sp³‐Rich Heterocycle Synthesis on DNA: Application to DNA‐Encoded Library Production

Abstract

DNA encoded library (DEL) synthesis represents a convenient means to produce, annotate and store large collections of compounds in a small volume. While DELs are well suited for drug discovery campaigns, the chemistry used in their production must be compatible with the DNA tag, which can limit compound class accessibility. As a result, most DELs are heavily populated with peptidomimetic and sp2‐rich molecules. Here, we show that sp3‐rich mono‐ and bicyclic heterocycles can be made on DNA from ketochlorohydrin aldol products through a reductive amination and cyclization process. The resulting hydroxy pyrrolidines possess structural features that are unique among DELs and occupy a distinct region of pharmaceutically relevant chemical space.