# Chiral α,α-Disubstituted Amine Synthesis by Dynamic Kinetic Resolution

> **NIH NIH R35** · UNIVERSITY OF MINNESOTA · 2020 · $361,067

## Abstract

Project Summary
Chiral α,α-Disubstituted Amine Synthesis by Dynamic Kinetic Resolution
Overview: This program targets a new paradigm in the synthesis of chiral α,α-disubstituted amines. This will be
accomplished by enabling a dynamic kinetic resolution of allylic azides. This approach takes advantage of the
innate properties of allylic azides and the allylic azide rearrangement. The proposed pathway is significant and
unique because it would establish the chirality of these amines without directly forming a C-C or C-N bond.
Instead, this approach brings additional functionality to the product while simultaneously establishing the chiral
α,α-disubstituted center.
 The various phases of this proposal concern expanding upon preliminary results to a wide array of target
systems. Three different approaches are provided to differentiate non-symmetric allylic systems and include
using: i) conjugation, ii) proximity effects, and iii) sterics. Each of these approaches is capable of providing
synthetically useful amines or amine surrogates. Many of the most common heterocycles, including those
present in a series of BACE-1 inhibitors, are conceivably available by one of these approaches.
Relevance to Public Health: Most pharmaceutical agents contain an amine or amine derivative. In many cases,
the carbon to which the amine is bound is a stereocenter. The configuration of this center is essential to
controlling the intended pharmacological effect. For simple amines, many efficient methods can establish the
desired chirality. However, for highly substituted amines, this is not the case. Robust and general methods are
lacking. BACE-1 inhibitors are an illustrative family. In the last several years, dozens of BACE-1 inhibitors have
been disclosed from >10 major pharmaceutical companies. All contain this motif. In all cases, establishing this
stereocenter was problematic. Supporting this program would simplify the syntheses of these chiral amines and
make them available for applications in medicinal chemistry and chemical biology.

## Key facts

- **NIH application ID:** 9999589
- **Project number:** 5R35GM124718-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Joseph John Topczewski
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $361,067
- **Award type:** 5
- **Project period:** 2017-09-01 → 2021-07-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999589

## Citation

> US National Institutes of Health, RePORTER application 9999589, Chiral α,α-Disubstituted Amine Synthesis by Dynamic Kinetic Resolution (5R35GM124718-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9999589. Licensed CC0.

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