| Summary: | 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.
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