Synthetic and biological studies of (+)-phorboxazole A: Second-generation total synthesis of (+)-phorboxazole A. Synthesis and biological evaluation of phorboxazole analogues. Progress toward the gram-scale synthesis of (+)-chlorophorboxazole A.

This dissertation describes synthetic and biological studies related to the marine natural product, (+)-phorboxazole A. Specifically, a convergent second generation total synthesis of (+)-phorboxazole A, the total synthesis and biological evaluation of phorboxazole analogues and the synthesis of seventy-two milligrams of a sub-nanomolar phorboxazole congener, (+)-chlorophorboxazole A will be described. Chapter one details the isolation, structure elucidation and biological activity of (+)-phorboxazole A and B. Previous total syntheses of (+)-phorboxazole A and B will be described including, the Forsyth total synthesis of (+)-phorboxazole A, the Evans total synthesis of (+)-phorboxazole B and a detailed account of the Smith group first generation total synthesis of (+)-phorboxazole A.* Chapter two will detail the more efficient and convergent Smith group second generation total synthesis of (+)-phorboxazole A. Several highlights of the synthesis include the late stage Stille union of advanced oxazole stannane sidechain and macrocyclic vinyl iodide fragments to construct the complete phorboxazole carbon backbone. The oxazole stannane sidechain was the tetrahydropyranyl hemiacetal and thus completion of the sidechain. Construction of the macrocyclic vinyl iodide called upon the Petasis-Ferrier union/rearrangement tactic to assemble the two 2,6 cis-tetrahydropyran moieties. Utilizing olefination protocols, the E and Z-macrocyclic olefins were constructed and thus completion of the macrocyclic vinyl iodide.* Chapter three will detail the design, total synthesis and biological evaluation of simplified phorboxazole analogues. Modification of the phorboxazole sidechain and macrocycle afforded structurally and synthetically simplified congeners, wherein highly potent antitumor activity was discovered when evaluated against a panel of human tumor cell lines. Specifically, exchange of the phorboxazole C(45-46) E-vinyl bromine for the corresponding vinyl chlorine revealed a congener that displayed sub-nanomolar (nM) antitumor activity.* Chapter three will also describe the synthesis of seventy-two milligrams of the sub-nanomolar phorboxazole analogue, (+)-chlorophorboxazole A. Specifically, a comparison between the analogue and large-scale synthetic routes toward an advanced vinyl chloride sidechain will be detailed as well as the ultimate conversion to (+)-chlorophorboxazole A.* *Please refer to dissertation for diagrams