新型系列3β-羟基孕甾双烯酮芳香族甲酸酯的合成与表征
摘要
以薯蓣皂素为原料,合成了甾体药物重要中间体妊娠双烯醇酮醋酸酯16-DPA,经两条路线分别考虑利用具有相同取代基但不同取代位置的苯甲酸为底物,合成了两个系列新型3p-羟基孕甾双烯酮芳香族甲酸酯化合物,这些化合物有望在5-还原酶抑制剂的研究、抗雄性激素活性以及降脂和抗氧化活性方面有很大研究前景,对生物活性的筛选研究也具有一定的潜在价值。利用1H-NMR,13C-NMR, IR和MS,LC-MS及元素分析对第一系列甾体化合物进行了结构表征,并对其中一新化合物3β-(p-甲氧基苯甲酸酯基)-4,16-孕甾双烯-6,20-二酮进行X射线单晶衍射后表明：甾体骨架结构中A,B,C,D四个环分别为半椅式,扭曲椅式,扭曲椅式和扭曲信封式构造,晶体结构中分子间以范德华间距相互堆积；利用1H-NMR,13C-NMR, IR对第二系列甾体化合物进行了结构表征。本论文主要包含以下几个方面的研究内容：
1.以廉价易得的薯蓣皂素为起始原料经开环,氧化合成妊娠双烯醇酮醋酸酯16-DPA,并在反应温度,反应时间,摩尔比方面对合成工艺条件进行了探索；发现薯蓣皂素经F环开环后处理得到假薯蓣皂苷元时,反应液充分冷却倒入冰水并不断搅拌,可以很大程度上改变所得固体的黏度,同时E环氧化得到16-DPA时反应时间5h,反应物摩尔比1：1,反应温度10-15℃可相对提高反应收率.
2.分别以两条合成路线对妊娠双烯醇酮醋酸酯16-DPA进行结构修饰,分别得到两个系列C3位含有酯基侧链的16-DPA衍生物---3β-羟基孕甾双烯酮芳香族甲酸酯,以供进行生物活性筛选.
第一系列衍生物：16-DPA经C5-双键环氧化,开环,消除,水解,酯化一系列反应得到C3-酯基侧链-C5,C6-α,β-不饱和酮-16-DPA衍生物
-3p-羟基-4,16-孕甾双烯-6,20-二酮芳香族甲酸酯；
在C5-双键环氧化过程中,我们尝试了两种方法H2O2/HCOOH体系和m-CPBA/CHCl3体系下的环氧化,发现m-CPBA/CHCl3体系具有操作方便,产物结构单一,产率高的特点。消除反应中,对溶剂吡啶进行无水处理,能得到较好的收率。水解反应后处理中采用萃取方法比直接过滤法收率较高。酯化反应是一个亲核取代反应,原料中羰基碳的正电性越大,其周围的空间位阻越小,越有利于反应的进行；从酯化产物收率来看,含有供电子基团或位阻较小的邻呋喃甲酸酯和对甲氧基苯甲酸酯收率较高分别达到77%和71%,而取代基较多,具有吸电子效应的3,5-二硝基苯甲酸酯产率相对较低(45%)第二系列衍生物：16-DPA经两种方法,分别在氢氧化钠甲醇体系和氢氧化钾叔丁醇体系下使C3位水解为羟基,再经酯化得到一系列C3-酯基侧链-16-DPA衍生物---3β-羟基-5,16-孕甾双烯-20-酮芳香族甲酸酯；
两种水解条件相比,氢氧化钠甲醇体系下水解反应时间长,收率高,这与水解反应机理相一致,KOH强碱条件下加强了亲核试剂的进攻能力,但t-BuOH的位阻效应降低了反应的收率.
3.系列衍生物的谱图分析和结构确证.以薯蓣皂素为原料按照第一条衍生路线合成了10种第一系列衍生物,并分别通过1H-NMR,IR,13C-NMR,MS,LC-MS及元素分析进行了结构确证；以薯蓣皂素为原料按照第二条衍生路线合成了8种第二系列衍生物并分别进行了1H-NMR,IR,C13-NMR,谱图分析和结构确证.
4.第一系列衍生物之一,3β-羟基-4,16-孕甾双烯-6,20-二酮对甲氧基苯甲酸酯单晶X射线单晶衍射；通过单晶衍射结构图和空间堆积图进一步确证了其结构.
