WO2022257086A1 - 一种不对称合成(–)-鱼针草酸的方法 - Google Patents

一种不对称合成(–)-鱼针草酸的方法 Download PDF

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WO2022257086A1
WO2022257086A1 PCT/CN2021/099492 CN2021099492W WO2022257086A1 WO 2022257086 A1 WO2022257086 A1 WO 2022257086A1 CN 2021099492 W CN2021099492 W CN 2021099492W WO 2022257086 A1 WO2022257086 A1 WO 2022257086A1
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compound
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reaction
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acid
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杨震
曾耀铭
于海昕
郑楠
江崇国
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杨震
甘肃安卓幸制药有限公司
曾耀铭
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Priority to US18/565,537 priority Critical patent/US20240287013A1/en
Priority to CN202180097258.6A priority patent/CN117500794A/zh
Priority to PCT/CN2021/099492 priority patent/WO2022257086A1/zh
Priority to TW110142083A priority patent/TWI802076B/zh
Publication of WO2022257086A1 publication Critical patent/WO2022257086A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4084—Esters with hydroxyaryl compounds

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  • the invention belongs to the field of organic chemical synthesis, and relates to a method of decomposing by ozonation, Horner-Wadsworth-Emmons (Horner-Wadsworth-Emmons; HWE) reaction, Peterson (Peterson) olefination reaction, cyclization Disproportionation (ring-closing metathesis; RCM) reaction, the synthetic strategy of expanding the 14-membered macrocycle from the 10-membered ring to complete the asymmetric synthesis of (–)-Anisomelic Acid (–)-Anisomelic Acid.
  • the inventor team has been breeding "guest mocao” (Anisomeles indica O.Kuntze) for more than 20 years (GenBank: GU726292), and has continued to carry out the fish planted at Zixiu Farm, Yuli Town, Hualien County, Taiwan.
  • a series of studies on the extracts of the whole herb of the needle grass specifically the extraction, separation, purification, analysis and identification of the natural products of the hinosaurus series, as well as anti-inflammation, anti-fatigue, anti-allergy, anti-asthma, anti-influenza virus, anti-Helicobacter pylori, anti- Cancer, anti-cancer stem cells and other pharmacological effects.
  • (–)-hinoxalic acid is a valuable molecular probe that can be used to study the mechanism of anticancer bioactivity.
  • Natural (–)-Anisomelic acid ((–)-Anisomelic acid) is a natural diterpene compound extracted from Anisomeles indica O. Kuntze.
  • the content of Anisomeles indica O. Kuntze in the whole plant is generally about 70 to 100 ppm on dry weight.
  • the abundance of (–)-hinoxalic acid is low in nature, the extraction is difficult, the sources are limited, and the lack of (–)-hinthalic acid and its derivatives hinders the comprehensive biological research of anti-cancer. At present, there is no report on the total synthesis of (–)-hinoxalic acid.
  • the present invention provides a method of decomposing by ozonation, HWE reaction, Peterson olefination reaction, RCM reaction, from ten yuan Synthetic strategy of ring-expansion fourteen-membered macrocycle to complete the asymmetric synthesis of (–)-hinoxalic acid.
  • the reaction in the synthesis is simple and can be widely used, providing sufficient samples for its activity test, and laying a foundation for further realizing the structural optimization of small molecules with complex macrocyclic skeletons and developing anticancer drugs with high activity and high selectivity.
  • a method for asymmetrically synthesizing (–)-hinoxalic acid comprising the following steps:
  • each compound is shown in Figure 2, wherein, the compound 6, the compound (Z)-3, the compound (E)-3, the compound 4, the compound (E)-5 and the compound (Z)- In 5, the R group can be an alkoxy group, an aryloxy group, an alkylamino group, an aromatic amine group, an alkylmercapto group, an aromatic mercapto group, or a silicon group.
  • step 1) uses the chiral compound (–)-Costunolide as a starting material, and the method for preparing aldehyde and ketone compound 1 under the conditions of ozonolysis includes:
  • the solvent of the reaction is selected from mixed solvents, dichloromethane-methanol, dichloromethane-acetone, and dichloromethane-acetic acid to obtain compound 1.
  • the reductive quenching reagent dimethyl sulfide and triphenylphosphine can be used. If acetic acid is used as a co-solvent, in addition to adding a reducing quenching reagent, it is necessary to neutralize the acetic acid in the reaction system with saturated sodium bicarbonate solution. The reaction can also be monitored for completion using Sudan III as an indicator.
  • step 2) utilizes aldehyde and ketone compound 1 and phosphate compound 6, and the method for preparing unsaturated lactone compound (Z)-3 and unsaturated lactone compound (E)-3 under alkaline conditions includes:
  • the unsaturated lactone is ⁇ , ⁇ -unsaturated lactone
  • the alkaline substance can be sodium hexamethylsilylamide, potassium hexamethylsilylamide, lithium hexamethylsilylamide, which is not easy to A large sterically hindered basic substance that undergoes Michael reaction on the external double bond.
  • the choice of solvent, reagent, and basic substance for this reaction will affect the ratio of compound (Z)-3 and compound (E)-3.
  • step 3 utilizes the unsaturated lactone compound (Z)-3, under the 1,2-addition conditions promoted by cerium trichloride, and then the method for preparing tetraene compound 4 through elimination includes:
  • the reaction system was quenched by adding acetic acid aqueous solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, and the solvent was removed. The residue was spin-dried and dissolved in dichloromethane again, and silica gel was added to promote elimination. After stirring for 24 hours, the solvent was spin-dried, and the residue was separated by silica gel column chromatography to obtain compound 4.
  • the reagent to promote elimination can be acidic or alkaline, such as concentrated sulfuric acid and potassium tert-butoxide.
