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

Abstract

The origins of stereoselectivity of the Nazarov reactions of α-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 "counterclockwise") 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.

Analyzing Reaction Rates with the Distortion/Interaction‐Activation Strain Model

“…A similar analysis has led to an understanding of the stereoselectivity of the Nazarov cyclization with Tiusschiral thiourea catalysts. [42]…”

Metal organic frameworks mimicking natural enzymes: a structural and functional analogy

“…279 The catalyst furnished an excellent yield for a series of amino acid derivatives and up to 99% and 499.5% enantiomeric excess of the major anti product. 280 The amide hydrogens of thiourea coordinate with the keto group to activate it while the amine group present in the catalyst forms an H-bonding interaction with the a-hydroxy group to afford the final enantiopure product. 28b) to catalyse the Nazarov reaction of a-hydroxydivinylketones and yielded the corresponding cycloaddition product with excellent enantioselectivity (enantiomeric ratio 90 : 10 to 98.5 : 1.5).…”

Das Distortion/Interaction‐Activation‐Strain‐Modell zur Analyse von Reaktionsgeschwindigkeiten

“…Der ungünstigere Übergangszustand zeigt erhebliche Deformation von der relaxierten ÜZ‐Geometrie und ist ursächlich für dessen höhere Energie. Eine ähnliche Analyse führt zum Verständnis der Stereoselektivität in Nazarov‐Cyclisierungen mit dem chiralen Thioharnstoffkatalysator von Tius …”