# Chemistry principles applied to the development of new catalytic C-H bond functionalization methods for amine and heterocycle preparation and to the design, synthesis and use of new enzyme inhibitors

> **NIH NIH R35** · YALE UNIVERSITY · 2020 · $739,409

## Abstract

Project Summary/Abstract
The discovery and development of new methods for the preparation and use of organic compounds has
considerable impact upon how drugs are discovered and synthesized. One overall objective of this application
is the development of catalytic C-H bond activation and carbon-carbon bond formation for the convergent
assembly of amine containing compounds present in 84% of small-molecule drugs. Methods for the
preparation of the subset of nitrogen heterocycles present in 59% of drugs are emphasized. Efficient syntheses
of these compound classes will be accomplished by C-H functionalization methods. One example is
stereoselective, catalytic two- and three-component C-H bond additions to C=O/C=N bonds to provide diverse
amine and alcohol products that in situ can be transformed into more complex, drug-relevant heterocycles.
New earth abundant Co(III) catalysts will be developed and studied for these transformations. Another
example is efficient syntheses of diverse piperidines, the heterocycle class with the highest frequency of
occurrence in drugs, by regio- and stereoselective elaboration of highly substituted 1,2-dihydropyridines
generated in situ by one step C-H bond functionalization/electrocyclization cascades. New methods will also be
achieved to prepare bridged and fused bicyclic and multicyclic piperidines, including pharmaceutical agents.
Innovative new types of reactivity will be explored in C-H bond functionalization and subsequent
transformations. These significant studies will enable the more rapid preparation of analogs in drug discovery
efforts and reduced cost and waste in drug production due to; (1) the ubiquitous presence of C-H bonds in
organic compounds, (2) the very high functional group compatibility of the Rh and Co catalysts used, and (3)
the importance of the compound classes prepared. The second overriding objective is the development and
use of potent and selective enzyme inhibitors discovered through substrate-based fragment approaches. Orally
available inhibitors of cruzain, an essential protease of the parasite responsible for Chagas disease, have been
developed as have near-IR quenched activity-based inhibitors of cathepsin S for imaging in vivo. The first
inhibitors of Striatal-Enriched Phosphatase (STEP), a protein tyrosine phosphatase (PTP) implicated in a
number of neurodegenerative diseases, including Alzheimer's disease (AD), will be advanced. Structure-
based optimization will be carried out using the first x-ray structures of STEP inhibitor complexes. Reversible
covalent inhibitors developed to recapitulate known physiological means of PTP regulation will also be
advanced. This innovative platform for PTP inhibition has already resulted in compounds that reverse cognitive
dysfunction in AD mouse models. The substrate fragment approach will also be applied to the increasingly
prominent class of protein post-translational modification enzymes, the protein arginine deiminases (PADs), for
which l...

## Key facts

- **NIH application ID:** 9910428
- **Project number:** 5R35GM122473-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JONATHAN A ELLMAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $739,409
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9910428

## Citation

> US National Institutes of Health, RePORTER application 9910428, Chemistry principles applied to the development of new catalytic C-H bond functionalization methods for amine and heterocycle preparation and to the design, synthesis and use of new enzyme inhibitors (5R35GM122473-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9910428. Licensed CC0.

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