Synthetic chemists can go around in circles trying to make the cyclic amides known as lactams. That’s because lactams with 4-, 5-, and 6-membered rings—known as β-, γ- and δ-lactams, respectively—are popular molecular motifs in drugs and other bioactive molecules. Famous examples include the β-lactam in the antibiotic penicillin and the γ-lactam in the COVID-19 antiviral Paxlovid. Chemists have now devised a new method for stereoselectively making β-, γ- and δ-lactams using an engineered enzyme that plucks a hydrogen from a C–H bond in dioxazolone reagents.
Although there are other ways to make lactams, this new method produces them stereoselectively from achiral precursors without using rare metals like iridium or ruthenium. “The reaction that we are catalyzing is particularly interesting and attractive because it proceeds through a C–H functionalization, which is generally challenging to do both efficiently and with a high chemo- and stereoselectivity,” says Rudi Fasan of the University of Texas at Dallas, who led the work along with Kendall N. Houk of the University of California, Los Angeles.
The chemists engineered the enzyme myoglobin to perform an intramolecular nitrene transfer on dioxazolone reagents thereby transforming them into β-, γ- and δ-lactams. The dioxazolone’s substituents determine which size of ring forms, and the enzyme determines the lactam’s stereochemistry.
Sukbok Chang, a professor at the Korea Advanced Institute of Science and Technology who has developed chemical catalysts for this transformation, say the work is a significant advancement. “The enzymatic strategy demonstrates versatility in producing diverse lactam products with varying ring sizes. This characteristic sets it apart from conventional chemical approaches, where each individual lactam ring necessitates an entirely different catalyst system,” he says in an email.
The team used the reaction to create a simple β-lactam (shown) on gram scale. They then used that β-lactam to make the natural product homaline as well as dapoxetine, a drug used to treat premature ejaculation (Nat. Catal. 2023, DOI: 10.1038/s41929-023-01068-2).
Thomas R. Ward, a chemistry professor at the University of Basel, who recently reported making lactams with artificial metalloenzymes calls the research a “superb piece of work.” He says in an email that “it significantly extends the potential of repurposed hemoprotein-catalyzed nitrene insertion, a very challenging transformation.”