Copper‐Catalyzed Enantioselective Reductive Aldol Reaction of α,β‐Unsaturated Carboxylic Acids to Alkyl Aryl Ketones: Silanes as Activator and Transient Protecting Group

• Published in: Chemistry : a European journal 2022-02, Vol.28 (9), p.e202104273-n/a
• Main Authors: Suzuki, Hirotsugu, Yoneoka, Kenji, Kondo, Sora, Matsuda, Takanori
• Format: Article
• Language: English
• Subjects: Acids; Aldehydes; Aromatic compounds; asymmetric synthesis; Carboxylic Acids; Catalysis; Catalysts; Chemistry; Copper; Enantiomers; Ketones; reductive aldol reactions; Silanes; Stereoisomerism; transient protecting groups
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202104273

The first enantioselective reductive aldol reaction of unprotected α,β‐unsaturated carboxylic acids was developed by employing a copper/bisphosphine catalyst. The reaction features in situ protection and activation of an α,β‐unsaturated carboxylic acid by a hydrosilane. The copper enolate formed in situ reacts with an alkyl aryl ketone to afford the β‐hydroxy carboxylic acid with excellent enantioselectivity (up to 99 % ee). The corresponding gram‐scale reaction with a low catalyst loading and the derivatization of the β‐hydroxy carboxylic acids highlight the practicality of this transformation. The first reductive aldol reaction of α,β‐unsaturated carboxylic acids was developed in the presence of copper/bisphosphine catalysts. The reaction demonstrated the usability of in situ protection of α,β‐unsaturated carboxylic acids by a hydrosilane for the reductive C−C bond formation. The Si−O bond in the aldol products is readily cleaved by a standard workup, showing the silane worked as not only an activator but also a transient protecting group.