Several Generations of Chemoenzymatic Synthesis of Oseltamivir (Tamiflu): Evolution of Strategy, Quest for a Process-Quality Synthesis, and Evaluation of Efficiency Metrics

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• 作者：Lukas Werner ; Ales Machara ; Bradford Sullivan ; Ignacio Carrera ; Michael Moser ; David R. Adams ; Tomas Hudlicky ; John Andraos
• 刊名：Journal of Organic Chemistry
• 出版年：2011
• 出版时间：December 16, 2011
• 年：2011
• 卷：76
• 期：24
• 页码：10050-10067
• 全文大小：730K
• 年卷期：v.76,no.24(December 16, 2011)
• ISSN：1520-6904

文摘

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).