New, efficient synthesis of oseltamivir phosphate (Tamiflu) via enzymatic desymmetrization of a meso-1,3-cyclohexanedicarboxylic acid diester.

Abstract

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 S(N)2 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 approximately 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.

• Authors: Ulrich Zutter, Hans Iding, Paul Spurr, Beat Wirz
• Journal: The Journal of organic chemistry (J Org Chem) Vol. 73 Issue 13 Pg. 4895-902 (Jul 04 2008) ISSN: 1520-6904 [Electronic] United States
• PMID: 18517254 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Dicarboxylic Acids
• Oseltamivir

Topics

• Antiviral Agents (chemical synthesis)
• Dicarboxylic Acids (chemistry)
• Molecular Structure
• Oseltamivir (chemical synthesis)