the solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 310.9mg of a yellow viscous compound shown as a formula 5 with a yield of 74%;¹H NMR(400MHz,CDCl₃):δ4.30-4.24(m,1H),3.89(s,1H),3.83-3.77(m,1H),3.70(s,3H),3.34(s,1H),2.50-2.48(m,2H),1.61-1.41(m,4H),0.92(t,J＝7.4Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ173.08,73.73,69.25,51.97,41.93,41.77,30.76,9.79；HRMS(ESI):m/z calcd for C₈H₁₆O₄Na[M+Na]⁺199.0941,found 199.0941。

example 4: synthesis of Compounds of formula 7

Under nitrogen protection, the starting material of formula 5(1.64g,9.3mmol)Dissolved in 46.5ml of dry dichloromethane, the reaction system is placed in an ice-water mixture and cooled to 0 ℃, 6.34ml of p-methoxybenzaldehyde dimethyl acetal is added dropwise, and then 160.15mg of p-toluenesulfonic acid is added. After TLC detection of reaction completion, saturated NaHCO was used₃Quenching the solution, extracting with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 2.402g of a yellow viscous compound of formula 7 with a yield of 88%;¹H NMR(400MHz,CDCl₃):δ7.41(d,J＝8.6Hz,2H),6.87(d,J＝8.6Hz,2H),5.51(s,1H),4.31-4.26(m,1H),3.76(s,3H),3.74-3.72(m,1H),3.69(s,3H),2.75-2.48(m,2H),1.72-1.35(m,4H),0.98(t,J＝7.5Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ170.20,158.81,130.24,126.36,112.50,99.51,76.81,72.08,54.23,50.63,39.80,35.06,27.75,8.43；HRMS(ESI):m/z calcd for C₁₆H₂₂O₅Na[M+Na]⁺317.1359,found 317.1358。

example 5: synthesis of Compounds of formula 8

The starting material of formula 7(1.7655g,6.002mmol) was dissolved in 120ml of dry dichloromethane under nitrogen, the reaction was cooled to-78 ℃ and 4.8ml of a 1M hexane solution of diisobutylaluminum hydride (i.e., the concentration of diisobutylaluminum hydride in hexane was 1mol/L) was added dropwise. After TLC detection reaction is completed, 12ml of methanol is slowly dropped and fully stirred for 10 minutes, and then 12ml of saturated sodium tartrate solution is added into the colorless reaction system, and the mixture is moved to room temperature and stirred until the solution is recovered to the room temperature. Then extracting with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 0.9627g of a colorless viscous compound of formula 8 with a yield of 92%;¹H NMR(400MHz,CDCl₃):δ9.84(s,1H),7.41(d,J＝8.6Hz,2H),6.88(d,J＝8.6Hz,2H),5.52(s,1H),4.40-4.34(m,1H),3.79(s,3H),3.76-3.73(m,1H),2.82-2.57(m,2H),1.73-1.39(m,4H),0.99(t,J＝7.5Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ199.56,158.93,130.08,126.38,112.61,99.67,76.93,70.88,54.32,48.50,35.22,27.77,8.45；HRMS(ESI):m/z calcd for C₁₅H₂₀O₄Na[M+Na]⁺287.1254,found 287.1255。

example 6: synthesis of Compounds of formula 9

Under the protection of nitrogen, titanium dichlorodiisopropoxide (7.3ml,14.58mmol) is dissolved in 49ml of refined toluene, the reaction system is placed at-78 ℃ and cooled to-78 ℃, and the raw material formula 8(2.57g,9.72mmol) is dissolved in 21ml of refined toluene and is added to the reaction system dropwise. After 10min compound of formula 6(6.7g,38.88mmol)

