Use of α-trifluoromethyl carbanions for palladium-catalysed asymmetric cycloadditions

The development of new methodologies that enable chemo- and stereoselective construction of fluorinated substituents, such as the trifluoromethyl (CF3) group, plays an essential role in the synthesis of new pharmaceutical agents. The exceptional ability of the CF3 moiety to prevent in vivo metabolism as well as improve other pharmacological properties has led to numerous innovative strategies for installing this unique functional group. One potential yet underdeveloped approach to access these trifluoromethylated products is direct substitution of α-trifluoromethyl carbanions. Although the electron-withdrawing nature of the CF3 group should facilitate deprotonation of adjacent hydrogens, the propensity of the resulting carbanions to undergo α-elimination of fluoride renders this process highly challenging. Herein, we describe a new strategy for stabilizing and utilizing transient α-trifluoromethyl carbanions that relies on a neighbouring cationic π-allyl palladium complex. These palladium-stabilized zwitterions participate in asymmetric [3 + 2] cycloadditions with a broad range of acceptors, generating valuable di- and trifluoromethylated cyclopentanes, pyrrolidines and tetrahydrofurans. Although methods exist for the construction of CF3-containing stereocentres, the utilization of α-trifluoromethyl carbanions remains challenging because of the propensity for fluoride elimination. A strategy has now been developed to stabilize these carbanions through a neighbouring cationic Pd complex and the corresponding Pd-stabilized zwitterions participate in asymmetric cycloadditions with a broad range of acceptors.