Enantiospecific Route To Marine Sponge Medicinals

Starting with just acetylene, iodoaniline, and five naturally occurring amino acids, chemists in California have managed to assemble two members of the kapakahine family of cyclic peptide natural products (J. Am. Chem. Soc., DOI: 10.1021/ja901573x). The kapakahines, originally isolated from the marine sponge Cribrochalina olemda, have shown promise as antileukemia agents. But the compounds' scant availability has prevented scientists from fully exploring their bioactivity. Phil S. Baran, Timothy Newhouse, and Chad A. Lewis, of Scripps Research Institute, in La Jolla, developed an enantiospecific synthesis of kapakahines B and F. These compounds feature a heptacyclic ring system that contains a twisted 16-membered macrocycle and a hindered quaternary center. Highlights of the synthesis include a direct indole-aniline coupling to form the quaternary center in a stereocontrolled manner and the use of dynamic equilibrium to shift the molecule's topology. With the exception of the last two stages of the synthesis, each reaction in the Scripps team's route can be performed with gram quantities of material. This scale makes it possible for the chemists to pursue more potent kapakahine analogs, as well as compounds that could provide insight into the natural products' mode of action.