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 alpha-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 alpha-elimination of fluoride renders this process highly challenging. Herein, we describe a new strategy for stabilizing and utilizing transient alpha-trifluoromethyl carbanions that relies on a neighbouring cationic pi-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.