CN110724043B - 一种抗疟疾药物watsonianones A的合成方法 - Google Patents

一种抗疟疾药物watsonianones A的合成方法 Download PDF

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CN110724043B
CN110724043B CN201910953896.8A CN201910953896A CN110724043B CN 110724043 B CN110724043 B CN 110724043B CN 201910953896 A CN201910953896 A CN 201910953896A CN 110724043 B CN110724043 B CN 110724043B
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谭海波
杨松光
张晓�
吴贵云
刘洪新
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Guangdong Jingzhong Biotechnology Co ltd
South China Botanical Garden of CAS
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Abstract

本发明公开了一种抗疟疾药物watsonianones A的合成方法。它是将syncarpic acid与异戊醛通过脯氨酸催化的Knoevenagel反应获得前体化合物4，再将化合物4与syncarpic acid发生脯氨酸催化的Michael加成反应，得到产物watsonianone A。本发明成功地完成了watsonianone A(1)的首次全合成，并为该类化合物的快速合成提供了简明的合成策略，并为快速获得该生物活性分子和结构衍生物提供了前提保障。

Description

一种抗疟疾药物watsonianones A的合成方法
技术领域
本发明属于合成药物化学领域，具体涉及watsonianones A及其类似物的制备方法。
背景技术
间苯三酚类化合物结构的复杂、新颖多样性及其广谱而显著的生物活性，近年来引起了合成与药物化学家们广泛的关注。Watsonianone A(1)(参见文献：Watsonianone A–C,anti-plasmodialβ-triketones from the Australian tree,Corymbiawatsoniana.Org.Biomol.Chem.,2013,11,453-458)是从桃金娘科香桃木属Orymbiawatsoniana中分离发现的新颖复杂间苯三酚类化合物，抗疟疾活性评价表明它具有非常良好的抗疟疾活性，特别是针对氯喹啉具有耐药性的Dd2和敏感性3D7疟原虫Plasmodiumfalciparum，其IC50值低达5.3umol/mL。此外，watsonianone A(1)抗疟疾活性相较正常的人体细胞毒性，具有高达100倍的选择性因子，因而具有非常明朗的成药性应用前景，被认为是开发新型抗癌新药的重要先导化合物。尽管这个化合物具有非常新颖的结构和突出的生物活性，然后它们在自然界中含量非常的稀少，难以通过分离进行大量的获取，当前也没有任何化学全合成的相关报道。因而本专利是抗疟疾化合物watsonianone A(1)的首次合成报道。
发明内容:
本发明的目的是提供一种具有显著的抗疟疾化合物Watsonianone A(1)的化学合成制备方法。
本专利通过分析watsonianone A(1)的结构特征，首次提出了它们的仿生合成途径(如式2所示)。基于该仿生合成设想，并成功地设计和实现了一条高效的合成策略，用于watsonianone A(1)骨架的快速构建和结构类似物的简洁合成。该合成策略包括两个主要的关键反应，即有机小分子催化的Knoevenagel缩合和Michael加成反应。在前述的合成分析中，watsonianone A(1)可以经过有机小分子催化的Michael加成反应逆推到关键的α,β-不饱和中间体4，关键中间体4则可以通过有机小分子催化的Knoevenagel缩合由前体化合物2和3快速得到。此外，介于有机小分子催化的Knoevenagel缩合和Michael加成反应都可以由脯氨酸作为催化剂进行催化；因而本发明设想，watsonianone A(1)可能经过脯氨酸催化的Knoevenagel缩合/Michael加成反应的仿生串联反应，一步就能快速合成。基于上述的合成设想，本专利开展了watsonianone A(1)的全合成探索，并首次成功地实现了watsonianone A(1)的仿生全合成，进而为大量便捷地获取watsonianone A(1)及其类似物以进行后续的构效关系、成药性开发和生产，提供了一种高效可靠、经济的制备方法。
