Synthetic Studies Towards The Cyclic Peptide Ilamycins

Ilamycins are a series of cyclopeptides isolated from the fermentation of marine Streptomyces atratus SCSIO ZH16 by Jianhua Ju,a professor from South China Sea Institute of Oceanology,Chinese Academy of Sciences.Bioactivity studies reveal that the Ilamycin E has a potent inhibitory effect to mycobacterium tuberculosis H37Rv(MIC = 9.8 nM),the selectivity indexs between anti-tuberculosis activity and cell toxicity are 400 to 1500,indicating a safety profile for the compound.Spectra analysis indicates that Ilamycins are cycloheptapeptides and possess a unique L-3-nitro-tyrosine moiety and L-2-amino-4-hexenoic acid structural unit,the latter has not yet been reported in other natural products.Therefore,the total synthesis of Ilamycins and their biological mechanism studies as well as the structure-activity relationship of Ilamycins are especially important.In this thesis,a [3+4] convergent strategy was applied to the total synthesis of Ilamycin B1,and the ring opening site was the peptide bond between L-Ala and L-3-nitro-tyrosine moieties.The key steps include the construction of the unique L-2-amino-4-hexenoic acid unit by Negishi coupling reaction and synthesis of N-substituted fluorene double bond by palladium catalyst.Moreover,the [3+4] synthetic strategy was also applied to the total synthesis of Ilamycin E1.Considering the steric effect,the peptide bond between N-substituted-L-trptophan with double bond and L-2-amino-4-hexenoic acid was chosen as the ring opening site,the acid labile 3-amino-6-hydroxy-2-piperidone(Ahp)unit was envisioned to be introduced at the late stage through Dess-Martin reaction.The key units have been synthesized successfully.Further optimization about protecting group and coupling condition will be conducted.Finally a high yield and efficient route of the total synthesis of Ilamycin E1 should be obtained.The implementation of this thesis provides an important preliminary result for the total synthesis of Ilamycins,and laid a solid foundation for further development of the molecules as anti-tuberculosis drugs.