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®) starting from Roche’s epoxide is described. Roche epoxide 2 was converted into N-acetyl aminoalcohol 3 in 95% yield via a BF3·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.

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(3R,4S,5R)-Ethyl 5-acetylamido-4-hydroxy-3-(pentan-3-yloxy)cyclohex-1-ene carboxylateC16H27NO5[α]D20=-171 (c 2.00, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4S,5R)

(3R,4S,5R)-Ethyl 5-acetylamido-4-methanesulfonyloxy-3-(pentan-3-yloxy)cyclohex-1-ene carboxylateC17H29NO7S[α]D20=-118 (c 1.30, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4S,5R)

(3R,4R,5R)-Ethyl 4,5-acetylimino-3-(pentan-3-yloxy)cyclohex-1-ene carboxylateC16H25NO4[α]D20=-46 (c 0.60, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4R,5R)

(5R)-Ethyl 5-acetylamido-3-(pentan-3-yloxy)cyclohexa-1,3-diene carboxylateC16H25NO4[α]D20=+118 (c 1.10, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (5R)

(3R,4R,5S)-Ethyl 4-acetylamido-5-diallylamino-3-(pentan-3-yloxy)cyclohex-1-ene carboxylateC22H36N2O4[α]D20=-30 (c 1.0, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4R,5S)

(3R,4R,5S)-Ethyl 4-acetylamido-3-(pentan-3-yloxy)-5-(2,2,2-trichloroacetimido)cyclohex-1-enecarboxylateC18H27Cl3N2O5[α]D20=-45 (c 1.0, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4R,5S)