本发明专利使用简洁明了的合成策略，实现了watsonianone A(1)的首次全合成。整个全合成过程中使用乙酰间苯三酚5作为起始原料商业可得并且价格低廉，反应条件温和同时操作简单，合成路线便于该类化合物快速大量的制备。首先，关键前体syncarpicacid 2的获得，即先是发生选择性的碳甲基化反应，然后是一个热促进逆Friedel Crafts酰化反应。
随后，syncarpic acid 2与过量的异戊醛3通过脯氨酸催化的Knoevenagel反应，缩合以直接安装上异戊基链，获得共同的前体化合物4，该合成步骤产率超过90％。最后，syncapic acid 2与关键共同前体化合物4发生脯氨酸催化的Michael加成反应，最终以高产率进一步转化成目标产物watsonianone A(1)。
此外，本课题还进行了不同催化缩合条件的探索，旨在通过一步反应就实现syncarpic acid 2和异戊醛3直接缩合，进而转化为watsonianone A(1)。令人满意的是，当使用稍微过量的syncarpic acid 2与异戊醛3作为反应条件时，经过预设计的Knoevenagel缩合/Michael addition串联反应，顺利地以93％的优异产率得到了本发明所预期的天然产物watsonianone A(1)。
式3-Watsonianone A的合成路线
本发明的化合物Watsonianone A的合成方法，是将syncarpic acid与异戊醛通过脯氨酸催化的Knoevenagel反应获得前体化合物4，再将化合物4与syncarpic acid发生脯氨酸催化的Michael加成反应，得到产物watsonianone A；
所述的syncarpic acid的结构如下式所示：
所述的化合物4的结构如下式所示：
本发明提供了第二种化合物Watsonianone A的合成方法，将过量的syncarpicacid与异戊醛经脯氨酸催化得到产物watsonianone A；
所述的syncarpic acid的结构如下式所示：
所述的过量是指syncarpic acid的量为异戊醛的2-10倍当量。
优选，所述的syncarpic acid是通过以下方法制备：
乙酰间苯三酚在碱性环境下与一卤代甲烷发生羟基氧化和选择性的碳甲基化反应获得化合物6，化合物6再经热促进逆Friedel Crafts酰化反应获得化合物syncarpicacid；
所述的化合物6的结构式如下所示：
所述的一卤代甲烷是碘甲烷。
本发明成功地完成了watsonianone A(1)的首次全合成，并为该类化合物的快速合成提供了简明的合成策略，并为快速获得该生物活性分子和结构衍生物提供了前提保障。
具体实施方式：
以下实施例是对本发明的进一步说明，而不是对本发明的限制。
实施例1：Watsonianone A的合成方法
除非另有说明，否则所有反应均在无水条件下、干燥溶剂中和氮气氛下进行。试剂均购买高质量的商业产品，无需进一步纯化即可使用。用0.25mm青岛硅胶板(60F254)进行薄层色谱(TLC)柱层析，并通过暴露于紫外光(254nm)或用高锰酸钾氧化显色。用于快速柱色谱的硅胶(ZCX-II，200-300目)购自中国青岛海洋化学工业有限公司。在Brüker Advance500(1H：500MHz，13C：125MHz)或BrükerAdvance 600(1H NMR：600MHz，13C NMR：150MHz)上，记录1H NMR和13C NMR光谱。CDCl3的相对化学位移定标为1H NMR：7.27ppm，13C NMR：77.00ppm；CD3COCD3的相对化学位移定标为1H NMR：2.05ppm，13C NMR：30.2ppm；CD3OD的相对化学位移定标为1H NMR：3.33ppm，13C NMR：47.5ppm和DMSO-d6的相对化学位移定标为1HNMR：2.50ppm，13C NMR：39.5ppm。使用ABI-Q Star Elite高分辨率质谱仪获得质谱数据。从钠-二苯甲酮中蒸馏出无水THF直至深蓝色持续出现，从氢化钙中蒸馏出CH2Cl2(DCE)。除非另有说明，本论文中涉及到的色谱纯化产率为纯化后产物的收率。本发明以下缩写形式解释核磁谱图和数据中质子的多重裂分性质：s＝单重态，d＝双重态，t＝三重态，q＝四重态，m＝多重态，brs＝宽单重态。
一、中间产物4的制备：
1、4-Acyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione 6的合成
