Novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (−)-shikimic acid via cyclic sulfite intermediates

A novel asymmetric synthesis of oseltamivir phosphate 1 from the naturally abundant (−)-shikimic acid via 3,4-cyclic sulfite intermediate 3 (Scheme 1) is described. Target compound 1 was obtained in 39% overall yield from this nine-step synthesis, and the characteristic step of the synthesis is the regio- and stereospecific nucleophilic substitution with sodium azide at the allylic (C-3) position of 3,4-cyclic sulfite 3. Since the yield of the direct-aziridine-formation from the unprotected dihydroxyl azide 4 was not satisfactory, two improved preparations of the established compound 7 via protected 3,4-cyclic sulfites 10 and 13 (Scheme 2) have been developed. In these two improved preparations, compound 7 was obtained from 3,4-cyclic sulfite 3 in 7-steps in 64% or 62% overall yield, respectively.

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Ethyl (3R,4S,5R)-3,4-cyclic sulfite-shikimateC9H12O6S[α]D20=+52.0 (c 1.5, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4S,5R)

Ethyl (3S,4R,5R)-3-azido-4,5-dihydroxycyclohex-1-ene-1-carboxylateC9H13N3O4[α]D20=+67.7 (c 4.3, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)

Ethyl (1S,5R,6S)-5-hydroxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylateC9H13NO3[α]D20=-219.8 (c 1.1, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (1S,5R,6S)

Ethyl (1S,5R,6S)-7-acetyl-5-hydroxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylateC11H15NO4[α]D20=-90.7 (c 1.0, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (1S,5R,6S)

Ethyl (3R,4S,5R)-5-O-benzoyl-3,4-cyclic sulfite-shikimateC16H16O7S[α]D20=+17.2 (c 9.7, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4S,5R)

Ethyl (3S,4R,5R)-3-azido-5-benzoyloxy-4-hydroxy-cyclohex-1-ene-1-carboxylateC16H17N3O5[α]D20=-4.7 (c 3.0, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)

Ethyl (3R,4S,5R)-5-O-acetyl-3, 4-cyclic sulfite-shikimateC11H14O7S[α]D20=+62.9 (c 2.6, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)

Ethyl (3S,4R,5R)-3-azido-5-acetoxy-cyclohex-1-ene-1-carboxylateC11H15N3O5[α]D20=+24.2 (c 1.2, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)

Ethyl (3S,4R,5R)-3-azido-5-acetoxy-4-methanesulfonyloxy-cyclohex-1-ene-1-carboxylateC12H17N3O7S[α]D20=+51.5 (c 4.3, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)

Ethyl (1S,5R,6S)-5-acetoxy-7-azabicyclo[4,1,0]hept-2-ene-3-carboxylateC11H15NO4[α]D20=-139.7 (c 1.4, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (1S,5R,6S)

Ethyl (1S,5R,6S)-5-acetoxy-7-acetyl-7-azabicyclo[4,1,0]hept-2-ene-3- carboxylateC13H17NO5[α]D20=-36.5 (c 1.9, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (1S,5R,6S)

Ethyl (3R,4R,5R)-4-acetamido-5-acetoxy-3-(1-ethylpropoxy)-cyclohex-1-ene-1-carboxylateC18H29NO6[α]D20=-76.4 (c 2.0, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4R,5R)