Mechanism and origin of enantioselectivity for Diels–Alder reaction catalyzed by chiral phosphoric acids in synthesising 1-trifluoroacetamido cyclohex-1-ene

A DFT investigation on the chiral phosphoric acid (CPA)-catalyzed Diels-Alder reaction between 2-trifluoroacetamido-1,3-dienes and α,β-unsaturated ketones has been reported. Four competing pathways were found. It is found that the lowest-energy route proceeds <i>via</i> sequential Michael addition and intramolecular cyclization within a CPA-substrate ternary complex held by dual hydrogen-bonding and π-stacking interactions. QTAIM and IGMH analyses reveal that the stereoselectivity is dictated at the cyclization transition state by an intricate balance of non-covalent interactions: (i) a compact, highly polarized O-H⋯OP hydrogen bond, (ii) van der Waals stabilization from bulky 3,3'-anthracene substituents, and (iii) minimal steric repulsion between the cyclohexene core and the CF₃CO^- directing group. Distortion/interaction energy analysis and SAPT energy decompositions were employed to further quantify the contributions of electrostatics and dispersion in stabilizing the transition state, rationalizing the experimentally observed 99% ee. These computations corroborate the experimental findings and provide transferable design principles for tuning CPA scaffolds in the future.