A new efficient synthesis of oseltamivir phosphate (Tamiflu) from (-)-shikimic acid

Article abstract of DOI:10.1016/j.tetlet.2012.01.017

New synthesis of oseltamivir phosphate was accomplished in 9 steps with a 27% overall yield from a readily available (-)-shikimic acid. Selective ring opening reaction of ketal and azide Mitsunobu reaction for facile replacement of a hydroxyl group by the N3 group at the C-3 position of (3R,4R,5R)-ethyl 4-hydroxy-5-(methoxymethoxy)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 4 and at the C-4 position of (3R,4S,5R)-ethyl 4-acetamido-5-hydroxy-3-(pentan-3-yloxy) cyclohex-1-enecarboxylate 7 successfully served as the key steps.

Full text of DOI:10.1016/j.tetlet.2012.01.017

Tetrahedron Letters 53 (2012) 1561–1563
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new efficient synthesis of oseltamivir phosphate (Tamiflu)
from (À)-shikimic acid
Hee-Kwon Kim a, , Kyoung-Joo Jenny Park b
⇑
a Department of Molecular and Medical Pharmacology, University of California Los Angeles, 570 Westwood Plaza, Los Angeles, CA 90095, USA
b Department of Chemical and Biomolecular Engineering, University of California Los Angeles, 420 Westwood Plaza, Los Angeles, CA 90095, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
New synthesis of oseltamivir phosphate was accomplished in 9 steps with a 27% overall yield from a
readily available (À)-shikimic acid. Selective ring opening reaction of ketal and azide Mitsunobu reaction
for facile replacement of a hydroxyl group by the N3 group at the C-3 position of (3R,4R,5R)-ethyl 4-
hydroxy-5-(methoxymethoxy)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 4 and at the C-4 position
of (3R,4S,5R)-ethyl 4-acetamido-5-hydroxy-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 7 successfully
served as the key steps.
Received 29 November 2011
Revised 4 January 2012
Accepted 5 January 2012
Available online 25 January 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Oseltamivir phosphate
Efficient synthesis
Tamiflu
Shikimic acid
Influenza
Influenza A virus is one of the members of the family Ortho-
myxoviridae.1 Highly virulent strains of influenza virus have
caused global pandemics that killed millions of people worldwide.1
These recurring outbreaks of influenza virus have attracted many
scientists’ attention toward the development of promising
therapeutics.
carboxylate, from (À)-shikimic acid (6 steps with a 63–65% overall
yield),7 and several syntheses for Tamiflu from the key intermedi-
ate were developed by the other scientists of Roche: Karpf’s meth-
od (35–38% in 5 steps) and Harrington’s method (61% in 7 steps).8
Synthetic routes developed by Roche have been used for the indus-
trial process. However, these synthetic routes contain many steps
(total 11–13 steps from (À)-shikimic acid). Recently Karpf and
coworkers of Roche published a new short synthetic method for
Tamiflu from (À)-shikimic acid with an overall yield of 20%
achieved in 8 steps.9
Usually, (À)-shikimic acid can be obtained by both extraction
from the Chinese star anise and the fermentation process of genet-
ically engineered Escherichia coli.10 In addition to such methods,
several independent synthesis routes to (À)-shikimic acid have
been developed.11 Here we report a novel efficient synthesis of
oseltamivir phosphate from (À)-shikimic acid (Figs. 1–3).
Our synthesis started from pentylidene ketal 2, which can be
prepared from (À)-shikimic acid via described procedures in the
literature: esterification using EtOH and benzenesulfonic acid and
protection of dihydroxyl group using the reaction with 3-penta-
none in the presence of triethylorthoformate.12
Oseltamivir phosphate (Tamiflu) was developed for the potent
neuraminidase inhibitor by Kim and coworkers of Gilead Sciences,2
and launched to the market in 1999. Since then, it has been utilized
as an orally active drug for the treatment and prophylaxis of both
type A and type B human influenza.3 Moreover, recently it has been
discovered that this compound is active against the H5N1 Avian
Flu virus, which causes disastrous influenza pandemic.4 Therefore,
there is an increasing demand for stocking a sufficient amount of
this compound in case of possible virulent outbreaks of influenza
virus. In response to the increasing demand for Tamiflu against
the spreading avian flu, significant efforts to develop efficient syn-
thetic strategies for Tamiflu have been devoted by several groups.5
Particularly, among all of the developed synthetic methods for
oseltamivir phosphate, several synthetic approaches to oseltamivir
phosphate 1 from shikimic acid have been reported. Rohloff and
coworkers developed a synthesis of Tamiflu from (À)-shikimic acid
in 10 steps with a 21% yield.6 Federspiel and coworkers of Roche
reported the synthetic routes to the key intermediate of Tamiflu,
ethyl(3R,4S,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-
The hydroxyl group of compound 2 was readily protected with
methoxymethyl ether in the presence of a catalyst of DMAP and
2 equiv of diisopropylethylamine in CH2Cl2 in a 94% yield. Ketal 3
was treated with Et3SiH and TiCl4 in CH2Cl2 at À78 and À10 °C,
for regioselective reductive ring opening reaction to provide
hydroxyether 4 as reported by Winchienukul and coworkers.5c
Then conversion of the hydroxyl group of compound 4 to azido
⇑
Corresponding author.