Dissolving in 12ml refined toluene, adding dropwise into the reaction system, detecting by TLC after 30min, and detecting with saturated NaHCO₃Quenching the solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 2.126g of a yellow viscous compound of formula 9 with a yield of 60%;¹H NMR(400MHz,CDCl₃):δ7.38(t,J＝8.7Hz,2H),6.99(dt,J＝15.1,7.4Hz,1H),6.90-6.83(m,2H),5.90(d,J＝15.7Hz,1H),5.48(dd,J＝14.9,7.2Hz,1H),4.10(ddd,J＝23.5,12.9,5.3Hz,2H),3.79(s,3H),3.72(s,4H),2.38(dd,J＝13.8,6.7Hz,2H),1.78-1.43(m,6H),0.97(t,J＝7.4Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ166.71,159.93,159.86,145.35,131.20,127.28,123.41,113.60,100.66,74.05,70.24,66.92,55.28,51.45,41.96,40.35,36.09,28.77,9.45；HRMS(ESI):m/z calcd for C₂₀H₂₈O₆Na[M+Na]⁺387.1778,found 387.1778。

example 7: synthesis of Compounds of formula 10

The starting material of formula 9(1.3097g,3.59mmol) was dissolved in 12.4ml of dry dichloromethane under nitrogen protection, the reaction was cooled to 0 ℃ in an ice-water mixture, 3.13ml of N, N-diisopropylethylamine and 0.8ml of chloromethyl methyl ether were added dropwise, and the mixture was reacted at room temperature for 12 hours. After TLC detection of reaction completion, saturated NaHCO was used₃Quenching the solution, extracting with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 1.233g of a yellow viscous compound of formula 10 with a yield of 84%;¹H NMR(400MHz,CDCl₃):δ7.41(d,J＝8.7Hz,2H),7.04-6.93(m,1H),6.87(d,J＝8.7Hz,2H),5.88(dd,J＝15.7,5.6Hz,1H),5.45(s,1H),4.74-4.61(m,2H),4.09(td,J＝9.5,5.1Hz,1H),4.04-3.90(m,1H),3.78(s,3H),3.70(s,4H),3.37(d,J＝5.2Hz,3H),2.62-2.33(m,2H),1.73-1.28(m,6H),0.98(t,J＝7.5Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ166.62,159.73,145.02,131.46,127.19,123.44,113.53,100.23,96.10,73.48,72.92,72.42,55.69,55.25,51.39,37.99,36.85,28.80,9.46；HRMS(ESI):m/z calcd for C₂₂H₃₂O₇Na[M+Na]⁺431.2040,found 431.2041。

example 8: synthesis of Compounds of formula 11

Under the protection of nitrogen, the raw material formula 10(305.2mg,0.75mmol) is dissolved in 3.75ml of refined methanol, the reaction system is placed at-20 ℃ and cooled to-20 ℃, and p-toluenesulfonic acid (508.7mg,3.0mmol) is added for continuous reaction for 2 h. After TLC detection of reaction completion, saturated NaHCO was used₃Quenching the solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 130.162mg of a yellow viscous compound of formula 11 with a yield of 60%;¹H NMR(400MHz,CDCl₃):δ6.92(dt,J＝15.2,7.5Hz,1H),5.87(d,J＝15.6Hz,1H),4.73-4.59(m,2H),4.12-4.01(m,1H),3.99-3.89(m,1H),3.81-3.74(m,1H),3.71(s,3H),3.39(s,3H),2.52-2.38(m,2H),1.64-1.38(m,6H),0.90(t,J＝7.4Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ166.60,144.66,123.60,96.59,74.10,74.05,68.99,55.88,51.44,42.51,37.97,30.68,9.61；HRMS(ESI):m/z calcd for C₁₄H₂₆O₆Na[M+Na]⁺313.1622,found 313.1619。

