Single and Double Diastereoselection in Azomethine Ylide Cycloaddition Reactions with Unsaturated Chiral Bicyclic Lactams

Double diastereoselectivity data were analyzed to provide insight into the structural features that influence π-facial selectivity in 1,3-dipolar cycloadditions of chiral and achiral azomethine ylides to chiral, unsaturated bicyclic lactams. Three major steric contributions to the differences in stability (ΔΔ G ⧧ ) between competing cycloaddition transition states were identified. The first major set of steric interactions involve that between the dipoles and the substituents on the left hemisphere (R 2 ) and concave faces of the bicyclic lactams. This effectively hindered both α- and β-approaches in the nonextended transition states shown in Figure 1. The second major steric interaction was provided by the nonbonded interactions (i) between the R 1 angular substituent on the bicyclic lactam and the π-system of the dipole as shown in Figures 3 and 4. This interaction was shown to be very significant, causing reversal in π-facial attack of chiral and achiral dipoles when the angular substituent is changed from phenyl or methyl to hydrogen. The high diastereoselectivity observed now opens a route to highly substituted chiral, nonracemic pyrrolidines.