Computational Explorations of Enzymes That Catalyze Ambimodal [4 + 2]/[6 + 4] Cycloadditions

Ambimodal transition states (TSs) lead to two or more products via post‐transition state bifurcations (PTSB). Over the past decade, numerous examples of ambimodal cycloaddition reactions have been reported, and a number of these are involved in enzyme‐catalyzed reactions in biosynthesis. This review covers enzymes known to catalyze [4 + 2]/[6 + 4] ambimodal cycloadditions, in which a single transition state leads to both [4 + 2] and [6 + 4] cycloaddition products. We also describe recent advances in computational methods for the study of bifurcations, and predictions of product ratios that are otherwise determined by calculating a large number of trajectories with quasi‐classical molecular dynamics. These methods include entropy path sampling, and product distribution predictions with correlational methods.