Asymmetric Synthesis of Functionalized 2,5-Pyrrolidinediones and β-Lactams through Diastereospecific Cycloisomerization/Rearrangement of Chiral Ethanolamine-Derived Ugi Adducts

A series of ethanolamine-derived Ugi four-component-reaction adducts were subjected to a base-mediated cycloisomerization/rearrangement cascade to give functionalized 2,5-pyrrolidinediones in good-to-excellent yields. The method was extended to amino-acid-derived chiral ethanolamines to access enantiomerically pure 2,5-pyrrolidinediones. The reaction is diastereospecific, and mixtures of 2,5-pyrrolidinediones and -lactams were formed with high enantiomeric excess. Mechanistic studies revealed that the reaction proceeds through the formation of a -lactam intermediate by intramolecular cyclization in a 4-exo-dig fashion. This then rearranges further to give the 2,5-pyrrolidinedione with the help of the hydroxyethyl appendage. Computational analysis of the reaction profile demonstrated that the intramolecular 4-exo-dig cyclization is energetically favoured over the 5-endo-dig pathway, so this results in the formation of the beta-lactam.