Issue 22, 2023

High-throughput determination of enantiopurity in atroposelective synthesis of aryl triazoles

Abstract

Atropisomeric scaffolds are a common design element found in pharmaceuticals, many deriving from an N–C axis of chirality. The handedness associated with atropisomeric drugs is oftentimes crucial for their efficacy and/or safety. With the increased use of high-throughput screening (HTS) for drug discovery, the need for rapid enantiomeric excess (ee) analysis is needed to keep up with the fast workflow. Here, we describe a circular dichroism (CD) based assay that could be applied to the ee determination of N–C axially chiral triazole derivatives. Analytical samples for CD were prepared from crude mixtures by three sequential steps: liquid–liquid extraction (LLE), a wash-elute, and complexation with Cu(II) triflate. The initial ee measurement of five samples of atropisomer 2 was conducted by the use of a CD spectropolarimeter with a 6-position cell changer, resulting in errors of less than 1% ee. High-throughput ee determination was performed on a CD plate reader using a 96-well plate. A total of 28 atropisomeric samples (14 for 2 and 14 for 3) were screened for ee. The CD readings were completed in 60 seconds with average absolute errors of ±7.2% and 5.7% ee for 2 and 3, respectively.

Graphical abstract: High-throughput determination of enantiopurity in atroposelective synthesis of aryl triazoles

Supplementary files

Article information

Article type
Edge Article
Submitted
24 Mar 2023
Accepted
11 May 2023
First published
11 May 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2023,14, 5992-5999

High-throughput determination of enantiopurity in atroposelective synthesis of aryl triazoles

J. Lim, M. Guo, S. Choi, S. J. Miller and E. V. Anslyn, Chem. Sci., 2023, 14, 5992 DOI: 10.1039/D3SC01559A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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