New Paper - DNA-compatible Heck reactions

Bioconjugate Chem. 2023, 34, 756-763

https://doi.org/10.1021/acs.bioconjchem.3c00051

https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.3c00051

Harriet A. Stanway-Gordon, Jake A. Odger and Michael J. Waring*

The capability of DNA encoded libraries (DELs) as a method of small molecule hit identification is becoming widely established in drug discovery. Although advantageous over conventional methods of hit identification with respect to the rapidity with which both the synthesis and screening of DELs can be achieved, the process suffers from limitations with regards to DNA compatible chemistry that can be employed in their construction. Significant advances have been made; however such procedures are still often burdened by substrate specificity and/or incomplete conversions, reducing the fidelity of the resulting libraries. 

In conventional (off-DNA) synthesis, the Pd-catalysed Heck coupling reaction has been employed in routes to a variety of clinical candidates and pharmaceutical agents, but current Heck methodology with DELs is somewhat limited.

We have previously shown that the application of micellar catalysis within DNA-compatible chemistry can be of great benefit.^[1-5] Utilising this micellar technology, we now report the development of a highly efficient DNA-compatible Heck reaction that yields on average 95% conversion to product across a broad variety of structurally significant building blocks and multiple DNA conjugates.

_{(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.; Potowski, M.; Stanway-Gordon, H. A.; Madin, A.; Pairaudeau, G.; Brunschweiger, A.; Waring, M. J. Functional Group Tolerance of a Micellar on-DNA Suzuki−Miyaura Cross- Coupling Reaction for DNA-Encoded Library Design.  2021, 86, 17930−17935.}

_{(3) 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.} 

_{(4) 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.}

_{(5) 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.}

Last modified: Sat, 27 May 2023 11:41:39 BST