Micelle‐Mediated Sonogashira Coupling for DNA‐Encoded Library Synthesis

Abstract

DNA‐Encoded Libraries (DELs) are becoming widely established as a hit identification strategy for drug discovery campaigns. Their successful application relies on the availability and efficiency of the reactions that can be carried out on DNA. These reactions should proceed with high conversion to the desired product and have a broad substrate scope to synthesise chemically diverse and drug‐like DELs. The Sonogashira coupling provides a unique means of coupling an sp‐hybridized carbon centre to an aryl halide and methods to achieve this reaction on DNA are highly desirable. We report the application of our micellar technology for on‐DNA chemistry to the Sonogashira reaction. This method gives highly efficient conversions for the coupling of (hetero)aromatic and aliphatic alkynes to (hetero)aryl iodides and bromides allowing the preparation of highly diverse DELs.

Aqueous Micelles as Solvent, Ligand, and Reaction Promoter in Catalysis

“…Organic reactions can be challenging in water due to the poor solubility of organic substrates in an aqueous medium. To overcome this issue, Kobayashi, − Lipshutz, − Uozumi, , Leahy, , our group, − and other researchers − have developed various micellar technologies that use water as a reaction medium and are potentially sustainable. These technologies showcased that the micelles are necessary to solubilize organic substrates in water, and they are broadly classified as ionic and nonionic, depending upon the charge present in the hydrophilic region.…”

Micelle‐Promoted Reductive Amination of DNA‐Conjugated Amines for DNA‐Encoded Library Synthesis

“…[12,13] Our group have previously reported the successful application of the surfactant TPGS-750-M in facilitating on-DNA amide couplings, Suzuki-Miyaura couplings, Buchwald-Hartwig aminations, Sonogashira couplings, and Heck reactions with high conversions and broad substrate scopes. [14][15][16][17][18] Reductive aminations have long played an important role in medicinal chemistry due to their ability to synthesise diverse amines, a fundamental structural motif in pharmaceutical compounds that imparts desirable drug-like properties. [19,20] This versatile transformation typically involves the coupling of a carbonyl compound with an amine to form an intermediate hemiaminal, which undergoes reduction via various approaches; most commonly through the formation of a Schiff base (imine) or iminium ion, and subsequent reduction using either borohydride-based reducing agents (NaBH 4 , NaBH 3 CN, NaBH(OAc) 3 ) or catalytic hydrogenation.…”