Total Synthesis of the Marine Cyclic Depsipeptide Lagunamide D.

Lagunamide D is a structurally distinct 26-membered cytotoxic cyclic depsipeptide, originally isolated from a marine cyanobacterium. It exhibits potent antiproliferative activity in the low nanomolar range against A549 human lung adenocarcinoma cells and HCT116 colon cancer cells. A significant challenge associated with lagunamide D is its propensity for intramolecular acyl migration, which leads to the formation of a contracted 24-membered analog, lagunamide D'. This structural rearrangement complicates its isolation, characterization, and synthesis. In this study, the total synthesis of lagunamide D was achieved in a 14-step longest linear sequence, starting from the known intermediate , with an overall yield of 4.6%. The synthetic strategy involved several key transformations, including Ghosh's TiCl-promoted anti-aldol reaction, Corey-Bakshi-Shibata reduction (CBS reduction), cross-metathesis, Pinnick oxidation, and Yamaguchi esterification. Furthermore, this synthetic effort unambiguously confirmed the stereochemistry of the natural product.