Metal-Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing
Autor: | Veit G. Haensch, Toni Neuwirth, Christian Hertweck, Florian Kloss |
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Rok vydání: | 2018 |
Předmět: |
chemistry.chemical_classification
Chemistry 010405 organic chemistry Aryl Total synthesis General Chemistry General Medicine 010402 general chemistry Combinatorial chemistry 01 natural sciences Coupling reaction Catalysis Sulfonamide 0104 chemical sciences chemistry.chemical_compound Metal free Pharmaceutical Preparations Metals Chemoselectivity Selectivity Linker |
Zdroj: | Angewandte Chemie. 130:14684-14689 |
ISSN: | 0044-8249 |
DOI: | 10.1002/ange.201805961 |
Popis: | 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, antihypertensive agents that rank among the top blockbuster drugs worldwide. This safe and convenient protocol is a valuable alternative for the widely used metal-dependent aryl cross-coupling methods. |
Databáze: | OpenAIRE |
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