# Biocatalytic C–H Functionalization Forms Nitrogen Heterocycles

> **NIH NIH F32** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2022 · $52,427

## Abstract

PROJECT SUMMARY & ABSTRACT
 Nitrogen heterocycles are ubiquitous pharmacophores found in nearly 60% of all pharmaceuticals. Despite
the prevalence of these moieties there are no catalyst classes that form C–N bonds enantioselectively to produce
diverse nitrogen-containing heterocycles (i.e. cyclic amines and lactams) in an industrially viable fashion.
Therefore, developing catalysts for direct and expedient access to nitrogen heterocycles is of great synthetic and
medicinal interest. A desirable method for nitrogen heterocycle synthesis is using intramolecular nitrene insertion
reactions to form a new C–N bond. The laboratories of Breslow, Du Bois, Betley, and Zhang have laid the
instrumental groundwork for developing these nitrene insertion reactions. But, current precious metal catalysts
are limited and display little to no enantioselectivity. Engineered enzyme catalysts can solve this longstanding
synthetic challenge as they have exquisite regio-, chemo-, and stereo-selectivity in mild conditions with fast
kinetics and are biosynthesized from renewable materials. Ongoing research on engineered hemoproteins
shows that they catalyze an ever increasing number of asymmetric reactions of carbenoids and nitrenoids.
 I propose to engineer hemoproteins to catalyze C–N bond formation by nitrene insertion reactions to directly
form important nitrogen-containing heterocycles (i.e. cyclic amines and lactams). Such reactions are unknown
in Nature and grant ready access to numerous bioactive molecules. The specific aims are: (1) to develop
hemoproteins for nitrene C–H insertion reactions to form cyclic amines; (2) to develop hemoproteins for nitrene
C–H insertion reactions to form lactams; (3) rationalize the origins of selectivity in developed hemoproteins for
engineering new reactivity. I will begin by screening compilation plates containing hundreds of the Arnold
laboratory’s hemoproteins that catalyze various carbene and nitrene transfer and insertion reactions against five
safe and easy-to-synthesize nitrene sources. This process will identify an enzyme-nitrene-source pair to optimize
with directed evolution. After multiple rounds of evolution, I will then analyze the biocatalyst evolutionary
trajectory with computational models to guide future evolutionary campaigns and streamline choosing mutational
sites for evolving enzymes to catalyze new-to-Nature reactions. In total, development and implementation of
such biocatalysts will allow for sustainable and asymmetric syntheses of highly valuable commodity chemicals,
pharmacophores, natural products and pharmaceuticals.

## Key facts

- **NIH application ID:** 10464644
- **Project number:** 1F32GM145009-01A1
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Cooper Stergis Jamieson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $52,427
- **Award type:** 1
- **Project period:** 2022-07-06 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464644

## Citation

> US National Institutes of Health, RePORTER application 10464644, Biocatalytic C–H Functionalization Forms Nitrogen Heterocycles (1F32GM145009-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464644. Licensed CC0.

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