Enantioselective Silicon-Directed Nazarov Cyclization

The Nazarov electrocyclization reaction is a convenient, widely used method for construction of cyclopentenones. In the past few decades, catalytic asymmetric versions of the reaction have been extensively studied, but the strategies used to control the position of the double bond limit the substituent pattern of the products and thus the synthetic applications of the reaction. Herein, we report highly enantioselective silicon-directed Nazarov reactions which were cooperatively catalyzed by a Lewis acid and a chiral Bronsted acid. The chiral cyclopentenones we synthesized using this method generally cannot be obtained by means of other catalytic enantioselective reactions, including previously reported methods for enantioselective Nazarov cyclization. The silicon group in the dienone substrate stabilized the beta-carbocation of the intermediate, thereby determining the position of the double bond in the product. Mechanistic studies suggested that the combination of Lewis and Bronsted acids synergistically activated the dienone substrate and that the enantioselectivity of the reaction originated from a chiral Bronsted acid promoted proton transfer reaction of the enol intermediate.

Automated summary

This study presents highly enantioselective silicon-directed Nazarov reactions cooperatively catalyzed by a Lewis acid and a chiral Bronsted acid, which allows for the synthesis of chiral cyclopentenones with diverse substituent patterns not achievable by other catalytic enantioselective reactions. The positioning of the double bond in the product is determined by the stabilizing effect of the silicon group in the dienone substrate on the beta-carbocation intermediate, and the enantioselectivity of the reaction is attributed to a chiral Bronsted acid promoted proton transfer reaction of the enol intermediate.