Mechanistic studies on a biomimetic cycloaddition between phloroglucinol and 2-hydroxyethyl-α,β-unsaturated ketone

The biomimetic domino cycloaddition between acylphloroglucinol and 2-hydroxyethyl-cyclohexenone has been previously established as an efficient strategy for constructing tricyclic ketal scaffolds and synthesizing the bioactive natural products, Myrtucommulone J and Myrtucommuacetalone. In this study, density functional theory (DFT) calculations were performed to elucidate the plausible reaction mechanism. The transformation proceeds via a tandem sequence involving hemiacetalization, dehydration, electrophilic attack, re-aromatization, protonation of the C = C bond, and annulation. The rate-determining step was identified as the electrophilic attack of an allylic cation on the aromatic ring of acylphloroglucinol, with an overall free energy barrier of approximately 23.5 kcal/mol. These mechanistic insights not only advance our understanding of this biomimetic cascade but also provide a foundation for the rational design of novel synthetic methodologies.

In this work, density functional theory (DFT) calculations were carried out using the Gaussian 16 software package. Geometry optimizations and vibrational frequency analyses for all stationary points were performed at the M06-2X/def2-SVP level of theory. The intrinsic reaction coordinate (IRC) calculations were employed to verify the connectivity between each transition state and its corresponding minima. Single-point energy calculations were subsequently conducted using the M06-2X functional in conjunction with the def2-TZVP basis set for all atoms. Solvent effects of toluene were incorporated through Truhlar's SMD continuum solvation model. All optimized structures and transition states were visualized with CYLview.