Enantioselective Synthesis of 5-Trifluoromethyl-2-oxazolines under Dual Silver/Organocatalysis

Abstract

The first enantioselective formal [3 + 2] cycloaddition between α-isocyanoesters and trifluoromethylketones to give 5trifluoromethyl-2-oxazolines bearing two contiguous stereogenic centers, one of them being a quaternary stereocenter substituted with a CF 3 group, has been developed. The reaction is based upon a multicatalytic approach that combines a bifunctional Brønsted basesquaramide organocatalyst and Ag + as Lewis acid. The reaction could be achieved with a range of aryl and heteroaryl trifluoromethyl ketones, and the resulting oxazolines were obtained with good to excellent diastereo-and enantioselectivity. Recently, on the basis of a cooperative strategy previously reported by Escolano et al. for the asymmetric cycloaddition of isocyanoacetates with vinyl ketones, 14 our group developed a highly catalytic enantioselective cycloaddition reaction between ketones and α-isocyanoesters using a multicatalytic approach that combined a bifunctional Brønsted base

Catalytic Enantioselective Isocyanide‐Based Reactions: Beyond Passerini and Ugi Multicomponent Reactions

“…[29] Blay, Pedro, and co‐workers recently described the use of (hetero)aryl trifluoromethyl ketones as the reaction components for such cycloadditions (Scheme 4 d). [30] In the presence of bifunctional squaramide 17 a (5 mol %) and Ag 2 O (2.5 mol %), the method showed wide substrate scope and provided rapid access to 5‐trifluoromethyl‐2‐oxazolines 18 in good yields and with fair to good diastereomeric ratios and high enantiomeric excesses. Moreover, the formal synthesis of LpxC inhibitor ( LPC‐083 ) from oxazoline 18 a further made this method valuable and attractive (Scheme 4 e).…”

Squaramide Catalyzed Asymmetric Synthesis of Five‐ and Six‐Membered Rings

“…Diastereoselectivity increases markedly with increase in steric bulk of the alkyl substituent in the ketone and only few examples were presented involving alkyl, alkyl ketones (Scheme 87a). This methodology was further extended with trifluoromethyl ketones leading to the access of chiral oxazolines 327 / 327′ including a trifluoromethylated quaternary stereocenter [134] . Variation of 260 was limited to only three substrates like methyl isocyanoacetate, tert ‐butyl isocyanoacetate, methyl 2‐isocyano‐2‐phenylacetate and the last one could afford the products bearing two contiguous quaternary stereocenters.…”

“…This methodology was further extended with trifluoromethyl ketones leading to the access of chiral oxazolines 327/327' including a trifluoromethylated quaternary stereocenter. [134] Variation of 260 was limited to only three substrates like methyl isocyanoacetate, tert-butyl isocyanoacetate, methyl 2-isocyano-2-phenylacetate and the last one could afford the products bearing two contiguous quaternary stereocenters. A range of aryl/heteroaryl/alkyl and trifluoromethyl functionalized ketones were screened to test the methodology delivering the chiral products with high yield, low to good diastereoselectivities and notable enantioselectivities.…”

Recent Advances in the Chemistry of Isocyanides with Activated Methylene Group

“…A reverse approach was used to introduce a CF 3‐ substituent in oxazole structure 152 by enantioselective formal [3+2] cycloaddition between α ‐isocyanoesters 1 and trifluoromethylketones 151 . [ 78 ] It is worth noting that in all cases the use of squaramide organocatalyst 139 and silver oxide led to trans 5‐trifluoromethyl‐2‐oxazolines 152 bearing two contiguous stereogenic centers with good to excellent diastereo‐ and enantioselectivity (Scheme 65).…”