Total synthesis, stereochemical assignment, and antimalarial activity of gallinamide A

Abstract

The total synthesis and stereochemical assignment of gallinamideA, an antimalarial depsipeptide of cyanobacterial origin, is described. Synthesis of the four possible N-terminal diastereoisomers of gallinamideA (including the natural product symplostatin4) was achieved using a divergent strategy from a common imide fragment. The natural product and corresponding diastereoisomers were synthesized in 30-33% overall yield in a longest linear sequence of 8 steps. Comparative NMR spectroscopic studies of the four synthetic diastereoisomers with the isolated natural product demonstrated that gallinamideA possesses a dimethylated L-isoleucyl residue at the N-terminus. As such, we have shown that gallinamideA is structurally and stereochemically identical to symplostatin4. GallinamideA and its N-terminal diastereoisomers were also shown to possess significant antimalarial activity with IC 50 values in the nanomolar range against the 3D7 strain of Plasmodium falciparum. Naturally active: The total synthesis of gallinamideA, a cyanobacterium-derived depsipeptide, is described. Four N-terminal diastereoisomers of gallinamide A were prepared by using two key fragments (see scheme). Spectroscopic comparison to the isolated natural product enabled the absolute configuration of the N,N-dimethylated isoleucyl residue to be determined as 25S, 26S. GallinamideA (and its diastereoisomers) were also shown to possess potent antimalarial activity. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.