Enantioselective Synthesis of Spiro[cyclopentane-1,3′-oxindole] Scaffolds with Five Consecutive Stereocenters

Abstract

A highly diastereo-and enantioselective cascade annulation reaction of Morita−Baylis−Hillman (MBH) maleimides of isatins with ortho-hydroxychalcones was achieved by a chiral N,N′-dioxide/Mg(II) complex Lewis acid catalyst. This strategy provides a concise and efficient route to densely functionalized spiro[cyclopentane-1,3′-oxindole] compounds with five consecutive stereocenters. The reaction itself features mild conditions, good functional group compatibility, and broad substrate scope (62 examples, up to 99% yield, up to >20:1 dr, 97% ee). In addition, an obvious ligand acceleration effect and chiral amplification effect were observed. DFT calculations were performed to elucidate the stereoselectivity observed. The gram-scale synthesis and the inhibitory effect of two products on the viability of A549 cells demonstrate the potential utility of the current method.