Selectivity control in inverse electron demand Diels–Alder reaction of o-Quinone methides catalyzed by chiral N,N′-Dioxide–Sc(III) complex

Abstract

The reaction mechanism and origin of asymmetric induction in inverse electron demand Diels-Alder (IEDDA) reaction of ortho-quinone methide (o-QM) and fulvene mediated by chiral N,N'-dioxide–Sc(III) catalyst were rationalized using B3LYP-D3(BJ) functional with def2-TZVP basis set. The uncatalyzed IEDDA reaction was concerted but highly asynchronous with activation barriers of 29.8∼31.8 kcal mol−1. Good linear relationship between the Hammett substituent constant (σP) of o-QM and the activation barrier (ΔG≠) of DA reaction was discovered. The secondary orbital interaction (SOI) between the conjugated diene of o-QM and fulvene moiety stabilized the endo-transition state, contributing to high endo-selectivity. The catalytic asymmetric IEDDA reaction occurred via a stepwise mechanism, including the construction of Cβ−C4 bond, followed by the formation of Cα−O1 bond. The bulky substituents (i.e., adamantyl or triphenylmethyl) in amide moiety of ligand furnished sufficient steric shielding for re-face of diene, inducing the attack of fulvene from si-face in endo-pathway. The substituent at exocyclic methylene of the unsymmetrical fulvene was crucial for the adjustment of E/Z selectivity. The steric repulsion between cyclohexyl group in fulvene and aromatic ring in o-QM raised the destabilizing strain energy (ΔEstrain) at the transition state in Z-configuration, contributing to the predominant E-product.