Fluorinated organoboranes serve as versatile synthetic precursors for the preparation of value‐added fluorinated organic compounds. Recent progress has been mainly focused on the transition‐metal catalyzed defluoroborylation. Herein, we report a photocatalytic defluoroborylation platform through direct B−H activation of N‐heterocyclic carbene boranes, through the synergistic merger of a photoredox catalyst and a hydrogen atom transfer catalyst. This atom‐economic and operationally simple protocol has enabled defluoroborylation of an extremely broad scope of multifluorinated substrates including polyfluoroarenes, gem‐difluoroalkenes, and trifluoromethylalkenes in a highly selective fashion. Intriguingly, the defluoroborylation protocol can be transition‐metal free, and the regioselectivity obtained is complementary to the reported transition‐metal‐catalysis in many cases.
Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201811266. Scheme 1. Difunctionalization of simple alkenes via CÀHorSi ÀH activation. BPO = benzoyl peroxide;TBHP = tert-butyl hydroperoxide; DTBP = di-tert-butyl peroxide.
Bivalent chemical degraders, otherwise known as proteolysis-targeting
chimeras (PROTACs), have proven to be an efficient strategy for targeting
overexpressed or mutated proteins in cancer. PROTACs provide an alternative
approach to small-molecule inhibitors, which are restricted by occupancy-driven
pharmacology, often resulting in acquired inhibitor resistance via
compensatory increases in protein expression. Despite the advantages
of bivalent chemical degraders, they often have suboptimal physicochemical
properties and optimization for efficient degradation remains highly
unpredictable. Herein, we report the development of a potent EED-targeted
PRC2 degrader, UNC7700. UNC7700 contains a unique cis-cyclobutane linker and potently degrades PRC2 components EED (DC50 = 111 nM; D
max = 84%), EZH2WT/EZH2Y641N (DC50 = 275 nM; D
max = 86%), and to a lesser extent SUZ12 (D
max = 44%) after 24 h in a diffuse large B-cell
lymphoma DB cell line. Characterization of UNC7700 and related compounds
for ternary complex formation and cellular permeability to provide
a rationale for the observed improvement in degradation efficiency
remained challenging. Importantly, UNC7700 dramatically reduces H3K27me3
levels and is anti-proliferative in DB cells (EC50 = 0.79
± 0.53 μM).
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