The depsipeptide lagunamide C was isolated by Tan and co-workers from the cyanobacterium Lyngbya majsucle in 2011 and was found to possess potent cytotoxicity towards various cancer cell lines: lymphoma (P388, IC50 24.4 nM), lung (A549, , IC50 2.4 nM), prostate (PC3, IC50 2.6 nM), colon (HCT8, IC50 2.1 nM), and ovarian (SK-OV3, IC50 4.5 nM). While it has impressive activity towards these five cancer types, synthetic efforts are being directed towards accessing this potentially game-changing natural product not only for its activity, but also to determine its final structural configuration. Four stereogenic centers within lagunamide C are in question, based upon comparison to structurally and genetic related compounds: aurlide, kulokekahilide, and palau’amide families of natural products. Three of these centers in question reside within the polyketide portion of lagunamide C, with the last within the pentapeptide backbone of the compound. In the efforts to determine the correct structural assignments within this compound, a robust and tunable three modular approach has been developed that will allow for the construction of all eight diastereomers of the polyketide through the use of select chiral auxiliaries, asymmetric Charette cyclopropanation with tandem ring-opens, and a facially selective reduction of a relatively non-biased ketone. Currently a model system has been undertaken to test each of these three key-steps, of which all of them have been successfully performed towards obtaining the desired functional group along with possible variability for diastereomer formation. To be presented will be the work accomplished on the model system, current efforts on the projected correct polyketide and diastereomers, the pentapeptide unit, macrocyclizations, and preliminary biological evaluation.

Lagunamide C: Efforts in total synthesis, biological evaluation, and drug delivery

255th National Meeting (2018)

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