Enantioselective Titanium-Catalyzed Cycloadditions of Thiophene-S,S-Dioxides with Indenes

Abstract

Asymmetric inverse electron-demand Diels-Alder (IEDDA) cycloadditions of thiophene S,S-dioxides (TDOs) remain largely unexplored. Here we report the development of highly enantioselective titanium-catalyzed IEDDA reactions between TDOs and indenes which enables the asymmetric construction of complex carbocyclic frameworks. In combination with TiCl2(OiPr)2, two chiral ligand classes proved capable of promoting this transformation, with BINOL-based catalysts offering optimal selectivity. The transformation exhibits broad substrate scope and high functional group tolerance, and is amenable to gram-scale synthesis; the chiral ligand can be readily recovered and recycled with no deterioration in yield or enantioselectivity. The resulting adducts are versatile synthetic intermediates, undergoing facile derivatization via reduction, esterification, Suzuki coupling, and further Diels-Alder transformations.