Study On Synthesis Of C-nor-D-homo Steroids And Microwave Promoted Wagner-Meerwein Rearrangement

This thesis is composed of three parts.The first part is about the synthesis ofC₁₈-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 OneIsosteroidal 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 C₂₇ 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 C₁₃ and an appropriate functionality at C₁₈ 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-â–³^17a(18)-olefin 2 and theâ–³^13(17a)-isomer 3,depending upon the reactionconditions.Since no preferable synthetic methods for perfect formation of exocyclicolefin,an essential building block for C₁₈-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 ThreeThe 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.