example 9: synthesis of Compounds of formula 12

Under the protection of nitrogen, the raw material of formula 11(178.9mg,0.616mmol) was dissolved in 6ml of purified toluene, the reaction system was heated under reflux at 140 ℃, and then potassium carbonate (425.79mg,3.08mmol) was added to continue the reaction for 12 hours. After TLC detection reaction is completed, cooling the reaction system to room temperature, and using saturated NH₄Quenching with Cl solution, extracting with ethyl acetate, mixing organic phases, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressureAfter the crude product is obtained, 118.074mg of yellow viscous compound of the formula 12 is obtained by silica gel column chromatography separation and purification, and the yield is 66%;¹H NMR(400MHz,CDCl₃):δ4.68(s,2H),3.88-3.79(m,1H),3.79-3.70(m,2H),3.69(s,3H),3.66-3.57(m,1H),3.36(s,3H),2.62-2.40(m,2H),1.57(dd,J＝9.1,4.7Hz,2H),1.54-1.37(m,2H),1.35-1.20(m,4H),0.91(t,J＝7.5Hz,3H)；HRMS(ESI):m/z calcd for C₁₄H₂₆O₆Na[M+Na]⁺313.1622,found 313.1619。

example 10: synthesis of Compounds of formula 13

The starting material of formula 13(51mg,0.18mmol) was dissolved in 1.8ml tetrahydrofuran under nitrogen: methanol: to a solution of water (2: 1: 1 by volume) was added lithium hydroxide (29.48mg,0.72ml) and the reaction was carried out at room temperature for 20 hours. Then spin-drying the solvent, dissolving in water, extracting with N-pentane, combining the aqueous phases, adjusting the pH to 2.0 with 1.0N hydrochloric acid, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and distilling under reduced pressure to give 43.71mg of the compound of formula 13 in 90% yield;¹H NMR(400MHz,CDCl₃):δ4.71(s,2H),3.90(d,J＝8.5Hz,2H),3.83-3.73(m,1H),3.73-3.63(m,1H),3.39(s,3H),2.63-2.42(m,2H),1.67(dd,J＝18.9,8.9Hz,2H),1.60-1.43(m,2H),1.39-1.24(m,4H),0.92(t,J＝7.3Hz,3H)；HRMS(ESI):m/z calcd for C₁₃H₂₄O₆Na[M+Na]⁺299.1465,found 299.1465。

example 11: synthesis of Compounds of formula 14

The starting material of formula 13(48.4mg,0.175mmol) was dissolved in 0.875ml of tetrahydrofuran under nitrogen, and triethylamine (36.6. mu.l, 0.2625mmol) and 2,4, 6-trichlorobenzoyl chloride (4136.6. mu.l, 0.2625mmol) were added dropwise and reacted at room temperature for 3 h. 4-dimethylaminopyridine (106.9mg, 0.2625mmol) was dissolved in 35ml of toluene and heated under reflux, and then 8.75ml of toluene was added dropwise to the above reaction system to react for 12 hours. After TLC detection reaction is completed, cooling the reaction system to room temperature, and using saturated NaHCO₃Quenching the solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain 36.195mg of the compound shown in the formula 14 with the yield of 40%;¹H NMR(400MHz,CDCl₃):δ4.83(ddd,J＝22.3,18.9,7.0Hz,2H),4.59(s,4H),4.25-3.36(m,6H),3.29(t,J＝6.8Hz,3H),2.52-2.11(m,4H),1.92-1.05(m,16H),0.78(dd,J＝11.6,5.8Hz,6H)；HRMS(ESI):m/z calcd for C₂₆H₄₄O₁₀Na[M+Na]⁺539.2827,found 539.2823。

example 12: synthesis of Compounds of formula 15

The starting material of formula 14(146.5mg,0.28mmol) was dissolved in 5.7ml acetonitrile under nitrogen: to a solution of water (volume ratio 204: 1), 1.42ml of a 1.0M solution of lithium tetrafluoroborate in acetonitrile was added dropwise, and then the reaction system was heated to 70 ℃ for reaction for 1 hour. After TLC detection reaction is completed, cooling the reaction system to room temperature, and using saturated NaHCO₃Quenching the solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain 77mg of a compound shown in the formula 15 with a yield of 63%;¹H NMR(400MHz,CDCl₃):δ5.08-4.85(m,2H),4.04-3.60(m,4H),3.46(t,J＝8.6Hz,2H),2.62-2.24(m,4H),2.06-1.37(m,16H),0.85(t,J＝7.0Hz,6H)；HRMS(ESI):m/z calcd for C₂₂H₃₆O₈Na[M+Na]⁺451.2302,found 451.2305。

