Abstract
An ideal DNA-encoded library (DEL) selection requires the library to consist of diverse core skeletons and cover chemical space as much as possible. However, the lack of efficient on-DNA synthetic approaches toward core skeletons has greatly restricted the diversity of DEL. To mitigate this issue, this work disclosed a "Mask & Release" strategy to streamline the challenging on-DNA core skeleton synthesis. N-phenoxyacetamide is used as a masked phenol and versatile directing group to mediate diversified DNA-compatible C-H functionalization, introducing the 1st-dimensional diversity at a defined site, and simultaneously releasing the phenol functionality, which can facilitate the introduction of the 2nd diversity. This work not only provides a set of efficient syntheses toward DNA-conjugated drug-like core skeletons such as ortho-alkenyl/sulfiliminyl/cyclopropyl phenol, benzofuran, dihydrobenzofuran but also provides a paradigm for on-DNA core skeleton synthetic method development.