异甾类化合物合成及微波化学促进Wagner-Meerwein重排反应研究
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摘要
本论文由三章组成。第一章为异甾类化合物的合成研究，制备了合成异甾类生物碱所需的具有C_(18)位活性官能团的异甾环中间体，并对合成工艺进行探讨。第二章为微波促进Hecogenin衍生物经Wagner-Meerwein Rearrangement反应生成异甾类化合物的初步研究。第三章为综述，对Cephalostatins和Ritterazines类吡嗪双甾生物碱的化学结构，活性以及相关的合成研究进行了文献综述。
第一章
异甾类生物碱是许多药用植物中的主要活性成分之一，主要分布在百合科贝母属和藜芦属植物中。该类生物碱也被称为藜芦类生物碱，其主要母核结构为C-去甲-D-高甾环(C-nor-D-homo steroid)与一个含氮杂环骈合而成，根据杂环的结构特征又可具体分为：黎芦胺型(veratramine type)、介黎芦型(jervine type)和瑟文型(cevanine type)。
经过对异甾类生物碱结构进行研究后，我们可以认为这类化合物由两部分组成，即C-nor-D-homo甾体骨架与合适的含氮杂环。
本研究以易得的天然甾族化合物Hecogenin为原料，依次经过乙酰化，选择性还原，取代反应，重排反应，硼氢化氧化反应，水解反应，氧化反应，差向异构化反应，还原反应，乙酰化反应，Baeyer-Villiger氧化反应裂解E／F环后构建具有与天然产物相同构型的13α-取代化合物，得到具有C_(18)位活性官能团的目标化合物13α-hydroxymethyl-17-ethyl-5α，12α-etiojervane-3，16，20-triol。总收率约为2％。初步建立了异甾类生物碱的A／B／C／D环骨架，为进一步合成黎芦胺型(veratramine type)、介黎芦型(jervine type)或瑟文型(cevanine type)生物碱打下基础。并对反应过程中的条件选择及其优化进行了讨论。对反应过程中的某些关键步骤进行工艺上的改良，提高收率和反应速度，以适应大量制备的要求。
第二章
在甾体化合物的生物合成途径中，很重要的一步是经过分子重排形成异甾环(C-nor-D-homo)结构。该结构也是黎芦胺型(veratramine type)、介黎芦型(jervinetype)和瑟文型(cevanine type)生物碱的基本骨架。C-nor-D-homo甾环结构可由番麻皂苷乙酸酯的12β-对甲苯磺酰基取代物经Wagner-Meerwein Rearrangement反应得到。该反应的产物由不同比例的环外双键化合物C-nor-D-homo-Δ~(17a(18))-olefin与环内双键化合物C-nor-D-homo-Δ~(13(17a))-olefin构成，其中环外双键化合物为进一步合成异甾类生物碱的重要中间体。
本研究结合微波辐射促进有机合成反应的优点，如：加快反应速度，能提高产物的收率，纯度，某些反应具有选择性，方便后处理，污染小等，设计了一种利用微波辐射技术进行Wagner-Meerwein Rearrangement反应的方法，并初步探讨了该重排反应发生的机理以及不同溶剂条件，反应时间和功率对该反应速度，收率以及选择性的影响。
无水吡啶由于其沸点较高，极性较小并且具有一定碱性，是作为Wagner-Meerwein Rearrangement反应的最佳溶剂。微波辐射较长时间能够获得良好的收率，并且有利于得到预期的环外双键产物化合物。
第三章
本文对Cephalostatins和Ritterazines吡嗪双甾体的分离，合成以及构效关系研究进行了文献综述，参考了该类化合物从1988年发现至今(2009年)的72篇文献，为该类化合物的进一步开发利用提供依据。
This thesis is composed of three parts.The first part is about the synthesis ofC_(18)-functionalized C-nor-D-homo steroidal intermediate which is the basic skeletonof isosteroidal alkaloids and the optimization of the preparation process.The secondpart of my work focuses on the microwave promoted Wagner-MeerweinRearrangement of Hecogenin derivatives into C-nor-D-homo steroids.The third partis a review section on the chemical study,bioactivity assay and synthetic research ofCephalostatins and Ritterazines.
Part One
Isosteroidal alkaloids,widely distributed in Liliaceae family,including Veratrum andFritillaria,have proved to be the active components of many folk medicines.Theyare characterized by a C-nor-D-homo ring system and can be further divided intocevanine,veratramine and jervine types.The C_(27) cholestane carbon skeleton with five or six carbocyclic or heterocyclic ringsis made up of two structural units:(a) C-nor-D-homo skeleton;(b) an appropriateheterocyclic nitrogen system.
