Post-transition State Bifurcations in Reactions That Form Pimarenyl Cation Diastereomers─Implications for Terpene Biosynthesis

The role of post-transition state bifurcations in carbocation rearrangements derived from copalyl diphosphate (CPP) and its diastereomers <i>syn</i>-CPP and <i>ent</i>-CPP were investigated using quantum chemical calculations, ab initio molecular dynamics (AIMD) simulations, and potential energy surface (PES) analysis based on principal component analysis (PCA). Proton transfer transition states of pimarenyl cations, which can give rise to multiple products through bifurcating pathways, were the focus. For normal CPP-derived systems, AIMD simulations revealed that <i>Re</i>-face proton transfer leads to a diverse array of products, whereas <i>Si</i>-face proton transfer predominantly follows a single pathway. In contrast, <i>syn</i>-CPP and <i>ent</i>-CPP-derived systems showed reduced product diversity, with bifurcations only observed for the <i>Re</i>-face proton transfer. Orbital alignment analyses highlight the influence of dynamic momentum effects on product distributions. PES analyses further demonstrate that the CPP-derived system possesses the flattest energy landscape. These results highlight how simple stereochemical changes can dramatically alter dynamical outcomes, thereby modulating the challenges faced by enzymes in shaping product selectivity.