# Complementary Activation of Hydroxylamine Derivatives by Hydrogen-Bond Donor Catalysts to Enable Enantioselective Nitrogen-Atom Transfer Processes

> **NIH NIH F32** · HARVARD UNIVERSITY · 2021 · $65,994

## Abstract

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.

## Key facts

- **NIH application ID:** 10176167
- **Project number:** 5F32GM137576-02
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Melanie Ann Short Blackburn
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $65,994
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176167

## Citation

> US National Institutes of Health, RePORTER application 10176167, Complementary Activation of Hydroxylamine Derivatives by Hydrogen-Bond Donor Catalysts to Enable Enantioselective Nitrogen-Atom Transfer Processes (5F32GM137576-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10176167. Licensed CC0.

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