Antonia F. Stepan; Alistair D. Richardson
Synfacts, 2025, 21(01), 87
https://doi.org/10.1055/a-2467-5525

Abstract

DNA-encoded library (DEL) platforms have emerged as a powerful tool for drug discovery. Combinatorial chemical synthesis, paired with the unique DNA identifiers, enable researchers to quickly generate large libraries and easily identify the subsequent hits. One of the major challenges facing DEL technology is the lack of DNA-compatible chemical reactions. Although much progress has been made in this area, expanding the DEL toolbox is imperative for continued growth. Building blocks with primary amine functionality are common in DEL synthesis. Thus, developing new transformations capable of on-DNA manipulation of amines is attractive. On-DNA diazo-transfer was initially reported in 2011, however the need for a more general procedure persists. This report outlines the advantages of using fluorosulfuryl azide (FSO2N3) for on-DNA diazo-transfer with high conversion and DNA fidelity. In addition to DNA-compatibility, successful DEL methods must also tolerate the functional groups needed for subsequent transformations. High conversion was achieved on substrates containing halides, alcohols, protected amines, nitro groups, nitriles, and heterocycles. Successful diazo-transfer was demonstrated with aliphatic amines as well as anilines, which were previously challenging substrates. Electron-deficient heteroaromatic anilines, such as 2-aminopyridines, were unsuccessful. Both dsDNA- and ssDNA-conjugated amines were utilized. DNA integrity was established through ligation of a DNA tag and subsequent gel electrophoresis. Quantitative assessment of DNA damage indicated ~94 % remaining amplifiable material. Further functionalization of the DNA-conjugated azide was also demonstrated. The authors include safety information in the Supporting Information.