Selective N-alkylation of azoles via anion-binding catalysis - Project Summary Azoles are ubiquitous amongst bioactive molecules, present in approximately one third of commercial pharmaceuticals. However, selective preparation of N-alkylated azoles is an outstanding synthetic challenge. As a result, stereochemistry and N-regioselectivity are often achieved through the separation of isomeric mixtures or introduced during de novo ring synthesis. This approach creates a significant synthetic barrier when evaluating analogs of bioactive molecules during drug discovery campaigns. Therefore, a selective method to install alkyl fragments on existing azoles is poised to advance the fields of chemical biology and medicinal chemistry. This proposal leverages anion-binding catalysis to induce enantio- and N-regioselectivity in azole alkylation. We will study how hydrogen-bond-donor catalysts engage azole nucleophiles through a network of noncovalent interactions to control selective nucleophile delivery. Aim 1. We are advancing an enantioconvergent SN1 reaction to form a-tertiary azoles. Aim 2. We are developing a novel method for N-regiocontrol to form the contra-thermodynamic azole product. The methods developed through this work will address long-standing challenges in azole chemistry, enabling the synthesis of medicinally relevant frameworks that are currently inaccessible. Additionally, the research plan will develop a deep understanding of the structural features required to engage azoles as competent nucleophiles in anion-abstraction catalysis, introducing a new class of nucleophiles to this approach. Beyond tackling a significant challenge in modern synthesis, I also designed my research plan to provide me with training in multiple important areas that I had limited exposure to in during my doctoral career. Through performing the proposed experiments, I will become proficient in asymmetric catalysis, supramolecular chemistry, carbohydrate chemistry, computational analysis, and mechanistic investigation. Furthermore, I will both enhance my existing synthetic repertoire through the synthesis of new catalyst architectures and become familiar with new experimental techniques such as measurement of enantioenrichment by HPLC. Therefore, the proposed research plan will prepare me with the skills I need to pursue an independent academic position.
