Robust Suzuki-Miyaura cross-coupling on DNA-linked substrates.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Chemical Biology

Background:

• The Suzuki-Miyaura cross-coupling reaction is a cornerstone of modern medicinal chemistry, widely utilized for constructing complex organic molecules.
• DNA-encoded library technology (ELT) offers a powerful platform for the high-throughput screening and discovery of small molecule drug candidates.
• Integrating robust chemical reactions into ELT is crucial for expanding the chemical space accessible to drug discovery.

Purpose of the Study:

• To adapt and validate the Suzuki-Miyaura cross-coupling reaction for application within DNA-encoded library technology (ELT).
• To investigate the efficacy of palladium catalysts in facilitating cross-coupling reactions on DNA-linked aryl halide substrates.
• To demonstrate the compatibility of this methodology with diverse boronic acid and ester coupling partners, including challenging heterocyclic variants.

Main Methods:

• Exploration of Suzuki-Miyaura cross-coupling conditions specifically tailored for DNA-linked aryl halides.
• Utilized palladium tetrakis(triphenylphosphine) [Pd(PPh3)4] as the catalyst.
• Performed reactions under aqueous conditions to ensure compatibility with DNA integrity.
• Tested a range of phenyl halides (iodides and bromides) and pyridinyl bromides as substrates.
• Coupled substrates with various boronic acids and esters, including heterocyclic examples.

Main Results:

• Pd(PPh3)4 was identified as an effective catalyst for Suzuki-Miyaura cross-coupling on DNA-linked halide substrates.
• The reaction proceeded efficiently under aqueous conditions, preserving the integrity of the DNA-linked molecules.
• Successful coupling was achieved with both phenyl halides and pyridinyl bromides.
• A diverse array of boronic acids and esters, including challenging heterocyclic compounds, were effectively coupled, demonstrating broad substrate scope.

Conclusions:

• The Suzuki-Miyaura cross-coupling reaction can be successfully implemented within DNA-encoded library technology (ELT).
• The use of Pd(PPh3)4 catalyst under aqueous conditions provides an efficient method for generating diverse libraries on DNA scaffolds.
• This optimized approach expands the capabilities of ELT for the discovery of novel small molecule hits and leads in medicinal chemistry.