Stereoselective reactions of N-(9-phenylfluoren-9-yl)-4-oxoproline enolates. An expedient route for the preparation of conformationally restricted amino acid analogues

Methodology for the stereoselective preparation of 3-alkylprolines from N-( 9-phenylfluoren-9-yl)4-oxoproline is presented. The enolate of a N-(9-pheny lfluoren-9-yl)-4-oxoproline ester was shown to give stereoselective aldol c ondensations with aromatic and aliphatic aldehydes. The enolate was prefere ntially approached by the electrophile through the Re face, and high three selectivity was also observed and provided a route to trans 3-substituted p rolines. The reactions are kinetically controlled except for the case of el ectron-rich or sterically hindered aromatic aldehydes. The ease of the equi libration between the erythro- and threo-aldolates is dictated by the elect ronic nature of the group at C-4 in substituted benzaldehydes, and the ster ic compression of the aldehyde group increases the rate of erythro/threo eq uilibration. Very high stereoselection was also observed in the reductions of the keto group in S-substituted 4-oxoproline esters. Alkylation or Micha el additions of the same enolate were poorly stereoselective, probably due to equilibration of the initially formed products. Kinetic protonation of e nolates of 3-alkyl-4-oxoprolines proceeded with high diastereoselection to provide the corresponding cis-3-alkylprolines.