E-mail address: hkkim717@ucla.edu (H.-K. Kim).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.017

1562
H.-K. Kim, K.-J.J. Park / Tetrahedron Letters 53 (2012) 1561–1563
Figure 1. Retrosynthetic analysis of oseltamivir phosphate from (À)-shikimic acid.
group employed the azide Mitsunobu reaction using PPh3, DEAD,
and azidoic acid in THF to produce monoazido compound 5 in good
yields.13 In this SN2 type displacement using the azide Mitsunobu
reaction, the (S)-configuration of the C-5 of compound 4 was suc-
cessfully inverted to the (R)-configuration.
The azide group of compound 5 was reductively acetylated by
treatment with thioacetic acid and 2,6-lutidined in CHCl3 at 55 °C
to give compound 6 in a 76% yield.5c Then, deprotection of
methoxymethyl group of compound 6 was performed in mild con-
ditions, instead of strong acid conditions using trifluoroacetic acid
or HCl in order to prevent deacylation of C-4. Deprotection of the
MOM ether group of C-5 using 0.5 equiv of ZrCl4 in dry isopropanol
gave compound 7 in a 92% yield.14
Compound 7 was then treated with PPh3, DEAD, and azidoic
acid in THF to afford the azide compound 8 in an 84% yield.14 It
was found that the yield of the one-step azide Mitsunobu reaction
for the azide group formation was better than the yield of the two-
step reaction (80%) of primary alcohol using methanesulfonyl chlo-
ride with triethylamine for the OMs group at C-5 of compound 7,
Figure 3. Completion of the synthesis of Tamiflu.
followed by the SN2 type nucleophilic substitution with sodium
azide.
Next, in order to produce the primary amine of C-5, hydrogena-
tion reduction of the azide functionality of compound 8 by hydro-
gen gas was performed in the presence of Lindlar catalyst because
of the possibility of hydrogenation on the double bond if Pd/C was
used instead. Finally, treatment with 1.2 equiv of phosphoric acid
in EtOH at 50 °C afforded oseltamivir phosphate 1 to be prepared
in a 90% yield via previously reported method.5f
In conclusion, a new efficient method for the synthesis of osel-
tamivir phosphate 1 from an easily available material 2, which is
readily prepared from (À)-shikimic acid, has been accomplished
via 7 steps and achieved a 29% overall yield (from (À)-shikimic
acid, 9 steps and a 27% overall yield). The key steps of this synthetic
approach are the selective ring opening reaction of ketal and the
employment of the azide Mitsunobu reaction contributing to the
concision of the synthesis. Moreover, the reagents used in all steps
are inexpensive, and each step is easy to carry out. Therefore, the
efficient synthetic route for the synthesis of Tamiflu will be a po-
tential and promising candidate applicable for industrial processes.
Acknowledgment
We thank Dr. Soo-Sung Kang (Northwestern University) for use-
ful discussions.
References and notes
1. Neumann, G.; Noda, T.; Kawaoka, Y. Nature 2009, 459, 931–939.
2. (a) Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H. W.; Zhang, L. J.; Chen, X. W.;
Escarpe, P. A.; Mendel, D. B.; Laver, W. G.; Stevens, R. C. J. Med. Chem. 1998, 41,
2451–2460; (b) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H. T.; Zhang, L. J.;
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver,
W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681–690.
3. Schmidt, A. C. Drugs 2004, 64, 2031–2046.
4. (a) Moscona, A. New Engl. J. Med. 2005, 353, 1363–1373; (b) Russell, R. J.; Haire,
L. F.; Stevens, D. J.; Collins, P. J.; Lin, Y. P.; Blackburn, G. M.; Hay, A. J.; Gamblin,
S. J.; Skehel, J. J. Nature 2006, 443, 45–49.
5. (a) Ishikawa, H.; Suzuki, T.; Orita, H.; Uchimaru, T.; Hayashi, Y. Chem. Eur. J.