  • step 4) utilizes tetraene compound 4, and the method for preparing fourteen-membered macrocyclic compound (Z)-5 and fourteen-membered macrocyclic compound (E)-5 under olefin metathesis conditions is:
  • reaction solvent the reaction concentration, the reaction temperature, the choice of catalyst for the reaction, the compound produced by the reaction, and the reaction time have an important impact.
  • step 5 utilizes the fourteen-membered macrocyclic compound (E)-5 to prepare the natural product (–)-hinoxalic acid under the conditions of desiliconization and hydrolysis, including:
  • tetrabutylammonium fluoride hydrogen fluoride aqueous solution and the like can be selected as the desiliconization reagent.
  • step 2) prepares key intermediate compound 6 by nucleophilic substitution reaction, comprising the following steps:
  • R group can be alkoxy group, aryloxyl group, alkylamino group, aromatic amine group, alkylmercapto group, aromatic mercapto group, silicon group,
  • R group can be phenyl, trifluoroethyl.
  • the R group can be chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy.
  • step 2-1) utilizes compound 2 and compound 3, and the method for preparing phosphate ester compound 6 under alkaline conditions includes:
  • the tetrahydrofuran solution of compound 2 was cooled to 0°C, under an inert gas atmosphere, slowly added sodium hydride, an alkaline substance, and after stirring at this temperature for a period of time, the tetrahydrofuran solution of compound 3 was slowly added dropwise, and then the temperature was raised until After the reaction was complete, the reaction system was quenched with saturated ammonium chloride solution, raised to room temperature, extracted with ethyl acetate, and the organic phases were combined; dried, the solvent was removed, and the residue was purified by silica gel column chromatography to obtain compound 6.
  • the R2 group of compound 3 has a greater influence on the reaction time.
  • the above reactions need to be carried out under an inert gas atmosphere, and are all carried out under an argon atmosphere.
  • the extractions of the above reactions are all performed using ethyl acetate.
  • drying in the above steps is to dry the organic phase with anhydrous sodium sulfate, and removing the solvent is to use a rotary evaporator to remove the solvent.
  • step 1) dichloromethane-acetic acid is used as a mixed solvent, acetic acid can react with secondary ozonide, and the generated peroxide intermediate is more easily reduced to compound 1; the reductive quenching reagent is preferably selected Dimethyl sulfide, after the reaction, the product is easier to separate and purify.
  • the alkaline reagent is sodium hexamethylsilylamide, and the solvent is tetrahydrofuran, until the proportion of compound (Z)-3 is the highest.
  • the cerium trichloride is anhydrous cerium trichloride, and the cerium trichloride with crystal water needs to be ground into powder, which is also possible, but requires a better drying process and longer drying time.
  • Selecting weakly acidic silica gel as the elimination accelerator can maximize the yield of compound 4.
  • step 4 because the Hoveyda-Grubbs second generation (Hoveyda-Grubbs II) catalyst has better thermal stability, the usage amount of catalyst can be reduced.
  • the reaction concentration is controlled at about 0.005M, which can effectively avoid the formation of intermolecular olefin metathesis products.
  • the anhydrous solution of tetrabutylammonium fluoride in tetrahydrofuran can provide the highest yield.
  • the R2 group of compound 3 is iodine, which can shorten the reaction time without adding iodide as a promoter.
  • compounds 2 and 3 are known compounds, that is, compounds 2 and 3 can not be prepared by the method of the present invention, but existing compound products are used, and other compounds must be prepared by the method of the present invention.
  • the present invention starts from the ten-membered carbocyclic chiral compound (–)-wooden lactone, develops a regioselective ozonation decomposition to cut off the double bond, and then completes the extension of the carbon chain through HWE reaction and Peteson olefination,
  • the key fourteen-membered carbon ring skeleton structure of (–)-hinoxalic acid was obtained by RCM reaction, and then the total synthesis of (–)-hinoxalic acid was completed by removing the silicon group.
  • the regioselective ozonolysis reaction can greatly improve the preparation efficiency of the key intermediate compound 1, providing sufficient raw materials for subsequent synthesis.
  • a variety of derivatized products can also be made from the intermediates constructed by the RCM reaction.
  • the reaction in the synthesis is simple to operate, can be widely used, and provides sufficient samples for biological activity testing.
  • Fig. 1 shows the chemical formula of (–)-hinoxalic acid of the present invention.
  • Figure 2 shows the various compounds used or produced in the asymmetric synthesis method of the present invention.
  • Fig. 3 is the chemical formula of compound 2 and compound 3.
  • Fig. 4 is the retrosynthetic analysis process for preparing (–)-hinoxalic acid from (–)-colinolactone in the present invention.
  • Figure 5 shows the synthesis of compound 1.
  • Figure 6 is the synthesis of compound 6.
  • Fig. 7 is the synthesis of compound (Z)-3 and compound (E)-3.
  • Figure 8 is the synthesis of compound 4.
  • Fig. 9 is the synthesis of compound (Z)-5 and compound (E)-5.
  • Figure 10 shows the synthesis of the natural product (–)-hinoxalic acid.
