Ⅰ.甾体化合物的合成、杂质分离鉴定以及生物活性研究 Ⅱ.五元环碳糖的立体选择性合成研究
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摘要
本论文工作包括两大部分：第一部分为甾体化合物的合成、杂质分离鉴定以及生物活性研究；第二部分为五元环碳糖的立体选择性合成研究。
第一部分：甾体化合物的合成、杂质分离鉴定以及生物活性研究,具体又可分为3个方面的工作：
(1)长期以来,油菜甾醇类化合物因具有极高的植物生长激素活性而备受关注。本文中,我们对其未报导的生物活性进行了研究,并设计合成了一系列的新型衍生物。为研究其新的适应症,我们首先选取部分有代表性的油菜甾醇类化合物,针对抗良性前列腺增生活性进行了体外活性测试,结果表明24-表油菜甾醇内酯(25)具有较好的活性。进一步通过对24-混表油菜甾醇内酯(BR-3)及其主要成分24-表油菜甾醇内酯(25)和(22S，23S)-24-表油菜甾醇内酯(59)分别进行体内试验,发现化合物25对大鼠前列腺增生有一定的特异性抑制作用,而其异构体59则基本无效。由于油菜甾醇类化合物的价格昂贵,来源稀缺,使其在应用特别是新药研发上受到很大的局限性,为此,我们以价格低廉的猪去氧胆酸为原料,设计并合成了一系列A／B环改造和边链简化的衍生物,并针对与前列腺疾病相关的受体靶点进行了活性测试。这些研究,对发现油菜甾醇类化合物的新活性,新用途,及构效关系的进一步探讨与总结提供了参考价值。
(2)抗早孕甾体药物米非司酮的合成工艺中,环氧化反应是最关键的步骤,提高其立体选择性始终是人们研究的重点,我们结合前人的研究基础,合成了8个金鸡纳碱的季胺盐(PTC A-H)作为相转移催化剂来催化雌甾-△5(10),9(11)-双烯的环氧化反应,结果显示,C8,C9同时为R构型的PTC G和H表现出比较好的催化性能,将a环氧产物的比例从4：1提高到7：1。我们的推测,手性中心的不同使得催化剂具有不同的构象,影响了底物与氧化剂的结合方式,通过在热力学和动力学上的最优过渡态来介导环氧化反应,从而造成了面选择性的差异,提高αα环氧产物的比例。
(3)根据当前欧美国家GMP要求,所有在欧美国家销售的药品,包括原料药均应有相应的杂质列表,GMP中特别强调对于0.1%以上含量的杂质应进行结构论证及毒理评判。为此我们对坎利酮生产过程(以4-AD作为起始原料)中产生的相关物质进行了分离和结构论证工作。在杂质分离提取过程中,分得并鉴定了11个甾体化合物。超过0.1%的杂质有3个,为化合物CAN-06, CAN-07和CAN-09。共有4个新化合物,分别是CAN-01, CAN-03, CAN-07和CAN-09。我们推测,绝大部分杂质都是Michael-1,6加成反应的结果,某些杂质可能是坎利酮生物转化中的代谢物或中间体。分离鉴定这些合成过程中产生的杂质,不仅可以帮助建立药物的质控标准,对于鉴定一些微量的代谢物和对了解代谢过程也会有所帮助。
第二部分：五元环碳糖的立体选择性合成研究
碳糖(carbasugars)是一类呋喃或吡喃糖环中的氧原子被亚甲基取代所形成的糖类似物。这类化合物的性质与母体糖相似,某些多官能团的碳环糖化合物具有特定生物活性,对某些以碳水化合物为底物的酶有一定的亲和力,但与碳水化合物不同,这些碳环糖化合物不会继续发生生化反应。基于这种特性,含特定官能团碳环结构的化合物常作为酶抑制剂而用于抗菌、抗病毒以及癌症、糖尿病、免疫性炎症等多种疾病的治疗。
碳糖的合成最早可追溯到上世纪60年代,随着碳糖类化合物的生物活性逐渐被发现,众多的化学家开始探索新的立体选择性全合成的方法。为找寻一条较为简洁的五元环碳糖的合成方法,我们从三方面进行了探索,最终以R-甘油醛缩丙酮134为起始原料,利用RCM反应合成了五元碳环化合物148和160,从这两个关键的五元环中间体出发,利用其环上的手性中心以及不饱和双键,可以引入多种不同的官能团,从而有可能合成出其他碳糖衍生物。
This doctoral dissertation is divided into two parts. Part I is Synthesis, Impurities Isolation and elucidation, Biological Activities Research on Steroids. Part II is Stereoselective Synthesis of Five-Membered Ring Carbasugars.
