Concise Six-Step Asymmetric Approach to Ramelteon from an Acetophenone Derivative Using Ir, Rh, Cu, and Ni Catalysis.

A concise six-step asymmetric synthesis of nearly enantiomerically pure ramelteon was developed from a monocyclic precursor with a 17% overall yield and a 97% ee in the asymmetric step. The synthetically challenging tricyclic 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan core of ramelteon was assembled by using Ir-catalyzed O-vinylation and Rh-catalyzed vinyl ether annulation through directed C-H bond activation, while the chirality was introduced with enantioselective reduction of an α,β-unsaturated nitrile moiety under hydrosilylation conditions using a CuII/Walphos type catalyst. The presented methodology represents the shortest synthetic approach to ramelteon.