Metal-Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing.

Metal-Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing.

Icon for Wiley Related Articles

Metal-Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing.

Angew Chem Int Ed Engl. 2018 10 26;57(44):14476-14481

Authors: Kloss F, Neuwirth T, Haensch VG, Hertweck C

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.

PMID: 30001481 [PubMed – indexed for MEDLINE]


https://www.ncbi.nlm.nih.gov/pubmed/30001481?dopt=Abstract

https://eutils.ncbi.nlm.nih.gov/entrez/eutils/erss.cgi?rss_guid=1BE6Yf6ex8r6DRZaKzQi_iKP-GeW6jP4zTLhuJ2dzIMGHW_IGQ
=====================
CannaSearch™ Breaking News on CBD + Hemp is another FREE service of “The Richard Rose Report“. Please Subscribe for FREE ♥
=====================