Project Summary / Abstract The prevalence of nitrogen-containing functionalities within health-relevant compounds is staggering. As such, synthetic methodologies to construct new carbon–nitrogen (C–N) bonds remain at the forefront of chemical innovation. The majority of investigations to date have been focused on the development of protocols to install C(sp2)–N linkages. Few advances have been made toward generalizable and stereoselective approaches to forging C(sp3)–N bonds, despite the recognized importance that three-dimensionality has on a compound’s biological efficacy. As a result, many C(sp3)–N-containing functional groups have been underevaluated as biochemical probes and therapeutic agents purely due to the difficulty of their preparation. Among the most challenging to install are unprotected nitrogen moieties, such as primary amines and unprotected aziridines. Current strategies to construct these motifs are plagued by multistep synthetic sequences, require precious transition-metal catalysts, or necessitate the use harsh reaction conditions and potentially hazardous reagents. To overcome these challenges, the proposed research engages organocatalysts to promote enantioselective nitrogen-atom transfer processes. Complementary modes of activation of a common and readily accessible synthetic precursor will deliver a diverse array of challenging synthetic targets. The research plan outlines specific tactics that will enable the desired transformations through identification of appropriate hydrogen-bond (H-bond) donor catalyst systems, which will serve to activate hydroxylamine derivatives through networks of covalent and non-covalent interactions. While H-bond donor organocatalysis has been adopted as a powerful strategy to convert simple starting materials into highly enantioenriched products, it has seen very limited use in asymmetric nitrogen-atom transfer reactions. Thus, mechanistic interrogation of the proposed processes will provide valuable insight into catalyst control over nitrogen installation, where current data for such technologies is scarce. The envisioned methodologies will deliver enantioenriched a-amino carbonyl and unprotected aziridine architectures, which are poised for further synthetic manipulation or direct biological evaluation. By improving access to these high-value functional motifs, underexplored molecular scaffolds will be surveyed in biological contexts, leading to discovery of new pharmaceutical leads and improvements in therapeutic technologies, ultimately advancing human health.