Chiral Phosphoric Acid Catalyzed Enantioselective Ring Expansion Reaction of 1,3-Dithiane Derivatives: Case Study of the Nature of Ion-Pairing Interaction

Chiral counterion controlled asymmetric catalysis via an ion-pairing interaction has attracted immense attention in recent years. Despite a number of successful studies, the mechanistic elucidation of the stereocontrolling element in the ion-pairing interaction is rarely conducted and hence its nature is still far from being well understood. Herein we report an in-depth mechanistic case study of a newly developed enantioselective ring expansion reaction of 1,3-dithiane derivatives catalyzed by chiral phosphoric acid (CPA). An unprecedented enantioselective 1,2-sulfur rearrangement/stereospecific nucleophilic addition sequence was proven to be the stereoselective pathway. More importantly, by thorough investigation of the intrinsic nature of the stereospecific nucleophilic addition to the cationic thionium intermediate, we discovered that the key interaction in this process is the nonclassical C-H···O hydrogen bonds formed between the conjugate base of the CPA catalyst and the cationic intermediate. These C-H···O hydrogen bonds not only bind the catalyst to the substrates to form energetically favored states throughout the overall processes but also firmly maintain the relative positions of these fragments as the "fixed" contact ion pair to sustain the chiral information generated at the initial sulfur rearrangement step. This mechanistic case study provides a very clear understanding of the nature of the ion-pairing interaction in organocatalysis. The conclusion encourages the further development of the research field with the focus to design new organocatalysts and cultivate novel organocatalytic transformations.