Au(I)-Catalyzed Enantioselective Synthesis of Functionalized Indenes

Molecules containing the 1H-indene scaffold show a wide range of biological activities, and possess great interest as functional materials, as well as precursors of metallocene complexes as for catalytic polymerization processes. So, several methodologies have been developed for their synthesis. Despite the unquestionable interest of optically active indenes bearing the C-1 as stereogenic center, as far as we know, only two closely related strategies for the enantioselective synthesis of these compounds from achiral substrates have been published. Both of them are based on the use of boronic acid derivatives as starting materials and dicationic Pd(II) complexes as catalyst. Thus, enantioenriched 1arylindenes have been obtained in a cascade 1,4-addition-aldol condensation process, whereas 1H-indenes bearing a CH2COR group at the C-1 position are formed from ortho-boronate substituted cinnamic ketones and internal alkynes. The scarcity of general methods for the synthesis of optically active indenes (in particular from achiral substrates) aimed us to initiate a project in this field. Our premise was the use of easily available starting materials and, therefore, we fixed our attention on the catalytic cyclization of ortho-(alkynyl)styrenes. In this context, it should be taken into consideration that the skeletal rearrangement of ortho(alkynyl)styrenes catalyzed by several metallic complexes has been described to afford naphthalene derivatives through a 6-endo cyclization process (Scheme 1, eq. 1). However, a careful examination of all these publications showed that reactions with o(alkynyl)styrenes where the terminal carbon of the alkene was disubstituted were not reported. So, we envisaged that o(alkynyl)styrenes possessing a highly substituted alkene moiety and an internal acetylene could favour the 5-endo reaction pathway, due to a better stabilization of the exocyclic carbocationic intermediate, to form the desired indene skeleton with a stereogenic center at C-1 (Scheme 1, eq. 2). Herein we report our success on this unprecedented metal-catalyzed 5-endo-dig cyclization of o(alkynyl)styrenes and the application of this reaction in the synthesis of enantiomerically-enriched indenes.