Micelle‐Promoted Reductive Amination of DNA‐Conjugated Amines for DNA‐Encoded Library Synthesis

Abstract

DNA‐encoded libraries (DELs) have become a leading technology for hit identification in drug discovery projects as large, diverse libraries can be generated. DELs are commonly synthesised via split‐and‐pool methodology; thus, chemical transformations utilised must be highly efficient, proceeding with high conversions. Reactions performed in DEL synthesis also require a broad substrate scope to produce diverse, drug‐like libraries. Many pharmaceutical compounds incorporate multiple C‐N bonds, over a quarter of which are synthesised via reductive aminations. However, few on‐DNA reductive amination procedures have been developed. Herein is reported the application of the micelle‐forming surfactant, TPGS‐750‐M, to the on‐DNA reductive amination of DNA‐conjugated amines, yielding highly efficient conversions with a broad range of aldehydes, including medicinally relevant heterocyclic and aliphatic substrates. The procedure is compatible with DNA amplification and sequencing, demonstrating its applicability to DEL synthesis.

Squaramide Formation for DNA-Encoded Library Synthesis

“…Their use in DNA-supported reactions is advantageous because of their favorable solubility in aqueous buffers, limited reactivity toward DNA, and high stability in organic solvents. Incorporation of amine building blocks in DEL have been achieved via multiple DNA-compatible chemistries, including Buchwald–Hartwig couplings, − nucleophilic aromatic substitutions (S N Ar), − Aza-Michael additions, reductive aminations, , amide couplings, ,,− and urea formation, (Scheme ). , The development of alternative coupling reactions that can take advantage of the wide chemical diversity afforded by amine building blocks is, therefore, highly relevant.…”