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Catalytic Asymmetric Synthesis of a Tertiary Benzylic Carbon Center via Phenol-Directed Alkene Hydrogenation

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posted on 01.07.2011, 00:00 by Seb Caille, Rich Crockett, Krishnakumar Ranganathan, Xiang Wang, Jacqueline C. S. Woo, Shawn D. Walker
An expeditious synthetic approach to chiral phenol 1, a key building block in the preparation of a series of drug candidates, is reported. The strategy includes a cost-effective and readily scalable route to cyclopentanone 3 from isobutyronitrile (10). The sterically hindered and enolizable ketone 3 was subsequently employed in a challenging Grignard addition mediated by LaCl3·2LiCl. A novel preparation of the lanthanide reagent required for this transformation is described. To complete the process, a highly enantioselective hydrogenation step afforded the target (1). The importance of the phenol group to the success of this asymmetric transformation is discussed.