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.

Key words

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

References and Notes

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1

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

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.

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.

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.

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.

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.

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.

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.

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.

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.