In our synthetic strategy,C-nor-D-homo steroidal derivative possessing the desiredαstereochemistry at C_(13) and an appropriate functionality at C_(18) has been synthesized byesterification,selective reduction,substitution,Wagner-Meerwein Rearrangement,hydroboration-oxidation,hydrolysis,oxidation,epimerization,reduction,esterrification,Baeyer-Villiger Oxidation with a total yield of 2%.The effects ofreaction solvents,catalysts,reaction time and other factors on the yields of each stephave been investigated and the optimization process has been discussed.
This work has achieved the goal of construction of basic A/B/C/D skeleton ofisosteroidal alkaloids for further synthesis of those compounds in veratramine type,jervine type and cevanine type.
Part TwoIn the biogenesis of steroids,an important step is to undergo molecularRearrangement to release C-nor-D-homo ring system carbon framework of which isclassified as the basic skeleton of isosteroidal alkaloids such as cevanine type,veratramine type,and jervine type from the Liliaceae family.Derivatives fromhecogenin acetate undergo solvolysis to give varying proportions of theC-nor-D-homo-△~(17a(18))-olefin 2 and the△~(13(17a))-isomer 3,depending upon the reactionconditions.Since no preferable synthetic methods for perfect formation of exocyclicolefin,an essential building block for C_(18)-functionalized isosteroidal derivatives,havebeen developed so far,the highly regioselective synthesis of 2 has been a topic ofinterest.
The recent findings have indicated that with the coupling of microwave irradiation,some chemical processes with special attributes are achieved,such as enhancedreaction rates,higher yields,greater selectivity and improved ease of manipulation.This methodology encouraged us to explore the Rearrangement of hecogeninderivatives into C-nor-D-homo steroids using microwave irradiation.The effects of reaction solvents,time,power and other factors on the yields of eachstep have been investigated and the mechanism in this process throughWagner-Meerwein Rearrangement has been discussed.We have found an efficientmicrowave-assitsted approach that is suitable for the Rearrangement of hecogeninderivatives into C-nor-D-homo steroids,which may offers advantages of shortreaction time,less amount of organic solvent,better isomer-selectivity,one-pottwo-step reaction and easy work-up.
According to the results,it has been found that anhydrous pyridine is the solvent ofchoice for the formation of 2 under these conditions,mainly due to its better solubilityof the substrate and its low polarity.
Part Three
The Cephalostatins and Ritterazines comprise a family of trisdecacyclic pyrazinesnatural products which are among the most powerful anticancer agents ever tested bythe National Cancer Institute.Our review on this topic has summarized the isolation,synthesis and structure-activity relationship study from the first discovery in 1988 tonow.It could be helpful to understand the history of these compounds and furtherdevelop their utilization.
第一章
异甾类生物碱是许多药用植物中的主要活性成分之一，主要分布在百合科贝母属和藜芦属植物中。该类生物碱也被称为藜芦类生物碱，其主要母核结构为C-去甲-D-高甾环(C-nor-D-homo steroid)与一个含氮杂环骈合而成，根据杂环的结构特征又可具体分为：黎芦胺型(veratramine type)、介黎芦型(jervine type)和瑟文型(cevanine type)。
经过对异甾类生物碱结构进行研究后，我们可以认为这类化合物由两部分组成，即C-nor-D-homo甾体骨架与合适的含氮杂环。
本研究以易得的天然甾族化合物Hecogenin为原料，依次经过乙酰化，选择性还原，取代反应，重排反应，硼氢化氧化反应，水解反应，氧化反应，差向异构化反应，还原反应，乙酰化反应，Baeyer-Villiger氧化反应裂解E／F环后构建具有与天然产物相同构型的13α-取代化合物，得到具有C_(18)位活性官能团的目标化合物13α-hydroxymethyl-17-ethyl-5α，12α-etiojervane-3，16，20-triol。总收率约为2％。初步建立了异甾类生物碱的A／B／C／D环骨架，为进一步合成黎芦胺型(veratramine type)、介黎芦型(jervine type)或瑟文型(cevanine type)生物碱打下基础。并对反应过程中的条件选择及其优化进行了讨论。对反应过程中的某些关键步骤进行工艺上的改良，提高收率和反应速度，以适应大量制备的要求。
第二章
在甾体化合物的生物合成途径中，很重要的一步是经过分子重排形成异甾环(C-nor-D-homo)结构。该结构也是黎芦胺型(veratramine type)、介黎芦型(jervinetype)和瑟文型(cevanine type)生物碱的基本骨架。C-nor-D-homo甾环结构可由番麻皂苷乙酸酯的12β-对甲苯磺酰基取代物经Wagner-Meerwein Rearrangement反应得到。该反应的产物由不同比例的环外双键化合物C-nor-D-homo-Δ~(17a(18))-olefin与环内双键化合物C-nor-D-homo-Δ~(13(17a))-olefin构成，其中环外双键化合物为进一步合成异甾类生物碱的重要中间体。
本研究结合微波辐射促进有机合成反应的优点，如：加快反应速度，能提高产物的收率，纯度，某些反应具有选择性，方便后处理，污染小等，设计了一种利用微波辐射技术进行Wagner-Meerwein Rearrangement反应的方法，并初步探讨了该重排反应发生的机理以及不同溶剂条件，反应时间和功率对该反应速度，收率以及选择性的影响。
无水吡啶由于其沸点较高，极性较小并且具有一定碱性，是作为Wagner-Meerwein Rearrangement反应的最佳溶剂。微波辐射较长时间能够获得良好的收率，并且有利于得到预期的环外双键产物化合物。