  • the detection data of compound 1 are as follows:
  • the detection data of compound 6 are as follows:
  • the detection data of compound 4 are as follows:
  • the detection data of the natural product (–)-hinoxalic acid are as follows:

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Abstract

一种不对称合成(–)-鱼针草酸((–)-Anisomelic Acid)的方法。以商业可得的手性化合物(–)-木香烃内酯((–)-Costunolide)为起始原料，通过区域选择性的臭氧分解反应得到关键中间体，后续经霍纳尔-沃兹沃思-埃蒙斯反应(Horner–Wadsworth–Emmons；HWE)反应，皮特森(Peterson)烯化反应进行碳链的延伸，通过环合歧化(ring-closing metathesis；RCM)反应构建(–)-鱼针草酸十四元碳环骨架，为后续的(–)-鱼针草酸生物活性研究奠定的了重要的基础，在合成路线中，关键中间体也可得到多种(–)-鱼针草酸类似物，该合成路线中的反应操作简单，可广泛推广使用。

Description

一种不对称合成(–)-鱼针草酸的方法 技术领域
本发明属于有机化学合成领域，涉及一种通过臭氧化分解，霍纳尔-沃兹沃思-埃蒙斯(Horner–Wadsworth–Emmons；HWE)反应，皮特森(Peterson)烯化反应，环合歧化(ring-closing metathesis；RCM)反应，从十元环扩建十四元大环的合成策略完成不对称合成(–)-鱼针草酸((–)-Anisomelic Acid)的方法。
背景技术
全合成鱼针草酸消旋混合物((±)-Anisomelic acid)首见于1987年。在最近十年来，芬兰唯一以瑞典语教学的埃博学术大学(Abo Akademi University)研究团队以之为基础，进行了一系列鱼针草酸与其衍生物抗人类乳突病毒引起的子宫颈癌研究。
发明人团队在最近的二十余年长期进行「客人抹草」即鱼针草(Anisomeles indica O.Kuntze)的育种(GenBank:GU726292)，并持续进行台湾地区花莲县玉里镇子修农场种植的鱼针草全草萃取物的系列研究，具体执行了鱼针草系列天然物的萃取分离纯化、分析鉴定，以及抗发炎、抗疲劳、抗过敏、抗气喘、抗流感病毒、抗幽门螺旋杆菌、抗癌、抗癌干细胞等药理作用等研究。尤其，确认了鱼针草含有之天然物(–)-鱼针草酸((–)-Anisomelic Acid)结晶纯物质的立体结构，如图1，发明特征的化学式(–)-鱼针草酸所示。
综上所述，(–)-鱼针草酸是一种有价值的分子探针，可用于研究抗癌生物活性机制。
天然物(–)-鱼针草酸((–)-Anisomelic acid)是提取自鱼针草(Anisomeles indica O.Kuntze)的天然双萜化合物，鱼针草酸在鱼针草全植株中的含量一般约为干重的70至100ppm。显然，(–)-鱼针草酸在自然界中丰度较低，提取困难，来源受限，缺乏(–)-鱼针草酸和其衍生物阻碍了抗癌的全面生物学研究。目前，尚未有对(–)-鱼针草酸的全合成报导。
发明内容
为了推动(–)-鱼针草酸((–)-Anisomelic Acid)对抗癌的全面生物学研究，本发明提供一种通过臭氧化分解，HWE反应，Peterson烯化反应，RCM反应，从十元环扩建十四元大环的合成策略完成不对称合成(–)-鱼针草酸的方法。合成中的反应操作简单，可广泛推广使用，为其活性测试提供充足的样品，并为进一步实现复杂大环骨架小分子的结构优化、发展高活性和高选择性的抗癌药物奠定基础。
所述的鱼针草酸的化学式如下所示：
Figure PCTCN2021099492-appb-000001
为了实现上述目的，本发明采用以下技术方案：
一种不对称合成(–)-鱼针草酸的方法，包括以下步骤：
1)利用手性化合物(–)-木香烃内酯((–)-Costunolide)为起始原料，在臭氧化分解的条件下制备醛酮化合物1；
2)利用该醛酮化合物1和化合物6，在碱性条件下制备不饱和内酯化合物(Z)-3和不饱和内酯化合物(E)-3；
3)利用该不饱和内酯化合物(Z)-3，在三氯化铈促进的1，2-加成条件下，随后经过消除制备四烯化合物4；
4)利用该四烯化合物4，于烯烃复分解条件下制备十四元大环的化合物(Z)-5和一十四元大环的化合物(E)-5；
5)利用该十四元大环的化合物(E)-5，在脱出硅基及水解的条件下制备天然产物(–)-鱼针草酸((–)-Anisomelic Acid)。
各化合物的化学式如图2所示，其中，该化合物6、该化合物(Z)-3、该化合物(E)-3、该化合物4、该化合物(E)-5及该化合物(Z)-5中，R基团可以是烷氧基，芳香氧基，烷胺基，芳香胺基，烷巯基，芳香巯基，硅基。
进一步地，步骤1)利用手性化合物(–)-Costunolide为起始原料，在臭氧化分解的条件下制备醛酮化合物1的方法包括：
化合物(–)-木香烃内酯的溶液在-78℃通入臭氧，薄层色谱监测反应，在反应结束后加入还原性试剂二甲硫醚淬灭反应，反应体系升至室温后，除去溶剂，剩余物使用硅胶柱色谱纯化，得到化合物1。
其中，该反应的溶剂选择混合溶剂、二氯甲烷-甲醇、二氯甲烷-丙酮、二氯甲烷-乙酸均可以得到化合物1。还原性淬灭试剂可以使用二甲硫醚、三苯基膦。如果使用乙酸作为共溶剂，除了加入还原性淬灭试剂后，需要用饱和的碳酸氢钠溶液中和反应体系内的乙酸。该反应也可以是用苏丹III作为指示剂来监测反应是否完成。