1. The first part of this dissertation consists of three subparts
(1) The synthesis of brassinosteroid derivatives and research on biological activities. Brassinosteroid, as a powerful steroidal plant growth regulator, has received much attention. In this subpart, we described the new biological activity and the synthesis of derivatives of brassinosteroid. In the aspect of new biological activity, the anti-prostatic hyperplasia activity was firstly reported. A series of brassinosteroids were tested in vitro, and 24-epibrassinolide (25) exhibited fairly good activity. Furthermore, through the test of the mixture of 24-epibrassinolide (BR-3) and its main components,24-epibrassinolide (25) and (22S, 23S)-24-epibrassinolide (59) in vivo, we found 24-epibrassinolide (25) could specifically inhibit the hyperplasia of prostate, while the isomer 59 was almost ineffective. In the aspect of the synthesis of derivatives, we started from the cheap and commercially available material, hyodeoxycholic acid to synthesize a series of derivatives with modificationon ring A and B. This structurally diverse modification will help us to investigate structure-activity relationship of brassinosteroids on new bioactivities.
(2) The epoxidation is the key step in the synthesis of antiprogestin drug, mifepristone. People always focus on the enantioselective to improve the desired alpha epoxide. In this subpart, a modified phase-transfer catalysed enantioselective epoxidation of estra-△5(10)9(11)-diene has been determined and investigated. Eight chiral ammonium salts (PTC A-H), used as phase-transfer catalysts, have been synthesized from cinchona alkaloids. Among them, PTC G and PTC H have exhibited satisfying catalytic activity to improve the ratio ofα/βepoxide up to 7:1. We presume that the chiral ammonium salts assembling the oxidant and the estra-△A5(10),9(11)-diene in a specific three-dimensional arrangement may channel epoxidation through an energetically and entropically favored transition state, which exerted an great influence on the ratio ofα/βepoxide. Meanwhile, this modified method significantly expanded the scope of phase-transfer catalysed epoxidation reaction.
(3) In this subpart, We have clarified the existence of the impurities in canrenone produced by the process starting from androsta-4-ene-3,17-dione (4-AD for short), and four new and seven known impurities have been confirmed. The structures and configurations of these compounds were elucidated by means of ID and 2D (HMQC, HMBC and ROESY) NMR. The discovery of the new and known compounds which have similar chemical structure may be useful in the quality control of the production of canrenone.
2. The second part is stereoselective synthesis of five member ring carbasugars.
Carbasugars are a series of derivatives in which the ring oxygen of a monosaccharide are replaced by a methylene group. The synthesis of carbasugars has undergone extensive development during the 20th century. Here, we wish to establish a simple way to construct the cyclopentene intermediate 112, which could be easily converted to entecavir 93, a powerful anti-HBV drug.
Starting from commercially available (R)-(+)-2,2-Dimethyl-1,3-dioxolane-4-carboxaldehyde 134, we have used ring-closing metathesis as the key step to prepare five-membered ring carbasugars mimics 148 and 160, in which the unsaturated double bonds provide potent reaction site for introducing other functional groups. For example, compound 160 could be recognized as the critical intermediate in the preparation of antiviral agent N-MCT. However, the whole synthetic route of entecavir hasn't completely finished yet. Further research is still in progress.
