# Methods and Strategies for Chemical Synthesis

> **NIH NIH R35** · TRUSTEES OF INDIANA UNIVERSITY · 2024 · $571,607

## Abstract

Project Summary/Abstract:
 The invention of new methods to access chiral organic molecules is a critical objective in modern organic
chemistry as it is essential for the efficient synthesis of pharmaceutical agents. This is especially relevant as the
pharmaceutical industry is making efforts to increase the 3D complexity of drug candidates. Despite substantial
progress in the field of stereoselective chemical synthesis, many structures remain challenging to prepare in
useful quantities. Therefore, development of new methods and strategies for the chemical synthesis of
stereochemically and topologically complex molecules is of contemporary interest. The long-term goals of our
research program are to introduce general and efficient strategies for the stereoselective synthesis of difficult-
to-access molecular frameworks found in important bioactive molecules. Towards this end, we are interested in
the conversion of abundant and readily available alkenes to more complex structures through difunctionalization
reactions. This approach is attractive because the rapid buildup of complexity can be achieved as two new bonds
and two new stereocenters are generated in a single operation. The studies described in this application focus
on three distinct programs. The first is the development of stereoselective cross-coupling reactions of Csp3-
nucleophiles that are catalytically generated in situ from simple alkenes. Our rationale for development of these
reactions is that widely available alkenes, diboron reagents, and organohalides are converted to synthetically
versatile intermediates. We will develop new Pd/Cu-catalyzed and Ni-catalyzed systems with a particular
emphasis placed on saturated heterocycle synthesis. In addition, with the advent of new catalytic systems we
will engage Csp3-electrophiles for the generation of multiple stereogenic centers. In the second program of
research, we are developing methods for the stereoselective synthesis of cyclobutanes by [2+2] cycloadditions
of alkenes that are enabled by boron. Our rationale for the development of these reactions is that due to the
unique feature of boron, a broad range of borylated cyclobutanes can be prepared. Finally, we are introducing
new classes of novel building blocks to enable drug discovery, such as bicyclo[2.2.0]hexanes as isosteres for
meta-substituted aromatic rings. Within this program, we are also developing novel strain release reactions
initiated by energy transfer. Overall, these studies in reaction development will introduce new concepts and
strategies, as well as provide access to new building blocks for chemical synthesis by exploring new cross-
coupling paradigms and cycloaddition reactions.

## Key facts

- **NIH application ID:** 10765166
- **Project number:** 2R35GM131755-06
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Michael Kevin Brown
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $571,607
- **Award type:** 2
- **Project period:** 2019-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765166

## Citation

> US National Institutes of Health, RePORTER application 10765166, Methods and Strategies for Chemical Synthesis (2R35GM131755-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10765166. Licensed CC0.

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