In conclusion, we developed a novel stereoselective chemoenzymatic synthesis of the 5/5/3-fused tricyclic fragment of lenacapavir, a key intermediate in the manufacturing of this essential anti-HIV drug. Key to the success of our chemoenzymatic synthesis lies in the development of an orthogonal set of heme protein catalysts, allowing for the scalable and fully stereodivergent cyclopropanation of a functionalized vinylpyrazole substrate. Among these engineered heme proteins, a newly evolved protoglobin double mutant ApePgb W59L Y60G F145G functioned as an effective carbene transferase, allowing the highly diastereo-and enantioselective gram-scale cyclopropanation to prepare the key chiral cis-cyclopropane. Combined with a newly devised chemical cyclization sequence, the lenacapavir 5/5/3 fused tricycle was prepared with excellent diastereo-and enantiocontrol without relying on the use of chiral separation or chiral starting materials. This stereoselective chemoenzymatic synthesis provides a rare example of applying very recently developed new-to-nature biocatalytic reactions in the preparation of clinically important pharmaceuticals, demonstrating the potential of newly developed biocatalytic tools in high-value pharmaceutical applications. We expect that the further development of other tailored biocatalytic reactions will ultimately provide efficient and highly stereoselective syntheses of anti-HIV drug lenacapavir possessing three stereogenic centers. Scheme 1. Completion of the stereoselective chemoenzymatic synthesis of the lenacapavir 5/5/3 fused tricyle (3bS,4aR)-2: gram-scale biotransformation and downstream stereoretentive chemical synthesis.