The Tamura Cycloaddition: Mechanism and Enantiocontrol

Abstract

This thesis documents attempts to employ succinimide derivatives as ‘anhydride surrogates’ in the organocatalytic cycloaddition between aryl succinic anhydrides and various electrophiles previously developed in our research group. Although such a process remains elusive, valuable insight into the required substrate reactivity has been gained. Thirty-eight years on from the original publication of the Tamura cycloaddition between homophthalic anhydride and activated alkenes/alkynes, a combined experimental and computational investigation has revealed the base-catalysed reaction previously thought of as a Diels-Alder type process proceeds via a stepwise mechanism involving conjugate addition and ring closure – verified by both DFT calculations and the isolation of an intermediate Michael-type adduct which represents the first example of a catalytic α- substitution reaction of anhydrides. The calculated reaction pathway was validated through the experimental confirmation of a theoretical prediction that a cyclisation step resistant to catalysis by Hünig’s base could smoothly occur in the presence of a smaller amine. Succinic anhydrides are also compatible with the process and react with maleimides to afford chiral α-substituted anhydride addition products of considerable synthetic potential. Cinchona alkaloid derived organocatalysts were later found to promote this reaction enantioselectively. The Michael adduct formed could be derivatised via aminolysis of the anhydride moiety at low temperature, which allowed the formation of a bis-imide structure bearing two contiguous stereocentres (one all carbon quaternary) in near optical purity. The scope of the reaction with respect to the anhydride component was later extended; however only aryl succinic anhydrides substituted with highly electron withdrawing groups were found to react at a practical rate. A number of substituted aryl succinic anhydrides synthesised for extension of the scope of the catalytic α-substitution were fortuitously employed in an asymmetric organocatalytic cycloaddition with imines to afford substituted γ-lactams in high levels of optical purity.