Study On The Synthesis And Activity Evaluation Of Daphniphyllum Alkaloid Calyciphylline N

As a kind of complex terpenoid alkaloids with polycyclic condensation characteristics,daphniphyllum alkaloids exhibit rich and diverse biological activities.However,due to the scarcity of isolation sources,the systematic study on the alkaloid activity and action mechanism of daphniphyllum alkaloids have not been clearly described and reported.Pharmacological activity screening requires a large number of compounds(including the requirements for the amount of tested compounds)as the research basis,which is difficult to be met by traditional plant isolation.Chemical synthesis can not only realize the total synthesis of target natural products,but also realize the synthesis of diversity oriented natural products,so as to establish a “compound library” for systematic biological activity research.Chapter 1 of the thesis,the structural classification,biological activity,biogenic synthesis hypothesis and synthesis of daphniphyllum alkaloids are summarized,with emphasis on the research progress of chemical synthesis of daphniphyllum alkaloids.Since the first separation of daphniphyllum alkaloid,in 1909,more than 320 such compounds have been found.Compared with its huge family,at present,only more than 20 daphniphyllum alkaloids have achieved total synthesis.The development of more efficient aggregation synthesis strategies are still a hot issue in the research of daphniphyllum alkaloids.Chapter 2 of the thesis,we carefully analyzed the published reports on the total synthesis of Daphmanidin A-type daphmanidin alkaloids,pointed out the advantages and disadvantages of the routes,and put forward the key synthesis strategy of Boc-Mediated oxidative dearomatization/Diels–Alder Approach,so as to carry out the synthesis of Daphmanidin A-type daphmanidin alkaloid Calyciphylline N.Preparation of precursor substrate by oxidative dearomatization;Exploration of oxidative dearomatization reaction;Exploration of constructing [6.6.7.5] tetracyclic skeleton by oxidative dearomatization/intramolecular Diels–Alder reaction;Further exploration of oxidative dearomatization/intramolecular Diels–Alder reaction;The strategies of construction of four ring skeleton and quaternary carbon center were discussed in detail.Finally,using commercially available 2,5-dimethylphenol as the starting substrate,we have successfully synthesized the [6.6.7.5] tetracyclic core of Calyciphylline N using a sequence of Boc-mediated oxidative dearomatization,intermolecular Diels-Alder reaction,intramolecular radical cyclization in 15 steps and 4% yield.The investigation of the oxidative dearomatiza-tion/IMDA reaction of such carbonate tethered ortho-quinols was also tested,giving [6.6.8.5] tetracyclic skeletons.In addition,the thesis preliminarily evaluated the biological activity of some advanced intermediates(2-116、2-133、2-134)prepared during the synthesis of Calyciphylline N.The results showed that the synthesized compounds showed no inhibitory activity on Breast cancer cells(MDA-MB-231).