New, Efficient Synthesis of Oseltamivir Phosphate (Tamiflu) via Enzymatic Desymmetrization of a meso-1,3-Cyclohexanedicarboxylic Acid Diester

• Published in: Journal of organic chemistry Vol. 73; no. 13; pp. 4895 - 4902
• Main Authors: Zutter, Ulrich, Iding, Hans, Spurr, Paul, Wirz, Beat
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 04.07.2008; Amer Chemical Soc
• Subjects: Antiviral Agents - chemical synthesis; Chemistry; Chemistry, Organic; Dicarboxylic Acids - chemistry; Molecular Structure; Oseltamivir - chemical synthesis; Physical Sciences; Science & Technology; INHIBITOR OSELTAMIVIR; ANTIINFLUENZA
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo800264d

A new, enantioselective synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate 1 (Tamiflu) and its enantiomer ent-1 starting from cheap, commercially available 2,6-dimethoxyphenol 10 is described. The main features of this approach comprise the cis-hydrogenation of 5-(1-ethyl-propoxy)-4,6-dimethoxy-isophthalic acid diethyl ester (6a) and the desymmetrization of the resultant all-cis meso-diesters 7a and 7b, respectively. Enzymatic hydrolysis of the meso-diester 7b with pig liver esterase afforded the (S)-monoacid 8b, which was converted into cyclohexenol 17 via a Curtius degradation and a base-catalyzed decarboxylative elimination of the Boc-protected oxazolidinone 14. Introduction of the second amino function via SN2 substitution of the corresponding triflate 18 with NaN3 followed by azide reduction, N-acetylation, and Boc-deprotection gave oseltamivir phosphate 1 in a total of 10 steps and an overall yield of ∼30%. The enantiomer ent-1 was similarly obtained via an enzymatic desymmetrization of meso-diester 7a with Aspergillus oryzae lipase, providing the (R)-monoacid ent-8a.