Enantioselective synthesis of oseltamivir phosphate Sadagopan Raghavan * , Vaddela Sudheer Babu Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500607, India article info Article history: Received 8 December 2010 Received in revised form 21 January 2011 Accepted 21 January 2011 Available online 27 January 2011 Keywords: Tamiflu Asymmetric DielseAlder reaction Iodolactonization Mitsunobu reaction Selenoxide elimination abstract The key steps in the enantioselective synthesis of Tamiflu include an asymmetric DielseAlder reaction, Mitsunobu inversion using Fukuyama modified Weinreb reagent, carbamate directed epoxidation. Ep- oxide opening with trimethylsilyl azide furnished a 3:1 mixture of regioisomers that converged to afford the same aziridine. Attempted preparation of the unsaturated ester regioselectively using 2-iodoxy- benzoic acid (IBX) following Nicolaou’s protocol failed. The unsaturated ester was prepared by phenyl- selenylation followed by selenoxide elimination. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Oseltamivir phosphate (Tamiflu) 1 , is an approved orally effec- tive neuraminidase inhibitor used for the treatment of human in- fluenza 1 and H5N1 avian flu. 2 Numerous people have fallen victim to human influenza and H5N1 avian flu and it still continues to be a threat. A ready stock of Tamiflu is desirable to protect people from a future outbreak. Currently, Tamiflu is manufactured from ()-shikimic acid or ()-quinic acid, 3 however the limited avail- ability of the chiral raw materials is a major drawback. This has propelled synthetic chemists worldwide to design alternate routes from non-natural readily available chemicals. Many interesting and ingenious laboratory scale syntheses, 3a,b,d,4 of which at least some can be adapted to commercial scale, have been reported. Herein we report an enantioselective synthesis of Tamiflu taking advantage of the DielseAlder reaction. 2. Results and discussion The retrosynthetic analysis is depicted in Scheme 1 . The in- stallation of the alkoxy group was envisaged by opening of the aziridine 2 towards the end of the synthesis. The aziridine 2 was envisioned to be obtained via regioselective opening of the epoxide 3. The epoxide was traced down to allylic alcohol 4, which is readily obtained from cyclohexene-3-carboxylic acid 5. The synthesis began with (R)-cyclohexene carboxylic acid 5 (>99% ee) obtained readily in large scale by an asymmetric Dielse Alder reaction following a reported procedure. 5 Iodolactonization of 5 and dehydroiodination of 6 following Trost’s protocol 6 yielded unsaturated lactone 7 , Scheme 2. Base catalyzed opening of 7 with ethanol furnished allylic alcohol 4. The amino group at C5 (Tamiflu numbering) was introduced using the Fukuyama 7 modification of the Weinreb reagent 8 to furnish sulfonamide 8. 9 Deprotection of the p-nosyl group under mild conditions using 2-thio ethanol 10 yielded allylic carbamate 9. Stereoselective epoxidation directed by the carbamate moiety 11 furnished compound 3 as the sole product, Scheme 2. Scheme 1. Retrosynthetic analysis of oseltamivir phospahate 1. * Corresponding author. E-mail address: sraghavan@iict.res.in (S. Raghavan). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.01.064 Tetrahedron 67 (2011) 2044e2050