A novel and high-yielding asymmetric synthesis of oseltamivir phosphate (Tamiflu) starting from (−)-shikimic acid

A novel and high-yielding asymmetric synthesis of oseltamivir phosphate 1 (Tamiflu®) is described. The target compound 1 was obtained in 55% overall yield via an 11-step asymmetric synthesis starting from the naturally abundant (−)-shikimic acid. The present synthesis is characterized by some advantages such as the easy separation of intermediate 6 from triphenylphosphine oxide by using its large water-solubility, the use of inexpensive reagents throughout the synthesis, the lack of toxic heavy metals, mild reaction conditions and high yields for all steps. The stereochemical structure of the key intermediate 6 was unequivocally confirmed by X-ray crystallographic analysis.

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C10H14O8S2Ethyl (3R,4S,5R)-3,4-O-thionyl-5-O-methanesulfonyl-shikimate[α]D20=+19 (c 1.5, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4S,5R)

C10H15N3O6SEthyl (3S,4R,5R)-3-azido-4-hydroxy-5-methanesulfonyloxy-cyclohex-1-ene-1-carboxylate[α]D20=+31 (c 2.3, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)

C9H13NO3Ethyl (3S,4S,5S)-5-hydroxy-3,4-imino-cyclohex-1-ene-1-carboxylate[α]D20=-296 (c 2.0, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4S,5S)

C11H15NO4Ethyl (3S,4S,5S)-3,4-acetylimino-5-hydroxy-cyclohex-1-ene-1-carboxylate[α]D20=-105 (c 0.8, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4S,5S)

C16H27NO5Ethyl (3R,4R,5S)-4-acetamido-3-(1-ethyl-propoxy)-5-hydroxy-cyclohex-1-ene-1-carboxylate[α]D20=-60 (c 2.5, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4R,5S)

C17H29NO7SEthyl (3R,4S,5S)-4-acetamido-3-(1-ethyl-propoxy)-5-methanesulfonyloxy-cyclohex-1-ene-1-carboxylate[α]D20=-29 (c 1.0, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4S,5S)

C16H25NO4Ethyl (3R,4R,5R)-4,5-acetylimino-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate[α]D20=-46 (c 1.6, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4R,5R)

C16H26N4O4Ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-cyclohex-1-ene-1-carboxylate[α]D20=-43 (c 1.0, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4R,5S)