# New Catalytic Methods for the Synthesis of Complex Molecules

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $558,873

## Abstract

Project Summary
One of the main bottlenecks to therapeutic development is the rapid synthesis of complex
organic molecules to evaluate for bioactivity. One of the best means of accomplishing the
discovery of the next generation of therapeutics is the late stage functionalization (LSF) of lead
structures, such that key properties (KD, log P, PK, PD, etc) are optimized along specific growth
vectors of the core structure. Consequently, synthetic methodologies that are able to modify
complex target molecules at specific aliphatic and aromatic sites either through C–H or C–O
bond functionalization are ideal so as to avoid de novo synthesis of the target of interest. The
aim of this MIRA grant is to merge two productive NIGMS-funded projects that broadly seek to
develop new catalytic chemical transformations for immediate use in the biomedical community
for rapid derivatization of complex organic molecules. More specifically, we aim to develop new
catalytic methods for functionalization of aliphatic C–H bonds and aromatic C–O bonds by
activation of organic substrates using potent single electron organic photooxidants. We envision
that activation of typically unreactive C–H bonds can be accomplished via the catalytic
generation of heteroatom radical species that is capable of selective H-atom abstraction. The
resultant radicals can engage in a number of radical group transfer reactions including
conjugate addition, halogenation, azidation and thiotrifluoromethylation. We aim to target
unreactive primary and secondary C–H bonds by modification of the heteroatom-centered
radical species. Importantly, enantioselective variants of the radical reactions herein will be
explored, as few reactions of this type are known. Further elaboration of these radical
transformations will allow for cascade-type reactions wherein complex chiral building blocks can
be forged without the need for prefunctionalization of the starting materials. Opportunities to
utilize some of these radical transformations in cascade sequences for natural product synthesis
will be exploited, as in the case of stemocurtisine, a member of the stemona alkaloid family. We
also will continue a program aimed at aromatic C–H and C–O bond functionalization. A novel
method for catalysis of the venerable nucleophilic aromatic substitution reaction using
alkoxyarenes as substrates will allow for direct substitution by amines, cyanide, fluoride and
azoles with the alkoxide acting as the nucleofuge. These newly developed transformations will
enable synthetic practitioners with new tools for complex molecule synthesis aimed at
therapeutic discovery.

## Key facts

- **NIH application ID:** 10146428
- **Project number:** 5R35GM136330-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** David A Nicewicz
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $558,873
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146428

## Citation

> US National Institutes of Health, RePORTER application 10146428, New Catalytic Methods for the Synthesis of Complex Molecules (5R35GM136330-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10146428. Licensed CC0.

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