example 13: synthesis of compound Cyanolide A analogue

Under nitrogen protection, compound of formula 16(166.33mg,0.5mmol), compound of formula 15(77mg, 0.18mmol) and

dissolving a molecular sieve in 2.25ml of refined dichloromethane, reacting at room temperature for 30min, moving the reaction system to-78 ℃, cooling to-78 ℃, dropwise adding boron trifluoride diethyl etherate (4.5 mu l, 0.04mmol), heating to-40 ℃, and continuing to react for 2 h. Then heating the reaction system to room temperature, continuing the reaction for 30min, detecting the reaction by TLC (thin layer chromatography), and using saturated NaHCO₃Quenching the solution, extracting by dichloromethane, combining organic phases, drying by anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain 15.356mg of Cyanolide A analogue with the yield of 11%;¹H NMR(400MHz,CDCl₃):δ5.11-4.80(m,2H),4.39-4.18(m,2H),4.03-3.86(m,2H),3.84-3.32(m,24H),3.23(d,J＝5.4Hz,2H),3.07(dd,J＝13.8,8.0Hz,4H),3.02-2.64(m,2H),2.63-2.22(m,4H),2.13-1.68(m,10H),1.67-1.45(m,6H),0.84(t,J＝7.4Hz,6H)；HRMS(ESI):m/z calcd for C₃₈H₆₄O₁₆Na[M+Na]⁺799.4087,found 799.4088。

the chemical structural formula of the synthesized Cyanolide A analogue is as follows:

the concentration of the hydrogen peroxide solution is mass concentration.

The purified methanol, the purified toluene and the purified dichloromethane of the invention refer to a pure methanol product with 100 percent, a pure toluene product with 100 percent and a pure dichloromethane product with 100 percent.

Claims

1. A novel method for synthesizing a natural product, namely a Cyanolide A analogue, is characterized in that: the chemical structural formula of the analogue of Cyanolide A is as follows:

the synthetic route is as follows:

(1) synthesis of Compounds of formula 3

Under the protection of nitrogen, 1.19g of 4.75mmol of chiral auxiliary agent formula 2 is dissolved in 31ml of dry dichloromethane, then the reaction system is placed in an ice-water mixture to be cooled to 0 ℃, and 1.04ml of titanium tetrachloride is slowly dripped; stirring at 0 deg.C for 5min, dissolving 1.65ml diisopropylethylamine in 3ml dry dichloromethane, and adding into the reaction system; subsequently, the reaction system is moved to-78 ℃, after 30min of reaction, 1ml of a solution of 14.25mmol of propionaldehyde formula 1 in 9ml of dry dichloromethane is added dropwise, and the reaction system is followed byReacting at-78 deg.C for 3h, detecting by TLC, and adding saturated NH₄After the Cl solution is quenched, the reaction system is moved to the room temperature, after the temperature of the solution is raised to the room temperature, dichloromethane is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying treatment, filtration and reduced pressure distillation are carried out to obtain a crude product, and then the crude product is separated and purified through silica gel column chromatography to obtain 0.94g of a yellow viscous compound in the formula 3, wherein the yield is 67%;

