Asymmetric Synthesis of Bicyclic Pyrazolidinones through Alkaloid-Catalyzed [3+2]-Cycloadditions of Ketenes and Azomethine Imines.

A versatile asymmetric synthesis of bicyclic pyrazolidinones through alkaloid-catalyzed formal [3+2]- and [3+2+2]-cycloadditions of ketenes with azomethine imines is described. The methodology was found to be tolerant of ketene and a variety of monosubstituted ketenes (R=alkyl, OAc). The products were formed in good to excellent yields (71-99 % for 24 examples, 39 examples in all), with good to excellent diastereoselectivity in many cases (dr 3 : 1 to 27 : 1 for 22 examples), and with excellent enantioselectivity for most examples (≥93 % ee for 34 products). In the case of most disubstituted ketenes, the reaction proceeded through a [3+2+2]-cycloaddition to form structurally interesting bicyclic pyrazolo-oxadiazepinediones with moderate diastereoselectivity (dr up to 3.7 : 1) and as racemic mixtures (3 examples). The method represents the first unambiguous example of an enantioselective reaction between ketenes and a 1,3-dipole.