Studies On The Synthesis Of Natural Product Thalassosamide

Due to the widespread use of antibiotics,especially the abuse of antibiotics,the bacterial resistance has been steadily increasing in recent years,.The emergence of multidrug-resistant(MDR)bacteria,especially superbacteria,has caused a serious threat to human health and safety.The Trajan Horse strategy for antibiotic discovery has become an active area,which couples an antibiotic with a siderophore in an appropriate way to enhance the antibacterial activity and safety of antibiotics employing the siderophore transport system unique to bacteria.A number of siderophore antibiotic conjugates have been developed.Thalassosamide is a macrocyclic hydroxamic acid siderophore natural product,which was isolated from thalassospira profundimaris.Thalassosamide could effectively inhibit the growth of Pseudomonas aeruginosa(MIC=64 μmol/L).There have been no reports on the synthesis and structural modification of the trimeric cyclic siderophore compounds represented by thalassosamide.Therefore,the research on the synthesis of thalassosamide is of significance: Firstly,it can expand the source of thalassosamide,allowing access to large quantities of thalassosamide;Secondly,the trimer structure of thalassosamide can be modified through traditional medicinal chemistry strategies,which could lead to the discovery of new compounds with improved antibacterial activity.Lastly,thalassosamide can be used as siderophore to couple with antibiotics for antibiotic conjugate studies.In this thesis,three synthetic routes for natural product thalassosamide were designed and explored starting from commercially available D-lysine hydrochloride and(S)-3-hydroxybutyrate methyl ester.The monomeric fragment of thalassosamide was synthesized in 11 steps.In its synthesis,classical organic reactions and protecting group strategies such as BPO oxidation,ester hydrolysis and condensation,have been utilized.During the optimization of the transformation,a number of difficulties,such as low yield,poor selectivity and racemization were overcome.These studies have laid a foundation for the total synthesis of thalassosamide.