# Development of Biocatalysts for Chemodivergent Functionalizations of Heterocycles

> **NIH NIH F32** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2023 · $69,080

## Abstract

PROJECT SUMMARY/ABSTRACT
 Methodological advances that allow for rapid and efficient access to a wide range of functionalized
heterocycles are imperative for streamlining drug discovery processes. Given the vast ubiquity of heterocycles
in bioactive compounds, the functionalization of existing heterocycles is a common strategy used to tune
important pharmacological properties of drugs. Cyclopropanations of heterocycles represent a particularly
attractive strategy to achieve synthetic diversification, as the corresponding fused bicyclic frameworks are not
only present in bioactive small molecules, but are key chemical synthons en route to more complex scaffolds.
The resultant motifs are classified as donor-acceptor cyclopropanes (or push-pull cyclopropanes) and exhibit
unique proclivities toward cyclopropane ring opening and subsequent reactivity. Transition metal complexes
have been used to access these important synthetic frameworks through metal-carbenoid cyclopropanation
reactions, however many of these strategies suffer from low levels of chemo and/or stereoselectivity or depend
on a specific class of carbene precursor to achieve high selectivity. Alternatively, enzymes can impart exquisite
chemo-, regio-, and stereoselectivities in reactions that are challenging in small molecule catalysis. Directed
evolution has provided a powerful platform by which Nature’s enzymes can be repurposed to develop new-to-
nature chemical transformations, including engineered P450 enzymes capable of olefin cyclopropanation and
C‒H functionalization. The focus of this proposal is to expand the breadth of activity of engineered iron-heme
carbenes to include cyclopropanations of heterocycles and to investigate their capacity to elicit cascade reactions
on the corresponding cyclopropanes. The specific aims are (1) to evolve hemoprotein variants capable of
catalyzing asymmetric cylopropanations of heteroarenes, (2) to expand the scope of this activity to a variety of
N-heterocycles, particularly those with no current asymmetric counterpart, and (3) to exploit the hydrogen-
bonding network of enzymes to harness the ring-opening reactivity of the corresponding push-pull
cyclopropanes. The overall goal is to develop an enzyme-controlled chemodivergent platform for the diversified
synthesis of functionalized heterocycles. On a practical level, such a development would represent a powerful
tool for medicinal chemists and would provide rapid and efficient access to privileged molecular frameworks in a
library fashion. Fundamentally, the proposed research will expand our understanding of enzymatic cascade
reactions and explore new catalytic processes that could inspire developments across all pillars of catalysis.

## Key facts

- **NIH application ID:** 10609441
- **Project number:** 5F32GM143797-02
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Jennifer L. Kennemur
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $69,080
- **Award type:** 5
- **Project period:** 2022-04-10 → 2025-04-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10609441

## Citation

> US National Institutes of Health, RePORTER application 10609441, Development of Biocatalysts for Chemodivergent Functionalizations of Heterocycles (5F32GM143797-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10609441. Licensed CC0.

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