Enantioselective synthesis of spirocyclic nitrogen-containing heterocycles catalyzed by an iridium-containing cytochrome

In the last 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, but most examples contain simple core structures with unsubstituted cyclopropyl moieties, and they require lengthy syntheses. 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 produced spiroazetidines, spiropyrrolidines, and spiropiperidines with up to 99% ee. These results demonstrate an expeditious route to valuable, rigid, sp3-rich amino acid linchpins.