# Nickel-Catalyzed Coupling Reactions of Alkyl Electrophiles

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2022 · $626,905

## Abstract

PROJECT SUMMARY / ABSTRACT
 The discovery of powerful new methods for the synthesis of organic compounds can be enabling for
biomedical research, e.g., by providing more ready access to known families of target molecules or access for
the first time to new classes of molecules. Catalytic and enantioselective methods for carbon–carbon formation
are of particular interest, due to issues including sustainability, the potentially divergent bioactivity of the two
enantiomers of a compound, and the predominance of carbon–carbon bonds in the backbone of organic
molecules.
 The substitution reaction of an alkyl electrophile by a nucleophile is a particularly straightforward
approach to the assembly of organic molecules. Classical pathways for substitution, such as the SN1 and the
SN2 reactions, are limited in scope with respect to both the electrophile and the nucleophile. Furthermore,
these pathways almost never provide access to highly enantioenriched product from readily available racemic
starting materials.
 It has recently been established that, by achieving substitution reactions via a transition-metal-catalyzed
pathway wherein an organic radical serves as a key intermediate, it is possible to begin to address both of the
key challenges–broader scope and control of enantioselectivity. For example, chiral nickel complexes can
catalyze the coupling of a variety of racemic secondary alkyl electrophiles with an array of nucleophiles with
good enantioselectivity.
 To date, only a small fraction of the conceivable permutations of electrophilic and nucleophilic partners for
substitution reactions of alkyl electrophiles have been explored, and still fewer such processes have been
rendered enantioselective. The goal of this proposal is to address this unsolved challenge. Efforts will focus
on the development of mild and versatile methods to couple families of electrophiles and nucleophiles that
have not previously been shown to be suitable reaction partners in aliphatic substitution reactions, while
controlling stereoselectivity at the same time (at up to two stereocenters). Success in this endeavor will
substantially facilitate the synthesis of enantioenriched molecules that have application across a broad
spectrum of biomedical research.
 Mechanistic studies will be pursued in order to provide insight into the pathways by which the new metal-
catalyzed enantioconvergent substitution reactions proceed. The mechanistic investigations will facilitate
reaction development, as well as enhance the community’s understanding of fundamental chemical reactivity.

## Key facts

- **NIH application ID:** 10319946
- **Project number:** 5R01GM062871-22
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** GREGORY C FU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $626,905
- **Award type:** 5
- **Project period:** 2001-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10319946

## Citation

> US National Institutes of Health, RePORTER application 10319946, Nickel-Catalyzed Coupling Reactions of Alkyl Electrophiles (5R01GM062871-22). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10319946. Licensed CC0.

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