进一步地，步骤2)利用醛酮化合物1和磷酸酯化合物6，在碱性条件下制备不饱和内酯化合物(Z)-3和不饱和内酯化合物(E)-3的方法包括：
在-78℃下，向化合物6的四氢呋喃溶液中以滴加的方式加入碱性物质，并在该温度下搅拌30分钟后，加入化合物1的四氢呋喃溶液，反应结束后加入淬灭剂，剩余物使用硅胶柱色谱纯化，得到化合物(Z)-3和化合物(E)-3。
其中，该不饱和内酯为α,β-不饱和内酯，该碱性物质可以选择六甲基硅基氨基钠，六甲基硅基氨基钾，六甲基硅基氨基锂，不易对环外双键发生麦可加成(Michael reaction)的大位阻碱性物质。该反应的溶剂，试剂，以及碱性物质的选择会对化合物(Z)-3和化合物(E)-3的比例产生影响。
进一步地，步骤3)利用不饱和内酯化合物(Z)-3，在三氯化铈促进的1，2-加成条件下，随后经过消除制备四烯化合物4的方法包括：
将三氯化铈加入圆底瓶中，真空条件下加热至135～150℃，并搅拌一定时间(如3小时)，充入惰性气体，将反应体系移至冰水浴中，加入四氢呋喃，后升至室温搅拌一定时间(如12小时)，将上述反应体系降至-78～-80℃，滴加三甲基硅基甲基锂试剂的正戊烷溶液，并保持相同温度继续搅拌一定时间(如1.5小时)，之后向上述反应体系中加入化合物(Z)-3，在-78～-80℃条件下搅拌一定时间(如1.5小时)。反应体系通过加入乙酸水溶液淬灭反应，分液，水相用乙酸乙酯萃取。合并有机相，干燥，除去溶剂，剩余物旋干后再次溶解于二氯甲烷，加入硅胶促进消除，搅拌24小时后，旋干溶剂，残留物经过硅胶柱层析色谱分离，得到化合物4。
其中，三氯化铈的质量对反应有着极其重要的影响。促进消除的试剂可以是酸性物质，亦可以是碱性物质，如浓硫酸，叔丁醇钾均可。
进一步地，步骤4)利用四烯化合物4，烯烃复分解条件下制备十四元大环的化合物(Z)-5和十四元大环的化合物(E)-5的方法是：
四烯化合物4的溶液加入烯烃复分解催化剂后，于惰性气体气氛下排出反应体系内残留的氧气一段时间，随后将反应体系升温至60℃，直到四烯化合物4转化完全，除去溶剂，剩余物使用硅胶柱色谱纯化，得到十四元大环的化合物(Z)-5和十四元大环的化合物(E)-5。
其中，反应溶剂，反应浓度，反应温度，反应的催化剂选择，对该反应生成的化合物，以及反应时间有着重要的影响。
进一步地，步骤5)利用十四元大环的化合物(E)-5，在脱出硅基及水解的条件下制备天然产物(–)-鱼针草酸的方法包括：
十四元大环的化合物(E)-5的四氢呋喃溶液，冷却至0℃，滴加脱硅试剂四丁基氟化铵溶液，在该温度下反应1个小时，反应体系用饱和氯化铵溶液淬灭，升至室温后，用乙酸乙酯萃取，合并有机相；干燥，除去溶剂，剩余物使用硅胶柱色谱纯化，得到天然产物(–)-鱼针草酸。
其中，脱硅试剂可以选择四丁基氟化铵、氟化氢水溶液等。
进一步地，步骤2)通过亲核取代反应制备关键中间体化合物6，包括以下步骤：
2-1)利用化合物2和化合物3，在碱性条件下制备磷酸酯化合物6；
化合物2和化合物3的化学式如图3所示，其中，化合物2中，R 1基团可以是烷氧基、芳香氧基、烷胺基、芳香胺基、烷巯基、芳香巯基、硅基，R 3基团可以是苯基、三氟乙基。
其中，化合物3中，R 2基团可以是氯、溴、碘、甲磺酰氧基、对甲苯磺酰氧基、三氟甲磺酰氧基。
进一步地，步骤2-1)利用化合物2和化合物3，在碱性条件下制备磷酸酯化合物6的方法包括：
化合物2的四氢呋喃溶液冷却到0℃，于惰性气体氛围下，缓慢加入碱性物质氢化钠，在该温度下搅拌一段时间后，缓慢以滴加的方式加入化合物3的四氢呋喃溶液，随后升温，直到反应完全后，反应体系用饱和氯化铵溶液淬灭，升至室温后，用乙酸乙酯萃取，合并有机相；干燥，除去溶剂，剩余物使用硅胶柱色谱纯化，得到化合物6。
其中，化合物3的R 2基团对反应时间影响较大。
优选地，以上反应需要惰性气体氛围下，均是在氩气气氛下进行的。
优选地，以上反应的萃取均是使用乙酸乙酯完成的。
优选地，以上步骤中干燥是用无水硫酸钠干燥有机相，除去溶剂是使用旋转蒸发仪除去溶剂。
优选地，步骤1)中，使用二氯甲烷-乙酸作为混合溶剂，乙酸可以于二级臭氧化物发生反应，生成的过氧化物中间体更容易被还原为化合物1；还原性淬灭试剂优先选用二甲硫醚，反应后，产物较易分离纯化。
优选地，步骤2)中，碱性试剂选用六甲基硅基氨基钠，溶剂选用四氢呋喃，等到化合物(Z)-3的比例最高。
优选地，步骤3)中，三氯化铈为无水三氯化铈，带有结晶水的三氯化铈需要研磨成粉末，也是可以的，但是需要更优的干燥工艺以及更长的干燥时间。选择弱酸性的硅胶作为消除促进剂，能使化合物4的产率最高。
优选地，步骤4)中，由于Hoveyda-Grubbs二代(Hoveyda-Grubbs II)催化剂具有更好的热稳定性，可以降低催化剂的使用量。该反应浓度控制在0.005M左右，能够有效的避免分子间的烯烃复分解产物生成。
优选地，步骤5)中，无水的四丁基氟化铵的四氢呋喃溶液，能够提供最高的产率。
优选地，步骤2-1)中，化合物3的R 2基团为碘，可以缩短反应时间，不必添加碘化物作为促进剂。
本发明中，化合物2、3为已知化合物，即化合物2和3可以不采用本发明的方法制备，而采用现有的化合物产品，其他化合物须通过本发明的方法来制备。
本发明的技术效果如下：
上述(–)-鱼针草酸的不对称全合成是通过臭氧化分解手性化合物(–)-木香烃内酯，随后经碳链的延伸，经RCM反应的合成策略构建十四元大环骨架而实现的，即本发明的基础是由(–)-木香烃内酯制备(–)-鱼针草酸，如图4所示。
