A Visible‐Light‐Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro‐Substituted Spirocyclic ORL‐1 Antagonist |
| |
Authors: | Dr James J Douglas Haley Albright Martin J Sevrin Dr Kevin P Cole Prof Corey R J Stephenson |
| |
Institution: | 1. Department of Chemistry, University of Michigan, Ann Arbor, MI 48109 (USA) www.umich.edu/~crsgroup/;2. Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 (USA) |
| |
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. |
| |
Keywords: | catalysis heterocycles photocatalysis radical reactions rearrangement |
|
|