Asymmetric Construction of Pyrrolidines Bearing a Trifluoromethylated Quaternary Stereogenic Center via Cu^I‐Catalyzed 1,3‐Dipolar Cycloaddition of Azomethine Ylides with β‐CF₃‐β,β‐Disubstituted Nitroalkenes

Abstract

A direct and convenient method has been developed for the synthesis of optically active pyrrolidines bearing a quaternary stereogenic center containing a CF3 group at the C-3 position of the pyrrolidine ring. The synthesis system, Cu(I) /Si-FOXAP-catalyzed exo-selective 1,3-dipolar cycloaddition of azomethine ylides with β-CF3 -β,β-disubstituted nitroalkenes, provides pyrrolidines with high diastereoselectivities (up to >98:2 d.r.) and excellent enantioselectivities (up to >99.9 ee) and performs well for a broad scope of substrates under mild conditions.

A Molecular Electron Density Theory Study of the Role of the Copper Metalation of Azomethine Ylides in [3 + 2] Cycloaddition Reactions

“…Interestingly, the generation of N -metalated AYs in the presence of chiral ligands has allowed the enantioselective synthesis of pyrrolidines. ,− In 1991, Grigg and co-workers demonstrated, for the first time, that the addition of a stoichiometric amount of chiral cobalt or manganese complexes with ephedrine derivatives as the chiral ligand in the generation of AYs derived from imines of glycine alkyl esters could give pyrrolidines with up to 96% ee. It was also reported that silver­(I) salts in combination with chiral phosphane ligands can catalyze the 32CA reaction of AYs.…”

“…Different metals, such as Zn, , Ag, ,,,, and Cu, ,− ,,,− and chiral ligands, such as 7 , 8 , ,,,,,, or 9 , ,, have been used in the 32CA reactions of N -metalated AYs with electrophilic ethylene derivatives, improving diastereo- and enantioselectivities. Interestingly, while stereoselectivities have been found to be dependent on the chiral ligands, the substitution of the electrophilic ethylene and even the nature of the metal, e.g.…”

Visible Light-Induced Radical Cyclization of Tertiary Bromides with Isonitriles To Construct Trifluoromethylated Quaternary Carbon Center

“…Michael addition reaction, S N 2′ reaction, cycloaddition, and transition-metal catalysis are used to synthesize compounds with TFQC by using electrophilic reagents such as trifluoromethylated olefins. We have shown great interest in using α-trifluoromethylated carbanions, which are challenging starting materials, with a facile defluorination before further functionalization.…”

Intramolecular Hydrogen Bond Activation: Thiourea-Organocatalyzed Enantioselective 1,3-Dipolar Cycloaddition of Salicylaldehyde-Derived Azomethine Ylides with Nitroalkenes

“…2 These metal-catalyzed methods have successfully provided access to a wide range of substituted enantiomerically enriched pyrrolidines. 4−9 …”

“…However, longer reaction times were required. The more challenging β,β-disubstituted nitroalkene 9 reacted efficiently with 1b and led to the pyrrolidine 3Lb with a good yield and enantioselectivity (entry 13). The absolute configuration of the asymmetric centers of 3Db was unequivocally assigned as 2 R , 3 S , 4 R ,and 5 S (Table 2, top right) by X-ray crystallographic analysis.…”