Unsaturated, differentially substituted Meldrum's acid derivatives undergo cascade cyclizations upon ester reduction with SmI(2)-H(2)O. The cascade cyclizations proceed in good yield and with high diastereocontrol and convert simple, achiral starting materials to complex molecular architectures, bearing up to four stereocenters, in a single operation. The cascades are triggered by the generation and trapping of unusual radical-anions formed by electron transfer to the ester carbonyl.

The intramolecular Diels−Alder reaction provides a useful synthetic methodology to build biologically active and synthetically useful isoindolone ring systems. An application of this methodology, providing an efficient manufacturing route to an mGluR2 positive allosteric modulator via a 1,5,7-substituted isoindolone, is reported herein.

The mechanism of a recently reported first mono-reduction of cyclic 1,3-diesters (Meldrum's acids) to β-hydroxy acids with SmI2-H2O has been studied using a combination of reactivity, deuteration, kinetic isotope and radical clock experiments. Most crucially, the data indicate that the reaction proceeds via reversible electron transfer and that water, as a ligand for SmI2, stabilizes the radical anion intermediate rather than only promoting the first electron transfer as originally proposed.

The SmI2-H2O reagent system mediates challenging 5-exo/6-exo lactone radical cascade cyclisations that deliver carbo[5.4.0]bicyclic motifs in a diastereoselective, one-pot process that establish two new carbocyclic rings and four stereocentres.