Transition-State Charge Stabilization through Multiple Non-covalent Interactions in the Guanidinium-Catalyzed Enantioselective Claisen Rearrangement

The mechanism by which chiral arylpyrrole-substituted guanidinium ions promote the Claisen rearrangement of O-allyl alpha-ketoesters and induce enantioselectivity was investigated by experimental and computational methods. In addition to stabilization of the developing negative charge on the oxallyl fragment of the rearrangement transition state by hydrogen-bond donation, evidence was obtained for a secondary attractive interaction between the pi-system of a catalyst aromatic substituent and the cationic allyl fragment. Across a series of substituted arylpyrrole derivatives, enantioselectivity was observed to vary predictably according to this proposal. This mechanistic analysis led to the development of a new p-dimethylaminophenyl-substituted catalyst, which afforded improvements in enantioselectivity relative to the parent phenyl catalyst for a representative set of substrates.