2010, 16, 12616–12626; (b) Ko, J. S.; Keum, J. E.; Ko, S. Y. J. Org. Chem. 2010, 75,
7006–7009; (c) Wichienukul, P.; Akkarasamiyo, S.; Kongkathip, N.; Kongkathip,
B. Tetrahedron Lett. 2010, 51, 3208–3210; (d) Osato, H.; Jones, I. L.; Chen, A. Q.;
Chai, C. L. L. Org. Lett. 2010, 12, 60–63; (e) Ishikawa, H.; Suzuki, T.; Hayashi, Y.
Figure 2. Synthesis of ketal azide 5.

H.-K. Kim, K.-J.J. Park / Tetrahedron Letters 53 (2012) 1561–1563
1563
Angew. Chem., Int. Ed. 2009, 48, 1304–1307; (f) Nie, L. D.; Shi, X. Tetrahedron:
Asymmetry 2009, 20, 124–129; (g) Nie, L. D.; Shi, X. X.; Ko, K. H.; Lu, W. D. J. Org.
Chem. 2009, 74, 3970–3973; (h) Mandai, T.; Oshitari, T. Synlett 2009, 783–786;
(i) Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. J. Org. Chem. 2008, 73, 4895–4902; (j)
Trost, B. M.; Zhang, T. Angew. Chem., Int. Ed. 2008, 47, 3759–3761; (k) Mita, T.;
Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 259–262.
6. Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D.
E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.;
Zhang, L. J. Org. Chem. 1998, 63, 4545–4550.
7. Federspiel, M.; Fischer, R.; Hennig, M.; Mair, H. J.; Oberhauser, T.; Rimmler, G.;
Albiez, T.; Bruhin, J.; Estermann, H.; Gandert, C.; Gockel, V.; Gotzo, S.;
Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper, S.; Rockel-Stabler, O.;
Trussardi, R.; Zwahlen, A. G. Org. Process. Res. Dev. 1999, 3, 266–274.
8. (a) Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044–2051; (b) Harrington, P.
J.; Brown, J. D.; Foderaro, T.; Robert, C.; Hughes, R. C. Org. Process. Res. Dev. 2004,
8, 86–91.
9. Karpf, M.; Trussardi, R. Angew. Chem., Int. Ed. 2009, 48, 5760–5762.
10. Draths, K. M.; Knop, D. R.; Frost, J. W. J. Am. Chem. Soc. 1999, 121, 1603–1604.
11. (a) Kancharla, P. K.; Doddi, V. R.; Kokatla, H.; Vankar, Y. D. Tetrahedron Lett.
2009, 50, 6951–6954; (b) Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Synthesis
2000, 10, 1375–1379; (c) Yoshida, N.; Ogasawara, K. Org. Lett. 2000, 2, 1461–
1463; (d) Hiroya, K.; Ogasawara, K. Chem. Commun. 1998, 18, 2033–2034; (e)
Jiang, S. D.; Singh, G. Tetrahedron 1998, 54, 4697–4753.
(c) Synthesis of compound 5. Azidoic acid (4.45 mL, 1.8 M, 8.01 mmol) in
benzene was added dropwise to DEAD (1.39 g, 7.97 mmol) and PPh3 (2.09 g,
7.97 mmol) in THF (30 mL) at 10 °C. Then, compound 4 (2.1 g, 6.64 mmol) in
THF (20 mL) was added to the mixture at 10 °C. After the reaction mixture
was stirred at 10 °C, the mixture was stirred at room temperature for 8 h. The
mixture was extracted with ethyl ether (2 Â 50 mL) and washed with water
(50 mL) and brine (50 mL). The organic phase was dried over MgSO4, filtered,
and concentrated under reduced pressure, and then the crude residue was
purified by silica gel flash chromatography using 1:3 hexane/EtOAc as eluent
to give compound 5 (1.85 g, 82%). 1H NMR (400 MHz, CDCl3) d 6.78–6.85 (m,
1H), 4.51–4.78 (m, 3H), 4.21 (q, J = 7.2 Hz, 2H), 4.01–4.07 (m, 1H), 3.63 (dd,
J = 8.2, 11.0 Hz, 1H), 3.41–3.48 (m, 1H), 3.35 (s, 3 H), 3.03–3.10 (m, 1H), 1.51–
1.62 (m, 4H), 1.30 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz CDCl3) d 166.3, 136.8, 129.7, 96.6, 82.7, 76.4, 66.1,
61.3, 55.4, 31.7, 27.2, 25.7, 14.1, 9.6, 9.5; HRMS (ESI) m/z (M+H)+ calcd for
C
16H27N3O5 = 341.4027, found 341.3987.