本发明从十元碳环的手性化合物(–)-木香烃内酯出发，发展了一种区域选择性臭氧化分解切断双键，随后经HWE反应和Peteson烯化完成碳链的延伸，通过RCM反应得到(–)-鱼针草酸的关键十四元碳环骨架结构，进而通过脱出硅基完成(–)-鱼针草酸的全合成。在(–)-鱼针草酸的合成中，通过区域选择性的臭氧化分解反应可极大提高关键中间体化合物1的制备效率，为后续合成提供充足的原料。同时，通过RCM反应构建的中间体也可做出多种衍生化产物。同时，该合成中的反应操作简单，可广泛推广使用，为生物活性测试提供足量的样品。
附图说明
图1所示为本发明的(–)-鱼针草酸的化学式。
图2所示为本发明的不对称合成方法中所使用或产生的各化合物。
图3为化合物2和化合物3的化学式。
图4为本发明由(–)-木香烃内酯制备(–)-鱼针草酸的逆合成分析流程。
图5为化合物1的合成。
图6为化合物6的合成。
图7为化合物(Z)-3和化合物(E)-3的合成。
图8为化合物4的合成。
图9为化合物(Z)-5和化合物(E)-5的合成。
图10为天然产物(–)-鱼针草酸的合成。
具体实施方式
以下通过具体的实施例进一步说明本发明的技术方案，具体实施例不代表对本发明保护范围的限制。其他人根据本发明理念所做出的一些非本质的修改和调整仍属于本发明的保护范围。
实施例1 化合物1的合成
如图5所示。
将(–)-木香烃内酯(800mg，3.54mmol)溶解在含乙酸(25mL，10％v/v)的二氯甲烷(250mL)中，并将所得混合物冷却至-78℃，将臭氧小心地通入到反应体系中，并通过薄层色谱监控反应过程，直到(–)-木香烃内酯完全消耗。加入二甲基硫醚(1.0mL)，并将混合 物缓慢升到室温，将饱和碳酸氢钠溶液(200mL)缓慢的加入到反应体系中，然后将混合物用乙酸乙酯(3×200mL)萃取。合并的有机相用饱和食盐水(300mL)洗涤，并经硫酸钠干燥。真空除去溶剂，并将残余物通过硅胶柱色谱纯化(石油醚：乙酸乙酯＝8∶1至4∶1)，得到无色油状化合物1(773mg，85％产率)。
化合物1的检测数据如下：
R f＝0.25(乙酸乙酯/石油醚＝1/1)。
Figure PCTCN2021099492-appb-000002
1H NMR(400MHz,CDCl 3)δ9.75(s,1H),6.24(d,J＝2.8Hz,1H),5.57(d,J＝2.5Hz,1H),5.17(d,J＝8.3Hz,1H),4.75(dd,J＝8.9,6.1Hz,1H),2.72(dt,J＝8.3,5.8Hz,1H),2.57-2.37(m,5H),2.19-2.06(m,4H),1.95(dt,J＝13.7,7.4Hz,1H),1.85-1.75(m,4H)。
13C NMR(101MHz,CDCl 3)δ207.29,201.26,170.00,142.50,138.76,123.25,122.02,79.36,45.06,41.53,39.69,31.39,30.07,25.66,17.17。
IR ν max(film):2949,2730,1726,1684,1450,1389,1250,1189,737cm -1。
HRMS(ESI)m/z:C 15H 20NaO 4[M+Na] +:计算值：287.1254；实测值：287.1248。
实施例2 化合物6的合成
如图6所示。
化合物2(5.0g，12.7mmol)溶解在四氢呋喃(350mL)中，0℃下向搅拌溶液中分批加入氢化钠(60％在矿物油中的分散体，720mg)，有气泡产生，将混合物在室温下再搅拌1小时，向反应体系内缓慢滴加化合物3(3.9g，21.6mmol)的四氢呋喃(10mL)溶液，然后将混合物加热至60℃48小时。通过薄层色谱监测完成后，向反应体系内缓慢的加入饱和氯化铵溶液(200mL)淬灭反应，然后将混合物用乙酸乙酯(3×150mL)萃取。合并的有机萃取物用饱和食盐水(500mL)洗涤，并经硫酸钠干燥。真空浓缩溶剂，并将残余物通过硅胶柱层析色谱纯化(石油醚：乙酸乙酯＝20∶1)，得到无色油状化合物6，(4.7g，83％产率)。
化合物6的检测数据如下：
R f＝0.5(乙酸乙酯/石油醚＝1/10)。
1H NMR(500MHz,CDCl 3)δ7.31(dd,J＝14.9,7.4Hz,4H),7.18(dd,J＝13.6,6.4Hz,6H),5.77(ddt,J＝12.6,10.2,6.2Hz,1H),5.06(dd,J＝13.7,7.1Hz,2H),4.31-4.21(m,2H),3.31(ddd,J＝23.1,10.5,2.8Hz,1H),2.39-2.08(m,4H),1.06-0.95(m,2H),0.04(d,J＝0.6Hz,9H)。
13C NMR(126MHz,CDCl 3)δ168.34,136.49,129.85,125.46,120.66,116.68,115.50,64.38,45.88,44.82,32.34,32.21,26.27,26.23,17.50,-1.45。
IR ν max(film):3442,2920,1696,1415,1257,1230,861cm -1。
HRMS(ESI)m/z:C 23H 31NaO 5PSi[M+Na] +:计算值：496.1571；实测值：496.1571。
实施例3 化合物(Z)-3和化合物(E)-3的合成
如图7所示。
