Mohammed Sharique; Bianca Matsuo; Albert Granados; Saegun Kim; Mahwish Arshad; Hyunjung Oh; Victoria E. Wu; Minxue Huang; Adam Csakai; Lisa A. Marcaurelle; Gary A. Molander
Chem. Sci., 2023, 14(48), 14193-14199
https://doi.org/10.1039/D3SC03731B

Abstract

The emergence of DNA-encoded library (DEL) technology has provided a considerable advantage to the pharmaceutical industry in the pursuit of discovering novel therapeutic candidates for their drug development initiatives. This combinatorial technique not only offers a more economical, spatially efficient, and time-saving alternative to the existing ligand discovery methods, but also enables the exploration of additional chemical space by utilizing novel DNA-compatible synthetic transformations to leverage multifunctional building blocks from readily available substructures. In this report, a decarboxylative-based hydroalkylation of DNA-conjugated N-vinyl heterocycles enabled by single-electron transfer (SET) and subsequent hydrogen atom transfer through electron-donor/electron-acceptor (EDA) complex activation is detailed. The simplicity and robustness of this method permits inclusion of a broad array of alkyl radical precursors and DNA-tethered nitrogenous heterocyles to generate medicinally relevant substituted heterocycles with pendant functional groups. Moreover, a successful telescoped route provides the opportunity to access a broad range of intricate structural scaffolds by employing basic carboxylic acid feedstocks.