Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals

The rapid generation of molecular complexity from simple starting materials is a key challenge in synthesis. Enantioselective radical cyclization cascades have the potential to deliver complex, densely packed, polycyclic architectures, with control of three-dimensional shape, in one step. Unfortunately, carrying out reactions with radicals in an enantiocontrolled fashion remains challenging due to their high reactivity. This is particularly the case for reactions of radicals generated using the classical reagent, SmI2. Here, we demonstrate that enantioselective SmI2-mediated radical cyclizations and cascades that exploit a simple, recyclable chiral ligand can convert symmetrical ketoesters to complex carbocyclic products bearing multiple stereocentres with high enantio- and diastereocontrol. A computational study has been used to probe the origin of the enantioselectivity. Our studies suggest that many processes that rely on SmI2 can be rendered enantioselective by the design of suitable ligands. Although samarium-mediated cyclizations have the potential to generate significant molecular complexity, historically it has not proven possible to exert enantiocontrol through the use of a chiral ligand in complex product synthesis. Now, an enantioselective SmI2-mediated radical cyclization has been developed using a chiral aminodiol ligand. Desymmetrizing 5-exo ketyl-alkene cyclizations and cyclization cascades of unsaturated ketoesters deliver complex products and typically proceed with high enantioselectivity and diastereoselectivity.