Part I: serial cycloadditions for the rapid assembly of synthetic building blocks and therapeutic leads, part II: new strategies for HIV eradication [electronic resource] : potent prostratin analogs induce latent HIV expression

My graduate studies have been focused on two separate projects that are unified by the theme of step economy and exemplify two major concepts within step economy. The first of these is the development of new reactions or serial reactions aimed at creating ways to achieve significant molecular complexity increases in a short synthetic sequence to access targets of value. Complementary to this is the concept of function-oriented synthesis, which involves the design and synthesis of novel structures of value that contribute to our understanding of the biological effects of the compound and results in the refinement of lead structures to produce clinically more optimal candidates. Chapter 1 reviews the development of serial cycloadditions and their application in organic synthesis. Serial cycloadditions are valuable reactions for organic chemists because of the significant increase in molecular complexity observed in a single step. The review separates the collective body of work into non-catalyzed serial cycloadditions and transition metal catalyzed cycloadditions. The non-catalyzed variants can involve the combining of simple starting materials into polycyclic ring systems, but are typically limited to more activated dienes or dienophiles. The transition metal mediated processes developed more recently have utilized unactivated reaction partners but, typically, rely on complex starting substrates. This review highlights the potential opportunity to develop serial cycloadditions that combine simple unactivated reaction partners to produce scaffolds of interest. Chapter 2 discusses the development of 4-trimethylsilyl-but-2-yn-1-ol as a regioselective butatriene equivalent for serial [5+2]/vinylogous Peterson olefination/[4+2] cycloadditions to produce linear polycyclic ring systems. 4-trimethylsilyl-but-2-yn-1-ol behaves as initial 2-carbon component in the Rh-catalyzed [5+2] cycloaddition with vinylcyclopropane and then subsequently eliminates to a diene that can be utilized for further elaboration. A diverse set of dienophiles was evaluated for the second cycloaddition and both alkynes and alkenes were found to be suitable reaction partners, with up to nearly quantitative yields obtained. The reaction was utilized to access a key intermediate for proposed simplified analogs of staurosporine. Chapter 3 begins by describing the current state of the HIV pandemic and the limitations of the current therapeutic options (Highly Active Antiretroviral Therapy - HAART). The principal barrier to developing a cure for HIV is the latent reservoir that is insusceptible to HAART. The natural product prostratin is a clinical lead for a promising HIV eradication strategy that involves the deliberate activation of these latent reservoirs. Novel analogs of prostratin were synthesized and found to exhibit activity that greatly exceeded the natural product in multiple biological assays. Most impressively, a lead analog was found to potently induce HIV expression in patient samples from HIV-infected individuals on suppressive HAART. Chapter 4 delves into the design, synthesis, and evaluation of 2nd-generation analogs of prostratin. These analogs were inspired by the realization of a key intramolecular hydrogen bond in prostratin and can be accessed in a more step-economical fashion than the original analogs because they circumvented a problematic deoxygenation step in the original synthesis. The new analogs that incorporated ether functionality at C12 of prostratin were found to have higher affinities for PKC, the presumed biological target for prostratin, and more potent induction of latent HIV in vitro and ex vivo. Finally, Chapter 5 describes the further manipulation of the prostratin scaffold in hopes of obtaining properties of a clinically optimized agent. Novel transformations on the scaffold are reported and preliminary biological evaluation of the new analogs is discussed. Based on these results, new information was obtained about the tolerability of the protein binding pocket for certain modifications and this will facilitate the future development of novel PKC modulators.

Keywords: Chemistry.
Advisor: Wender Paul A. primary advisor. Thesis advisor
Huestis Wray advisor. Thesis advisor
Kool Eric T. advisor. Thesis advisor