Novel Catalyst System for Suzuki-Miyaura Coupling of Challenging DNA-Linked Aryl Chlorides

Abstract

A novel Pd catalyst system, [(t-Bu)P(OH)]PdCl (POPd) with the ligand sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxy-[1,1'-biphenyl]-3-sulfonate, is reported. It effectively catalyzes the Suzuki-Miyaura coupling of challenging phenyl chlorides and pyrimidinyl chlorides that are covalently linked to a double-stranded DNA-template with various boronic acids/esters.

Arylation Chemistry for Bioconjugation

“…[245] These aryl halide handles were further conjugated to aryl or heteroaryl boronic acids and esters using Pd(PPh 3 ) 4 as the catalyst. [247] Increased conjugation yields were observed with this catalyst system for various aryl and heteroaryl boronic acids and esters. [246] In 2016, Ding and Clark reported an ew catalyst system using [(t-Bu) 2 P(OH)] 2 PdCl 2 (POPd) as the palladium source and sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxy-[1,1'-biphenyl]-3-sulfonate (sSPhos) as the ligand for the on-DNASuzuki-Miyaura coupling of challenging phenyl chlorides and pyrimidinyl chlorides (Figure 47 B).…”

Palladium‐Mediated Labeling of Nucleic Acids

“…Suzuki–Miyaura cross‐coupling was then performed with a variety of aryl halide substrates and gave the desired conjugates with various boronic acids and heteroaryl boronates with medium to high coupling yields . More recently, a new palladium catalyst system—[( t Bu) 2 P(OH)] 2 PdCl 2 (POPd) with the ligand sodium 2′‐(dicyclohexylphosphino)‐2,6‐dimethoxybiphenyl‐3‐sulfonate—was reported to be more efficient that the previously Pd(PPh 3 ) 4 catalyst for coupling with challenging aryl halides and sterically hindered boronate and heterocyclic boronic esters . This Suzuki–Miyaura cross‐coupling is currently being applied in DNA‐encoded library technology (DNA‐ELT) for the production of several DNA‐encoded libraries.…”

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

“…In a typical affinity-based selection experiment, when non-and low-affinity binders are washed away, the DNA tag of the remaining compounds can be amplified using polymerase chain reaction and the relative frequency of the remaining compounds before and after selection is determined by counting the number of DNA tags in high-throughput DNA sequencing experiments. Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. [14] Several drug candidates derived from their corresponding DEL hits, such as soluble epoxide hydrolase inhibitor GSK2256294, and death domain receptor-associated adaptor kinase RIP1 inhibitor GSK2982772 have progressed to latestage clinical development, [15,16] further emphasizing DEL as a powerful technology for small molecular drug discovery.…”

“…Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. One of the most fundamental challenges is the synthesis of high-quality libraries with more structural diversity, which in turn depends on the development of new and robust DNA-compatible reactions that allow more flexibility in DEL's design and synthesis.…”