# A Reverse Polarity Stereoselective C-C Bond-Forming Strategy for Preparing Chiral Amines

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $285,497

## Abstract

Project Abstract:
The development of new methods for the efficient and stereoselective preparation of amine-containing
chemical building blocks is a compelling objective in organic synthesis as a large number of biologically active
compounds contain an amino group bound to a stereogenic carbon. The chemical functionality that may flank
the amine in these compounds is vast, including a number of commonly-encountered motifs, such as amino
alcohols and diamines; additionally, the amine-bearing stereogenic center may be tri- or tetrasubstituted.
Despite their frequency in targets of biological importance, methods for the stereoselective synthesis of 1,3-
diamines, 1,3-amino alcohols, and amino-containing tetrasubstituted stereogenic centers are sparse, with the
mode of their generation often labor intensive and/or circuitous. Several scaffolds within these frameworks
have only rarely been produced. The long-term goal of this research program is to design and develop novel
stereoselective C–C bond-forming methods for preparing difficult-to-access but highly sought-after chiral
amines. Our strategy employs a polarity reversal of an imine (umpolung): rather than act as an N-substituted
carbon electrophile, we transform the reagent to an N-substituted carbon nucleophile—a 2-azaallyl anion—
that may be combined stereoselectively with a number of electrophilic partners to furnish alpha-substituted
chiral amines. In these investigations, we will focus on C–C bond formations with 2-azaallyl anions for: 1) the
stereoselective synthesis of challenging 1,3-diamine and amino alcohol functionality, 2) the enantioselective
preparation of homoallylic amines with N-containing tetrasubstituted stereogenic centers, and 3)
stereoselective three component coupling reactions with a silyl-substituted 2-azaallyl anion as a double alpha-
amino anion equivalent. The new methods developed under the aegis of this project provide innovative
solutions to long-standing challenges in the preparation of chiral amines that will permit streamlined synthesis
of several biologically important complex molecules. The new chemical space that will be garnered might
enable exploration of novel medicinal leads that may lead to active pharmaceutical ingredients to improve
human health.

## Key facts

- **NIH application ID:** 9975183
- **Project number:** 5R01GM124286-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Steven Joseph Malcolmson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $285,497
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975183

## Citation

> US National Institutes of Health, RePORTER application 9975183, A Reverse Polarity Stereoselective C-C Bond-Forming Strategy for Preparing Chiral Amines (5R01GM124286-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9975183. Licensed CC0.

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