Stereoselective De Novo Construction of Cyclopropane by a Multifunctional Class I Aldolase

Cyclopropane is a widely distributed structural unit in natural products and pharmaceuticals. Current strategies in both organic and enzymatic synthesis of cyclopropane scaffolds mainly rely on alkene-based transformations, and de novo construction of all three carbon-carbon bonds of cyclopropane using a single catalyst has not been documented to date. Here, we report that class I pyruvate aldolase NahE can be engineered to catalyze this challenging transformation. NahE facilitates a cascade involving sequential aldol reaction, dehydration, Michael addition, and intramolecular S_N2-like substitution, forging all three C-C bonds and establishing three stereocenters in a single catalytic cycle. Three engineered NahE variants synthesize 30 diverse aromatic and aliphatic cyclopropanes in up to 84% isolated yield with excellent stereoselectivity (>20:1 dr, >99% ee).