title: A Visible-Light-Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro-Substituted Spirocyclic ORL-1 Antagonist.
abstract: 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)3Cl2] 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.
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109 (USA) www.umich.edu/∼crsgroup/|Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 (USA).
authors.forename: James J
authors.initials: JJ
authors.lastname: Douglas
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109 (USA) www.umich.edu/∼crsgroup/
authors.forename: Haley
authors.initials: H
authors.lastname: Albright
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109 (USA) www.umich.edu/∼crsgroup/
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Sevrin
authors.affiliation: Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 (USA).
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Cole
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109 (USA) www.umich.edu/∼crsgroup/. crjsteph@umich.edu.
authors.forename: Corey R J
authors.initials: CR
authors.lastname: Stephenson
mesh_terms: D005609:Free Radicals / Q000737:chemistry* / Q000528:radiation effects; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008027:Light; D015394:Molecular Structure; D011957:Receptors, Opioid / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000094942:Nociceptin Receptor
chemical_list: D005609:Free Radicals; D006571:Heterocyclic Compounds; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor
keywords: catalysis; heterocycles; photocatalysis; radical reactions; rearrangement