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

DNA-encoded libraries (DELs) are an increasingly popular approach to finding small molecule ligands for proteins. Many DEL synthesis protocols hinge on sequential additions of monomers using split-pool combinatorial methods. Therefore, compatible protecting group strategies that allow the unmasking reactive functionality (e. g. amines and alcohols) prior monomer coupling, or removal less desirable g., alkenes alkynes) highly desirable. Hydrogenation/hydrogenolysis procedures would achieve these ends but have not been amenable chemistry. We report a catalytic hydrogen transfer reaction Pd/C, HCONH4 micelle-forming surfactant, TPGS-750-M, which gives efficient conversions hydrogenolysis Cbz-protected benzyl protected alcohols hydrogenation nitros, halides, nitriles, aldehydes, alkynes. Application multicycle encoded compound was fully with DNA-amplification sequencing, demonstrating its applicability synthesis. This method will enable synthetic sequences orthogonal groups.