| Euphorbia L.is the largest genus in Euphorbiaceae.There are about 2160species in the world and more than 80 species in China.Most species of this plant have a long history of medical use and indicate important values in medicine.Macrocyclic diterpenoids and polycyclic diterpenoids are the main characteristic components feature anti-tumor,antibacterial,anti-HIV,anti-inflammatory and analgesic effects.As a traditional Chinese medical material,Leptochloa chinensis（L.）Nees,dried mature seeds of Euphorbia lathyris L.located in more than 10 provinces in China.In this thesis,the macrocyclic diterpenoids and biological activity of Leptochloa chinensis（L.）Nees purchased from Yuzhou were studied starting from phytochemical research,and a total of 9 macrocyclic diterpenoids were isolated and identified.Among them,two new compounds(Euphorbia factor L27,Euphorbia factor L28)were found for the first time with the C3-αconfiguration Lathyrane diterpenoid types.The in vitro antitumor activity of these compounds were tested.The new compound(Euphorbia factor L28)exhibited significant inhibitory effects on human breast cancer cells（MCF-7）and human liver cancer cells（Hep G2）.Then,skeletal transformation of the isolated Euphorbia factor L1 occurred through a Lewis acid-mediated tandem reaction,and the biogenetic relationship of the three types of euphorbia diterpenes skeletons was verified chemically.Subsequently,through the analysis of the new skeleton compounds,we obtained a new method for the synthesis of arylpyrrole compounds with cyclopropyl ketone as the substrate.Finally,this method was used to concisely complete the synthesis of a natural polyhydroxy alkaloid（–）-codonopsinine,further expanding the methodology.This thesis has done the following work:1.Preparation of lathyrol study on the diterpenoids in Qian JinziQian Jinzi（Leptochloa chinensis（L.）Nees）is the dry mature seed of Euphorbia lathyris L.which is distributed in more than 10 provinces in China and is a traditional Chinese medicinal material.In this thesis,three kinds of high-consistent alcohols from Qian Jinzi purchased from Yuzhou City,Henan Province were prepared;the diterpene components in the remaining part were studied,a total of nine C20macrocyclic diterpenoids were isolated and identified,all of which were lathyrane type.There were two new compounds(Euphorbia factor L27,Euphorbia factor L28)among them.Euphorbia factor L27 and Euphorbia factor L28 are both the first C3-αformed type diterpenes.The known compounds include Euphorbia factor L1-3,Euphorbia factor L7a,Euphorbia factor L8-9and Euphorbia factor L26.The effect of the isolated compounds on the proliferation inhibition rate of human breast cancer cells（MCF-7 and MDA-MB-468）,human kidney cancer cells（786-0）and human liver cancer cells（Hep G2）cultured in vitro was evaluated by MTT assay.Euphorbia factor L28 has a significant inhibitory effect on MCF-7 and Hep G2 cells,with IC50values of 9.43μM and 13.22μM respectively(IC50 of positive control drug DDP was 16.55μM and 2.29μM,respectively),which is expected to be developed as a new antitumor drug.2.Transformation of Euphorbia diterpenes skeleton and biogenesis analysisUsing a large number of easily available Euphorbia factor L1 as raw material,different series-linked reactions occurred in different solvents under the catalysis of BF3:1)With the participation of ethyl acetate,two natural Diterpenes（Euphoractine B and Myrsinol）and an unnatural tetracyclic diterpene of type 5/7/7/4 were obtained;2)With the participation of acetonitrile,acetonitrile was as nitrogen source to introduced nitrogen atom to the macrocyclic skeleton,forming three types 8 new diterpenes"alkaloids",including four Euphoractine A,one Euphoractine B,and three non-natural 5/7/7/4 diterpene"alkaloids".The biogenic inference of several diterpenes of euphorbia has been confirmed from a chemical perspective.At the same time,the MTT assay showed that each compound had no inhibitory activity against the proliferation of four cancer cells cultured in vitro.3.Methodological study inspired by the transformation of Euphorbia diterpenes skeleton:Synthesis of arylpyrrole compoundsBased on the interesting reaction of Euphoractine B-type diterpene"alkaloids"containing oxazine ring obtained in 2,a methodology of"one-pot"synthesis of arylpyrroles using acetonitrile as the nitrogen source and cyclopropyl ketone as the substrate was constructed.The process involves tandem cyclopropyl ring-opening amination followed by cyclization and rearrangement.The influence of solvent,temperature,reaction time and Lewis acid on the reaction was investigated,and more than 30 kinds of substrates were expanded.The study found that the ring closure mechanism is related to the substituents on the cyclopropyl group.In addition to arylpyrrole compounds,arylpyrrolidone organisms can also be generated.The method with simple and mild reaction conditions,good substrate compatibility and without metal catalysts or metal additives was green and environmentally friendly.It could provide an efficient strategy for total synthesis of natural products and drug development.4.Methodological applications:Synthesis of（–）-codonopsinineThe methodology developed in 3 was applied to the total synthesis of natural polyhydroxyalkaloid（-）-codonopsinine.By the"one-pot"method,the key intermediate 2-（p-methoxyphenyl）-5-methyl-3,4-dihydropyrrole was quickly synthesized.The formal synthesis of（–）-codonopsinine was achieved efficiently by two"one-pot methods"with general bromination,reduction,and elimination,providing methods for the total synthesis of similar natural products. |
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