(d) Synthesis of compound 6. Thioacetic acid (1.79 g, 23.50 mmol) was added
dropwise to compound (1.15 g, 3.36 mmol) and 2.6-lutidine (2.52 g,
5
23.50 mmol) in CHCl3 (30 mL) at room temperature. After the reaction
mixture was stirred at 55 °C for 6 h, the mixture was concentrated under
reduced pressure, and then the crude residue was purified by silica gel flash
chromatography using 1:2 hexane/EtOAc as eluent to give compound
6
(0.91 g, 76%). 1H NMR (400 MHz, CDCl3) d 6.77 (m, 1H), 4.71 (d, J = 7.0 Hz,
1H), 4.64 (d, J = 7.0 Hz, 1H), 4.36–4.42 (m, 1H), 4.21–4.13 (m, 3H), 3.89 (t,
J = 6.7 Hz, 1H), 3.61 (s, 1H), 3.43 (s, 3 H), 3.30 (q, J = 6.7 Hz, 1H), 2.71 (d,
J = 17.3 Hz, 1H) 2.46 (dd, J = 18.1, 4.8 Hz, 1H), 2.01 (s, 3H), 1.47–1.62 (m, 4H),
1.31 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) d
171.8, 166.4, 136.3, 129.4, 96.7, 82.4,72.9, 67.1, 61.3, 55.7, 55.2, 31.8, 26.9,
26.0, 23.7, 14.3, 9.7, 9.6.; HRMS (ESI) m/z (M+H)+ calcd for
12. Carr, R.; Ciccone, F.; Gabel, R.; Guinn, M.; Johnston, D.; Mastriona, J.;
Vandermeer, T.; Groaning, M. Green Chem. 2008, 10, 743–745.
13. Skarzewski, J.; Gupta, A. Tetrahedron: Asymmetry 1997, 8, 1861–1867.
14. Procedures and selected data.
(a) Synthesis of compound 3. Diisopropylethylamine (4.30 g, 33.29 mmol) and
DMAP (406 mg, 3.33 mmol) were added to compound 2 (4.5 g, 16.66 mmol)
in CH2Cl2 (50 mL). The mixture was cooled to 0 °C. Methoxymethyl chloride
(2.01 g, 25.00 mmol) was added dropwise to the mixture. After the reaction
mixture was stirred at 0 °C for 10 min, heated to 40 °C, and stirred for 5 h, the
mixture was extracted with Et2O (2 Â 50 mL) and washed with brine (50 mL).
The organic phase was concentrated under reduced pressure, and the crude
residue was purified by silica gel flash chromatography using 1:1 hexane/
EtOAc as eluent to give compound 3 (4.95 g, 94%). 1H NMR (400 MHz, CDCl3)
d 6.83–6.92 (m, 1H), 4.64–4.81 (m, 3H), 4.37–4.42 (dd, J = 6.2, 6.2 Hz, 1H),
4.14 (q, J = 7.2 Hz, 2H), 3.36 (m, 1H), 3.23 (s, 3 H), 2.73 (dd, J = 16.4, 4.9 Hz,
1H), 2.24 (dd, J = 17.8, 6.5 Hz, 1H), 1.53–1.64 (m, 4H), 1.31 (t, J = 7.2 Hz, 3H),
0.91 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
166.4, 134.7, 130.1, 114.1, 96.8, 76.8, 72.8, 68.7, 61.3, 55.5, 30.1, 29.4, 28.7,
14.2, 8.8, 8.2; HRMS (ESI) m/z (M+H)+ calcd for C16H26O6 = 314.3563, found
314.3574.
C18H31NO6 = 357.4418, found 357.4392.
