Enantioselective Synthesis of Spirocyclic Nitrogen-Containing Heterocycles Catalyzed by an Iridium-Containing Cytochrome

In the past decade, thousands of synthetic building blocks, intermediates, and drug candidates containing a spirocyclopropane core with at least one nitrogen atom have been investigated for a range of biological activities. These compounds create three-dimensional architectures that maintain the rigidity of their more sp²-rich analogs. Most examples contain simple core structures with unsubstituted cyclopropyl moieties, and only one has been made enantioselectively. Therefore, a straightforward method to produce more complex spirocyclic amines with high stereoselectivity would be of great synthetic utility. Here, we report the stereoselective cyclopropanation of methylene-substituted saturated heterocycles catalyzed by an iridium-containing cytochrome. After just four rounds of mutagenesis, we identified a variant that forms spiroazetidines, spiropyrrolidines, and spiropiperidines with enantioselectivities up to 99%. These results demonstrate an expeditious route to valuable, rigid, sp³-rich amino acid linchpins.