A highly enantioselective intramolecular 1,3-dipolar cycloaddition yields novel pseudo-natural product inhibitors of the Hedgehog signalling pathway

Abstract

De novo combination of natural product (NP) fragments by means of efficient, complexity- and stereogenic character-generating transformations to yield pseudo-natural products (PNPs) may explore novel biologically relevant chemical space. Pyrrolidine- and tetrahydroquinoline fragments rarely occur in combination in nature, such that PNPs that embody both fragments might represent novel NP-inspired chemical matter endowed with bioactivity. We describe the synthesis of pyrrolo[3,2-c]quinolines by means of a highly enantioselective intramolecular exo-1,3-dipolar cycloaddition catalysed by the AgOAc/(S)-DMBiphep complex. The cycloadditions proceeded in excellent yields (up to 98%) and with very high enantioselectivity (up to 99% ee). Investigation of the resulting PNP collection in cell-based assays monitoring different biological programmes led to the discovery of a structurally novel and potent inhibitor of the Hedgehog signalling pathway that targets the Smoothened protein.