Intramolecular carbene C–H functionalization, which forges carbon–carbon bonds from inert C–H bonds, is an appealing approach to assembling complex cyclic molecular scaffolds. Synthetic chemists have developed small molecule catalysts with precious metals and complex ligands to perform this transformation but have been limited in scope to energetically favored ring sizes. Enzymes, nature’s catalytic workhorses, by comparison, have an exquisite ability to control reactive intermediates and furnish complex products that defy thermodynamic preferences. Here we introduce a set of non-natural ‘carbene transferases’ evolved from a heme-dependent cytochrome P450 enzyme that assemble cyclic structures with high complexity through intramolecular carbene C–H functionalization. These novel enzymes are able to build ring structures of various sizes and overcome the ring-size limitations of small-molecule catalysts. Using two engineered cytochromes P411, we can make 5- and 6-membered lactones starting from their corresponding diazo ester carbene precursors. Further evolution from the same parent enzyme furnishes a new variant that assembles 7-membered lactones, challenging targets in chemical synthesis. We have also extended this platform to more complicated cyclic systems, including fused, bridged, and spiro rings of various sizes, rendering these complex and previously difficult structures easily accessible from simple substrates in two steps. We believe this enzyme platform can be a significant addition to the toolkit of synthetic chemistry, especially for the synthesis of complex cores of pharmaceuticals and natural products.

Enzymatic access to diverse molecular structures through C–H functionalization

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