Synthesis and characterization of two series of new aromatic esters based on 4,16-pregnadiene-6,20-dione skeleton and 5,16-pregnadiene-20-dione skeleton was reviewed.We mainly synthesized the objective compounds through two different derived routes based on the intermediate compound called 16-DPA,which was first synthesized from diosgenin.These compounds may show potential reactivities in the fieds of inhabitor of 5a-reductase,antiandrogenic,antioxidant and lower blood lipid and so on,and could be also used for the biological selection. The structures of the steroids were characterized by 1H-NMR, C-NMR, IR and mass spectrum. Single crystal X-ray diffraction measurement on one of the new compounds, (3β)-(p- methoxybenzoyloxy)-4,16-pregnadiene-6,20-dione revealed that the A, B, C, and D ring adopted half chair, distorted chair, distorted chair, and distorted envelope conformation, respectively. The molecules in the crystal were packed face-to-face at the normal van der Waals distances. This dissertation mainly contains the following aspects:
l.We synthesized the intermediate compound 16-DPA by a two-step synthetic sequence: ring-opening reaction and oxidation reaction,using the inexpensive diosgenin as the start material.The reactive temperature、time and N/P(molar ratio) conditions were studied respectively to find the optimal reaction conditions. Experimental results showed that the highest yield was obtained under 10～15℃,5h and 1:1(N/P) conditions.We also find that pulling the result solution of the E-ring-opening reaction into ice-water with stirring can reduce the viscosity of the solid effectively.
2. Synthesis and characterization of two series of new aromatic esters based on 4,16-pregnadiene-6,20-dione skeleton and 5,16-pregnadiene-20-dione skeleton.The target compounds were synthesized by structural modifation of 16-DPA through two different routes.They may be used for the biological selection.
The first serial derivatives called aromatic esters based on 4,16-Pregnadiene-6,20-dione skeleton was synthesized via a five-step reaction:epoxidation reaction of double bond、ring-opening reaction、elimination reaction hydrolysis reaction and esterification.
We tried two methods for the epoxidation reaction in H2O2/HCOOH and m-CPBA/CHCl3 reaction system respectively. Experimental results showed that it's convenient and with high yield an single stucture in m-CPBA/CHCl3 reaction system.
We got high yied respectively when using the anhydrous pyridine in the elimination reaction and extraction instead of filtration in the post-treatment of hydrolysis reaction. Because esterification is essentially a nucleophilic substitution reaction,so the strong electropositive and small stereo-hindrance effect is favorable.The result indicated that the yields of o-furoic acid ester and p- methoxybenzoyloxy ester were higher,77% and 71% respectively, compared to 45% yield of 3,5-dinitrobenzoic acid ester,whose structure includes more substituent groups with strongly absorb-electron effect.
The second serial derivatives called aromatic esters based on 5,16-pregnadiene-20-dione skeleton was synthesized via a two-step reaction:hydrolysis reaction and esterification at C3.After compared the two hydrolysis conditions between NaOH/CH30H and KOH/t-BuOH systems,we find that the former need long reaction time but higher yield than the latter,which is coincidence with the mechanism of hydrolysis reaction. The strong basicity of KOH enhances the nucleophilic attack,but the stereo-hindrance effect of t-BuOH decreases the yield.
3.Characterization of the serial derivatives.All the first serial products including 10 compounds were characterized by IR spectra,1H NMR spectra,13C NMR spectra and LC-MS,while the second serial ones including 8 compounds were characterized by IR spectra,1H NMR spectra,13C NMR spectra.
4.Characterization of (3β)-(p-methoxybenzoyloxy)-4,16-pregnadiene-6,20-dione via single crystal X-ray diffraction measurement.
1.以廉价易得的薯蓣皂素为起始原料经开环,氧化合成妊娠双烯醇酮醋酸酯16-DPA,并在反应温度,反应时间,摩尔比方面对合成工艺条件进行了探索；发现薯蓣皂素经F环开环后处理得到假薯蓣皂苷元时,反应液充分冷却倒入冰水并不断搅拌,可以很大程度上改变所得固体的黏度,同时E环氧化得到16-DPA时反应时间5h,反应物摩尔比1：1,反应温度10-15℃可相对提高反应收率.
2.分别以两条合成路线对妊娠双烯醇酮醋酸酯16-DPA进行结构修饰,分别得到两个系列C3位含有酯基侧链的16-DPA衍生物---3β-羟基孕甾双烯酮芳香族甲酸酯,以供进行生物活性筛选.
第一系列衍生物：16-DPA经C5-双键环氧化,开环,消除,水解,酯化一系列反应得到C3-酯基侧链-C5,C6-α,β-不饱和酮-16-DPA衍生物
-3p-羟基-4,16-孕甾双烯-6,20-二酮芳香族甲酸酯；
在C5-双键环氧化过程中,我们尝试了两种方法H2O2/HCOOH体系和m-CPBA/CHCl3体系下的环氧化,发现m-CPBA/CHCl3体系具有操作方便,产物结构单一,产率高的特点。消除反应中,对溶剂吡啶进行无水处理,能得到较好的收率。水解反应后处理中采用萃取方法比直接过滤法收率较高。酯化反应是一个亲核取代反应,原料中羰基碳的正电性越大,其周围的空间位阻越小,越有利于反应的进行；从酯化产物收率来看,含有供电子基团或位阻较小的邻呋喃甲酸酯和对甲氧基苯甲酸酯收率较高分别达到77%和71%,而取代基较多,具有吸电子效应的3,5-二硝基苯甲酸酯产率相对较低(45%)第二系列衍生物：16-DPA经两种方法,分别在氢氧化钠甲醇体系和氢氧化钾叔丁醇体系下使C3位水解为羟基,再经酯化得到一系列C3-酯基侧链-16-DPA衍生物---3β-羟基-5,16-孕甾双烯-20-酮芳香族甲酸酯；
两种水解条件相比,氢氧化钠甲醇体系下水解反应时间长,收率高,这与水解反应机理相一致,KOH强碱条件下加强了亲核试剂的进攻能力,但t-BuOH的位阻效应降低了反应的收率.
