Nickel‐Catalyzed Enantioconvergent Arylation of Unactivated Cyclic Electrophiles: Asymmetric Synthesis of 3‐Substituted Pyrrolidines

ABSTRACT The enantioconvergent substitution of unactivated alkyl electrophiles by carbon nucleophiles is a largely unsolved challenge in asymmetric catalysis, with virtually all of the progress to date focused on acyclic electrophiles. Expanding the scope of such transformations to cyclic electrophiles is of significant interest, given that cyclic scaffolds that bear stereocenters are common in bioactive molecules. One particularly attractive family of unactivated cyclic electrophiles is 3‐halopyrrolidines, since a chiral 3‐substituted pyrrolidine subunit is found in drugs such as Trikafta TM , Rinvoq TM , and Paxlovid TM (#4, #11, and #13, respectively, among small‐molecule drugs in retail sales in 2024). In this study, we establish that a chiral nickel catalyst can achieve enantioconvergent substitutions of racemic 3‐iodopyrrolidines by arylzinc reagents to generate the desired coupling products with good enantioselectivity under mild conditions. We apply this new catalytic asymmetric method to the streamlined synthesis of three bioactive pyrrolidines that had previously been synthesized as racemates.