One-Pot Enantioselective Synthesis of 2-Pyrrolidinone Derivatives Bearing a Trifluoromethylated All-Carbon Quaternary Stereocenter

Abstract

A new methodology for the one-pot enantioselective construction of 2-pyrrolidinone derivatives bearing a trifluoromethylated all-carbon quaternary stereocenter at the 4-position has been described. This strategy combines an organocatalytic conjugate addition of nitroalkanes to isatinderived α-trifluoromethyl acrylates and a reduction/lactamization process, affording the corresponding products in moderate to high yields (50−95%) with generally excellent stereoselectivities (up to 96% ee and >20:1 dr).

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

“…Chan, Zhao and co‐workers demonstrated two‐ step one pot technique to construct chiral 2‐pyrrolidinones 256 bearing a trifluoromethylated quaternary stereocenter [105] . The reaction involves isatin derived α ‐trifluoromethyl acrylate 253 and nitro alkane 254 and the first step is triggered by chiral squaramide G catalyzed stereoselective 1,4‐addition of nitroalkane to enone moiety of 253 generating 255 as intermediate reaction product.…”

“…Chan, Zhao and co-workers demonstrated two-step one pot technique to construct chiral 2-pyrrolidinones 256 bearing a trifluoromethylated quaternary stereocenter. [105] The reaction involves isatin derived α-trifluoromethyl acrylate 253 and nitro alkane 254 and the first step is triggered by chiral squaramide G catalyzed stereoselective 1,4-addition of nitroalkane to enone moiety of 253 generating 255 as intermediate reaction product. In subsequent steps, À NO 2 was reduced to À NH 2 by introducing Raney Ni/H 2 as the reducing agent into the system and follow up lactamization would cleave oxindole moiety to afford chiral γ-lactams 256 as the final outcome (Scheme 66).…”

Catalysts’ evolution in the asymmetric conjugate addition of nitroalkanes to electron-poor alkenes

“…80 An effective asymmetric synthesis of pyrrolidinones 52 can be realized in a two-step procedure reacting alkylideneoxindoles 50 with nitromethane in the presence of cinchonidinederived squaramide 51 (Scheme 38). 81 The nitro group of the initially formed adduct is reduced by catalytic hydrogenation, and the resulting primary amine is then involved in a thermodynamically controlled transamidation leading to the target pyrrolidinone 52 as a single diastereomer and very good ee value. The trifluoromethyl group in the electrophile seems to play an essential role in enhancing the steric constraint of the transition state through an additional hydrogen bonding with the ammonium ion.…”