3.系列衍生物的谱图分析和结构确证.以薯蓣皂素为原料按照第一条衍生路线合成了10种第一系列衍生物,并分别通过1H-NMR,IR,13C-NMR,MS,LC-MS及元素分析进行了结构确证；以薯蓣皂素为原料按照第二条衍生路线合成了8种第二系列衍生物并分别进行了1H-NMR,IR,C13-NMR,谱图分析和结构确证.
4.第一系列衍生物之一,3β-羟基-4,16-孕甾双烯-6,20-二酮对甲氧基苯甲酸酯单晶X射线单晶衍射；通过单晶衍射结构图和空间堆积图进一步确证了其结构.
Synthesis and characterization of two series of new aromatic esters based on 4,16-pregnadiene-6,20-dione skeleton and 5,16-pregnadiene-20-dione skeleton was reviewed.We mainly synthesized the objective compounds through two different derived routes based on the intermediate compound called 16-DPA,which was first synthesized from diosgenin.These compounds may show potential reactivities in the fieds of inhabitor of 5a-reductase,antiandrogenic,antioxidant and lower blood lipid and so on,and could be also used for the biological selection. The structures of the steroids were characterized by 1H-NMR, C-NMR, IR and mass spectrum. Single crystal X-ray diffraction measurement on one of the new compounds, (3β)-(p- methoxybenzoyloxy)-4,16-pregnadiene-6,20-dione revealed that the A, B, C, and D ring adopted half chair, distorted chair, distorted chair, and distorted envelope conformation, respectively. The molecules in the crystal were packed face-to-face at the normal van der Waals distances. This dissertation mainly contains the following aspects:
l.We synthesized the intermediate compound 16-DPA by a two-step synthetic sequence: ring-opening reaction and oxidation reaction,using the inexpensive diosgenin as the start material.The reactive temperature、time and N/P(molar ratio) conditions were studied respectively to find the optimal reaction conditions. Experimental results showed that the highest yield was obtained under 10～15℃,5h and 1:1(N/P) conditions.We also find that pulling the result solution of the E-ring-opening reaction into ice-water with stirring can reduce the viscosity of the solid effectively.
2. Synthesis and characterization of two series of new aromatic esters based on 4,16-pregnadiene-6,20-dione skeleton and 5,16-pregnadiene-20-dione skeleton.The target compounds were synthesized by structural modifation of 16-DPA through two different routes.They may be used for the biological selection.
The first serial derivatives called aromatic esters based on 4,16-Pregnadiene-6,20-dione skeleton was synthesized via a five-step reaction:epoxidation reaction of double bond、ring-opening reaction、elimination reaction hydrolysis reaction and esterification.
We tried two methods for the epoxidation reaction in H2O2/HCOOH and m-CPBA/CHCl3 reaction system respectively. Experimental results showed that it's convenient and with high yield an single stucture in m-CPBA/CHCl3 reaction system.
We got high yied respectively when using the anhydrous pyridine in the elimination reaction and extraction instead of filtration in the post-treatment of hydrolysis reaction. Because esterification is essentially a nucleophilic substitution reaction,so the strong electropositive and small stereo-hindrance effect is favorable.The result indicated that the yields of o-furoic acid ester and p- methoxybenzoyloxy ester were higher,77% and 71% respectively, compared to 45% yield of 3,5-dinitrobenzoic acid ester,whose structure includes more substituent groups with strongly absorb-electron effect.
The second serial derivatives called aromatic esters based on 5,16-pregnadiene-20-dione skeleton was synthesized via a two-step reaction:hydrolysis reaction and esterification at C3.After compared the two hydrolysis conditions between NaOH/CH30H and KOH/t-BuOH systems,we find that the former need long reaction time but higher yield than the latter,which is coincidence with the mechanism of hydrolysis reaction. The strong basicity of KOH enhances the nucleophilic attack,but the stereo-hindrance effect of t-BuOH decreases the yield.
3.Characterization of the serial derivatives.All the first serial products including 10 compounds were characterized by IR spectra,1H NMR spectra,13C NMR spectra and LC-MS,while the second serial ones including 8 compounds were characterized by IR spectra,1H NMR spectra,13C NMR spectra.
4.Characterization of (3β)-(p-methoxybenzoyloxy)-4,16-pregnadiene-6,20-dione via single crystal X-ray diffraction measurement.
引文
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[2]杜计燕.7a-羟基DHEA、5a-雄甾-16-烯-3-酮及4-羟基雄甾化合物合成研究.华东师范大学硕士学位论文.2005.
[3]江昕.生物学重要的甾体化合物的设计和合成.南京大学理学博士论文.1999.
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