Towards the synthesis of cyclic depsipeptides Kohamamides A, B and C

Kohamamides A, B and C are cyclic depsipeptides that belong to the kulolide superfamily. These molecules present a β-hydroxyoctanoic acid coupled to well-defined amino acid or α-hydroxy acid residue sequences and have been isolated from the marine cyanobacteria Okeania sp. in Japan, 2017.1 Kohamamides chemical structures were elucidated by nuclear magnetic resonance (NMR) and mass spectrometry analyses. Isolated kohamamides showed pronounced cytotoxic activity against cell lines of human leukemia, being kohamamide B the most active (IC50 = 6.0 µM). In this context, we propose the first total syntheses of Kohamamides A, B e C, in a total of 15 steps. The synthetic retro analysis consisted in the fragmentation of main blocks, 4 and 5. Initially, the intermediates 2 and 3 were obtained with high yield (2, 79% for 2 steps, and 3 with quantitative yield) and the synthesis of fragment 11 in good yield (68%). Additional efforts will be directed to the synthesis of intermediate 1, followed by the coupling of 1, 2 and 11 to form fragment 4. Finally, the synthesis of 5 and coupling between the key intermediates 4 and 5 will furnish the desired natural products Kohamamides A, B and C. With the final compounds in hands, in vitro cytotoxicity evaluation will be conducted.