To further explore the synthetic potential of new-to-nature biocatalysis in pharmaceutical applications, we set out to advance a chemoenzymatic strategy for the stereoselective catalytic synthesis of lenacapavir's chiral 5/5/3 fused tricyclic fragment (2) featuring a disubstituted cyclopropane moiety (Figure ). Groundbreaking research by Arnold, Fasan , and other pioneers has elegantly established the efficiency of engineered heme proteins in the stereoselective cyclopropanation of olefins using ethyl diazoacetate (EDA) as the carbene precursor. On the basis of these results, we envisioned a chemoenzymatic strategy featuring an intermolecular biocatalytic cyclopropanation for the stereoselective assembly of this 5/5/3 fused tricycle 2 (Figure and). In particular, we surmised that efficient heme protein catalysts could be identified and further evolved to allow for the diastereo-and enantioselective synthesis of cyclopropane (1R,2S)-4 using vinylpyrazole 5, which could be conveniently prepared by Suzuki-Miyaura coupling. Furthermore, we postulated that downstream chemical cyclization of (1R,2S)-4 under appropriate conditions could effect the formation of ketone (3bS,4aR)-3. Finally, through desulfurative difluorination , the gem-difluoro moiety of (3bS,4aR)-2 could be introduced to ketone (3bS,4aR)-3 (Figure ). Herein, we report the successful implementation of this synthetic plan. Importantly, through the identification and evaluation of heme protein biocatalysts, all the four possible stereoisomers of disubstituted cyclopropane 4 could be accessed with excellent diastereo-and enantiocontrol (Figure ). In light of the central role of stereochemistry in medicinal chemistry campaigns, these results are expected to allow further study and preparation of related antiviral agents.