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

Abstract

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 (ΔΔG ⧧) 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 (R2) and concave faces of the bicyclic lactams. This effectively hindered both α- and β-approaches in the nonextended transition states shown in Figure . The second major steric interaction was provided by the nonbonded interactions (i) between the R1 angular substituent on the bicyclic lactam and the π-system of the dipole as shown in Figures and . 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.

Asymmetric 1,3-Dipolar Cycloaddition Reactions

“…264 Meyers et al have studied the addition of azomethine ylides 255 to chiral unsaturated bicyclic lactams 256 (eq 42). [268][269][270][271] The diastereoselectivities are dependent on the various substituents R 1 -R. 4 For R 1 ) Me, Ph, the major storeoisomer obtained is 257 (eq 42), whereas for R 1 ) H the other diastereomer is formed. 269 Furthermore, it was found that for R 3 ) H, the π-facial selectivity is insensitive to the chiral substituents of the dipole (R 4 ) chiral group), whereas for R 3 ) CO 2 Me or CO 2 t-Bu lower selectivities were observed.…”

An Asymmetric Route to the Conanine BCDE Ring System. A Formal Total Synthesis of (+)-Conessine

“…From previous work dealing with the synthesis of chiral cyclopentenones and 3,4-disubstituted pyrrolidines derived from chiral bicyclic lactams, it was felt that a potentially efficient route to the tetracyclic ring system B of (+)-conessine could be accessed. Thus, a synthetic plan was devised (Scheme ) which would utilize a (3 + 2) azomethine ylide addition to the suitably substituted chiral, nonracemic lactam 7 .…”

Pyrrolidinones derived from (S )-pyroglutamic acid. Part 1. Conformationally constrained glutamate

“…61 A related bicyclic system has been investigated exhaustively by Meyers and co-workers, who have examined various types of ring manipulations to access a diversity of functionalised products. [62][63][64]…”