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Volumn , Issue 5, 2009, Pages 0783-0786

Efficient asymmetric synthesis of oseltamivir from D-mannitol

Author keywords

Anti influenza drugs; Chiral pool; Dihydroxylations; Intramolecular aldol condensation; Tamiflu

Indexed keywords


EID: 62349109401     PISSN: 09365214     EISSN: 14372096     Source Type: Journal    
DOI: 10.1055/s-0028-1087941     Document Type: Article
Times cited : (43)

References (46)
  • 21
    • 46849088854 scopus 로고    scopus 로고
    • for a recent review on the synthesis of oseltamivir (1), see: Shibasaki, M.; Kanai, M. Eur. J. Org. Chem. 2008, 1839; see also ref. 3.
    • for a recent review on the synthesis of oseltamivir (1), see: Shibasaki, M.; Kanai, M. Eur. J. Org. Chem. 2008, 1839; see also ref. 3.
  • 23
    • 62349111842 scopus 로고    scopus 로고
    • R = 11.4 min, 14.5 min, 18.7 min, and 22.2 min, respectively. This observation surely indicates that 2 and 3 are formed without racemization throughout the sequential reactions.
    • R = 11.4 min, 14.5 min, 18.7 min, and 22.2 min, respectively. This observation surely indicates that 2 and 3 are formed without racemization throughout the sequential reactions.
  • 25
    • 62349109545 scopus 로고    scopus 로고
    • 4: 256.1675; found: 256.1655.
    • 4: 256.1675; found: 256.1655.
  • 26
    • 62349091651 scopus 로고    scopus 로고
    • A solution of ester 4 in toluene was added dropwise to a solution of DIBAL-H in toluene. As the relevant papers, see: (a) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593.
    • A solution of ester 4 in toluene was added dropwise to a solution of DIBAL-H in toluene. As the relevant papers, see: (a) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593.
  • 28
    • 62349097421 scopus 로고    scopus 로고
    • First we prepared a corresponding dibenzyl ether of 5a, which proved to be cleaved in a later azide-formation step affording a complex mixture.
    • First we prepared a corresponding dibenzyl ether of 5a, which proved to be cleaved in a later azide-formation step affording a complex mixture.
  • 30
    • 62349141909 scopus 로고    scopus 로고
    • 4/NMO and with AD-mix-α provided a 1:1 to 1:2 mixture of diastereomers with respect to the 3-pentyloxy group.
    • 4/NMO and with AD-mix-α provided a 1:1 to 1:2 mixture of diastereomers with respect to the 3-pentyloxy group.
  • 31
    • 62349111844 scopus 로고    scopus 로고
    • Hydrogenolysis (10% Pd/C, EtOAc, r.t., 48 h) of 7a also provided 7b with poor reproducibility probably owing to poisoning by the accumulated contaminations.
    • Hydrogenolysis (10% Pd/C, EtOAc, r.t., 48 h) of 7a also provided 7b with poor reproducibility probably owing to poisoning by the accumulated contaminations.
  • 33
