Synthesis and biological evaluation of jasplakinolide analogs and studies toward a total synthesis of neopeltolide
Abstract
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.
Degree
Ph.D.
Advisors
Ghosh, Purdue University.
Subject Area
Chemistry|Organic chemistry
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.