第一部分：甾体化合物的合成、杂质分离鉴定以及生物活性研究,具体又可分为3个方面的工作：
(1)长期以来,油菜甾醇类化合物因具有极高的植物生长激素活性而备受关注。本文中,我们对其未报导的生物活性进行了研究,并设计合成了一系列的新型衍生物。为研究其新的适应症,我们首先选取部分有代表性的油菜甾醇类化合物,针对抗良性前列腺增生活性进行了体外活性测试,结果表明24-表油菜甾醇内酯(25)具有较好的活性。进一步通过对24-混表油菜甾醇内酯(BR-3)及其主要成分24-表油菜甾醇内酯(25)和(22S，23S)-24-表油菜甾醇内酯(59)分别进行体内试验,发现化合物25对大鼠前列腺增生有一定的特异性抑制作用,而其异构体59则基本无效。由于油菜甾醇类化合物的价格昂贵,来源稀缺,使其在应用特别是新药研发上受到很大的局限性,为此,我们以价格低廉的猪去氧胆酸为原料,设计并合成了一系列A／B环改造和边链简化的衍生物,并针对与前列腺疾病相关的受体靶点进行了活性测试。这些研究,对发现油菜甾醇类化合物的新活性,新用途,及构效关系的进一步探讨与总结提供了参考价值。
(2)抗早孕甾体药物米非司酮的合成工艺中,环氧化反应是最关键的步骤,提高其立体选择性始终是人们研究的重点,我们结合前人的研究基础,合成了8个金鸡纳碱的季胺盐(PTC A-H)作为相转移催化剂来催化雌甾-△5(10),9(11)-双烯的环氧化反应,结果显示,C8,C9同时为R构型的PTC G和H表现出比较好的催化性能,将a环氧产物的比例从4：1提高到7：1。我们的推测,手性中心的不同使得催化剂具有不同的构象,影响了底物与氧化剂的结合方式,通过在热力学和动力学上的最优过渡态来介导环氧化反应,从而造成了面选择性的差异,提高αα环氧产物的比例。
(3)根据当前欧美国家GMP要求,所有在欧美国家销售的药品,包括原料药均应有相应的杂质列表,GMP中特别强调对于0.1%以上含量的杂质应进行结构论证及毒理评判。为此我们对坎利酮生产过程(以4-AD作为起始原料)中产生的相关物质进行了分离和结构论证工作。在杂质分离提取过程中,分得并鉴定了11个甾体化合物。超过0.1%的杂质有3个,为化合物CAN-06, CAN-07和CAN-09。共有4个新化合物,分别是CAN-01, CAN-03, CAN-07和CAN-09。我们推测,绝大部分杂质都是Michael-1,6加成反应的结果,某些杂质可能是坎利酮生物转化中的代谢物或中间体。分离鉴定这些合成过程中产生的杂质,不仅可以帮助建立药物的质控标准,对于鉴定一些微量的代谢物和对了解代谢过程也会有所帮助。
第二部分：五元环碳糖的立体选择性合成研究
碳糖(carbasugars)是一类呋喃或吡喃糖环中的氧原子被亚甲基取代所形成的糖类似物。这类化合物的性质与母体糖相似,某些多官能团的碳环糖化合物具有特定生物活性,对某些以碳水化合物为底物的酶有一定的亲和力,但与碳水化合物不同,这些碳环糖化合物不会继续发生生化反应。基于这种特性,含特定官能团碳环结构的化合物常作为酶抑制剂而用于抗菌、抗病毒以及癌症、糖尿病、免疫性炎症等多种疾病的治疗。
碳糖的合成最早可追溯到上世纪60年代,随着碳糖类化合物的生物活性逐渐被发现,众多的化学家开始探索新的立体选择性全合成的方法。为找寻一条较为简洁的五元环碳糖的合成方法,我们从三方面进行了探索,最终以R-甘油醛缩丙酮134为起始原料,利用RCM反应合成了五元碳环化合物148和160,从这两个关键的五元环中间体出发,利用其环上的手性中心以及不饱和双键,可以引入多种不同的官能团,从而有可能合成出其他碳糖衍生物。
This doctoral dissertation is divided into two parts. Part I is Synthesis, Impurities Isolation and elucidation, Biological Activities Research on Steroids. Part II is Stereoselective Synthesis of Five-Membered Ring Carbasugars.