(2) synthesis of Compound of formula 4

2.8297g, namely 9.14mmol of the raw material formula 3 are dissolved in 36.56ml of dry tetrahydrofuran under the protection of nitrogen, the reaction system is placed in an ice-water mixture and cooled to 0 ℃, then 2.85g, namely 18.28mmol of monomethyl malonate potassium salt, 1.24g, namely 18.28mmol of imidazole and 1.74g, namely 18.28mmol of anhydrous magnesium chloride are added, the reaction system reacts for 44 hours at room temperature and is reacted with saturated NH₄Quenching with a Cl solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 1.2106g of a yellow viscous compound of formula 4 with a yield of 76%;¹H NMR(400MHz，CDCl₃)：δ3.99(s，1H)，3.72(s,3H)，3.48(s,2H)，2.78-2.75(m,1H)，2.74-2.59(m,2H)，1.57-1.40(m,2H)，0.93(t,J＝7.4Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ203.48，167.42，68.87，52.35，49.63，49.25，29.40，9.70；HRMS(ESI):m/z calcd for C₈H₁₄O₄Na[M+Na]⁺197.0784，found 197.0784；

(3) synthesis of Compounds of formula 5

Under the protection of nitrogen, 414.4mg, namely 2.38mmol of the raw material formula 4 is dissolved in 14ml of dry tetrahydrofuran, the reaction system is placed in an ice-water mixture, the temperature is reduced to 0 ℃, then 7.14ml of triethylboron is dropwise added, 7.2ml of refined methanol is dropwise added after the dropwise addition of the triethylboron is finished, and the reaction is continued for 1 h; the reaction was then moved to-78 ℃ and 269.99mg NaBH was added₄Stirring for 1 hour at the temperature, and detecting by TLC until the reaction is completely finished; with saturated NH₄Quenching with Cl solution, extracting with ethyl acetate, mixing organic phases, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain crude productThe mixture was dissolved in 15mL of ethyl acetate, 3% hydrogen peroxide solution (20 mL) was added dropwise, and after completion of the TLC detection, saturated NaHCO was used₃Quenching the solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 310.9mg of a yellow viscous compound shown as a formula 5 with a yield of 74%;¹H NMR(400MHz,CDCl₃):δ4.30-4.24(m,1H)，3.89(s,1H)，3.83-3.77(m,1H)，3.70(s,3H)，3.34(s,1H)，2.50-2.48(m,2H)，1.61-1.41(m,4H)，0.92(t,J＝7.4Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ173.08，73.73，69.25，51.97，41.93，41.77，30.76，9.79；HRMS(ESI):m/z calcd for C₈H₁₆O₄Na[M+Na]⁺199.0941，found 199.0941；

(4) synthesis of Compounds of formula 7

Under the protection of nitrogen, 1.64g of the raw material formula 5, namely 9.3mmol, is dissolved in 46.5ml of dry dichloromethane, the reaction system is placed in an ice-water mixture, the temperature is reduced to 0 ℃, 6.34ml of p-methoxybenzaldehyde dialdehyde 6 is dropwise added, and then 160.15mg of p-toluenesulfonic acid is added; after TLC detection of reaction completion, saturated NaHCO was used₃Quenching the solution, extracting with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 2.402g of a yellow viscous compound of formula 7 with a yield of 88%;¹H NMR(400MHz,CDCl₃):δ7.41(d,J＝8.6Hz,2H)，6.87(d,J＝8.6Hz,2H)，5.51(s,1H)，4.31-4.26(m,1H)，3.76(s,3H)，3.74-3.72(m,1H)，3.69(s,3H)，2.75-2.48(m,2H)，1.72-1.35(m,4H)，0.98(t,J＝7.5Hz,3H)；¹³C NMR(100MHz,CDCl₃)：δ170.20，158.81，130.24，126.36，112.50，99.51，76.81，72.08，54.23，50.63，39.80，35.06，27.75，8.43；HRMS(ESI):m/z calcd for C₁₆H₂₂O₅Na[M+Na]⁺317.1359，found 317.1358；

