Animesh Roy; Thomas Kodadek
Angew. Chem. Int. Ed. Engl., 2021, 60(21), 11983-11990
https://doi.org/10.1002/anie.202100230

Abstract

There is considerable interest in the development of libraries of scaffold-diverse macrocycles as a source of ligands for difficult targets, such as protein-protein interaction surfaces. A classic problem in the synthesis of high-quality macrocyclic libraries is that some linear precursors will cyclize efficiently while some will not, depending on their conformational preferences. We report here a powerful quality control method that can be employed to readily distinguish between scaffolds that do and do not cyclize efficiently during solid-phase synthesis of thioether macrocycles without the need for tedious liquid chromatography/mass spectrometry analysis. We demonstrate that this assay can be employed to identify largely linear “impurities” in a DNA-encoded library of macrocycles. We also use the method to establish a useful quality control protocol for re-synthesis of putative macrocyclic screening hits.