Electronically Activated Organoboron Catalysts for Enantioselective Propargyl Addition to Trifluoromethyl Ketones

• Published in: Angewandte Chemie International Edition Vol. 56; no. 30; pp. 8736 - 8741
• Main Authors: Mszar, Nicholas W., Mikus, Malte S., Torker, Sebastian, Haeffner, Fredrik, Hoveyda, Amir H.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 17-07-2017
• Edition: International ed. in English
• Subjects: Alcohols; Ambient temperature; Aminophenol; Aromatic compounds; Arthritis; catalysis; Catalysts; Enantiomers; enantioselective synthesis; homopropargylic alcohols; Ketones; propargyl groups; Rheumatoid arthritis; Temperature effects; trifluoromethyl group; enantioselective synthesis; homopropargylic alcohols; catalysis; propargyl groups; trifluoromethyl group
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201703844

A broadly applicable, practical, scalable, efficient and highly α‐ and enantioselective method for addition of a silyl‐protected propargyl moiety to trifluoromethyl ketones has been developed. Reactions, promoted by 2.0 mol % of a catalyst that is derived in situ from a readily accessible aminophenol compound at ambient temperature, were complete after only 15 minutes at room temperature. The desired tertiary alcohols were isolated in up to 97 % yield and 98.5:1.5 enantiomeric ratio. Alkyl‐, alkenyl‐, alkynyl‐, aryl‐ or heteroaryl‐substituted trifluoromethyl ketones can be used. Utility is highlighted by application to a transformation that is relevant to enantioselective synthesis of BI 653048, a compound active against rheumatoid arthritis.
Fast and selective: When armed with a trifluoromethyl group, readily accessible chiral organoboron catalysts can promote highly enantioselective addition of a silyl‐protected propargylboron compound to a wide range of trifluoromethyl ketones with high efficiency. Utility is demonstrated through a process that may be used for enantioselective synthesis of BI 653048 (active against rheumatoid arthritis).