# DiversityExpanding the Synthetic Utility of a Flavin-dependent Monooxygenases

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $22,519

## Abstract

Project Summary
Natural products are an essential source of inspiration for medicines. The World Health Organization estimates
that ~80% of the world's population relies on traditional medicines made from natural products (ref). The
Pharmaceutical industry has ~50% of all drugs based on or derived from natural products. Unfortunately, the
synthesis of these molecules is often prohibitively complex, requiring the installation of multiple functional
groups with very specific 3D architecture critical to their biological activity.
Oxidative dearomatization of phenolic compounds is a powerful transformation for the synthesis of complex
molecules, as it introduces stereochemistry and generates products primed for further reaction. For example,
this reaction is the key step in the biosynthesis of isochromophilone II and luteusin A, inhibitors of the
interaction between gp120, a glycoprotein found on the surface of HIV, and CD4, on the surface of T-cells
central to the HIV invasion mechanism. Inhibition of this protein-protein interaction is hypothesized to disrupt
the entry of the human immunodeficiency virus (HIV) into cells. Only a limited number of enantioselective
methods have been reported for oxidative dearomatization, limiting the application of this transformation in
synthetic chemistry. To achieve high degrees of stereoselectivity, stoichiometric amounts of the chiral metal
complexes are required in addition to lengthy reaction times, cryogenic temperatures, and harsh conditions.
Biocatalytic reactions embody many features of ideal chemical transformations, including the potential for
impeccable selectivity, high catalytic efficiency, mild reaction conditions and the use of environmentally benign
reagents. These advantages have created a demand for new biocatalysts that expand the portfolio of
complexity-generating reactions available to synthetic chemists. However, the tradeoff that often exists
between the substrate scope of a biocatalyst and its selectivity limits the application of enzymes in synthesis.
On this proposal, we explore a panel of FAD-monooxygenases, TropB, AfoD, AzaH, and SorbC containing
complementary substrates scopes and high levels of site- and stereoselectivity across a range of structurally
diverse substrates.
This research proposal aims to aim to develop a suite of catalysts with complementary selectivities in order to
provide an efficient route to valuable chiral intermediates for the synthesis of bioactive molecules. This
research will focus on FAF-monooxygenases, TropB, AfoD, AzaH, and SorbC. Were I will (1) Determine the
binding of the panel of enzymes (2) Transpose this information to expand the substrate scope of TropB by
modification of residues utilizing protein engineering (3) Further enhance the reactivity of the biocatalyst by
utilizing C8-FAD analogs. Such tools will provide an efficient route to valuable chiral intermediates for the
synthesis of bioactive molecules.

## Key facts

- **NIH application ID:** 10063422
- **Project number:** 5F31GM134671-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Attabey Rodríguez Benítez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $22,519
- **Award type:** 5
- **Project period:** 2019-08-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063422

## Citation

> US National Institutes of Health, RePORTER application 10063422, DiversityExpanding the Synthetic Utility of a Flavin-dependent Monooxygenases (5F31GM134671-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10063422. Licensed CC0.

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