This research program (CA-19033), now in the twenty-eighth year, embodies our long-term commitment to the complete structural characterization and efficient, enantioselective synthesis of architecturally challenging anticancer agents. The principle goals for the 29-31 years can be divided into two major thrusts. In the (+)-phorboxazole area, we will: (A) deliver a minimum of one gram of (+)-phorboxazole A employing our now effective second-generation route, in order to make this important agent available for pre-clinical evaluation; (B) exploit the advanced phorboxazole intermediates for a detailed structure-activity study; (C) design and synthesize, guided by the structural activity results, less complex analogs; and (D) prepare chloroacetate, fluorescent, and radiolabeled photoaffinity analogs to define the protein receptor(s), binding site(s), and molecular mechanism(s) of action of this important antitumor agent. In the area of new target molecule/analog synthesis, we will: (E) complete our synthetic strategy for peloruside A; (F) design and synthesize, based on modeling studies, a series of (+)-peloruside A analogs to define the mode of action and binding site(s) of this new tubulin stabilizing antitumor agent; (G) complete the total synthesis of lituarines A, B and C, exploiting a non-aldol paradigm for the construction of polyketide structural units; and (H) initiate a new program directed at the total synthesis of the remarkably potent antitumor agents, (+)-irciniastatin A and B. In each case, the ultimate goal will be to deliver sufficient synthetic material for future biological study. In the area of new reactions/synthetic methods, the specific goals include: (I) develop and explore the scope of the non-aldol tactic to access diverse polyketide fragments of importance to complex molecule synthesis; and (J) demonstrate the utility of the non-aldol tactic for the ready construction of focused libraries based on known natural product scaffolds of biological interest. Beyond these specific synthetic objectives, a general, long-range goal of this program is the identification of the molecular architecture responsible for biological activity. Thus, as we develop an approach to each target structure, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships.
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