    • 62349140382 scopus 로고    scopus 로고
    • Compound 8b: [α]D21.5 -19.2 (c 1.07, CHCl3, mp 142.1-143.5°C. 1H NMR (500 MHz, CDCl3, δ, 7.85-7.70 (m, 4 H, 6.77 (d, J, 9.8 Hz, 1 H, 4.77-4.72 (m, 1 H, 4.60-4.54 (m, 1 H, 3.80-3.60 (m, 5 H, 3.25-3.14 (m, 2 H, 2.28-2.18 (m, 1 H, 1.98 (s, 3 H, 1.95-1.86 (m, 1 H, 1.75 (br s, 1 H, 1.55-1.30 (m, 5 H, 1.11-0.98 (m, 2 H, 0.78-0.72 (m, 6 H, 13C NMR 125 MHz, CDCl3, δ, 171.7, 169.2, 134.2, 131.6, 123.3, 79.2, 75.3, 61.8, 60.4, 52.5, 51.1, 29.2, 26.1, 25.5, 25.3, 22.9, 9.39, 9.37. Anal. Calcd for C22H32N2O6: C, 62.84, H, 7.67, N, 6.66. Found: C, 62.70, H, 7.85, N, 6.65
    • 6: C, 62.84, H, 7.67, N, 6.66. Found: C, 62.70, H, 7.85, N, 6.65.
  • 34
    • 62349093853 scopus 로고    scopus 로고
    • Dialdehyde 9 was pure enough to be used for the next step. However, it was labile to purification on silica gel column chromatography for combustion analysis, affording a complex mixture involving cyclized products.
    • Dialdehyde 9 was pure enough to be used for the next step. However, it was labile to purification on silica gel column chromatography for combustion analysis, affording a complex mixture involving cyclized products.
  • 40
    • 62349123375 scopus 로고    scopus 로고
    • Compound 10: obtained as an off-white solid by washing with hot toluene; [α]D22.5 -46.5 (c 1.10, CHCl 3, mp 202.3-202.7°C. 1H NMR (500 MHz, CDCl 3, data of a mixture of rotamers, δ, 9.55 (s, 0.13 H, 9.53 (s, 0.87 H, 7.86-7.72 (m, 4 H, 6.70 (s, 0.13 H, 6.67 (s, 0.87 H, 5.53 (d, J, 7.6 Hz, 0.87 H, 5.26 (d, J, 7.6 Hz, 0.13 H, 4.95-4.90 (m, 0.87 H, 4.75-4.71 (m, 0.87 H, 4.45-4.38 (m, 1.13 H, 4.20-4.18 (m, 0.13 H, 3.46-3.37 (m, 1 H, 3.05-2.98 (m, 1 H, 2.75-2.65 (m, 1 H, 2.05 (s, 0.4 H, 1.78 (s, 2.6 H, 1.60-1.50 (m, 4 H, 1.00-0.85 (m, 6 H, 13C NMR 125 Hz, CDCl3, data of a mixture of rotamers, δ, 192.3, 170.3, 168.1, 147.6, 138.8, 134.2, 131.6, 128.5, 123.5, 82.5, 74.6, 54.3, 47.8, 26.3, 25.7, 25.5, 23.3, 9.7, 9.4. Anal. Calcd for C22H26N 2O5: C, 66.32; H, 6.58; N, 7.03. Found: C, 66.15; H, 6.72; N
    • +]: 399.1920; found: 399.1925.
  • 42
    • 62349091021 scopus 로고    scopus 로고
    • Evaporation of the volatiles and addition of a large excess of H 2O to the residue provided an off-white solid, which was collected by filtration and washed successively with H2O and MeOt-Bu. Compound 11: obtained as a white solid (mp >280°C) with poor solubility in organic solvents such as MeOH or CHCl3: [α] D25 -58.4 (c 0.54, DMSO, 1H NMR (500 MHz, DMSO-d6, δ, 12.6 (br s, 1 H, 7.92-7.80 (m, 4 H, 6.69 (s, 1 H, 4.38-4.20 (m, 3 H, 3.42-3.10 (m, 2 H, 2.63-2.50 (m, 1 H, 1.50-1.32 (m, 4 H, 0.86 (t, J, 7.3 Hz, 3 H, 0.75 (t, J, 7.3 Hz, 3 H, 13C NMR 125 Hz, DMSO-d6, δ, 169.1, 167.6, 167.0, 137.5, 134.3, 129.0, 123.0, 81.0, 74.7, 51.5, 48.9, 26.6, 25.8, 25.1, 22.4, 9.5, 8.9. Anal. Calcd for C22H26N 2O6: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.76; H, 6.45; N, 6.71
