Electronically Activated Organoboron Catalysts for Enantioselective Propargyl Addition to Trifluoromethyl Ketones

Abstract

Ab roadly applicable,p ractical, scalable,e fficient and highly a-a nd enantioselective method for addition of asilyl-protected propargyl moiety to trifluoromethyl ketones has been developed. Reactions,promoted by 2.0 mol %ofacatalyst that is derived in situ from areadily accessible aminophenol compound at ambient temperature, were complete after only 15 minutes at room temperature.T he desired tertiary alcohols were isolated in up to 97 %y ield and 98.5:1.5 enantiomeric ratio.A lkyl-,a lkenyl-, alkynyl-, aryl-or heteroaryl-substituted trifluoromethyl ketones can be used. Utility is highlighted by application to atransformation that is relevant to enantioselective synthesis of BI 653048, acompound active against rheumatoid arthritis.

Access to enantioenriched compounds bearing challenging tetrasubstituted stereocenters via kinetic resolution of auxiliary adjacent alcohols

“…Inspired by the success of accessing diaryl tertiary alcohols using KRA* method, we further surveyed tertiary alcohols with all aliphatic substituents (three sp 3 carbons), which represents one of the most challenging topics in the field of asymmetric catalysis. Very limited methods have been developed to address the issue, and to date the most effective methods were reported by Hoveyda and co-workers, using asymmetric allylation and propargylation of methyl and mono, di, or trifluoromethyl ketones 31 , 32 , 56 – 58 and the kinetic resolution of methyl tertiary alcohols 39 . Asymmetric desymmetrization has also been developed, but with specific types of substrates 59 – 62 .…”

Recent Advances in Catalytic Asymmetric Synthesis of Tertiary Alcohols via Nucleophilic Addition to Ketones

“…Although Fandrick's method accomplished high yields, it suffered from the high catalyst loading (25 mol%), long reaction time (2 days) and moderate enantiocontrol (60–86% ee ). In pursuit of a more efficient and practical approach using a readily accessible catalyst and avoiding the low reaction temperature (−40 °C), Hoveyda, Mszar and co‐workers recently developed a mild method utilizing a Lewis acid Zn(OMe) 2 (4 mol%) with an activated aminophenol ( 52 )‐based catalyst (2 mol%) (Scheme ) . This catalyst system was applicable for aryl‐, heteroaryl‐, alkyl‐, alkynyl‐ and alkenyl‐substituted trifluoromethyl ketones, enabling the desired addition products to be obtained in up to 97% yield and 97% ee at room temperature in just 15 min.…”