(5) synthesis of Compounds of formula 8

1.7655g,6.002mmol, of the starting material of formula 7 are dissolved in 120ml of dry dichloro under nitrogen protectionIn methane, placing a reaction system at-78 ℃, cooling to-78 ℃, dropwise adding 4.8ml of 1M hexane solution of diisobutylaluminum hydride, after TLC detection reaction is completed, slowly dropwise adding 12ml of methanol, fully stirring for 10 minutes, adding 12ml of saturated sodium tartrate solution into the colorless reaction system, moving to room temperature, stirring until the solution returns to the room temperature, extracting with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 0.9627g of a colorless viscous compound of formula 8, wherein the yield is 92%;¹H NMR(400MHz,CDCl₃)：δ9.84(s,1H)，7.41(d,J＝8.6Hz,2H)，6.88(d,J＝8.6Hz,2H)，5.52(s,1H)，4.40-4.34(m,1H)，3.79(s,3H)，3.76-3.73(m,1H)，2.82-2.57(m,2H)，1.73-1.39(m,4H)，0.99(t,J＝7.5Hz,3H)；¹³C NMR(100MHz,CDCl₃)：δ199.56，158.93，130.08，126.38，112.61，99.67，76.93，70.88，54.32，48.50，35.22，27.77，8.45；HRMS(ESI):m/z calcd for C₁₅H₂₀O₄Na[M+Na]⁺287.1254，found 287.1255；

(6) synthesis of Compounds of formula 9

Under the protection of nitrogen, 7.3ml, namely 14.58mmol of dichlorodiisopropoxytitanium is dissolved in 49ml of refined toluene, the reaction system is placed at minus 78 ℃ and cooled to minus 78 ℃, and 2.57g, namely 9.72mmol of raw material formula 8 is dissolved in 21ml of refined toluene and is dripped into the reaction system; after 10min, 6.7g of 38.88mmol

Dissolving in 12ml refined toluene, adding dropwise into the reaction system, detecting by TLC after 30min, and detecting with saturated NaHCO₃Quenching the solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 2.126g of a yellow viscous compound of formula 9 with a yield of 60%;¹H NMR(400MHz,CDCl₃)：δ7.38(t,J＝8.7Hz,2H)，6.99(dt,J＝15.1,7.4Hz,1H)，6.90-6.83(m,2H)，5.90(d,J＝15.7Hz,1H)，5.48(dd,J＝14.9,7.2Hz,1H)，4.10(ddd,J＝23.5,12.9,5.3Hz,2H)，3.79(s,3H)，3.72(s,4H)，2.38(dd,J＝13.8,6.7Hz,2H)，1.78-1.43(m,6H)，0.97(t,J＝7.4Hz,3H)；¹³C NMR(100MHz,CDCl₃)：δ166.71，159.93，159.86，145.35，131.20，127.28，123.41，113.60，100.66，74.05，70.24，66.92，55.28，51.45，41.96，40.35，36.09，28.77，9.45；HRMS(ESI):m/z calcd forC₂₀H₂₈O₆Na[M+Na]⁺387.1778，found 387.1778；

(7) synthesis of Compounds of formula 10

Under the protection of nitrogen, 1.3097g of the raw material formula 9 of 3.59mmol is dissolved in 12.4ml of dry dichloromethane, the reaction system is placed in an ice-water mixture and cooled to 0 ℃, 3.13ml of N, N-diisopropylethylamine and 0.8ml of chloromethyl methyl ether are added dropwise, and then the reaction is carried out for 12h at room temperature; after TLC detection of reaction completion, saturated NaHCO was used₃Quenching the solution, extracting with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 1.35g of a yellow viscous compound of formula 10 with a yield of 92%;¹H NMR(400MHz,CDCl₃)：δ7.41(d,J＝8.7Hz,2H)，7.04-6.93(m,1H)，6.87(d,J＝8.7Hz,2H)，5.88(dd,J＝15.7,5.6Hz,1H)，5.45(s,1H)，4.74-4.61(m,2H)，4.09(td,J＝9.5,5.1Hz,1H)，4.04-3.90(m,1H)，3.78(s,3H)，3.70(s,4H)，3.37(d,J＝5.2Hz,3H)，2.62-2.33(m,2H)，1.73-1.28(m,6H)，0.98(t,J＝7.5Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ166.62，159.73，145.02，131.46，127.19，123.44，113.53，100.23，96.10，73.48，72.92，72.42，55.69，55.25，51.39，37.99，36.85，28.80，9.46；HRMS(ESI):m/z calcd for C₂₂H₃₂O₇Na[M+Na]⁺431.2040，found 431.2041；

