# Next-generation C-H functionalization methods for organic synthesis and their applications to biological inquiry

> **NIH NIH R35** · YALE UNIVERSITY · 2022 · $755,936

## Abstract

PROJECT SUMMARY/ABSTRACT
Catalytic C-H bond functionalization has emerged as a powerful approach in synthetic organic chemistry for the
discovery and production of new pharmaceuticals. The next generation C-H bond functionalization methods
described in this proposal will enable the rapid assembly of pharmaceutically relevant compounds from simple
and readily available inputs. In one program, we will access complex molecular architectures in a single step
from simple precursors by the sequential three-component coupling of a C-H bond and two different types of
coupling partners. Because many different coupling partners are effective for conventional C-H bond additions
to one coupling partner, sequential three-component reactions utilitizing different combinations of coupling
partners should provide access to an enormous diversity of motifs relevant to drug and natural product synthesis.
Preliminary results obtained with MIRA funding have established the feasibility and utility of this approach. In a
second program, we will apply reversible light-mediated C-H bond activation to obtain the most stable from the
most accessible heterocycle stereoisomer. Saturated heterocycles such as piperidines, morpholines,
piperazines, and lactams are prevalent in drugs and drug candidates but are often most efficiently prepared as
the less stable stereoisomer. However, light-mediated processes can enable their highly stereoselective
conversion to the more stable stereoisomer as we recently demonstrated for piperidines with MIRA funding. In
a third program, we will broadly develop nitrogen heterocycle synthesis by imidoyl C-H functionalization. Imines
derived from readily available aldehydes and primary amines are centrally important intermediates in organic
synthesis. With MIRA funding, we developed a new approach for the efficient preparation of purine bioisosteres
by imidoyl C-H activation of imines followed by in situ annulation with different coupling partners. Purine
bioisosteres are found in large numbers of drugs and drug candidates, especially those that interact with
biomolecular targets that have purine recognition motifs such as receptors, kinases, and mRNA. We will leverage
our methods for the synthesis of purine bioisosteres to target the transcriptome and will apply imidoyl C-H
activation and annulation to prepare other important heterocycles. With MIRA funding we advanced new enzyme
inhibitor discovery approaches and potent and selective inhibitors to challenging enzyme targets. In proposed
research, we will directly apply C-H functionalization to biological inquiry. For example, our methods for the
synthesis and elaboration of dihydropyridines enable the rapid preparation of amine-containing structures with
three-dimensional display of functionality and stereoselective introduction of multiple stereogenic centers,
features increasingly sought after in medicinal chemistry endeavors. These approaches will be applied to the
discovery of potent and sel...

## Key facts

- **NIH application ID:** 10406549
- **Project number:** 2R35GM122473-06
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JONATHAN A ELLMAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $755,936
- **Award type:** 2
- **Project period:** 2017-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406549

## Citation

> US National Institutes of Health, RePORTER application 10406549, Next-generation C-H functionalization methods for organic synthesis and their applications to biological inquiry (2R35GM122473-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10406549. Licensed CC0.

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