Organocatalysed transformations of enolisable cyclic anhydrides

Abstract

Herein is reported our attempts at the first formal cycloaddition reaction involving either glutaric anhydride derivatives or cyclic anhydrides including an endocyclic electron-withdrawing heteroatom with different electrophiles promoted by cinchona alkaloid derived catalysts. Despite the promising advantages of employing anhydrides bearing enol-stabilising groups, the optimisation of the synthetic pathway proved difficult.

The use of cinchona alkaloid-derived bifunctional organocatalysts to promote the dynamic kinetic resolution of cyclic anhydrides by alcoholysis was investigated. Initial studies were aimed at evaluating the regioselectivity of the nucleophilic addition using phenylsuccinic anhydride. Experiments aimed towards the development of optimal reaction conditions have been conducted and several bifunctional cinchona alkaloid substituted organocatalysts were evaluated. Although the novel sulfonamide-based organocatalysts failed to promote a potential DKR strategy, they proved to be excellent catalysts for highly efficient PKR of enolisable cyclic anhydrides with unprecedent enantiocontrol. Evaluation of the steric properties of the alcohols nucleophiles was also undertaken but did not give the desired results, while varying their electronic properties was found to influence the resulting regio- and enantioselectivity of the reactions under scrutiny. Furthermore, the enantioselective resolution of cyclic anhydrides with variable substituents was also explored. The results obtained demonstrated the feasibility of the process; which allows for the PKR of substituted succinic anhydrides with a regioselectivity which depends on the steric bulk of the anhydride. Finally, the possibility of using iminophosphorane bifunctional catalysts to promote the enantioselective cycloaddition reaction of enolisable anhydrides with various aldehydes to form annulated structures was investigated. The first example of a cycloaddition reaction between phenylglutaconic anhydride and aromatic aldehydes has been demonstrated. The evaluation of several aldehydes as substrates was also studied and the expansion of the substrate scope with regard to the anhydrides was also reported.