Abstract: Lagunamides are a class of novel cyclic depsipeptides obtained from a marine cyanobacterium, Lyngbya majuscula. With an array of biological activity and impressive IC50 values including anti-malarial properties (IC50 0.19-0.91 micro-M), significant cytotoxic properties against P388 murine leukemia cell lines (IC50 6.4-20.5 nano-M) and Ileocecal colon cancer (1.6 nano-M), lagunamide A shows promise as an extremely powerful therapeutic agent. Unexpectedly, in a recent total synthesis of Lagunamide A, an incorrectly assigned configuration of stereochemistry was reported. Moreover, natural lagunamide A is isolated in 0.00012% yield from 15 L (~169 g isolated dry, powdered weight) of the cyanobacterium Lyngbya majuscule via arduous processes, reaffirming the need for an economically robust total synthesis to further encourage biological study. In light of this information we proposed an efficient alternative total synthesis. Through this optimized approach we synthesized the target molecule in significantly higher overall yield and greater selectivity. Specifically, remote stereocontrol via two iterative vinylogous Mukaiyama aldol reactions (VMAR) lead us to a formal total synthesis of the C27-C45 fragment in record yield. We explored both solution and solid phase peptide coupling methodology to construct the C1-C26 fragment of lagunamide A. 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. Our optimized convergent strategies lead to the synthesis of lagunamide A and a small library of analogs to be tested against malaria and cancer in the future. Acknowledgements: CSUPERB, NIH, US Army and the SDSU Foundation.

Synthesis of the potent anti-malarial, anti-cancer natural product, lagunamide A, via iterations of the vinylogous Mukaiyama aldol reaction

251st National Meeting (2016)

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