Origins of the Stereoselectivity in a Thiourea-Primary Amine-Catalyzed Nazarov Cyclization

The origins of stereoselectivity of the Nazarov reactions of alpha-hydroxydivinylketones catalyzed by a vicinal thiourea primary amine first reported by Tius have been explored with density functional theory. The electrocyclization transition structures in which the thiourea group of the catalyst donates two hydrogen bonds to the keto carbonyl group of the Nazarov reactant and the primary amine accepts a hydrogen bond from the hydroxyl group of the reactant have been modeled. The enantiomeric Nazarov transition structures, which are conventionally described by the absolute sense of conrotation of the dienone termini (clockwise or counter-clockwise) in the literature, are nonplanar and adopt helically chiral conformations. The interactions of these helical electrocyclization transition structures with the chiral catalyst are studied in detail. The organocatalyst is found to employ a combination of hydrogen bonding and steric effects to achieve helical recognition of the Nazarov transition state.