Total synthesis of (−)-α-cyclopiazonic acid: a study in perseverance

Abstract

Abstract Enantioselective total syntheses of the prenylated indole alkaloids, (−)-α-cyclopiazonic acid and (+)-iso-α-cyclopiazonic, have been achieved in nine steps (longest linear sequence, 13 steps in total). The molecules were assembled using a combination of three key methodologies: (1) an asymmetric aziridination of an activated imine with a chiral sulfur ylide; (2) a bioinspired intramolecular aziridine-alkene formal cycloaddition; and (3) an unprecedented carbonylation/N–O bond reduction cascade to install the challenging tetramic acid. A key lesson learned was that new technologies can enable routes previously discarded as nonviable, with the final synthesis much further from the original proposal in time than in design.