第三章
本文对Cephalostatins和Ritterazines吡嗪双甾体的分离，合成以及构效关系研究进行了文献综述，参考了该类化合物从1988年发现至今(2009年)的72篇文献，为该类化合物的进一步开发利用提供依据。
This thesis is composed of three parts.The first part is about the synthesis ofC_(18)-functionalized C-nor-D-homo steroidal intermediate which is the basic skeletonof isosteroidal alkaloids and the optimization of the preparation process.The secondpart of my work focuses on the microwave promoted Wagner-MeerweinRearrangement of Hecogenin derivatives into C-nor-D-homo steroids.The third partis a review section on the chemical study,bioactivity assay and synthetic research ofCephalostatins and Ritterazines.
Part One
Isosteroidal alkaloids,widely distributed in Liliaceae family,including Veratrum andFritillaria,have proved to be the active components of many folk medicines.Theyare characterized by a C-nor-D-homo ring system and can be further divided intocevanine,veratramine and jervine types.The C_(27) cholestane carbon skeleton with five or six carbocyclic or heterocyclic ringsis made up of two structural units:(a) C-nor-D-homo skeleton;(b) an appropriateheterocyclic nitrogen system.
In our synthetic strategy,C-nor-D-homo steroidal derivative possessing the desiredαstereochemistry at C_(13) and an appropriate functionality at C_(18) has been synthesized byesterification,selective reduction,substitution,Wagner-Meerwein Rearrangement,hydroboration-oxidation,hydrolysis,oxidation,epimerization,reduction,esterrification,Baeyer-Villiger Oxidation with a total yield of 2%.The effects ofreaction solvents,catalysts,reaction time and other factors on the yields of each stephave been investigated and the optimization process has been discussed.
This work has achieved the goal of construction of basic A/B/C/D skeleton ofisosteroidal alkaloids for further synthesis of those compounds in veratramine type,jervine type and cevanine type.
Part TwoIn the biogenesis of steroids,an important step is to undergo molecularRearrangement to release C-nor-D-homo ring system carbon framework of which isclassified as the basic skeleton of isosteroidal alkaloids such as cevanine type,veratramine type,and jervine type from the Liliaceae family.Derivatives fromhecogenin acetate undergo solvolysis to give varying proportions of theC-nor-D-homo-△~(17a(18))-olefin 2 and the△~(13(17a))-isomer 3,depending upon the reactionconditions.Since no preferable synthetic methods for perfect formation of exocyclicolefin,an essential building block for C_(18)-functionalized isosteroidal derivatives,havebeen developed so far,the highly regioselective synthesis of 2 has been a topic ofinterest.
The recent findings have indicated that with the coupling of microwave irradiation,some chemical processes with special attributes are achieved,such as enhancedreaction rates,higher yields,greater selectivity and improved ease of manipulation.This methodology encouraged us to explore the Rearrangement of hecogeninderivatives into C-nor-D-homo steroids using microwave irradiation.The effects of reaction solvents,time,power and other factors on the yields of eachstep have been investigated and the mechanism in this process throughWagner-Meerwein Rearrangement has been discussed.We have found an efficientmicrowave-assitsted approach that is suitable for the Rearrangement of hecogeninderivatives into C-nor-D-homo steroids,which may offers advantages of shortreaction time,less amount of organic solvent,better isomer-selectivity,one-pottwo-step reaction and easy work-up.
According to the results,it has been found that anhydrous pyridine is the solvent ofchoice for the formation of 2 under these conditions,mainly due to its better solubilityof the substrate and its low polarity.
Part Three
The Cephalostatins and Ritterazines comprise a family of trisdecacyclic pyrazinesnatural products which are among the most powerful anticancer agents ever tested bythe National Cancer Institute.Our review on this topic has summarized the isolation,synthesis and structure-activity relationship study from the first discovery in 1988 tonow.It could be helpful to understand the history of these compounds and furtherdevelop their utilization.
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