New, Efficient Synthesis of Oseltamivir Phosphate (Tamiflu) via Enzymatic Desymmetrization of a meso-1,3-Cyclohexanedicarboxylic Acid Diester
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-eth...
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Published in | Journal of organic chemistry Vol. 73; no. 13; pp. 4895 - 4902 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
American Chemical Society
04.07.2008
Amer Chemical Soc |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | General remarks and copies of 1H NMR spectra for compounds 11, 12, 6a, 7a, 7b, 8b, 13, 14, 17, 18, 20, 21, 1, ent-8a, ent-8b, and 19 and the 13C NMR spectrum for compound 19. This material is available free of charge via Internet at http://pubs.acs.org. istex:098AAA0EA3AF1E3DE0DC1445806F75BFD0B50652 ark:/67375/TPS-DPWR23CD-W ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3263 1520-6904 |
DOI: | 10.1021/jo800264d |