将化合物6(1.0g，2.27mmol)溶解在四氢呋喃(100mL)中，在-78℃下向反应体系内缓慢滴加六甲基硅基氨基钠溶液(1.0mL，2.0M的THF溶液)，滴加完毕后，继续在-78℃下搅拌1小时，然后逐滴加入溶于THF(20mL)中的化合物1(500mg，1.89mmol)，反应30分钟后，通过薄层色谱监测反应过程，向反应体系内加入饱和氯化铵溶液(100mL)淬灭反应，然后将混合物用乙酸乙酯(3×150mL)萃取。合并的有机相用饱和食盐水(500mL)洗涤，并用硫酸钠干燥。真空浓缩溶剂，并将残余物通过硅胶柱层析色谱纯化(石油醚：乙酸乙酯＝8∶1)，得到无色油状化合物(Z)-3(514mg，59％产率)和无色油状化合物(E)-3(201mg，产率23％)。
化合物(Z)-3的检测数据如下：
R f＝0.4(乙酸乙酯/石油醚＝1/1)。
Figure PCTCN2021099492-appb-000003
1H NMR(500MHz,CDCl 3)δ6.28(d,J＝2.9Hz,1H),5.82-5.72(m,2H),5.58(d,J＝2.5Hz,1H),5.20(dd,J＝9.1,1.2Hz,1H),5.03-4.93(m,2H),4.80(dd,J＝9.1,5.9Hz,1H),4.25-4.19(m,2H),2.78-2.71(m,1H),2.58(dd,J＝15.2,7.4Hz,2H),2.50(t,J＝7.6Hz,2H),2.35-2.30(m,2H),2.20-2.13(m,7H),1.98(ddd,J＝14.0,7.4,6.0Hz,1H),1.84(td,J＝14.4,7.7Hz,1H),1.78(d,J＝1.3Hz,3H),1.06-1.01(m,2H),0.05(s,9H)。
13C NMR(126MHz,CDCl 3)δ207.06,167.97,143.67,140.51,138.92,137.80,132.35,122.89,121.85,115.09,79.54,62.46,45.14,39.66,39.06,34.00,33.36,30.08,27.43,25.76,17.53,16.99,-1.47ppm。
IR ν max(film):3310.2926,2375,1507,1262,1019,1011,851,837,799cm -1。
HRMS(ESI)m/z:C 26H 40NaO 5Si[M+Na] +:计算值：483.2537；实测值：483.2537。
化合物(E)-3的检测数据如下：
R f＝0.35(乙酸乙酯/石油醚＝1/1)。
Figure PCTCN2021099492-appb-000004
1H NMR(500MHz,CDCl 3)δ6.70(t,J＝7.3Hz,1H),6.29(d,J＝2.9Hz,1H),5.80(ddt,J＝17.0,10.1,6.8Hz,1H),5.59(d,J＝2.5Hz,1H),5.22(dd,J＝9.0,1.2Hz,1H),5.05-4.93(m,2H),4.80(dd,J＝9.0,5.9Hz,1H),4.26-4.18(m,2H),2.83-2.69(m,1H),2.57- 2.43(m,2H),2.42-2.35(m,2H),2.31(dd,J＝15.2,7.5Hz,2H),2.21-2.12(m,7H),2.03-1.92(m,1H),1.86(tt,J＝14.4,7.2Hz,1H),1.80(d,J＝1.2Hz,3H),1.02(ddd,J＝10.5,7.2,3.8Hz,2H),0.05(s,9H)。
13C NMR(126MHz,CDCl 3)δ207.06,169.98,167.78,143.20,141.06,138.82,137.91,132.59,123.21,121.97,115.12,79.41,62.76,45.13,39.67,38.47,33.37,30.06,26.66,26.46,25.77,17.42,17.06,-1.44。
IR ν max(film):3440,3310,2926,2375,1262,1250,1019,1011,861,837,799cm -1。
HRMS(ESI)m/z:C 26H 40NaO 5Si[M+Na] +:计算值：483.2537；实测值：483.2539。
实施例4 化合物4的合成
如图8所示。
将无水三氯化铈(493mg,2.0mmol)加入圆底瓶中，抽真空条件下加热至150℃，并搅拌3小时，充入氩气，将体系移至0℃冰浴中，加入四氢呋喃(5mL)，后升至室温搅拌24小时以上。将上述体系降至-78℃，滴加三甲基硅基甲基锂(1.5mL，1.5mmol，1.0M的正戊烷溶液)，并保持相同温度继续搅拌1小时，之后向上述体系中加入化合物(Z)-3(460mg，1.0mmol，在2.0mL四氢呋喃中)，-78℃搅拌1小时。薄层色谱检测反应完成，加入10％乙酸水溶液(10mL)淬灭，分液，水相用二氯甲烷萃取，合并有机相，干燥，减压除去溶剂。将残留物重新溶解于二氯甲烷(5.0mL)中，加入硅胶(2.4g，500％w/w)，搅拌24小时后，减压除去溶剂，残留的硅胶经柱色谱分离(石油醚/乙酸乙酯＝20:1)得无色油状化合物4(341mg，75％产率)。
化合物4的检测数据如下：
R f＝0.5(乙酸乙酯/石油醚＝1/10)。
Figure PCTCN2021099492-appb-000005
1H NMR(500MHz,CDCl 3)δ6.26(d,J＝2.8Hz,1H),5.82-5.70(m,2H),5.57(d,J＝2.5Hz,1H),5.22(dd,J＝9.1,0.8Hz,1H),5.04-4.92(m,2H),4.84(dd,J＝9.1,5.7Hz,1H),4.76(s,1H),4.68(s,1H),4.25-4.19(m,2H),2.74-2.67(m,1H),2.57(dd,J＝15.1,7.4Hz,2H),2.34-2.27(m,2H),2.19-2.12(m,4H),2.05(t,J＝7.9Hz,2H),1.86-1.75(m,4H),1.75-1.62(m,4H),1.10-0.96(m,2H),0.05(s,9H)。