在0℃下将氢氧化钠(5.3g，133mmol)缓慢溶解在无水甲醇(60mL)中。向该澄清溶液中小心加入乙酰基间苯三酚5(2.8g,，16.5mmol)，并在氮气下搅拌混合物10分钟后，缓慢加入碘甲烷(14.2mL，228mmol)。然后除去冰浴，将混合物在室温下搅拌24小时。得到的粗混合物用2N盐酸水溶液(60mL)淬灭，并用CHCl3(5×60mL)萃取三次。合并有机相并用盐水洗涤后，用无水Na2SO4干燥并过滤，真空减压浓缩。得到的粗产物通过硅胶柱层析法(正己烷：乙酸乙酯＝5：1)快速纯化，得到目标产物6(3.0g，13.5mmol，产率为82％)，为黄色棒状晶体。1H NMR(500MHz,CDCl3):δH 1.33(s,6H),1.42(s,6H),2.57(s,3H)；13C NMR(125MHz,CDCl3):δC 23.8,24.3,27.4,52.0,56.7,109.4,196.7,199.1,201.7,210.0。
2、Syncarpic acid 2的合成
向干燥洁净的50mL烧瓶中加入6N盐酸水溶液(30mL)和产物6(3.0g，13.5mmol)，并将反应混合物在回流下剧烈搅拌12小时。将混合物冷却至室温，并用乙酸乙酯(5×50mL)萃取。合并的有机相用盐水(30mL)洗涤，用无水Na2SO4干燥并过滤。通过旋转蒸发除去溶剂，并快速通过硅胶柱色谱法(正己烷：乙酸乙酯＝1：1)纯化，得到产物2-syn carpic acid(2.04g，11.2mmol，产率为83％)。1H NMR(500MHz，CDCl3)：酮：δH1.31(s,12H),3.61(s,2H)；烯醇：δH1.40(s,12H),5.74(brd,J＝2.3Hz,1H),8.00(brs,1H)；13C NMR(100MHz,CDCl3)：酮：δC 21.8,50.2,59.1,204.3,208.9；烯醇：δC24.5,51.2,59.1,101.7,191.9,204.3,212.6。
3、2,2,4,4-Tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione4的合成
将syncarpic acid 2(91mg，0.5mmol)溶解在CH2Cl2(6mL)中，加入异戊醛3(86mg，1.0mmol)和脯氨酸(5.7mg，0.05mmol)。将所得混合物在室温下搅拌30分钟，然后通过3cm长的硅胶柱色谱快速纯化，用CH2Cl2洗脱，得到所需产物4(119mg，收率为95％)，为无色油状物。1HNMR(500MHz，CDCl3)：δH0.95(d，J＝6.7Hz,6H),1.30(s,6H),1.31(s,6H),1.89(m,J＝6.7Hz,1H),2.59(dd,J＝3.0,3.0Hz,2H),7.51(dd,J＝3.0Hz,1H)；13C NMR(125MHz,CDCl3)：δC21.9,22.3,22.6,28.7,38.9,57.9,58.6,133.1,159.1,196.4,199.5,208.8。
二、Watsonianone A(1)的合成(methodA)
将α，β-不饱和三酮(产物4)(50mg，0.2mmol)溶解在CH2Cl2(6mL)中，然后加入syncarpic acid 2(36mg，0.2mmol)和脯氨酸(2.3mg，0.02mmol)。将所得混合物在室温下搅拌30分钟，然后通过10cm长的硅胶柱色谱(正己烷：乙酸乙酯＝10：1)快速纯化，得到所需产物1(83.8mg，产率为97％)，为无色油状物。1H NMR(500MHz，CDCl3)：δH0.85(d,J＝6.6Hz,6H),1.37(s,6H),1.38(s,6H),1.44(s,12H),1.84(t,J＝7.5Hz,2H),4.11(t,J＝7.8Hz,1H),13.31(s,1H)；13C NMR(125MHz,CDCl3)：δC22.4,24.0,24.9,25.3,25.9,26.9,29.5,38.0,51.5,52.1,114.1,191.4,191.7,212.3.HRESIMS m/z 431.2443[M-H]–(C25H35O6的计算值为431.2439)。产物1即为Watsonianone A(1)。
三、Watsonianone(1)的合成(methodB)
将syncarpic acid 2(182mg，1.0mmol)溶解在CH2Cl2(10mL)中，加入异戊醛3(43mg，0.5mmol)和脯氨酸(5.7mg，0.05mmol)。将得到的混合物在室温下搅拌30分钟，然后通过3cm长的硅胶柱色谱(正己烷：乙酸乙酯＝10：1)快速纯化，得到所需产物1(201mg，收率为93％)，为无色油状物。1H NMR(500MHz,CDCl3)：δH0.85(d,J＝6.6Hz,6H),1.37(s,6H),1.38(s,6H),1.44(s,6H),1.44(s,6H),1.84(t,J＝7.5Hz,2H),4.11(t,J＝7.8Hz,1H),13.31(s,1H)；13C NMR(125MHz,CDCl3)：δC22.4,24.0,24.9,25.3,25.9,26.9,29.5,37.9,51.5,52.1,114.0,191.4,191.7,212.3.HRESIMS m/z 431.2443[M-H]–(C25H35O6的计算值为431.2439)。产物1即为Watsonianone A(1)。

