Computational Study on a Copper‐Catalyzed Atroposelective Dehydro‐Diels–Alder Reaction of Ynamide via Vinyl Cation: Mechanistic Investigations and Chiral Induction Model

Dehydro-Diels-Alder (DDA) reaction serves as one of the most prominent methods for the synthesis of aromatic compounds. Herein, our study elucidates the mechanism and origin of atroposelectivity of Cu(I)-catalyzed DDA reactions of aryl-substituted 1,6-diyne substrate via density functional theory calculations. The intramolecular nucleophilic cyclization is identified as the rate- and stereo-determining step, with a 2.3 kcal/mol free energy difference between the two atropo-determining transition states. Chiral induction arises from a global-local synergy: the chiral ligand's bulky side arms shape the topological portrait of the catalytic pocket, restricting substrate orientation, while local π-π interactions stabilize the transition state leading to the major product. Absence of the bulky side arms diminishes the atropo-selectivity ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mrow><mml:mi>Δ</mml:mi> <mml:mi>Δ</mml:mi></mml:mrow> <mml:annotation>$\Delta \Delta$</mml:annotation></mml:semantics> </mml:math> G^‡ = 0.1 kcal/mol), thus validating our chiral induction model. This work highlights the critical role of microenvironments within catalytic pocket in asymmetric catalysis and provides insights for designing new catalysts.