Science of Synthesis

Hou, W.; Yang, G.; Xu, H., Science of Synthesis: DNA-Encoded Libraries, (2024) 1, 213.

Considering the importance of C—X (X = N, O, S, Se, P) bonds in medicinal chemistry and bioactive molecules, the recent innovations in DNA-compatible C—X bond formation chemistry not only provide more flexibility in DNA-encoded library (DEL) design and synthesis, but also will reinforce the influence of DELs in drug discovery. Micelle-surfactant- and/or RASS-enabled reactions are powerful strategies to translate conventional organic chemistry to on-DNA synthesis for several C—X bond formation methods, such as those for C—N and C—S bonds. Some new C—X bond forming reactions diverge from earlier DEL methodology. For instance, in an example of C—H activation that is also the first incorporation of selenium into DELs, the C2 position of DNA-conjugated N-(pyrimidin-2-yl)indoles can be selanylated by rhodium(III)-catalyzed C—H selanylation using benzoselenazol-3-ones as selenium source (see Section ‌2.4.1.5.3‌). In another impressive example (see Section ‌2.4.1.3.3‌), glycosyltransferases have been used to construct di- and tri-saccharide DNA conjugates that could be further elaborated via enzymatic and chemical means. Among the various C—X bonds, the chemistry for C—N bond formation is the most well-developed, and some of these methods have been used in DEL synthesis; however, the C—N coupling efficiency varies considerably among the synthetic methods used and the chemical properties of the amines. Optimal reaction conditions could be found for certain sets of amines, and therefore multiple reaction schemes maybe conducted when assembling large libraries with highly diverse amine building blocks. While these reports are encouraging, a few key challenges remain to be addressed for several new chemistries. For some reactions, a broader substrate/building-block scope should be demonstrated for direct applicability to library production, while other reactions incorporate building block classes that are limited in commercial availability, thus diminishing the true potential of a DEL. New and improved methods for C—X bond formation, particularly for the less-developed C—O, C—Se, and C—P bond formation reactions, are highly needed.