Scope of on-DNA nucleophilic aromatic substitution on weakly-activated heterocyclic substrates for the synthesis of DNA-encoded libraries. (1st June 2022)

• Record Type: Journal Article
• Authors: Castan, Isaline F.S.F.; Madin, Andrew; Pairaudeau, Garry; Waring, Michael J.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 63(2022)
• Publication Date: 2022-06-01
• Subjects: Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116688
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: DNA-Encoded Libraries (DEL) represent a promising hit finding strategy for drug discovery. Nonetheless, the available DNA-compatible chemistry remains of limited scope. Nucleophilic aromatic substitution (SN Ar) has been extensively used in DEL synthesis but has generally been restricted to highly activated (hetero)arenes. Herein, we report an optimised procedure for SNAr reactions through the use of factorial experimental design (FED) on-DNA using 15% THF as a co-solvent. This method gave conversions of >95% for pyridine and pyrazine scaffolds for 36 secondary cyclic amines. This analysis provides a new DNA-compatible SN Ar reaction to produce high yielding libraries. The scope of this reaction on other amines is described. This work identifies challenges for the further development for DNA-compatible SN Ar reactions. 2009 Elsevier Ltd. All rights reserved.