Subscribe to RSS
DOI: 10.1055/s-0030-1260478
Asymmetric Synthesis of (S)-Ketoprofen
Contributor(s):Philip KocienskiMerck Center for Catalysis at Princeton University, USA
Enantioselective α-Arylation of Aldehydes via the Productive Merger of Iodonium Salts and Organocatalysis
J. Am. Chem. Soc. 2011, 133: 4260-4263
Publication History
Publication Date:
17 June 2011 (online)
Key words
ketoprofen - organocatalysis - iodonium salts - iminium ions - α-arylation
Significance
A synthesis of the non-steroidal anti-inflammatory drug (S)-ketoprofen exemplifies a new general tandem catalysis approach to the enantioselective organocatalytic α-arylation of aldehydes. The scope of the reaction is illustrated by 22 examples (67-95% yield, 91-94% ee) involving ten different aldehydes and 13 different diaryliodonium salts. A five-step synthesis of catalyst C (17% overall) from l-phenylglycine N-methylamide is provided.
Comment
A mechanism is proposed involving reaction of the aryl copper(III) species G (derived from oxidative addition of CuBr to the diaryliodonium salt A) with the enamine H (derived from condensation of the organocatalyst C with propanal) to give the η¹-iminium copper(III) species I. Reductive elimination with retention of configuration then gives the α-aryl iminium salt J, which hydrolyzes to the product with regeneration of the organocatalyst C.