(8) synthesis of Compounds of formula 11

Under the protection of nitrogen, 305.2mg, namely 0.75mmol of the raw material formula 10 is dissolved in 3.75ml of refined methanol, the reaction system is placed at minus 20 ℃ and cooled to minus 20 ℃, 508.7mg, namely 3.0mmol of p-toluenesulfonic acid is added for continuous reaction for 2 hours; after TLC detection of reaction completion, saturated NaHCO was used₃Quenching the solution, extracting with ethyl acetate, and mixingDrying the organic phase with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 130.162mg of a yellow viscous compound of formula 11 with a yield of 60%;¹H NMR(400MHz,CDCl₃)：δ6.92(dt,J＝15.2,7.5Hz,1H)，5.87(d,J＝15.6Hz,1H)，4.73-4.59(m,2H)，4.12-4.01(m,1H)，3.99-3.89(m,1H)，3.81-3.74(m,1H)，3.71(s,3H)，3.39(s,3H)，2.52-2.38(m,2H)，1.64-1.38(m,6H)，0.90(t,J＝7.4Hz,3H)；¹³C NMR(100MHz,CDCl₃)：δ166.60，144.66，123.60，96.59，74.10，74.05，68.99，55.88，51.44，42.51，37.97，30.68，9.61；HRMS(ESI):m/z calcd for C₁₄H₂₆O₆Na[M+Na]⁺313.1622，found 313.1619；

(9) synthesis of Compounds of formula 12

Under the protection of nitrogen, 178.9mg, namely 0.616mmol of the raw material formula 11 is dissolved in 6ml of refined toluene, the reaction system is heated and refluxed at 140 ℃, and then 425.79mg, namely 3.08mmol of potassium carbonate is added to continue the reaction for 12 hours; after TLC detection reaction is completed, cooling the reaction system to room temperature, and using saturated NH₄Quenching with Cl solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain 118.074mg of a yellow viscous compound of formula 12 with a yield of 66%;¹H NMR(400MHz,CDCl₃):δ4.68(s,2H)，3.88-3.79(m,1H)，3.79-3.70(m,2H)，3.69(s,3H)，3.66-3.57(m,1H)，3.36(s,3H)，2.62-2.40(m,2H)，1.57(dd,J＝9.1,4.7Hz,2H)，1.54-1.37(m,2H)，1.35-1.20(m,4H)，0.91(t,J＝7.5Hz,3H)；HRMS(ESI):m/z calcd for C₁₄H₂₆O₆Na[M+Na]⁺313.1622，found 313.1619；

(10) synthesis of Compounds of formula 13

51mg, i.e. 0.18mmol, of the starting material of formula 12 are dissolved in 1.8ml of tetrahydrofuran under nitrogen: methanol: water volume ratio 2: 1: 1, then adding 29.48mg of lithium hydroxide monohydrate, reacting at room temperature for 20h, then spin-drying the solvent, dissolving in water, extracting with N-pentane, combining the aqueous phases, adjusting the pH to 2.0 with 1.0N hydrochloric acid,then extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain 43.71mg of the compound shown in the formula 13 with the yield of 90%;¹H NMR(400MHz,CDCl₃)：δ4.71(s,2H)，3.90(d,J＝8.5Hz,2H)，3.83-3.73(m,1H)，3.73-3.63(m,1H)，3.39(s,3H)，2.63-2.42(m,2H)，1.67(dd,J＝18.9,8.9Hz,2H)，1.60-1.43(m,2H)，1.39-1.24(m,4H)，0.92(t,J＝7.3Hz,3H)；HRMS(ESI):m/z calcd for C₁₃H₂₄O₆Na[M+Na]⁺299.1465，found 299.1465；

