Metal‐Free and Open‐Air Arylation Reactions of Diaryliodonium Salts for DNA‐Encoded Library Synthesis

Abstract

A successful DNA‐encoded library (DEL) will consist of diverse skeletons and cover chemical space as comprehensive as possible to fully realize its potential in drug discovery and chemical biology. However, the lack of versatile on‐DNA arylation methods for phenols that are less nucleophilic and reactive poses a great hurdle for DEL to include diaryl ether, a privileged chemotype in pharmaceuticals and natural products. This work describes the use of “substrate activation” approach to address the arylation of DNA‐conjugated phenols. Diaryliodonium salt, a highly electrophilic and reactive arylation reagent, is employed as Ar+ sources to ensure highly selective on‐DNA arylation of phenols and oximes with both high yields and DNA fidelity. Notably, the new on‐DNA arylation reaction can be applied to the late‐stage modification of peptides containing tyrosine side‐chain and to synthesize DNA‐tagged analogues of existing drug molecules such as sorafenib, a known pan‐kinase inhibitor. The new on‐DNA diaryliodonium salts chemistry affords a greater flexibility in DEL design and synthesis.

DNA-compatible synthesis of enaminones via amination of allenic ketones

“…19 Generally, substituted benzenes are important pharmaceutical backbones. 20 The classical approach to generate polysubstituted benzene rings in DELs relies on the introduction of a substituent into the given arene, mainly through nucleophilic or electrophilic substitutions 21 and cross-coupling reactions, 22 which may suffer from multi-step reaction sequences. To the best of our knowledge, DNA-compatible direct synthesis of polysubstituted benzenes has not been achieved yet.…”

Incorporation of viridicatin alkaloid-like scaffolds into DNA-encoded chemical libraries

“…Therefore, it would be important to modify the hydroxy group. Although the conversion of c10 into the corresponding O -arylation product by the recently reported on-DNA arylation of phenols by using diaryliodonium salts failed, 45 we succeeded in conducting an O -acylation reaction to provide a 3- O -benzoyl product, which was validated by mass spectrum analysis (see the ESI†). This amenable one-step on-DNA modification gives possibilities to explore the role of the hydroxyl group in the core scaffold.…”

DNA-encoded librariesvialate-stage functionalization strategies: a review

“…The design of DELs follows a sequence of reactions such as solid phase synthesis as well as DNA-compatible reactions. 19,20 Each of the derivatized DELs on synthesis can be identified via barcodes as each DEL has its own unique DNA sequences. 21 Recent years have seen a rapid rise in the area of nucleoside/ nucleotide modifications with the nucleoside-based treatment regime being applied extensively in Covid-19 treatment in the form of Remdesevir, 22,23 Molnupiravir, 24,25 m-RNA or DNA-based vaccines.…”