UC San Diego

Natural products have long been looked to as sources for novel therapeutics. Perhaps the most notable example of a therapeutic natural product is the venerated Penicillin, which for decades was the gold standard for the treatment of bacterial infection. As bacterial infection has proliferated, Scientists have had to develop novel antimicrobial compounds, rather than isolating them from natural sources as they had done initially. An efficacious strategy for developing new drugs is through the diverted total synthesis of natural products, wherein analogs of natural products are synthesized to increase their potency while still maintaining the original biological profile imbued by their structural archetype. Taking inspiration from this strategy, we identified four natural products of related biological activity and conserved structural features. We resolved to substitute the shared structural motifs through total synthetic chemistry to generate new compounds in the hopes of developing a novel platform for antibiotic discovery. The first chapter of this thesis covers the synthetic studies toward this end. Our strategy demonstrates the ability to target different intramolecular Diels-Alder reaction pathways to selectively direct toward endo-axial or endo¬-equatorial decalins. It then covers our successful manipulation of this key intermediate to remove all protecting groups and chiral auxiliaries while avoiding undesirable side reactions. We then demonstrate our ability to install the requisite E-Z diene and tricarbonyl motifs to show the feasibility of our strategy to make the final natural product analogs.The second part of this thesis details a study into the fundamental reactivity modes of aminoboranes. Over the course of my studies on macrocyclic polyketides I experienced firsthand the intrinsic inefficiencies of synthetic chemistry. The compounding loss of material through each transformation can make the preparation of large quantities of final product challenging, even for longest-linear-sequences of twenty steps. The easiest way to avoid material loss is to shorten synthetic sequences by avoiding unnecessary steps and manipulations. Difunctionalization reactions, where two functional groups are installed in one synthetic transformation are a powerful way to shorten synthetic sequences. We identified aminoboranes as useful reagents for difunctionalization reactions because they are amphiphilic, giving us multiple activation modes from which to work; furthermore, amination and borylation reactions are of immense interest to the synthetic community and there is a dearth of difunctionalization reactions that use aminoboranes. We set out by examining the nature of coordination between aminoboranes and neutral Lewis bases in solution, using NMR spectroscopy to quantify coordination and chemical shift. We then determined the redox potential of aminoboranes using cyclic voltammetry. From these data we screened a library of commercially available photocatalysts and identified two that were competently quenched by aminoboranes. Finally, we derived Stern-Volmer quenching constants for these photocatalysts and our library of aminoboranes. Using these data we attempted to develop a difunctionalization reaction employing photoactivated aminoborane species, however these pursuits were unfruitful. Ultimately, we were able to discover and develop a ground-state carbene-insertion reaction of aminoboranes.