title: Several generations of chemoenzymatic synthesis of oseltamivir (Tamiflu): evolution of strategy, quest for a process-quality synthesis, and evaluation of efficiency metrics.
abstract: Four generations of chemoenzymatic approaches to oseltamivir are presented. The first two generations relied on the use of cyclohexadiene-cis-diol derived enzymatically from bromobenzene. The third and fourth generation used the corresponding diol obtained from ethyl benzoate by fermentation with E. coli JM109(pDTG601a). Oseltamivir was obtained from ethyl benzoate by intersecting intermediate 39 (third-generation synthesis) and intermediate 45 (fourth-generation synthesis). Both of these advanced approaches benefited from symmetry considerations and translocation of the acrylate double bond with concomitant elimination of the C-1 hydroxyl. The syntheses are evaluated for overall efficiency by the use of efficiency metrics and compared with other syntheses of oseltamivir (both academic and industrial).
authors: Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada.
authors: Lukas
authors: L
authors: Werner
authors: Ales
authors: A
authors: Machara
authors: Bradford
authors: B
authors: Sullivan
authors: Ignacio
authors: I
authors: Carrera
authors: Michael
authors: M
authors: Moser
authors: David R
authors: DR
authors: Adams
authors: Tomas
authors: T
authors: Hudlicky
authors: John
authors: J
authors: Andraos
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis*; D001565:Benzoates / Q000737:chemistry; D001969:Bromobenzenes / Q000737:chemistry*; D053138:Cyclohexenes / Q000138:chemical synthesis*; D004926:Escherichia coli / Q000201:enzymology; D005285:Fermentation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D053139:Oseltamivir / Q000138:chemical synthesis*; D013237:Stereoisomerism
chemical_list: D000998:Antiviral Agents; D001565:Benzoates; D001969:Bromobenzenes; D053138:Cyclohexenes; D053139:Oseltamivir; C032036:bromobenzene; D009439:Neuraminidase