Lagunamides are an interesting group of macrocyclic depsi-peptides with excellent anti-malarial and anti-cancer properties. Recent experiments suggest the mode of action of the natural product as an intrinsic apoptotic pathway by cleavage of capsase-9, activating a downstream cascade that results in mitochondrial-mediated apoptosis, a popular target for therapeutics. With an array of biological activity and impressive IC50 values including anti-malarial properties (IC50 0.19-0.91 mM), significant cytotoxic properties against P388 murine leukemia cell lines (IC50 6.4-20.5 nM) and Ileocecal colon cancer (1.6 nM), Lagunamide A shows promise as an extremely powerful therapeutic agent, presenting the need for an efficient total synthesis of the target compound. We present a highly convergent asymmetric synthetic route to establish five of the 10 crucial stereocenters that form the absolute stereochemical backbone of the Lagunamide A target compound. Specifically; two highly stereoselective VMARs (Vinylogous Mukaiyama Aldol Reactions) are employed to establish 4 contiguous stereocenters in high yield and excellent diasteromeric ratios. Moreover, new and optimized convergent strategies introducing methodologies for coupling of N-methylated unnatural peptide fragments, completed via solid phase synthesis, to afford an advanced functionalized pentapeptide fragment will be presented. In addition, several advanced synthetic intermediates will be presented, all of which have been fully characterized by NMR spectroscopy, X-ray crystallography, FTIR, HPLC and LCMS. We will present our tunable total synthesis of Lagunamide A, which also enables points of diversity necessary for accessing a large and diverse molecular library of anticipated bioactivity. Analogs for structure-activity relationship (SAR) experiments and cell tests against malaria and various cancers are set as future work. Acknowledgements: NIH, US Army and the SDSU Foundation

Highly stereoselective total synthesis of Lagunamide A

249th National Meeting (2015)

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