Total Synthesis Of Thiazole-Containing Marine Cyclopeptides Microcyclamides MZ602,MZ568,and Balgacyclamide C

This thesis first completed the total synthesis of the proposed structures of the marine natural products Microcyclamide MZ602 and MZ568.Our study revealed that the proposed structures of natural microcyclamides MZ602 and MZ568 required revision.Also,in this thesis,we completed the total synthesis of balgacyclamide C,a novel thiazole-containing marine natural product with potential antimalarial.1.Research on the total synthesis of marine natural products Microcyclamides MZ602and MZ568Cyclization of the small linear peptide,especially to all-L linear peptide precursor（6～8 amino acids）,remains a notoriously difficult task.Microcyclamide MZ602 was typical thiazole-containing all-L natural cyclic peptides,which was separated from marine cyanobacteria in 2010.In a limited biological screening,Microcyclamide MZ602 exhibited mild inhibitory activity against Molt4 cells（20%cell growth inhibition at 83μM）and displayed moderate inhibitory activity against chymotrypsin(IC₅₀=75μM).Our first convergent synthetic strategy towards Microcyclamide MZ602 is based on one-pot thiazole formation reaction from commercially available modified amino acids and classical HATU-mediated amide coupling.Unfortunately,the macrolactamization of linear precursor can not be promoted using a variety of condensation conditions.Fortunately,after changing the synthetic strategy and embeding two pseudoproline（ΨMe,Me Pro）into the linear peptide precursor,the macrolactamization problem was solved.We successfully completed the total synthesis of the proposed structure of Microcyclamide MZ602 in 11 linear steps with 12.5%yield.However,after careful comparison of the spectral data,although the ¹H NMR,¹³C NMR,and HRMS data of the synthetic compound were consistent with the natural product,the optical rotation value was opposite to the natural product.To solve the structure mystery of natural Microcyclamide MZ602,a series of control experiments were carried out.All results proved that we had completed the total synthesis of the proposed structure of Microcyclamide MZ602cyclo-[L-Thr-L-Phe-Synthesis of L-Thr-Gly-L-Ile（Thz）].Another secondary metabolite,named Microcyclamide MZ568,was isolated together with MZ602.Microcyclamide MZ568 and MZ602 have the similar structure and constituent amino acid residues.Biological studies showed that MZ568 exhibied good cytotoxicity towards the leukemia cancer cell line Molt 4（36%cell inhibitory at 1.8μM）.To further verify the structure of Microcyclamide MZ602,a similar synthesis strategy towards MZ568 was designed and carried out.Highlights of this synthetic strategy are as follows:1.One-pot thiazole formation reaction,2.Pseudoproline-assisted macrolactamization of linear precursor.Finally,we completed the total synthesis of the proposed structure of Microcyclamide MZ568（2-27）in 11linear steps with 16.8%yield.Unexprectedly,significant differences in ¹HNMR and ¹³C NMR spectrum were obsvered between the synthetic compound（2-27）and natural Microcyclamide MZ568 although the absolute configuration of key intermediate was unambiguously determined by single-crystal X-ray analysis.These results proved that the proposed structures of natural Microcyclamide MZ568 and Microcyclamide MZ602 in the isolation literature need to be revised.2.Research on the total synthesis of marine natural product Balgacyclamide CBalgacyclamides A～C were a class of novel thiazole-containing marine cyclic peptides,which were isolated from Microcystis aeruginosa（EAWAG 251）in 2014.Biological studies showed that both Balgacyclamides A and B exhibited good antimalarial activity.The IC₅₀ values of Balgacyclamide A and B towards the chloroquine resistant strain K1 of Plasmodium falciparum up to 9μM and 8.2μM,respectively.However,no biological activity of Balgacyclamide C was reported so far.To unravel the biological mystery,we carried out the total synthesis of Balgacyclamide C in this thesis.A[3+3]convergent synthesis strategy was designed and carried out.Highlight of this studies include:DAST-mediated oxazoline formation reaction,one-pot cascade thiazole formation,and HATU-mediated macrolactamation.We first completed the total synthesis of natural product Balgacyclamide C in 10 linear steps with 7.2%yield.Notably,all spectral data of the synthetic compound were completely consistent with the natural product.