Enantioselective organocatalytic cycloaddition reactions between enolisable anhydrides and imines

Abstract

Cycloaddition reactions between enolisable anhydrides and imines have long been known as excellent tools for the synthesis of natural products. The racemic version is well known to be capable of providing products with excellent diastereoselectivity, however, asymmetric variants of these reactions have remained elusive. The main challenge associated with this chemistry relates to the propensity for the imine to behave as a base. The use of an N-mesyl substituent on the imine allows for suppression of the uncatalysed reaction, rendering the reaction amenable to the asymmetric catalysis. Promoting the reaction with a bifunctional organocatalyst has allowed for the first catalytic, asymmetric cycloadditions of imines with homophthalic anhydride, affording products with ee up to 82%. Under the influence of anion-binding bifunctional catalysis a wide range of α,β-unsaturated imines have been shown to undergo reaction with enolisable anhydrides to form highly synthetically useful α-tetralones with excellent enantio- and diastereocontrol. The presence of an N-trityl protecting group on the imine diverts the reaction towards the Tamura reaction exclusively. The cycloadducts were converted through a facile 2-step elaboration into an α- haloketone. The scope of the anhydride component has been extended to various activated arylsuccinic anhydrides to form γ-lactams with excellent levels of enantiocontrol.