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

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. Herein, 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 hydroxypyrrolidines possess structural features that are desirable for DELs and target a distinct region of pharmaceutically relevant chemical space.

High-Throughput Solid-Phase Building Block Synthesis for DNA-Encoded Libraries.

Herein we provide a generalizable method for the cost-effective synthesis of thousands of building blocks (BBs) employing DNA-incompatible chemistries. The ability to produce large numbers of crude products via solid-phase synthesis has existed for decades; however, our work demonstrates a practical use of such crude reaction mixtures and employs DNA-conjugation to simultaneously encode, purify, and rapidly analyze the desired products. This workflow generated sp3-rich BBs that could be encoded by DNA in a high-throughput manner.

Development of DNA-Compatible Van Leusen Three-Component Imidazole Synthesis.

DNA-encoded libraries (DELs) have generated recent interest due to their ability to provide new small molecule ligands for pharmaceutically important proteins. The chemical diversity of DELs determines their ability to provide potent, novel, and drug-like chemical matter, and DEL chemical diversity is limited by the scope of DNA-compatible chemical reactions. Herein, the one-pot three-component Van Leusen chemistry is applied to DEL synthesis, providing the first reported DNA-compatible method to generate novel highly functionalized imidazoles.

Copper carbenes alkylate guanine chemoselectively through a substrate directed reaction.

Cu(i) carbenes derived from α-diazocarbonyl compounds lead to selective alkylation of the O6 position in guanine (O6-G) in mono- and oligonucleotides. Only purine-type lactam oxygens are targeted - other types of amides or lactams are poorly reactive under conditions that give smooth alkylation of guanine. Mechanistic studies point to N7G as a directing group that controls selectivity. Given the importance of O6-G adducts in biology and biotechnology we expect that Cu(i)-catalyzed O6-G alkylation will be a broadly used synthetic tool. While the propensity for transition metals to increase redox damage is well-appreciated, our results suggest that transition metals might also increase the vulnerability of nucleic acids to alkylation damage.