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

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. A two-step reductive amination reaction between DNA-conjugated amines and aromatic, aliphatic, or heterocyclic aldehydes, utilising the micelle-forming surfactant, TPGS-750-M, borate buffer, and NaBH4. The methodology is applicable to a broad substrate scope, with regards to both on-DNA amine and aldehyde, and is fully compatible with DNA-amplification and sequencing; it is a new method for secondary and tertiary amine formation in DEL synthesis. image