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

ACS Catalysis, Journal Year: 2025, Volume and Issue: 15(3), P. 2045 - 2052

Published: Jan. 21, 2025

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

Language: Английский

Rhodium- and Iridium-Catalyzed (Enantioselective) Fluoroamidation of gem-Difluoroalkenes via Chelation Assistance

ACS Catalysis, Journal Year: 2025, Volume and Issue: unknown, P. 6555 - 6562

Published: April 7, 2025

Language: Английский