Studies On The Asymmetric Total Synthesis Of Melleumins

Depsipeptides with complex and diversified structures are widespread in nature. Many of them exhibit various biological activities, such as, antibiotic, antitumor, antiviral, immunosuppressive effect and pesticidal. As promising lead compounds in drug discovery, cylcopeptides are receiving more and more attention. And the studies on the asymmetric total synthesis of these compounds have become a new focus. A novel peptide lactone, melleumin A, and its seco acid methyl ester, melleumin B, were isolated from cultured plasmodium of the myxomycete Physarum melleun.At present, the total synthesis of melleumin A haven't been reported and the absolute stereochemistry at C-4 position remained undefined, thus the synthesis of such compounds is of important significance. In this dissertation, the malimides-based asymmetric synthesis methodology was expanded to the total synthesis of some depsipeptides, which includes melleumins A, 4-epi-melleumin A and 4-epi-melleumin B.The main results and observations made from these studies are listed as follows:1.N-Allyl-malimide was developed as a new variant of the malimides-based asymmetric synthesis methodology. Regioselective addition of BnOBnMgCI to 126 afforded an asymmetric synthetic access to the corresponding P-hydroxy-γ-amino acids.2.Starting from 126, the total synthesis of 4-epi-melleumin A was completed in9 steps with an overall yield of 5%,and the total synthesis of 4-epi-melleumin B wascompleted in 7 steps with an overall yield of 14%. 3.Starting from (S)-tyrosine, the first total synthesis of melleumin A was completed in 8 steps with an overall yield of 4.6%, which provided further evidence for all the absolute stereochemistries of melleumin A. 4.The Wnt signal inhibitory activity of the synthesized compounds was examined using a luciferase reporter gene assay, detected the novel structure of the melleumin group may be included as a candidate for a small-molecule Wnt signal inhibitor.