Design And Synthesis Of New Artemisinin Derivatives;Studies On The Total Synthesis Of Daphenylline

ObjectiveIn order to provide some new antimalarial drug candidates with higher activity and low toxicity and to face the challenges brought by artemisinin resistance in the future,some new artemisinin derivatives were designed and synthesized from 7?-hydroxy artemisinin which were obtained by microbial fermentation technology.And some piperazine ring derivatives were designed and synthesized to provide synthetic blocks for medicinal chemistry.To study on the total synthesis of a special Daphniphyllum alkaloids named Daphenylline,which contains a 6?electron conjugated system.And also aimed to provide a feasible method for the total synthesis of other Daphniphyllum alkaloids analogues.Methods1.7?-hydroxy artemisinin,a new artemisinin mother nucleus structure,were prepared from artemisinin(Qinghaosu)by using the method of microorganism fermentation.2.The mono N-protected piperazines were reacted with acyl chloride or halogenated alkane under the catalysis of triethylamine.Then the obtained products were deprotected by hydrochloric acid to prepare the new monosubstituted piperazine derivatives.3.Artemisinin Derivatives were synthesized from 7 ?-hydroxy artemisinin with different acyl chlorides under the base catalysis.4.The final products were identified by HRMS,'H-NMR,and 13C-NMR spectroscopic methods.5.A synthetic method is that triphosgene,N,N-carbonyldiimidazole,and 4-nitrophenyl methyl chloride were along reacted with ?-hydroxyl artemisinin so as to obtain various artemisinin carbamate derivatives.6.Dihydroartemisinin was converted into bromine alkyl ether,and the product was reacted with different amines.7.In the total synthesis research of the Daphniphyllum alkaloids Daphenylline,a Horner-Wadsworth-Emmons reaction starting from 2-acetyl-5-methyl pyridine and indene phosphonate derivatives was performed,and an enone with E geometry was obtained as a major product.Then,numerous reactions including intramolecular Michael addition were carried out,aiming to find out an efficient intramolecular cyclization reaction.ResultsA new artemisinin structured 7 ?-hydroxy artemisinin and three new analogues were obtained by microorganism fermentation.Some ester and ether derivatives can be obtained successfully.Although amino acid ester and piperazines derivatives were failed,sixteen monosubstituted piperazines with various side chains were prepared as building blocks.The total synthesis of Daphniphyllum alkaloids Daphenylline starting with indene is involved alkylation,reduction,phosphorylation,synthesis of olefinic bond,and cyclization reaction as the key steps.ConclusionThe failure of amidation reaction of artemisinin may be related to the destruction of 7?-hydroxy artemisinin in the process of using alkaline reagents.A feasible method for the establishment of various monosubstituted piperazine side chains is developed.