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Angew Chem Int Ed Engl. 2018 Oct 26;57(44):14476-14481. doi: 10.1002/anie.201805961. Epub 2018 Aug 16.

Metal-Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing.

Author information

1
Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745, Jena, Germany.
2
Transfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology (HKI), 07745, Jena, Germany.
3
Friedrich Schiller University Jena, 07743, Jena, Germany.

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, 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.

KEYWORDS:

biaryls; cross-couplings; photochemistry; sulfonamides; synthetic methods

PMID:
30001481
DOI:
10.1002/anie.201805961
[Indexed for MEDLINE]

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