Study On The Total Synthesis Of Bioactive Marine Natural Products Of Hapalosin And Tubulysin V

In the life of the intrinsic, the human body is different from the ordinarycreatures, the vast majority of natural products with important physiological activitydoes not directly interact with the human protein. With the gradual deepening ofstructural biology, proteomics and chemical biology research to enable an effectiverole in biological macromolecules new target-oriented natural product librarysynthesis has become an important part of natural product chemistry. Diversitysynthesis of natural products is a direct source of drug discovery, the ultimatedestination is found the drug molecules can function in the human body. With thegradual depletion of land resources and the worsening of the human environment,sustainable development and maintenance of the balance of ecosystems has becomethe major issues of human lives and breeds. Therefore, based on the modern organicsynthesis of new approach, new technologies to carry out important physiologicallyactive natural product diversity synthetic interaction is of great significance to furtherreveal the natural product and organisms.In this thesis, the application of malic acid in the synthesis of marine naturalproducts Hapalosin and Tubulysins as the goal, the main results are as follows:1. Based on inexpensive malic acid as start materials, established a new methodby one pot of high selective synthesis of trans-4-hydroxy-5-substituted pyrroleamide (84a~k), which induced by a chiral tert-butyl-methanesulfonamide iminecofactor.2. Based on the above new method, established a new way of using inexpensivemalic acid as start materials for the synthesis of (3R,4S)-Statine; After protection,ring opening, and deprotection of the three-step reaction to give the (3R,4S)-Statine89, nearly85%yield. 3. Based on the above new method, completed the total synthesis of marinenatural product Hapalosin, which has a strong inhibitory effect against multi-drugresistance for tumor cells.First, by using Evans cofactor induced asymmetric Aldol reactions highselectivity prepared the chiral fragment112(dr>99:1) of Hapalosin molecules, thenusing such as Yamaguchi condensation reaction, prepared the precursor compound114of Hapalosin, and finally, the large ring cyclization in45%yield to giveHapalosin.4. Based on inexpensive malic acid as start materials, established a new methodof the high selectivity synthesis the key fragment Tuv224of Tubulysin V, whichinduced by a chiral tert-butyl-methanesulfonamideimine cofactor. 5. Based on Evans/chiral tert-butyl-methanesulfonamide cofactor inducedasymmetric alkylation/addition reaction, established a process for the preparation ofanother key fragment Tup209of Tubulysin V molecule.6. Based on the above fragment, the thesis initially explored the synthesis ofTubulysin V, because of the time, ultimately failed to obtain the target productisolated.