13C NMR(126MHz,CDCl 3)δ170.31,167.99,144.37,142.94,140.58,139.42,137.81,132.27,123.19,121.50,115.06,110.96,79.85,62.44,45.48,39.05,34.37,34.02,33.38,30.77,27.36,22.41,17.52,16.92,-1.47。
IR ν max(film):2845,2410,1825,1260,1176,1132,1114,1012,934,857,835,797cm - 1。
HRMS(ESI)m/z:C 27H 42NaO 4Si[M+Na] +:计算值：481.2745；实测值：481.2743。
实施例5 化合物(Z)-5和化合物(E)-5的合成
如图9所示。
将化合物4(100mg，0.22mmol)溶于二氯甲烷(1.0L)中，室温下加入Hoveyda-Grubbs二代催化剂(6.8mg，0.01mmol)。随后，向反应体系内通入氩气，持续30分钟。置换反应体系内气体后，升温至60℃，搅拌48小时。薄层色谱检测反应完成，直接减压除去溶剂。残留物经硅胶柱色谱分离(石油醚/乙酸乙酯＝10:1)得无色油状化合物(E)-5(65mg，69％产率)和无色油状化合物(Z)-5(13mg，14％产率)。
化合物(E)-5的检测数据如下：
R f＝0.35(乙酸乙酯/石油醚＝1/10)。
Figure PCTCN2021099492-appb-000006
1H NMR(400MHz,CDCl 3)δ6.24(d,J＝2.6Hz,1H),5.64(t,J＝6.6Hz,1H),5.57(d,J＝2.3Hz,1H),5.21-5.15(m,1H),5.05-4.96(m,1H),4.88(dd,J＝9.7,4.0Hz,1H),4.23(ddd,J＝8.0,5.0,1.3Hz,2H),2.86-2.73(m,1H),2.71-2.56(m,2H),2.47(dd,J＝13.1,6.6Hz,1H),2.32-2.02(m,7H),1.78(d,J＝1.0Hz,3H),1.76-1.67(m,2H),1.59(s,3H),1.07-0.99(m,2H),0.05(s,9H)。
13C NMR(101MHz,CDCl 3)δ170.58,168.13,142.21,141.22,140.76,132.19,131.00,125.61,124.18,121.66,79.17,62.52,43.04,38.49,36.18,34.71,32.30,25.71,25.13,17.67,16.59,15.76,-1.40。
HRMS(ESI)m/z:C 25H 38NaO 4Si[M+Na] +:计算值：453.2432；实测值：453.2430。
化合物(Z)-5的检测数据如下：
R f＝0.25(乙酸乙酯/石油醚＝1/10)。
Figure PCTCN2021099492-appb-000007
1H NMR(400MHz,CDCl 3)δ6.23(d,J＝3.2Hz,1H),5.75(dd,J＝10.1,4.2Hz,1H),5.55(d,J＝2.9Hz,1H),5.30(d,J＝8.9Hz,1H),5.21(t,J＝7.9Hz,1H),4.73(t,J＝8.6Hz,1H),4.22-4.15(m,2H),3.14-2.99(m,1H),2.69(dd,J＝8.1,3.3Hz,1H),2.59-2.50(m,1H),2.38-2.19(m,5H),2.13-2.03(m,3H),1.98-1.92(m,1H),1.81(s,4H),1.68(s,3H),1.03(dd,J＝9.9,7.6Hz,2H),0.06(s,9H)。
13C NMR(101MHz,CDCl 3)δ170.50,168.19,145.53,141.93,140.27,135.90,134.14,125.10,123.71,120.34,80.01,62.49,47.17,39.17,35.26,30.28,29.93,29.71,25.84,23.00,17.73,16.43,-1.38。
HRMS(ESI)m/z:C 25H 38NaO 4Si[M+Na] +:计算值：453.2432；实测值：453.2430。
实施例6 天然产物(–)-鱼针草酸((–)-Anisomelic Acid)的合成
如图10所示。
将化合物(E)-5(50mg，0.12mmol)溶于四氢呋喃(5mL)中，0℃加入四丁基氟化铵溶液(0.17mL，0.17mmol，1.0M的四氢呋喃溶液)，搅拌1小时后，薄层色谱检测反应完成，向反应体系内加入饱和氯化铵溶液(10mL)淬灭反应，然后将混合物用乙酸乙酯(3×5mL)萃取。合并的有机相用饱和食盐水(10mL)洗涤，并用硫酸钠干燥。真空浓缩溶剂，并将残余物通过硅胶柱层析色谱纯化(石油醚：乙酸乙酯＝4∶1)。
天然产物(–)-鱼针草酸的检测数据如下：
R f＝0.3(乙酸乙酯/石油醚＝1/2)。
Figure PCTCN2021099492-appb-000008
1H NMR(500MHz,CDCl 3)δ6.25(d,J＝2.6Hz,1H),5.88(t,J＝6.5Hz,1H),5.59(d,J＝2.3Hz,1H),5.18(d,J＝9.6Hz,1H),4.99(d,J＝5.3Hz,1H),4.88(dd,J＝9.6,4.2Hz,1H),2.88(ddd,J＝21.6,14.2,7.1Hz,1H),2.77-2.64(m,2H),2.50(t,J＝13.4Hz,1H),2.36-2.16(m,6H),2.11-2.02(m,1H),1.78(d,J＝0.8Hz,1H),1.76-1.63(m,2H),1.60(s,3H)。
