Development of a Micellar-Promoted Heck Reaction for the Synthesis of DNA-Encoded Libraries

The capability of DNA encoded libraries (DELs) as a method
of small
molecule hit identification is becoming widely established in drug
discovery. While their selection method offers advantages over more
traditional means, DELs are limited by the chemistry that can be utilized
to construct them. Significant advances in DNA compatible chemistry
have been made over the past five years; however such procedures are
still often burdened by substrate specificity and/or incomplete conversions,
reducing the fidelity of the resulting libraries. One such reaction
is the Heck coupling, for which current DNA-compatible protocols are
somewhat unreliable. Utilizing micellar technology, we have developed
a highly efficient DNA-compatible Heck reaction that proceeds on average
to 95% conversion to product across a broad variety of structurally
significant building blocks and multiple DNA conjugates. This work
continues the application of micellar catalysis to the development
of widely applicable, effective DNA-compatible reactions for use in
DELs.