# Access to Strained Rings and Heterocycles: Applications in the Synthesis of Bacterial Metabolites and Chemical Building Blocks

> **NIH NIH K99** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2024 · $125,000

## Abstract

Project Summary/Abstract
The studies described in this proposal seek to develop strategies for the synthesis of strained rings and
heterocycles for two purposes: 1) the first total syntheses of novel azetidine-containing metabolites, and 2) rapid
access to bifunctional strained ring and heterocycle building blocks. Regarding the first purpose, total syntheses
of azetidomonamide A, azetidopyridone, and diazetidomonapyridone do not exist and are sorely needed so their
biological functions in quorum-sensing behavior can be evaluated. These metabolites affect biofilm formation
and production of redox-active metabolites in P. aeruginosa, which is partially implicated in adverse outcomes
for cystic fibrosis patients. Thus, total syntheses of these metabolites are highly needed and will have a broader
impact on human health through expanding understanding of biofilm formation by P. aeruginosa, and potentially
allowing for development of anti-virulence treatments for it in the long term. For the second purpose, strained
rings and heterocycles are increasingly prevalent in pharmacological motifs; strategies to access modular
components are needed to enable expedient diversification and access to new bioactive molecules.
 For the syntheses of azetidomonamide A and diazetidomonapyridone (K99), we envision the
development of intramolecular cyclization reactions to establish key challenging frameworks in the molecules,
such as Z-exocyclic azetine moieties, 4/6 bicyclic pyridones, and 4/7 bicyclic carbamates. These efforts will not
only allow us to establish the total syntheses of these metabolites, but contribute more broadly to chemical
synthetic efforts in the development of new reactions to access these strained heterocyclic motifs.
 In the R00 component, we propose the development of organometallic methods to achieve the syntheses
of bifunctional strained ring and heterocycle chemical building blocks. In the first phase, we anticipate diverting
organometallic intermediates to Favorskii-type reactivity to generate N-heterocycles that contain multiple
handles for further functionalization; in the second, we propose tuning organometallic intermediates to Ramberg-
Bäcklund reactivity to access substituted strained-ring derivatives. In doing so, we will broaden knowledge of
current chemical reactivity as well as provide strategies to make molecular scaffolds relevant to multiple
industries, including those pertaining to pharmaceuticals.
 Overall, the proposed research is significant because it provides creative strategies to 1) establish the
first total syntheses of azetidomonamide A and diazetidomonapyridone, which will enable their biological study,
and 2) develop new reactivity paradigms for accessing modular molecular scaffolds with pharmacological
relevance. Performing the K99 research in Prof. Reisman’s group at Caltech aligns well with their current success
in the efficient total synthesis of complex natural products; this experience in the synthesis of...

## Key facts

- **NIH application ID:** 11033895
- **Project number:** 1K99GM157554-01
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Stanna Dorn
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,000
- **Award type:** 1
- **Project period:** 2024-09-12 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11033895

## Citation

> US National Institutes of Health, RePORTER application 11033895, Access to Strained Rings and Heterocycles: Applications in the Synthesis of Bacterial Metabolites and Chemical Building Blocks (1K99GM157554-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11033895. Licensed CC0.

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