13C NMR(126MHz,CDCl 3)δ173.11,170.62,146.93,141.15,140.66,132.52,129.68,125.36,124.36,121.77,79.16,43.07,38.46,36.18,34.44,32.21,26.16,25.08,16.64,15.83。
HRMS(ESI)m/z:C 20H 26NaO 4[M+Na] +:计算值：353.1723；实测值：353.1723。
以上所述实施例的各技术特征可以进行任意合适方式的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅描述了本发明的几种实施方式，便于具体和详细理解本发明的技术方案，但并不能因此而理解为对发明保护范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。应当理解，本领域技术人员在本发明提供的技术方案的基础上，通过合乎逻辑的分析、推理或者有限的试验得到的技术方案，均在本发明所述权利要求的保护范围内。

Claims (8)

  1. 一种不对称合成(–)-鱼针草酸((–)-Anisomelic Acid)的方法，其特征在于，包括：
    1)利用手性化合物(–)-木香烃内酯((–)-Costunolide)为起始原料，在臭氧化分解的条件下制备醛酮化合物1；
    2)利用所述醛酮化合物1和磷酸酯化合物6，在碱性条件下制备不饱和内酯化合物(Z)-3和不饱和内酯化合物(E)-3；
    3)利用所述不饱和内酯化合物(Z)-3，在三氯化铈促进的1，2-加成条件下，随后经过消除制备四烯化合物4；
    4)利用所述四烯化合物4，于烯烃复分解条件下制备十四元大环的化合物(Z)-5和十四元大环的化合物(E)-5；以及
    5)利用所述十四元大环的化合物(E)-5，在脱出硅基及水解的条件下制备天然产物(–)-鱼针草酸；
    其中，各化合物的化学式如下所示：
    Figure PCTCN2021099492-appb-100001
    且其中，所述化合物6、所述化合物(Z)-3、所述化合物(E)-3、所述化合物4、所述化合物(E)-5及所述化合物(Z)-5中，R基团可以是烷氧基、芳香氧基、烷胺基、芳香胺基、烷巯基、芳香巯基、或硅基。
  2. 如权利要求1所述的方法，其特征在于，所述步骤1)臭氧化分解的方法包括：所述化合物(–)-木香烃内酯的溶液在低温下通入臭氧，在反应结束后加入还原性试剂淬灭反应，反 应体系升至室温后，除去溶剂，剩余物使用硅胶柱色谱纯化，得到所述化合物1。
  3. 如权利要求1所述的方法，其特征在于，所述步骤2)的方法包括：所述化合物6的溶液中于低温下下加入碱性物质，随后，加入所述化合物1的溶液，反应结束后加入淬灭剂，剩余物使用硅胶柱色谱纯化，得到所述化合物(Z)-3和所述化合物(E)-3。
  4. 如权利要求1所述的方法，其特征在于，所述步骤3)的方法包括：将三氯化铈加入圆底瓶中，真空条件下加热，并搅拌一定时间，充入惰性气体，将反应体系移至冰水浴中，加入四氢呋喃，后升至室温搅拌一定时间；在低温下加入锂试剂，并保持相同温度继续搅拌一定时间，之后向反应体系中加入所述化合物(Z)-3，在相同的温度下继续搅拌一定时间；反应体系通过加入乙酸水溶液淬灭反应，分液，水相用乙酸乙酯萃取；合并有机相，干燥，除去溶剂，随后在剩余物中加入促进消除的试剂，最终使用硅胶柱色谱纯化，得到所述四烯化合物4。
  5. 如权利要求1所述的方法，其特征在于，所述步骤4)的方法包括：所述四烯化合物4的溶液加入烯烃复分解催化剂后，于惰性气体气氛下排出反应体系内残留的氧气一段时间，随后将反应体系升温，直到所述四烯化合物4转化完全，除去溶剂，剩余物使用硅胶柱色谱纯化，得到所述十四元大环的化合物(Z)-5和所述十四元大环的化合物(E)-5。
  6. 如权利要求1所述的方法，其特征在于，所述步骤5)的方法包括：所述十四元大环的化合物(E)-5的溶液，冷却至0℃，滴加脱硅试剂，在所述温度下反应1个小时，反应体系用饱和氯化铵溶液淬灭，升至室温后，用乙酸乙酯萃取，合并有机相；干燥，除去溶剂，剩余物使用硅胶柱色谱纯化，得到所述天然产物(–)-鱼针草酸。
  7. 如权利要求1所述的方法，其特征在于，所述步骤2)进一步包括以下步骤：
    2-1)利用所述化合物2和所述化合物3，在碱性条件下制备所述磷酸酯化合物6；
    其中，所述化合物2及所述化合物3的化学式如下所示：
    Figure PCTCN2021099492-appb-100002
    其中，所述化合物2中，R 1基团可以是烷氧基、芳香氧基、烷胺基、芳香胺基、烷巯基、芳香巯基、或硅基；R 3基团可以是苯基或三氟乙基；且
    其中，所述化合物3中，R 2基团可以是氯、溴、碘、甲磺酰氧基、对甲苯磺酰氧基、或三氟甲磺酰氧基。
  8. 如权利要求7所述的方法，其特征在于，所述步骤2-1)的方法包括：所述化合物2的溶液冷却到0℃，于惰性气体氛围下，缓慢加入碱性物质，在所述温度下搅拌一段时间后，缓慢以滴加的方式加入所述化合物3的溶液，随后升温，直到反应完全后，反应体 系用饱和氯化铵溶液淬灭，升至室温后，用乙酸乙酯萃取，合并有机相；干燥，除去溶剂，剩余物使用硅胶柱色谱纯化，得到所述磷酸酯化合物6。
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