Ross, S. P.; Hoye, T. R. Nature Chem. 2017, 9, 523–530.
An important question in organic chemistry concerns the extent to which benzynes—one of the classical reactive intermediates in organic chemistry—can react in discriminating fashion with trapping reagents. In particular, whether these species can react selectively with substrates containing multiple functional groups and possible sites of reactivity has remained unanswered. Natural products comprise a palette of multifunctional compounds with which to address this question. Here, we show that benzynes produced by the hexadehydro-Diels–Alder (HDDA) reaction react with many secondary metabolites with a preference for one among several pathways. Examples demonstrating such selectivity include reactions with: phenolics, through dearomatizing ortho-substitution; alkaloids, through Hofmann-type elimination; tropolone and furan, through cycloaddition; and alkaloids, through three-component fragmentation–coupling reactions. We also demonstrate that the cinchona alkaloids quinidine and quinine give rise to products (some in as few as three steps) that enable subsequent and rapid access to structurally diverse polyheterocyclic compounds. The results show that benzynes are quite discriminating in their reactivity—a trait perhaps not broadly enough appreciated.