# Methods and Strategies for Chemical Synthesis

> **NIH NIH R35** · TRUSTEES OF INDIANA UNIVERSITY · 2021 · $520,207

## 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 two 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. Based on our earlier work, we are
developing Pd/Cu-cooperative catalytic systems for the arylboration of activated alkenes and in particular
demonstrating the functionalization of nitrogen containing heterocycles. In addition, we are developing a
general strategy for unactivated alkene difunctionalization with Ni-catalysis. In the second program of
research, we are developing methods for the enantioselective synthesis of cyclobutanes by [2+2] cycloaddition
of alkenes and electron deficient allenes. Our rationale for the development of these reactions is that due to
the concerted asynchronous nature of these processes, a broad range of alkenes can be utilized. This allows
for the synthesis of a diverse range of stereochemically complex cyclobutanes. The rings generated by these
transformations are directly found in bioactive molecules, can be subjected to a variety of reactions, and
represent novel building blocks for drug discovery. 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:** 10113653
- **Project number:** 5R35GM131755-03
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Michael Kevin Brown
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $520,207
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113653

## Citation

> US National Institutes of Health, RePORTER application 10113653, Methods and Strategies for Chemical Synthesis (5R35GM131755-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10113653. Licensed CC0.

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