Stereodivergent Assembly of δ-Valerolactones with an Azaarene-Containing Quaternary Stereocenter Enabled by Cu/Ru Relay Catalysis

Abstract

Developing methodologies for the expedient construction of biologically important δ-valerolactones bearing a privileged azaarene moiety and a sterically congested all-carbon quaternary stereocenter is important and full of challenges. We present herein a novel multicatalytic strategy for stereodivergent synthesis of highly functionalized chiral δ-valerolactones bearing 1,4-nonadjacent quaternary/tertiary stereocenters through orthogonally merging borrowing hydrogen and Michael addition between α-azaaryl acetates and allylic alcohols followed by lactonization in a one-pot manner. Enabled by Cu/Ru relay catalysis, this cascade protocol owned the advantages of atom/step economy, redox-neutrality, mild reaction conditions, and broad substrate tolerance. Scale-up experiment and synthetic transformations further demonstrated the potential of synthetic application. Mechanistic experiments support the envisioned bimetallic relay catalytic mechanism, and the key role of Cs2CO3 to promote lactonization was also revealed.