The Syntheses Of Lycopodium Alkaloids Phleghenrine A And(±)-Cermizines B-D

This dissertation is composed of four chapters.Chapter 1 briefly introduced some syntheses of Lycopodium alkaloids.In chapter 2,we discussed the study on the synthesis of the phleghenrine A;In chapter 3 and 4,we discussed the syntheses of（±）-cermizine B and（±）-cermizines C-D.We attempted to synthesize phleghenrine A by multiple Diels-Alder reactions and Heck coupling reaction.The total synthesis of（±）-cermizine B was achieved by 9steps and 24%total yield.Through the four-step reaction and the five-step reaction,we completed the total synthesis of（±）-cermizine D and the formal synthesis of（±）-cermizine C.These syntheses include Diels-Alder reaction,selected Michael addition,Heck coupling reaction,Dess-Martin oxidation,Luche reduction,Krapcho decarboxylation,and PtO₂ hydrogenation.Chapter 1.Syntheses Introduction of Lycopodium AlkaloidsLycopodium alkaloids,which are isolated from plants of Lycopodium and their related,are natural alkaloids.Lycopodium alkaloids have the same source pathway,similar structure,uniqueness and variable structure.Lycopodium family mainly include plants of the family Huperziaceae and Lycopodiaceae.In 1881,German scientist Bodeker isolated the first lycopodium from Diphasiastrum complanatum（L.）Holub.In 1986,Liu Jia-sen and his co-workers isolated the most representative alkaloids: huperzine A from H.serrata,which is a folk medicinal plant in China.In This chapter,we introduce the structure types and biosynthetic pathways of Lycopodium alkaloids.A brief introduction to some of the representative examples of total synthetic work of Lycopodium alkaloids.According to the structural type of Lycopodium alkaloids,we list some recent achievements in total synthesis of Lycopodium alkaloids.Chapter 2.The Total Synthesis of Lycodine-type Lycopodium alkaloid Phleghenrine APhleghenrine A,which isolated from Phlegmariurus henryi（Baker）Ching,is a new Lycopodium alkaloids and contains 6/6/7/6 ring skeleton.This new alkaloid contains a bicyclo[3.2.2]nonane structure that was first discovered in the Lycopodium alkaloids.In addition,phleghenrine A showed a good inhibitory effect on ACh E through biological activity screening experiments.Moreover,some inhibitory effects on Bu Ch E have also been performed.In this chapter,we attempts to synthesize phleghenrine A through two synthetic routes.The first synthetic route is based on the construction of a bicyclo[3.2.2]nonane skeleton by multiple Diels-Alder reactions.The second synthetic route is based on Heck coupling reaction.Chapter 3.The Synthesis of Phlegmarine-type Lycopodium alkaloid（±）-Cermizine BCermizine B is a phlegmarine-type alkaloid that belongs to the Lycopodium family,which was isolated from the club moss Lycopodium cernuum in 2004 by Kobayashi and co-workers.This compound is structurally characterized by a 5,7-disubstituted decahydroquinoline ring and a C16N2 tricyclic skeleton and exhibits promising cytotoxicity against murine lymphoma L1210 cells（IC50 = 5.5 μg/m L）.In this chapter,a practical total synthesis of（±）-cermizine B was successfully accomplished in 24% overall yield using a process requiring only seven steps from methyl 4-methyl-6-oxocyclohex-1-ene-1-carboxylate.On this basis,after consulting the literature,we optimized the reaction route via using acrolein instead of acrylonitrile as the secondary Michael addition electron acceptor.Chapter 4.The Total Synthesis of Cernuane-type Lycopodium alkaloid（±）-Cermizine D and The Formal Synthesis of（±）-Cermizine CCermizine C and D,are members of the cernuane-type alkaloids,which are structurally characterized by a 5,7-disubstituted quinolizidine ring.Along with cermizine A and B,cermizine C and D were isolated from the club moss Lycopodium cernuum in 2004 by Kobayashi and coworkers,and cermizine D was found to exhibit significant cytotoxicity against murine lymphoma L1210 cells（IC50 = 7.5 μg/m L）.In this chapter,a practical total synthesis of（±）-cermizine D and a formal synthesis of（±）-cermizine C were successfully accomplished in 13.7% and 29.7% overall yield through two effective sequences from commercial methyl crotonate.These syntheses will benefit the syntheses of other cernuane-type alkaloids and ring-fused Lycopodium alkaloids.