Abstract
MA026, a novel lipocyclodepsipeptide, exhibits selective antiviral activity against enveloped viruses such as influenza and herpes. An antiviral compound with complex depsipeptide structure like MA026 is scarce, and MA026 has the potential to inhibit viral infections with a novel mechanism. However, the availability of MA026 from natural resources is limited, therefore, the chemical synthesis is essential to accomplish the biological investigation. Here, we present synthetic studies to establish an efficient synthetic pathway to MA026. MA026 consists of (3R)-hydroxydecanoic acid, linear peptide six amino acids and cyclodepsipeptide eight amino acids. Nine of the amino acids posses the D-configuration. The retrosynthetic analysis of MA026 (1) is shown in Figure 2. MA026 was devided into three key segments to maximize the convergency : branched cyclic depsipeptide 2, tripeptide 3 and fatty acid moiety 4. Key to the total synsthesis of MA026 is the macrocyclization of depsipeptide, so we chose two macrocyclization sites, (A) D-Val - D-Leu and (B) L-Leu - D-Gln. Protected amino acids were condensed to gave tripeptide 3. Fatty acid moiety 4 was synthesized from n-octylaldehyde through samarium mediated Reformatsky reaction. The macrocyclization substrate 5 was prepared by the condensation of peptide fragments. Then, 5 was cyclized and the formation of branched cyclic peptide 2 was confirmed by mass spectorometry, however, the 2 was not obtained as a single compound. Five dipeptides were condensed to gave the macrocyclization substrate 6. Attempts to cyclize the precursor 6 is in progress.
