On-DNA Palladium-Catalyzed Hydrogenation-like Reaction Suitable for DNA-Encoded Library Synthesis

Abstract

Herein we describe a method to orthogonally remove on-DNA N-Cbz, N-Alloc, N-Allyl, O-Bn, and O-Allyl protecting groups in the presence of other common protecting groups to afford free amines and carboxylic acids, respectively. The developed method uses NaBH 4 as the source of hydrogen in the presence of Pd(OAc) 2 under DNA aqueous conditions. In addition, under the developed conditions we were able to successfully hydrogenate triple and double bonds to totally saturated compounds. Furthermore, we introduce a new alternative procedure to reduce azides and aromatic nitro compounds to primary amines.

DNA-Encoded Chemical Libraries: A Comprehensive Review with Succesful Stories and Future Challenges

“…While the synthesis of conventional chemical libraries for HTS may cost as much as USD 1 billion, the synthesis and screening of DELs comprising billions of compounds only requires standard laboratory infrastructure and moderate investments . The implementation of new DNA-compatible reactions has stimulated the exploration of broader chemical spaces, expanding the structural diversity of DELs. − In addition, the incorporation of chemical complexity for library synthesis has been enhanced by the development of new synthetic approaches …”

Enolate–Azide [3 + 2]-Cycloaddition Reaction Suitable for DNA-Encoded Library Synthesis

“…Actually, the idiosyncratic properties of DNA and the properties of combinatorial synthesis have excluded many conventional organic reactions that have been widely used in modern synthetic medicinal chemistry from the DEL chemistry toolbox. Fortunately, researchers worldwide have dedicated themselves to developing a set of DNA-compatible chemical reactions, for instance, diazo-transfer, diarylether synthesis, amide formation, hydrogenation, cross-coupling reaction, − ring-closing metathesis, C–H activation and functionalization, − photopromoted reaction, sulfur-fluoride exchange (SuFEx) click chemistry, bioinspired click selenylation, , cycloaddition reaction, and the on-DNA synthesis of privileged heterocycles such as isocoumarin, azoles, benzimidazole, pyrazoline, pyrrole, and others. ,− Even so, continuously expanding the toolbox of DNA-compatible chemical reactions that can fulfill the stringent criteria of high fidelity, good conversions, chemoselectivity, predictability, and broad substrate scope is still the pillar to promote the future development of DEL technology.…”

On‐DNA Transfer Hydrogenolysis and Hydrogenation for the Synthesis of DNA‐Encoded Chemical Libraries

“…During the course of this work, an alternative method for hydrogenation using Pd(OAc) 2 and NaBH 4 as the hydrogen source was published. [23] To compare the performance of our method Cbz‐protected phenyl alanine 3 , benzyloxyacetamide 9 , benzonitrile 25 and benzaldehyde 26 were subjected to the Pd(OAc) 2 /NaBH 4 conditions (Table S4). They performed similarly for 3 (100 % conversion) but failed to give any conversion with 9 or 25 .…”