# Biocatalytic C-H Functionalization Logic in the Chemoenzymatic Synthesis of Therapeutic Natural Products

> **NIH NIH R35** · SCRIPPS FLORIDA · 2020 · $100,000

## Abstract

Project Summary
Direct oxidation and functionalization of C–H bonds, though ubiquitous in Nature’s biosynthetic machinery, have
only recently gained traction as a viable strategy in chemical synthesis. Despite remarkable advances,
contemporary chemical methods for C–H oxidation still face significant challenges in achieving useful levels of
selectivity on complex scaffolds. In contrast, the oxidative enzymes that have evolved to perform these
transformations are capable of achieving unprecedented levels of selectivity. However, studies on these
enzymes have mainly focused on their mechanistic features, and very little attention has been given to their
applications in organic synthesis. This proposal seeks to bridge the gap between organic synthesis and
mechanistic enzymology and establish a novel paradigm in complex molecule synthesis by integrating Nature’s
repertoire of oxidative biocatalysts into the synthetic organic toolbox. We contend that a synergistic interplay
between chemo- and biocatalytic methods will lead to unsurpassed levels of efficiency in accessing clinically-
relevant small molecules. As a proof-of-principle demonstration, we have recently completed preliminary
investigations that illustrate the viability of this chemoenzymatic strategy in the preparation of small natural
products and valuable building blocks with therapeutic potential. Building on this success, this proposal aims to
demonstrate the universality of this strategy in the efficient and practical syntheses of two medicinally relevant
natural product scaffolds. Significant elements of innovation in this work include (1) the discovery of previously
uncharacterized enzymes with novel activities from various secondary metabolite biosynthetic pathways, (2) the
pursuit of new strategies for optimizing their catalytic efficiencies, and (3) the identification of appropriate
avenues to demonstrate their applications in chemical synthesis. Though there are significant challenges
associated with this project, its scientific impacts will be far-reaching. If successful, our ability to strategically
incorporate enzymatic functionalizations into the design of complex molecule synthesis will stimulate the
development of new logic in chemical synthesis centered on the use of Nature’s biocatalytic repertoire, radically
altering the way chemists’ approach synthetic planning. Thus, new small molecule therapeutics can be prepared
in a more efficient and practical manner.

## Key facts

- **NIH application ID:** 10135498
- **Project number:** 3R35GM128895-02S1
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Hans Renata
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $100,000
- **Award type:** 3
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135498

## Citation

> US National Institutes of Health, RePORTER application 10135498, Biocatalytic C-H Functionalization Logic in the Chemoenzymatic Synthesis of Therapeutic Natural Products (3R35GM128895-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10135498. Licensed CC0.

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