# Dearomatization of Planar Aromatic Cores into Three-Dimensional Scaffolds with Defined Stereochemistry

> **NIH NIH F32** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2022 · $67,174

## Abstract

Abstract
Naphthalenones are bicyclic scaffolds found in many natural and synthetic compounds which display diverse
biological activities and serve as building blocks to access more complex molecules. Naphthalenones have been
successfully synthesized via dearomatization of naphthols with simultaneous installation of new C–C or C–X
bonds. Formation of these new quaternary centers with stereoselective control has proven to be a synthetic
challenge and commonly requires use of expensive, rare, or toxic transition metals. In few cases where earth
abundant iron or organic catalysts are utilized, enantioselective control and/or yield are compromised. Biocata-
lysts provide a great alternative for a more sustainable synthetic route which operate under mild conditions,
generate enantioenriched products, reduce side products, and achieve high substrate selectivity. Through itera-
tive rounds of genetic mutation and natural selection, enzymes can evolve to catalyze new-to-nature reactions.
Herein, I propose to engineer an alternative catalytic route to synthesize chiral naphthalenones utilizing the di-
verse library of hemoproteins developed by the Arnold group. This work will be achieved through engineering
and evolving hemoproteins for (i) dearomative amination of 2-naphthols by nitrene insertion, (ii) dearomatization
of 2-naphthols by carbene insertion, and (iii) further functionalization of naphthalenone core scaffolds by stereo-
specific biocatalytic reactions. These reactions will be the first of its kind to be characterized in hemoproteins.
The products of these reactions will feature new quaternary carbon centers and will expand current mechanistic
knowledge of the robust hemoproteins and their abilities to tame reactive carbenes and nitrenes for highly en-
antioselective reactions. This work will explore new methods to access substituted polycyclic structures in a
facile and sustainable approach expanding the synthetic feasibility of biologically relevant naphthalenones. The
biocatalytic method generated in this proposal will begin to elucidate new strategies for dearomatization and
allow for transformation of many readily available 2-dimensional aromatic feedstocks into intricate pharmaco-
phores.

## Key facts

- **NIH application ID:** 10464808
- **Project number:** 1F32GM145123-01A1
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Kathleen M Sicinski
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,174
- **Award type:** 1
- **Project period:** 2022-09-06 → 2025-09-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464808

## Citation

> US National Institutes of Health, RePORTER application 10464808, Dearomatization of Planar Aromatic Cores into Three-Dimensional Scaffolds with Defined Stereochemistry (1F32GM145123-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464808. Licensed CC0.

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