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 en