Researchers in Ryan Shenvi’s lab at Scripps Research debuted a new way to make cyclopropanols in which each of the three carbon atoms in the ring comes from a different source (Science 2026, DOI: 10.1126/science.aej0194).
Beyond being a modular approach to a medicinally relevant molecular motif, the iron-catalyzed reaction offers an improved way to generate silyl enol ethers, versatile building blocks that are often hard to make stereoselectively.
“I’m actually more of a fan of the intermediate, I think, than the product,” Shenvi says, though the whole project is a testament to the team’s creativity and determination.
Postdoctoral researcher Lingran Kong and PhD student Kevin Zong built directly on earlier chemistry they had developed with thioesters and cobalt carbenes, as well as work from the David A. Nagib lab at the Ohio State University on iron carbenes.
“We thought, maybe we can merge two different carbene precursors into the same reaction” to make cyclopropanols, Zong says. He and his teammates got products they expected, but the reaction worked even when they left out the nickel cocatalyst they had been using, which hinted that the mechanism was different than the original hypothesis.
The researchers determined that the reaction is a complex dance of outer-sphere processes, starting with pyridine coordinating to the iron to make the normally electrophilic carbene a nucleophile. An intermolecular rearrangement followed by an iron-mediated reduction creates the key enol ether intermediate. That species reacts with a dichloromethane-derived carbene to finally furnish a cyclopropanol.
The researchers mixed and matched ester and carbene starting materials to generate a variety of cyclopropanol products with previously hard-to-achieve cis stereochemistry. They also used the enol ethers as a jumping-off point to make other types of products, including acyclic ketones and intramolecular macrocycles.
“It’s a nice example of being able to form new products in very different ways from very different kinds of building blocks,” Shenvi says. He and his team plan to continue exploring the macrocyclization reaction for synthesizing natural products and other complex molecules, aided by computational reactivity prediction tools.
