# Site-Selective Catalysis for Bioactive Scaffold Diversification

> **NIH NIH R35** · YALE UNIVERSITY · 2021 · $837,446

## Abstract

Project Summary/Abstract
We wish to continue our study of a new paradigm for the selective functionalization of complex molecules. Our
approach is predicated on the development of fundamental reactions of functional groups that are ubiquitous in
bioactive agents. Importantly, bioactive analog generation by this approach spans multiple therapeutic areas,
and categorizes these chemical studies as a quintessential “General Medical Science.” The main emphasis of
this proposal is the development of simple-to-make catalyst libraries that target functionalization through a vast
array of reactions. These will include site-selective reactions of hydroxyl groups, amines, arene C-H bonds,
olefins and ketones. In addition, we target a host of redox-active functional groups, as well as an array of C-C
bond-forming reactions. Many of these processes have been developed in our laboratory, with our initial studies
often focusing on enantioselective catalysis – a field of great importance in its own right, with high significance
for the synthesis of pharmaceuticals. Yet, our focus is increasingly on the study of highly complex molecular
environments, wherein our enantioselective chemistry serves as a prelude to exploration of substrates for which
stereoselectivity represents just a subset of the issues that need to be addressed. We have extensive preliminary
results in a number of complex molecular frameworks, including those provided by some venerable natural
products, such as erythromycin, vancomycin, teicoplanin and thiostrepton. We wish to continue these studies,
but in addition we wish to expand them to analog generation in contexts presented by structures like oligomycin,
rapamycin and the aminoglycoside antibiotics. All of these objectives will require the development of new
catalysts and new reactions. Foci will include high value catalytic, site-selective deoxygenation chemistry, site-
selective amine functionalization, site-selective C-H bond functionalization, site-selective redox reactions, and
site-selective C-C, C-O and C-N bond formations – all in complex molecular scaffolds. An important parallel effort
in our group includes the development of catalysts for selective control over unusual stereochemical issues, such
as atropisomerism, which is an area of growing concern in medicinal chemistry. These projects will expand as
well, also as a prelude to mastery of this stereochemical issue in complex molecular environments. The
significance of our overall goals may be in new catalysis principles, and in their application to the site-selective
modification of complex, bioactive natural products. These investigations thus extend fundamental studies of
enantioselectivity to the less well-studied arena of regioselectivity. These efforts will also set the stage for the
site-selective chemical alteration of complex polypeptides, and maybe even proteins. Thus, we wish to expand
greatly our studies of the selective derivatization of fascinating biologically ac...

## Key facts

- **NIH application ID:** 10158499
- **Project number:** 5R35GM132092-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Scott J Miller
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $837,446
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158499

## Citation

> US National Institutes of Health, RePORTER application 10158499, Site-Selective Catalysis for Bioactive Scaffold Diversification (5R35GM132092-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10158499. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*