Cooperative Asymmetric Dual Catalysis Involving a Chiral N‑Heterocyclic Carbene Organocatalyst and Palladium in an Annulation Reaction: Mechanism and Origin of Stereoselectivity

The increasing number of examples on cooperative dual catalysis involving organocatalysts and transition metal catalysts indicate their wider acceptance and utility in synthetic applications. In such reactions, the concurrent activation of substrates is likely to present mechanistic complexities. In one of the studies, designed for intermolecular annulation aimed at making a biologically important class of benzazepines, chiral N-heterocyclic carbenes engage an enal in the form of a Breslow intermediate (nucleophilic partner) and Pd(0) activates rac-vinyl benzoxazinanone as a Pd-π-allyl intermediate (electrophile). Given the current importance and the lack of molecular insights on the origin of high enantio-/diastereoselectivities and cooperativity in such dual catalytic reactions, we have undertaken a detailed computational investigation using density functional theory. The kinetically most accessible Pd-π-allyl intermediate from the (S)- and (R)-vinyl benzoxazinanone is found to be C_re and C_si (where re and si denote the open prochiral faces through which the nucleophile can add), respectively. An energetically favorable change in configuration from C_si to C_re, via a PPh₃-induced π–σ–π isomerization, suggests that an enantioconvergent mechanism was responsible for the enrichment of the desired C_re Pd-π-allyl species. Ready availability of C_re and the higher energy transition state (TS) for the alternative nucleophilic addition to the C_si is responsible for the high ee (computed >99%, experimental 99%). Improved shape complementarity between the chiral electrophile and nucleophile in the most preferred C–C bond formation TS as well as the noncovalent interactions (C–H··· π, π···π, and H-bonding) therein dictates the diastereoselectivity. An intramolecular C–N bond formation to the final annulated product is the turnover-determining TS. Molecular insights and energetic features, as obtained through our computations, are found to be in concert with several experimental observations, even beyond the sense and extent of stereoselectivities.