(11) synthesis of Compounds of formula 14

Under the protection of nitrogen, 48.4mg, namely 0.175mmol of the raw material formula 13 is dissolved in 0.875ml of tetrahydrofuran, 36.6 mu l, namely 0.2625mmol of triethylamine and 4136.6 mu l, namely 0.2625mmol of 2,4, 6-trichlorobenzoyl chloride are added dropwise, and the mixture reacts for 3 hours at room temperature; dissolving 106.9mg, namely 0.2625mmol of 4-dimethylaminopyridine in 35ml of toluene, heating to 125 ℃ for reflux, then dropwise adding 8.75ml of toluene into the reaction system, and reacting for 12 hours; after TLC detection reaction is completed, cooling the reaction system to room temperature, and using saturated NaHCO₃Quenching the solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain 36.195mg of the compound shown in the formula 14 with the yield of 40%;¹H NMR(400MHz,CDCl₃)：δ4.83(ddd,J＝22.3,18.9,7.0Hz,2H)，4.59(s,4H)，4.25-3.36(m,6H)，3.29(t,J＝6.8Hz,3H)，2.52-2.11(m,4H)，1.92-1.05(m,16H)，0.78(dd,J＝11.6,5.8Hz,6H)；HRMS(ESI):m/z calcd for C₂₆H₄₄O₁₀Na[M+Na]⁺539.2827，found 539.2823；

(12) synthesis of Compounds of formula 15

Under nitrogen protection, 146.5mg, i.e. 0.28mmol, of the starting material of formula 14 are dissolved in 5.7ml of acetonitrile: volume ratio of water 204: 1, dropwise adding 1.42ml of 1.0M lithium tetrafluoroborate acetonitrile solution, heating the reaction system to 70 ℃, and reacting for 1 h; after TLC detection reaction is completed, cooling the reaction system to room temperature, and using saturated NaHCO₃Quenching the solution, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain the compound of formula 1577mg, yield 63%;¹H NMR(400MHz,CDCl₃)：δ5.08-4.85(m,2H)，4.04-3.60(m,4H)，3.46(t,J＝8.6Hz,2H)，2.62-2.24(m,4H)，2.06-1.37(m,16H)，0.85(t,J＝7.0Hz,6H)；HRMS(ESI):m/z calcd for C₂₂H₃₆O₈Na[M+Na]⁺451.2302，found 451.2305；

(13) synthesis of compound Cyanolide A analogue

Under nitrogen protection, 166.33mg, i.e. 0.5mmol, of the compound of formula 16, 77mg, i.e. 0.18mmol, of the compound of formula 15 and

dissolving a molecular sieve in 2.25ml of refined dichloromethane, reacting at room temperature for 30min, moving a reaction system to-78 ℃, cooling to-78 ℃, dropwise adding 4.5 mu l of 0.04mmol boron trifluoride diethyl etherate, heating to-40 ℃, and continuing to react for 2 h; then heating the reaction system to room temperature, continuing the reaction for 30min, detecting the reaction by TLC (thin layer chromatography), and using saturated NaHCO₃Quenching the solution, extracting by dichloromethane, combining organic phases, drying by anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain 15.356mg of Cyanolide A analogue with the yield of 11%;¹H NMR(400MHz,CDCl₃):δ5.11-4.80(m,2H)，4.39-4.18(m,2H)，4.03-3.86(m,2H)，3.84-3.32(m,24H)，3.23(d,J＝5.4Hz,2H)，3.07(dd,J＝13.8,8.0Hz,4H)，3.02-2.64(m,2H)，2.63-2.22(m,4H)，2.13-1.68(m,10H)，1.67-1.45(m,6H)，0.84(t,J＝7.4Hz,6H)；HRMS(ESI):m/z calcd for C₃₈H₆₄O₁₆Na[M+Na]⁺799.4087，found 799.4088。