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A Visible‐Light‐Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro‐Substituted Spirocyclic ORL‐1 Antagonist
Author(s) -
Douglas James J.,
Albright Haley,
Sevrin Martin J.,
Cole Kevin P.,
Stephenson Corey R. J.
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201507369
Subject(s) - moiety , chemistry , antagonist , combinatorial chemistry , aryl , catalysis , stereochemistry , functional group , photochemistry , receptor , organic chemistry , biochemistry , alkyl , polymer
A visible‐light‐mediated radical Smiles rearrangement has been developed to address the challenging synthesis of the gem ‐difluoro group present in an opioid receptor‐like 1 (ORL‐1) antagonist that is currently in development for the treatment of depression and/or obesity. This method enables the direct and efficient introduction of the difluoroethanol motif into a range of aryl and heteroaryl systems, representing a new disconnection for the synthesis of this versatile moiety. When applied to the target compound, the photochemical step could be conducted on 15 g scale using industrially relevant [Ru(bpy) 3 Cl 2 ] catalyst loadings of 0.01 mol %. This transformation is part of an overall five‐step route to the antagonist that compares favorably to the current synthetic sequence and demonstrates, in this specific case, a clear strategic benefit of photocatalysis.