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.