Asymmetric Nazarov cyclizations

Abstract

The Nazarov cyclization1 is described as the 4 π electron conrotatory cyclization of a pentadienyl cation. The past 20 years have brought resurgent interest in this reaction most likely due to the realization that it can provide rapid and efficient access to multisubstituted cyclopentenones with excellent stereochemical control at two (or even three) contiguous ring carbon atoms.2 Typically, stoichiometric or super-stoichiometric Bronsted or Lewis acid is used to generate the conjugate acid 2 of pentadienone 1 reversibly (Scheme 1). 3 Electrocyclization subsequently leads to allylic cation 3 in which the trans relationship between substituents R2 and R4 is dictated by the conrotation. The process is normally terminated through proton loss from cation 3, leading typically either to cyclopentenone 4 or to 5, or to a mixture of the two. The trans stereochemistry between R1 and R2 in 4 or between R3 and R4 in 5 reflects the thermodynamically more stable product. The trans relationship between R2 and R4 in 3 can be preserved in the final product if loss of an exocyclic proton from R1 or R3 terminates the reaction. Scheme 1 Acid Catalyzed Conrotatory Cyclization. Several obstacles must be overcome in order to render such a process general and synthetically useful. Super-stoichiometric strong acids must be avoided so as to suppress undesired competing processes, e.g. Wagner-Meerwein rearrangements. The absolute stereochemistry of the product is determined by the absolute sense of conrotation: the stereochemistry indicated for 3 is a consequence of clockwise conrotation of 2, viewed from the bottom of the structure as it is shown in Scheme 1. Therefore in an enantioselective Nazarov cyclization the absolute sense of conrotation, or the torqoselectivity, must be controlled. The course of the termination step must also be controlled so as to avoid the production of isomeric mixtures of cyclopentenones. Some bias must be present to direct proton loss from 3 so that it does not take place indiscriminately. This Report will examine these constraints in the context of the asymmetric Nazarov cyclization. Enantioselective Nazarov cyclizations that employ asymmetric chiral effectors either catalytically or stoichiometrically will be examined, as well as processes in which transfer of chirality to the cyclic product takes place.