Isothiourea-catalyzed enantioselective reactions of imines with α,β-unsaturated esters employing α,β- unsaturated acyl ammonium intermediates

  • Jerson Lapetaje

Student thesis: Doctoral Thesis (PhD)


The use of isothioureas as Lewis base organocatalysts has been widely studied by the Smith group and shown to be effective in various Michael addition and annulation reactions, which is associated with the formation of the reactive α,β-unsaturated acyl ammonium intermediates. To further explore the reactivity of these reactive intermediates, this research project focuses on employing α,β-unsaturated acyl ammonium intermediates to perform various reactions such as (i) aza-Michael addition reactions, (ii) Michael addition reactions, and (iii) a Michael- addition-cyclisation-lactonisation cascade reactions using imines and other imine derivatives as nucleophiles to access a range of chiral compounds with important structural motifs (e.g. β-amino acids, γ-imino esters and amides, γ-lactam compounds, and pyrrolidine compounds) in high enantio- and diastereoselectivity.

In this work, successful protocols for the highly selective aza-Michael addition reaction and Michael addition reaction of imine nucleophiles to α,β-unsaturated ester substrates were established to obtain various β-imino esters, β-imino amides, various γ-imino amide and ester products via the access of the reactive α,β-unsaturated acyl ammonium intermediate using an enantiopure isothiourea organocatalyst showing moderate to excellent yield (20% – 81%) and enantio- and diastereoselectivity ((<97:3 er, <96:4 dr). A proof of concept for the highly enantio- and diastereoselective formation of a chromeno-pyrrolidine product was highlighted from the reaction of a Schiff base and α,β-unsaturated ester substrate using isothiourea organocatalyst showing moderate yield (48% yield) but with excellent selectivity (99:1 er, >99:1 dr). The reaction was deduced to follow a highly stereoselective Michael addition, followed by a 5-endo-trig cyclization reaction to generate the pyrrolidine core, and a subsequent lactonization reaction to form the chromeno-pyrrolidine product in excellent enantio- and diastereoselectivity.
Date of Award29 Nov 2023
Original languageEnglish
Awarding Institution
  • University of St Andrews
SupervisorAndrew David Smith (Supervisor)


  • Isothiourea organocatalyst
  • α,β-unsaturated acyl ammonium intermediates
  • aza-Michael addition reactions
  • Michael addition reactions
  • Michael- addition-cyclisation-lactonisation cascade reactions

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