Synthesis of a DNA-Encoded Macrocyclic Library Utilizing Intramolecular Benzimidazole Formation.

Macrocycles occupy chemical space "beyond the rule of five". They bridge traditional bioactive small molecule drugs and macromolecules and have the potential to modulate challenging targets such as PPI or proteases. Here we report an on-DNA macrocyclization reaction utilizing intramolecular benzimidazole formation. A 129-million-member macrocyclic library composed of a privileged benzimidazole core, a dipeptide sequence (natural or non-natural), and linkers of varying length and flexibility was designed and synthesized.

One Reaction Served Three Ways: The On-DNA Ugi 4C-3C Reaction for the Formation of Lactams.

Developing new on-DNA reactions is paramount to the development of new encoded libraries in the pursuit of novel pharmaceutical lead compounds. Lactam-containing molecules have been shown to be effective in a wide range of therapeutic areas and therefore represent a promising target for further investigation by DNA-encoded library screening. In pursuit of this motif, we report a novel method for the introduction of lactam-containing structures onto a DNA headpiece through the Ugi four-center three-component reaction (4C-3CR). This novel method is successful in three different approaches to give unique on-DNA lactam structures: on-DNA aldehyde coupled with isonitriles and amino acids; on-DNA isonitrile coupled with aldehydes and amino acids; and on-DNA isonitrile coupled with amines and acid aldehydes.

SNAr and C-H Amination of Electron Rich Arenes with Pyridine as a Nucleophile Using Photoredox Catalysis.

This report describes the development of two photocatalytic methods for the pyridination of electron rich arenes. First, an SNAr-type reaction between aryl halides and pyridine is developed and optimized. This transformation affords selective substitution of C(sp2)-halogen over C(sp2)-OR bonds to afford arylpyridinium products under anaerobic conditions. Under complementary aerobic conditions, analogous substrates are shown to undergo oxidative C(sp2)-H pyridination.