A novel azide-free asymmetric synthesis of oseltamivir phosphate (Tamiflu) starting from Roche's epoxide

A novel azide-free asymmetric synthesis of oseltamivir phosphate 1 (Tamiflu (R)) starting from Roche's epoxide is described. Roche epoxide 2 was converted into N-acetyl aminoalcohol 3 in 95% yield via a BF3 center dot OEt2-catalyzed epoxide-opening with acetonitrile as a nucleophile. Compound 3 was then transformed into a methanesulfonate 4 in 98% yield. Compound 4 was converted into aziridine 5 in 91% yield. Aziridine 5 was subsequently converted into oseltamivir phosphate 1 via two paths (a and b). In the path a, compound 5 underwent aziridine-opening with diallylamine as a nucleophile to afford compound 7 in 93% yield; compound 7 could then be converted into oseltamivir phosphate 1 in 88% yield. In path b, compound 5 underwent aziridine-opening with isopropyl 2,2,2-trichloroacetimidate as a nucleophile to afford compound 8 in 94% yield, which was then converted into oseltamivir phosphate 1 in 82% yield. (C) 2013 Elsevier Ltd. All rights reserved.