Efficient Asymmetric Synthesis of Oseltamivir from d-Mannitol

Abstract

A highly practical asymmetric synthesis of oseltamivir has been accomplished in 18 steps from d-mannitol without any chromatographic purification, which features intramolecular aldol condensation of dialdehyde with a 3-pentyl ether moiety in constructing densely functionalized cyclohexene ring of oseltamivir.

anti-influenza drugs - Tamiflu - chiral pool - dihydrox­ylations - intramolecular aldol condensation

References and Notes

1

Present address: School of Pharmaceutical Sciences, Teikyo University, 1091-1 Suarashi, Sagamiko, Sagamihara, 229-0195, Japan.

2a Kim CU. Lew W. Williams MA. Liu H. Zhang L. Swaminathan S. Bischofberger N. Chen MS. Mendel DB. Tai CY. Laver WG. Stevens RC. J. Am. Chem. Soc.  1997,  119:  681 

2b Rohloff JC. Kent KM. Postich MJ. Becker MW. Chapman HH. Kelly DE. Lew W. Louie MS. McGee LR. Prisbe EJ. Schultze LM. Yu RH. Zhang L. J. Org. Chem.  1998,  63:  4545 

2c Federspiel M. Fischer R. Henning M. Mair H.-J. Oberhauser T. Rimmler G. Albiez T. Bruhin J. Estermann H. Gandert C. Göckel V. Götzö S. Hoffmann U. Huber G. Janatsch G. Lauper S. Röckel-Stäbler O. Trusssardi R. Zwahlen AG. Org. Process Res. Dev.  1999,  3:  266 

2d Karpf M. Trussardi R. J. Org. Chem.  2001,  66:  2044 

2e Harrington PJ. Brown JD. Foderaro T. Hughes RC. Org. Process Res. Dev.  2004,  8:  86 

3 Farina V. Brown JD. Angew. Chem. Int. Ed.  2006,  45:  7330 

4a Yeung Y.-Y. Hong S. Corey EJ. J. Am. Chem. Soc.  2006,  128:  6310 

4b Fukuta Y. Mita T. Fukuda N. Kanai M. Shibasaki M. J. Am. Chem. Soc.  2006,  128:  6312 

4c Cong X. Yao ZJ. J. Org. Chem.  2006,  71:  5365 

4d Mita T. Fukuda N. Roca FX. Kanai M. Shibasaki M. Org. Lett.  2007,  9:  259 

4e Yamatsugu K. Kamijo S. Suto Y. Kanai M. Shibasaki M. Tetrahedron Lett.  2007,  48:  1403 

4f Bromfield KM. Graden H. Hagberg DP. Olsson T. Kann N. Chem. Commun.  2007,  3183 

4g Satoh N. Akiba T. Yokoshima S. Fukuyama T. Angew. Chem. Int. Ed.  2007,  46:  5734 

4h Shie J.-J. Fang J.-M. Wang S.-Y. Tsai K.-C. Cheng Y.-SE. Yang A.-S. Hsiao S.-C. Su C.-Y. Wong C.-H. J. Am. Chem. Soc.  2007,  129:  11892 

4i Trost BM. Zhang T. Angew. Chem. Int. Ed.  2008,  47:  1 

4j Zutter U. Iding H. Spurr P. Wirz B. J. Org. Chem.  2008,  73:  4895 

4k Shie J.-J. Fang J.-M. Wong C.-H. Angew. Chem. Int. Ed.  2008,  47:  5788 

4l Satoh N. Akiba T. Yokoshima S. Fukuyama T. Tetrahedron  2009,  in press

4m Yamatsugu K. Yin L. Kamijo S. Kimura Y. Kanai M. Shibasaki M. Angew. Chem. Int. Ed.  2009,  48:  1070 

Ishikawa H. Suzuki T. Hayashi Y. Angew. Chem. Int. Ed.  2009,  48:  1304 

5

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.

6 Schmid CR. Bradley DA. Synthesis  1992,  587 

7

The optical purity of 3 was determined as follows. The HPLC analysis [Chiralcel OD; λ = 254 nm; eluent: hexane-EtOH (9:1); flow rate: 1.3 mL/min] of 3,5-dinitrobenzoate of 3 showed the two peaks based on their two diastereomers at t _R = 11.4 min and 22.3 min, respectively. On the other hand, those of racemic 3, prepared from glycerol via acetalization, Swern oxidation, and Grignard reaction, showed four peaks at t _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.

