# Harnessing Alkyl Amines and Alkyl Alcohols in Cross-Coupling Reactions

> **NIH NIH R35** · UNIVERSITY OF DELAWARE · 2024 · $460,319

## Abstract

The discovery of new medicines requires the synthesis and evaluation of new molecules, and the
incorporation of saturated atoms and three-dimensional (3D) shape is increasingly important in advancing
bioactive leads to medicines. Recognizing this need to incorporate saturated carbons, including stereocenters,
this research will focus on the development of new cross-coupling reactions to enable efficient construction of
bonds to saturated carbon atoms. These methods will rely on alkyl alcohol and amine derivatives as alkyl
electrophiles, because they are widely available (including in enantioenriched form), offer outstanding diversity
of alkyl fragments that is complementary to other alkylating agents, are easily prepared, and can be used in both
early and late-stage functionalization strategies.
 All-carbon quaternary stereocenters and other fully substituted stereocenters are prevalent in bioactive
natural products, but these motifs remain synthetically challenging to prepare in high enantiomeric purity,
especially if they are not near a carbonyl or alkene. On the other hand, tertiary alcohols are readily prepared in
exceptional enantiomeric excess (ee), making them ideal substrates for stereospecific cross-coupling reactions.
Building on strong preliminary results, this program will develop a suite of methods to deliver highly
enantioenriched products from tertiary benzylic alcohol derivatives. These efforts will be bolstered by mechanistic
studies to understand and rationally optimize challenging steps in these catalytic processes.
 Primary alkyl amines comprise an extremely diverse feedstock class, extending from simple building blocks
to pharmaceutical intermediates to biomolecules. By activating them as Katritzky pyridinium salts, the PI’s group
was the first to show that these ubiquitous starting materials can be used as alkyl electrophiles in nickel-catalyzed
cross-coupling reactions. This program will now develop new deaminative cross-couplings to provide efficient
access to a tremendous diversity of products, meeting needs in medicinal chemistry efforts for pharmaceutical
discovery.
 The successful development of this research will establish novel methods to deliver 3D molecules with
potential bioactivity from readily available precursors. It will also change the way that chemists use alcohols and
amines in synthesis. The ultimate goal is to develop cross-coupling methods for forging bonds to C(sp3) atoms
that are as useful for the preparation of bioactive molecules as those long known for C(sp2) atoms. By enabling
new methods for the synthesis of novel, potentially bioactive molecules, this research will advance the discovery
of new molecules for the study and treatment of disease.

## Key facts

- **NIH application ID:** 10842716
- **Project number:** 2R35GM131816-06
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Mary P Watson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $460,319
- **Award type:** 2
- **Project period:** 2019-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842716

## Citation

> US National Institutes of Health, RePORTER application 10842716, Harnessing Alkyl Amines and Alkyl Alcohols in Cross-Coupling Reactions (2R35GM131816-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10842716. Licensed CC0.

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