Synthesis and biological evaluation of jasplakinolide analogs and studies toward a total synthesis of neopeltolide

This dissertation comprises the design, synthesis, and biological evaluation of nine new jasplakinolide analogs and studies toward a total synthesis of neopeltolide. Dissertation Chapter 1 explains the rationale for analog design, synthetic strategy, and biological results for new jasplakinolide derivatives. Jasplakinolide is an F-actin-inducer and potent cytotoxic agent, which has the potential to treat cancer. The general synthesis path which allowed access to these analogs was based on a previous route designed by our group for the synthesis of jasplakinolide. Key reactions include a Yamaguchi macrolactonization step, an Evans' syn-aldol reaction, and an efficient ortho-ester Claisen rearrangement. Structural changes to the non-peptide portion of jasplakinolide produced analogs which maintained potent anticancer activity. One compound, which has shown similar activity to jasplakinolide, was accessed via a simplified synthetic scheme and was less structurally complex than the parent molecule. This simplified analog presents an advantageous platform for further derivative studies. Chapter 2 of this dissertation details research toward a total synthesis of the marine natural product (+)-neopeltolide. Neopeltolide has shown impressive biological activity, including selectivity for certain cancer cell lines. Our synthetic strategy allowed for the construction of the macrocyclic core by utilizing a hetero Diels-Alder reaction catalyzed by Jacobsen's chromium tridentate complex. Additional key reactions include a Horner-Wadsworth-Emmons reaction, a Yamaguchi macrolactonization, and two Brown asymmetric allylations. Also described in this chapter is the recent progress toward a novel synthesis of the oxazole side chain of neopeltolide. The key reactions for the synthesis of the oxazole side chain are a copper-zinc coupling and a Wipf-type cyclodehydration reaction to form the oxazole ring. This approach to the oxazole side chain and the macrolactone should allow for access to novel derivatives.