8 Johnson WS. Werthemann L. Bartlett WR. Brocksom TJ. Li T.-T. Faulkner DJ. Petersen MR. J. Am. Chem. Soc.  1970,  92:  741 

9

Compound 4: colorless oil; [α]_D ^²¹.6 +24.0 (c 1.23, CHCl₃); bp 110-112 ˚C/6.66˙10^-4 bar. ^¹H NMR (500 MHz, CDCl₃): δ = 5.80 (dt, J = 15.3, 6.4 Hz, 1 H), 5.48 (dd, J = 15.3, 7.9 Hz, 1 H), 4.45 (ddd, J = 8.25, 7.95, 6.1 Hz, 1 H), 4.13 (q, J = 7.0 Hz, 2 H), 4.10 (dd, J = 7.95, 6.1 Hz, 1 H), 3.51 (dd, J = 8.25, 7.95 Hz, 1 H), 2.43-2.36 (m, 4 H), 1.68-1.60 (m, 4 H), 1.25 (t, J = 7.0 Hz, 3 H), 0.95-0.88 (m, 6 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 172.7, 133.3, 128.5, 113.0, 77.3, 69.9, 60.3, 33.5, 29.9, 29.8, 27.4, 14.2, 8.1, 8.0. HRMS (EI⁺): m/z calcd for C₁₄H₂₄O₄: 256.1675; found: 256.1655.

A solution of ester 4 in toluene was added dropwise to a solution of DIBAL-H in toluene. As the relevant papers, see:

10a Takano S. Akiyama M. Sato S. Ogasawara K. Chem. Lett.  1983,  1593 

10b Mori A. Fujiwara J. Maruoka K. Yamamoto H. Tetrahedron Lett.  1983,  24:  4581 

11

First we prepared a corresponding dibenzyl ether of 5a, which proved to be cleaved in a later azide-formation step affording a complex mixture.

12 Sharpless KB. Amberg W. Bennani YL. Crispino GA. Hartung J. Jeong K.-S. Kwong H.-L. Morikawa K. Wang Z.-M. Xu D. Zhang X.-L. J. Org. Chem.  1992,  57:  2768 

13

The attempted dihydroxylations with OsO₄/NMO and with AD-mix-α provided a 1:1 to 1:2 mixture of diastereomers with respect to the 3-pentyloxy group.

14

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.

15 Worster PM. Leznoff CC. McArthur CR. J. Org. Chem.  1980,  45:  174 

16

Compound 8b: [α]_D ^²¹.5 -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.

17

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.

18a Anelli PL. Biffi C. Montanari F. Quici S. J. Org. Chem.  1987,  52:  2559 

18b Anelli PL. Montanari F. Quici S. Org. Synth.  1990,  69:  212 

18c Leanna MR. Sowin TJ. Morton HE. Tetrahedron Lett.  1992,  33:  5029 

19a Corey EJ. Danheiser RL. Chandrasekaran S. Siret P. Keck GE. Gras J.-L. J. Am. Chem. Soc.  1978,  100:  8031 

19b Snyder SA. Corey EJ. Tetrahedron Lett.  2006,  47:  2083 

20

Compound 10: obtained as an off-white solid by washing with hot toluene; [α]_D ^²².5 -46.5 (c 1.10, CHCl₃); mp 202.3-202.7 ˚C. ^¹H NMR (500 MHz, CDCl₃, 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 C₂₂H₂₆N₂O₅: C, 66.32; H, 6.58; N, 7.03. Found: C, 66.15; H, 6.72; N, 7.05. HRMS (FAB⁺): m/z calcd for C₂₂H₂₇N₂O₅ [MH⁺]: 399.1920; found: 399.1925.

21 Gonzalez-Bello C. Coggins JR. Hawkins AR. Abell C. J. Chem. Soc., Perkin Trans. 1  1999,  849 

22

Evaporation of the volatiles and addition of a large excess of H₂O 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]_D ^²5 -58.4 (c 0.54, DMSO). ^¹H NMR (500 MHz, DMSO-d ₆): 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-d ₆): 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 C₂₂H₂₆N₂O₆: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.76; H, 6.45; N, 6.71.

23 Osby JO. Martin MG. Ganem B. Tetrahedron Lett.  1984,  25:  2093 

24

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]_D ^²².8 -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 C₂₂H₃₀N₂O₆: C, 63.14; H, 7.23; N, 6.69. Found: C, 62.89; H, 7.37; N, 6.73.

25

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]_D ^²³.0 -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.

26

Oseltamivir (1), obtained as a white semi-solid: [α]_D ^²5.0 -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]_D ^²³.0 -56.1 (c 1.24, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 6.79 (br s, 1 H), 5.79 (d, J = 7.95 Hz, 1 H), 4.26-4.17 (m, 3 H), 3.57-3.49 (m, 1 H), 3.38-3.32 (m, 1 H), 3.26-3.18 (m, 1 H), 2.75 (dd, J = 17.9, 4.9 Hz, 1 H), 2.18-2.10 (m, 1 H), 2.04 (s, 3 H), 1.66-1.60 (m, 2 H), 1.56-1.47 (m, 4 H), 1.29 (t, J = 7.0 Hz, 3 H), 0.95-0.87 (m, 6 H). ^¹³C NMR (125 Hz, CDCl₃): 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.