Claims (4)

1.一种化合物瓦生桉酮A的合成方法，其特征在于，是将化合物B与异戊醛通过脯氨酸催化的Knoevenagel反应获得前体化合物4，再将化合物4与化合物B发生脯氨酸催化的Michael加成反应，得到产物瓦生桉酮A；
所述瓦生桉酮A的结构式如下式所示：
；
所述的化合物B的结构如下式所示：
；
所述的化合物4的结构如下式所示：
。
2.一种化合物瓦生桉酮A的合成方法，其特征在于，将过量的化合物B与异戊醛混合经脯氨酸催化得到产物瓦生桉酮A；
所述瓦生桉酮A的结构式如下式所示：
；
所述的化合物B的结构如下式所示：
；
所述的过量是指化合物B的量为异戊醛的2-10倍当量。
3.根据权利要求1或2所述的方法，其特征在于，所述的化合物B是通过以下方法制备：
乙酰间苯三酚在碱性环境下与一卤代甲烷发生羟基氧化和选择性的碳甲基化反应获得化合物6，化合物6再经热促进逆Friedel Crafts酰化反应获得化合物B；
所述的化合物6的结构式如下所示：
。
4.根据权利要求3所述的方法，其特征在于，所述的一卤代甲烷是碘甲烷。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105859537A (zh) * 2016-04-27 2016-08-17 中国科学院华南植物园 开环桃金娘酮类似物及其制备方法和在抗菌药物中的应用
CN108752305A (zh) * 2018-08-24 2018-11-06 中国科学院华南植物园 闭环桃金娘酮类似物及在抗菌药物中的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105859537A (zh) * 2016-04-27 2016-08-17 中国科学院华南植物园 开环桃金娘酮类似物及其制备方法和在抗菌药物中的应用
CN108752305A (zh) * 2018-08-24 2018-11-06 中国科学院华南植物园 闭环桃金娘酮类似物及在抗菌药物中的应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Watsonianone A-C, anti-plasmodial β-triketones from the Australian tree, Corymbia watsoniana;Carroll, Anthony R.等;《Organic & Biomolecular Chemistry》;20121122;第11卷(第3期);第453-458页 *

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