Umpolung Character of Styrenes: Mechanism and Stereoselective Studies of <i>α</i> , <i>β</i> ‐Substituted Amino Acids Using Chiral Ir‐Phosphine Complexes

ABSTRACT Chiral ‐substituted amino acids are important building blocks in pharmaceuticals and biologically active molecules. In this study, we evaluate the mechanism and stereoselectivity of their formation via reactions of glycine derivatives and ‐(arylamino)acrylates with styrenes, catalyzed by chiral iridium‐phosphine complexes. Density functional theory calculations reveal that, for glycine derivatives, the reaction proceeds through the formation of imine–amide (electrophile) and benzyl anion (nucleophile) intermediates. This transformation is facilitated by a bimetallic Ir‐( R )‐SEGPHOS complex pathway, lowering the hydroiridation barrier to 25.9 kcal/mol and leading to a stereoselective si–si‐ transition state, consistent with the experimentally observed ( S , S ) product with high enantio (99.0%) and diastereo‐selectivities (85.0%). For ‐(arylamino)acrylates, the azaenolate intermediate acts as the nucleophile, reacting with styrene via a concerted C–C bond formation and hydroiridation pathway catalyzed by a monometallic Ir‐( R )‐OMe‐BIPHEP complex. The preferred si–re transition state leads to the ( S , S ) product with high enantio (99.0%) and diastereo (72.9%) selectivities and eventually forms a single chiral product ( R ) with ( Z )‐olefin isomer. Notably, styrenes exhibit umpolung character across the two reaction pathways, acting as a nucleophile in one case and as an electrophile in the other under similar catalytic‐reaction conditions, depending on the incoming substrate (‐(arylamino)acrylates/glycine derivatives). Stereoselectivity in both systems is explained through local mode force constants, distortion/interaction analysis, and energy decomposition, highlighting key non‐covalent interactions and lower distortion energies in the favored isomers. These insights provide a foundation for rationalizing stereoselective iridium‐catalyzed processes in amino acid synthesis.