A Visible-Light-Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro-Substituted Spirocyclic ORL-1 Antagonist

• Published in: Angewandte Chemie International Edition Vol. 54; no. 49; pp. 14898 - 14902
• Main Authors: Douglas, James J., Albright, Haley, Sevrin, Martin J., Cole, Kevin P., Stephenson, Corey R. J.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.12.2015; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: catalysis; Catalysts; Chemistry; Chemistry, Multidisciplinary; Free Radicals - chemistry; Free Radicals - radiation effects; heterocycles; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Light; Molecular Structure; Nociceptin Receptor; Opioid receptors; photocatalysis; Photochemicals; Physical Sciences; radical reactions; rearrangement; Receptors, Opioid - metabolism; Science & Technology; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Synthesis; ACTIVATION; COMPLEX; radical reactions; catalysis; COPPER; FLUORINATION; PHOTOREDOX CATALYSIS; DIFLUOROMETHYLATION; heterocycles; BONDS; OLEFINS; ALKENYL; photocatalysis; rearrangement
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201507369

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. A reason for Smiles: A visible‐light‐mediated radical Smiles rearrangement addresses the challenging synthesis of the gem‐difluoro group present in an opioid receptor‐like 1 (ORL‐1) antagonist and enables the introduction of the difluoroethanol motif into a range of aryl and heteroaryl systems. When applied to the target compound, the photochemical step could be conducted on 15 g scale at a [Ru(bpy)3]Cl2 loading of 0.01 mol %.