Diastereo- and Enantioselective Chemoenzymatic Synthesis of Chiral Tricyclic Intermediate of Anti-HIV Drug Lenacapavir

Despite its great potential, the development and implementation of scalable new-to-nature biocatalytic transformations in the chemoenzymatic synthesis of clinically significant pharmaceuticals still present a considerable challenge. We developed a chemoenzymatic synthesis of very recently developed anti-HIV drug lenacapavir’s 5/5/3 fused tricyclic fragment featuring an unusual chiral cyclopropane moiety. Key to this development is a biocatalyst-controlled, fully diastereo- and enantiodivergent cyclopropanation of a highly functionalized vinylpyrazole substrate, granting access to all four possible stereoisomers of lenacapavir cyclopropane. High-throughput experimentation led to the discovery of heme-dependent globins, including nitrous oxide dioxygenase (NOD) and protoglobin (Pgb), as promising cyclopropanation biocatalysts. Directed evolution furnished a highly diastereo- and enantioselective cyclopropanation (up to 99:1 d.r. and 99:1 e.r.). Further developed downstream chemical cyclization afforded the desired lenacapavir 5/5/3 fused tricycle with great stereochemical purity.