Nature’s Enzymes Tricked with Xenobiotic Oxidants

The relationship between enzyme engineers and synthetic organic chemists is simultaneously symbiotic and competitive. Synthetic chemists often find their inspiration in the active sites of enzymes, but celebrate any ability to outmaneuver nature’s catalysts. Scientists who create new enzymes, for their part, are quick to point out how elegantly and rapidly catalytic proteins stitch together molecules under ambient conditions and without need for protecting groups. What happens, then, when scientists introduce enzymes to chemicals out of their element? Arnold and co-workers report a new enzymatic method to put together aziridines (strained three-membered nitrogencentered rings) relying on in vitro evolution of cytochrome P450. Aziridines are useful tools for installation of carbon− nitrogen bonds, the glue that holds together biologically active amines and amides in chemical synthesis. These threemembered rings have garnered a lot of attention in the area of amine synthesis. However, development of synthetic transformations of aziridines has lagged behind that of epoxides, the analogous oxygen-containing molecules. This comparative lack of application is why some in the synthesis community regard aziridines as epoxides’ “ugly cousins”. Looking back into the natural world, the question arises as to why there are so few aziridine-containing natural products (less than 20) compared to epoxides (in the thousands). The answer, without a doubt, lies in the accessibility of a direct biosynthetic path to three-membered nitrogenous rings. For oxygen, P450 enzymes have evolved into competent systems for epoxidation, using dioxygen as the terminal oxidant. Within the active sites of these enzymes, transiently generated FeO intermediates transfer oxygen atoms to alkenes (Figure 1). There is no comparable nitrogen variant in nature because the energy required for the generation of the corresponding FeNR intermediate is substantially higher. Arguably, there has never been any evolutionary pressure to produce the high-energy nitrogen analogue of dioxygen. Perhaps the existence of only a few aziridinecontaining natural products is a testament to that. In fact, all of the aziridine natural products are believed to come from intramolecular SN2 reactions, a distinctly different, and longer path.