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

ABSTRACT 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.