A Predictive Model for the Pd‐Catalyzed Site‐Selective Oxidation of Diols

A predictive model, shaped as a set of rules, is presented that predicts site‐selectivity in the mono‐oxidation of diols by palladium‐neocuproine catalysis. For this, the factors that govern this site‐selectivity within diols and between different diols have been studied both experimentally and with computation. It is shown that an electronegative substituent antiperiplanar to the C−H bond retards hydride ion, resulting in a lower reactivity. This explains the selective oxidation of axial hydroxy groups in vicinal cis‐diols. Furthermore, DFT calculations and competition experiments show how the reaction rate of different diols is determined by their configuration and conformational freedom. The model has been validated by the oxidation of several complex natural products, including two steroids. From a synthesis perspective, the model predicts whether a natural product comprising multiple hydroxy groups is a suitable substrate for site‐selective palladium‐catalyzed oxidation. Site‐selectivity in the palladium‐catalyzed mono‐oxidation of diols can be predicted by a model, supported by experiments and computation. It explains the selective oxidation of hydroxy groups in cis‐diols and the dependency of the rate on the configuration and conformational freedom. The model predicts whether a natural product comprising multiple hydroxy groups is suited for site‐selective palladium‐catalyzed oxidation.