An enzymatic Alder-ene reaction

An ongoing challenge in chemical research is to design catalysts that select the outcomes of the reactions of complex molecules. Chemists rely on organo- or transition metal catalysts to control stereo-, regio-, and periselectivity (selectivity among possible pericyclic reactions). Nature achieves these types of selectivity with a variety of enzymes such as the recently discovered pericyclases – a family of enzymes that catalyze pericyclic reactions.(1) To date, the majority of characterized enzymatic pericyclic reactions are cycloadditions and it has been difficult to rationalize how observed selectivities are achieved.(2-13) We report here the discovery of two homologous groups of pericyclases that catalyze distinct reactions: one group catalyzes an Alder-ene reaction, previously unknown in biology; the second catalyzes a stereoselective hetero-Diels–Alder reaction. Guided by computational studies, we rationalized the observed differences in reactivities and designed mutants that reverse periselectivities from Alder-ene to hetero-Diels–Alder and vice versa. A combination of in vitro biochemical characterizations, computational studies, enzyme co-crystal structures, and mutational studies provide a picture of how high regio- and periselectivities are achieved in nearly identical active sites.