    • 6: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.76; H, 6.45; N, 6.71.
  • 44
    • 62349095224 scopus 로고    scopus 로고
    • Crude 12a deposited efficiently on dilution of the reaction mixture with a large excess of diluted HCl. Filtration and washing with water provided pure 12a as a white solid: [α]D22.8 -79.2 (c 1.07, CHCl3-MeOH, 4:1, mp 180.4-180.8°C. 1H NMR (500 MHz, CD3OD, δ, 7.43-7.23 (m, 4 H, 6.73 (br s, 1 H, 4.75-4.50 (m, 2 H, 4.25-3.80 (m, 3 H, 3.37-3.33 (m, 1 H, 2.73-2.65 (m, 1 H, 2.33-2.27 (m, 1 H, 1.50-1.35 (m, 4 H, 0.86-0.77 (m, 6 H, 13C NMR 125 Hz, CD3OD, δ, 173.9, 172.0, 169.4, 140.9, 139.1, 136.3, 131.7, 130.7, 129.8, 128.7, 128.6, 83.8, 77.3, 63.5, 55.9, 31.5, 27.3, 26.8, 23.0, 9.9, 9.6. Anal. Calcd for C22H 30N2O6: C, 63.14; H, 7.23; N, 6.69. Found: C, 62.89; H, 7.37; N, 6.73
    • 6: C, 63.14; H, 7.23; N, 6.69. Found: C, 62.89; H, 7.37; N, 6.73.
  • 45
    • 62349125842 scopus 로고    scopus 로고
    • Dilution of the reaction mixture with a large excess of water deposited a white solid, which was washed successively with H2O and MeOt-Bu to give unmingled 12b as a white solid: [α] D23.0 -48.0 (c 1.11, CHCl3, mp 209.3-210°C. 1H NMR (500 MHz, CDCl3, δ, 7.43-7.23 (m, 4 H, 6.73 (br s, 1 H, 4.75-4.50 (m, 2 H, 4.25-3.80 (m, 3 H, 3.37-3.33 (m, 1 H, 2.73-2.65 (m, 1 H, 2.33-2.27 (m, 1 H, 1.50-1.35 (m, 4 H, 0.86-0.77 (m, 6 H, 13C NMR 125 Hz, CDCl3, δ, 171.5, 169.9, 165.9, 139.8, 137.8, 135.1, 131.2, 130.7, 129.1, 128.1, 127.9, 82.2, 75.7, 64.4, 60.9, 54.3, 48.7, 30.5, 26.2, 25.6, 22.8, 14.1, 9.6, 9.2. Anal. Calcd for C24H34N2O6: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.25; H, 8.03; N, 6.21
    • 6: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.25; H, 8.03; N, 6.21.
  • 46
    • 62349093851 scopus 로고    scopus 로고
    • Oseltamivir (1, obtained as a white semi-solid: [α] D25.0 -55.8 (c 2.05, CHCl3, 1H NMR (500 MHz, CDCl3, δ, 6.79 (br s, 1 H, 5.48 (d, J, 7.6 Hz, 1 H, 4.25-4.18 (m, 3 H, 3.55-3.48 (m, 1 H, 3.38-3.32 (m, 1 H, 3.27-3.20 (m, 1 H, 2.75 (dd, J, 17.9, 5.2 Hz, 1 H, 2.19-2.11 (m, 1 H, 2.04 (s, 3 H, 1.60-1.47 (m, 6 H, 1.29 (t, J, 7.1 Hz, 3 H, 0.95-0.88 (m, 6 H, 13C NMR (125 Hz, CDCl3, δ, 170.9, 166.3, 137.5, 129.5, 81.6, 74.8, 60.8, 58.9, 49.2, 33.6, 26.2, 25.7, 23.6, 14.2, 9.5, 9.3. 1H NMR and 13C NMR spectra and optical rotation value were in full accordance with those of the authentic sample obtained through a basic extraction (sat. aq NaHCO3-5% aq Na2CO3-CHCl3) from commercial Tamiflu: [α]D23.0 -56.1 c 1.24, CHCl3, 1H NMR
    • 3): δ = 170.9, 166.3, 137.5, 129.5, 81.6, 74.8, 60.8, 59.0, 49.2, 33.6, 26.2, 25.7, 23.6, 14.2, 9.5, 9.3.


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