New Paper - Micellar Buchwald-Hartwig couplings for DELs

J. Org. Chem. 2021, 86, 17257-17264

https://doi.org/10.1021/acs.joc.1c02325

https://pubs.acs.org/doi/10.1021/acs.joc.1c02325

Jessica S. Graham, James H. Hunter and Michael J. Waring*

DNA-encoded Libraries (DELs) have attracted attention as an efficient means to identify hit compounds for drug discovery campaigns. Arylamines are privileged motifs in drug-like molecules and methods for their incorporation into DELs is highly desirable. 

In recent years, the palladium catalysed cross-coupling reaction between an amine and an aryl halide (Buchwald-Hartwig reaction) has emerged as one of the most direct methods to synthesise aromatic amines. It is essential to be able to carry out efficient reactions on DNA-conjugated substrates, however the Buchwald-Hartwig coupling does not perform well on-DNA conjugates using current approaches. Hence the development of a robust method for on-DNA Buchwald-Hartwig reactions that is broadly applicable across a range of drug-like substrates, particularly heteroarylamines, is highly desirable. 

Reactions on DNA-conjugated substrates are traditionally carried out in aqueous medium at high dilution using reagents that do not react with the DNA tag. To ensure high fidelity of the libraries, the reactions must proceed cleanly with high conversions across a range of substrates. One solution to the challenge of performing reactions in aqueous media is to use micellar surfactants and we have previously reported the use of the surfactant TPGS-750-M to promote other on-DNA coupling reactions. 

Building on previous work of former PhD student, James Hunter who developed the first micellar on-DNA reactions in the group and applied it to Suzuki reactions, this new work was carried out by MoSMed PhD student Jess Graham, who developed the on-DNA Buchwald-Hartwig reaction and tested all the substrates.

Optimisation of conditions led to a robust, high yielding method for the synthesis of DNA-conjugated aryl and heteroarylamines, which is broad in substrate scope for both the arylamine and the DNA-conjugated aryl halide and is fully compatible with DNA-encoding and decoding procedures. The broad substrate scope, coupled with the synthesis of a multicycle fully DNA encoded compound establishes that this method is of great utility in the synthesis of DELs.

Last modified: Wed, 30 Mar 2022 10:58:54 BST