Mechanism and Selectivity of the Oxidative Ring Contraction of Cyclic α-Formyl Ketones

The oxidative contraction of α-formal ketone to form continuous all carbon chiral centers promoted by H₂ O₂ is widely used in natural product total synthesis. Typically, using this transformation, chiral cyclic ketones are obtained as the major products and ring-opening products as the minor products. Herein, DFT calculations have been used to investigate the detailed reaction mechanism and chemoselectivity. In addition, with the widely accepted mechanism of H₂ O₂ -promoted transformation, our systematic investigation with various explicit-solvent-model calculations for the first time shows that H₂ O and H₂ O₂ are comparable at catalyzing the rate-determining step of this reaction, which emphasis the importance of solvent effect in such transformations. It is found that both the less ring-constrain and a later transition state in an exothermic reaction account for the origin why the reaction favors ring-contraction pathway rather than ring-opening one. By a comprehensive analysis for the substituted groups, it has been disclosed that the steric effects of the substituted groups on R² and R³ contribute to the selectivity with larger steric hindrance favoring the chiral cyclic products. Moreover, the electronic effects on R¹ but not R³ affect the selectivity with electron-donating groups leading to the cyclic products. Based on our calculations, some predictions for higher selectivity have been made.