(e) Synthesis of compound 7. ZrCl4 (0.24 g, 1.02 mmol) in isopropanol (10 mL)
was added to compound 6 (0.72 g, 2.04 mmol) in isopropanol (20 mL). After
the reaction mixture was stirred at 50 °C for 4 h, the mixture was extracted
with ethyl acetate (2 Â 30 mL) and washed with water (30 mL) and brine
(30 mL). The organic phase was dried over MgSO4, filtered, and concentrated
under reduced pressure, and then the crude residue was purified by silica gel
flash chromatography using 1:4 hexane/EtOAc as eluent to give compound 5
(0.59 g, 92%). 1H NMR (400 MHz, CDCl3) d 6.78 (s, 1H), 5.73 (d, J = 6.3 Hz, 1H),
4.36 (m, 1H), 4.28–4.14 (m, 3H), 3.90 (t, J = 6.7 Hz, 1H), 3.61 (s, 1H), 3.32 (q,
J = 6.7 Hz, 1H), 2.70 (d, J = 17.3 Hz, 1H) 2.47 (dd, J = 18.2, 5.1 Hz, 1H), 2.04 (s,
3H), 1.43–1.62 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.4 Hz, 6H); 13C
NMR (100 MHz, CDCl3) d 171.9, 166.8, 136.4, 129.4, 82.3,72.9, 67.4, 61.1, 55.2,
31.9, 26.7, 26.1, 23.8, 14.3, 9.8, 9.7.; HRMS (ESI) m/z (M+H)+ calcd for
(b) Synthesis of compound 4. Et3SiH (1.94 g, 16.67 mmol) was added to
compound 3 (4.05 g, 12.82 mmol) in CH2Cl2 (50 mL) at À78 °C. TiCl4 (2.92 g,
15.38 mmol) in CH2Cl2 (20 mL) was added dropwise to the mixture. After the
temperature of the reaction mixture was raised to À10 °C, the mixture was
stirred at À10 °C for 6 h, TiCl4 (0.73 mg, 3.85 mmol) was added dropwise, and
the mixture was stirred for 1 h. 10% NH4OH (10 mL) was added and the
suspension was filtered. The mixture was extracted with CH2Cl2 (3 Â 50 mL)
and washed with water (50 mL) and brine (50 mL). The organic phase was
dried over Na2SO4, filtered, and concentrated under reduced pressure, and
then the crude residue was purified by silica gel flash chromatography using
C16H27NO5 = 313.1889, found 313.1871.
(f) Synthesis of compound 8. Azidoic acid (1.48 mL, 1.8 M, 8.01 mmol) in
benzene was added dropwise to DEAD (0.47 g, 2.68 mmol) and PPh3 (0.71 g,
2.68 mmol) in THF (20 mL) at 10 °C. Then, compound 6 (0.70 g, 2.24 mmol) in
THF was added to the mixture at 10 °C. After the reaction mixture was stirred at
10 °C, the mixture was stirred at room temperature for 8 h. The mixture was
extracted with ethyl ether (2 Â 30 mL) and washed with water (30 mL) and
brine (30 mL). The organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure, and then the crude residue was purified
by silica gel flash chromatography using 1:2 hexane/EtOAc as eluent to give
compound 7 (0.64 g, 84%). 1H NMR (400 MHz, CDCl3) d 6.78 (s, 1 H), 5.93 (d,
J = 7.4 Hz, 1 H), 4.55 (d, J = 7.2 Hz, 1H), 4.16–4.48 (m, 3 H), 3.25À3.37 (m, 2 H),
2.85 (dd, J = 17.6, 5.6 Hz, 1H), 2.18À2.31 (m, 1 H), 2.04 (s, 3 H), 1.46À1.51 (m, 4
H), 1.28 (t, J = 7.1 Hz, 3H), 0.82À0.95 (m, 6 H); 13C NMR (100 MHz, CDCl3) d
171.2, 165.9, 137.9, 128.2, 82.1, 73.4, 61.2, 58.4, 57.2, 30.6, 26.3, 25.7, 23.6, 14.2,
9.6, 9.4; HRMS (ESI) m/z (M+H)+ calcd for C16H27N4O4 = 339.2032, found
339.2041.
9:1 CH2Cl2/MeOH as eluent to give compound
4
(2.81 g, 70%). 1H NMR
(400 MHz, CDCl3) d 6.77–6.83 (m, 1H), 4.61–4.93 (m, 3H), 4.29–4.38 (m,1H),
4.12 (q, J = 7.2 Hz, 2H), 4.08–4.13 (m, 1H), 3.35–3.75 (m, 1H), 3.23 (s, 3 H),
2.81–2.88 (m, 2H), 2.71–2.74 (m, 1H), 1.56–1.67 (m, 4H), 1.31 (t, J = 7.2 Hz,
3H), 0.93 (t, J = 7.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.5, 135.9, 130.0, 128.3, 96.7, 86.1, 74.2, 69.7, 61.6, 55.6, 29.1, 28.3, 27.8,
14.2, 9.7, 9.2; HRMS (ESI) m/z (M+H)+ calcd for C16H28O6 = 316.3899, found
316.3952.