1. The first part of this dissertation consists of three subparts
(1) The synthesis of brassinosteroid derivatives and research on biological activities. Brassinosteroid, as a powerful steroidal plant growth regulator, has received much attention. In this subpart, we described the new biological activity and the synthesis of derivatives of brassinosteroid. In the aspect of new biological activity, the anti-prostatic hyperplasia activity was firstly reported. A series of brassinosteroids were tested in vitro, and 24-epibrassinolide (25) exhibited fairly good activity. Furthermore, through the test of the mixture of 24-epibrassinolide (BR-3) and its main components,24-epibrassinolide (25) and (22S, 23S)-24-epibrassinolide (59) in vivo, we found 24-epibrassinolide (25) could specifically inhibit the hyperplasia of prostate, while the isomer 59 was almost ineffective. In the aspect of the synthesis of derivatives, we started from the cheap and commercially available material, hyodeoxycholic acid to synthesize a series of derivatives with modificationon ring A and B. This structurally diverse modification will help us to investigate structure-activity relationship of brassinosteroids on new bioactivities.
(2) The epoxidation is the key step in the synthesis of antiprogestin drug, mifepristone. People always focus on the enantioselective to improve the desired alpha epoxide. In this subpart, a modified phase-transfer catalysed enantioselective epoxidation of estra-△5(10)9(11)-diene has been determined and investigated. Eight chiral ammonium salts (PTC A-H), used as phase-transfer catalysts, have been synthesized from cinchona alkaloids. Among them, PTC G and PTC H have exhibited satisfying catalytic activity to improve the ratio ofα/βepoxide up to 7:1. We presume that the chiral ammonium salts assembling the oxidant and the estra-△A5(10),9(11)-diene in a specific three-dimensional arrangement may channel epoxidation through an energetically and entropically favored transition state, which exerted an great influence on the ratio ofα/βepoxide. Meanwhile, this modified method significantly expanded the scope of phase-transfer catalysed epoxidation reaction.
(3) In this subpart, We have clarified the existence of the impurities in canrenone produced by the process starting from androsta-4-ene-3,17-dione (4-AD for short), and four new and seven known impurities have been confirmed. The structures and configurations of these compounds were elucidated by means of ID and 2D (HMQC, HMBC and ROESY) NMR. The discovery of the new and known compounds which have similar chemical structure may be useful in the quality control of the production of canrenone.
2. The second part is stereoselective synthesis of five member ring carbasugars.
Carbasugars are a series of derivatives in which the ring oxygen of a monosaccharide are replaced by a methylene group. The synthesis of carbasugars has undergone extensive development during the 20th century. Here, we wish to establish a simple way to construct the cyclopentene intermediate 112, which could be easily converted to entecavir 93, a powerful anti-HBV drug.
Starting from commercially available (R)-(+)-2,2-Dimethyl-1,3-dioxolane-4-carboxaldehyde 134, we have used ring-closing metathesis as the key step to prepare five-membered ring carbasugars mimics 148 and 160, in which the unsaturated double bonds provide potent reaction site for introducing other functional groups. For example, compound 160 could be recognized as the critical intermediate in the preparation of antiviral agent N-MCT. However, the whole synthetic route of entecavir hasn't completely finished yet. Further research is still in progress.
引文
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