New Paper – Micellar Sonogashira couplings for DELs

Chem. Eur. J. 2023, e202300603

https://doi.org/10.1002/chem.202300603

https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/chem.202300603

Jessica S. Graham, Harriet A. Stanway-Gordon and Michael J. Waring*

DNA-Encoded Libraries (DELs) have emerged as a powerful screening strategy to identify hit compounds for drug discovery campaigns, though 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 to synthesize a sp-sp² C-C bond from an aryl or alkenyl halide and a terminal alkyne and methods to achieve this reaction on DNA are highly desirable. 

We have previously reported^[1-4] the use of micelle-forming surfactants to promote on-DNA reactions that offers a versatile means of carrying out organic reactions in an aqueous medium. The reactions that we have reported proceed with excellent conversion, tolerate a broad substrate scope and use the commercially available surfactant TPGS-750-M.

We now report the application of our micellar technology for on-DNA chemistry to the Sonogashira reaction. The optimized micelle-mediated conditions provide a highly efficient method for carrying out Sonogashira coupling of DNA-conjugated aryl halides with a range of aromatic and aliphatic alkynes. To our knowledge, the work provides the first example of expanding this method to DNA-tagged bromide substrates, which will enable the synthesis of more diverse DELs due to the increase in available building blocks for the on-DNA aryl halide. 

In summary, 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.

(1) Hunter, J. H.; Prendergast, L.; Valente, L. F.; Madin, A.; Pairaudeau, G.; Waring, M. High Fidelity Suzuki−Miyaura Coupling for the Synthesis of DNA Encoded Libraries Enabled by Micelle Forming Surfactants. Bioconjugate Chem. 2020, 31, 149-155.

(2) Hunter, J. H.; Anderson, M. J.; Castan, I. F. S. F.; Graham, J. S.; Salvini, C. L. A.; Stanway-Gordon, H. A.; Crawford, J. J.; Madin, A.; Pairaudeau, G.; Waring, M. J. Highly efficient on-DNA amide couplings promoted by micelle forming surfactants for the synthesis of DNA encoded libraries. Chem. Sci. 2021, 12, 9475-9484.

(3) Stanway-Gordon, H. A.; Graham, J. S.; Waring, M. J. On-DNA Transfer Hydrogenolysis and Hydrogenation for the Synthesis of DNA-Encoded Chemical Libraries. Angew. Chem., Int. Ed. 2022, 61, 1-5.

(4) Graham, J. S.; Hunter, J. H.; Waring, M. Micellar Buchwald−Hartwig Coupling of Aryl and Heteroarylamines for the Synthesis of DNA-Encoded Libraries. J. Org. Chem. 2021, 86, 17257-17264. 

Last modified: Sat, 27 May 2023 11:38:43 BST