Metal-Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing

Angewandte Chemie
Florian KlossChristian Hertweck

Abstract

Many pharmaceuticals feature biaryl motifs that are crucial for their binding to the target. Yet, benchmark methods for selective cross-couplings rely on highly toxic heavy metal catalysts, which are unfavorable in the synthesis of pharmaceuticals. Metal-free coupling reactions, on the other hand, may require harsh conditions and lack selectivity. We report a novel, metal-free cross-coupling reaction that involves the tethering of two phenyl groups by a temporary, traceless sulfonamide linker that directs a photochemical aryl fusion into a single coupling product. The perfect regio- and chemoselectivity of the reaction could be rationalized by a cyclic intermediate, which fragments into the biaryl and volatile side products. Using a flow reactor, we synthesized numerous substituted biaryl building blocks for important therapeutics in high yields, such as antibiotics, antitumor, neuroprotective and cholesterol-lowering agents as well as antiarthritic non-steroidal antiinflammatory drugs (NSAIDs). The new method was successfully employed in a total synthesis of cannabinol, an important analgesic and antiemetic therapeutic. We also report a metal-free synthesis of key building blocks used for the preparation of sartans, antihypert...Continue Reading

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Citations

Jun 5, 2019·Chemistry : a European Journal·Manoj K GhoshMarcin Kalek
Oct 18, 2019·Chemistry : a European Journal·Veit G HaenschChristian Hertweck
Apr 30, 2020·Chemical Communications : Chem Comm·Sakamuri Sarath BabuPurushothaman Gopinath
May 20, 2020·Chemistry : a European Journal·Thomas H Rehm
Oct 24, 2020·Chemical Communications : Chem Comm·Tatsuya MorofujiNaokazu Kano
Dec 29, 2020·Beilstein Journal of Organic Chemistry·Hisham QrareyaMaurizio Fagnoni
Aug 14, 2021·Chemical Reviews·Xue-Qiang ChuChao-Jun Li
Jul 25, 2019·Organic Letters·Diego CaprioglioGiovanni Appendino
Jul 17, 2019·The Journal of Organic Chemistry·Fazhi YuYonghui Wang

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